FRIDAY, December 3, 2004

Session 6: Seeking Morally Unproblematic Sources of Human Embryonic Stem Cells

Howard A. Zucker, Department of Pediatrics, College of Physicians and Surgeons, Columbia University

Donald W. Landry, Professor of Medicine, College of Physicians and Surgeons, Columbia University

Council Member William Hurlbut

This council, I think, has distinguished itself in the discussion of these questions, notwithstanding our sharp differences of opinion about the conclusion, in recognizing that all parties to the existing debate, in fact, have something vital to defend — not just for themselves, but for all of us.  We have recognized the importance of the scientific research and the medical benefits to which it will lead.  We recognize the supreme and important value of respecting human life, indeed in all of its stages.  People may differ about how much respect and at which stage, but these are important human goods and it would be very exciting if ways could be found in which these two goods did not have to be pitted against one another, but, in fact, could be embraced by all people whichever way they pitch the balance amongst them.  And therefore it's, I think, of great interest to this council that we have for presentation today two such proposals: one presented by Howard Zucker and Don Landry, both from the College of Physicians and Surgeons at Columbia University, Howard Zucker from the Department of Pediatrics, Don Landry from the Department of Medicine.  And their proposal, which we will have had occasion to read, talks about the possibility of deriving human embryonic stem cells from no-longer-living, not merely just non-viable, not merely doomed-to-destruction, but actually no-longer-living embryos. And our own colleague, Bill Hurlbut, has a proposal for deriving — that would enable people to derive human embryonic stem cells from embryoid-like bodie,s but which are not in the strict sense embryos proper.  We look forward to the presentations.

I should say, so that there won't be any misunderstanding, these are not at the moment presented as council proposals.  The council is simply eager to hear about this and we will see in the discussion afterwards what council members think about these things. But first, we have to inform ourselves about them both with respect for the question of the ethical issues and of the scientific feasibilities.  So Howard Zucker and Don Landry, welcome to you and the floor is first yours and then we'll proceed to Bill.

DR. ZUCKER:  Thank you, Dr. Kass, and Don and I would like to thank the entire Bioethics Council for giving us the opportunity to present before this illustrious panel.  We recognize that the stem cell controversy has resulted in a very polarized and heated debate but it is our personal opinions that there is a common ground for medicine, for law, science, and ethics that can be reached, and we published this view in the Journal of Clinical Investigation last month which you all have a copy of.

Scientists cannot go anywhere without a laptop and visuals and so, in the interest of efficiency, Don will present our paper, after which we will be happy to answer any questions that you have for us, thank you. 

DR. LANDRY:  I also thank you for the opportunity to present our ideas to you.  Let me say also that I'm Director of the Division of Experimental Therapeutics in the Department of Medicine at Columbia.  I don't engage in stem cell research, so I don't have a vested interest in this beyond that of a concerned citizen.  I do take care of critically ill patients in a small private practice and I think it's the context of seeing death in a close and personal way and seeing the issues of organ donation that informs to some extent the ideas we're going to present today.

I'm going to present some things that are painfully obvious to you but I think are important just to state the premises upon which the proposal was based.  The creation of human embryonic stem cells involves the destruction of an embryo, well known to you.  What that means to an individual depends on how they answer certain questions.  When it's formulated in the most general sense, when does life begin, it doesn't make very much sense to me but these are my answers to these questions.  Life begins two billion years ago, human life begins 200,000 years ago.   A new human life, a new human being, a genetically unique entity begins at conception.  A human person, however, is not a question — the origin of a human person is not a question that science alone can answer.  And so this tension between human being and human person results in a conflict.  We have on the one hand a requirement for respect, for human dignity, to treat humans as subjects and not objects, pitted against the drive to relieve human suffering. 

And there is no easy compromise.  This is not an economic matter.  The differences cannot be split.  And so between, on the one hand, persuasion, which is difficult to achieve, and imposition of will, which is unseemly, there's a third way, a search for a common ground, which I think is one of the central activities of this committee.  Our general notion is that death is such a common ground because the death of the human being subsumes the death of the human person and so whatever the disagreements about the origin of a new person, with the death of a new human being that issue of person is also resolved. 

Some background from the death of a developed human person can inform our thoughts on the death of the developing human person, and so just a quick review of some recent history and our notions of death for developed individuals.  Prior to the 1960s going back for thousands of years, irreversible cessation of cardiopulmonary function was the definition of death and improvement in respiratory technology led to a crisis.  It was possible to maintain ostensibly dead individuals for extended periods of time and this crisis was addressed by an ad hoc committee of the Harvard Medical School with a definition of irreversible coma that becomes the basis of our modern notion of brain death.

And in that context of a definition of brain death, not driven by it but in the context of it, cadaveric organ donation went from speculation to standard of care and so I would abstract from this slide the idea that the availability of material, if obtained in an ethically reasonable fashion, can actually drive research and drive progress. 

Some comments also about the legal definition of death.  First of all, it's a specific question of fact, not a question of law, and so it's determined by physicians.  And yet there are legislative attempts to codify it.  Originally, there were two separate definitions of death contingent on the desire to harvest organs, clearly a problematic issue.  This was resolved by Capron and Kass in 1972 articulating a single concept of death, but application of a particular criterion would depend on the circumstances, the circumstances of machinery maintaining a dead individual that makes the application of one or another criteria particularly difficult or facile.  A variety of laws follow, tend not to precede some consensus on the issue and we conclude with the Omnibus Reconciliation Act of 1986 that, at brain death, the removal of vital organs for transplant is legally and ethically permitted.

We have criteria for brain death.  Our notion is an irreversible action critical in brain stem function that gets translated through observational studies, when does someone no longer wake up, finally to diagnostic tests, unresponsiveness to pain, inability to breathe off ventilators, certain eye movements upon putting cold water in the ear canal, a flat EG and the absence of conditions that might otherwise suppress EG activity.

Embedded in all of this is the concept of organismic death, the human — the adult or developed human that has died is not thoroughly dead.  Organs are alive, they're available for transplant.  The tissues that make up those organs, the cells that make up those tissues are alive, and so we like to extend this idea to the developing human. The developing human, just as for the developed human, is more than the sum of the lives of constituent cells, and so just as the nervous system integrates tissues and organs in the developed human, so too there's a system of chemical communication and surface recognition that integrates cells in the developing human.  Deprived of the necessary internal signals, an irreversible arrested cell division can occur.

Our specific proposal, then, is a new definition of death for the human organism, an organism in development, and that is the irreversible arrest of cell division. 

Now, what are the prospects for producing normal cells from dead embryos?   Just as a backdrop to this consideration, consider for a moment that 60 percent of IVF embryos fail to meet criteria for viability.  Non-viability is one of those vague terms.  It's an incapacity to develop to live birth and so it contains a number of categories embedded in it, but there is a morphologic criterion, abnormal appearances of one sort or another, also a functional criterion, failure to cleave at 24 hours.  Important to note, non-viability does not mean dead but the functional criterion, cleavage arrest, likely correlates.  Now, cleavage arrest most often reflects various genetic abnormalities and this might seem to eliminate any prospect for some useful development occurring from these considerations, not that the considerations are invalid but that nothing good would come of them. 

But there are several studies, two that I include in the binder, and summarize very briefly here, that suggest some prospect for producing normal cells from dead embryos.  So Laverge et al observed mosaicism and, briefly, from 166 frozen embryos that were thawed, 78 remained arrested at 24 hours, 71, no further sign of cleavage at 48 hours, and fluorescence in situ hybridization, which allowed examinations of chromosomes X, Y and 1, on all blastomeres of 63 arrested embryos, was performed.  Eighty percent showed chromosomal abnormalities.  Aneuploidy, severe aneuploidy was common but mosaics were present with normal diploid blastomeres embedded in this sea of abnormality.  Voullaire et al also observed mosaicism, 63 blastomeres from 12 unselected embryos thawed after five years of cryopreservation, two out of 12 were in cleavage arrest, partial arrest was observed in others. 

In this case, they used comparative genomic hybridization, a powerful technique that's able to look at all chromosomes with the exception of several that overlap, 17, 19, 20, 22.  Again, they noted marked aneuploidy, very common but also the eggs were identified —

PROF. WILSON: Excuse me.

DR. LANDRY:  — with no diploid blastomeres in five of 12 embryos.

PROF. WILSON: Could you define aneuploidy, please?

DR. LANDRY:  Aneuploidy is multiple copies of chromosomes, and so, instead of the normal diploid, we can have tetra and beyond, sometimes five full sets of chromosomes, and this is a marked abnormality that does not bode well. 

Now, if one could obtain live cells from dead embryos, are they truly normal, what is their developmental potential?  I've presented human data till now.  This is the one bit of animal data that I'm going to mention but it's so marked that — and understanding limitations in animal data, it's still worth mentioning here.  In one experiment, cloned tadpole embryos showed 99 percent irreversible arrest, 95 percent early on, 99 percent overall.

