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Meeting Transcript
April 1, 2004


Hyatt Regency Crystal City at
Ronald Reagan Washington National Airport
2799 Jefferson Davis Highway
Arlington, VA 22202

COUNCIL MEMBERS PRESENT

Leon R. Kass, M.D., Ph.D., Chairman
American Enterprise Institute

Benjamin S. Carson, Sr., M.D.
Johns Hopkins Medical Institutions

Rebecca S. Dresser, J.D.
Washington University School of Law

Daniel W. Foster, M.D.
University of Texas, Southwestern Medical School

Francis Fukuyama, Ph.D.
Johns Hopkins University

Michael S. Gazzaniga, Ph.D.
Dartmouth College

Robert P. George, D.Phil., J.D.
Princeton University

Alfonso Gómez-Lobo, Dr. phil.
Georgetown University

William B. Hurlbut, M.D.
Stanford University

Charles Krauthammer, M.D.
Syndicated Columnist

Peter A. Lawler, Ph.D.
Berry College

Gilbert C. Meilaender, Ph.D.
Valparaiso University

Janet D. Rowley, M.D., D.Sc.
The University of Chicago

Michael J. Sandel, D.Phil.
Harvard University

Diana J. Schaub, Ph.D.
Loyola College

James Q. Wilson, Ph.D.
Pepperdine University




INDEX


WELCOME AND ANNNOUNCEMENTS

CHAIRMAN KASS:  Would members please take their seats, so that we can begin?

Good morning.  Welcome, members of the Council, to this the 16th meeting of the President's Council on Bioethics, the first of our second term.

Welcome also to members of the public.  We're delighted to have you with us.

I would like first to recognize the presence of Dean Clancy, the Designated Federal Officer in whose presence this is a legal meeting.  Not everybody here will recognize Dean Clancy, who has, in honor of his forthcoming 40th birthday, emerged from hiding and shed his whiskers.

Dean, on behalf of all of us, a hearty congratulations.

(Laughter.)

I would also at this time like to introduce to the Council our three new members.  To my left, Dr. Ben Carson, who is Professor and Director of Pediatric Neurosurgery at Johns Hopkins Medical Institution; two to my right, Peter Lawler, who is the Chairman of the Department of Government and International Studies and the Dana Professor of Government at Berry College; and three to my left, Diana Schaub, who is Professor and Chairman of the Department of Political Science at Loyola College of Maryland.

Welcome to the three of you.  You've joined an interesting, sometimes contentious, but I would like to say civil and productive group.  We are very much looking forward to working with you over the coming months and year.

SESSION 1: BIOTECHNOLOGY AND PUBLIC POLICY: COUNCIL'S REPORT TO THE PRESIDENT

CHAIRMAN KASS: The main purpose of this first session on biotechnology and public policy is the release of the Council's report to the President, "Reproduction and Responsibility:  The Regulation of New Biotechnologies," copies of which members should have at their places.

The procedure for this session is as follows.  I will make some relatively lengthy remarks introducing the report and trying to summarize its contents and conclude with some statements of what I regard to be the report's major achievements and caveats.

Individual members who have expressed the wish to comment will then do so.  I think by my list we have either eight—we have either nine or 10 such people who want to say something briefly, two to three minutes. 

There are, I believe, some members of the public with whom we have consulted over the course of writing this report who have submitted personal statements, and some of them I think would like to read them, and then the floor will be open for comments and questions from the media.

Let me begin.  The report that we release today, "Reproduction and Responsibility:  The Regulation of New Biotechnologies," examines policy and regulatory issues that arise at the intersection of assisted reproductive technologies and genomic knowledge—an increasingly busy intersection and one that raises a daunting array of opportunities and dilemmas for patients suffering with infertility and for doctors and researchers.

It raises the prospect, but also certain kinds of risks, of new life for children born with these procedures.  And it has certain social implications important for regulators and policymakers and, indeed, for the American public as a whole.

The report is the product of a two-year process for us, which really began at the very first meeting of this Council in January 2002 when, you will recall, Frank Fukuyama expressed the hope that as one of its projects this Council might explore how new biotechnologies are regulated in the United States and perhaps recommend some ways that regulatory practices could be improved, given new technologies and the new sorts of challenges that they represent.

With time, and given the other projects in the last term of the Council, the term of which this report is, in fact, the final product, we put that focus of regulation on the more particular domain of assisted—of the issues that arise at the confluence of assisted reproductive technologies, genetic testing and selection, sex selection, and embryo research.

In the cloning report published in July of 2002, the Council stated frankly that further inquiry into the current state of regulation in this entire area was necessary.  And since that time we have, in fact, been taking this up.

We've devoted a very significant amount of our time to this project.  We've had 26 public sessions devoted to it.  We've had presentations from a great many experts and stakeholders, including patient groups, professional societies, government agencies, policy experts, and people who are involved in the regulation of these areas in other countries.

We put out a call for public comment and received valuable written comments from dozens of groups and individuals around the country, and in the report we list and acknowledge the help that we have received from all of these people, and we are very grateful to those present and those not present for your help.

The Council, with the help of the staff, produced this—took all of this in and produced the report that we have before us.  The bulk of this report is, in fact, a diagnostic document laying out the present state of regulation of these fields to the United States, public and private, governmental and professional, federal and state.  And it concludes with some modest interim recommendations for how a few outstanding problems might be dealt with in ways that we think should be agreeable to just about everyone involved.

We have not at this time recommended major institutional reform or major institutional innovations, because a great deal of what we have found in our review of this field is that much remains to be known.  We need more basic data regarding current practices and their impact to find out how big a problem this really is. 

We need to figure out the effectiveness of the rules and regulations that now exist, both governmental and professional, and we need to explore the costs—the benefits and the harms of any kind of new innovations that anybody would like to propose.

Before going on, I want to say—I want to say something about the staff work that has gone into this.  I mean, the members have contributed enormously, reading many, many drafts.  But the real credit for this report belongs to the staff, and especially to Carter Snead, our General Counsel, who has taken the lead on this project.

And let me say that this staff has put out five volumes, four reports and an anthology, in 26 months.  They are extraordinarily devoted to their work, top to bottom.  The morale in the office is extraordinarily high, because people like what they do.  They work well with one another.  They believe in what we've done. 

And I would like at this point simply to express my profound gratitude on behalf of all the members to the entire staff, top to bottom, for what you've done.  So thank you very much.

Before I get to the actual content of the report, we should point out that people who read the transcripts of our meetings and the discussions that produced this report will give you a sense of the fact that this Council has deep disagreements and differences. 

And if you read the recommendations in this report, you will discover that—which are made unanimously by this Council—you can see how people who nevertheless disagree profoundly on some issues can nevertheless find some common ground.  And I think this—as I will say at the end, I think this is really one of the great achievements of this report.

And I hope it offers an example to policymakers about the way in which, notwithstanding our continuing disagreements and arguments, we can find common ground and even seize it as we continue to debate those other things that don't lend themselves so easily.

I think most people are going to be interested, at least on this occasion, in the recommendations.  But before I get to that, let me give you a kind of overview, a guided tour to the whole document, so that you can have a sense of what's in the report.

The report is in three parts.  There's an introduction; Part 1 is the diagnostic survey, which is the bulk of the report; Part 2 explores policy options and concludes with recommendations.

The brief introduction lays out just why the Council has set out to explore this area and what we take to be some of the most important concerns and values that should guide anybody interested in exploring regulation—from the health and well-being of infertility patients and their children, to the desire to seek new therapies for the suffering and the sick, to the responsibility to protect and respect human life, and to a number of other critical issues of privacy, equity, freedom, and dignity.

The report is guided and motivated by all of these, and the introduction lays out these values at least in some beginning detail.

The great bulk of the document, to repeat, is devoted to a diagnosis of current regulatory practices in different areas having to do with the intersection of assisted reproduction and genetic knowledge.  Assisted reproduction is not, as such, our focus, though we have looked at how it is currently regulated in the course of our diagnosis, because assisted reproduction is, in practice, the necessary gateway to all of the newer technologies present and projected that will affect human reproduction.

Any oversight or regulation of the use of genetic technologies in human reproduction will, therefore, necessarily depend on the systems that oversee and regulate assisted reproduction itself.  Therefore, in Chapter 2, we begin by looking at the state of the art in assisted reproduction, laying out in general some relevant ethical issues that need to be addressed, and then examining in great detail the variety of ways in which the practice is regulated.

And by the way, "regulated" here is a very loosely used term.  I mean, it doesn't mean law and proscriptions.  It means anything that affects the practice by deliberate design, professional guidelines, and norms primarily preeminent amongst them.

This three-part approach—techniques and practices, some ethical questions, and exploration of existing regulation—is the model for how we examine the rest of the techniques that we take up in the diagnostic portion of the report. 

In Chapter 3, Genetic Screening and Selection; in Chapter 4, Modification of Traits and Characteristics, where it's important for me to point out that in this report, as the Council has done before, we point out that significant genetic modification of traits through genetic manipulation is simply not in the offing in the foreseeable future.

In Chapter 5, research on in vitro embryos; in Chapter 6, some issues of commerce that arise in the various fields and that carry their own regulatory challenges; in Chapter 7, we briefly conclude and summarize the diagnostic section.

All of this is brought together in the report's eighth chapter, which offers in a succinct and organized form the Council's findings in the light of the extensive diagnostic survey.  These findings you can find listed in the Executive Summary, Roman Numeral pages 43 to 44.

And I won't read them all here, but one of the things that we have discovered is that there really is a lack of basic data on the effects of assisted reproduction and associated technologies on the health and the well being of the women and the children involved.

The findings show that right now, although there are various kinds of regulatory practices in place, there is really no uniform comprehensive or enforceable system of data collection, monitoring, or oversight for the biotechnologies affecting human reproduction, and that there is minimum government involvement in the regulation of these technologies with the notable exception of gene transfer technologies, where regulation is really quite effective through the RAC and the NIH.

There is, however, fairly extensive professional self-regulation of some of these practices, even if compliance is voluntary.  We find that there are no uniform rules regarding access to assisted reproduction or insurance coverage, and with regard to the new technologies we find that experimental technologies that work move very quickly into general practice where their use becomes widespread pretty rapidly, though not necessarily with prospective studies to study their effects.

These are some of the findings that emerged from the Council's review of the field, and it's important to understand that none of them mean simply that some particular action is called for.  In some cases, what we have found is that the field does not differ from how things are really done in medicine in general, and in some cases we have not found that the present situation really calls for change.

In short, this preliminary review and diagnosis has not led the Council at this stage to make any sweeping suggestions for institutional reform or institutional change.  Nevertheless, we thought to at least advance the discussion, in the ninth chapter we set forth certain kinds of policy options that might be available, just to show the range of the options that exist, or that have been pursued elsewhere in the world or in other fields.

We lay these out to offer a sense of the range of what might be done rather than as examples of what we now think should be done.  And we make it quite clear that, given the preliminary character of this report and the fact that our review of the field has turned up a number of areas where crucial data are still lacking, the Council is not prepared to recommend sweeping institutional reform or innovation.

Instead, members have sought—in the interim while the conversation and discussion proceeds—we have tried to see whether we could agree on some modest measures to alleviate some clear and significant present problems, including especially the lack of information on certain key practices and their consequences.

And these measures are laid out in the chapter's tenth and final chapter, the recommendations chapter.  And in that chapter we offer interim measures that we believe should be adopted immediately, and these recommendations, I repeat, have been offered by the Council unanimously.

The strategy here in the recommendations chapter was let us set aside for the time being those things on which we disagree, and let us see whether we can in the interim, as modest temporary measures, make proposals that all of us could stand behind.

The recommendations fall into three categories, and for those who would like to follow, you can find these recommendations in the Executive Summary.  The defense of them is in Chapter 10, but if you want to see them succinctly they appear in Roman numerals 46 to 49 of the Executive Summary, in the front matter of the book.

Three categories of recommendations—the first are federal studies, data collection, reporting, and monitoring regarding the uses and effects of these technologies.  Here we are recommending federally funded studies to examine the impact of various assisted reproductive technologies on the health and development of children born with their aid and on women who undergo treatment.

We also recommend a few discrete steps to strengthen and augment the one existing piece of federal legislation—the Fertility Clinic Success Rate and Certification Act—the Act which provides information to people seeking fertility treatments.

These measures we recommend to help bring the law up to speed with new technologies that have developed since the law was enacted and to better protect consumers and patients.  They are very much in the spirit of the law that already exists on this subject, and these recommendations have been drafted with—in consultation with the professionals who work in the field.

Let me emphasize one item here that I think is of special interest.  This Council has taken special note of the importance of learning about the implications and effects of these technologies on the children who are born with their aid. 

There have been no longitudinal prospective studies of the children born as a result of assisted—with the help of assisted reproductive technologies—despite the fact that these practices have been flourishing since 1978.   There are lots of reasons for this.  We're not second-guessing the failure to do so.  There's questions of funding.  There's questions of privacy.  There are all sorts of matters.

But one of the reasons I think that there hasn't been this much attention is that the profession of—the reproductive endocrinologists—have, for perfectly obvious reasons, regarded the infertile couples and the adults as their primary patients.  When the pregnancy is achieved, the patients are turned over to the obstetricians, and it is only late in the day that the pediatricians get into the story.

One of the real important contributions, I think of this report, is to shine the light on the importance of attending to the children and learning much more about what this means for them now and in the future.

The second set of recommendations are addressed to the professional societies and the practitioners in the field of assisted reproduction.  There is a fair amount of regulation that is self-regulation in this area, as there is in medicine in general, but we have suggested a few ways in which that self-regulation might be improved for the benefit of all involved.

These include a strengthening of informed patient decisionmaking, improved enforcement of the societies' own existing guidelines, and suggests to them development of additional standards for human subject protection.  And these you could find on page 47.

The third category of recommendations, the ones that are likely to get the most public attention, consist of a few targeted legislative measures.  In the course of our review, the Council has observed the fast-moving pace of research and innovation in this field.  We have noticed that there are various kinds of values and goods connected with human reproduction that we hold dear and that we would like at least to protect.

And since we do not know whether or when or even—whether or when any kind of more formal regulatory or oversight mechanism would be developed in the future, we thought that since we are making this as an interim report we ought to think about whether there are interim measures that we could suggest that could at least set certain kinds of boundaries to protect things that we hold dear while the public deliberation goes on.

And we have decided that there are certain areas that need special attention, and we recommend in this report that Congress should consider some special targeted legislative moratorium. 

The report itself in Chapter 10 offers extensive discussion of the reasons for these recommendations and gives the reasons for—and it also discusses the aims that we think that these targeted measures should serve.  And these are found on pages 222 through 225, 227, of the report.

These recommendations are in order to help preserve a reasonable boundary between the human and the non-human, or between the human and the animal in human procreation, to preserve respect for women and human pregnancy, preventing certain exploitive and degrading practices, to show respect for children conceived with the aid of assisted reproductive technologies, securing for them the same rights and human attachments naturally available to children conceived in vivo, and to set some agreed-upon boundaries on how embryos may be used and treated notwithstanding the fact that we have lots of disagreement in this Council about the embryo question in its entirety.

Returning to the particulars, therefore, with respect to the first point, the Council calls for the prohibition of the transfer for any purpose of a human embryo to the body of any member of a non-human species for purposes of research to prohibit the formation of hybrid human-animal embryos by fertilization of human egg and human sperm.

Under the second category, that there should not be pregnancies initiated for any purpose other than to produce a live-born child.  That is to say, pregnancies are not for the purpose of experimentation or for harvesting body parts.

With respect to the child, we call for a proscription on conceiving a child by any means other than the union of egg and sperm, where conceiving a child is carefully defined to mean the creation of an embryo ex vivo with the intent of transferring it to a woman's body to begin a pregnancy.

I'll say something more about this, but it has been noted that one of the practices that this would include would be, of course, the cloning of an embryo with the intent to transfer it.  And so with respect to cloning, this recommendation is really a restatement in greater detail of an earlier Council position unanimously opposed to cloning for producing children.

The differences, of course, on the cloning for research remain, and I will allude to that further.  We have also called for a prohibition on conceiving a child using gametes obtained from fetuses or derived from embryonic stem cells, or by fusing blastomeres from two or more embryos.  No child should be able to say, "My mother or father is a fetus," "an embryo," or a "stem cell," or that "I come from fusions of two or more embryos."

On the embryo research question, notwithstanding our continued deep differences, we have called for setting a limit on the use of—a prohibition on the use of embryos in research past a certain stage in development—again, a position that many sides, as they presented testimony to us, said that would make sense.  And our approach here is also different from that proposed in other countries or proposed in Congress.

We not here call for research on embryos. We do not call for proscription of research on embryos.  We simply say that where research on embryos proceeds, it shall not proceed past a certain stage of development.

I think that really is the gist of the recommendations.  Let me say in summary what I think are the major accomplishments, and then I would invite members to offer their comments.

First, I think one of the great accomplishments of this report is that this really is the first comprehensive survey of current regulations in this area—what's going on, whose business is it to do what, and how, what are the gaps in what it is we would like someone to be paying attention to, what more do we need to know in order to intelligently advance this conversation.

Second, we've placed a highlight on the well-being of the women in these procedures, and especially on the children born with their aid.  And as the new technologies come to augment the existing practices, the attention to these matters can only increase, and it would be very important to try to beef up our—our monitoring and oversight of their well-being now.

Third, we have been sensible and moderate with respect to institutional reform.  This is but a first step down that road.  We have not leapt in with both feet before thinking through carefully the implications of doing something rather than nothing, and of doing this something rather than something else.

We're not shying away from that further conversation, but we are taking this slowly and carefully as we should.  Regulation has its costs, and they have to be assessed in the process.

Third, this is a very divided council on certain kinds of questions.  Once we get away from certain kinds of questions I have no idea how divided we are going to be, and I'm very much looking forward to the opportunity of moving into some areas where it's going to be impossible to predict what the various members around the table are going to say.  And that starts in session two this morning.

However, I think it was a wonderful idea in this project to say, "Look, let us search for common ground.  We disagree about much, but there's much more that we might agree about if we are willing, in fact, to look for it." 

And given the polarities and divisiveness in the nation, not only on our questions but on lots of other questions, and given the fact that this is a council that is Democrats and Republicans, liberals, conservatives, pro-choice, pro-life, pro-research, scientists, humanists, theologians, that we could show by example what could be done if one, in fact, chooses to seek for common ground is I think a very exciting development.  And I suspect that that will get a lot of attention.

People will snipe at us for not getting everything that they wanted out of this, but I think fair-minded people will see, "Look what these people have done when they, in fact, decided to look for the values that they can mutually endorse rather than the ones about which they disagree."

Next, although we have sought common ground and achieved some kind of unanimity—and let me not exaggerate the unanimity, because there are people here who are nervous about some things, and not wrongly.  If you tread in the area of legislation, even if we agree as reasonable people that these things make sense, when they're handed over to—to the legislative process, who knows who will jump on this with what kinds of additional things, and that's a concern.  And it's been voiced by people here, and I share it.

Nevertheless, the agreement that we've reached here is not a compromise.  I want that to be stressed.  These are principled agreements.   These are principled agreements on the recommendations in the tenth chapter.  Principled agreements—everybody is supporting these for their own principles, but remarkably for different principles.  People are on board with these recommendations, not for the same reasons but for very different reasons.  And that's I think also not surprising, but a very appropriate matter.

And the personal statements in this document—a great contribution—as were the personal statements in the cloning report, indicate the multiple and different reasons why—that members of the Council have for supporting these recommendations and for what it is that they think the report doesn't do sufficiently or what it thinks that it perhaps borders on too much.

But—so we have achieved unanimity not compromise, on principled grounds, different principled grounds—we haven't, in order to gain this unanimity, aimed at the lowest common denominator as other attempts to gain consensus would have done.  We haven't done anything earthshaking here.  This is modest, but this is a modest but significant first step in an area where there have not been first steps before.

No one has gotten everything that they want.  We've all gotten something I think that we care about.

Let me conclude by offering some kind of caveats, and this—these caveats are not addressed to members of the Council as much as they are addressed really to the members of the public, given the likelihood of misunderstanding because we are revisiting here, especially in the recommendations, certain things that the Council has, in fact, spoken about both in its cloning report and its monitoring stem cell report.

Certain incomplete and, therefore, possibly misleading news stories earlier this week written before the report's release—have given some people the impression that the Council's unanimity extends beyond what, in fact, it does extend to—namely, to the still contested matters of embryonic stem cell research, federal funding, and cloning for research.

This is not the case, and I think the public should understand this.  The personal statements in this report make it perfectly clear that we still have deep divisions in this Council about those matters, and that the conversation will continue. 

What we've tried to do in this report, to repeat, is to develop those concrete set of proposals that people on different sides of the embryo question can accept for their own principled reasons, but without foreclosing the crucial continuing argument which all of us I hope will continue to make.

Second, concretely on the way in which this recommendation relates to the cloning debate in Congress and how it relates to our own previous cloning report, because I don't want this to be misunderstood. 

When we moved again to recommend something that overlapped with previous recommendations, I wanted it to be perfectly clear that no one in this Council was going to be asked to repudiate a position that they had taken previously, nor was the Council as a whole going to repudiate its report on cloning.  We didn't revisit that to debate that question.

The proposal we are offering here is fundamentally different, therefore, from the two cloning bans that are now before Congress.  One of them would ban the creation of cloned embryos for any purpose whatsoever.  The other will endorse research cloning and prohibit the transfer of cloned embryos to initiate a pregnancy, thus mandating that all cloned embryos be destroyed at some point in the process.

This recommendation does neither of these things.  It neither prohibits the creation of cloned embryos, nor does it endorse the creation of cloned embryos for research.  On this question our report is silent.

It does not create a class of embryos that must be destroyed.  It does not prohibit the transfer of cloned embryos were they do exist.  It does not prohibit creating cloned embryos for research.  All it asks is that it creates—it prohibits the act of creating a cloned embryo with the intent to initiate a pregnancy.  That's all we're saying on that subject.

In the Council's—this is a clarification and a way forward on the Council's recommendation in the cloning report where you will recall we unanimously called for a ban on cloning to produce children, a report—a call we here clarify—to repeat and clarify.

On cloning for research, the majority then called for a moratorium.  The minority recommended that this practice should proceed with recommendation.  The Council has not, in this report, changed its mind on that report.

Second and last, I don't think that there should be misunderstanding about what the Council is saying in this report on things touching embryo research and stem cell research.  We have called here for a moratorium on the buying and selling and patenting of human embryos for any reason, and a moratorium on research that uses latter-stage human embryos once they have reached a certain stage of development.  We have left it to the Congress to settle that between 10 or 14 days.

Regarding embryo research in earlier stages, and federal funding of such research, those stages where embryonic stem cells are derived, the nation and the Council, alas, are still divided.  Some members continue to believe that all embryo research should be restricted or banned; other members believe that it should be encouraged, accelerated, and federally funded much more than it now is.

What we agree on is only what we've got here—namely, that research on embryos at a later stage is either wrong or imprudent, at least for the time being, and should be placed under a moratorium.  In calling for this prohibition for the time being, the Council neither endorses federal funding for embryo research nor opposes it, nor does it propose limitations on research conducted with the very early stage embryos. 

On those contested matters this report and this Council is still silent.  We are calling only for a restriction of the practice that everyone believes should, for the time being, be restricted.  I think with these important clarifications, because there is a great deal of danger of misunderstanding, lots of people on various sides hoping to make use of this, I think we should simply say we've agreed on certain things.  I'm delighted that we have.  I wish it was possible to agree on more, but the society is divided on those things.

We will take a respite from those arguments here in the Council, but that is where we stand.

I think that's both too much and too little, but that's all I would like to say on behalf of the report as a whole, and then placing my own particular emphasis on what I think are our achievements, and try to correct some likely misunderstandings that have already produced a flurry of phone calls to the office saying, "You did what?"

So there it is, and the floor is open for discussion.  Before I ask for individual members who have asked to make comments, are there any questions to me in terms of what I've just said?  Well, that's it.

Good.  Well, I have a list of people who have asked to make comments.  And, Frank, since you are the founding father of this venture, even if it hasn't produced quite the child yet in full maturity that you had hoped for, perhaps you would be willing to lead off.  Frank Fukuyama.

PROFESSOR FUKUYAMA:  All right.  Thank you very much, Leon.  I am in fact extremely happy with the publication of the Reproduction and Responsibility report.  I want to thank the staff of the Council for its assiduous, you know, pursuit of this issue.  And I think that the result, for all of the reasons that Leon just laid out, is something that we can all be quite proud of.  And let me also thank the other members of the Council for working together to agree on it.

I think that since it's a relatively short statement I'm simply—and since Professor Wilson has also signed on to this, I will simply read the personal statement that I have written, because I don't want to put words in Jim's mouth.

We believe that the Reproduction and Responsibility report is a very important document that articulates a broad, moral consensus over the limits that our society should place on new reproductive procedures that are now made possible by technology.  Proposed legislation, if passed, would ban certain clearly unacceptable techniques, including reproductive cloning, while at the same time neither prohibiting nor condoning research cloning or other forms of embryo research.

As such, it shows a way to get past the current deadlock that leaves the United States as one of the few developed countries without guidelines in this area, and I think that's an important point to stress.

Appropriate as these guidelines are, however, we believe that they represent only a first step towards a more complete regulatory approach needed to deal with these new technologies.  Today we can foresee possibilities like reproductive cloning or human-animal hybrids that should be banned, but the technology will move quickly and in the future pose ethical challenges as well as scientific and medical opportunities that we have not today imagined.

It would be difficult and inappropriate for Congress to intervene seriatim as these developments occur.  What is called for instead is a modernization of our existing regulatory structure to allow it to respond with flexibility in such cases, taking into account not simply the safety and efficacy of the new procedures but ethical concerns that would be widely shared in our society.

Our hope is that the current report will represent not a final word on the subject of the legislative limits but a beginning of a broader discussion of regulatory oversight of new reproductive technologies.  As a general rule, we do not welcome government intrusion into scientific inquiry and into the reproductive choices made by parents. 

But regulation frequently facilitates scientific advance and individual choice by reassuring the public that it is being done responsibly.  That is the light in which the current report should be seen as well as hope for future efforts to update and modernize our regulatory system.

Then, I would simply add in my own name.  I have been working independently through a study group to, you know, look at further measures.  I think at this point it is really not clear when you talk about the modernization of a regulatory system what that involves, whether you need actually new institutional powers, whether the existing institutions can actually be modified in one way or another to do that.

But I do think that we are at a juncture where we need to consider this further.  So I do hope that—that this, as I said in the statement, will not be the last word on this subject.  And I also would like to, again, stress the point that regulation is not in this instance an obstacle, I believe, to further scientific research. 

I think that as in the case of biomedical technology more generally, regulation is a—is something that actually promotes the possibility of future research by making sure that people understand that it is being, in fact, done safely and responsibly.  And I hope that people will take all of this in that light.

Thank you.

CHAIRMAN KASS:  Michael Gazzaniga?

DR. GAZZANIGA:  Well, there's going to be a certain redundancy to these messages.  And what I would like to offer here has already been said as part of the record.  It's not—it's my earlier thoughts on this enterprise, and so there are no surprises here that I have really never been happy with this effort since it was launched.  And the final report continues, really, to leave me unsatisfied.

While drafts of this report have been freely available for almost a year on the web, and while they have been updated and revised as we all know, and we have certainly extensively discussed these comments—all of this material at these meetings, I have never felt comfortable with the thrust.

This is despite the fact that a few of us, in addition to the time spent at these meetings, have spent many, many hours reading it, suggesting changes to its language, and yet I get the sense of—I was going to try some French here, but the more things change the more they stay the same.  But I never did well in French, so I won't give you the translation.

Somehow this report starts out examining the regulatory atmospheres of various reproductive technologies and concludes with a set of recommendations that really have a newsworthiness.  And, as Leon has just pointed out, on this cloning issue the objective stated time and again is to frame a set of recommendations that would break the logjam in Congress on the issue of cloning.

This is achieved in the present document by suggesting we outlaw any other means of making a baby except by the union of egg and sperm, whether it be through normal sexual activities or through IVF technologies.  At this point in human history, this is certainly fine with me.

The report also recommends any research use of leftover embryos from IVF has to be completed by 14 days, and that, too, is fine.  What is not said, however, and as Leon has alluded, so this is the redundancy here of the message and is left open, is whether or not federal funding can be used to study those leftover embryos, or clumps of cells as I would prefer to call them.  They would serve as a rich source, as we all know, for stem cell research. 

It is also not stated that somatic cell nuclear transfer procedures—so crucial for therapeutic cloning—could go forward with federal funding.  Sometimes I think we have the sort of cloning version here of the "Don't Ask, Don't Tell."  I say again, let's be explicit, and that's what my difference here is I'm drawing—is I think we should move forward to being explicit on these important issues.

And, finally, this Council has been through the issue before—these issues before, as you all know.  The one time we did vote on anything in the Council, in 2002, the majority of us voted—10 to seven—to reject an outright ban on biomedical cloning.  Ten of us had no ethical objections in principle to biomedical cloning.  Of that majority, three major—three members wanted to, nonetheless, have a moratorium until regulations were in place.

I now think we are moving towards having those recommendations in place, and I hope and assume that these Councilors will soon be ready to move forward and support federal funding of biomedical cloning.

Thank you.

CHAIRMAN KASS:  Thank you very much, Mike.

I have Alfonso Gómez-Lobo next, please.

DR. GÓMEZ-LOBO:  Thank you.  Now, the specific reasons I had to endorse the report are really spelled out in the two additional statements to which I added my signature, so I won't repeat those.

Now, what I'd like to do in this very brief statement is, on the one hand, again call attention to the cultural and deep background against which we are addressing these things, and then I'll move to the specific recommendations. 

In my view—and I feel very strongly that because of my professional background I may be called to insist on this in this Council—from my perspective, I view our culture as moving at a swift pace towards the radical instrumentalization and exploitation of early human life. 

We're going by incremental steps, and early human life I think is, of course, an expression that refers to human beings who find themselves at a stage at which we all found ourselves at the beginning of our own lives.  We all started as a one-celled organism and grew to be what we are today—namely, the same organism but with millions of cells.  And I am, of course, always willing to rediscuss the question of identity through time.

But one of the consequences of that is that if we deserve protection today, we deserved equal protection then.  Of course, I could expand this argument for hours. 

However, in my view, going now to the recommendations, the document we are unveiling today is a minimalist document.  The recommendations in the closing section of the report should be understood, in my view, as minimal protections, as the least we should do. 

It seems to me that the transfer of a human embryo into the body of a member of a non-human species, the production of a human-animal hybrid, if it works, the buying and selling of human embryos, the patenting of whole human organisms, are all activities that reasonable people should reject as basic violations of our dignity.  That is, as forms of instrumentalization.  I think that's basically what dignity means here.