Now, cells from arrested blastocysts were aggregated and an individual cell is injected into a normal tadpole blastocyst.  Twenty-five percent resumed division and were stably incorporated into differentiated tissues, becoming muscle, for example.   And so blastomeres from an arrested embryo can be reprogrammed for differentiation and growth if placed in the proper environment.  And this is a natural environment, but in principle it could be an artificial environment made up of cell surface proteins and various chemical mediators. 

Back to human data, an experiment by Alikani and Willadsen, 107 "non-viable" human IVF embryos were disaggregated.  Two hundred forty-seven intact cells were isolated and they were combined in 36 aggregates, approximately six to seven cells per aggregate.  Thirty-three percent of these went on to develop and form normally organized blastocysts with defined inner cell masses, again indicating that a new environment can re-establish growth and development.

So a summary; we're proposing a new definition for human death, irreversible arrest of cell division.  The criteria for determining irreversibility would begin with the natural history study of cleavage arrest and progress to biochemical markers for irreversibility.  Many embryos generated for IVF are organismically dead.  Aneuploidy is present but, due to mosaicism, normal cells are found and it's at least arguable that they could have normal developmental potential. 

The signals required for transforming blastomeres into stem cells without recourse to the formation and destruction of human blastocysts is an area of current research.  Interest in this area would increase markedly if, in fact, there were material to pursue this work.  And we propose an ethical framework for investigating embryonic cells from organismically dead embryos, and this framework would parallel the cadaveric donation of central organs with consent of next of kin, in particular organs donated from children with the consent of parents. 

So, in conclusion, application of the ethical framework for central organ donation to the harvesting of human embryonic cells from organismically dead embryos maintains respect for human dignity and can advance biomedical research.  Now, two corollaries that do not appear in the paper but I would be interesting in hearing your thoughts on: with a clear and clean recognition of embryonic death also comes the recognition of embryonic life in extremis.   And one can apply the ethical norms for research on a patient in extremis, which are different from the average patient, to the embryo in extremis.  And so, for example, the extraction of a single blastomere from an embryo in extremis would not seem to be an enterprise that would have severe ethical or moral problems.  And I've engaged in research on adults in extremis with the approval of our IRB, engaging in interventions that would not be permissible with someone not in the last few hours of life.

This is not an idle consideration with respect to the embryo.  Consider on the one hand organs harvested from an executed prisoner, mesenchyme from an aborted fetus, versus cells obtained from an IVF embryo that died despite best efforts for its life.  It would seem that there's a very bright line separating these.  What if cells from a cryo-preserved embryo that is thawed after five years of storage and allowed to succumb, some may feel this is all right, some may feel it's problematic but certainly an embryo in that position is in extremis, and harvesting a single cell a potential risk but not a lethal, unnecessarily lethal event, might be considered morally acceptable.  And that concludes my remarks, and Howard and I are available to answer questions as best we can.

CHAIRMAN KASS:  I think that — let me suggest that we discuss each of the presentations briefly rather than have them both together and to raise any kind of technical question.  The presentation was luminously clear as is the paper.  I mean, I think everybody understands what this is about, so there might be people who have either technical questions about the scientific feasibility or what we might know about the likelihood of this, but let's take at least a few minutes to make sure that everybody understands what they need to and get ideas clarified.  Then we'll have Bill's presentation and then we can discuss the two things together.  So the floor is open to Doctors Landry and Zucker.

Now, Paul McHugh?

DR. McHUGH:  Just one question; you told us you could take a cell out of an embryo that you had demonstrated aneuploidy in the embryo and then those cells would reproduce when placed — this, I guess, was the tadpole work.  Aneuploidy cells can reproduce and they produce cancer.  How will we be sure that this method won't technically lead to the implantation and the use of cells that will have cancerous potential?

DR. LANDRY:  You can simply screen for that.  The cells you isolate, you know, are grown.  You can take one of those cells having now grown and analyze it, so I don't think there would be any risk of cancer in that circumstance.

DR. McHUGH:  Even after you've transplanted them?  I just need to understand the technology a little bit.  You have this embryo.  You say you find aneuploidy in it in various cells.  You find 33 percent of them will grow later in the tadpole.  Were those 33 percent of cells you grew in the tadpole demonstrated to lack aneuploidy in every one of them?

DR. LANDRY:  No, and remember that we're not suggesting that this be used for reproductive purposes.  This is meant for in vitro use and as such, while it's always possible that there could be unforeseen events, one gets to observe these cells for extended periods of time.  I mean, after all, the ultimate objective of stem cells, stem cells are indefinitely reproducing ideally by definition, and so it's possible to go and at any point now having produced this cell, to examine it and one would seek to eliminate, for instance abnormalities such as marked aneuploidy and —

DR. McHUGH:  Let me just continue on this because I just want to be sure I've got it.  And sticking with the tadpole experiment, the cells that were later put into the tadpole from frog embryos that were known to be non-viable for a variety of reasons including aneuploidy, that those cells had gone through a sufficient phase themselves to know that they did not carry an aneuploidy potential and a cancer potential.

DR. LANDRY:  The experiment on tadpoles involved arrested embryos.  They were not examined for aneuploidy. 

CHAIRMAN KASS:  Gil Meilaender?

PROF. MEILAENDER:  What is luminously clear to our Chairman is not necessarily so clear to me.  So can you just explain to me or help me be sure I'm clear, cleavage arrest correlates with death of the embryo according to your proposed definition.  And that's the — so that's the test that you'd use to determine whether an embryo was available for use in this way, and would you therefore be using some embryos which were dead and some which were conceivably still living according to your definition?  That's what I don't understand in terms of the correlation business. 

DR. ZUCKER:  They would be dead — if they're at 24 hours, they are not cleaving and 48 hours they're not cleaving, those are dead.  They wouldn't be — that's the concept that they would be organismically dead at that point.  It wouldn't be that we would take cells that were then dividing further and try to redefine that as being dead.

DR. LANDRY:  And the precise moment, also is something that's open to a natural history study and observation.  So the precise moment when, you know, a group of disinterested observers would reasonably conclude that death has occurred is — and to devise a definition for death, would occur as a result of observation by analogy to observations of, you know, comatose patients. 

DR. ZUCKER:  And as Don mentioned in the presentation also that we would be able to find specific markers to match up with cleavage arrest.

CHAIRMAN KASS:  What begins as phenomenological account of the natural history of this would then be supported by the discovery of various kinds of biological markers that would give one confidence that cleavage not only hasn't occurred, but isn't going to occur.  I think that's the —

PROF. MEILAENDER:  So it was luminously clear to you and it was luminously clear to you and not to me.

CHAIRMAN KASS:  It was not luminously clear to you.  Other — yes, Robby George.

PROF. GEORGE:  Thank you.  I'm trying to see if I understand what is new in what you're proposing and what is not new.  It sounds to me — and please correct me if I've misunderstood you — it sounds to me as though you're not proposing a new criterion of death or a different criterion of death.  It sounds as though the criterion of death you're proposing is what we might now call the standard one of the complete and irreversible loss of integrated or integral organic functioning.  Is that right?

DR. LANDRY:  I would call that the concept.

PROF. GEORGE:  It's the concept of death.

DR. LANDRY:  And then the criterion is what you take down from that concept.

PROF. GEORGE:  So the concept of death is the same whether we're talking about, you know, an 80-year old person or we're talking about an embryo.

DR. ZUCKER:  Correct.

PROF. GEORGE:  And so now what you're looking for is what is the reliable evidence and I guess this you would then call a criterion?  All right, what is the reliable evidence of the complete and irreversible loss of integrated organic functioning.

DR. LANDRY:  Correct, so we would define it as arrested cleavage and then the criteria for defining that arrested cleavage would come down from that, a certain amount of time, the absence of Oct4, you know, a series of biochemical markers in its fullest state.

PROF. GEORGE:  Okay, so just again to be very clear, there's no proposal here for a new concept of death —

DR. LANDRY:  No.

PROF. GEORGE:  — in order to accommodate the harvesting of stem cells from embryos.

DR. LANDRY:  No.

PROF. GEORGE:  Okay, a second point, just a minor point of clarification, I was interested in what you were saying about the legitimacy of interventions on patients, and let's again consider say an 80-year old person in extremis, that you were saying there were circumstances in which it's ethically legitimate to do certain things to patients in extremis that you couldn't do to patients who were not in extremis.   And I wonder if — what the norms are governing those interventions.  Are such interventions legitimate but only when the purpose is to benefit or attempt to benefit the patient himself, or is it sometimes permissible to do some things to patients in extremis that you couldn't legitimately do to patients not in extremis, not for the benefit of those patients but for the benefit of others?