The report also seeks minimally to restrict destructive or harmful experimentation after a certain period in the life of an embryo, because at present those legal restrictions simply do not exist.  We make no recommendation, however—and Leon has insisted on this—on what should be permissible or impermissible during the first few days of life, nor is there any recommendation with regard to federal funding.

In fact, I join many Americans in thinking that destructive or harmful experimentation on human embryos, either produced by cloning or by union of the gametes, should be prohibited altogether.  The Dickey Amendment, of course, is I think, again, the minimal we could do.

If enacted, the recommendations of this report would raise a very basic fence in front of activities that are, I think, deeply dehumanizing, and I'm glad we could all agree on them.

Thank you.

CHAIRMAN KASS:  Thank you very much.

Rebecca?  Rebecca Dresser.

PROFESSOR DRESSER:  This report responds to a significant information gap.  More information is needed on ART outcomes.  Few people would argue against the position that novel ART interventions should be evaluated according to the criteria used to evaluate other novel biomedical interventions, and that is safety and efficacy.

Yet a combination of circumstances has produced relatively weak oversight for ART.  Because the NIH and other federal agencies rarely support research relevant to ART, innovative approaches may be tried in patients without prior scientific or research ethics review.

Because novel ART procedures are ordinarily not subject to the FDA approval process that governs drugs and other medical products, ART procedures may be offered and performed without meeting the agency's safety and efficacy standards.  Because insurance coverage for ART is limited, insurance company demands for properly qualified practitioners and adequate facilities have less impact on the quality of care than they do in other medical areas.  And because causation, negligence, and harm can be difficult to detect, much less to prove, the tort system is ineffective in deterring substandard practice. 

Now, the profession I think has made an important and significant effort to assess its methods and encourage ethical practice by clinicians, but more is needed.  There is a professional medical duty to make reasonable efforts to discover risks associated with interventions that are offered to patients.

Fulfilling this duty is also in the profession's self-interest, for careful evaluation of ART interventions will lessen clinicians' exposure to liability for any alleged harm related to the interventions. 

And there is also a broader social interest in learning more about the effects of ART—for example, in learning more about the possible health effects in children born after the use of these interventions, and in learning more about the health of the women undergoing superovulation, either as part of their own treatment or to provide oocytes to others.

Now, if researchers are going to increasingly seek human oocytes for research purposes, such as to create embryos through cloning or IVF to serve as sources of embryonic stem cells, more women are going to be exposed to these high doses of hormones and to other parts of the oocyte retrieval procedure.

We really need to find out whether there are any long-term consequences of oocyte retrieval.  At minimum, we ought to have solid information about risks to give to women who are thinking about undergoing this procedure.  And at a broader level, we should have this information when decisions are made about whether the potential knowledge gains generated through creating research embryos would justify the harms it could produce.

Finally, the legislative recommendations the Council endorses in this report are narrow and are designed to shift the burden to those proposing certain questionable practices.  These recommendations seek to change the U.S. status quo from one in which individuals seeking to engage in such practices have no obligation to explain or give reasons for proceeding, to one in which such individuals would be required to make their case—that is, to give reasons that a substantial portion of the community would accept as justifications for going forward.

This kind of a shift would place the United States with many other developed nations engaged in ART and embryo research where researchers and infertility specialists proposing novel investigations or procedures must establish an appropriate basis for doing so. 

Our constitution establishes a very general framework for decisions about reproduction and research, but leaves most of the issues discussed in this report to be resolved through the democratic process.  People dissatisfied with the present U.S. situation, whether they are dissatisfied with the absence of constraints on embryo research and ART practice in the private sector, or dissatisfied with the absence of federal support for research involving embryos, or dissatisfied with the lack of attention to potential social effects of increased control over children born through ART—all of these people face a choice.

Those who insist on securing every change they desire will reduce the chance of securing any change.  A more fruitful alternative is to sit down with those who see things differently and to try to craft policies reflecting points of agreement.

In developing this report, the Council chose the second path.  I hope those considering our recommendations will choose this path as well.

Thank you.

CHAIRMAN KASS:  Thank you, Rebecca.

Gil Meilaender?

PROFESSOR MEILAENDER:  To gestate and give birth to this report has been for us considerable labor.  It is, I believe, a small beginning at thinking about some very difficult topics, difficult morally but also difficult in terms of the everyday life of many people.

Biotechnologies touching the beginnings of human life have, for the most part, simply grown up around us.  Not without thought, to be sure, but largely without the kind of thought that gives direction and sets limits.

It is not hard to praise their benefits, and it is not hard to bemoan their effects on our understanding of parenthood and childhood.  But it is very hard to say what, if anything, we ought to do or might be able to agree to do, given the circumstances in which we now find ourselves.

This report at least gives us a developed context in which to think about such questions.  It makes clear our need for further information, though I'm not confident that the information for which we call will provide all we need to know, in particular sufficient information about the condition of children born with the aid of IVF or detailed information about the numbers of embryos produced for our reproductive purposes but never brought to live birth.  So this is a very modest beginning.

The report does, however, move beyond calls for information and conclude with some recommendations for interim legislation, recommendations on which we have been able to reach consensus despite our disagreements on a variety of related issues.

The problem with consensus, of course, is that it can often be too cute by far, blurring rather than clarifying important disagreements.  And that will certainly be the case if we do not keep faith with each other about the nature of the agreement we have actually achieved.

It may be useful, therefore, simply to note for the record where these interim legislative recommendations leave us, what we have said, and where we have been silent.  With respect to cloned embryos, the Council here says nothing that goes beyond or qualifies what we said in our report "Human Cloning and Human Dignity."

Hence, the majority recommendation of that report, coupling together a ban on cloning to produce children with a four-year moratorium on cloning for biomedical research, has not been altered in any way and remains our majority recommendation for legislation.  We have not uncoupled those two forms of cloning or recommended uncoupling them.

With respect to the use in research of so-called spare IVF embryos, the Council has been able to agree only that there should be a point in the life of an embryo at which such research should be prohibited.  We have not endorsed research prior to that point in an embryo's life. 

We have certainly not recommended government support for research on human embryos at any point in their life, nor do our recommendations in any way suggest that the current prohibition on federal funding of all research that destroys embryos should be changed.

We have not recommended a prohibition upon the implantation of any embryo, and we have not said anything at all about what should be done with embryos at the point where research must stop. 

In the context of all those silences, we have said only this:  recognizing that there is research not governed by the restrictions on federally funded research, we have simply recommended that if anyone carries out research on living human embryos there be a point at which such research must stop.

Thus, the silences surrounding our agreements are very large and complex.  And lest good faith be replaced by duplicity and mistrust, I hope their complexity and their largeness will be both appreciated and honored by all of us.

Thank you.

CHAIRMAN KASS:  Thank you.

Michael Sandel.

PROFESSOR SANDEL:  Thank you.  Much of this report concerns fertility clinics.  But as the comments around the table have already made clear, the two elephants in the living room are cloning and stem cell research.  A great merit of the regulations in the report is that they point to a possible solution to the vexed issues of cloning and stem cell research that could overcome the current impasse in the United States Senate.

First on cloning. Despite the widespread opposition to reproductive cloning, the Senate hasn't been able to ban it because of disagreement about cloning for biomedical research.  This report offers an ingenious way of detaching those two questions.  It proposes that Congress prohibit attempts to conceive a child by any means other than the union of egg and sperm.

This language provides a way for Congress to ban reproductive cloning while agreeing to disagree on the question of cloning for biomedical research.  Congress could prohibit attempts to create cloned children while allowing debate to continue about cloning for stem cell research and regenerative medicine.

The proposed regulations taken together also point toward a possible compromise on federal funding of stem cell research.  They do so by addressing at least one of the main worries people have about stem cell research, which is the slippery slope worry.  This is the worry that without clear limits, embryo research could lead down a slippery slope of exploitation and abuse.

If we allow stem cells—stem cell research today, the argument goes, tomorrow some people might try to transfer embryos into a woman's uterus, or even a pig's uterus as we've heard said, to grow organs for transplant, creating the nightmare prospect of embryo farms, fetuses exploited for spare parts, and the commercialization of human life.

The regulations contained in this report address that slippery slope argument.  They do so by assuring that such research is done responsibly, within carefully prescribed limits.  No embryos used for research could be used or preserved beyond a 10- or 14-day limit, or transferred into a woman's uterus or into an animal's body to grow organs for harvest, nor could embryos be bought and sold.

By assuring that stem cell research is conducted within these limits, these regulations address the slippery slope objection, the worry about exploitation and abuse.  And so they point the way, or so it seems to me, toward a compromise on federal funding along the lines that were proposed back in July of 2001 by Senator Bill Frist. 

Senator Frist argued then that both embryonic and adult stem cell research should be federally funded, but within a carefully regulated framework, and these regulations begin at least to create such a framework. 

Now, why is this important?  Well, recent scientific developments illustrate the need to adjust federal funding policy along the lines that Senator Frist proposed.  Only 17 cell lines are currently available on the NIH registry for federally funded research. 

Just a few weeks ago, Harvard Biologist Douglas Melton announced the creation of 17 new embryonic stem cell lines that he is making available free of charge to scientists for non-commercial research purposes.  The Harvard stem cell lines meet all of the criteria proposed by Senator Frist. 

They were derived using private funds from blastocysts left over from IVF clinics, not from— nothing involved with cloning—blastocysts left over that would otherwise be discarded and with the consent of the donors.  They meet all of the requirements.

And yet, under current federal policy, research on these cell lines is ineligible for federal funding.  Despite meeting all other ethical and legal requirements, these new cell lines were derived after 9:00 p.m. on August 9, 2001.  That's the only difference between them and the approved lines.

Now, the August 9th cutoff may have been a reasonable compromise two and a half years ago when it was thought that some 60 or 70 cell lines would be available.  But in the light of what we know now, that August 9th cutoff looks less and less sustainable, both practically and ethically, because whatever one's view of the moral status of the embryo it is difficult to understand the moral distinction between research on stem cell lines created before 9:00 p.m. on August 9, 2001, and research on stem cell lines created according to all of the same ethical requirements except for the fact that they were created later.

And so I endorse the regulations proposed in this report in the hope that they can point the way to a national compromise on both cloning and on federal funding of stem cell research—a compromise that will enable this country to promote the promise of stem cell research while upholding the highest ethical standards.

CHAIRMAN KASS:  Thank you, Michael.

I have just two more people, so that people know where we're going.  I have Robbie George and Dan Foster.

PROFESSOR GEORGE:  Thank you.  I wish to begin by associating myself with the careful exposition of the content of our report this morning that was provided by Dr. Kass.  And also, I wish to thank him for the careful clarifications which I hope will help to prevent misunderstanding of the report, some of which is already abroad.

I'd like to direct my comments this morning not so much to my friends and colleagues on the Council, but broadly to citizens who are following our deliberations, and particularly to those citizens who share my own basic perspective on the fundamental ethical questions having to do with embryo research.

So I ask:  how ought the targeted measures proposed in Chapter 10 of the report we released today be regarded by members of Congress and by citizens who share the belief that human beings in every stage and condition, including the fetal and embryonic stages, are entitled as a matter of strict justice to full respect and legal protection?

I hope that they will be regarded as, in Dr. Kass' apt words, significant, yet modest, steps forward.  Of course they will be regarded, and in my opinion should be regarded, as not enough, for even if all of our recommendations were enacted into law injustices would remain in my view.

The moral ideal and the ultimate political goal must be full legal protection for all living members of the species homo sapiens, all human beings, irrespective of age or size or stage of development or condition of dependency or location.  It should never be lawful to treat a human being as a mere property or as disposable research material or as a collection of cells or tissues or organs to be harvested for the benefit of others.

As Professor Gómez-Lobo and I say in our statement attached to today's report, biomedical science should move forward aggressively by all ethically legitimate means in its mission of curing diseases and ameliorating suffering, but also adding to the sum of human knowledge.  Respect for human dignity requires nothing less than this.

But the very same principle of respect for human dignity also requires strict adherence to ethical norms protecting the moral equality and inviolability of each human being.  It is my hope that our law and public policy will move steadily in the direction of full respect for human dignity and protection for human life in all stages and conditions.

The targeted measures proposed in Chapter 10 should be supported, I believe, because they move us in the right direction.  They do not weaken or diminish any protection of nascent human life currently in place.  They do not alter the prohibition, for example, of federal funding for destructive embryo experimentation and research.

Their sole legal effect would be the desirable one of restricting unethical practices which are currently unrestricted by federal law, including some that are unfortunately encouraged by some state legislation. 

Today's recommendations are being proposed unanimously by our Council.  Although for some of us they are worthy of support as important steps in the right direction, for others they represent all or most of what should be done by way of restricting research involving the destruction of nascent human life.  As Chairman Kass has indicated, we remain divided on these basic moral questions.

We remain divided as a Council on the question whether all embryo destructive research should be forbidden.  We remain divided on whether cloning to create embryos for research should be permitted or proscribed.  Today's report leaves unaltered our recommendation on that issue contained in the Council's report entitled "Human Cloning and Human Dignity."

But these continuing divisions should not obscure the considerable consensus we have reached.  Even members favoring embryo research agree that even privately funded research should be subject to significant federal restrictions.

Even those who support research involving the destruction of human embryos in the blastocyst stage agree that after a certain point in development—10 to 14 days or fewer—the use of embryos for research involving their destruction should be banned.

Moreover, in an important preemptive strike against the emergence of fetus farming for transplantable tissues and organs, the Council is united in recommending a ban on transferring a human embryo into the body of a member of a non-human species for any purpose or into a woman's uterus for any purpose other than attempting to produce a live-born child.

I know that many of my fellow citizens of New Jersey, alarmed by legislative developments in our state, will applaud the President's Council on Bioethics for its moral leadership in making these particular recommendations.  On the other hand, it is already clear that two of our recommendations are being received with caution and concern by citizens who believe in the full dignity of human beings at every stage of development, including the embryonic stage.

The first of these is the proposed day limit on privately funded embryo destructive research.  Some people fear that this will be perceived as an authorization of embryo destructive research prior to the limit. 

I would respectfully ask those who share this view, this concern, to consider the points advanced by Professor Gómez-Lobo and myself in our statement attached to today's report, as well as those developed in the statement in which we are joined by Professors Meilaender, Glendon, and Hurlbut.

The second point of concern has to do with the operational definition of the proposed ban on attempts to conceive a child by any means other than the union of sperm and egg.  On this point, the Council has attempted to find a way to preempt development of industries that would produce children who would be deprived of the rights and human attachments naturally available to children conceived in vivo.

A substantial body of opinion on the Council, and which I share, believes that the right way to proceed here is to ban the creation of such embryos by certain processes. 

For now, however, this does not appear to be feasible politically.  So our goal has been to design an approach that would provide an effective deterrent in the face of disagreement to the development of an unethical industry while at the same time avoiding any suggestion of legally mandated embryo destruction or placing limits on bona fide embryo rescue.

It's also important to note that we leave untouched the Council's recommendation of a four-year moratorium on the production of embryos by cloning for biomedical research, during which time those of us favoring a permanent and complete ban on human cloning would continue vigorously to make the case for such a ban to state and federal legislators and to our fellow citizens.

Whether our proposal on this particular point is a prudent way to proceed is a legitimate question that should be reflected on and carefully discussed by people who share the goal of protecting human life in all stages and conditions.  People who share the foundational ethical conviction may differ in the matter of prudential judgment, yet careful thought and discussion may yet yield consensus.

So to those who have concerns on this point, I would respectfully say that we should embrace those recommendations made by the Council today, which all of us can see advance the goal of respect for the life and dignity of the human person, while resolving to work together in carefully thinking through the matters on which differences of prudential judgment persist.

Thank you.

CHAIRMAN KASS:  Thank you very much.

Dan Foster, last but by no means least.

DR. FOSTER:  Well, you'd better not say that yet.  So anyway, I want to make a real-world comment, sort of in response to Leon's earlier explanations, and not comment on the report itself.  I thought the statements were very good.

One of the characteristics of the Council in its first two years has been open discussion, so that there has always been a transparency to the thoughts of the members, and that was one of its—has been one of its great strengths.  And in that spirit, I want to acknowledge a transparent fact briefly and without polemic.

And that fact is this:  that the reconstitution of the Council has evoked strong concern externally, especially amongst the scientific community.  The concern is that the Council has become unbalanced.  Two strong members of those who hold science to be a high good have left and have not been replaced.

Consequent to that, some members of the Council itself have been concerned and have conveyed that to Leon—this issue of the perceived imbalance that I have mentioned.  And I thought it would just be crazy to have a meeting here and not acknowledge that rea-world fact.

My colleagues would say, "What is this with all of this going on that there's no comment about the reconstitution?"  And that's the purpose of my statement here.

I want to point out that the concerned Council members are all here.  And, further, I think it fair to say that they think that the Council has been a good thing, and has done good work, despite the disagreements.

Now, three quick comments, and I'm through, about how to deal with this.  First, the Chairman has always been fair in letting issues be amply discussed in meetings.  He frowns a lot, but he has allowed ample discussion to take place.

Second—and this is to many of our scientific colleagues who felt that those—that we should not stay on the Council.  I can tell you that there are many, many of the major scientists in the United States who felt that the reconstitution was such that we should not serve. 

But my view is that it's almost certainly better to have the voice for science present in future discussions than absent, even though we're smaller in number.  And that's because science and scientific medicine is a very high good, and most of the people in this country know that.  So it's good, I think, to those who say "leave" that we stay.

And, third, there is always the possibility that rationality will conquer and that Leon and the older members on the "other side" will change their view.  And I certainly assume that as we welcome the new members to the Council we will do everything we can to make them become more rational, too.

(Laughter.)

CHAIRMAN KASS:  Charles?

DR. KRAUTHAMMER:  I just wanted to make a—I have no statement to make about the report, but I have been provoked by Daniel, as I have been in the past many times.

DR. FOSTER:  Charles, I've been provoking you ever since I joined this Council.

DR. KRAUTHAMMER:  Well, it finally worked.

I respect what you say, and I understand the sincerity and depth from which it comes.  But you talked about perceived imbalance.  We've heard about that perceived imbalance for two years now, including the Council as composed in the past, which we are now idealizing, and which when the Council began two years ago was characterized in the press and elsewhere as analogous to the Taliban, among others.  So let's remember where we started from.

I think anybody either reading this report, anybody hearing our discussion this morning, would say that the idea of perceived imbalance is only a perception.  We have just heard from Michael Gazzaniga a reference to the embryo as a clump of cells.  We have heard it referred to by Robbie George as the—deserving the dignity afforded a full human being.

We have the full range of philosophical approaches on this Commission, and I think it reflects very much the divisions and disagreements in society itself.  I believe this Council is the most diverse, open, and reflective of any bioethics council ever constituted in this country. 

And I think the fact that we produced a report today where we achieved unanimity despite our differences is a tribute, a) to the sincerity and the willingness of us to work together on common goals, and b) to the fact that in a diverse society we can actually have ultimate agreement on basic goods.

So I understand how there is a perception about a lack of diversity, but I don't think anybody with a fair mind, hearing what we have heard today, reading our report, could conclude anything except the opposite.

CHAIRMAN KASS:  Thank you very much.

Thanks to all Council members.  And, Dan, let me single you out.  Thank you very much for that comment.  I think it is good that the concern of the larger community is acknowledged here, and we will continue to strive in every way possible to make sure that every respectable opinion is heard, welcomed, and given the full weight that it deserves.

And on the question of being able to listen to reason, the conversation is always open, and persuasion is the ultimate possibility, and we look forward as we move forward to new topics to learn from one another and try to reach greater clarity, either about what we can't agree on, but certainly to try to find common ground as we proceed.

We have run over.  I'm long-winded.  Council members are wonderfully articulate.  Let me say the following.  We want to have at least—without stealing too much time for the next session—we have a couple of people—we have five sort of personal statements, four or five.

There are two who have asked to speak, people who have worked very closely with us in preparing this report.  Pam Madsen from the American Infertility Association, the Executive Director there, and Erin Kramer, who is the Director of Government Affairs from Resolve, would like to offer a comment at this time.

Then, we're going to have to take at least a few questions from the press for maybe five minutes.  The rest of them we can deal with at the break.  But let's at least have these comments.  I will call attention to the other press releases that we have, so that people can read them, and I won't take up valuable time here.

Ms. Madsen, would you please come forward?  And welcome back to our gathering.  It's nice to see you.

MS. MADSEN:  I do have a prepared statement that is out front, but I've actually chosen not to read from it, because if you want to read that you can read it.

First of all, I stand before you as probably one of the most recognizable faces and voices of the infertile community, as I have been doing this work for 15 years, and I was an infertile person.  I'm now a mother of ART children.

I want to first begin and thank you all for listening, listening to the stakeholders that have come to you.  I want to thank you for responding to us, because the responses—and, yes, there obviously has been division, and there has been division even when I've been thanking you.  I've been told maybe I shouldn't thank you.  So division has always been quite present.  But your staff and your chairman and all of you have worked very, very hard to be attentive and responsive listeners. 

And on behalf of the community that I represent, I do think we feel responded to.  Many things that we were extremely unhappy with are no longer in the report, and we thank you for that.  There are wonderful things as well that we support, that we do think is going to help the patient community—the women, the husbands.  You know, we don't talk about the husbands around this table.  It's always about the woman.

But there's actually usually two people who go in for treatment.  It's the man and the woman, and then there's the resulting children.  So for the protections for the couple and our children, we support any help that you can give us to get funding for prospective, balanced studies for the health and welfare of our kids.  And nobody cares more about that than patient organizations, because we are the mothers and the fathers of our children. 

As many of you know, the American Infertility Association, in partnership with Randt, is working to get funding for Footprints, which will be the first prospective IVF study in children in this country.  And it will be run by stakeholders, not by people with political agendas.  All we care about is an honest outcome, because we care about our kids.

We care about you supporting funding to help the women who are taking known and unknown risks for the dream of a child.  We want to know what we will face later in life, and very well nothing.  Maybe something.  But do we really know?  No, we don't.  So thank you for supporting that.

We thank you for preserving the rights of the individual to pursue collaborative reproduction without government interference.  We thank you for listening to us.  We thank you—I have to acknowledge Carter Snead, who has been a great ear to bring things to the Council for us.  We said, "How come you're not talking about insurance?"  And in this final report we see mention of the importance of insurance.

And we agree with your recommendation for publicly reported data to include the cost of ARTs to patients, as well as a number of ART patients, in addition to the number of cycles.  We feel that this is very critical information that all patients should have.

Do we have some issues with the report?  Everybody has issues.  Everybody comes to the table with different viewpoints.  And, yes, we too have some issues and anxieties, as Dr. Kass mentioned I think in the very beginning.

We have some issues with what we consider ambiguous language in some of the recommendations, such as the union of egg and sperm and creating a child.  Well, does that mean we can't do ooplasm transfer or cytoplasm transfer?  What does that mean?

I've been assured by the Council that it doesn't mean that, but this is a political document.  It's going to travel up.  Are you going to be there to explain exactly what it means to members of Congress?  I think you need—this is a pre-publication report.  There's a possibility for clarity of language.  It would help everybody interpreting your report to have a bit more clarity around some of these recommendations.

Thank you for inviting me repeatedly.  Thank you for listening.  Thank you for responding.  And I bet that you will respond yet again.

CHAIRMAN KASS:  Thank you very much, Ms. Madson.

Erin Kramer, please.  Welcome back.

MS. KRAMER:  Thank you so much.  We also at Resolve, the National Infertility Association, would very much like to acknowledge the time and effort of the Council members, the chairman, who has spent a great deal of time trying to be responsive to the various occasions when we've expressed concern about elements of earlier drafts, as well as the staff.

We think that there has been a great effort in at least being responsive and trying to be clear about what is the Council's intent in different versions.  And we want to acknowledge that you responded to our concerns about what we originally have thought were very overly burdensome proposed regulations of pro-pregnancy treatments.  Again, that's what we're talking about here is pro-pregnancy treatments for these couples.

We do, however, remain concerned about some aspects of the final report.  You know, the stated intent is consumer protections.  Yes, we know that.  But we feel that it may also make these medical treatments for the infertility of infertile couples more costly and less successful.  We think that's going to be the reality.

And we are wary of proposed governmental monitoring and publication of all aspects of fertility treatments to a degree that we still think is unheard of in other areas of medicine.

Our challenge, of course, is the next steps.  Our challenge is seeing this as it moves forward.  And we are going to make sure that if and when these recommendations are acted upon, they are implemented in a manner that is fair, is unambiguous, and is in the best interest of the millions of U.S. patients and their children.

We are going to remain vigilant to ensure that any further application of these recommendations does not limit access to medically necessary infertility treatments, does not unduly restrict the privacy of the people working so hard to build their families, and also the privacy of their reproductive choices.

We do applaud the Council for removing earlier recommendations and language that we thought was very hostile to ART, and that we thought in the end would be damaging to those seeking medical assistance to build their family. 

And we also recognize the Council for pointing out the important need for federal funding for the studies of assisted recommendation and also for including language in the final document that speaks to the issue of insurance, although we still feel that we will continue in our efforts for what we do think is the most important consumer protection, and that is procuring insurance coverage for those individuals working to build their family.

Thank you.

CHAIRMAN KASS:  Thank you very much.

Let me make an administrative decision.  We have a distinguished guest who is—we have already held—we have run 15 minutes over our time.  There are—I would be remiss if I didn't simply mention that we have a press release from the American Society of Reproductive Medicine and the Society for Assisted Reproductive Technologies.  They have released a statement.  This statement is available on the press table.

I was going to read it, but I will not do so.  They've been wonderful to work with, and we've learned a lot from them, and we will continue to work with them as we will with the patient groups.

We have a joint statement from the group Our Bodies Ourselves jointly issued with the Center for Genetics in Society, Judy Norsigian—and I've just lost page 2—and Marcy Darnovsky.  This statement is out there, and they are willing to be called about this report.

And we have a statement from John Kilner from the Center for—President for the Center of Bioethics and Human Dignity, and a statement from Lori Andrews who has been one of our consultants.  I will not read these.  These are available to people who would like them.

In the interest of not spoiling the rest of the day, let me simply say I will stay here through the break and be available for questions from the press.  Members of the media may also, of course, speak to other members of the Council.

Let us take a break, and let us reconvene here at a quarter of 11:00, so we can hear Dr. Jessell's presentation.

Apologies to those members of the press who wanted the microphone, but I think we can try to help you get your stories written if you speak to us individually.  And I'll simply stay here.

This session is adjourned.  We'll convene in 12 minutes.

      (Whereupon, the proceedings in the foregoing matter went off the record at 10:33 a.m. and went back on the record at 10:52 a.m.)

 

SESSION 2: NEUROSCIENCE, BRAIN, AND BEHAVIOR I: BRAIN DEVELOPMENT IN CHILDREN

CHAIRMAN KASS:  Session 2 of our meeting, Neuroscience, Brain, and Behavior I: Brain Development in Children.  From reproduction and the beginning of bodily life to the brain and the functions and flourishing of mental and emotional life.  Everyone senses the great excitement of neuroscience and modern psychology, methodical investigations by the mind of the mind to increase the human understanding of the human, prospects for addressing mental illness and aberrant behavior, and improving our abilities to make the most of our native mental capacities.  Everyone also vaguely senses that those exciting new discoveries might be accompanied by new ethical, social, and philosophical challenges precisely because these studies touch so directly on many of the powers and activities that make us who we are: awareness, memory, imagination, desire, motivation, thought, feeling, and moral judgment itself.

The Council is interested in learning about the developments in neuroscience and psychology present and projected that might raise significant ethical and social issues either because of the technological interventions to which they might lead, or because of changes in human self-understanding that they might invite.  In our Beyond Therapy report, we explored some of the psychotropic drugs that alter behavior, memory, and mood, in the service of goals beyond therapy.  But we sense that this was just one of a number of challenging issues that might emerge from this field.  At the last meeting we got a beginning in this area with introductory presentations from Robert Michaels on neuropsychiatry, by Jonathan Cohen on brain imaging and reward and decision, and you'll recall that we decided at that meeting before proceeding further to find out which aspects of this large domain were most worthy of our attention, that we should try to learn something about just the foundations, about normal brain and mental development, especially in children.  So today and the rest of today is about those foundations, the scientific foundations of normal brain and mental development in infants and in children.

The questions behind these discussions are really these.  What can neuroscience and developmental psychology tell us, either now or soon, that might be relevant for understanding how best to raise flourishing children and adults?  What can neuroscience and developmental psychology tell us that might be relevant for understanding and preventing disordered or dysfunctional children or adults?  But the explicit discussion, as opposed to these larger questions, the explicit discussion will be the science itself, neuroscience in the morning, psychology in the afternoon, and at the end of the day we'll have a chance to take stock of what we have done and how far we have come.

It's my great pleasure to welcome Dr. Thomas Jessell who is Professor of Biochemistry and Molecular Biophysics, the Center for Neurobiology and Behavior, and Howard Hughes Investigator, at Columbia University.  He is a distinguished researcher in the field of brain development.  It's a great pleasure to welcome you to the Council.  Apologies for detaining you, and we very much look forward to your presentation.  Dr. Jessell has asked me to announce that he would very much welcome our interruptions if we have questions or things on clarity.  He wants to make sure that we're following.  Dr. Jessell, the floor is yours, and thank you again.

DOCTOR JESSELL:  Well, first I would like to thank Dr. Kass for this opportunity to participate in this discussion of brain science and its relation to behavior.  And just to echo these comments that I really would encourage interruptions, comment, dissent, clarification.  If I lapse into jargon, then please bring me back to clarity.

Perhaps in the light of the first session this morning, an interesting place to start this discussion is in fact early in embryonic development, because it's at a relatively early stage in development that nervous systems form, that nerve cells are generated, and that those nerve cells begin to acquire identities that drive the subsequent formation of connections within the developing brain.  And one of the things that I'd like to suggest or argue in my comments this morning is that to a large extent the precision with which those connections form governs the intrinsic behavior or repertoire of any organism, whether it be a child, any type of mammalian organism, even lowly invertebrates.  Behavior is in large part dependent on the nature of the circuits that exist within those nervous systems. 

Now that is not to say that the wiring diagram, if you like, of the nervous system is the only determinant of behavior.  I think we've understood for many years that this provides an architectural substrate upon which environment and experience then mold those connections and refine those connections to produce the full, rich repertoire of behaviors that any given organism is characterized by.