DR. ZUCKER:  I guess one of those, you can use the analogy of a chid who is critically ill lying there in an intensive care unit and needs to be placed on let's say extracorporeal membrane oxygenation or life support, and one may say at that point that that person, you're doing a procedure on somebody and providing a new therapy obviously through an IRB that you wouldn't routinely do on other patients that weren't at that teetering on the edge, and in the same way, we would feel that — as Don mentioned before with the embryos in extremis, you could make that analogy.

PROF. GEORGE:  Perhaps I'm being obtuse here, but —

DR. LANDRY:  Since I've actually done this, maybe I can —

PROF. GEORGE:  Go ahead.

DR. LANDRY:  Maybe I can just —

PROF. GEORGE:  Please.

DR. LANDRY:  Okay, we're dealing with patients in extremis and by definition the intervention we're engaged in is not going to benefit that patient.  It is not anticipated that a patient in the last few hours of life is going to be pulled from that moment by the intervention.  With the approval of the IRB, with the assent of next of kin, it's possible to, for instance, provide experimental drugs to observe their physiologic effect, understanding that it's not a therapeutic effect.

PROF. GEORGE:  I see.  So it would be to benefit others and it would be considered legitimate.  But it wouldn't be considered legitimate to do precisely the same thing if a patient were not in extremis.

DR. LANDRY:  Exactly.

PROF. GEORGE:  And this is an accepted norm of medicine.

DR. LANDRY:  Right, accepted norm.

CHAIRMAN KASS:  Gil, I think, wants in on this subject.

PROF. MEILAENDER:  Yeah, just the very same thing; you wouldn't extract the organs of that infant, though, right?

DR. LANDRY:  No, no, we're not talking about activities that would kill or that would immediately hasten death, but activities that might entail some risk and yet you would argue that, in the last few hours of life, that risk is less than incremental to that person at that time.  Of course, if they're looking at the next 80 years of their life, then perhaps this is not a risk that should be undertaken on their behalf.  And so removing a cell from an embryo that's about to expire, that activity  not killing the embryo necessarily although entailing a risk to that embryo if we wanted to implant that embryo, we could take direct analogy from that activity and the activity of experimentation in developed humans.

CHAIRMAN KASS:  This really — this matter if I understand, what you would be talking about would be the equivalent of single blastomere biopsy that's used say in PGD which, though we haven't had the studies to give us absolute confidence in this, there are lots of children who have been born perfectly, apparently perfectly normally, so that the removal of a biopsy or the removal of a cell is already practiced in that case, I suppose you could say for the benefit of that particular individual.  Here you would not be adding any extra risk and the act would be no more dangerous to that embryo in extremis than that act is to an embryo that's headed for implantation in the diagnostic procedure at PGD.

DR. LANDRY:  Yes.

CHAIRMAN KASS:  Is that —

DR. LANDRY:  That's correct. 

CHAIRMAN KASS:  Now Gil.

PROF. MEILAENDER:  But these are two different sorts of justifications that you're thinking through.  Am I right about that?  That is to say one sort of justification is if we have an embryo that in terms of the criteria you've developed is dead, we may use it in these ways.  The other sort of justification is that the rules for what we may do experimentally with a human organism change when the organism though not dead is in extremis.  That's a different kind of justification.  Am I correct on that?

DR. LANDRY:  That's why I included it after the conclusion.

PROF. MEILAENDER:  Yeah, and that general issue there's actually a long history of discussion and argument about and I would be more inclined to worry about — I would want to think that one through considerably more.  It gets to do with the issue about whether equal treatment must involve identical treatment, whether you can wrong someone without harming them and various kinds of questions like that and there is a long history of discussion about that.  So I just want to be clear, these are two different sorts of justifications, and one might be persuaded by one but not the other, for instance.

CHAIRMAN KASS:  I want to turn to Bill, but only if there aren't any questions to simply clarify what this proposal is so that everybody should understand what Doctors Zucker and Landry are proposing here.  Alfonso and Jim Wilson, I think, have technical questions rather than argumentative ones.

DR. GÓMEZ-LOBO:  Yeah, this is, I think, a clarification question.  Of course, from a moral point of view, it seems to me the idea of using cadaveric tissue for instance, should be less problematic but I think we shouldn't forget that there's going to be questions about the cause of the death or what led to the death.  I'm thinking out loud about the circumstance in which say, a child or an older person is about to die, the death is expected, in order to extract organs in circumstances, say, where a rescue could have been possible.  So I'm just leaving that question open, because it is going to be ultimately of importance for the moral judgment on the whole project.

CHAIRMAN KASS:  Jim Wilson. 

PROF. WILSON: Should your techniques prove with further scientific inquiry to be valuable and the removal of non-viable embryos can become a routine medical —

DR. LANDRY:  Don't use the word "non-viable".

PROF. WILSON: I understand.  What would you like?  I like the —

DR. LANDRY:  Organismically dead.

PROF. WILSON: Organismically dead, thank you.   But at one point in their history, they were —

DR. LANDRY:  They were alive?

PROF. WILSON: Yes.

DR. LANDRY:  If they were classified as non-viable, they may have been dead, dying or doomed but we would restrict, you know, our inquiry to those that are organismically dead.

PROF. WILSON: Organismically dead, fine.  My question is, should this procedure become widespread, what would be the source, the principal source of these organismically dead entities?

DR. ZUCKER:  The IVF embryos that are presently frozen that then would be thawed for the purpose of creating life.

PROF. WILSON: And they would go through the test you've just described.

DR. ZUCKER:  Correct.

PROF. WILSON:  Thank you.

CHAIRMAN KASS:  Bill.

DR. HURLBUT:  Can I ask you what stage of development you anticipate most of these cells would come from?

DR. LANDRY:  Eight to 12 cells.

DR. HURLBUT:  It's my understanding that nobody's ever seen a single eight-cell embryo lose seven of its blastomeres as often happens after freezing and thawing, but is it absolutely clear that a single cell from an eight-cell embryo cannot form a full embryo?

DR. LANDRY:  That's our understanding.  And if evidence came to the contrary, then we would move to 12 cells but the idea is to avoid any question that that cell could by itself go on.  The loss of aggregate cytoplasm when you're dealing with a single cell out of eight, would seem to preclude it.

DR. HURLBUT:  Yeah. 

CHAIRMAN KASS:  Let's just stop on this and invite Bill to make a presentation of his proposal and then we'll follow the same procedure and we'll still have some time to discuss both of these together and what we think about it. 

DR. HURLBUT:  Thank you.  So what I want to say has some similarity to the previous proposal.  Death is the loss of potential for future life through the disintegration of organismal life.  What we propose is the creation of entities that never rise to the level of integrated organismal existence essential to be designated human life with potential.  I want to present some ideas that seem worthy of discussion and possibly preliminary scientific investigation.  Those of us who have been working on these ideas have already explored some of the philosophical and technical dimensions but there are important theoretical and practical issues that need further consideration. 

We offer these ideas not as an assertion of certitude but as a promising avenue of inquiry, one that might move us beyond our current conflict over the procurement of embryonic stem cells by providing a third option, a technological solution to our moral impasse.  In the broadest sense, we propose a creative exploration of a full range of scientific approaches.  More specifically, we raise the possibility that, using the technique of nuclear transfer, it may be possible to produce embryonic stem cells within a limited cellular system that is biologically and morally akin to a complex tissue culture and thereby bypass moral concerns about the creation and distruction of human embryos.

I want to make two points very clear from the beginning. What is proposed here is a concept, an approach to a problem.  The specific examples, which may or may not be morally acceptable or scientifically feasible, are offered only to make clear the larger concept as a starting point for discussion.  Second, we are at the stage of a constructive dialogue; if these ideas are deemed feasible, extensive studies with animal models must follow.  We do not propose any projects involving human cells until we can be certain that embryos are not created by these methods. 

The present conflict over the moral status of the human embryo reflects deep differences in our basic convictions and is unlikely to be resolved through deliberation or debate.  May Americans oppose embryo destruction for the procurement of embryonic stem cells, believing that there is an implicit dignity and inviolability in the individual continuity of a human life from fertilization to natural death.

Many others, however, believe that the benefits of advances in biomedical science outweigh these moral concerns.  A purely political solution will leave our country bitterly divided, eroding the social support and sense of noble purpose that is essential for the public funding of biomedical science.  While there are currently no federal legislative constraints on the use of private funds for this research, there is a consensus opinion in the scientific community that, without NIH support for newly created embryonic stem cell lines, progress in this important realm of research will be severely constrained. 