So one of the things I'd like to discuss this morning initially at a relatively reductionist level is really to review what the field in general has learned about the nature of brain development during embryogenesis and postnatal development.  What is the relationship between genes, neurons, circuits, and behavior?  What are the molecular determinants that begin to establish the structure of the nervous system?  Then discuss the interplay between these genetic programs and environmental influences.  When does the nervous system cease to develop, if you like.  When is the pattern of connections established in a way that cannot be changed?  And our views on that have also changed rather dramatically over the last 10 to 20 years.  So we're dealing with questions of plasticity of the nervous system in relation to circuits and the way that those circuits influence behavior.  So these are all normal developmental processes, if you like, and perhaps if we have time at the end I will turn to the way in which those normal developmental processes become subverted in brain disease, in various types of neurological and psychological, psychiatric disorders.  Now those are very large problems, so I think at best I will be really scratching the surface on some of those later issues.

So just to put things into a general context.  Now, I hope that everybody can see some of these images, because some of my comments will really be dependent on them.  And those on my left are in danger of being attacked by this laser pointer, but I think we're working at the moment.  So what you are looking here is in very superficial terms the process of human brain development as a function of the nine months of gestation.  And so somewhere within the third to fourth week, the nervous system begins to form.  So cells in one of the major germ layers of the embryo, the ectoderm, make a decision that they're going to acquire neural character as opposed, for example, to acquiring the properties that eventually give rise to skin.  So the first steps in the formation of the nervous system occur at a surprising early stage.  And then as you can see because this is drawn relatively to scale, what happens over the subsequent eight months of embryonic development is a process by which the nervous system at least in large part accumulates large numbers of cells.  So the nervous system is exceedingly small at these early stages, but as you can see, by the time an embryo is born at nine months of gestation, there is a very highly organized nervous system which is much, much larger than the anlage that was seen at three to four days.  And so what we're really looking at at this period, and this process continues, not just in embryonic life, but in postnatal development.  Neurons continue to be added. 

So in a sense what the field of developmental neuroscience at these early stages has been trying to address are two basic questions.  So one of these relates to numerology.  So these are estimates, but the human brain is thought to contain some 1011 neurons.  This is a staggeringly large number of neurons.  And it also contains, and again this is simply an estimate, at least 1,000 different classes of nerve cells.  So by comparison, with most other tissues and organs in the body, the extent of cell diversity inherent in the nervous system is observed at a much more extreme level than in the liver, or in the heart, or in other tissues.  And so one of the major questions is to understand how during development the nervous system controls the number of nerve cells that are produced. 

And the other thing that this image shows is that not all nerve cells, once they're produced, are the same.  Individual nerve cells have discrete functional properties, and some of those functional properties are inherent or derived from the fact that the morphology, the shape, the structure of those nerve cells is markedly different.  So on the right-hand side of the screen here we're looking at one nerve cell that is found in a part of the brain called the cerebellum that is involved in motor control and many other functions.  And you can see that that cell, that neuron, looks very different from a neuron found in the retina that is involved in visual processing.  So one of the things that development does is ensure that not only do you generate very large numbers of neurons within the developing human brain, but you make these neurons different from a very early stage in fundamental structural ways that presumably influence their later functional properties. 

And I'll talk a little bit about what we currently understand about how these two problems of generating neurons and making neurons different are achieved at a developmental level.  Now these neurons don't exist in isolation.  The functional property of the neuron is dependent on that neuron becoming incorporated into a functional neural circuit, a network of neurons interconnected in different regions of the brain such that the combined activities of many neurons in different parts is necessary to produce a given behavior.

So the problem becomes even more complicated at this point.  So if we look at a typical region, for example the cerebral cortex, what we're seeing here is a complex, dense mesh work of neurons.  And this has been appreciated from classical anatomical techniques for the last century or more.  So each of these individual neurons as you can see from their morphology is subtly different from their neighbors.  One of the questions is how do these differences in morphology, these differences in structure, relate to the types of connections that they produce. 

So the two general questions that I want to begin to address, at least in the first part of my comments, are really going to be the issue of the impact of genes and genomes on neurons, on neuronal identity, and the way that those neurons begin to assemble interfunctional circuits.  So if you like, this is a reductionist view in which many aspects of brain organization are achieved through a genetic program to result in a wiring diagram of the brain.

So how are neurons generated?  This is perhaps the fundamental problem, the event that has to proceed if all other aspects of circuitry and behavior are going to be achieved.  And this is a problem that has been appreciated for, again, almost a century.  But it's only very recently that we have any molecular understanding of the way in which a cell in a primitive ectoderm acquires a neuronal property.  And this is a process that is reiterated many, many times to produce this vast diversity of neurons that exists in the human brain.

And so if we look from classical studies by Pasko Rakic and others, what we're looking at here is a small region of the developing brain, in this case a region of cortex.  And so in this region what you can see is a layered, a striated structure here.  One particular region called the ventricular zone, which you can't really see properly here, is the site of the precursors that will give rise to nerve cells.  These are neuro-precursors if you like.  They're stem cells in a particular context of neural development.  So these cells lie at one side of this epithelium, this sheet of neural cells.  And those cells divide under tightly controlled programs.  And the process of division here will determine whether that precursor cell continues to remain a precursor cell with a capacity to divide further, or whether that cell will leave the cell cycle and acquire so-called post-mitotic neuronal property.  One of the characteristic features of neurons is that once they're generated, they never undergo further divisions.  So this is a crucial event in determining the number of cells that populate the nervous system to determine how many of the precursor cell population remain, and how many post-mitotic non-dividing neurons are produced.

And the classical view until a few years ago had been that these cells divide in this restricted germinal or ventricular zone, and then they migrate through a complex process series of cellular events away from this germinal zone into their eventual settling positions in other regions of the nervous system.  And one of the ways that they're thought to undergo this migration process is along a series, if you like, of tram lines, or structural elements called radial glial cells which act as conduits for this migration process.  So really there are two processes going on here at these very early stages.  The process of cell proliferation coupled with the decision to give rise to a neuron, and then the migration of the neuron along these processes. 

Until very recently, and part of the reason I'm mentioning this, is to indicate that some of our thinking on these processes, even though the problem has been identified in classical terms.  Some of our thinking and some of the information is really very, very recent.  So much of what I'm saying is really a current 2004 view of these processes.  But this is still a field that is in a state of considerable flux.

So the classical view, which is shown on the left-hand image here, is that neurons achieve their final position within the nervous system through this migration.  They ensheath, they intertwine around these radial glial cells, and that's the way they move.  But the radial glial cell and the neuron have been thought of distinct cell types with no relationship.  What we now know from work in the last five years or so from many people is that this is certainly true, but this is an oversimplification, because it turns out that the radial glial cells, these structural elements, not only serve as a scaffold for neuronal migration, but they also represent in many ways the precursors of neurons themselves.  So the radial glial cells have a dual role.  They not only generate neurons, but they then act as a scaffold.  And I'll just give you one example of this new view.  So here we're looking almost in real time at one of these radial glial cells.  You can see its processes spanning the length of the future cortex.  And if we follow that cell in real time, although I'm showing it in a series of static images, what you can see is this cell divides at around Time Zero.  And then there are two cells.  And as we follow with time, one of the progeny remains in the ventricular zone, presumably to remain a precursor cell, but the other cell begins to migrate along this structural element.  And by using various genetic markers, some of which are not showing actually on this slide here, what we can see—there's a slight technical problem here, because this cell would be labeled Red with a neuronal molecular marker.  So this type of real-time imaging here is showing that radial glial cells are in fact the precursors of neurons.  So this is a piece of cell biology that has emerged over the last few years that has radically changed the way that we think about neuronal production in the developing brain.

So can we move then from this cellular description of where neurons throughout the central nervous system, throughout the brain, come from, into a molecular understanding of this decision.  What are the genes that determine whether a cell remains proliferative, or whether it exits the cell cycle and acquires a neuronal fate And over the last decade there have really been very substantial advances in understanding the nature of genes that drive this neuronal differentiation process.  And one can show that some of these genes are sufficient when expressed in a proliferative cell to produce the neuronal phenotype, to produce the neuronal fate.  And I'm showing you one example of this.  The nature of the genes don't really matter here.  But what we're looking at is a top-down view of an early vertebrate embryo.  And so this has a left side and a right side.  And on the left side, if we concentrate on, for example, the image in Panel B, you can see a few blue dots here.  Those are the neurons that have been generated under a normal developmental condition.  And you can see that there's a sea of non-neuronal tissue in which are interspersed individual nerve cells.  So in this experimental situation, a single gene that is one of these genes that promotes neuronal formation, has been introduced into these precursor cells, and the consequences for neuronal production have been examined.  And what I hope you can see is that to the right of this dotted line there is a vastly greater number of nerve cells that have been generated as a consequence of introducing that one gene.  So neuroscientists now are beginning to be able to control this early decision as to whether to give rise to a proliferative cell or whether to generate a nerve cell.  And these are genes that are operating in the embryo normally, and this is part of a genetic program that in a sense is determining the fact that the human brain has 1011, not 1012, not 1010 neurons.  So there's a tightly orchestrated genetic program that ensures the production of neurons.

This image indicates, at least with this sort of color-coding, that all neurons are the same.  So there are really two problems here.  One, as we saw, to generate large numbers of neurons.  But the second is to make those neurons different.  And so if we consider that the human brain at the time of birth contains some 1,000 different cell types, how are those different cell identities?  They're all neurons, but each of them acquires a characteristic identity that suits its particular later function.  How is that diversity of neuronal identity controlled?  So if there are 1,000 different classes of neurons, does that imply that there must be 1,000 different signaling mechanisms that are operating with one pathway of signal, one signal per neuron, which would provide extreme constraints on the number of genes necessary to generate this diversity.  Or has the nervous system evolved more efficient ways of generating diversity from a relatively small number of signaling systems.  So as a generality in the nervous system, as in the embryo as a whole, the way in which cells acquire their different identities is through the intersection of two different pathways. 

The fate of no cell in the nervous system is really preordained from an early stage.  So there is no such thing as a central nervous system homunculus.  Cell identities are acquired because of their position in an early developing neural epithelium.  And what their position really is doing is defining the environment to which that individual neural precursor cell is exposed.  So if you're in one position you're exposed to a different set of signals then being in a different position.  So really, neuronal generation and neuronal identity involves the intersection of environmental signals with programs of gene expression that are going on within the nerve cell itself.  And it turns out that this vast diversity of neuronal identities, 1,000, 2,000, whatever that number turns out to be, is generated through a surprisingly small number of environmental signals, where those signals operate in combinations.  So the nervous system has evolved efficient ways of using a small number of signals to generate this vast degree of diversity. 

And I just wanted to give you one principle by which diversity comes, how you can generate many different cell types, neuronal cell types, from just one signal.  And it turns out that some of these signals, which are secreted proteins produced by one cell which influence neighboring cells, have been termed morphogens.  So what we're looking at here is an early primitive region of the nervous system.  This particular region is going to give rise to the spinal cord, but if you looked in the brain, you'd see a very similar morphology. 

So this is the nervous system.  These are non-neural tissues.  There are localized sources of these secreted factors in non-neural tissues.  You can see by the shading of the color blue here which represents a site of gene expression.  And one of these proteins, which has been known as Sonic Hedgehog for various reasons, is a secreted protein.  That protein functions as a morphogen.  So what a morphogen is is a protein that can induce or change or compose different cell fates as a function of the different concentrations of that one substance that a cell is exposed to.  So the exposure of a naïve precursor neural progenitor cell to a low concentration of this factor will induce one neuronal fate.  But as you double the concentration of that factor, that same recipient cell acquires a different fate.  And so in this way, one single signaling factor, by acting at different concentrations can induce different classes of neurons.  And so for example, the local source of this factor establishes a concentration gradient throughout the early nervous system, the neural epithelium.  And in this particular example at least five different classes of neurons—their identity doesn't really matter—are generated in response to this one factor through twofold differences in concentration.  So this type of mechanism is used again and again in the nervous system.  In some cases it's concentration, in some cases it's the convergent exposure to two different signals that results in differences in identity.  But numerically, a relatively small number of these signals imposes the vast degree of neuronal diversity that we see within the nervous system.

So I want to switch now.  And you'll see that this is going to be of necessity a relatively superficial overview of all of these processes away from generating neurons.  Let's assume that you have generated vast numbers of neurons in the early nervous system.  How do those neurons begin to form connections?  Because one of the things that these early programs achieve are neurons with distinct identities.  And in reality, what the identity of a neuron does is enable it to extend a long process, kind of an axon, from the site at which it's generated into the vicinity of its target cell.  So neurons need to connect.  And so in some cases—and I'm going to show you an example from the visual system throughout some of these comments—you can see that the distance over which a nerve cell has to project in order to connect to its eventual target is very considerable.  Some several orders of magnitude longer than the diameter of the cell body at that cell itself.  So here we're looking at a sort of schematic view of some aspects of the visual system.  These are the eyes.  And in the retina there are neurons which process visual information, process light, convert light into electrical signals.  And the job of these retinal neurons is to take that information that is arriving from the environment, from the periphery, and to transfer that information into higher centers in the central nervous system.  And in many ways it does this by extending this long process called an axon from the site at which the cell is generated into its eventual target regions.  And then once it reaches that target region, it then has to choose particular sets of target neurons with which to form connections.

So there are many challenges here for a developing neuron in order to be able to establish an appropriate wiring pattern.  For example, if you focus on this retinal neuron, it has to make a decision to leave the retina, to extend this process out of the retina, along the optic nerve.  It then has to make a decision as to whether to cross, as most axons do, or stay on the same side of the brain.  So there are important guide post or path-finding decisions.  It then has to reach an appropriate position within its target region.  And then it alters trajectory, and then reaches an appropriate depth within the target region.  So all of these are different environmental problems that the developing neuron has to negotiate in order to reach its target.  And again, over the last several years we've begun to understand the complexity of this organization, again, has been appreciated for over a century.  But what we haven't known are any of the mechanisms, the molecular mechanisms that ensure these precise patterns of connectivity.  And the last 10 to 15 years has revealed almost a greater degree of molecular information than is currently processable.  But I want in very brief terms just to go through some of the thinking about how neurons, once they have acquired an identity, begin to be able to connect with target cells.

So the business end of the neuron is a sensory motor apparatus which is called the growth cone.  So the neuronal cell body gives rise to a long axon.  And at the end of that axon is a highly motile cellular structure, the growth cone.  And so what we're looking at here are various views of growth cones.  So the axon would then move out of below the screen and some many yards away would be the cell body.  But what you can see is that the growth cone which really senses information in the environment and converts that sensory information into a direction, into a vector or trajectory, is a highly organized structure.  And the general view is that the ability of the growth cone of the neuron to navigate this complex terrain en route to its target depends on the expression of a variety of receptor molecules which are sensing information in the environment, mediating that information through these receptors and converting that into directed behavior. 

And so what this involves, both the reception of information in the environment and the conversion of that into a motor response.  The growth cone has to crawl physically through a variety of substrates.  So in this process of extension of the axon, there is a highly complicated cellular machinery that is occurring where, for example, the actin cytoskeleton is tightly linked to these receptors on the cell surface.  So that information from the environment is converted through the actin cytoskeleton into directed movement.  And we're beginning to understand a great deal about the way in which neurons, growth cones, use their cytoskeletal, use their structural properties to influence their direction of growth.

The other thing that we've begun to understand is the nature of the environmental symbols that influence the behavior of axons, behavior of growth cones.  Now I'm going to show you an example from an isolated in vitro experiment that the assumption is that same mechanisms are going on in the developing brain in situ.

So what we're looking at here in this panel is the axon of a growing neuron and here is the growth cone.  You can see that this is a highly elaborate process, the small protrusions called Filopodia that if this was a real time image are constantly changing, constantly moving.  These are the sensory apparatus.  This is the sensory apparatus that is looking for cues in the environment.

We know a lot about the molecules in the environment that influence the structure and the direction of axon growth cone movement.  So the details of this don't matter, but we now understand many, many classes of molecules that are distributed at key points along the trajectory of a growing axon and that influence direction directly by impinging, by imposing, changes in shape and motility in the growth cone.

So what we're looking at in the bottom panel is the exposure of the same growth cone to a protein that we know guides axons and the way that it guides those axons is by inducing a very dramatic collapse of this complicated cellular structure.  So essentially it prevents growth cones and axons from moving in that direction because the growth cone is necessary for motility in a directionally sensitive manner.  This will then prevent growth continuing in this direction and then the axon will move off in another direction.

Some of these molecules influence guidance if you like in a negative, repellant way.  They form no-go zones in which axons are simply incapable of moving.  Others act in a more positive way.  That is they act as lures or attractants to direct in a positive way axons towards a particular target.  Through the combination of these negatives factors and positive factors, it's thought to guide axons from the site in which the neuron is generated in a set of complicated steps to the vicinity of its targets.  So this have been a very dramatic advance in understanding as we will see later on and may have implications in therapy in the context of regeneration in the adult state.

Once an axon through these guidance mechanisms has reached the vicinity of its target cell the next challenge it faces is actually to select which of the small subset of neurons it's going to form stable connections with.  There may be 1,000 different potential target neurons for that one neuron, one axon, to connect with.

How does it choose which of those 1,000 neurons it's going to form a stable association with?  Now this is an area that even though has been the subject of intensive study is still relatively poorly understood.  It's only in the last five years or so that we have any understanding in the central nervous system in the brain of the mechanisms for forming functional synaptic connections because communication between nerve cells depends on the formation of these functional connections.  There are many problems inherent in this process of recognition of how you recognize the target cell to form connections.

So in various schematic ways, there are sort of where type questions.  That is this is one target cell.  This in-growing axon has chosen to form a connection on that one target cell, but not on a neighboring cell which would be off the screen here.  So that is the first type of question.  Which cell do you choose to form a connection with?

The second type of question which is very important for the function of the neuron is where do you form the connection.  Do you form the connection close to the cell body of that target neuron or do you form because neurons are such highly polarized structures way out from the distal processes of the so-called dendrites of the neuron?  So there are questions of sub-organization as well as which cell you choose.

Frankly we don't have a good understanding in molecular terms of how these processes operate even though we do know that there's a high degree of stereotypity of selectivity in those processes.  So what the field currently trying to understand in a way that I think will eventually be important for understanding how circuits control behavior and how those behaviors are eroded in disease is understanding the biochemical mechanism that is essentially a recognition process between the arriving neutron, the pre-synaptic neuron and its pos-synaptic target.  We have little information yet on the nature of the molecules that drive this process.

But interestingly and I'll come onto this later, the few molecules that have been implicated in this process are known to be mutated in certain forms of human neuro-developmental disorders.  So it begins to suggest that actually understanding the machinery of synaptic connectivity may say a lot about the normal and pathological function of the human brain.  I'll elaborate on that point.

So the final step in this brief overview of the wiring diagram in the brain occurs after neurons have made connections with their target cells.  You might imagine that this is the end of the process.  Once you have generated the neuron, you've managed to reach the target region.  You form the connection with the target cell.  The job of development is done.  But it's very far from done.  As we'll see, there are many processes that have to operate.

One of those processes relates again to this basic problem I started with of numerology.  That is in order for a circuit to function appropriately, there has to be a precise matching of the number of neurons that are generated in one region and the number of target cells or target neurons that are found in a completely different region.

And one of the very surprising things that emerged some 50 years ago is that the nervous system is extremely wasteful in the generation of neurons.  In fact in most regions of the nervous system, two to three-fold more neurons are generated than are eventually incorporated into functional circuits which would seem a wasteful process.

But one of the rationalizations of that process has been that perhaps one of the things that permits one to do is to achieve numerical matching between two sets of interconnected neurons.  If you generate neurons in larger numbers, those that are generated in excess become dispensable and can be eliminated.  There is a lot of evidence, cellular and molecular evidence, that this type of process occurs and this is generally known under the term of neurotrophic factor hypothesis.

The basic idea that seems to operate is that you have a restricted target cell and many neurons that have the potential to innovate that target cell.  But what happens again and again during brain development is that only a small set of those neurons that are originally generated eventually form stable connections with that target cell.  The reason at least that this occurs in part is that one of the things the target cell is doing is communicating back to the neuron.

There is a two-way process of communication and the target cell is producing factors that support the survival of the neuron and it's producing those factors in limited amounts and limited availability.  So in a sense, this target cell produces only half as much of this survival factor as is needed to support the entire compliment of neurons.  As a consequence through a competitive process, only perhaps 50 percent of those neurons that are alive in the vicinity of the target cell form stable connections.  What we'll see in the next section is that this process of competition, excess production and competition, is really paramount in linking the genetic programs of neuro-wiring to experience and activity in the way that experience and activity sculpt these basic projections.

Without going into details, we know the basic elements of this competition, target-celled derived support factor hypothesis.  In many cases, we know the nature of the molecules that promote cell survival.  One of the dramatic advances in all biology over the last 10 to 20 years has been the appreciation that in fact the default state of most cells in the body is not to survive, but to die.

There's an intrinsic death program that is inserted into every cell.  Cell survival really only is permitted under conditions in which that intrinsic death program is suppressed and is subverted and the first inkling of that information in fact derived from these sorts of experiments in the nervous system.  So we know the nature of these neuronal survival factors and we know a lot about the biochemical mechanisms by which they promote cell survival.  This is the first example really in a normal developmental epoch of ways in which competition and interactions between cells shapes this genetic programming of the wiring diagram.

I'm going to move now unless there are questions or comments that I could elaborate on from this simplistic but nevertheless I think valid idea that genes in large part program the basic wiring diagram of all nervous systems from invertebrates to vertebrates, from mouse to man.  Many basic aspects of the connectivity are programmed in a way that involves serial developmental decisions to give this basic neural blue print.  But at that point, the precision of connections, which connections are maintained, which connections are reinforced, which are eliminated then begins to be impacted in an extremely profound way by environmental signals.

So I want to begin to talk now about how activity of nervous systems, how the experience and the environment shape these connections.  Again I'm going to use the classical example which emerged from studies by Hubel and Wiesel in the 1960s and the 1970s focusing on the organization and structure of the visual system and the influence of environmental deprivation on the structure because I think that there are many, many examples of this general paradigm but that the first realization came from these classical cellular and physiological studies.

We're now back in the visual system.  These are the eyes.  This is the optic nerve projecting to a set of relay nuclei to a second order neurons in the thalamus and those thalamic neurons then relay visual information from the eye via this one relay station to the cortex.  So most vertebrates can extract information from the visual world and use two eyes to do that.

How does the brain extract information from the left visual field, the right visual field, keep that information separate as it begins to form these projections, form these connections, and where is that information integrated?  One of the important things that occurs is that you keep the information from the left eye and the right eye separate at many of the early processing stages in the developing brain.  What you can see is as one traces through and then looks in higher magnification, that an input from say the right eye here will eventually project to a region of cortex that is spatially distinct from that region of cortex that receives information from the left eye.

What the great discovery of Hubel and Wiesel together with Vernon Mountcastle in the somatosensory system was that the cortex is basically organized in columnar fashion.  Information doesn't arrive in an indiscriminate, anatomically mixed fashion.  Information from the two eyes is physically separated.  One can see that physiologically as Hubel and Wiesel first saw that but you can also see that anatomically.

For example, if we provide a tracer into one eye such that that tracer is incorporated through all of the neurons that form that right eye circuit, you can then see the consequence of the projection of that right eye in relation to the unlabeled left eye.  So that if we look here, this is a cross section through a mammalian cortical structure.  This is true of humans.  This is true of primates.  This is true of cats, many mammalian organisms.  What we are looking at are the terminal fields of axons that receive information let's say from the right eye.  They would be shown as these light patches here.

What you can see is the cortex consists of the mosaic of light and dark patches which is a reflection of information coming in from the right eye as opposed to the left eye.  This is a relatively mature state.  This is what 13 week post-natally in this cat experiment here.

But what is interesting is if you look at a much earlier but still post natal stage, what you can see on the top here is that these stripes or banded patterns don't exist.  What the implication of that is is at this early developmental stage information from the left and right eyes is arriving in the same spatial region within the developing cortex.  What you can see is that over the intervening 11 weeks of post natal development in a so-called critical period, the information, the axons from the left and the right eyes are segregating to form these distinct domains.

This is a process of development of connectivity that is occurring in the post-natal period which then follows most of the earlier embryonic patterning mechanisms that are described in the first section.  What is particularly dramatic about this sort of structural organization of visual input is that it's critically dependent on visual experience.  An early set of classical experiments looked at the consequences of eliminating visual input into one of these eyes and examining anatomically and physiologically the consequences for the structure of the brain.  What happens if you deprive one eye of the normal sensory information that it receives?  And you see very dramatic changes.

So we are now going to switch orientation and we're going to be looking at top down images of the brain, of the cortex with sections or slices cut through in this plane.  What you see here is in the top panel—I hope you can see that from the back—that you have again these alternating stripes, so-called ocular dominance columns of left eye, right eye where the width of each of these stripes which is an anatomical representation of information coming from the two eyes is roughly equally proportioned, that equal black stripes and white stripes here.  This is a diagram showing this mosaic of information.

What you can see in these intervening panels is that structural reorganization of information in the brain in the cortex has a consequence of monocular sensory deprivation, depriving one eye of visual input.  For example here, and it really doesn't matter, what you can see in this case is if the eye that was represented by these dark stripes was deprived, you can see here that there's a massive over representation of the structure, the inputs, from the eye that is still receiving visual information.  The white patches greatly exceed the dark patches.

Conversely if you design the experiment in a different way and you deprive the light patch eye, you can see that the dark patches prevail.  This is very dramatic evidence that visual experience produces a structural change in the brain.  One of the things that one can now begin to understand is the nature of the process by which environment and experience produces structural changes in the central nervous system in the cortex.  This is just a diagram of what we were looking at in real images before.

Early on the information from the two eyes is essentially overlapping over this post natal, critical period.  The information gets segregated into distinct ocular dominance columns in the developing cortex.  And that under conditions where sensory information is eliminated from one input, then the other input predominates.  So these are gross structural changes in the organization of the brain that are the consequences of presumably the inability of experience and activity of those neurons to maintain a spatial territory.

You can actually see this influence of experience and the environment at the level not of just domains of the cortex but individual neuronal branching patterns and morphologies.  These are just four diagrams showing essentially the normal change in development of an axon, a nerve that is going to innovate the cortex and the consequence of deprivation.

On the left-hand side here, we've traced the terminal projections of one of these axons arriving in the cortex conveying visual information in a young post natal animal.  You can see that the region of space or cortex occupied by this axon that it's relatively broad that the density of terminals of branches in any given region is relatively small, relatively low.

Now as the animal matures under the consequences of normal visual experience you can see that there's a dramatic change in the shape of that projection.  A much smaller region of the cortex is now innervated, but that region that is innervated now receives a much higher density of axonal branches and synapses.  So this is the process of post natal structural reorganization that is occurring.

We know that this structural reorganization is again dependent on experience upon sensing the visual world because if we deprive one eye then you can see that at the level of an individual neuron those structural changes are very dramatic.  The neuron has few axons, few terminals.  We are seeing this level of structural reorganization in the nervous system as a consequence of visual experience at many, many levels.

Here we're looking—and I'm going to emphasize this point because I think it's one of the major features in the way in which environment, the experiential world influences the structure of the mature nervous system—at the level of the axons that are arriving in the cortex, but we can also see this at a finer level of resolution if we look at the target neurons that are going to receive that information.

I'll do this first.  Here is one of these cortical neurons.  The cell body, it has a very extensive set of processes called dendrites and the synaptic input, the information that is coming into this neuron is occurring on a series of very small micro structures that come out from one of these dendrites which are so-called dendritic spines.  The spines here, these protrusions, are really the units of synaptic information.  Each of these spines is going to be occupied by an incoming synaptic terminal.

We know that some of the same activity experience dependent changes that I was showing you in the previous slide at the level of the pre-synaptic terminal also influenced the dynamics of these spines.  Whether these target neurons have many spines, have few spines, these are very dynamic cellular structures which come and go as a consequence of activity.  Both on the pre-synaptic input side and the post-synaptic target side, experience and activity in the circuit is having an dramatic impact on the structure.

This information all of which is derived initially from the visual system raises the question of whether this is something special about the way the visual system works, or whether in fact all sensory systems are subject to the same structural change in organization of the brain as a consequence of sensory information coming in from the environment.  There are many, many examples as one moves out of the visual system that the same thing is true.  I'll show you just one example from the auditory system.

This is again a slightly varied organization here, but we're now looking at a map of a region of auditory cortex.  This is the region of the brain that processes normal sound, auditory information.  The wonderful thing about the auditory system as opposed to the visual system is that sound is tuned according frequency.  Different regions of the auditory cortex are tuned to optimal frequencies.

There's a so-called tonotopic map.  Different sound frequencies get projected to different regions of the auditory cortex.  By applying a single sound you can make that region of the cortex that receives that particular sound frequency.  That's what we're looking at here in an early post natal rat in fact this is.

Now the relatively large region of cortex associated or devoted to that particular tonotopic frequency.  If we look some 34 days later, the region of cortex that is devoted to that same sound frequency has reduced in a very dramatic way.  This looks a lot like what we saw in the visual system.  We know that auditory experience, the sound that we experience, over that critical post natal period has a dramatic influence on how this auditory, tonotopic map forms.  Because if we now apply to an experimental situation, apply in a sense a white noise preventing the auditory system from extracting normal variation in sound frequency, then applying this distracter noise  produces a very dramatic slowing of the normal maturation of this cortical map.

We're now looking at the same map here but under conditions in which a distracter noise had been applied.  You can see that not only does deprivation of visual information but deprivation of important auditory information erodes the normal formation of the structure of the brain, the structure of the cortex.   You see this same information, this same principle, occurring in all sensory systems.

What this means I think is that during this critical post natal period information coming from the environment and from the visual senses, the auditory senses, the tactile senses and the somatosensory system, taste, smell, all of this information is converging on the central nervous system and providing these structural refinements in the basic wiring diagram that are essential for accurate perception of the environment, accurate performance of motor commands in response to that information.  This I think highlights what we've known for many years that this critical post natal period is essential for the appropriate structural information within the nervous system.

CHAIRMAN KASS:  This sounds as if this is mostly a certain kind of openness is then restrained and pruned and that there's a greater sort of amorphousness which then becomes more specialized as a result of this experience.  Have I gotten that particular point right first?

PROFESSOR JESSELL:  Yes, perhaps the easiest way of showing it is just to go back to this image which is essentially a pruning image.  What is happening at these post natal stages in development is that the map is roughly correct.  So visual information is coming into the visual cortex and not to the auditory cortex.  But the fine details of the working of those cortical structures is not sufficient to achieve this rough map.  You have to proceed.  You have to achieve a precise map.  That precision is achieved by this pruning process.

So in a sense what we're looking at here as you go from young to mature is the pruning of one neuron.  That has functional consequences because then you achieve a much greater degree of point to point precision in connections. This pruning process is activity, is experience driven.  Without that experience, without the range of information coming in from the outside world, this pruning process fails to occur.  We can see that at the single cell level and we can see that at the level of the auditory example.

CHAIRMAN KASS:  May I just follow up?  Would there be—I don't even know what I'm asking here, but is there something that you could call pre-natal experience that is at work even before?  Sound I suppose is still transmitted intrauterinely.  Visual would be a different matter.  But do we have environmental and "intrauterine" experiential things that are already doing this or does the major effect take place after birth?

PROFESSOR SANDEL:  And what about the Mozart effect?  Even if that's not true, would that be an instance of this?

PROFESSOR JESSELL:  Yes.  I haven't mentioned it and stressed the post natal period, but there is strong evidence that this activity-driven wiring of the nervous system occurs during fetal development as well as post natal development.  There is very strong evidence in one of the articles I distributed.

Carla Shatz is one of the people who has really provided some of the strongest evidence that in fetal development the retinal ganglion neurons that are first arbiters of processing of visual information  are firing in patterns during embryonic development that is thought to be important for setting up perhaps the first aspects of organization superimposed on this basic genetic wiring program.

That is certainly true for the visual system.  I think there is good evidence that is true in the auditory system.  Whether it's true in some of the other sensory systems, the evidence is less.  So this process even though it's been most heavily studied at a post natal period for reasons of accessibility probably is beginning during the embryonic stage and when it begins you can put limits on to in the nature of the basic connections that have to be formed before the information from the environment can even reach relevant areas of the cortex.  But it's a relatively early process.

DR. ROWLEY:  But if I can follow on with that.  It was my impression from reading Carla's article that what's formed are some of these intermediate connections or the way stations or the relay stations rather than the specific connection with the fine processing neuron in the cortex.

PROFESSOR JESSELL:  Yes.

DR. ROWLEY:  In her example in the visual cortex.  So you set up the systems that are necessary already before birth so that these intermediate processes that connections have been made and then the pruning of the final one is what's then done after birth.

PROFESSOR JESSELL:  Yes, that's absolutely correct.  The system that Carla is looking at which is shown on this slide back here, I've been concentrating on the cortex which is the final target.  Carla has looked at this intermediate thalamic relay station because those are the targets of retinal ganglion neurons that are spontaneously active during fetal development.

I suspect that wherever you look you will find evidence that the activity experience dependent structural changes traditionally this has been looked at first in cortical structures.  We now know it's true in subcortical structures in the thalamus.  I suspect even at the level of the first sensory relay station, perhaps even in the retina itself, activity is having an influence in terms for example of the morphology of neurons or fine details.  I suspect that this is happening in a very pervasive manner and where you look depends on what type of experimental system accessibility of that particular region of the nervous system.

PROFESSOR SANDEL:  You've been speaking about the plasticity in the early post natal period.  Do we know when it stops?

PROFESSOR JESSELL:  Yes.

PROFESSOR SANDEL:  When experience dependent changes no longer affect the structure of the brain?

PROFESSOR JESSELL:  That's the next section.  So maybe I can come onto that.  Yes.  The answer is that if you'd asked me this or asked the field this ten years ago, the idea would have been that this critical period closes at some point two to three months after birth in an experimental animal. It perhaps closes in the first several post natal years in the human infant.  What we now know is that to some  extent that process of plasticity persists throughout adult life.  I'll give you some examples of that.  Probably I think as a generality the nervous system is most plastic at early stages and plasticity is essential for connectivity in the way that we've seen in an immediate post natal period.  But there are striking functional elements of plasticity albeit at a reduced level even in the mature organism.

CHAIRMAN KASS:  Dr. Jessell, would you like to complete the presentation?  We can take questions then.

PROFESSOR JESSELL:  If they are burning questions, now is a good point.  We've reached the end of this stage.

CHAIRMAN KASS:  Bill Hurlbut and then Gil.

DR. HURLBUT:  In saying that there is a longer phase of plasticity at some point whether now or in your further presentation, can you talk about the possibility of actual revisions like the slide you showed Mike Merznich's information?  I know Mike is very interested in revisions of neural process.

PROFESSOR JESSELL:  Yes, I will comment on that perhaps in this context of the adult stage and what some of the Merznich observations, some of those implications are.  Yes.

CHAIRMAN KASS:  Gil, very briefly.  Then I think we should let Dr. Jessell complete.

PROFESSOR MEILAENDER:  Yes.  Whether I can make sense of this question or not I don't know.  I don't belong to the party of rationality.  But could you or would you use in describing this process of development a word like optimal?  Is there an optimal point anywhere along the way?  Or is that not the kind of word that you would use?  Is it just a process that you describe in which one couldn't find a place to use that sort of word?

PROFESSOR JESSELL:  I think what we've learned is that development as I'm describing it is a process of gradualism.  That there is constant change as a consequence of influence of the environment.  To use the word "optimal" presupposes to some extent that we know how the circuit should function in all its aspects.  What we see are erosions of performance in behavior that presumably can be linked to changes in circuits.  So that is suboptimal.

What the optimal wiring of these circuits are I think we don't understand.  So dramatic perturbations I think we can interpret.  As we'll see, maybe it's a matter of give and take that in considering for example the plasticity of the adult nervous system.  One is balancing two forces.  One is that you want some constancy in connections because that constancy allows you to perform at a high cognitive level.  Learning and memory are thought to be encoded at least in part in the constancy and the strengths of individual connections.  So constancy there is a desired attribute perhaps something approaching optimal.

On the other hand if you think about regeneration of the nervous system under conditions of lesional injury, then the nervous system, that constancy becomes a liability in terms of the ability to reform connections.  Where optimal is along that sort of line, I don't know and I don't think anybody perhaps knows at this point.

I'd now like to come onto the question that we were just discussing which is over what period does plasticity really persist.  Is there as classically viewed a critical period and once you reach the end of that critical period in post natal development, the wiring diagram of the brain is fixed and activity simply operates on the structure that exists without having the ability to change it further?  Work from Michael Merznich and many other people I think has very dramatically changed our view of the extent of plasticity in the adult brain.

What I was going to do is to talk about three aspects of this balance between constancy or stability and change in an adult context in three different sections.  One comes back to what we were talking about earlier in terms of just the generation of neurons.  The second is the reorganization of circuits.  The third is the regenerative capacity of the nervous system as a function of age.

One of the dogma that has been overturned in the last 10 to 15 years relates not only to the reorganization of circuits but to this idea that neurons are born early in development and then once they're born the nervous system has acquired its mature cohort of neurons and there's not much you can do to change that situation.  I think that now we know that that is not the case and that there are certain privileged sites within the brain that are capable of new neuronal production even in the adult stage.  This obviously has many implications in a clinical, in a therapeutic way.

If Rusty Gage who I think was due to be here, he would expounded on this view because he's been one of the major contributors.  But in his absence, I'm going to really review very briefly some of the evidence that I think provides persuasive evidence that at least in the mammalian brain although I think whether this is really true and the extent to which it's true in human brain is still a matter of debate that in the mammalian brain, in mice and many experimental animals, neurons are produced in the adult nervous system, in the adult brain.

But they are not produced everywhere.  There seem to be two privileged sites where neurons can be produced.  One of those is in a region in the forebrain in the subventricular zone.  The details really don't matter, but many of these neurons will then migrate into the olfactory bulb, one of the regions that is involved in processing sensory information.  It's been known for many years that neurons that convey odor perception from the external world turn over even in the adult state.  These are the primary sensory neurons.

What has been appreciated more recently is that they are target neurons, the neurons that have to receive that incoming odor information also turn over at some rate.  So the olfactory system for whatever reason and one might speculate on that is a privileged site within the human brain in which neurons are constantly being replenished.  What impact that has on one's ability to respond to odorant information to pheromone information, the environment, is something that could be discussed.  What this shows very clearly is one site in which neurons are produced in the adult brain contravening existing dogma that had persisted for many decades.

There is also a second site and so far only a second site of new neurogenesis and that is found in a cortical structure called the hippocampus.  This is an area which has been implicated in many interesting cognitive functions, learning and memory  amongst them, but also mood and emotional disorders.  It's very clear here that there is a small group of precursor cells that in the adult animal in just the same way that we've seen in the embryonic period of neurogenesis, there are progenitor cells which make the decision whether to leave the cell cycle and become post mitotic neurons in the adult.

You can visualize them with various molecular tricks.  What people now think that at some slow rate these neurons are produced.  They begin to acquire all the hallmark structural features of neurons and there is some, albeit weak, evidence that these neurons can actually contribute, reconstitute themselves, into functional neural circuits although I think it remains unclear as yet what the functional consequence or contribution of these adult generated neurons is.

But this has been a very surprising set of observations that initially met with some resistance and then some over enthusiasm and interpretation.  But I think that it's now clear that these two regions of the adult mammalian brain can produce new neurons.

There are further implications of this observation in terms of plasticity of the mature brain  because the production of neurons for example in the hippocampus in the adult brain doesn't proceed at a constant rate.  It itself, this process of neurogenesis, can be influenced by environmental stimuli.

Rusty Gage is one of the people who've show that rearing experimental animals in deprived or enriched environments can have a relatively significant impact on the rate of new neuronal production in this region of the hippocampus.  One of the experiments that Gage performed is to rear mice in a relatively deprived experimental laboratory environment or to give them enriched environments or environments in which exercise and motor systems are activated at a much higher level.

You won't be able to see this because of this technical problem, but maybe if we concentrate of the middle panels here, each of these black dots represents that region of the hippocampus where new neurons are produced and each black dot is a newly generated neuron under these control conditions and under conditions of exercise or an enriched environment.  Here you can see that stimulating the environment of the animal produces a significant increase in the rate of new neuronal production.  Again this is a much later example of the way in which an animal's environment influences plasticity in the mature state.

DR. ROWLEY:  I was wanting to ask you to define more precisely the age both of the animals and of the equivalent age in humans.

PROFESSOR JESSELL:  Yes.  In these animals, these are mice in this case.  You can see the same thing in experimental rats.  These are so-called mature which would be two to three to four months of age, something like that.  The issue with humans is, I think, at a more fundamental level and there are people more expert than I who could address this as to whether the same process that we see in lower mammalian species occurs in a significant way in the adult human brain.  I think that is a matter of debate.

It's clear that there are progenitor cells that are proliferating in the adult human brain.  The question as I understand it is whether those progenitor cells produce, overt fully authenticated post-mitotic neurons in the human brain at the rate that they do in the lower mammalian brain.  This phenomenon can be seen at six months of age in mice.  This is a very robust phenomenon.  It's not the trailing edge of a developmental process.  I think new neurogenesis is really occurring at a relatively constant level probably until middle age for the mouse.  But again there are fundamental issues as to what extent—and maybe other people will have views on this, to what this really occurs in the human brain.

So one form of plasticity change in the human brain as a consequence of the environment is seen through simply modifying the environment.  But there are also experiments which suggest that pharmacological intervention can also influence the rate of neurogenesis in the hippocampus at least in experimental animals.

Eric Nessler and Ronald Dumond, some years ago, not too long ago, came up with a very striking observation that anti-depressant treatment using a serotonin uptake inhibitor, Fluoxetene, has a dramatic effort on the rate of neuronal production in the hippocampus in this same system.  I've just taken one image which is exactly the same type of experimental approach. Under the control conditions, there are relatively few of these black dots.  You probably can't even see them there.

Under Fluoxetene treatment, then the rate of neurogenesis increases in the hippocampus.  This suggests that clearly these drugs have behavioral consequences and raises the question of whether some of the behavioral consequences of mood-altering drugs are in fact a consequence of changes in the rate of new neuronal production.  Clearly these drugs may have many effects.  So this could be an incidental rather than a causal influence.

My colleague at Columbia, Rene Hen, has performed an interesting series of experiments recently that were reported in Science last year which actually while not proven at least keep open the idea that adult neuronal production is in fact perhaps a causal contributing factor to changes in the behavioral consequences following serotonin uptake inhibitors.  This is a very active field at the moment, but I think it have many people galvanized about thinking not only about natural experiences but also the way in which pharmacology and drug treatment influences this aspect of brain plasticity and behavior.  This is a recent set of observations so the consequences of this I think remain to be discussed and thought about.  This is one example which really takes the information.

DR. HURLBUT:  Those studies are on mice.

PROFESSOR JESSELL:  These are on mice.

DR. HURLBUT:  And are these mice that are in any sense depressed so to speak or are they in an enriched environment?

PROFESSOR JESSELL:  Yes.  There are a behavioral assays that the Hen group have done in particular where they've used certain behavioral, open field trial responses.  It's a complicated issue.  One of the things that the Hen study tried to do is actually prevent adult neurogenesis and then ask about the behavioral consequences of Fluoxetene administration.  One of the ways they tried to do that is to irradiate the hippocampus, killing the progenitor cells, preventing neurogenesis and they have some behavioral evidence that many of the behavioral consequences of Fluoxetene treatment are belated as a consequence of irradiation.

That raises all sorts of additional questions about whether irradiation is specific and whether you can contribute the effects of irradiation to the loss of neurons and whether the behavioral parameters being measured in mouse really are a reflection of the state of elation or depression as viewed in a human.  I think all of these are open questions and hopefully will emerge with further studies.

DR. HURLBUT:  So essentially you are saying that there is to date no evidence that an otherwise normally functioning enriched mouse would have increased rates of neurogenesis under an SSRI.

PROFESSOR JESSELL:  I think many of these things are suggestive correlations at the moment that drugs and environmental experience that change the behavior of the mouse change neurogenesis.  The Hen experiment to my knowledge is the experiment that most closely links causality or implies causality in the process, but I think Hen himself would not argue that that case has been proven at the moment.  I think there are experimental designs that will emerge over the next two to three to four years that will establish causality or not.  Then I think things become interesting.

This has been plasticity in the adult context viewed from neuronal production.  There is extensive evidence that aspects of circuitry are also plastic beyond the traditionally viewed critical period.  We've discussed the Merznich type of experiments and Michael Merznich has been the person who has promoted this idea most persuasively.  It again comes back to mapping in regions of the cortex, particular regions of a peripheral sensory receptive field.

Merznich has done this to a great extent in the somatosensory system where individual regions of the body surface can be mapped to particular locations in the somatosensory cortex.  Then the basic gist of these Merznich type of experiments is to change the level of information that is applied to that peripheral receptor field by training in way or another and ask in a mature central nervous system in the mature brain whether the cortical representation of that peripheral receptor field changes using physiology and to a lesser extent using anatomy.

Then there are striking examples that the cortical representation of a given receptor field for example on the digits in a primate, in a monkey, changed dramatically as a function of training.  So here is the receptor field on the digits of a monkey.  This is the normal region of cortex that receives that information.  This darkly shaded area represents the normal area, the normal region of cortex, that receives information from those three receptor fields on the digits.  After training you can see a very significant expansion in the area of cortex that processes that information.

This is a functional reorganization of the nervous system as a consequence of experience or training.  It raises the issue of what is the structural basis of this.  Is this a structural reorganization in the way that we've seen at earlier stages of development in the visual system or is this really a functional reorganization?  Are some synapses normally just not operative and sitting there in a quiescent state?  But upon training, these synapses suddenly start to work?  So at a physiological level, you see a change in the map.  These are questions that I think are currently being examined.

The extent to which this clear and established functional reorganization which is the important thing reflects a structural change or reflects changes in the efficacy of synaptic communication between neurons.  Merznich's group has some evidence for structure, but whether structure accounts for all of the dramatic changes in mapping of sensory inputs I think remains to be seen.  Nevertheless this very clearly, I think, shows that there can be reorganization of circuits as well as simply the generation of neurons at a much later stage in an adult stage.

Then finally I want to deal with, if you like, the flip side of plasticity in the adult nervous system.  The ability of the nervous system to adapt to a changing environment probably is a good thing.  It allows you to optimize perhaps circuitry in relation to particular environmental conditions.

But one of the things the nervous system is not good at doing is reorganizing in the wholesale way so all of the processes I described at early stages in development, the extension of axons, the ability to form connections, the ability to refine those connections in a very dramatic way, decrease dramatically with age.  One of the major problems from a clinical perspective is the relative constancy here.  I've focused on examples were things can change.  Neurons can be produced.

But by and large, the mature nervous system is a relatively static structure.  This has dramatic consequences following damage or injury to particular regions of the nervous system.  In one well-talked about example in spinal cord injury, one of the reasons that people with high spinal cord injuries recover so poorly is because of a poor regenerative capacity of the nervous system.  This is if you liked limited plasticity.  Damage to a particular region, all of the descending fibers from the brain that are necessary to activate the motor system to restore motor control, the extension of those processes across a lesion or scar region is extremely poor at the moment.  This again has been appreciated for 100 years.

Over the last ten years I think partly through work on developmental mechanisms, there is now some hope that plasticity in this context can be enhanced dramatically by changing the environment in which regenerating axons are trying to grow.  One could view this in two ways.  One is that perhaps the failure of adult neurons to extend axons effectively to recover function is an intrinsic property of those neurons.  They just somehow with age lost the capacity to grow axons.  That probably is not the case.

A major influence on the inability of axon regeneration is nothing to do with the neuron itself, but is the fact that the environment of that neuron is now extremely non-permissive for axon growth whereas at an earlier stage in development, it was highly conducive to growth.  The last five years or so has seen very dramatic advances in understanding the molecular basis of that non-permissive adult environment.  It turns out that many of the supporting glial cells in the nervous system—we focused here on neurons—in particular a class of cells called oligodendrocytes express proteins on their surface that will inhibit axon regeneration.

Since most axons are trying to grow in the mature central nervous system in the highly myelinated oligodendrocyte rich environment, the reason they don't grow well at least in part is because oligodendrocytes with maturity acquire proteins that inhibit axon regeneration.

Again the details don't matter, but this slide is really just to show that there are now some molecular reality to proteins that are expressed on the myelinating oligodendrocyte and receptors expressed on the sensitive neuron.  Many studies now are underway to try and eliminate thes proteins and see whether that has the ability to enhance some regeneration.  This is viewed from a clinical perspective to recover motor function for example in cases of spinal cord injury, but I think it has interesting implications because it comes back to this issue about what is optimal in terms of stability and plasticity in the mature state.  If you could find ways of allowing perhaps in order to maintain faithful function of neural circuits, you have to find a way to cement them in place.

The downside of that fixation process is the inability to recover function from more dramatic traumas to the nervous system.  What happens if we can now unleash plasticity to a much greater extent than had previously been possible?  What will be the consequence in terms of other aspects of nervous system function, cognitive processes?  Will one generate complete disorder?  Will animals become more intelligent as judged by behavioral methods under conditions where they can reorganize circuits in the mature state?

I think these are issues that one is only just beginning to scratch the surface with.  With the technical abilities that come in part through molecular biology over the last five years, one will likely be able to manipulate circuitry in the adult central nervous system in a much more profound way than has been possible for the last century.  Thinking about how one then designs, at least initially experimental tests to examine the consequences of reorganization in the mature state, I think is something that needs considerable thought.  The last thing I want to do is if I still have five minutes.  I can stop at this point.

CHAIRMAN KASS:  Why don't we stop and take a few questions if that's all right?

PROFESSOR JESSELL:  Okay.

CHAIRMAN KASS:  Janet.

DR. ROWLEY:  I'd like to hear the rest of what's been prepared please.

CHAIRMAN KASS:  Okay.  All right.

DR. ROWLEY:  We all can have a shorter lunch.

PROFESSOR JESSELL:  This will be two minutes so hopefully it won't impose too much.  What I've talked about so far has really been normal developmental processes, the influence of environment and genetic programs and predetermination on the structure and function of the nervous system.  But this has as we've begun to talk about in regeneration  a clinical consequence.  One of the other things that has emerged I think from understanding normal molecular genetic programs that have developed is that those processes are likely to be precisely the processes that go awry in many neurological and psychiatric disorders.  This is a very new field, but I think there are enough small examples to indicate how this will really change or produce a convergence of clinical neuroscience and these basic developmental mechanisms.

One example just comes from looking at many classically defined neurodevelopmental or cognitive disorders.  In the few cases where genes associated with those disorders have been identified, many of those genes affect precisely the processes that we've been talking about this morning, the process of neuronal identity through genes that control cell identity, transcription factors, the nature of signaling factors, the nature of synaptic proteins, so two examples that I won't stress.

Some of the proteins that I've mentioned briefly that are involved in synapse formation, how one neuron communicates to another, it's been shown that mutations in those genes are associated with forms of autism and with the Asperger Syndrome.   Signaling factors that are involved in neuronal communication have been associated, albeit not completely persuasively, with schizophrenia.

      In the case of transcription factors, one has the surprising example that quite highly complex, cognitive disorders relate to genetic defects in genes that are DNA-binding proteins that control patents of gene expression.  So two good examples of that exist.

One is a syndrome known as Rhett Syndrome which again if you like is a variant form of autism.  There is a gene that probably accounts for the vast majority of Rhett Syndrome cases.  These are children who acquire gradually over the first two to three years of post natal life progressive cognitive impairments, stereotypic motor behaviors.  They lack function of a gene involved in methylating many target genes.  Some  of those target genes are now known and one of those are the trophic factors that we talked about in the context of keeping neurons alive.

An even more striking example is in the case of genes that influence human ability for language and integration of spatial information.  So there is a syndrome described by Tony Monaco and by Vaga Cadan associated with facial abnormalities and with dyspraxias.  There is a clear pedigree.  So these people have abnormal impaired language acquisition.  The gene associated with that pedigree turns out to be a transcription factor which is expressed and involved in the determination of neuronal identity.

This raises very profound questions of taking a disease which appears highly specialized in a cognitive manner and finding out that the gene that causes that is a gene expressed at a relatively early stage of development, probably involved in establishing some aspects of circuitry.  One of the challenges that I think is going to face the field is now understanding causally how the mutation in that one gene influences a relatively specialized set of cognitive behaviors.

Another example is Williams Syndrome which is associated in contrast to for example Down's Syndrome and this KE language defect with in fact an over elaborate use of language by children.  They have a very extensive vocabulary.  They are extremely articulate, but they have very poor ability to extract and integrate information from a visual world.  This is a very highly localized cognitive disorder that has been studied by Ursula Belugi in particular.  All of the children who have this cognitive disorder have a small chromosomal deletion that probably eliminates in large part a transcription factor that controls cell differentiation.

So here is another example where very specialized cognitive dysfunctions are mapping to genes that we can now begin to understand in terms of their role in developmental processes.  Yet there is a very large gap between understanding the nature of the gene, the neuron, the circuit and the behavior.  But I think over the next several years as human genetics begins to give us more information on the nature of these behavioral disorders many of which affect this early childhood period, we're going to be faced with trying to link in very relevant clinical context some of the early developmental mechanisms that we've talked about with some of these behavioral events.  Perhaps that's all I want to say.  I'll stop there.

CHAIRMAN KASS:  Thank you very much.  I'd like to run over and as Ms. Janet says we'll have a slightly shorter lunch because we shouldn't waste the opportunity of having some conversation with Dr. Jessell after this very comprehensive and very stimulating presentation.  Thank you.  Dan Foster please would you start and could we get the lights?

DR. FOSTER:  I have just—I don't know whether you can answer this in 30 seconds, but it's always intrigued me.  From the very beginning, you've talked of a necessity of scaffolding and we move here  in the spinal cord and you have some sort of signaling, a way that neurons can grown and so forth.  I understand a little bit about oligodendrocytes and astrocytes and jagged and notched and so forth.

My question is something different in terms of therapy.  At least in rodents, it looks like that if you inject a neurogenic stem cell even in a peripheral vein that it's going to circulate and get to the brain and then somehow will target to a damaged cell—it might be a stroke or a glial blastoma—you put a human tumor in there.  So the more I listen to you it's almost as though they are chemotactically or someway attracted rather than going on scaffolding.  I'm just dying to know what you think about how that process goes in ten words or less.

PROFESSOR JESSELL:  The first slide I showed I think illustrates the nature of the problem a little bit.  At early embryonic stages the brain is small.  The adult brain is extremely large.  So just distance imposes great challenges.  The environment of the adult brain is completely different from the embryonic brain.  Many of those scaffolds that we talked about have disappeared in the adult brain.

So in an example that you describe where cells seem to be smart enough to get to the right place, I think we have very little understanding of how that homing behavior is actually achieved given that the normal developmental cues are now missing.  I would say that the evidence that that happens in a highly efficient way is not so great.

I think it can happen whether it happens as efficiently as it would in a normal developmental context so maybe only one in a million perhaps by some random probabilistic nature ends up in the right place and then those cells proliferate in an appropriate environment.  The shorter answer is no one knows how this process occurs, but whether it occurs in an efficient way is, I think, also a matter of debate.

DR. FOSTER:  But just to follow, I mean I saw a picture in PNAS where you put a green fluorescent protein on and you were tracking infiltrating cells from a glial blastoma and there were a lot of these neurogenic stem cells that got into the lesion.

PROFESSOR JESSELL:  Yes.

DR. FOSTER:  Not only in the mass but moving in there and honing in on it.  So maybe you're saying—

PROFESSOR JESSELL:  I'm completely receptive to the idea that perhaps under conditions where in a tumor the blood brain barrier has broken down, one of the things the tumor does is produce attractants that then guide cells.  I think there is likely to be that process.

CHAIRMAN KASS:  Dr. Carson.

DR. CARSON:  Yes, early on, you were discussing the periventricular glial cells which divide and then give rise to neurons.  There's always left behind a glial cell.  Now is it possible later on to provoke that residual glial cell to differentiate?

PROFESSOR JESSELL:  Yes, this relates to why most of the adult nervous system doesn't actually produce neurons, only these two little epicenters.  So does that mean that the precursor cells simply don't exist in those other regions or whether they exist and they're quiescent and something needs to happen in order as you say to provoke them?

There's a lot of evidence, for example, in the spinal cord, one of the areas that is not noted for neuronal production.  If you damage the spinal cord, ependymal cells around the central canal will start to proliferate and start to produce glial cells.  So there clearly are environmental stimuli or trauma that can kick these cells into action.

What they can't do still even under those conditions is produce neurons.  They seem to produce glial cells.  So is there a single gene?  As we saw there are single genes that produce neurons.  Is there just one gene missing from those cells that impairs their ability to produce neurons?  These are things that I think will emerge over the next five years as many people are looking at this as now some of the molecular players in the normal developmental process can be applied to the conditions of cell regeneration in an adult context.

CHAIRMAN KASS:  Mike Gazzaniga.

DR. GAZZANIGA:  Dr. Jessell, a wonderful talk.  I wish my mentor, Roger Sperry, could have been alive to hear your first section of it and that beautiful molecular work.  When one hears the sweep that you gave today, sometimes people can misunderstand the extent to which the people come to think of the brain as a set piece to the extent to which it can be infinitely plastic and change.  Plasticity is used in this funny way.  We all still are capable of learning Leon tells me.  So plasticity in that sense is going on all the time.

But plasticity in the infrastructure of the nervous system aspect is probably not as much as we would like to think it is.  So when we hear these beautiful examples of Merznich and of Rusty Gage and so forth, I would be interested in your opinion on a scale of the set piece—I think those were your words—versus the changing at the edges.

PROFESSOR JESSELL:  Yes.

DR. GAZZANIGA:  And as you go through maybe by decade, just give us a sense of your feel for that.

PROFESSOR JESSELL:  I think there's no region of the nervous system in which the two extremes of a genetic predeterminism and environment don't contribute.  I think the question is what are the relative contributions of those types of programs according to a particular region.

I tend to agree with you that there is a remarkable degree of molecular genetic programing of connectivity.  The more one understands the more remarkable that observation is.  In regions like the spinal cord where motor commands are essential for processes like locomotion, I think there is very compelling evidence that many basic features of those sensory-motor integration processes can get wired up in the absence of experience, in the absence of activity.

One of the early sets of experiments as Sperry did before he worked on the visual system really demonstrated that that essentially if you misconnect so that the sensory information coming from an extensor muscle is now rerouted to a reflexor motor neuron, an adult animal has a hard job in adapting to that surgically induced misconnectivity.  So what that says which I think was the basic thesis of Sperry is that essentially there are strong molecular cues that drive the specificity of circuitry.  That will occur in the spinal cord.  It will occur in the cortex.

What I think we're seeing in the cortex for example but probably in other regions is that the extreme view that in the adult state all of those connections are fixed at a functional and structural level is beginning to be eroded a bit.  But the real challenge I think is to work out to what extent the environmental influence what are the constraints achieved by these early molecular programs on which environment can work.

Now all of these experiential influences have to have a molecular basis.  This is not some mystery.  So presumably environment and activity is changing connectivity through a molecular program.  If we knew more effectively the nature of that molecular program—what does the firing of an action potential in the neuron really do biochemically to that cell, what molecules change—then we will be able to integrate more effectively the plasticity environment together with these molecular programs.  To me that's one of the great things to emerge from understanding the molecular biology of development.  It allows you to perhaps demystify some of the environmental influences that clearly do exist.

CHAIRMAN KASS:  Janet, please.

DR. ROWLEY:  Well we spoke about this earlier in our general discussion and the release of this report and the one issue that was not touched on directly is the whole issue of cloning for therapeutic uses.  I would be interested in your opinion on how you think embryonic stem cells for example could be used therapeutically either to deal with those problems of the central nervous system or of course for spinal regeneration.  The second part of that is what kind of research is needed, what kind of support for that research is needed to see whether embryonic stem cells do have a potential in dealing with these very serious problems.

PROFESSOR JESSELL:  So this is something that in a slightly different context we in the lab experimentally got very interested in because what we do on a day-to-day basis is work on spinal cord organization and development and an important set of neurons there are motor-neurons which really mediate all the central nervous system control of action and movement.  There is a reasonably good understanding of the normal developmental processes that take a naive progenitor cell and convert that to a motor neuron.

So one of the things we asked is if we really understand that process as it occurs in the normal embryo, can we then apply that information in the context of other precursor cells like embryonic stem  cells and apply the right embryonic signals in the right order and the right time and the right concentration and simply ask the question of whether you can now convert an embryonic totipotent stem cell and can drive that to a motor neuron using normal developmental signals?  Rather surprisingly that turns out to be quite easy to do.  So the same signals that operate in the normal embryo will operate in the context of an ES cell such that you can produce fully differentiated motor neurons from embryonic stem cells.

One of the things that I think development has taught is how to manipulate other classes of progenitor cells along defined pathways.  That raises all of the questions that you mentioned about what use is that going to be in regenerative medicine.  It may be that the motor neuron is not the ideal neuron in which to test this because of the details of circuitry that are necessary.

So we come back to this question of if you put these cells back in, how are they going to find their right targets in a very different adult environment.  But in some diseases, in demyelinating disorders where one is trying to reintroduce oligodendrocytes or in Parkinson's disease where there is almost proof of principle that if you can put back dopaminogic neurons, you can ameliorate their motor deficit.