Notwithstanding this apparently irresolvable impasse, we believe there may be morally uncontroversial ways to obtain embryonic stem cells.  Drawing on our increasing understanding and control of developmental biology, the techniques of altered nuclear transfer may allow us to generate embryonic stem cells even apart from the organismal system that is their natural origin.  In order to evaluate the potential solutions and allow forward progress within moral consensus, we have to understand the perspectives and address the concerns of those who believe that life begins at conception.  By this view, the most fundamental principle on which all other moral principles are built is the intrinsic dignity and inviolability of human life across all of its stages. 

In both constitution and conduct, the zygote and all subsequent embryonic stages differ from  any other cell or tissues of the body.  They contain within themselves the organizing principle for the self-development and self-maintenance of the full human organism.   The activation of an egg by the penetration of a sperm or the equivalent events in nuclear transfer cloning procedures, triggers the transition to active organismal existence with the potential to develop into an adult human.  But without all of the essential elements, the necessary complement of chromosomes, proper chromatin configuration, the cytoplasmic factors for gene expression, et cetera, there can be no living whole, no organism and no human embryo.  Recent scientific evidence suggests incomplete combinations of the necessary elements, failures of fertilization, are the fate of many, perhaps most early natural initiations in reproduction.  Altered nuclear transfer proposes the artificial construction of such a cellular system mimicking these natural examples, a system that lacks the essential elements for embryological development but contains a partial developmental potential capable of generating embryonic stem cells.

It is important to realize that many of these naturally occurring failures of fertilization may still proceed along partial trajectories of organic growth without being actual organisms.  For example, grossly abnormal karyotypes such as trisomies of Chromosome Number 1, the largest chromosome with the most genes, you may know that chromosomes are named by the largest to the smallest.  These grossly abnormal karyotypes will still form a blastocyst but will not implant.  Even an egg without a nucleus when artificially activated, has the developmental potential to divide to the eight-cell stage; yet, clearly is not an embryo or even an organism.

The messenger RNA in these activated enucleated cells has the protein already in it, the protein synthesis that drives the early cell divisions, it's generated during the maturation of the egg and then activated after fertilization.  Like a spinning top, the cells contain a certain biological momentum that propels a partial trajectory of development but unlike a normal embryo, they are unable to bootstrap themselves into becoming an integrated and self-regulating organismal entity.

Some of these aberrant products of fertilization that lack the qualities and characteristics of an organism appear to be capable of generating embryonic stem cells or their functional equivalent.  Mature teratomas are neoplasms that generate all three primary embryonic germ cell types as well as more advanced cells and tissues including partial limb and organ primordia and sometimes hair, fingernails and even fully formed teeth.   If you look at the radiograph there, the little bright white areas to the left of the spinal chord are teeth, fully formed teeth.

Yet these chaotic disorganized and non-functional masses lack entirely the structural and dynamic character of organisms.  These benign ovarian tumors are is some cases derived by spontaneous and disorganized development of activated eggs.  They generally have a complete karyotype, 46 XX, and they produce a diversity of cell and tissue types that suggest that they may proceed through a developmental process similar enough to natural embryogenesis to produce pluripotent stem cells.  In fact, through intentional parthenogenic activation of monkey eggs, which mimics teratoma formation, one private US company was able to coax them to a blastocyst-like stage and harvest ES cells.  Serious scholars and scientists including the geneticist and Dominican priest, Nicanor Austriaco, have made serious moral arguments supporting such a source of human ES cells.  Furthermore, there may soon be patent applications for such a procedure. 

The disorganized character of teratomas appears to arise not from changes in the DNA sequence but from genetic imprinting and epigenetic modification that affects gene expression, keeping some genes turned off and others on.  In natural reproduction the sperm and egg have different but complementary patterns of imprinting, allowing a coordinated control of embryological development.  When an egg is activated without a sperm, the trophectoderm and its lineages fail to develop properly and the differentiation of the trophectoderm and the inner cell mass which forms the ES cells is considered to be the first globally coordinated divergence into distinct cell lineages, so it's an important indicator of organismal integrity and it lays the pattern for the whole future of that organism.  Nonetheless, in this entity it fails to generate. 

The trophectoderm is necessary for the cross-inductions that are the foundation for all further coordinated and organismal growth of the embryo.  Later it contributes to the formation of the extra-embryonic membranes, but early in development it is crucial for both embryo structural integrity and for the development, continued development at least, of a normal inner cell mass. 

In the absence of the complementary genetic contribution of the male, the activated egg is simply inadequately constituted to direct the integrated development characteristic of human embryo genetic process.  Interestingly, an inverse failure of formation characterizes development driven only by genetic elements from the male where the complementary contribution of the female is missing.  In hydatidiform moles, an egg missing its nucleus is fertilized by one or more sperm but this time, lacking the maternal genetic contribution with its complementary imprinted genes, there is an over-growth of trophectoderm with no apparent inner cell mass or embryonic stem cell-like cells and little or nothing in the way of fetal parts. 

Recent evidence suggests that in their development both of these disorganized growths may proceed to the blastocyst stage.  They may appear on visual inspection to be growing normally but they carry an intrinsic insufficiency, making them incapable of the essential formation of body axis and infrastructure characteristic of human embryogenesis.  The cause of the aberrant and disordered growth of these failures of formation is not fully understood, but studies with parthenogenic mice provide a remarkable window into the organizing or disorganizing role of a single genetic alteration. 

Employing a form of altered nuclear transfer, Japanese scientists produced a fully formed mouse using only female chromosomes but with a single modification of an imprinted region to simulate the necessary male contributions.  They produced something that absolutely can't happen in nature, just by modifying a single gene.  With — actually, it wasn't even a gene; it was a promoter region expressing a gene — with this one change in genetic regulation, directly affecting expression of just two genes downstream, instead of disordered growth, normal offspring were produced and then to everyone's amazement, the simple restoration of the male/female complementarity of gene expression resulted in changes further downstream of gene expression of over 1,000 other genes.  This striking example of our increasing power to intervene and alter natural processes points to a coming era of challenging ethical dilemmas through advances in developmental biology. 

With new tools from cytology to synthetic biology, we are gaining control of not just component parts and their partial trajectories of growth but the very principles and dynamics of organismal systems.  Beyond highlighting our strange and challenging new powers over developmental biology, the parthenogenic mouse points to another level of advance in our understanding, our new appreciation of systems biology in which we see how even a small change of one gene can affect the entire balance of an enormous network of biochemical processes within a cell.   What's going on here?  That's too bad not to see that one [referring to a slide that did not project correctly]. 

Systems biology offers us the view of an organism as a living whole, a dynamic network of inter-dependent and integrated parts.  If severed from the whole, these partial sub-systems may temporarily proceed forward in development but, without the larger environment of their organismal system, they will ultimately become merely disorganized cellular growth.  Altered nuclear transfer proposes that small but precisely selected genetic alterations will allow the harnessing of these sub-systems of partial development apart from their full natural organismal context in order to produce embryonic stem cells.

Eventually, we will understand the biochemical factors that can transform a somatic cell to a pluripotent state.  But while the ultimate goal for the generation of embryonic stem cells is the direct nuclear reprogramming of an adult nucleus, it may be many years before our scientific knowledge and control of cellular factors will make this approach feasible.  More immediately, we may be able to use the techniques of nuclear transfer but with an intentional alteration of the nucleus before transfer to the cytoplasm to construct a biological entity that by design and from its very beginning lacks the attributes and capacities of a human embryo. 

Studies with mice already provide evidence that this altered nuclear transfer may be able to generate functional embryonic stem cells from a system that is not an embryo but possesses the limited organic potential of a tissue or cell culture.  For the sake of specifics in this discussion, let me propose one particular example of how this could be accomplished.  This may not be an acceptable ultimate solution but it will allow us to consider the necessary criteria for scientific success and moral acceptability. 

As well demonstrated in the work of Dr. Janet Rossant at Mount Sinai Hospital in Canada, the gene cdx2 is essential for embryogenesis.  This gene is expressed immediately after compaction around the 16 to 32-cell stage and is crucial for the differentiation of the trophectoderm, the outer layer of cells that seals the embryo and controls the flow of water and ions into the inner cavity of the cell.  Without this, there's just an open space and the cell just can't form its own integrity of an inside and an outside.  Although the trophectoderm is ultimately the source of embryonic membranes, it is more properly considered part of the embryo as it plays a central part in the interactive cell inductions that generate all subsequent embryonic development.  Studies confirm that a functional trophectoderm is absolutely essential in embryogenesis.  In experiments with mouse models when cdx2 is not expressed, there is only a partial and disorganized developmental process resulting in a visibly abnormal blastocyst. 