If you could make infinite numbers of purified dopamine, mid-brain dopamine neurons, with that be an interesting route to self-therapy in that particular neuro-degenerative disorder.  I think all of those issues are soluble now.  What I think we've learned that molecular biology has taught us how to turn embryonic stem cells let alone the issue of adult progenitor cells.

But I think embryonic stem cells I think can be converted to any class of central nervous system cell that one now is interested in on the basis of the normal developmental program.  To what extent that information is useful in a clinical context I think will very much depend on which disease one is thinking about.  Somewhere it won't be useful and there is somewhere where I think it's promising.

But the technology just from the point of view of cell differentiation I would say exists today.  So if one wanted to generate one class of CNS cell, I think there are good ways now of thinking about how to do that.

DR. ROWLEY:  Then I ask a second part.  What's needed to move this field along?

PROFESSOR JESSELL:  Yes.  Much of the work that is at an experimental stage has been done on mouse embryonic stem cells.  Mouse cells, ES cells, are remarkably constant from cell line to cell line.  The first thing that is needed is to ask whether the developmental potential of human embryonic stem cells mimics or reflects that in the mouse.  I think what we know at the moment is that many of the existing human ES cells, until Melton's recent studies, have shown a remarkable variability in their properties in differentiation along neuro-pathways, a much greater diversity of properties than would be predicted simply from the mouse experiments.

One of the virtues of the report from Melton and his collaborators in generating new cell lines is that many of these cell lines now are going to increase the probability that some of them will behave like their mouse counterparts.  We have actually been working together with the Melton group to extend some of the work on mouse embryonic stem cells to ask which of those human lines that Melton has generated behave most closely to their mouse counterparts.  That's a first step.

DR. ROWLEY:  But then this brings the point which some of us have again dealt with tangentially that these are not cell lines that you can study with Federal funding.

PROFESSOR JESSELL:  No, that's right.  There's a separation.

DR. ROWLEY:  So that one of the critical things that's needed is Federal funding for these new cell lines as they become available to see whether or not they are useful.

PROFESSOR JESSELL:  I would absolutely endorse that.  They are technical limitations.

DR. ROWLEY:  And have you tried any adult stem cell lines to see whether they too can produce functional neurons?

PROFESSOR JESSELL:  Yes.  So using the mouse embryonic stem cell as a positive control, that is we can now turn those cells into motor neurons at will with the addition of two chemical factors.  You are now in a position to ask whether adult progenitor cells from the nervous system can recapitulate the properties of the mouse embryonic stem cell as we currently understand how to do that.  If you do then adult neuro-progenitor cells will not generate motor neurons under the conditions that the mouse embryonic stem cells do.

What that tells us is there are some constraints on adult progenitor cells.  It doesn't mean it can't happen in the future.  It just means as of today I think the developmental repertoire of an adult neuro-progenitor cell is very much more limited than its embryonic counterpart.  Just in a practical sense what you can do with embryonic stem cells today in the context of neutral pathways of differentiation far exceeds what can be achieved with adult neuro-progenitor cells.

CHAIRMAN KASS:  Could I ask before?  We're going to have to draw to a close fairly soon, but stepping back from some of the particular phenomena that you've described and looking at their possible human-social-education significance because we'll be talking about this later on, and the question is exciting and wonderful though this is scientific matter.  If one wanted to think about the possible human implications of this over the next decade or so—I know you're not a prophet, you are a scientist—but the question is what are the one or two areas or questions that you would like us to keep our eye on when we think of the significance of this?

One thing I gather has to do with the knowledge of some of these horrible behavioral and mental disorders and the capacity to be able to learn some of their sources and perhaps ultimately to intervene.  The other vaguer thing when Michael Sandel talks about Mozart and the like and there's all kinds of faddishness out there with respect to taking advantage of this alleged early environmental stimulation to enhance the pre natal capacities, could you say again along those lines and have we missed or did I miss something, some other areas of significance?

PROFESSOR JESSELL:  To me the greatest challenge is that the very few, relevant interesting human behaviors, do we have any idea about the principles of circuitry that underlie those behaviors?  We don't yet know.  We have through imaging methodologies, through other methods of intervention, we have a sketchy idea of some regions of the brain that are more involved in learning and memory, mood disorders.  But the nature of the circuitry and the ability to intervene in that circuitry and relate that to important forms of behavior, I think is still at a very, very primitive state.

So one of the things that I haven't emphasized but I think at a practical level is going to have important consequences, both experimentally and in terms of studies of human behavior, is what molecular biology of circuit assembly has given one so far are a large number of genes that show that neurons that behave differently are molecularly distinct.  The advantage of that is that certainly in experimental animals that is going to give you an unprecedented way of manipulating the circuit on the basis of a neuron by neuron change which hasn't been possible with conventional anatomy and conventional physiology.

So for example if we knew in some region of the cortex a gene that defined one very small subset of functionally coherent neurons, how do you get at those neurons and how do you tell what their contribution to circuit and behavior is at the moment?  Through the gene what we can now do as a field is introduce genetically encoded proteins which allow you to manipulate that set of neurons in a coherent way.  For example you can introduce proteins that allow you  selectively and conditionally to take those neurons out of the circuit and look the consequences for behavior.  Or you can introduce sensors that allow you to selectively activate those neurons and leave all of the other neurons intact and look at the consequence of that particular micro circuit for a given behavior.

So what I think will emerge from this is a much clearer understanding of what behavior in any context really means in terms of the details of the circuit.  What are the core elements of the circuit that contribute to that behavior?  If one knew that, then I think the diversity of range of human behaviors that one sees in the normal population together with pathological behaviors one can start now to analyze that from the level of single neuron or dysfunctions.  What is the relevant aspect of circuit that we're trying to look at?

I think, and Michael will have thoughts on this, my feeling is at the moment is that we simply don't know enough about the basic circuitry that underlies many of these interesting behaviors even to know how to approach the problem.  What I would hope is that link between circuit and behavior becomes consolidated over the next ten years.

CHAIRMAN KASS:  Thank you.  Look we are 12:50 p.m.  We have guests coming at 2:00 p.m.  I don't know how quickly people will serve lunch where we're going.  If Dr. Jessell might be willing to simply standby for people who didn't get a chance to ask their questions, I fear that if I don't discharge you now I won't see you back here before 2:30 p.m. and that's not permitted.  So, Dr. Jessell, thank you for an enormously interesting and stimulating presentation.  It's a massive amount of stuff to present in a kind of coherent way.  I learned a great deal and I trust my colleagues did too.  Thank you and we'll reconvene at 2:00 p.m. 

      (Whereupon, at 12:48 p.m., the above-entitled matter recessed to reconvene at 2:03 p.m. the same day.)

SESSION 3: NEUROSCIENCE, BRAIN, AND BEHAVIOR II: EMOTIONAL AND COGNITIVE DEVELOPMENT IN CHILDREN

CHAIRMAN KASS:  This afternoon's session, the first of two, is titled "Neuroscience, Brain, and Behavior II:  Emotional and Cognitive Development in Children."  And I've been asked to say at least a sentence or two about, well, to be blunt, what's going on here.  This will not be long, and we'll have more to say about what's going on here in the last session when we're talking amongst ourselves, but I remind everybody that the purpose of today's session agreed to last time was that before we took up and searched for various ethical or social or philosophical issues raised by advances in neuroscience and psychology, we ought to learn some of the basic facts.

And the purpose of these discussions is to lay the groundwork for anything further that we would do.  The morning was on the neuroscience.  This afternoon is on the side of psychology.

There are no axes here, and there are no agendas, other than getting us informed about the current state of knowledge about the developing brain and the developing mind and behavior of children.  So if anybody is impatient, just soak up this knowledge.  It's terrific stuff.

The relation of the brain and the mind, of the activities of molecules and synapses to mentation, never mind consciousness, is, as everybody knows, a venerable question, a deep philosophical issue that has occupied and vexed and challenged the best minds since classical antiquity, and one simply has to mention the names of Lucretius and Aristotle to show you how old these controversies are.  There are idealists; there are dualists; there are compatiblists; there are  epiphenomenalists.

Yet even as those sort of prize questions continue to be discussed and debated, even people who are committed to fully neurochemical and mechanistic account of all mental and behavioral activity recognize the prime importance of studying the mental and behavioral phenomena in their own right and on their own level, leaving for later any attempts to connect the domains of psychology, the study of the psyche, and the domain of neuroscience, the science of the brain.

So with no prejudice regarding this deferred questions about the relation of mind and behavior to the brain, we also want to know not only about the neural development, normal development of the brain and nervous system in children, but the normal and also abnormal development in all of its variations of the emotional and temperamental side of human development, and of the cognitive capacities and activities of children, and that is the theme for this afternoon's discussion, and we're very fortunate to have two colleagues from Harvard's Department of Psychology, Jerome Kagan, who is the Daniel and Amy Starch Research Professor of Psychology at Harvard University, and Elizabeth Spelke, who is Professor of Psychology, also at Harvard University.

Dr. Kagan is going to speak about  the temperament and affective side, and Professor Spelke will speak about the cognitive side, and I think the procedure is we will let each of them make their presentations, perhaps with small questions of clarification after each talk, and then the general discussion will follow.

Thank you both very much for coming down and being with us, and we're delighted to have you here and look forward to the presentations.

Professor Kagan, would you like to start?

PROFESSOR KAGAN:  Yes.  Can you hear?

Thank you very much for inviting me, and let me also follow Professor Jessell's suggestion that interrupt me if there are any questions that you have during the presentation.

And I promise to hold it to 40 minutes, ten of three, so that you can hear Dr. Spelke and have time for discussion.

Unlike the area you heard this morning, the growth of the brain, which is, you know, mid-volume, the systematic work on human temperament is about 50 years old.  Since American psychology was committed to a behaviorism that did not want to acknowledge biology, and although there have been many essays going back to Hippocrates on temperament, there is no empirical work.

So this is a field that is in Chapter 1, and therefore, we can't show off the wonderful findings you heard this morning, but we can give you a scaffolding.

Also, you should appreciate that in biology when a speaker says "dendrite," everybody knows what he means.  But when you get to psychological concepts, people have different understandings, and so I will try to give you the understanding that I'm using.  Remember the meaning of words, as Virginia Wolf said, is a function of how they're used.

So the concept of temperament as it is used today in the Western world means variation within humans in mood and behavior that is biologically based.  My own view is that it should be restricted to inherited variation, but there are those who say any variation, even variation caused prenatally.

Now, the analogy would be we talk about breed differences in dogs.  So some people like Rhodesian ridgebacks.  Some people like cocker spaniels.  They belong to the same species.  Their behaviors are different, and we say those are breed differences.

When we talk about humans, that is the domain we're talking about, but we use the word "temperament."  My own view is that most of the temperamental variation—one should never say "all" in the life sciences—that most of the temperamental variation will be due to inherited differences in neurochemistry.  There are over 150 molecules discovered.  Many more may be discovered.  We all have the same molecules, but we differ in their concentrations, and we differ in the density receptors, those proteins that sit on the neurons.  How dense are those receptors.

And we differ in the distribution of those receptors.  Thomas Insel, who now is the Director of NIMH, provides us with a perfect example of what we mean by a neurochemical variation that causes a big difference in behavior.  So let me use it, and it will help you understand the work on humans.

The vole is a very small rodent.  It looks like a mouse.  Now, there's one strain of voles called prairie voles.  They pair bond.  Once the male and female mate for six hours they will never mate again with anyone else.

The montane vole that shares 99.99 percent of its genes with the prairie vole doesn't pair bond.  Now, that is a dramatic difference in behavior, and Insel in 20 years of really elegant research finds that the main cause of that difference is a change.

Remember a gene is a strip of DNA, but in front of each gene is an area called the promoter region which governs the DNA.  Well, in the promoter region for two molecules, one is called vasopressin and the other is called oxytocin, secreted during sexual intercourse incidentally, both of these molecules; that that explains the difference.

So tiny, tiny genetic differences, not even in the DNA, but in the promoter region for the DNA.

Now, I wish I could tell a story.  Here are some of the molecules, and remember there are over 150.  At the moment they look relevant.  So children could be born with differences in opioid concentrations or the receptors for opioids.

For example, right here in our neck is the structure called the medulla.  All pain, information from your heart and gut come up through your body, and they have to pass through that gateway.

Well, supposed some individual was born with a light set of receptors for opioids.  Then they would experience pain and muscle strain more easily than others.

GABA is an inhibitory molecule prevalent throughout the entire brain and its job is to mute excitability.  I'm going to say in a moment that some infants are very irritable, extremely irritable.  It looks like a temperamental trait that expresses itself in certain behaviors later in life.

It could be that what these children inherit, these very irritable infants is a failure, a compromised function in GABA.

Dopamine is a powerful molecule.  Every time any one of us anticipate a trip, a holiday, a good meal tonight at 6:30, dopamine pours out of our central nervous system.  When a rat is about to get food it wants, it pours out dopamine from its source in the brain.

Now, individuals, and it is believed by many that there's a subtle surge of pleasure when one is looking forward to seeing Rome for the first time and you're there.  People differ in their hedonic tone, in the amount of pleasure they take from experience.  It is not beyond reason that someone some day will find that dopamine is playing a role.

Notice there's no determinism here.  I'm going to use words like "enable," "determine a role," "contribute to."

Norepinephrine is a very important molecule.  If you're listening hard for a signal that your wife is coming home because it's midnight.  Norepinephrine acts on sensory neurons so that you hear the signal you're interested in and not the noise or when you're trying to hear a conversation several feet away.  So children are extremely vigilant to change, any subtle change, and some children seem oblivious.  Perhaps norepinephrine makes a contribution there.

And finally, just to have a flavor for these, corticotropin releasing hormone is often secreted but not always when one is under stress, and I'm sure most of you know that all of us when we're under stress secrete a small hormone called cortisol from our adrenal cortex, and variation in corticotropin releasing hormone could play a role here.

Now, I wish we could go to a book and look up everything we've learned about neurochemistry and now talk about human temperaments.  One day, but not today.

So those of us who study temperaments must begin with behavior.  That would be like medicine 250 years ago when one knew nothing about what's happening in the immune system, and so the patient tells you, "I have an ache in my body.  I itch in my arm," and so on.  You go to the surface, and one day, of course, we will tie together the behavior with the biology.

Now, many psychologists have been studying the temperamental traits, and here are four that look like they might be temperamental, that is, due to inherited variation in this neurochemistry.

I mentioned irritability.  Some infants are extremely irritable, and the data indicate that that persisted the first year.  Now, you stop being extremely irritable when you're one and two years of age, but investigators who have followed such infants find that they are different at five, six, and seven years of age.  Some children are very active and show very high levels of muscle tension, and we'll be talking about that in a moment.

Believe it or not, in the first six months some infants smile a lot, and you'll see in about ten minutes I regard this as a very powerful temperamental trait in humans.  Children who smile a lot in the first six months spontaneously tend to preserve a more sanguine view of life through adolescence.  Some infants don't smile at all.   As a matter of fact, in the laboratory they'll show a frown on their face, and they tend to be more pessimistic children later in life.

Now, in order to concretize this discussion, let's tell two stories.  I'm going to tell you one story.  It's the story that I've been writing for 25 years, but it only reflects two temperaments of the many.  There are going to be thousands of temperaments.

If there are 150 molecules and they vary in their concentration and receptor density, remember from your algebra how many combinations of 150 things you can have.  There are going to be millions of temperaments, and even if half were not functional, you're going to have a very large number, some being very rare like the Unabomber or Mozart, and some more common.

I'm going to talk about two common temperaments only because the work on them is more extensive than others, and they're relatively frequent, but not that they are necessarily the most important temperaments, and it has to do with reaction to unfamiliarity.

In every vertebrate species, within every vertebrate species, fish, birds, cats, mice, monkeys, and of course, humans, there are some members that react to novelty and unfamiliarity by become immobile if you're an animal, freezing if you're a rat, not exploring an unfamiliar area if you're a mouse or if you're a child, closing down and exploring the situation before you assimilate it and move forward.

And other children are just the opposite.  Now, in animals, this is extremely heritable.  You can breed it.  You can breed quail, rats, mice, and Steve Suomi of NIH believes even breed monkeys so that after 20 generations you have either very timid or very bold monkeys, mice or rats.

Now, it is believed by the work of many scientists that deserve a great deal of credit, it looks like the amygdala, which is a small structure right in back of your temporal lobe, tiny, shape of an almond.  It's very important because whenever you present novel stimuli to any animal and you record from neurons in the amygdala, those neurons respond.

And so if you presented a novel event to a monkey and you had electrodes down the amygdala, it would respond, but if you kept on presenting the stimulus, the neurons would stop responding.  The amygdala response is a novelty, and you can see why this is important.

You're a monkey out in the savannah, and you're munching your bananas, and suddenly an odd sound occurs.  The amygdala fire, makes you alert, and then you decide whether you're going to flee or it's an unimportant event and you keep on eating your bananas.

Now, I have been interested for many years in timid versus bold children, and so to abbreviate ten or 15 years of work, we decided that perhaps these were temperamental traits traceable to infancy, and so we began a study of 500 healthy, middle class, four month old infants.

Now, why did I restrict it?  Because if you want to study temperament, you have to eliminate all of the other causes of possible timidity:  a mother took drugs during her pregnancy; drank too much; smoked cigarettes; drank coffee.  And so you want mothers who cared about their pregnancy and gave birth to healthy babies at term.

That means that if one did the study I'm about to describe on infants born to compromised pregnancies we might get different results.  Okay?  So these are healthy babies born at term.

Now, the reason why the amygdala is important is that if you stimulate the amygdala of a cat or a monkey, you get limb movements and you get distress cries, and of course, human infants will display those two responses.

So here is the central idea behind the work.  This is a schematic of the amygdala.  Vision audition and touch come into this area of the amygdala, send their information up to this nucleus, and then out to the body to produce tension, immobility, a rise in heart rate, a rise in blood pressure or other biological consequences.

Assumption:  if some infants were born with a chemistry unknown at the moment that rendered the amygdala excitable to unfamiliar events, then they should show a lot of motor activity and crying when you present these unfamiliar events.  If you were born with a different chemistry, then you should show low motor activity and not be very distressed, and we call those infants high and low reactive.

So after testing 500 infants by showing them unfamiliar mobiles of different colored elements moving in front of them, listening to speech on a tape with sentences like, "Hello, baby.  How are you today.  Thank you very much for coming," or presenting a cotton swab dipped in butyl alcohol to their nostril, olfactory, auditory, visual, what you see is that 20 percent of the babies are very different from all other babies.   They begin to thrash.  They arch their backs.  They become very aroused motorically and cry.  They should have a more excitable amygdala.

Forty percent, twice as much, are just the opposite.  They don't move.  They lie there.  They move an arm.  They don't cry.

Now we call the first group high reactive and the second group low reactive, and now briefly I'm going to show you what happens if you follow these infants through 11 years of age.  Okay?

So you bring these infants back at 14 and 21 months for two hours with their mother and they encounter unfamiliar events.  Nothing threatening, no snakes, no mice, just people they don't know, a clown, people dressed in clown costumes, robots that move, novel events that are not obviously dangerous.

Some children do not become very frightened.  Some cry and clutch their mother.  I didn't bring my laser so if you follow me, you see the high reactives are in the light color, the low reactives in the dark purple.  So at 14 months those who are high reactive at four months were more fearful.  At 21 months they were more fearful. 

At seven and a half years the IRB of the university, in order to make children cry, you have to do things that are unethical.  So we don't do that.

Now, with age what happens is that these traits become internalized, and so rather than cry you begin to show the traits of the introvert.  You don't smile or talk easily with a stranger.  So if you're interviewed by an examiner for two hours, you talk less.  You see at seven and a half years you smile less.

You remember I said that smiling is very sensitive, and based on observations of children and interviews with the mothers and the teachers, you're more likely to have anxious symptoms.  Now, notice I'm not calling this child as having an anxiety disorder.  This is a child who doesn't want to sleep over at a friend's house, needs night light on, asks their mother will they be kidnapped, is their mother going to die.  They're afraid of large dogs or insects.

And you'll see that 45 percent of this group who are high reactive had anxious symptoms.  Remember only 20 percent of the group was high reactive.  So that's twice as many as you'd expect.  Only ten percent of low reactives had symptoms, while 40 percent of the sample.  So that's much less than you would expect.

So these children are developing in a way that one would anticipate, given the assumption about their amygdala.  Okay?

Now, by the time they're 11 years of age, a lot of them aren't shy anymore.  What happens with increasing age is that you get an increasing dissociation between your behavior, what you have called your persona, and what's going on inside.  Your grandmother knew it as "don't judge a book by its cover."

But we believe that they retain their biology.  So we have to measure their biology, and I apologize for doing this quickly.

There are four measures that based on the research of many scientists one would reasonably assume should characterize the high reactive children at 11 years, but not the low reactives, and they are:  One is to have greater activation in the right hemisphere than the left.  For example, if you take a newborn baby and put lemon juice on its tongue, you get right hemisphere activation.  If you put sugar water on its tongue, you left hemisphere activation.

Now, there are exceptions here, but as a rough rule the right hemisphere is more active under states of uncertainty and adversiveness, the left hemisphere under the complimentary state.  So we measured that using EEG.

Let's do the behavior first.  When they come in at 11 years of age, we watch their behavior, and if we combine their behavior at seven years and ten years of age, and here's the important result, 40 percent of the children who had been high reactive made many low comments.  You see the turquoise blue bar on the left, and very low smiles, 40 percent, while less than ten percent of the low reactives did.

While if you said who talked and smiled a great deal, it's just the opposite.  So, in other words, temperament constrains what you will become.  Forty percent are honest to their early temperament, but only six or seven percent cross over.  So that means temperament doesn't determine what you will be, but its power is to prevent a high reactive infant from becoming an extremely social, exuberant child, while a low reactive temperament constrains that child from becoming an extremely timid and subdued child.  We'll return to this in a moment.

Now, here are the data on hemisphere activation.  The high reactives are in pink, and the low reactives in yellow, and on the left side of the graph is showing right hemisphere activation, and on the right side of the graph is left hemisphere activation.  So follow the pink line, and you'll see that 43 percent of the high reactives showed greater right hemisphere activation, and as you move towards the left fewer and fewer high reactives, while the yellow line, only 18 percent of low reactives were right hemisphere active and they moved up. 

So there's the first prediction.  AT 11 years of age, you can do better than chance at predicting hemisphere activation at 11 years of age from what they were like at four months.

Now, the next measure is more direct.  In the system for hearing, when you hear any sound it goes through a series of ganglia, first your basilar membrane in your ear.  Then it goes through a series of nuclei and ends up in the mid-brain in a structure called the inferior colliculus.

And if you present clicks to an infant or a child, if you get a series of brain waves from those clicks, every infant in Massachusetts is tested this way to insure that it can hear.  Now, notice pk V.  That is the evoke potential from the inferior colliculus.  It occurs in about six milliseconds.

Now, here's why that's important.  The amygdala, our friendly amygdala, sends projections down to the colliculus, pk V, but not to any other structure before it, and that means that if you had an excitable amygdala, you should show a larger pk V, a larger wave V than if you were a low reactive.

I hope that's clear.  So the 11 year olds wore earphones, and they heard clicks for 90 seconds, and sure enough, as we expected, the children who had been high reactive at four months had large wave forms, especially when the loudness was 70 decibels and you were measuring it on the opposite side of where the information came in. 

So there's our second prediction, and that one does support the notion that high reactives have a more excitable amygdala.

The third, many scientists over the last 35 years have made an important discovery.  Whenever you're presented with a visual or auditory event that surprises you, you have a very distinctive wave form.  If you were sitting in a laboratory with EEG electrodes on and you heard the following, "Washington, D.C. is a vegetable," that on the word "vegetable," you would have a wave form like that.

But if you heard "Washington, D.C. is a city," there would be no wave formed.  So whenever you're surprised by an event you don't expect, you get a very distinctive wave form.

Now, remember what I said about high reactive infants.  They are very sensitive to unexpected events.  So we then hope to see that at 11 years of age, the high reactives would show larger, evoke larger event related potentials as you saw in the last slide to scenes that were totally unfamiliar.

Go to the far right where it says "invalid."  These are ecologically invalid scenes, none of which are dangerous.  For example, a baby's head on an animal's body or a car in midair or a chair on one leg.

While for the frequent, if you go over to the far left where it says "frequent," that's a fire hydrant being shown 70 percent of 169 trials. 

So there's our third prediction affirmed.  Right hemisphere activation, a larger wave V, and a large event related potential to surprising scenes.

And the last measure, the amygdala sends projections to the sympathetic nervous system, and therefore, one should show greater sympathetic tone in the cardiovascular system, and we measured that in several ways, and so the term sympathetic means that you have greater priming of the circulatory vessels and the heart, while the vagal system means you have less priming because it is mediated by the parasympathetic system, and as you can see, about 65 percent of the high reactives at age 11 were sympathetic compared with about 38 percent of the low reactives and the opposite for vagal tone.

Now, let's put it together.  A temperamental bias constrains what you will become.  Let me skip that, and here is the final line.  About one in four high reactives and one in four low reactives combined expected behavior with biology versus one of 20 who do not.

That means that if outside that door there were 100 adults and I said—they're 20 years old—I said they're high reactive infants, every one of them.  If I predict that they will not be exuberant, bold, highly sociable 20 year olds who show right hemisphere—they wouldn't show right hemisphere activation; they wouldn't show a big wave V; they wouldn't show sympathetic tone; I'm going to be right 95 percent of the time.

If you say they're going to be quiet introverts who have high sympathetic tone in a large wave V, you'll be right 20 percent of the time.

And of course, the same thing shows for the environment.  If I say, "I have this beautiful girl born to nurturing parents in a lovely suburb of Boston who went to good schools, she's 25 years old.  Tell me about her," you will be more correct if you what she is not.

She's probably not a drug addict.  She's probably not a prostitute.  She's probably not on welfare, but what else?  Who did she marry?  What did she major in?  What will she do?  You have no idea.

And that's an important message which we have in psychology, tend to think of the environment and biology as deterministic, and we should begin to think of it rather as constraining rather than deterministic.

Because of time, let me go to some of the implications because I don't want to take much time from Professor Spelke.  Here are some implications.

Individuals with similar public profiles can differ in the origins of those profiles.  Current psychiatry, 99 percent of all you read in the papers about the epidemiology of psychiatric illness is based only on interviews.  They never assess the biology of the person.

And so two people can say that they worry.  They're worried about the war or they're worried about terrorists, but one person has an extreme emotional reaction, and once psychiatrists begin to add not necessarily these measures, biological measures to the interview, then you will see all of the prevalence figures for mental illness change because right now they're based on one source of evidence.

Second, the ancients understood a temperamental bias does not imply that will is impotent with respect to a behavior.  Remember the ancients said that temperaments control your mood.  They don't control your action. 

So I can feel anxious, but I can control my tendency to avoid.  I can feel angry easily, but I can control my impulse to strike, and so on.  And so we're in a dangerous period because biological determinism is so popular in having the public believe, well, after all, if this is genetic, then why should I be held responsible for my behavior.

The third implication will come in about 20 or 25 years from now because there will be variation in temperaments across reproductively isolated populations.  When mutations occur and they change the shape of your eyes, the color of your hair, whether you're vulnerable to spina bifida or not, nature doesn't stop there.  Obviously the genes that separate reproductively isolated populations are going to affect the neurochemistry, too, and so we're going to discover in a quarter century that there are temperamental differences among Asians, Africans, aborigines of Australia, Europeans.  No question about it.

Although the work is preliminary, it is pretty clear now that Asian and European infants differ dramatically.  There are three studies:  Daniel G. Freedman, Caudill, Michael Lewis, my own.

Asian infants tend to be very low arousal, whether they are born in America or born in Beijing, while European infants are much more active, more easily distressed, and those look like temperamental differences, and I'm sure when we are less self-conscious—unfortunately we are—about ethnic differences, right now it's focused unfortunately on school performance and IQ and that will vanish, but there will be temperamental differences.  I think that the benevolent consequence of that is that we'll recognize that every reproductively isolated group, as is true for humans, is true for animals, has a special set of advantages and a special set of disadvantages, and that's the way it goes, and that will be, I think, beneficial.

But there will be differences in risk for particular moods and psychological symptoms.  There's an Asian psychiatrist in Los Angeles who has written several papers that, for example, Asian patients in Los Angeles require half the dose of Prozac or Valium than Caucasian patients with exactly the same psychiatric diagnosis.

So we return to voles again.  This research has just begun.  I must confess to you as I now stop that I'm surprised by these results.  I wouldn't have expected them.

When I was a graduate student, I was very hostile to the role of biology in human affairs.  I was convinced that most of the variation among 20 year olds was a function of what happened within the walls of their family, but I've been dragged to this conclusion by their data, even though as I've shown you the role of the environment is powerful for temperament constrains rather than determines.

Thank you very much.

(Applause.)

CHAIRMAN KASS:  Let's agree to have just a couple of minutes for questions of clarification, although the two papers I think might be best discussed at the end.

Diana Schaub, Diana.

DR. SCHAUB:  You spoke of ethnic and racial differences.  Are there sexual differences also?  Do girls tend to be more high reactive than boys?

PROFESSOR KAGAN:  Right.  Surprisingly, there's no difference at four months.  High reactive and low reactive infants, it's equal on the sexes.

Now there's an interesting story.  Under age seven or eight more high reactive girls are timid, shy, introverted than boys.  But by adolescence, it has changed.  Now, I think this may be—here's my hypothesis.

At 15, it's just the opposite, and I think it's because girls in this culture are gentler with timid girls than boys are.  Boys are very cruel, and so at 15, which is the age we're studying now, high reactive boys who have not lost their persona, they are very shy, very frightened, very introverted.

Our girls are garrulous, have many friends, and my own belief is that that's all environmental.  It's because girls are less cruel toward a girl who is initially timid in her personality.

But there is no difference at four months.

CHAIRMAN KASS:  Jim Wilson.

PROFESSOR WILSON:  Thank you very much, Jerry.

You said toward the end of your remarks, speaking, I think, of adult populations, that psychiatrists should gather biological evidence.  What kind of biological evidence, and how do they gather it?

PROFESSOR KAGAN:  I would say I think it would be very useful if as part of the psychiatric  examination, I'm thinking of something that could be done in the office.  You could easily gather sympathetic and vagal tone, easily.  Given the fact that many are associated with the hospital, you could order an EEG and get right and left hemisphere dominance, yeah, and I think that would help the diagnosis.

CHAIRMAN KASS:  Other questions?  Michael Sandel.

PROFESSOR SANDEL:  This is a simple minded question, Jerry, but what was the question that drew you to this?  Were you trying to figure out what makes some kids shy and some kids bold?

PROFESSOR KAGAN:  No.

PROFESSOR SANDEL:  What was the animating question for you?

PROFESSOR KAGAN:  The animating question was this.  My first job was at the Fels Research Institute in Yellow Springs, Ohio, in the campus of Antioch College.  I inherited a corpus of data that has been gathered since 1929, and Howard Moss and I studied the adults, and he rated the children, and only one trait was stable from the first two years of life to adulthood, and it was these two traits, but I didn't understand it in 1957.

But I was thinking about it, but I resisted.  Then Zowazo, Richard Kiersley, and I were doing a study of the effect of day care.  Remember years ago, in 1978, the Congress was going to vote day care, and we were certain day care was bad for infants.  So we got an NIH grant, and we began to study in the South End the role of day care on young infants.

But we needed political protection.  Things were very bad then if you remember, and so the Chinese Christian Church said, "We'll protect you, but you must take Chinese American infants from Boston's Chinatown." 

So we had half Chinese American infants and there it was, and that's when I saw that these children were temperamentally so different.  Then I remembered the Fels, and of course, I had been studying children for 40 years, and I realized I was resisting the notion of temperament.  I was resisting it.

And my resistance collapsed, and that's why I did this.

CHAIRMAN KASS:  Peter Lawler.

DR. LAWLER:  You seem to have, as far as I can understand, covered some of the wisdom of Machiavelli, right?  Some people are impetuous; some people are cautious.  These are natural things.  We really can't change them very readily, and which is better sort of depends upon circumstances, and the point of education is to rein in the destructive aspects of one or the other.

But then the last page of the very fine chapter that you gave us you said what we now have to do through education we will eventually be able to do through pills.  Do you really think this is so?

PROFESSOR KAGAN:  Oh, no.  I'm sorry.  I hope you didn't misinterpret the last page.  This book says in our technological culture both types have advantages.  There's a line, I think, in the chapter which says if we ask T.S. Eliot the day after he won the Nobel prize, you know, you—if you read his biography, he was a very inhibited child—you know, would you have wanted your mother to give you medicine, he would have said no, because he wouldn't have become a playwright.

We need people who like to work alone, bench scientists, programmers, and of course, that's where our high reactives drift, and we need statesmen and surgeons and trial lawyers, and I think the account is balanced.

If I can tell an anecdote that Steve Suomi told me, on the island of Cayo Santiago, which lies off Puerto Rico, there are 1,000 Rhesus monkeys.  No one lives there, but graduate students code their behaviors.  They know which ones are timid, which bold.

And one spring, Steve—

PARTICIPANT:  (Speaking from an unmiked location.)

PROFESSOR KAGAN:  Sorry?  No, the monkeys.  Sorry.

In one year two juvenile males died of starvation.  They were the timid ones.  Because food is put out once a year, and they wait, and if you wait too long, you die of starvation.

Two bold monkeys died because they attacked two large alpha males, and so four males died, two from one temperament, two from another, and the account is balanced.

We don't tell our mothers of high reactors that, you know, this is a trait you should change.  In an earlier study, one of our most inhibited boys said to an examiner at nine or ten, to the question what do you want to be, he said, "I want to be a scientist, physicist."

"Why?"

He paused, and he said, "I like being alone."  That boy is getting a Ph.D. in physics from Berkeley this year.  He's going to be a productive member of our society.

So in a society as diverse as ours, it is not obvious that one of these temperamental types has advantages and you wish to change it.

DR. LAWLER:  So although you try to be nonjudgmental here at the end, you actually are quite judgmental on this.  That is, nature has given us a pretty good deal.  We shouldn't mess with it that much.

PROFESSOR KAGAN:  Yeah, I think in our society, which is mobile and youth leave their homes and so many jobs require dealing with strangers and risks with minimal uncertainty, at this historical moment, not in colonial times, there probably is a slight advantage to the low reactive, slight, yeah.

CHAIRMAN KASS:  Let's just take one more, and then we can hold the rest of the conversation.  Gil, do you want something short?

PROFESSOR MEILAENDER:  I think so.

You used the words "bold" and "timid" with respect to temperament.  Moralists in speaking about virtues sometimes use words like "courageous" and "cowardly."  What would be the relationship do you think between your words "bold" and "timid" and the moralists talk about "courage" and "cowardice"?

PROFESSOR KAGAN:  I'm glad you asked that.  Very different.  When I use the word "bold" and "timid," I mean what is your initial reaction to a challenge or a novel event.  Is the initial tendency to psychologically freeze, encase it, or go forward?

That has got nothing to do with defending your values, and as a matter of fact, the interviews at age 15 are revealing that it's the high reactives who are more likely to defend their beliefs.

Let me end by reminding you of that wonderful paragraph in Portrait of an Artist.  Remember Stephen Daedalus is Joyce, who is a frightened, timid boy, and remember his mother.  He's talking to a friend, and he says, "I'm not going to Easter mass.  I don't believe in it."

He says, "But your mother wants you to go."

And then he says, "No, I shall be a hypocrite."

He says, "So what?  You don't believe.  Go to please your mother."

And Stephen says, "I can't."

That's often the reaction, so that in terms of courageously defending your beliefs, I have the inkling—and I'll stop—that those are the high reactives.  They're often ideologically more courageous.

CHAIRMAN KASS:  Let's hold the rest of the discussion until we have Dr. Spelke's presentation.

PROFESSOR SPELKE:  While we're waiting for the PowerPoint to come up, can I just ask if anyone has a laser?  That would be great.  If not, I'll make do.

CHAIRMAN KASS:  Do we have one or not?

PROFESSOR SPELKE:  If not, it's okay.  I can do without.

Thank you for inviting me today,  My task is both exciting and impossible.  There's no way that in 40 minutes I'm going to really be able to convey to you what we've been able to learn about children's cognitive development, but I do want to try to talk about three aspects of the work that has been going on.

First, I want to tell you a little bit about the methods that have been developed over the last 50 years or so for addressing questions that people have asked for 2,000-plus years about the origins of our understanding of the world, the experiences of young infants, the states of knowledge of infants and how our knowledge grows and changes with development.

These questions are very old, but research strategies for addressing them have really emerged in the last 50 years, and I want to introduce you, in particular, to two research strategies that have been important and will do so in talking about space perception.

Then I want to turn to some substantive topics and talk about two core systems of knowledge that I think these strategies have given us evidence for in young infants.  One is a system for representing and reasoning about the physical world, particularly solid, manipulable objects, and the other a system for representing and reasoning about people.

And then my final substantive topic, I want to turn from the systems of knowledge that infants have to some central systems of knowledge that they appear to lack and that children appear to construct over the course of the preschool years from about age two to about five.

And although there's many such interesting systems, because of time limits I'll just give you one example and talk about the construction of natural number concepts, and then if there's time at the end and you'll permit me, I wanted to lay out just a couple of themes that I thought might suggest questions that you would want to consider in this group.

So beginning then with the origins of space perception, as I said, this is a very old question, but until relatively recently, "recently" being around the mid-1950s or so, there weren't systematic attempts to answer it because there seemed to be this insurmountable obstacle.  In order to answer these questions, we needed to understand what human infants experience about the world.

Yet human infants have extremely limited abilities to act on the world, to communicate with other people, to convey to us what their experience is.  And that seemed to place a major obstacle in the path of pursuing this research.

Well, I think the first serious progress in overcoming this obstacle came about around the end of the 1950s through the work of Eleanor J. Gibson and her collaborators, and the crucial research strategy that she employed was a comparative strategy.

She started with incidental observations on newborn goats, that if you took a goat just born and put it on a flat surface, it would start walking around, but if instead you put it on a tiny stool, it wouldn't move.  It would freeze and not move off the stool, and Gibson wondered what role visual information might be playing for the goat in controlling this behavior. 

So she designed the now-famous visual cliff.  This is a simple apparatus where there's a center board that you put an animal on, and two plexiglass surfaces immediately below the center board.  So immediately below the center board on both sides are two surfaces that will support the animal, which if the animal reaches out and touches them, they'll feel that they're rigid surfaces of support.

However, on one side, she put—if I had a pointer, I would point to the right there—she put a visual pattern directly below the plexiglass.  So the surface not only was solid.  It also looked solid.

Whereas on the other side, she put that pattern much further away.  So it looked as if there was no surface of support there, even though there was one, and what she found was that newborn goats placed on the center board would readily go scampering off on the visually shallow side and avoid the visually deep side.

Now, of course, this is useful to goats, since they live on mountains and need not to fall off them, but this observation raised the question, is this an ability that we'll only see in animals living in those kinds of environments or will we see them more generally? 

And to address that, Gibson repeated the visual cliff experiments on a wide range of different animals, including rats and kittens and human infants.

The findings are easy to summarize.  For any terrestrial animal that she studied, at the point at which the animal becomes capable of locomoting on its own, which is at birth for some animals; it's after a few weeks or months of birth for other animals; for human infants, it's about six to eight months after birth.  At whatever point an animal begins locomoting on its own, they would locomote over the visually shallow side and avoid the deep side.

The next question Gibson asked then was:  is each of these abilities in different animals due to a distinct mechanism or, rather, is there a single general mechanism for perceiving depth and using depth to guide locomotion that evolved in some distant ancestor common to all of these animals and, therefore, the same mechanism at work across animals?

To address that question, Gibson did a whole further series of studies, which I don't have time to describe, looking for each animal at the signature limits for cliff avoidance.  That is to say, the conditions under which they would succeed in avoiding a visual cliff and the conditions under which they would fail, in which she found across this range of animals was common limits across the animals, providing evidence that common mechanisms were at work in all of these animals.

Finally, a question arises.  What about for those animals that don't locomote at birth and that require some weeks or months of postnatal experience before they start engaging in visually-guided locomotion?  What role does experience play for those animals?

Well, this is a question that one can't ethically ask for human infants, but one can ask for other animals by doing controlled rearing experiments, and Gibson did a whole series of experiments where she reared rats or kittens in darkness or with nonspecific visual stimulation or with specific experience with cliffs.

And to make a long story short, what she found was that in those animals this ability developed independent of any specific learning about the effects of cliffs.  In some animals nonspecific visual stimulation was necessary for the development, probably for the reasons that Dr. Jessell talked about earlier today, but no animal needed to learn to avoid the drop-off.

So the conclusion from all of these studies is that depth perception is innate in the sense that it develops independently of specific learning in mammals, including humans, given the evidence that common mechanisms are at work across these animals.

Nevertheless, there's two general related limitations to this line of work.  It doesn't allow—when you study systematic, coordinated behaviors that only emerge late in human infancy, you don't have the possibility of studying the actual development in humans of these abilities until those behaviors emerge.

And the second limitation, this comparative method works great for studying the development of abilities that we share with other animals.  It's less clearly applicable to studying developments that are uniquely human.

So let me introduce the second research strategy that has been important for this field.  There are a number of people responsible for it, but I think one watershed set of studies were provided by the psychologist Robert Fantz, again, in the late '50s.  He focused on the fact that human infants from the moment of birth do engage in at least one highly systematic and controlled behavior.  They look around the world, and they will show systematic tendencies to look at some things more than others.

So drawing on this observation, Fantz developed the preferential looking method, which you see a picture of here.  What you have is a baby lying on its back.  It's looking at two visual displays side by side, and between the displays is a peep hole.  Back in the '50s you didn't have a video camera, I guess, to do this, and a person looking through the peep hole and just judging which of the two displays infants looked at.

And he found that down to newborns infants would show systematic visual preferences under certain conditions, and two particularly interesting ones.  First, they would tend to look longer at novel arrays.  So if you presented an infant over a whole series of trials with, say, two red circles on both sides of the peep hole, and then after they had seen those for a while you presented one red circle and one green square, the infants would tend to look longer at the new display, showing that they were showing some form of memory and visual discrimination, and I'll come back to that novelty preference later.  It's not incompatible with the novelty weariness when you present an entirely new situation that babies show under other conditions.

The second finding was that infants looked longer at three dimensional displays than at two dimensional displays, and that's actually the study that's being pictured here.  What a baby is being shown is a sphere, three dimensional sphere on one side of the peep hole and a flat disk on the other side, and the babies looked reliably longer at the sphere.

Now, this may seem to show that babies perceive depth, but actually it doesn't because there's two different accounts one could give of that visual preference, as the psychologist Richard Held pointed out some 20 years later.

One way to illustrate these two different accounts is to consider some experiments that Held did himself.  Now, these experiments were looking, testing for the development of a certain kind of depth perception, not the only kind, but the one whose neural mechanisms Professor Jessell was talking about this morning, perception of depth from stereopsis.

And for these studies, Held put stereoscopic goggles on infants such that each of the two eyes was seeing a different display, different pair of visual displays.

One of the displays that was projected to both eyes projected exactly the same array to both eyes, and for an adult with normal stereoscopic depth perception, that looks like an array of flat stripes.

The other display presented stripes that were two patterns that were slightly offset with respect to each other, to the two eyes, and when you put on stereoscopic goggles and look at that display, you will see stripes arrayed in depth.

Now, the first thing that Held found was that at about four months of age, between three and four months of age, infants start looking longer at the display that we adults see as stripes arranged in depth than at the display that we see as flat.

But Held pointed out there's two very different stories you could tell here about this preference.  On the one hand, maybe infants are also seeing depth just like we do.

On the other hand, it's possible that when infants look at the display on the right, they just see a pair of double images, whereas when they look at the display on the left, they see a pair of coincident imagines that fuse into a single imagine, and so a very different experience could be underlying their preferential looking relative to our depth perception.  So how do you get around that problem?

Well, what Held suggested, and this is the critical research strategy that I think has been followed in most of the work that has been done since this time looking at perceptual and cognitive development, what he suggested relies on 100 years of work on the type of physics of depth perception in adults, work that reveals that we adults perceive depth from stereoscopic information only under a very restricted and well defined set of conditions.

So, for example, in a display like this, we'll see depth if the edges are slightly offset from each other, but not if they're very far offset from each other.  We'll perceive depth if the edges are vertical, but not if they're horizontal.  We'll perceive depth if we look through the stereogram with the glasses on, but not if we take the glasses of.

And so Held suggested we can look across this range of conditions at when infants do and don't show the preference for the display on the right.

And what he found was that infants' preferences lined up down the line with adults' perception of depth.  Infants preferred the display on the right, starting at about four months under all and only the conditions in which adults perceived depth.  So that common set of signature limits suggests that infants aren't just responding to double images.  Rather, they've got the same mechanism that we have and it's working in the same way, giving us reason to attribute to infants the same kind of experience of a three-dimensional world at that point in development as we have as adults.

So to conclude this first section, what this work put together suggests is an answer to a 2000 plus year long debate.  The tendency to look out into the world and see a stable array of surfaces at a distance from ourselves and stable, coherent three-dimensional arrangements appears to develop largely independently of experience.  We seem to be built to perceive space.

The mechanisms by which we do so are not unique to humans.  They're shared with other animals.  And the mechanisms by which we do so as adults have a long developmental history in us.  We see the same mechanisms at work in human infants.  And these continuities, ontogenetic and phylogenetic, provide  a set of tools that we can use for shedding light on infant's perception capacities and also on some of their cognitive capacities.

So what I want to do now is use these tools and take you very briefly through some of the highlight conclusions of research looking at what infants understand about inanimate objects and what they understand about people.

I'll be particularly fast in talking about objects because this work is relatively older and some of it was in some of the supporting materials that there circulated to all of you, but basically starting as using Gibson's approach focusing on adaptive behaviors on objects and particular in these studies the adaptive behavior would be reaching out for objects and manipulating them and also studies using Fantz's approach focusing on preferential looking and in particular the tendency to look longer at novel events.  These two lines of studies have both been conducted to ask, what do infants see when you present them with an array of objects.  And they converge on the same set of conclusions.

One conclusion is that infants have capacities that we also have as adults, starting as young as about 2 months of age, maybe younger, though.  It's hard to do these studies when infants are younger.  Capacity is to take a continuous array of surfaces and break it into units.  And the boundary of those units generally coincide with the boundaries that we take to be the objects, in a scene.

So, for example, if you present a baby with two objects sitting on top of one another, one of which slides over the other but remains in contact with it throughout that motion, present it until babies are bored with it, and then reach out and lift up the top object and either it moves by itself or the two objects move together, babies look longer if the two move together, suggesting that even though the objects were in contact throughout the time the babies were becoming bored with them, they were nevertheless perceiving a boundary between them.

Other studies have asked whether babies are able to interpolate parts of objects that are hidden from view.  If you see an object whose top and bottom are visible and its center is hidden behind another object, can babies ever extrapolate that connection between the two and see a connected object?  And again  the answer is they can, if you bore them with a display like this, a rod moving together behind a block, never enough for its center to come into view.  They will be relatively bored if you then take the block away and show them a complete rod, suggesting that that's not new to them, that's what they were seeing before and relatively more interested if you show them a rod with a gap in the center.

Further studies have asked whether babies are able to represent objects as continuing to exist when they move fully out of view.  And these studies show that they can, under certain conditions, and that they keep track of objects that move in and out of view in accord with the basic principle that objects are going to move on spaciotempororally connected paths.  They're not going to jump from one place in time to another.

So, for example, the study of ours took four months old infants looked just at the—I'll just describe the case on the right.  Four-month-old infants and presented within an array where there's two screens, an object moves behind one screen.  Then there's a pause.  And an object that looks just like it moves out into view from behind the other screen.

Now, adults looking at that will infer that there's two objects in that event behind the screen because one thing couldn't move from far on the left to far on the right without traversing the space between the two.

To see if babies perceive that, we again bore them with the event I just described and then remove the screens and alternately show them arrays with one versus two objects.  They look longer when you show only one, suggesting that they like us, perceived two objects in that scene.

And one last example, studies have asked whether babies are able to make inferences about mechanical relationships between objects.  And in particular, if babies infer that objects will act on each other when and only when they come into contact.  This is one of the earliest experiments that was done by, I think, an undergraduate at the time.  It may have been an undergraduate of Jerry's, William Ball.

Here's the events that he presented to infants.  There's a screen.  There's an object that's partly hidden behind the screen and another object that moves behind the screen, and when it's fully out of view, the object that's initially half hidden and stationary starts to move, okay.  Now adults look at that and infer that the first object hit the second and set it into motion.  But actually, the event is physically consistent both with that possibility and with the second.  The screen is big enough that the first object could have stopped short of the second object, and it could have started moving on its own.

So to see whether babies made the same inference as adults, we bored with the top event, and when took the screen away and then indeed they looked longer at the event where the first object stopped short of the second, suggesting that they inferred that the two would come into contact.

Well, putting all this work and other related work together, I proposed and others have proposed that babies starting at about two to four months have a system for building representations of objects that accord with three general spaciotemporal constraints on object motion.

They build objects that are cohesive, that is, bodies that are internally connected and move relative to one another, that are spaciotemporally continuous, that is, that these are things that bodies can't do.  They move on connected paths, but they don't jump from one place to another and their paths also don't intersect, such that two things occupy the same space at the same time.  And they move when and only when they come into contact, there's no action at a distance.

But interestingly, this is not to say that infants perceive objects under all the conditions that adults do.  My colleague Susan Carey has discovered some interesting limits to infants' abilities to perceive objects.  If you present them with situations where spaciotemporal information for properties like cohesiveness and continuity do not dictate where the boundaries of objects are.  For example, you place a toy duck on top of a toy cup, presenting no relative motion between the two, no motion at all in the scene, infants' perception of the boundary of those objects is indeterminate.

Now recently there's been a lot of beautiful work, some of it on the island of Cayo Santiago that Jerry was talking about asking whether this same system of representation exists in nonhuman primates and also asking whether the same system exists in adults.  And like the strategies of Gibson and Held, the way of asking whether the same system exists is to ask do we see the same abilities and the same limits.  Well, to just simply give you the answer, since I don't have time to take you through the studies, the answer appears to be yes in both cases.  This system exists in adult rhesus monkeys.  It also exists in human adults when you test us under conditions where we're not able to use our specific knowledge about the world, our language, other strategies that infants lack to track things through time.  We show the same patterns of success and failure as infants do.

Well, let me turn to the other core system that I wanted to lay out for you.  This, I think, is a system for reasoning about persons, and there have been many signs from studies of infants over the last 20 years or so that the system exists and is at least as important for infants as the system for representing objects. 

One source of evidence for this system comes from some studies conducted by the psychologist John Morton and Mark Johnson with newborn infants.  They took brand new babies, put them on the lap of an experimenter, and presented them with simple schematic oval-shaped patterns, either a pattern representing a face or one of a number of other kinds of displays.  And when the baby was looking at the pattern, they slowly moved it to the left or right, and the measure was how far would the baby follow the pattern, how far could they move it before the baby would lose interest, turn away, no longer track it?  And what they found was that babies would track for the face pattern at birth reliably longer than for the patterns that clearly were not face-like and not reliably, but somewhat longer when they tracked a simplified face pattern as well.  And this study and others suggests initial sensitivity to the structure of the human face.

Here's another ability that comes in by about two to three months of age from studies by Bruce Hood.  In these studies, infants view the face of a person on a computer screen looking straight at them and then, I don't know if you can see it up here, but the person's eyes turn either to the left or to the right, and right after that the person disappears and an object appears either on the left or on the right.  Now no matter which side the object appears on, the babies turn to look at it.  But when Hood measured how fast babies turned to look at it, it turned out that they turned to look to the object faster if the person's eyes had—if it appeared on the same side where the person's eyes had turned than if it had appeared on the opposite side.

So from about two to three months of age, babies are sensitive to human gaze, and they're following the gaze of a person who's looking straight at them to an object that's facilitating their attention to other objects.

Well, what about people's actions?  Do babies form any sensible representations of other people's actions?  Well, this is something that psychologist Amanda Woodward has been studying for the last five years or so through some simple ingenious preferential looking experiments.  In these experiments, she shows a baby two objects and a person whose hand reaches repeatedly for one of the two objects, so for example, for a given baby it might be the ball.  After the baby has gotten bored with looking at this, she then switches the positions of the two objects and has the hand alternately reach to one versus the other. 

Here's the reason for doing the experiment.  The question is, when the baby sees the person reach for an object how do they encode what the person is doing?  Do they think the person is just like an inanimate object that would move from one position in space to another position in space or do they encode the action as goal-directed, directed to the goal, in this case reaching for the ball?  Well, if they encoded the action as simply a movement through space, then this should be the event that's most similar to it.  But if they encoded it as an action directed at a goal, then when the two objects move, it's the new action to the new position to the old goal that should be seen as more similar, and infants' looking time was consistent with that second possibility.  Okay?  Infants looked longer when the goal changed than when the physical trajectory of the action changed.

PROFESSOR SANDEL:  Could I just ask you, the test, though, is looking longer?

PROFESSOR SPELKE:  Right.

PROFESSOR SANDEL:  How do you know what that means?  How do you know whether they're looking longer because they're making sense of it or they're looking longer because it doesn't make sense?

PROFESSOR SPELKE:  Okay, in all of these studies, the pattern of data internal to the study answers that question, okay?  So for example, you can have conditions in which you don't change the positions of the objects.  Right, and so if they're looking longer to something that's familiar or sensible, they look longer to the old motion than to the new, but that's not what they do.  Does that make sense?

So I mean this is a situation that pits two kinds of novelty against each other and when we see they look longer to this, we're assuming they're going to look longer to novelty. 

PROFESSOR SANDEL:  That's my question.  Why do you assume that looking longer corresponds to novel—the perception of novelty?

PROFESSOR SPELKE:  Right, because you can also do studies where instead of pitting two kinds of novelty against each other, you can pit an event which by any description is more novel against an event which by any description is more familiar.  So suppose, for example, instead of switching the positions of these two objects, we just left them where they were, let the babies get bored with one and then alternately show reaching to the old one versus reaching to the new.  Infants will look longer at the new one, and so that's suggesting that in this situation when they're bored, they will tend to prefer the more novel event.  Did that make sense?

PROFESSOR SANDEL:  I thought the question—

PROFESSOR SPELKE:  Let me—

PROFESSOR SANDEL:  Please, so ahead.

PROFESSOR SPELKE:  Let me keep going because I think in principle that is a real concern and in practice the pattern of results across the studies addresses it.

The one last thing I want to tell you about the Woodward studies is that this effect is specific to people.  When she's repeated these experiments with inanimate objects moving towards—and the inanimate object she used was superficially in some ways similar to a human hand and arm.  It was a stick with a sponge like deformable thing on the end of it and she bores babies with the stick moving to the ball and then switches the positions of the two objects.  She does not get a preference for moving to the same goal, suggesting that this propensity to understand actions as goal-directed is applied to people in infants of this age and I should have said these are five-month old infants.  It's not applied to inanimate objects.

Finally, there are other studies, infant sensitivity to human actions, that show that babies are sensitive to relationships between what they themselves do and what other people do.  The most famous studies, also were very controversial for a long time, were conducted by Andy Meltzoff some 25 years ago and showed that when, for example, he sticks out his tongue at an infant, infants will reliably not really stick out their tongue in kind, but act in a way that a blind observer looking at it would judge to be more like sticking out your tongue than like other events that the model engaged in.

We now know after many years of controversy that this ability in newborn infants is extremely limited, but it is real and it leads to much more dramatic abilities to attend to the actions of other people and reproduce their actions on objects later in infancy.

I have just one example here to share with you.  This is also from a study that Meltzoff conducted with much older infants.  Starting at about nine months of age, if an infant views a person acting in a particular way on an object and then that object is presented to the infant, the infant will tend, if possible, to reproduce the action that they saw the person perform.  In this study, which is with infants that are somewhat older, they're about 14 months.  Meltzoff went a step further and asked what will happen if an infant sees a person attempting to do something but failing, and in this study the person is attempting to take this little barbell and pull it apart and failing to pull it apart.  What he found was that when he then gives the barbell to the infants they grab it and pull it apart.  And again, this is specific to people when they see the very same series of motions, but it's a machine that's doing the actions, they don't show that effect.

Okay, so these are all ways in which infants seem to be able to make sense of the actions of other people.  But we can ask, do infants also apply their understanding of inanimate objects to other people?  Do they expect that people will interact on contact, that people will exist and move continuously.  And some experiments have begun to ask this.  In particular, Woodward did a series of studies where she took up the old experiment by Bill Ball showing that babies infer that two inanimate objects that move in succession come into contact and asked, will they make the same inference for people?  So for this study she presented infants with videotaped events of real people or real large complicated inanimate objects, things like potted plants and high chairs, not the objects that I've diagrammed there, conducting the same experiment that I described earlier.

What she found is that as in the previous experiments, when the objects were inanimate, infants inferred that when two objects moved in succession, they came into contact, but when the objects were people, they did not.  Okay?  No inference that the first person slammed into the second to set them into motion.

Finally, very recent set of studies being conducted at Yale in the lab of Paul Bloom have asked whether infants infer that people's motion is subject to continuity.  And here they took our method for studying continuity that I already described to you, two screens and an object that moves behind one and then another object that appears behind the other and they found, like us, that when the objects are inanimate infants infer that if there's been discontinuous motion there must have been two objects.  Interestingly though, they don't infer that in the case of people, even though it's true, right?  A person can't move from the first place to the second without passing through the space in between, but infants don't infer that people's behavior is subject to that constraint.

So to summarize what I've told you about infants' understanding of inanimate object motion and human action, I think we see evidence here for two quite distinct systems of knowledge.  In the case of inanimate objects, infants reason about object motion in accord with a principle of no action at a distance, contact mechanics, if you will.  They infer that such objects are not goal-directed.  They don't show goal-directed inferences in the Woodward kinds of studies.

In the case of people, you see just the reverse.  People are predicted to act in relation to goals and not in relation to proximal mechanical forces. 

Similarly, tracing people over time may involve making inferences about their intentionality.  Certainly babies seem to be sensitive to intentionality, and it doesn't involve making inferences about continuity, whereas for inanimate objects the reverse would seem to be the case. 

So it looks like we have two distinct systems here.  Now I've raised the question that I can't, unfortunately, answer about whether these systems show continuity over phylogeny and also over ontogeny.  In the case of studies of nonhuman primates, there are a number of studies now of nonhuman primates showing that pieces of the abilities that we see in infants are shared by other animals, but there's currently a debate in the field as to whether the entire set of abilities that we see in human infants are part of our primate heritage of whether any of them are unique to us.  I think that's a question we have to leave on the table for the moment.  The decisive studies on nonhuman primates just haven't been done.

In the case of ontogeny, I want to throw out a speculation to you.  This is an interesting group, I think, in which to do this because I believe you may have already heard presentations from some neuroscientists saying there's really only one system of causal relationships that underlies all behavior.  Human beings are just complicated machines.  Our minds and brains operate in accord with the same mechanical principles as inanimate objects.  And if one takes these claims seriously, it would seem to suggest that people can come to overcome this notion that people and inanimate objects are fundamentally different from one another.

My own experience though, for what it's worth, is that colleagues who say these things to me about human action tend to agonize over personal decisions as much as anybody else does, tend to experience moral indignation.  I think that this notion that people choose their actions and could have acted otherwise is actually very deeply ingrained within us, and I think we're seeing the origins of it in these studies with infants.

Okay, I want to completely shift for the remainder of my time and talk about some capacities that we don't see in other animals for sure and that we also don't see in human infants but that we do see in most children at the time that formal education begins, a set of distinctively human concepts and abilities—one of the abilities which I didn't put up here is the capacity for language—that allow us to communicate with one another, to use symbols and to use abstract concepts that are at the basis of all science and technology and much of modern life.

Now, what I want to suggest in the case of all of these concepts is first of all that infants lack them; second of all, that these concepts aren't explicitly taught to anyone.  They develop spontaneously in children, most children between the ages of about 2 and 5; third, that their development depends, in part, on experience; and fourth, that their development is absolutely necessary for formal education, that a child who hasn't developed these fundamental concepts will be at serious disadvantage in formal educational setting.

Now if I had hours and hours I would try to tell you about all of these.  Since time is very limited, I want to try to flesh out these claims by looking just at one set of concepts, natural number concepts.  And what I will try to do in my last few minutes here is begin by telling you very quickly about two core systems for capturing numerical information that we do find in infants and nonhuman primates, as well as in us adults, one for dealing with small numbers, the other for dealing with large approximate numerocities.

Then I want to talk about the construction of the uniquely human natural number concepts over the course of the preschool years and then finally, I want to give you a bit of evidence that this construction depends, in part, on experience.  So the first core knowledge system that serves as a building block for children's number concepts I've already introduced you to in talking about objects.  This is a system for representing small numbers of objects and all I want to point out here is that it has some of the properties of our system of natural number.  So this is a system, for example, that research by Karen Wynn has shown babies are able to use to do something like compute the effects of adding an object to a scene or taking an object away from a scene.  If you place an object on the stage, this is again a preferential looking experiment, 5-month-old infants; place an object on a stage, cover it by a screen, add a second object to the scene and then ask infants, in effect, how many objects are there by lowering the screen and presenting either the right or wrong number of objects.  Infants will look longer if you present the wrong number, and they do that both in this one plus one kind of problem and also in other similar problems.