Nonetheless, there is the formation of an inner cell mass from which functional embryonic stem cells have been harvested as reported in the May 2004 Proceedings of the National Academy of Sciences.  For the purposes of altered nuclear transfer, cxd2 might be deleted from the somatic cell nucleus before transfer.  Once the partial embryonic stem cells have been generated, the gene in these cells could then be reinstalled to allow fully potent embryonic stem cells.  This technologically created limited cellular subsystem from which the embryonic stem cells would be obtained would fail to establish even the most basic features of human organismal infrastructure.  A deficiency at the first differentiation of cell type, the formation of the trophectoderm, means the absence of the most fundamental order.  According to Dr. Maureen Condic, a developmental biologist at the University of Utah, she says, "When the trophoblast," which is immediately after the trophectoderm, "when the trophoblast does not form, subsequent development follows a chaotic pattern suggesting that organismal development has not been disrupted in the absence of the trophoblast but rather that an organism never existed in the first place." 

The resulting cells would have no inherent principle of unity — that is, the entity produced, not the embryonic stem cells, but the entity produced would have no inherent principle of unity, no coherent drive in the direction of the mature human form and no claim on the moral status due to a developing human life.  Rather, such a partial disorganized organic potential would more readily be designated a biological artifact, a term I owe to my colleague, Paul McHugh, when talking about early discussions of cloning.  This entity would be more rightly designated  a biological artifact, a human creation for human ends.  The fact that some part of such a constructed entity will carry a certain momentum of development is morally analogous to the fact that we can grow skin in a tissue culture and may one day grow whole organs or  limbs in isolation.  Lacking crucial elements of its fundamental constitution, such an entity would never rise to the level of a living being. 

The scientific prospects for altered nuclear transfer remain largely unexplored but, as stated by Rudolf Jaenisch in testimony to this council, they are already within the reach of our current technology.  Unlike other proposals, ANT — I'm calling this alternate nuclear transfer ANT — ANT would allow a uniquely flexible approach by providing a wide range of embryonic stem cell types that would have the full normal complement of human chromosomes, would be of specific genetic types for tissue-compatible transplantation and would not carry the danger of contamination from animal components.  In addition, this technique would offer a far wider range of scientific and medical possibilities than embryonic stem cell lines derived from leftover IVF embryos, including generation of diverse and predesigned embryonic stem cell lineages for disease modeling and pharmaceutical development.

Indeed, in allowing controlled and reproducible experiments, altered nuclear transfer might serve as a temporary bridge to transcendent technologies such as direct nuclear reprogramming.  Furthermore, in establishing a morally acceptable means for the procurement of embryonic stem cells, this important realm of scientific investigation would be open to federal funding and have the advantage of both broad public support and cooperative research collaboration on a national level.

Altered nuclear transfer would also unburden ES cell research from the additional ethical concerns of the leftover IVF embryos including the attendant clinical and legal complexities in a realm of great personal and social sensitivity.  The one remaining link with in vitro fertilization, the procurement of oocytes is the subject of intense scientific research and there appear to be several prospects for obtaining eggs without the morally dubious and expensive superovulation of female patients, the specifics of which we can discuss later if you want. 

The crucial principle of any technological variation of altered nuclear transfer, however, must be the pre-emptive nature of the intervention.  This process does not involve the creation of an embryo that is then altered to transform it into a non-embryonic entity.  Rather the proposed genetic alteration is accomplished ab initio, the entity is brought into existence with a genetic structure insufficient to generate a human embryo.  From the beginning and at every point along its development, it cannot be designated a living being.  If such a limited biological entity were accorded a certain cautionary respect, as with all human tissues, this project would not compromise any fundamental moral principle.  Moreover, such techniques could be developed using animal models and confidently extended to work with human cells without engaging in research that involves the destruction of human embryos.  The moral distinctions essential to discern and define the categories of organism, embryo and human being will inevitably be vital as we go forward with scientific research involving human embryonic stem cells, chimeras and laboratory studies of fertilization and early embryogenesis.  Advances in developmental biology will depend on clarifying these categories and defining the moral boundaries in a way that at once defends human dignity while clearing the path for scientific progress. 

At this early stage in our technological control of developing life, we have an opportunity to break the impasse over stem cell research and provide moral guidance for the biotechnology of the future.  This may require a constructive refinement of some aspects of moral philosophy together with creative exploration of scientific possibilities, but any postponement of this process will only deepen the dilemma as we proceed into realms of technological advance unguided by forethought.  We must initiate the cooperative dialogue that is essential to frame moral principles that can, at once, defend human dignity and promote the fullest prospects for scientific progress and its medical applications.  Thank you.

CHAIRMAN KASS:  Thank you very much, Bill.  As before, we'll just direct questions to Bill for technical clarification but also certain moral questions.  I'm sure some people might have some.  Jim Wilson, please.

PROF. WILSON: Bill, thank you very much.  Could you describe for us now the scientific procedure you or someone else would follow and the entities on which they would work that would test the viability of this theory?

DR. HURLBUT:  Well, we already know that you can take, at least in this example I gave, that you can take an entity which — from which you can get disorganized growth and yet functional embryonic stem cells.  What we would have to do is — I think the first thing that would happen is, there should be a very thorough discussion about what the criteria to meet both the moral concerns and functional scientific goals would be.  Once those were decided, you would have to see if you could do it.  And the way to do this would be, and I have scientists including Evan Snyder at the Burham Institute in San Diego who are interested in working on this and enthusiastic about the idea.  You would have to start with mice, probably — they're the easiest and quickest to work with — and just go through the genes that might be of interest and they could probably do this fairly easily because you can use — for the initial research, you can use techniques called short interfering RNA, which are very easy to apply and do a first scan to see what genes might serve the functional purposes that we want.  Doing it fully and officially with human cells, you might want to knock out the gene, a technique that I've checked out with my colleagues, Ron Davis, who's head of the Human Genome Technology  Center at Stanford and Andy Fire, who basically invented RNA interference, these scientists both confirm that to be finally and ultimately sure the best way to do this is likely to be the knockout and then replacement of the gene, but the preliminary studies could be done with short interfering RNA.  You could scan through many, many possible genes, and by the way, gene combinations to double and complementarily assure your success and refine your technique. 

Then I think it would have to — once you identified something that worked in mice, you'd have to move on to primates which has already been done, as I mentioned, harvesting of embryonic stem cells but you'd have to do the knockout and then the harvesting to see if it worked and the thinking is among all the developmental biologists I've spoken with, that there is such a conservation of biology of these developmental genes and developmental processes that we could, with assurance, go forward with human cells without the fear of creating a human embryo.

PROF. WILSON: Which human cells would you use?

DR. HURLBUT:  That is probably going to be dictated by which human cells most effectively go forward with nuclear transfer.  It appears that some cells are better than others.  Cumulus cells are what they used in South Korea.  They're the cells around the egg during its development.  We would have to use a cell, if we were going to knock out the gene, a cell that multiplied through numerous cycles in vitro because you want to be sure you've got the gene knocked out, but I think that's just a technical problem and it wouldn't be that hard to do and there's great advance going on constantly in this technique of nuclear transfer.

CHAIRMAN KASS:  Questions of clarification on the technical side first so that we — I want to make sure that everybody here understands precisely what it is that Bill is proposing.  Gil and then Paul.

PROF. MEILAENDER:  Bill, I'm just trying to think this through, and let's just suppose hypothetically that you could, through some technique, produce an entity which had the capacity to implant but would absolutely not develop beyond eight weeks something like that, how would that procedure — and I realize that may never — perhaps that would never be technically possible, but just suppose you could produce an entity which from the start is characterized that way, how would that differ from what you're proposing?

DR. HURLBUT:  Well, that's an important question and I might add that one — what I think one of the positive dimensions of my proposal is that for the concerns that these techniques might lead to implantation of human embryos perfected through this technique and surreptitiously implanted without the genetic alterations, it's important to note that these cells produce, if it's done with a gene knockout and replacement, would carry a bar code that would identify them as having undergone this transformation, but to get to your central issue — in other words, it would not lead to human reproductive cloning in the sense of child-producing. 

To get to your fundamental question, you're saying will this not lead us to push the process forward and say well, this wasn't an organized human entity and so forth.  That's a very challenging question.  What level of organization defines an organism?  I've gone back to what is considered the primary tissue differentiation of the organism and by the way, these would be abnormal from the beginning as are also all nuclear transfer cells.  Some of them are abnormal to the extent they can right themselves. 

As we saw in the paper that, as presented earlier, nuclear transfer greatly disrupts the gene expression patterns.  But we would have to be certain that this was to the very most primary level of disrupted organismal organization.  And I think there is some scientific thinking to be done, but I think we should turn to scientists to help us with that.  I think we have to be very careful that the principle we set up does not allow it to be pushed forward to regions that are — that evoke our natural moral sentiments and to the most minimal possibility.  What's being said is we want embryonic stem cells.

CHAIRMAN KASS:  You follow, Gil.