Infants can also use representations of small numbers of objects to make numerical comparisons, and these are studies that have been explored most thoroughly with older infants about 12-month-olds.  Research in Susan Carey's lab has taken 12-month-old infants and presented them with graham crackers, putting one plus one equals two graham crackers into one box.  Two minus one equals one graham cracker into the other box, pushing the boxes apart and encouraging the infants to crawl to them.  And infants will tend to crawl to the box that has the larger number of graham crackers, showing that it can both represent the numbers in each box and compare those numbers.

But as always with infant research, the limits to infants' abilities are as interesting as the abilities themselves and in particular, in these situations we see two general limits.  The first is a domain limit.  You see these abilities when you present babies with solid, manipulable objects.  You don't see them when you present them with nonsolid substances or many other kinds of perceptible entities and the second is a set size limit.  You see these abilities when you present up to three objects, but when you present more than three objects babies fall apart.

So here is the results, for example, of the box choice study, one versus two graham crackers, they go to two.  Two versus three, they go to three.  But if you then test with three versus four or even four versus eight, they're choosing at chance between the two.  They're not able to keep track of more than about three objects.

Now we see the same limits in monkeys.  This is research by Mark Hauser and the same limits in human adults when you prevent us from counting or otherwise verbally encoding the displays, suggesting this is the system that shows considerable continuity.

The second system has been revealed through experiments using an even simpler novelty preference method.  For example, a method that's been used a lot in studies of speech perception where you take an infant and present them with the sequence of sounds coming out of one of two side speakers, simply measure how interested they are in the sound sequence by seeing how long they will turn their head in the direction of the speaker.  Then you can test for their abilities to discriminate different numbers by familiarizing infants to a set of different sequences all presenting the same number and then testing them with new sequences alternately presenting the same number of a different number.  I hope this is clear.

So what's illustrated here, half the babies are bored with four sound sequences, with four sounds; half with sequences of eight and then everybody is tested with sequences of four and eight, and you see will they turn their head to the speaker longer when they hear a new number?

And very quickly, the findings, the study has been done with many different numerical discriminations.  The findings are at about six months of age, the first age at which you can use this method, babies do show abilities to discriminate on the basis of number.  They'll discriminate sequences of four from sequences of eight, for example.  Their number discriminations are imprecise.  So if you repeat the experiment to test discrimination of four from six, they fail.  And what determines whether they succeed or fail is the ratio of the two numerocities.  So a baby who succeeds with 4 versus 8 will succeed with eight versus 16.  If they fail with 4 versus 6, they'll fail with 8 versus 12.

And finally, as you test older babies, you find that the critical ratio for discrimination narrows.  A 9-month old in particular, will succeed with a two to three ratio that the 6-month-old fails with.

Now one can vary the kinds of events or displays presented to infants to see whether this is an abstract system of number representation by instead of presenting sequences of sounds you can present sequences of actions, a puppet that jumps some number of times.  You can also present visual spatial arrays, arrays of dots, of one or another numerocity.  The findings from those studies line up perfectly with the findings from the studies with sound sequences.  If babies can discriminate a given pair of numbers of sounds, they can also discriminate that pair of numbers of dots or visible actions.

Now these large number representations show two signature limits.  One that I've already described is the ratio limit on discrimination.  The other limit I also described earlier in talking about the first system.  It's a tracking limit.  Babies are able to discriminate 8 events from 16 events when the events occur in immediate succession in an object that's continuously visible.  But if they see one at a time, four objects going into a box versus eight objects going into a box one at a time, and they have to track each of these individuals as it's hidden, they are not able to use this large number system in that case.  So the same limits have been found in monkeys and also in human adults, people like us, when we're prevented from counting or otherwise use language to encode the displays, suggesting that the second system is also showing continuity.

So it looks like we have evidence for two systems capturing aspects of numerical information in infants, one focused on small numbers, the other focused on large numbers, each system showing successes and failures under a distinctive pattern of conditions.

So the question then is what happens to these two systems, as children learn verbal counting, as they interact with other people, and as they develop the kinds of number systems that they're going to need to use in school? 

Now clearly, when children go to school, the assumption is made that they've got one system of number concepts, not two; that the system shows neither a set size limit nor a ratio limit.  Natural number concepts allow you to represent whole numbers precisely with no clear upper bound.  And that each number concept refers to a set of numerically distinct individuals.  And the question is where did these representations come from?

Well, I think some very interesting work that began again with Karen Wynn and has been pursued by a number of different investigators since then suggests that these number concepts actually emerge well after children first learn the verbal counting routine.

So in most American households, somewhere around age 2 or two and a half, children start engaging in counting.  I'm sorry this is so distorted.  There are supposed to be about nine fish on this table, and if you take an average two year old and say how many fish are here, the child will very likely go through the routine of pointing at each of the fish one at a time and going one, two, three, four, five, etcetera, engaging in verbal counting.

What Wynn showed, though, is that at this early point when children are engaging in this activity, they don't have the faintest idea what these words mean or what the activity is about.  And one way to show that is to ask them a simple question.  After this child has counted all nine fish—here's a pair of questions that shows this.  After the child has counted nine fish, you ask the child would you put one fish in the pond?  And the child succeeds.  That shows the child understood the question, is motivated to answer correctly.

So now you ask would you put two fish in the pond?  And I can tell you the reaction of my son, aged two years or so at the time that Karen conducted this experiment on—she was conducting it at the time, and she came to visit us and did it on him.  He looked at her as if she had suddenly switched to a foreign language.  He didn't have the faintest idea what she wanted, and he then grabbed a handful of fish and put them in the pond.  What her data showed was that at this point there was no relation between the number asked for and the number given, except that a child always gave one when asked for one and always gave more than one when asked for another number.

Now this state persists for about nine months.  For about nine months children are using all of these number words in the verbal counting routine without understanding what any of them mean.  And then somewhere around age three and a quarter or so, children learn the meaning of the word two and at that point when you ask for two, you get two.  When you ask for three, you'll get a handful, but not one and not two.  And about another three months later, they learn what the word three means, and then something magical happens, and they figure out what the whole counting routine is about.

Now what could be going on here?  I think in light of the work on infants, we can make the following suggestion, that in the initial step of learning verbal counting, children figure out that the word one applies when you've got a single object, a single individual to represent, and the system for representing small numbers of individuals may support that induction.

They also know that the other number words apply when you've got a set, a bunch of things, some nonspecific number of things.  When they learn the meaning of two, what they have to learn is the word two applies just in case your system for representing small numbers picks out an individual and another individual, and your system for representing large numbers picks out a set of things, a small set of things.  And then three can be learned in the same way, and then the child can't go any further because the small number system, remember the core system, has a limit of three.

But what the child can do at this point is discover that the progression from two to three and the counting routine involves two things, adding an individual to the set and increasing the cardinal value of the set.  And once they've got that and can generalize that to the other number words, they've worked out the meaning of the counting routine.

Now I've gone through all this because there's no evidence for any of these developments in any nonhuman animal.  This is, I believe, a distinctively human achievement.  And what it consists of, what the child is doing with support from parents but without any explicit instruction by anyone is putting together representations from two core systems with a system of number words and quantification that's emerged through communication with other people through their natural language and their culturally specific counting routine.  And I certainly don't have time to give you this evidence, but there's a wealth of evidence now suggesting that the same three systems are at work in us as adults when we use and reason about natural number concepts.

So the last question I want to ask does experience play a role in this construction?  In one trivial sense it must.  The number words of English are different from the number words other languages, and they have to be learned, but I mean to be asking a deeper question.  Do the concepts that those words pick out emerge, does experience play any role in the emergence of those concepts?

Now I think there's evidence from the research of two educational psychologists, Robbie Case and Sharon Griffin, that indeed experience does play a role.  What they showed first is that in the United States and Canada, although most children from middle class families have developed these number concepts by the time schooling begins, many children from disadvantaged families have not.  In particular, Case and Griffin did a set of studies where first they would take children and have them count and show that all of the children, these are in kindergarten classes, all of the children could count to a nice satisfyingly high number, and then they would take numbers that were in the list that the child had produced, him or herself, and simply ask questions like if I have five apples and you have four apples, who has more applies, testing their understanding that the word "five" picks out a larger numerosity, a larger number than the word "four." 

Now when they asked these questions to children from high or middle income families, almost everybody can answer them.  When they ask them to children from economically disadvantaged families, they got a much lower rate of success in kindergarten.

The next question was why would the kindergarten children from the disadvantaged families be succeeding less?  And one possibility that they pursued was that these children may just not be having the interactions in their homes that middle class children are having and that lead children to make this construction spontaneously on their own.  He found, for example, they found that in middle class families there was lots of talk about number, lots of play with board games, rolling dice and counting up moves and things like that, much less of that in the disadvantaged homes. 

So Case and Griffin designed a series of intervention studies where they simply took kindergartners from disadvantaged backgrounds who tested badly on these number concepts initially and played a set of games with them, a set of board games, no explicit teaching, but played games involving talking about number, rolling dice, counting out moves and so forth and reported dramatic improvements in the children's understanding of number which were followed up in one year and three year follow-ups with dramatic advantages in their formal mathematics education.

So to summarize this, it looks like preschool children construct natural number concepts spontaneously without formal instruction, as long as they're given supportive environments.  Without environmental support, it's not clear that these concepts will develop on their own.  Children who don't develop them then would be at a disadvantage when formal schooling starts, because that schooling presupposes that when a teacher uses the word "three" and the child uses the word "three", they're talking about the same thing.  This failure, though fortunately, the work of Case and Griffin suggests, can be remedied.

Well, I think this general picture applies to many of our most interesting uniquely human concepts, so I could have given a different talk about mental state concepts, concepts like beliefs and desires, propositional attitude concepts.  There's good evidence that infants don't understand these concepts, but that most 4-year-olds do and that children aren't explicitly taught what beliefs and desires are, they figure it out on their own in supportive environments. 

Similarly, for understanding symbols, young children may look like they understand symbols when they point to a picture of a cow and say "cow", but do they really understand that that set of marks on paper is a representation of a cow, a symbol that stands for a cow, not a cow itself.  There's evidence that that understanding is not present in infants, that it develops over the years from two to three or so.  The research of Judy DeLoache; again, distinctively human ability constructed by children without formal instruction, but only in supportive environments, same for concepts of works of art and tools.  So in each case, I think these concepts are developing in the ways that natural number concepts did.  And I think this suggests that this time from age two to five is really a critical time in human development, for the development of a whole host of uniquely human cognitive abilities, abilities that mark us from other animals and also abilities that make us capable of formal instruction.

So what I want to do, I'm probably over time, but I'm just about done, is just end with three general themes and suggestions that I think this work may support, at least that I wish to offer to you to consider whether you think this work might support them.  The first theme goes back to the thing you questioned me about, this preference for novelty.  I think it's the case that as early as we look in infancy, we see that infants are motivated to learn.  Now they're motivated, in part, to learn on their own seeking out situations that give them new information.  But they're especially motivated to learn from other people, and we see this in everything from the following a person's gaze to the objects that they're looking at, to reproducing their actions, to reading through their actions to the intentions behind them.

But I think a possible implication of this work is that while infants are built to learn, they're not built to learn alone.  They're built to learn in interaction with other people who already are immersed in the culture into which they will be growing.  They need social partners to do this, and I think arguably the best social partners to do this would be one or both of the infant's parents.

In that context, I think you might consider whether our society is well advised to give so many parents the cruel choice between having to decide between the economic welfare of their families, on the one hand, and their opportunity to be there as a participating parent during the first year of a child's life, on the other.  Should we be requiring single mothers on welfare to work when their children are infants?  Should we be requiring families that require two incomes to support their children to be choosing between giving their children that economic support and giving the children the presence of a full-time parent in the first year?  I think that's one issue worth considering.

The second theme, which I just ended the substantive presentation with, is that we should pay more attention to the years from two to five, that this is a critical time for children's cognitive development.  This isn't a time when I think we need to be putting children in schools or starting formal education.  It's a time when children are learning great things on their own.  But they're only learning those things in supportive environments.  And I think that suggests a further duty that we may have to children that you may want to consider in this panel, the duty, first of all, of understanding what are these capacities that are developing in the years from two to five, and what kinds of environmental support are necessary for the development of them.  The kinds of studies that Case and Griffin have done for number need to be done, I think, in other domains as well.

      And second, to assure that children throughout our country are able to grow in environments that provide the resources that they need for that development.

The final theme is maybe the most speculative one, but for me, I think it may go the deepest and it takes me back to the first part of my talk in talking about systems of core knowledge in infants.  Now I think that a general conclusion that's emerged over the last 50 years is that to a surprising extent young infants, not always newborns, but 3-month-olds, 5-month-old infants share ways of conceiving the world with us adults, that they experience the world in distinctive ways that are much like the ways that we, as adults, experience the world.  And that's true, I think, in the case of space and objects and other people, the three cases that I talked about.

But there's a way in which infants are radically different from us.  When we experience negative situations, we're capable of acting to change those situations.  When we find our own resources for acting are limited, we can communicate our needs to other people and seek help from them.  But infants, though they share many of our experiences and capacities, radically lack the capacities to act that we have to ensure that their environments are safe and healthy, that they're cared for and that their needs are met.  And I think that gives us the most fundamental ethical responsibility of all, vis-a-vis infants, and that is to care for these creatures who are so like us in our experiences, but so unlike us in their capacities to provide their own care.

Thank you.

(Applause.)

CHAIRMAN KASS:  Thank you very much, Dr. Spelke, Professor Kagan.  The floor is open for discussion. 

Michael Sandel.

PROFESSOR SANDEL:  Thank you very much for that great presentation which really covered an enormous amount.  I would like, if I could, to go back to the question about the looking longer test of novelty, the preferential looking test and what we can infer from it. 

Thinking back to that two by two diagram that summarized the study of children's perceptions of what makes inanimate objects and people move, contact in the case of inanimate objects, goals in the case of people, it's a lovely result, so lovely that it's also a suspicious result because what it discovers is that the way children perceive the world and the laws of movement recapitulates the 17th century split between explanation in the physical sciences and in the human sciences where we concluded in the last 300 years that mechanism governs the movement of inanimate objects, not teleology.  But the teleology or goal-directed explanations govern the human sciences, the way people behave, and it just turns out, lo and behold, that children naturally, so to speak, perceive that relatively recent discovery, the way that the modern science has bequeathed this split between the modes of understanding in the physical and human sciences.  So this is really to explore that suspicion. 

What's the warrant for inferring from the looking longer test one thing rather than another?  And here's another experiment, and I wonder what you would read from these results.  You can imagine you could time, never mind children, even adults, how long some adults might gaze at the sunset or the rising of the sun as those events naturally occur, familiar though they are, not novel.  People gaze sometimes for long periods of time out of appreciation or contemplation or who knows what.  And then suppose you, as the counter example, you did an experiment of the kind that occurs in the movie, The Truman Show.  You remember in The Truman Show, unbeknownst to Truman, he was the character, the Jim Carrey character.  He's living within an elaborately constructed television set where everything, including the seasons and the weather and the rising and the setting of the sun is governed by a producer who's in a control room.  And at a certain point this fiction is maintained, but at a certain point the producer, they're desperately looking for Truman who has escaped, but it's the middle of the night.  And they can't find him, and so the producer decides he has to spoil the fiction in order to bring up the lights.  And he says "cue the sun," and the sun rises in the middle of the night.  That would be novelty.

Now suppose you timed, you applied the looking longer test to the sun that arose at that unnatural moment, unfamiliar moment, would people, infants or would we—would you expect that we would look longer at that unnatural, unfamiliar rising of the sun, than we do when we sit in contemplation of a natural sunrise?  And how would you know if we looked longer at the one rather than the other that one was novel and the other familiar?

PROFESSOR SPELKE:  Right.  Actually, in that case, I think we probably would.  If the sun suddenly rose in the middle of the night, I think we'd all run outside and look at it.  However, I completely grant your general point.  And in fact, the reason I went through the whole discussion of the Held experiments is that for any given behavior that an infant chose, looking longer at one thing than at another, we could tell multiple stories about the causes of that behavior.  That's absolutely true.

So one thing that I had to do in making this presentation because I wanted to cover a lot of ground was give you the results of single experiments, but it's when you look across experiments that I think the following things emerge.  First of all, it is not the case that infants will absolutely and under all circumstances prefer novelty.  That's not true any more than we as adults will always prefer novelty.  Actually, one case I think in which it's least likely to be true is cases involving human action where if other people do things that are bizarre, we may avert our eyes from it rather than look at it.  So it's not at all the case that one can take as a given whenever an infant looks longer at something, that must be more novel to them.

However, within a series of experiments what you do in these studies is the following.  You start with an analysis of an ability.  Under what conditions would we, as adults, see something as goal-directed or not.  Then you make a set of focused predictions about what you would see in an infant if they had the same system for representing things as we have.  And then you test down the line whether those predictions hold.  Now if you get a coherent pattern across them, all involving when you change something in a way that would lead an adult to say that's funny, the goal just changed, the baby looks longer. 

Across that series of studies, there isn't a coherent explanation to give if the baby were preferring the familiar one and there is a coherent explanation to give if they're preferring the novel one.  So that's one answer to your question.

The other answer to your question, though, is that both in the case of research on infants' reactions to people and in the case of research on infants' reactions to inanimate objects, the examples I gave were all preferential looking experiments.  But in fact—actually, they weren't all.  In both cases, multiple methods have been used to converge in on the same abilities.  So for understanding infants' representations of other people's actions, you can use imitation tasks where they repeat people's actions and ask is their repetition true to the goal or is it true to superficial properties of the actions?  And the answers you get from those studies converge with the looking time studies. 

Similarly, in the studies of object representations, you can ask what do babies see as the bounded objects in a scene, either using preferential looking with the assumption of a novelty preference or by using reaching, and you see a convergence across them.  So I think in both cases it's the converging findings of series of studies within each method in relation to adult abilities and also series of studies across methods that lead to these conclusions.  And you're quite right, that if you single out any single experiment, then you're in the situation that Richard Held was in when he only had the first experiment on the 4-month-old infants looking longer at the side with double image stripes than single image, and you don't know what the basis of the response is.

CHAIRMAN KASS:  Bill Hurlbut.

DR. HURLBUT:  If our question here, fundamentally, is nativism versus empiricism, I want to ask you about the sort of fullest form, that being the development of the moral mind, because building on what Michael was just talking about, I believe there are studies that indicate that infants will look at things, certain things, longer than others based on what you might call intrinsic value.  So, for example, you mentioned faces.  There are studies that indicate that certain faces rated as attractive faces by adults and across cultures command the longer attention of infants.  Now that's really amazing.  That means somehow—and this is quite early infants, I believe.  Some sort of pattern, and it's not just symmetry, some pattern has an intrinsic value.  It's built in, it would sound like.  And that's the first thing.  I'd like you to elaborate on that.

The second thing is not just intrinsic value, but the roots of our relationship between awareness and action.  You cited Meltzoff's work of imitating faces.  When you stop and you ponder that capacity, that again requires that the infant somehow has a pattern that it knows sensorially how to apprehend, but also how to reproduce.

Now I know there are some findings that suggest there are cells, Rizzolatti's so-called mirror cells that could mediate this.  But it would imply that quite high order constructions that somehow there was already a connection between sensory input and motor action.  And of course, the concomitant of that is that if there is motor action, even with a sensory input, that the subjective states that accompany those muscle actions would already be communicated in a kind of inter-subjectivity.  All this seems to add up to a foundation for the moral mind.

Can you just comment on all of that?

PROFESSOR SPELKE:  Sure.  On your last point first, I think there's actually quite rich evidence that babies are sensitive really early to the correspondences between their own actions and other people's actions.  One thing I didn't talk about from the Woodward studies is that if you look at the kinds of actions that babies can attribute goals to, they develop hand in hand with the child's own capacities to act.  So it's at the point at which a child, him or herself, will start pointing to objects, that they will interpret a pointing action that they see another person perform as goal directed by the Woodward test.  So I think that goes along with your line of thinking.

And you're also quite right that we don't know whether this is unique to humans or not.  There's clearly pieces of it in monkeys as shown by the Rizzolatti work and other work like that.

I'm going to have to punt on the morality question, not because I don't think it's important, but because I really think that the jury is out.  There are hints of pieces of what will become a system of moral reasoning that I think we can discern in infants, but whether we have a full blown system that's showing itself in a glimmer here and a glimmer there, or whether a full blown system of moral sense is going to require the kinds of constructions that a system of numerical reasoning requires, constructions that children will put together, perhaps without explicit teaching, perhaps learning by example and by observing other people.  I think we just don't have the evidence at this point to say.

There's, of course, a long tradition of studying moral development in children.  I think unfortunately much of that tradition has focused not on children's moral intuitions, but on their justifications, and then what you find, not surprisingly, is that young children who are pretty terrible at giving coherent justifications for anything they believe, don't give very sophisticated looking moral justifications either.

But the question of whether they have underlying intuitions, like our intuitions as adults and whether there's a core to morality is, I think, going to be a very interesting and important question to pursue, and we don't have the answer yet.

DR. HURLBUT:  Can you say at least a little bit about intrinsic value, like beauty in faces?

PROFESSOR SPELKE:  Here I want to voice some of the skepticism I think related to what Dr. Sandel was saying before.  We can say that a baby will look longer at one thing than another, but do we know that that means that they're esteeming it, that they're endowing it with value?  I'm not sure that we do.  But maybe Jerry—I think this goes out of my domain of sort of cold cognition and into emotion, and maybe Jerry wants to speak to that?

PROFESSOR KAGAN:  Babies prefer symmetry.  I thought Liz was going to say that actually, and that's why, they prefer vertical symmetry so I agree with Liz.  They don't understand beauty or that that face is pretty, but they will look at vertically symmetrical designs, and pretty faces are vertically symmetrical.

Incidentally, that doesn't mean that I don't believe that biologically human children don't inherit a foundation for moral sense.  They do somewhere in the second year, but I don't believe they have it in the first six or eight months of life.  They get it later.

CHAIRMAN KASS:  I have Janet, Ben Carson, Mike Gazzaniga and then myself.

DR. ROWLEY:  I actually have three questions, if I may, two probably for Liz and one for Jerry.

So neither one of you actually talked about the change in the complexity of the brain connections that develop over time and focus really, you focus on early cognition which is certainly important, but all of the evidence, of course, which I know you would agree with, that the brain certainly matures over a long period of time and so there are certain kinds of skills that children should be exposed to and experiences they should get relatively early, but then there are other things that are going to evolve later, and trying to force a child to learn some things at three or four is futile or frustrating.

Would you say a little bit more just in general about conductivity, and then I've got two more parts.

PROFESSOR SPELKE:  I agree completely, and I think one of the values of the work on cognitive development is there's a huge gap between what we understand about learning and cognition on a functional level and what we understand about neural growth and conductivity on a structural level.  So I think that the beautiful work on neural development tells us to expect that children will be optimally ready to learn different things at different ages, but it doesn't in itself yet tell us what things they're ready to learn at what ages, and we need the behavioral work to do that.  And I quite agree with you.  For example, based on the work that I presented on number, I think it would be futile at best and possibly harmful to be pushing infants or very young children to be developing mathematical concepts before they even have a system in place for representing them, and I think there's many cases of that where we can use work on basic cognitive development to make more informed decisions about what children are ready to learn at different ages.

DR. ROWLEY:  Now the other—one of your final concerns or practical consequences of what you've described was that it's very important for parents to be able to be with their children for the first couple of years of life and you weren't really in favor of child care at that point.  But the concern is that there are, unfortunately, a fair proportion of families in the United States where the parents themselves are not really in a position to give the children these kind of early stimuli.  And so I wonder if there isn't really a place for child care and nursery schools at a very, very early age for—at least some availability for these, some portion of the population.

PROFESSOR SPELKE:  Thank you for that clarifying question.  I did not mean to be arguing against child care.  I mean to be arguing that every infant needs to be growing up with adults who are responsive to them, who have the time to take to be interacting with them, to be attending to them, that infant development doesn't happen in a vacuum.  And in many cases, it's the parents who would want to be playing that role if it were economically possible for them.  But that is not to say that a biological parent is the only person who can play that role.

DR. ROWLEY:  And finally, the question for Professor Kagan, when does a sense of right and wrong or moral judgment really develop in children?  It's partly a question that Bill asked, but we didn't get into—when can you really hold a child responsible and what kind of actions can you hold them responsible for?

PROFESSOR KAGAN:  Three stages in moral development which I believe are universal.  In the middle of the second year, if you're late by, I don't know, 30 months, but most kids by 2, understand the concepts right and wrong, good and bad, in their language.  They have a concept of prohibited actions.  That's not morality, but that's the beginning.

Between five and seven, and that's why the Church and English Common Law and Freud and Piaget, I mean everyone knows that a profound change in brain occurs between five and seven.  We don't know what it is.  Now children have a more abstract concept of good and bad and understand that going to school is good and watching the cow from 9 until dinner is something I should do.  Now we hold them responsible.  And the last phase is at adolescence, again, I think a maturational change occurs, of course, all supported by the environment.

Now one has, one looks for consistency and one looks for consistency in your beliefs which 7-year-olds don't.  So the child of seven can hold these beliefs.  My father is a wonderful man.  My father is much too harsh with my mother.  One of those has to go.  That's the change in adolescence.  Now the adolescent seeks consistency among their moral premises, and that's the last phase maturationally.  Of course, experience and culture—morality is like language.  You're given the capacity, and now you're culture teaches you whether you're going to learn Swahili, French or Germany, and your culture teaches you, with the exception, I think, of unprovoked aggression.  I have the intuition that that is universal.  But with that exception it teaches you what is moral and what is immoral. 

CHAIRMAN KASS:  Ben Carson.

DR. CARSON:  Thank you both for those illuminating discussions.  This morning we talked a little bit about the neurophysiological and anatomical aspects of the developing human brain and this afternoon more about some of the cognitive social developmental issues.  In both cases, there's an implication that the nurturing environment plays a very significant role, it provides very significant advantages.  I was particularly struck by the slide that indicated the numerical reasoning at a 95 percent versus an 18 percent range in children in nurturing environments versus those in lower socio-economic classes.

The question is is there a point at which it is too late to close the gap?  If so, what is that, and secondly, how do you explain late bloomers?

PROFESSOR SPELKE:  Both really good questions.  The work of Case and Griffin is actually, I think, very encouraging here because although the middle class children tend to develop these concepts in the years from two and a half to four, their intervention was aimed at 5-year-olds starting kindergarten and it was not too late.  The 5-year-olds in their program did extremely well.  That doesn't tell us is there a point later on that is too late.  There will be a cumulative problem though if you wait too long which is that when kids start elementary school, they're getting exposed to a whole curriculum that presupposes that those concepts are in place.  So if the concepts aren't in place, even if the child is biologically still capable of gaining them, they're going to get further and further behind because what the teacher is saying is just not going to be making any sense to them.  So I think just on those grounds one would want, these kinds of building block concepts, one would want interventions that put them in place at the time that formal education begins.

On the issues of late bloomers, I think there's lots of reason to think that nature is flexible and there are many paths to success and many different rates and patterns that children will follow to get there, and I don't think it follows from any of the work that Jerry or I talked about today.  In fact, certainly not what Jerry talked about, but not the work that I talked about either, that there is one royal road that one must progress down and one specific time table to get there.

PROFESSOR KAGAN:  There's a difference between the ability to reason and where you are in the rank order.  And this is where you are in the rank order.  A great moment for me when I had a sabbatical leave 30 years ago was to sit on the edge of Lake Atitlan in northwest Guatemala with illiterate Mayan Indians who had no schooling and asking 12-year-olds what would happen if the lake dried up and getting perfect syllogistic reasoning.

I agree with the thrust of Liz's talk.  I mean, look at the conditions under humans grow up.  We have to have a basic set of cognitive abilities, but in our societies, technological societies, it doesn't make any difference how good your reason, that's irrelevant.  It's where you are in the rank order because we can have just so many chiefs, and that's the problem.  We don't want to confuse that.  We don't want to confuse the class differences in rank with the ability to reason.  That would be very dangerous.

CHAIRMAN KASS:  Mike Gazzaniga.

DR. GAZZANIGA:  Are you sure we have the time?

CHAIRMAN KASS:  No, go ahead.  Let's take just a few more minutes because we don't want to lose again the benefit of having some questions.

DR. GAZZANIGA:  First of all, I hope everybody appreciates how Jerry and Liz asked these fundamental questions of biology in the most low tech imaginable way with looking longer at a stimulus.  You didn't get into the peek-a-boo experiments, but they're as captivating.  And sometimes I think we should throw our brain scanners out and just give the field to these two and have them answer questions for us.  But once you get past the critical period issue here and where you might have said constructionist ideas were needed to bring the kids along to get them up to the sort of the level of conceptual development that you might just call baseline normal level, but then you've introduced this idea of the social context, so you really don't know what it is that's going on.  Something is going on that's needed in a group of kids.

Now let's imagine that we've got our group of kids up to the baseline level.  And now you're trying to introduce other concepts where people start to differentiate in their understanding of the world.  So you want to teach Newtonian physics versus our natural naive physics.  What then?  What are the tricks you have up your sleeve?  Are there tricks up your sleeve that can bring along the next level of conceptual thinking, and is there a level, a definable level where you start seeing separations that are very hard to overcome on any social group?

PROFESSOR SPELKE:  Yes.  One of the things that I was sorry to have to leave out of my already too long talk was the evidence that when adults reason about number or physics or other things, we bring together the same core systems that we see children using when they assemble these concepts in the first place.  I think the general answer to your question is that at any point in the educational system the way education works is that it builds new concepts out of old concepts and that the way to get a child, a high school student, to understand Newtonian mechanics is not to ignore their intuitive notions of mechanics which are profoundly not Newtonian, right, there's no action at a distance and so forth, not to ignore them but to work with them, to work with them and to build on them and then by connecting them to their intuitive number concepts, to see that there's a problem with them.  And that there's another way of thinking about how objects move, building on what you know about number, that does a better job than your intuitive notions of how objects move, building on this kind of Medieval or Aristotelian notion of things in motion and giving forces to each other.

So I think at every step of the educational system, good teachers intuitively figure out what people's pre-existing concepts are and work with them.  And because in many cases, especially early on in the educational system, it can be extremely difficult to intuit what the concepts are of a child when they're different from yours.  The research can be helpful in helping teachers to understand and that can be helpful for designing curricula that takes those concepts and build on them.

CHAIRMAN KASS:  I'm next in line.  I want to make a comment and then a question.

The comment is partly inspired by Mike's question and your answer.  I understand that the core knowledge is somehow the foundation and one builds upon that, but there really might be certain kinds of real discontinuities and in the area of number you'd have the primary case because the modern concept of number bows the difference between a multitude and a magnitude so that you have a number line to which—a Greek would find it unintelligible. 