PROF. MEILAENDER:  Yes, I'm still just trying to think through the description, kind of.  You're talking about producing an entity that appears — I mean, the kind of language you use — and I might not get this quite adequately translated, but it's about an entity that appears to be growing normally but really lacks the capacity to continue that development beyond a certain point.  And again, I'm just thinking analogously.  Could I use that same sentence about a child born with Tay-Sachs disease?  I'm not trying — I'm just trying to think — could we say of that same child — of that child that it appears to be growing normally but lacks the capacity for continued development beyond a certain point?  I'm just trying to think through where that kind of language goes and I may not have the language technically sophisticated enough and you know, that may be part of what you want to say to me but what — how would you answer that?

DR. HURLBUT:  I mean, that's a very important question but to — I think to think clearly about that question you have to have some sense of how the organismal process unfolds.  There is a — as I said earlier, there is a certain momentum of substance in the egg.  There's a certain kind of primordial automaticity to the way things happen initially.  Without the coordinated interaction of subsystems as I tried to show in the systems biology, you just simply can't go there.  I think it's a difference, an ontological difference between something that never organizes itself in what is meaningfully called an organism and I don't mean meaningfully like they say in Marin County in California.  I mean rightly by scientific criteria not organizing itself in the minimal constructions.  And what those would actually  be would have to be clearly and carefully worked out by both scientists and moral philosophers  but I would include at the very least one or maybe several of these entities and I would think at least it should not be able to form the infrastructure and body plan of a human organism. 

That's — I think that's too far.  I would go back to the most primary lineage differentiation and I don't think that's analogous to a fully formed self-evidently human entity.  I mean, there's been a big debate about whether an anencephalic baby is a human person.  I think it's self-evident.  If not a human person in the full sense of what it is, it has a radiance of respect due to it just by its humanness somehow, its human likeness.  And I don't — those are very difficult definitional terrains, but let me say again, we are heading into this terrain inevitably whether this proposal goes forward or not.  We're creating hybrid human animal creatures.  We're going to generate human parts apart from the whole.  We're going to have to start doing the hard work of defining what is the minimal construction of a moral entity called a human being.

CHAIRMAN KASS:  Look, can I intervene?  It seems to me this — I don't want to dissent from what Bill has just said, but on the limited question that you asked, I don't think you need to go in that full theoretical direction to say — he's given you a couple of examples here of things that grow on their own, teratomas and hydatidiforms cysts which are developing but are not organisms.  And I think anything that you would say that gets to develop to be a fetus at eight weeks with the human form is not a mole and it's not a cyst.   But Bill, I think what we want to say is what we're talking about here is not an organism and not a being, in the same way as a cyst or a mole is not a being.  It's not just that it will not develop further.  It's not a developing thing.  It's a thing — there is growth that takes place here but it is not an organism, growth in the sense of increase but there isn't somehow a pre-given form that is being developed in the way an eight-week old embryo would and I don't think you need — and I think that's sort of descriptively accurate without having to get into ontological questions.  You don't really have a being here, in the same way as those moles and things —

DR. HURLBUT:  Let me show you something interesting on this slide.  This is — on the top is a normal human embryo forming.  On the bottom is an embryonic stem cell in a culture forming a so-called embryoid body.   I mean, it's not identical but what I use this for is to show that there are biological qualities within just the chemistry, the cell that will organize to some degree.  And so organization, per se, is not — is not indicative of organism in the meaningful sense of the word.  There's — biology has a certain self-organizing power.  So —

PROF. MEILAENDER:  And what is indicative of organism?  It's not just growth but it's also not organization?

DR. HURLBUT:  It is organization but it's organization of the species- typical kind. 

PROF. MEILAENDER:  Okay. 

CHAIRMAN KASS:  Paul McHugh and then Mike Gazzaniga.

DR. McHUGH:  Well, Bill has talked with me several times before about this.  It's nice to hear the whole thing laid out, and I still have some technical questions.  I don't want to talk about the ethical issues right at the moment, because they are deep and important, but I do, with Gil, want to follow along on this terminological business because at one level this procedure that you propose to us, and we've talked about before, is really to build a weird genetic hybrid that in its next steps of development, call it what you will, that next steps of development, would lack the features that would render it ultimately viable as an independent organism.  Isn't — first of all, is that right? 

This is a strange genetic hybrid that you've made but it — and it's going to go through a process, a process of embryonic-like development built in as it is —

DR. HURLBUT:  Partial.

DR. McHUGH:  — and you don't want to call that an embryo because you said it doesn't have the potential for full independent —

DR. HURLBUT:  Well, it doesn't have the actual at any level that is embryo-like.  It's different.

DR. McHUGH:  Well, it's very embryo-like.  I mean, that's the whole thing about these hydatidiform moles for that matter, is that they are embryo-like.

DR. HURLBUT:  Well, okay, embryo-like but embryo truly?

DR. McHUGH:  No, and now we're back right at square one again.  Do you want to call everything that follows along this developmental process an embryo or not, and the real issue with SCNT right from the start as we've discussed before, and that Rudy Jaaenisch tended to emphasize was that, in point of fact, it differed from in vitro fertilization in that its origins were not through fertilization but through this remarkably different process so that no new creature had appeared and, as well, it lacked the potential at least in the primate form of ever getting through the pregnancy and therefore, perhaps by your definition, it also cannot be called an embryo, and if it cannot be called an embryo, but rather a source for embryonic stem cells, is it listed? 

That gets us into the ethical problem.  I just want to be sure I understand that the process that you are proposing here is fundamentally to interfere with the nucleus, with the genome, really, of these things so that you have made a genetic hybrid.  Now to come to the ethical problem, we have just heard our Canadian friends tell us that you cannot make, under their laws, a chimera or a hybrid with in vitro fertilization or other kinds of things, and they reject that.

This would seem to be making a deadly hybrid and therefore, might be saluted in this purpose but it would be an opening to make — to propose or make — the process of making a new model chimera or hybrid which would be super-human in some kind of way and therefore, enter a domain that — I haven't finished my thoughts on this because this is so important what you're telling us, Bill, this is very, very important stuff but at the same time, I begin to get — a few red flags begin to come up for me over what we have done and or what we're thinking of doing here and what it might mean.

DR. HURLBUT:  Well, Paul, let me make one comment about that.  I'm not suggesting you create a deadly hybrid.  To be — to use that term, you'd have to say that the thing was alive first.  The point is, you do this ab initio.  You never — you create an entity that never rises to the level of what can properly be called a living being. 

DR. McHUGH:  That brings us back to the point I made about our friends here.  It brings us back to our friends here.  They are very — they want to use what you want to use, the organismically integrated organism and are very fearful of the use of the word "non-viable" unless by their definition non-viable means dead, dying or doomed.  Those are a rattle of Ds that I thought were very helpful to me in thinking about this process.  Well, what you have done is made a doomed hybrid, doomed.

DR. HURLBUT:  Not doomed.  Only doomed if it's alive first. 

DR. McHUGH:  Well, it's doomed in the sense that it will never get out.

DR. HURLBUT:  Well —

DR. McHUGH:  Develop.

DR. HURLBUT:  — you mean somebody with only potential, like any chemicals mixed together.

DR. McHUGH:  No, no, that these are cells — they want to make the point that non-viable means, as I understand it, I'd refer back to Dr. Landry and Dr. Zucker, who brilliantly presented their views on the concept of death and discussed it nicely with Robby.  They want to make the — they want to use your point of organismically integrated as being the issue of — the concept of death but they want to not use the word non-viable because the cells they want are, of course, viable.  They want to use those cells, at least as I've understood the conversation this morning in relationship to life processes and life organization and systems.  But as I say, I'm still groping here.

CHAIRMAN KASS:  Paul, can I try to help, Bill?  Look, Doctors Landry and Zucker don't like the language of non-viable here because there are things which are non-viable which are still alive and to use them might be to kill them.  They want an embryo — they want to develop criteria for embryonic death that would make this exactly analogous to the determination of death in a developed being.  But the reason that they insist on those criteria is because they know perfectly well that what they're starting with is, in fact, a being of a human sort and alive, which will be first doomed by somebody's decision, and then, if they can develop the criteria, can be pronounced dead. 

That doesn't apply to the way Bill is speaking because what Bill is talking about doesn't yet rise to being a living human being.  The cells are of human origin and that says they're human. But no more than is a hydatidiform mole a human being would Bill's re-engineered entity be an organism.  It would simulate certain organic activities, in the sense that there would be cell division, but it would have been engineered in such a way that you couldn't — if you understood what you were doing and what you have done, you could not call it a living human embryo.  It would be embryo-like only in the sense that it went through certain stages of cell division but it would not be embryonic in the sense that it had no — it was incapable ab initio of being embryonic in the sense that it is pointed toward and developing — it is not a being to begin with, with that kind of future. 