A number is a discrete multiple and to have a line in which each point is somehow a number and that you blow the difference between the discrete and the continuous is strange.  And you've got to somehow overturn your fundamental idea of multitude in order to acquire the modern idea of number, but that raises some kind of question about the difference between the things which are somehow naturally ours and the things which are somehow acquired as a result of new conceptual schemes, and some people have a hell of a time learning algebra which is based really upon our Cartesian coordinate system. 

The question and you can comment on that if you'd like, but the question really has to do with the division of labor in this discussion between the cognitive capacities, and let me give to Jerry Kagan not just questions of temperament, but also emotion, motivation and interest.  And I wonder whether this perfectly respectable division of labor doesn't introduce—isn't based on a kind of distortion in which the question is whether crucial to cognition are not just the native capacities for discrimination and awareness, but interest, desire, motivation and concern. 

One could talk about the game playing way of remedying, a board game way of remedying the difficulties in numerosity either as the acquisition of cognitive ability or as actually caring about the matter because there's winning and losing involved and somehow certain kinds of things now come to the fore.  So I'm wondering whether this sort of bifurcation of cognition and motivation or cognition, temperament, emotion and drive, whether that's an accurate representation of how we should be thinking about how children learn. 

Aristotle's remark "all children by nature desire understanding," that's somehow put all human beings, but begins really in childhood.  And I just wondered whether you would comment on how the two sides of the street meet in your own understanding of what we're talking about here.

PROFESSOR KAGAN:  Yes, I'll be brief, and then Liz might want to add.  I don't think temperament has anything to do with it, but emotion does.  As Liz intimated earlier, all humans as a species enjoy mastery.  That's not a new idea.  They enjoy understanding and enjoy using their talents at the next level of challenge.  But we can't run a society that way.  That is, each society has a set of requirements, and we know the requirements for technological societies.  They require reading, mathematics, writing essays.  Those aren't the tasks that come naturally.  So we are forced, we must say to children, I'm sorry, these are the tasks that you have to master.  They are less natural to the human species. 

Now we need motivation, special motivation, acquired motivation.  This is what Liz was driving at, why we need parents.  And because no human being, child or adult, will invest energy at a task they do not believe they would be successful in.  An animal won't do it, and a human won't do it.  So once you have a child in grades one, two, three and four who comes to the decision every child able to do this except those with a damaged brain, that there's no way I'm going to be in the top third of my class.  There's no way that I'm—because there's no idea of absolute skill.  It's always relative, right?  The adults and the peers determine what is called mastery.  And so by grades four or five you lose motivation.  That is the boat we're in and so the task is not to say yes, we won't teach you any reading, what do you wish to do?

The task is to devote more effort to the children who are behind.  And now my last point, not just in America or Europe, in every country, every country where this study has been done, the lower the educational level of the parents, the poorer the academic record, period.   Class is everything. 

There are studies.  NIH spent $50 million on the effect of various forms of day care, home care, home alone.  This is a very famous study.  And when you look at the data, the best predictor of cognitive performance in the second grade is the class, and after that everything else has trivial variance.  This is the issue that we have to deal with.  It's profound.  It's not just—it's our problem in America, seriously, but it's a problem around the world, and we have to get—we have to communicate, we have to do more for those who are less well educated in our society to get them to understand the importance of the task requirements we set for children in our culture.  They don't understand it.  Many of them are fatalistic.  That is a very difficult job. 

Now speaking for myself, I can imagine no more important task this nation might undertake, no more important task.

PROFESSOR SPELKE:  Let me just add that I think—I agree with what Jerry said, but I think that in addition to children having an intrinsic desire for mastery, there's an intrinsic desire for connecting to other people for becoming able to do the things that other people are doing and that this is driving much of the observational learning and of coming to gain the skills that mark the people in their community and in their culture and that, on that basis I completely agree with you. 

Certainly in the preschool years, the division between cognition and motivation or emotion which is useful for figuring out how to organize talks is quite artificial, and any program aimed at children to enhance their cognitive development is going to need to be building on these needs intrinsic to children to be connecting.

If I can just say one thing quickly, though, about the point you made about number, one of the reasons that number is so fascinating is that both in the history of mathematics and in the education that children and high school students and college students go through in studying mathematics now, we see a progression of revolutions in the concept of number.  I think the first revolution is the one I talked about between age two and a half and age four, where children go from having two quite different notions of number, neither of which has the power of the natural number system to constructing the natural number system.  And although this is partly an expression of faith and only partly based on data, I also think that if we turn to the later constructions, understanding of number lines, constructing notions of rational numbers, real numbers and so forth, the general story that one advances to a new level of understanding by taking one's pre-existing understanding, in this case we'd have to look at understanding of points and lines and spatial intuitions, which I didn't talk about at all, but which young children have.  One takes these, one connects them in new ways and often with the help of teachers who can point out what connections are useful, what properties of points and lines are useful in thinking about number?  You then get to a new level of development.

CHAIRMAN KASS:  Briefly, Robbie and then Peter and then we'll break.

PROFESSOR GEORGE:  Thank you.  Anyone who has been a parent or even an older sibling knows what a pleasure it is to observe the reactions that children have to various things.  It must be wonderful to be able to do that in a professional capacity as well and be paid for it.  And, of course, it was very interesting material that you presented to us from so many sources.

My impression is that—I want to ask you about something that hasn't been raised yet, which is research ethics.  My impression is that while anyone who works with human subjects is working under fairly strict ethics rules, that when it comes to working with children there are an even richer set of ethics rules, and I wondered if you could say a little bit about them, and I'm particularly interested to know whether the ethical norms that apply in working with children are truly salient or whether they're mostly or merely symbolic.  In other words, do we sacrifice some knowledge?  Do we sacrifice some advances for the sake of respecting those norms that are meant to protect children?

PROFESSOR SPELKE:  Yes, we do, and I think it's an excellent thing that we do, and one can't subject children and one shouldn't subject children to any of the controlled rearing studies that one can do on other animals.  One would be very wary of subjecting children to any kind of stressful situation.  I mean, our own rule of thumb for our experiments is the parents are always present during the studies.  They should be completely happy at every second for what's going on, with what's going on in the study.  It should be the kind of events that go on in children's lives or that the parents would want to see going on in children's lives outside the lab.  So I think the standards are very high, particularly for research like mine where there is no immediate benefit to that child.  We're asking basic questions about the development of human knowledge.  We hope that the answers to those questions will be a benefit to society, in general, but we have no illusion that the particular child who comes in for our study is going to benefit.  So they better have a very good time and experience no negative consequences from being in the research.

PROFESSOR GEORGE:  Now in foregoing some knowledge for the sake of respecting ethical norms, the norms themselves, I take it, cannot be supplied by science or by scientific reasoning?  Is that right?

PROFESSOR SPELKE:  I don't know about the history, how the ethical norms developed actually.

PROFESSOR GEORGE:  In other words, are they themselves the fruit of scientific inquiry or are they—do they come from another source?

PROFESSOR KAGAN:  No, they come from the consensus of a society that one does not cause distress.

PROFESSOR GEORGE:  And that itself is not a scientific—is it a rational concern?

PROFESSOR KAGAN:  Moral choice.

PROFESSOR GEORGE:  It's a moral choice, but one that comes to science from the outside.  Okay.  thank you.

CHAIRMAN KASS:  Peter's last comment.

DR. LAWLER:  On the basis of what you said, couldn't you argue that they could come from what we know about the distinctive nature of children?  They could come from science, right?

PROFESSOR KAGAN:  I'm sorry, I didn't hear the question.

DR. LAWLER:  The moral norms, the ethical norms, why couldn't they come from—what you two do in such a great way is restore the idea of a distinctively human nature.  We're distinctive in many respects, but we're also natural beings.  We have these potentials which are actualized, right?  So given all that we know about the nature of children in some ways as distinct beings, social beings who take a joy in learning and everything you've said, why couldn't the norms come from what we know through science?

PROFESSOR KAGAN:  I hope you meant that to provoke me.  I hope I speak for Liz.  Science is a wonderful thing.  It's one of the great, great human missions, and those of us in science feel privileged. 

Do not look to science for moral norms.  Science tells us that male primates are promiscuous, therefore we should change the norms of adultery?  No?  No.  Science tells us that most boys are much better at spatial problems like geometry than girls.  Therefore, we probably should have sex segregated classes for teaching geometry.  A referendum next November would be defeated by Americans who are wise.  Wittgenstein understood this.  The ancients understood this.  Jim's written about this in his book The Moral Sense

Morality is very special.   Very special.  It has to do with the sentiment of community, and that lies outside science.  We want to say to the scientists the following.  Thank you.  Those are very interesting facts, very interesting, but in this instance I don't choose to implement them, and that's neither silly nor dumb.

CHAIRMAN KASS:  We're going to stop.  Thank you both, very, very much for a wonderful afternoon and also for the work that you're doing.  This is really eye opening and very important foundational work that will, I'm sure, benefit all of us.

To the Council Members, we're behind as we so often are.  We had left the last hour, it will now be closer to half an hour for stock taking and discussion of development here.  I see there are motions to adjourn.  We can't partly because this Ethics Council is required by law to be instructed about ethics.  We had an ethics lesson the very first time we met.  I think we escaped by somebody's inattention.  I think we require these annually, do we?  And someone forgot to give us lessons in ethics last year, but someone will be arriving at 5:15, so you can't leave.  We'll take 15 minutes.  We'll talk amongst ourselves.  Thank you to our guests.

(Applause.)

(Off the record.)

SESSION 4: NEUROSCIENCE, BRAIN, AND BEHAVIOR III: COUNCIL DISCUSSION

CHAIRMAN KASS:  Could we get started, Dean?  This last session, it will be abbreviated, and it will have to be followed up by some staff work with your advice to take us to the next stage.  This last session, abbreviated because we've been behind for most of the day, is supposed to be devoted to council discussion in which we are to take stock of what we might have learned today, about what new kinds of knowledge and inquiry we would like ourselves to pursue and how to formulate any implicit ethical or social issues that are here, and also to raise for ourselves other kinds of topics in this large area, not only deserving of our attention, but in a way ripe for our attention. 

I mean, there was some discussion at the very end of Dr. Jessell's presentation about how soon one might be able to move between these neuroscientific findings and our interests in behavior, and we got a rather, an answer which says not for awhile, and that means that somehow we're trying to move rapidly from that to some kind of issue worthy of our attention.  Important though those studies were, if one's looking for somehow the secret of preventing abnormal behavior or mental illness, we've got a little time to go.

This is a large and inchoate area.  We are attempting to find out whether this is a topic for us or not, even as we are learning some very interesting things.  I've asked Mike Gazzaniga if he wouldn't mind too, and if you want to wait, I'll sing a song, to offer something in this discussion. 

It was partly, indeed, on the basis of suggestions that you made last time, and Janet and Dan Foster, where the question was well, we really ought to learn something about what people know about normal brain development and early childhood development before we wander off into some more esoteric topics.  The suggestion was well, if you want to—there was a discussion whether we should read these things and treat them as background, or whether we ought to hear them in the flesh from people who are working in the field. 

Speaking specifically for myself, it was very, very good to have the live presentations of people who are in the forefront of these neuroscientific and psychological studies.

Mike, would you be prepared to say something about what have we learned today that's relevant to our own ongoing work, and can we begin to formulate certain kinds of questions for further investigation?   By the way, I'll set a limit on this discussion for today of 5:15, 5:20, so we're not going to go over.  This will be a start, and we will continue with staff prepared papers and the like.  We're not going to cheat on your free time.

DR. GAZZANIGA:  Well, don't worry about my taking the time.  As I reconstruct this in my mind, we were having a conversation last time about possible issues in neuroscience that might bubble up to the level of an ethical concern.  A conversation was starting on those various issues, and some of them are fascinating issues in neuroscience, and they moved all the way from looking at issues of consciousness to issues of determinism and all the like, down to issues of, perhaps, intervention in early education, and what was the nature of what we know about neurodevelopment that might make that rise to the level of ethical concern.

Now, oddly, even though I love all those topics, I'm not really pushing this because I don't know that, given the mandate of this council, that those issues are appropriate for the council in the sense that if we are supposed to be looking at biotech advancements that impact society at large, I think these issues of neuroscience are very active, very fascinating, very interesting, but I don't see any huge issue around the corner that is being provoked by our knowledge of neuroscience.  I may get a lot of pushback on that from my fellow neuroscientists, but that is sort of my take on things.

I think there are things to be discussed, but I don't think there's urgency to it in a sense like there has been with the cloning issue and all that is associated with it.

On this particular issue that we examined today, the point was to sort of bring everybody up to speed on how one thinks about how much comes with the baby, with the child, how much conceptual work is already done by the process that finds us all being humans.  Then in that context, if you understand that, what you might mean about a deeper learning experience, deeper educational experience.

So, here we had today a wonderful discussion on the richness of the concepts that the young child comes with, basically, and the limits on those and then how those are developed and how they're sometimes not met in this critical period and so forth and so on.  So, those are general interests, and unless we want to get into the social policy questions that were raised indirectly or directly by Dr. Spelke, I'm not sure where the ethical question is.  So, I really yield to how you want to think about this.

I don't know—I'm not pushing an agenda here.  I'm just trying to think out loud about where ethics meets the advancements in neuroscience in the context of this council.

CHAIRMAN KASS:  Let me make a small comment on that, and I'm sure others would like to get in on this as well.  I read from the mission as stated in the Executive Order.  "To undertake fundamental inquiry to the human and moral significance of developments in biomedical and behavioral science and technology, to explore specific ethical and policy questions related to these developments."

Ethical questions need not be conundra.  They need not be things that are highly changed, and policy questions need not only be those things about which we are divided.  There seems to be at least a certain human significance to the kinds of work that's being done here insofar as it bears upon early childhood education and the prospects for rearing well the next generation in a world in which we don't do that all that well.

I'm not proposing that that be our focus, but I don't think it would be outside the mandate of this body to think about, and this was the force really of Ben Carson's question and the way of Janet's questions.  How does this somehow translate into education.  Is it too early to offer certain kinds of suggestions there, or is there some kind of social significance of the things that these people are showing us, and should we find out more?

Again, I'm not pushing that either, but I wouldn't say that this is off the table and irrelevant to our mission, at least insofar as the mission is described.

DR. GAZZANIGA:  Just to finish my little—there certainly are large social issues and implications to this.  I think it's a shift in what the council has been considering if we go there.  I just leave it for the council to advise and consent on that.

CHAIRMAN KASS:  Yes, I'm not proposing it as a shift.  I'm not proposing that shift, but I'm saying that it would fall under the larger umbrella that we have. 

Let's see, I had Rebecca and Jim Wilson, and Robbie and Alfonso, and Ben.

PROFESSOR DRESSER:  Well, I wanted to push my—first, one hopes that policy decisions rest on some ethical views or judgments.  So, if you're talking about policy implications, it seems to me underneath there would be policies putting into play some sort of views that about right and wrong or what's good and what's bad. 

You said that some of your colleagues would disagree with you that, you know, it's premature to start talking about applications, but I wondered, what would your colleagues who disagreed with you say are issues that are social issues with ethical implications?

DR. GAZZANIGA:  Well, I say that in the context that we have put out this book called "Beyond Therapy," which addressed a lot of the issues that are currently being discussed within the neuroscience community of enhancements, the memory issues, and all the rest that were reviewed in that book.  So, we're trying to get beyond those.  We've done those, and move forward.

So, if the "Beyond Therapy" effort had not been completed, then we could go through that whole list of things that we discussed for six months.

PROFESSOR DRESSER:  What about free will and criminal responsibility and education?  You can't think of anything?

DR. GAZZANIGA:  I mean, those are all issues.  I'm not sure that the neuroscience twist on it, though, is that tight at this point.  Those are issues that can come out more out of the sort of work that Liz Spelke talked about and then any deep understanding of the neurocircuits involved in learning.

CHAIRMAN KASS:  Jim?

PROFESSOR WILSON:  In order to sharpen the discussion, let me make two different kinds of proposals for what we might do next.  I'm sorry I was not here at our last meeting.  I was traveling on a trip that I much preferred to being with all of you people, much as I admire you.

I think that there are two issues which have policy significance which have deeply involved medical and biological implications.  One we will talk about tomorrow, and that's the problem of aging.  We will hear from Rebecca and Gil and others about how you manage an increasingly aging population when people are trying to assert for themselves some degree of authority over how they shall end their lives or what kind of treatment will be provided.  I think this is a terribly important subject. 

Allied to it is a second subject that is also related to aging, and that is organ transplants.  Medical science has become extraordinarily skilled at transplanting organs.  We're getting older.  The demand for transplanted organs will get greater.

I do not believe personally, without having made a deep examination of this, that we necessarily have a very good system whereby we either collect or distribute organs.  The ethical questions that arise about how you collect them and how you distribute them and indeed what you do with them, it seems to me are very important.

Now, this is a lot different from talking about criminality and free will.  If you're going to talk about criminality and free will, about which I've written a great deal, tell me when you're going to do it because I don't plan to attend that session because I can assure you that there is nothing to say on this topic, having gone through countless seminars about it.

If you want to talk about something where there is a clear bioethical problem, these two aspects of aging strike me as being quite deserving.

CHAIRMAN KASS:  Robbie?

DR. GEORGE:  Well, if everybody's in the mood for another rumble, I can think of a good topic that we could generate a lot of divisiveness about, which is the topic that was suggested in the one area in which our guests made some suggestions towards social policy, and that is education.  Of course, we begin with a shared conviction.  I'm sure everybody believes that it's better for children to be placed in circumstances and given opportunities and resources to fulfill their abilities.  We all want that for our children and for everyone's children.

But it would be interesting to know what the best science had to say about the desirability of putting children between ages two and five in schools or daycare centers or having them in homes, having in mind what Janet said about the inability to completely generalize here and imagine that the answer is going to be the same for everybody.  There are special circumstances.

Even trying to decide that question, I'm sure, would be very controversial, and we would probably divide over it, but gee, I'd like to know the answer to it, and I'd like to know what's out there by way of research that would lead us to be able to at least form some tentative conclusions.

Having said that, let's just say for the sake of argument, and I'm not trying to prejudice the case.  Let's say for the sake of argument that all things considered in most cases, it's rational to conclude based on the science that we would look at that it's better for kids to be between ages two and five, to be at home with a parent, or someone who is functioning very much like a parent rather than being in a school or a daycare center or something like that.

Well, then of course there would be a profound division about how you create social circumstances or what social policies would facilitate that.  I've heard this argued at completely polar extremes.  Some people say that well, what that puts into place is the predicate for the establishment of a true form of socialism where through a heavy taxation system, we would put the government in a position to be able to provide resources that would enable people to keep kids at home who would otherwise have to be in the work force.

Then there are other people who say at the opposite extreme that what created the need for the two earner family was the Constitutional amendment that authorized the income tax and what we should do is abolish the income tax and solve the problem that way.

I can imagine us usefully discussing, although it would be extremely controversial, usefully discussing and having our staff look into and having us read studies about what's best for kids between ages two and five.  I can't imagine us usefully debating then the policy question, should we abolish the income tax, should we establish some form of socialism or something like that.

So, if when we went down this road, I think we could only go down so far, not toward any concrete policy conclusions about how to make it possible for people to have a parent at home, but only looking at the question whether all things considered, our society is heading in the right direction by having an awful lot of kids, perhaps most kids today between two and five, in some sort of daycare situation.

CHAIRMAN KASS:  Yes, thank you.  Let me make a procedural suggestion.  Jim Wilson has added non-neuroscience questions to our agenda.  One of them we will take up tomorrow, and he has put forth the business of organ transplantation.  Let's keep the rest of this discussion still on where we might be on this topic.  We are free to abandon it if it turns out that we cannot make it tractable or focused.  This does not preclude adding other topics, at least for provisional consideration as we go along.  Jim?

PROFESSOR WILSON:  Early childhood education, as you may know, currently involves a major study effort by the National Institutes of Health that involves several dozen scholars around the country.  They regularly produce reports.  The reports are filled with conflicting interpretations about what the data mean, and conflicting ethical arguments about what they ought to mean.

If we're going to look at this, I suggest it will take some deep staff work into what the National Institute has done in this area to see if there's anything left over.  I say this, urging us to bear in mind that in our second reincarnation, we have roughly seven meetings left.

CHAIRMAN KASS:  I have Alfonso, Ben, Peter, and Michael.

DR. GÓMEZ-LOBO: I'm going to contribute to the rambling I guess in a way, but I'm going to go back to the question of neuroscience, just to give you my personal thoughts. 

First of all, I've enjoyed these two meetings, the meeting today and the last meeting tremendously.  I mean, it's really fascinating to hear people who really know a lot about these things, and always initially divided in my mind in the following way.

On the one hand, it seems to me that any ethical concerns would have to do with actions, with what people do.  There I really don't see that there's much going on.  In other words, no one seems to be proposing sort of radical interventions into the brain so as to make people, you know, different or something like that.  I mean, Mike has shown that rather clearly.

So, that concern on my part has faded away.  I just don't see that there are ethical issues along those lines.

My second concern had to do more with questions in ethical theory.  Now, one of them was to what an extent progress in neurology was driving us away from ethics and from the replies we heard today from Professor Kagan, et cetera.  I'm reassured that there's a big gap there and that in no way are we giving up issues of freedom of the will or that.

Now, the last thing about which I was concerned, and it's connected to this, were issues connected with the presentation by Professor Jonathan Cohen last time.  I thought they were quite fascinating, and I tried to think about them, not necessarily because they were new.  I think that the emotional reaction to certain kinds of actions is known for a long time.

It became clear to me later on that his field is really a field very different from ethics, in fact, because even if a PET scan tells you what the reaction of certain agents are to certain kinds of actions, that, unfortunately, does not tell us anything about whether it's true that those actions are morally right or morally wrong.  That, in a way, put me to rest because it means that we are really in a world of multiple dimensions in which we have to think about certain domains in certain ways and about other domains in other ways.

So, in a way, I'm at peace, if I should say so, with everything that I've heard right now.  Now, that said, it seems to me that Jim is pointing in a very promising direction.  As far as I can see, aging and connected with that the questions of justice related to organ transplantation are really going to be pressing issues, and I think issues that will demand public policy and therefore will demand some kind of ethical advice.

CHAIRMAN KASS:  Ben?

DR. CARSON:  If, in fact, there is scientific evidence, as was suggested this morning, that the intrauterine environment can have a positive effect on the potential of a child, and if in fact it is true that a caring and nurturing environment can improve their subsequent intellectual performance, I guess an ethical question becomes do we as a society have a responsibility to at least disseminate this information in a wide fashion and try to facilitate both the pre-natal and post-natal environments for all of our citizens.

CHAIRMAN KASS:  Thank you.  Peter, Michael, and Gil, and then we will halt, just arbitrarily.

DR. LAWLER:  I would like to agree with Jim Wilson that our main focus probably should be on questions concerning an aging society, but I'm not a scientist, but I do think science is a very high human good, and I do want to become more rational.

With this in mind, I was really fascinated by the presentations today.  I agree with Alfonso.  I'm at peace with them.  I don't see any lurking danger to anything that we need to deal with immediately or anything like that.  It does seem like in many respects, neuroscience is in the early stages of development and so forth, but it does seem to me it's really important.

One breakthrough I noticed in the materials we read and what we heard is that basically behaviorism is dead.  Basically in a certain way, sociobiology is dead because we're now getting solid scientific evidence that many of our distinctively human qualities, like for example, language, have a natural foundation, that they're innate in some sense.

So, it might be, from a theoretical point of view, good to reflect on this, but I'm not quite sure what public policy implications would derive from this, and it might be as interesting and as futile as free will versus determinism finally.

Nonetheless, in my project to become more rational, if someone could conceive a way of studying this with public policy implications, I'd be all for it.

CHAIRMAN KASS:  Michael Sandel?

PROFESSOR SANDEL:  Well, Leon, after the lunch break, you addressed some rumbling doubts around the table about the practical and ethical public policy implications of the kinds of presentations we were hearing today, and I for one was greatly heartened and relieved when you tried to address those doubts by saying well, it would take us back to Lucretius, these issues.  We have an expansive executive order that would encompass Lucretius, and that's good enough for me.

CHAIRMAN KASS:  I said we were going to bracket the Lucretian question, and we were going to learn something about the science, but never mind.

DR. GEORGE:  But we also heard about studies described as classical studies from the 1970's.

PROFESSOR SANDEL:  So, Lucretius would please me, but thinking about what really will sustain a project for this council.  I think that in the neuroscience area, what worked, what was stimulating, what educated us, and Alfonso says he's at peace now, which worries me because I like Alfonso when he's agitated.  That's what makes things interesting.  So, I would oppose any topic that would leave Alfonso at peace.

I think that what agitated all of us and excited and intrigued all of us about the neuroscience topic were the two provocative presentations of Pinker and Cohen.  That's what got this group interested in neuroscience.  The thing about brain imaging and cognitive mapping and what were the implications for free will versus mechanism and what were the implications for responsibility and maybe ultimately for criminal responsibility.  So, people got all excited about that, and we were in a combat, some of us, with Pinker and Cohen.  That was interesting.  That was the part of neuroscience that seemed to be sort of rich with implications for ethics.

But as we delve into sort of the main lines of work and research in these sessions today, it turns out that that's more, if we're framing a project, it's not easy to frame a project around the topics that excited us and interested us with the Pinker and the Cohen.  The mundane state of the discipline doesn't really lend itself, I don't think, to a project that we can really usefully undertake.

So, my suggestion would be that we shouldn't take up the neuroscience thing after all.

CHAIRMAN KASS:  That we should not?

PROFESSOR SANDEL:  Should not, and instead maybe the aging and the elderly thing will have something useful.  I would go back to Jim's idea.  Organ transplants not necessarily by itself is a topic but is one way of getting at the broader question that we've toyed with taking up before, the issue of commodification of the body, organ transplants being one practical question that's looming on the horizon that would enable us to take up the commodification question.  Listening to the presentations today, I think we'd be better off with that than we would with the neuroscience.

CHAIRMAN KASS:  Mike, did you want a quick comment to this?

DR. GAZZANIGA:  Well, at the risk of being inconsistent.  So, let's take Jim's concern about aging, and let me raise a question that neuroscience has a lot to speak about, death of the person versus death of the brain.  Now, that will get you all going.

There are many, many current brain imaging studies that touch on what we know about the parts of the brain that are involved in self and parts of the brain that have to be active in various states of conscious experience and so forth and so on.   The model is that right now, Dr. Carson would know about this more than I do, that in cardiology, the current cardiologist is faced very commonly now with the ethical question, a patient comes in who has a pacemaker in them and it's working fine and it's sustained their life, and now other diseases have caught up with them, and they want the pacemaker turned off.  It's a tough decision. 

Some doctors won't turn it off, some will.  They want it reprogrammed.  They want to check out.  They've had enough.

It's easy to imagine down the pike that they're going to be—there's already deep brain stimulators that have this wonderful effect on some Parkinson's cases.  There could be similar critical implants in the brain that are life sustaining, and then the question is if other things catch up with the patient, some form of cancer, heart disease, and if it's the brain, does the medical community have the right to turn this off after they've turned it on, and how do you think through that moral issue.

So, one could get back into it real quickly.

PROFESSOR SANDEL:  Then that would be one subset under the general heading of end of life issues, which would be fine.  That wouldn't be neuroscience as a broad category as we've been thinking of it here.

CHAIRMAN KASS:  Gil, please?

PROFESSOR MEILAENDER:  My first and last view on this is also doubt whether I really see a way forward for us.  Having said that, I mean, I do think there is a project here.  I just don't know whether we're the people to do it, or we're up for it.

I think that what Professor Spelke gave us this afternoon was in some ways a bunch of empirical evidence in support of what, if I'm remembering correctly, Kant called something like the transcendental unity of apperception.  So, there are profound questions about the relation between behavior and biology that were raised here, and questions, Alfonso, that aren't so clear to me.

In other words, if there are structures that are really given, what does that—does that have any implications for morality or not?  I mean, there are very deep questions that could be raised there, and I think we could do something interesting, or someone could do something interesting on that.

It would not be the kind of project that had immediate public policy implications.  It would be more like Beyond Therapy in the sense that it would simply seek to educate the public about some very deep issues which are never going to go away, which are very old and are just raised in different contexts now but are still always worth thinking about.

So, I would have no objection in doing that.  I think it could be very useful and provocative in various ways.  Having said all that, I'm not sure I see a way forward for us to do it or whether we're the body that's up to it in a way.

So, I do want to go on record as saying I think there's a serious project actually here of deep philosophical import, but I'm not confident that it's wise for us to really try it.

CHAIRMAN KASS:  Good.  Let me make a procedural suggestion here.  Speaking simply for myself, I'm not ready to toss in the towel on this, partly because, as I said at the beginning of the day, the background here today, the purpose of the day was to give us some fundamental background and to see whether on the basis of this foundation we could then develop the kind of project that would suit this body, focused with some kind of practical implications, not without some theoretical or deep human significance, but not to have a simply philosophical project like "Beyond Therapy."  I would agree with Gil.  That's not for this group.

There were topics tossed out before about neural imaging, its promise, its perils.  However primitive it is, people are making use of it for all kinds of purposes, and we could do a service simply to call attention to how much is known and what the possible misuses or good uses of that would be.  That would be one thing.

There are other people who are talking about the re-emergence of deep brain stimulation and various other kinds of interventions in which the question is not whether you just turned the machine off, but what actually does this mean for questions of autonomy and control and the like.  We could begin to at least explore some of the sub-areas, both of a technical sort that does raise ethical and social questions.  It's not for today.

What this discussion shows me at least is that if this project is to go forward, I and the staff have to do some hard work with your advice, to put together a working paper to try to focus this somewhat before we bring anything back to you for the next meeting, and we'll take that as our assignment, mindful of the fact that there's at least some skepticism around the table as to whether there is a clear enough focus in this neuroscience area.

The importance of this stuff is, I think, clear.  There's no sense that there's anything ominous here about which we have to go ring the alarm bell, but this is science coming home to work on certain fundamental things of our humanity, and we would be foolish, I think, if we simply turned away our eye, especially when no one else has bothered to take it up, and neuroethics is a growing field, and the train shouldn't leave the station without our at least paying some attention as to whether there's something here ripe for our attention—weighty, ripe, and doable.

We have to go to an ethics class across the hall in the break room.  Someone is waiting for us there.  The formal session is adjourned until tomorrow morning, 8:30 we will convene.  I'm happy to say that our colleague, Bill May, will be with us.  He is the senior consultant on this aging project, and will be joining us at the table.

(Whereupon, the above-referenced matter was adjourned at 5:23 p.m., to reconvene the next day at 8:30 a.m.)


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