And I think for me the question is, can you make such things.  It seems to me it's a technical question less than it is a philosophical one if I have understood what he has told us.

PROF. GEORGE:  You mean more than it is.

CHAIRMAN KASS:  I'm sorry.

PROF. GEORGE:  More than it is.  A technical question more than a philosophical one.  In other words, you're saying it's not really a philosophical question, it's a technical.

CHAIRMAN KASS:  Yeah, exactly.  Yeah, I'm sorry.  Mike Gazzaniga.

DR. GAZZANIGA:  Well, we're not capable of — first of all, thanks, Bill.  I appreciate what you're trying to do and I think it's admirable.  In many ways, I'd just like to make a couple of observations, it does say to us that we do need more stem cell lines and —

DR. HURLBUT:  More what?

DR. GAZZANIGA:  More stem cell lines.  We need more lines if we're going to get this job done.  Why else would we be torturing ourselves with this proposal.  The — I do take exception and I just want to bring a little clarity to those of us who don't have this deep moral dilemma with using a 14-day old blastocyst to harvest stem cells and therefore the need for this bio-engineering project.  And the other point I want to make, is that what we're trying to do here, it seems to me, is, normally, we generate a word to describe a biologic phenomenon and here we seem to be tinkering with biologic phenomenon to have it fit the meaning of a word, and that's not what you do. 

So this rests a little bit back to Paul's point of two years ago and basically the question underlying now is you are building something here and we're going to have to call it something.  And it's not an embryo, it's something else if you want to have it play out this way.  And finally, I would just say, I — because of my position on the moral status of a 14-day old blastocyst, that has no brain, so we don't have to worry about brain dead and all that sort of stuff — I forgot what I was going to say.  What was I going to say?  Oh, that — excuse me, I'm sorry, that the money and investment and time and trying to develop a science of this, postpones, if we were doing it serially, what we now know how to do, what I gather will be going forward in the State of California and many other nations that — that's right, well, many of them not as big as California, that it has the risk, and I'm sure you've thought about this, of delaying the important advances that could come from the sort of research to alleviating pain and suffering and people who surely would like care. 

DR. HURLBUT:  Mike, I don't even understand how you make laws.  I start all my classes  at Stanford by saying, "We're going to not really talk about laws in this class.  We're going to talk about  ideals, what we should do if we could", and I quote that saying, "Never ask what goes into sausages and laws".  I truly do not raise this issue with a political agenda.  I raise it with the desire to see our society go forward, in both forward progress in science, and forward progress in our moral thinking.

You say we need new embryonic stem cell lines.  I think with — if the scientific goals are the ones we're after, I agree with that.  As far as I've been able to understand from my colleagues, I'm not a stem cell biologist, but I think it was obvious that when the President put forward his policy, we would seek moral ways to get new embryonic stem cell lines.  So I don't think any reasonably educated person in science is going to contend with that, but at the same time we also need to confirm and solidify those moral principles that will help us go forward into increasingly complex terrains with development biology and if you could say that progress walks forward on two legs, one technical and one moral, we need to solve this — in my opinion we need to solve this in a way that we can, as human beings, as a collective, cooperative society in a way that creatively and intelligently recognizes that neither side in this debate is — nobody is a fool in this debate.  Both sides are upholding important human goods and the amazing thing is there might be ways to do this so that we could both be confirmed in the positive things we're trying to defend.

CHAIRMAN KASS:  Okay, Dan, and after Dan, I want to suggest that we be thinking about the general conversation while we consider both of these proposals and I would like to know what the council thinks of either or both of this general direction.  We can't settle that today, but Dan, please, first.

DR. FOSTER:  Yeah, I only want to make a brief statement and I'm one of the minority, you know, in the original thing but it seems to me that one of the fundamental principles that we started off in this discussion about the bioethical concern was that you had a series — you had two sets of goods.  You had two sets of goods, and one of them has to be dominant and the other one did not in the 10 to 7 vote, but the principle that I think that Bill is working on here and others is that this may be a way to accomplish both of these goods without violating either of the issues which are there, so I think it's a — and I'm not worried about the cost because I believe that scientists always learn things if you're working with one of these, what, "new creations" or whatever you want to call it.  We're going to learn things that are also powerfully important. 

I don't think you're going to have any dearth of scientists that want — that would not want to explore this.  Whether it's going to work, I mean, the whole issue, I mean, from Dolly on, as we were talking about, you know, I mean, it's really hard to get — you know, to do this sort of stuff.  I mean, it took 270, 280 attempts to do it.  The Koreans took — you know, so there are many technical problems but that's what science is all about.  So I would say, to me, this is a very attractive way to remove the issues that were of major concern about destroying human life and at the same time, extending the stem cell things where we can get diseased molecules and things of that sort, so I'm adding my side in contrast to some of the view, in very strong support, not of any technical aspects of this, but the principle that one might be able to accomplish both of these goods with some model like Bill or the Columbia people have put forward. 

CHAIRMAN KASS:  If I might, I would be interested in hearing from especially the people we haven't heard from what you think about this, Diana, Peter, Alfonso, Robby, Mary Ann, Jim Wilson.  Peter?

DR. LAWLER:  Let me ask Bill, what's your objection to the other proposal which is basically to work with dead embryos?

DR. HURLBUT:  Well, it's not really an objection.  In fact, by the way, if you can get embryonic stem cells out of eight-cell morula, my project is a snap.  I'm not sure you can.  I know Verlinski claims to have done that but the stem cell biologists I've talked to say that at least at this point we don't know how to coax them up and that they are more primordial cells still, but maybe that's true.  You know, the one thing we just have to stop doing is being so narrow in our view of what science can accomplish.  I mean, science is a wonderfully creative process and can yield for us all sorts of new ways to do things that we have concerns about one direction, get them another way.  I basically think this is wonderful thinking at the heart of this proposal and by the way, I'd be perfectly happy if my proposal was bypassed by other easier, more practical ones and I think that eventually it will.

Every stem cell biologist I talked to has told me that they think it's just a little period here we have to get through eventually to understand all of this well enough to create these entities with no moral concerns at all.  Is that what you asked me?

DR. LAWLER:  Well, right, so the answer would be the question is, which is more possible then.

DR. HURLBUT:  Which is more possible?

DR. LAWLER:  Yeah, which proposal can —

DR. HURLBUT:  I mean, that's anybody's call but we don't have any markers for the death of these things and when you say that at 24 hours of rest, 10 percent still go onto 48 hours, that is a little bit of a problemmatic moral question.  You've in a way endorsed in vitro fertilization in the first place.  That would be a problem for some people.  You've got a limited number of cell types you can work with.  You've got the question that Paul put forward and it's not a trivial question, whether even a mosaic, a normal appearing karyotype from a mosaic cell may still have something in the constitutional cell that provoked the aneuploidy in the first place.

There's some evidence that aneuploidy is promoted by certain factors in the developmental powers of the cell themselves, although it may just be pushing the growth too fast.  But these are all really fundamental questions... but again, they're technical questions.  The moral principles that were put forward before me I think make sense.  If something is not integrated, if it does not have the principle of life in it, that's what we're trying to defend.  We're not trying to defend parts of things.  We have to find the locus of our concern.  In the twentieth century, we came to terms with the fact — I'm sorry — we came to terms with the fact that cells like in transfusions were not the moral locus of the person, although some cultures still believe that.  We came to terms with the idea that genes were not the locus.  We put human genes into bacteria.  We learned that organ transplants were okay.

I was at Stanford Medical School when the first heart transplant was done and some people were saying, "Well, that's just too much of the person, or that's the person".  It took a few months and we figured that that wasn't the — in this area of developmental biology, we're going to learn that seemingly alive, partial trojectories of organic growth without the full integrated principle of life organizing unity of their organismal context, are not — even if they're human I'm speaking of, without that principle of life, they are not moral entities.

CHAIRMAN KASS:  Look there are people who have to make a plane and we also have a public comment session, so I really want — if anybody wants to — we're not forced here to choose between these things.  The question is, does the concept appear to the council, knowing that the technical questions are not in our hands to determine, and I don't think — I'd rather not have arguments for the proposal as much as I would like to hear, from the people who haven't spoken, what they think about this.

DR. LAWLER:  I completely agree with what Dan said on this, it's a promising area to explore, bound to benefit us and resolve a question that might not be resolved any other way. 

CHAIRMAN KASS:  Diana?

DR. SCHAUB:  Yeah, it seems to me almost too good to be true that scientific advance — well, that scientific advance itself would solve these moral dilemmas, and if — I mean, I guess I am persuaded that you are not creating an embryo and therefore, it doesn't trigger my concern about the equality principle.  I guess the only question I would have, I think it does not trigger that concern about equal treatment of all human beings because you're not creating a human being.  Is there any concern that you were doing something even more radical than that, namely, that you're tampering with the organizing principle of, I don't know of life itself.  I mean, is there —

DR. HURLBUT:  I think that principle is only of moral concern only when it's instantiated in a living human being.  What I'm trying to do here is define more clearly the boundaries of our moral concern and that's what I'm saying, it's the integrated human organism. 

G.K. Chesterton has a beautiful little metaphor, little boys are playing soccer on a field but right at the edge of a field there are cliffs that go down 2,000 feet to the crashing waves on the rocks below, so where are they playing soccer, in the middle 20 yards of the field.  And then somebody comes and draws a clear line at the borders, puts up a fence and they can play to the field. 

Right now, and even more in the future, if we don't define these moral boundaries clearly, we're going to impede forward progress in science or many people are going to feel like moral purposes are being violated, moral goods are being violated.  We need to do that hard work of defining these boundaries, but I think the meaningful boundary is the integrated human organism at all of its stages, and just make one sentence more: I, as everybody in this council knows, have stood very strongly for the principle that human life is present from conception.  When I looked at the scientific facts — and I didn't come in like some rubber stamp agent of this counsel to do what somebody told me to do — I looked as plainly as I could and I simply could not think — could not agree that the early embryo was, as some scientists are saying, an inchoate clump of cells.  It's a living whole human being.

CHAIRMAN KASS:  Bill, look, I think we've had your elaboration on this and I really do want to get people who have to leave, their comments on the record, so if you'd hold back until we've heard from Jim and Mary Ann and Alfonso and I want to have a word, too.  Jim.

PROF. WILSON: I support this venture for all the reasons that have been indicated.  I do agree with Mike that you have to find a name for this.  It's extremely important.  We can't go around saying we're producing ANTs because the ant lovers — the name is already used and widely admired by some close friends of mine.  But we have to find a name for it.  Being a gardener, I would call what we're doing as producing weed, not an animal and not a desirable plant but I certainly support the venture.

CHAIRMAN KASS:  It's not weed in the California sense. 

(Laughter)

CHAIRMAN KASS:  Mary Ann.  Jim, thank you.

PROF. GLENDON:  Well, I think that this may turn out to be one of the most fruitful meetings that the council has had and I'm very grateful to both of — all three of the presenters.  I think a problem for some of us is we don't want to get over-excited about these indications that there may be a path through the thicket of technical and moral problems that we've been struggling with for so long but I think you've all been so careful and nuanced and at least as clear to us lay people as it's probably possible to be although I — with Gil I can't pretend that I followed everything, but I do think that this may be the beginning of very, very significant turn in our history.  So thank you very much.

CHAIRMAN KASS:  Alfonso.

DR. GÓMEZ-LOBO:  At present, my thinking is still hypothetical on both proposals.  On the Columbia University proposal, if I may call it like that, of course, if indeed the extraction of the cells proceeds from a dead organism, I would say that's morally viable and extremely interesting.  I'm sure there has to be a lot of refinement in terms of the concept of death of the criteria and the actual tests, I mean, the empirical evidence. 

With regard to Bill's proposal, we've talked a lot about it and I'm very close to the affirmation of the conditional hypothetical question, but of course, there has to be a lot more elaboration in the sense of making it very clear to the public that we're not talking here about mutilation, because that's, I think, what is lurking in the back of many people, whether what's going on here may be the moral equivalent of generating a human embryo but you just  knock some genes so that it becomes non-viable, which  was Rudolph Jaenisch's position.  I remember discussing it with him and I insisted that we had to distinguish between genetic modification that makes an organism non-viable from a genetic modification that made it non-human and I think that's very important.  Now, your argument, Bill, is an argument fortiori at present.

DR. HURLBUT:  A what?

DR. GÓMEZ-LOBO:  A fortiori —

DR. HURLBUT:  Yes, I get it.

DR. GÓMEZ-LOBO:  — in the sense that since it's not an organism, therefore, it cannot be a human organism.  It seems to me that that concept has to be refined in terms of what would be necessary and sufficient conditions for the organism to be human.  I know that that's a major, major enterprise, but I think both proposals are very, very interesting, worth pursuing. 

CHAIRMAN KASS:  Robby George.

PROF. GEORGE:  Thank you, Leon.  Bill, it's always seemed critical to me in this debate that the embryo is a whole living member of the species homo sapiens at the earliest stage of his or her natural development.  It's also always seemed clear to me and I've seen no one here or elsewhere dispute this, that a hydatidiform mole or a teratoma is not a whole living member of the species of the homosapiens at any developmental stage.

So it seems to me that the whole ball game as far as your proposal is concerned is the question whether an entity created by the altered nuclear transfer process would be the equivalent of a hydatidiform mole or teratoma or would be a severely damaged embryo or an embryo programmed for an early death and I think this goes to the heart of what Gil raised originally.  Now, when I ask myself why are we so sure that a teratoma is not a whole living member of the species homosapiens, why are we so sure we can distinguish the teratoma from an embryo, my conclusion is that the teratoma, unlike the embryo, lacks, you know, from the start and always, the active disposition for self-organization and self-directed development in the direction of human maturity.

There may be additional things we can say about that but it seems that we begin by saying at least that much. 

Now, is it critical to you that we not go forward with your proposal, at least with ANT, at least in humans, until we've reached moral certainty that in fact, the product would be analogous to a hydatidiform mole or teratoma rather than to an embryo?  Is that critical to you?

DR. HURLBUT:  Yes, it is.

PROF. GEORGE:  So you, yourself, would not want to see the proposal go forward unless it could be shown that in the human case, we would not be creating an embryo.

DR. HURLBUT:  Yeah, that would violate the very principle we're trying to defend.

PROF. GEORGE:  Right.  Animal experimentation then would be critical to determining whether, in fact, the entities created are non-embryonic —

DR. HURLBUT:  Yes.

PROF. GEORGE:  — truly non-embryonic in which case, I think then you're saying that all you're proposing to us is animal experimentation to determine whether when we examine the products of ANT we have on the basis of our, you know, biochemical and molecular examination entities that are truly analogous to teratomas or hydatidiform moles and therefore, are non-embryonic, no more than that, right?

DR. HURLBUT:  Yes, that's right.

PROF. GEORGE:  So you're not proposing that we do this in human beings now.  That proposal has gone on the table.

DR. HURLBUT:  Absolutely no.

PROF. GEORGE:  Okay, one other very brief line of questions; you have used as an example of a method of ANT the switching off of the cdx2 gene which would then be switched on later when the stem cells are derived.  That possible method was described in an article in The Boston Globe by the science writer Gareth Cook recently.  And my own e-mail tells me that a lot of people interpreted what was said in that article to imply that ANT just is the method involving switching off cdx2.  But I thought I heard you say today, and you can correct me if I'm wrong, I thought I heard you say today that that method is simply one of perhaps any of a number of possible methods of altered nuclear transfer which you, yourself, think has some promise but may turn out to be inadequate to the task of creating a truly non-embryonic entity in which case you would look to another method.

DR. HURLBUT:  Yes, or a combination of methods with great surety.  See, it doesn't have to be just one thing.  SiRNA, you can put several in at once. You can knock several genes out if you have to, just maybe a little more complicated, but you know, the idea is that we've beginning to understand the biology of development enough to determine to some degree what is going on with teratomas.  And if we biologically could artificially mimic that or some equivalent of it that was ontologically equivalent, that would be what I would be after.

PROF. GEORGE:  So the method involving the switching off of cdx2 could prove in the animal experimentation to be inadequate to the project of producing a truly non-embryonic entity, in which case you would abandon that as a morally legitimate method of ANT if used in humans.

DR. HURLBUT:  Oh, yes, I didn't put the one project forward with the specific gene as anything but an example of how amazing it is that you can get a fully normal functional embryonic stem cell out of an entity that is grossly abnormal, with a trophectoderm not forming in that entity, the thing doesn't even hold together — the inner cell mass over-grows the center of the blastoseal, the cavity of the blastocyst — and yet, you still get functional cells out of it.  That was why I used that example, but I specifically am not tied to any one gene or any suggestion at this point.  I'm proposing an exploration of this.

PROF. GEORGE:  Thank you.

CHAIRMAN KASS:  We are just about at the end and want to have the public comment session.  Let me put my own thoughts on the record and also make a proposal to the residual of the council.  I know people have had to go to catch planes, but if you — the Communist party's slogan was to come to the meeting early and stay late and those of us who stay till the end can actually approve the next procedures, but I think these are two extremely interesting, extremely interesting, very creative proposals, absolutely worth not only our consideration but much more public consideration.  Bill has been working on this for two years and has consulted enormously widely with moral leaders and religious leaders and with scientists and there has been a tremendous amount of encouragement.

And I was a foot-dragger on this, not so much on moral but aesthetic grounds, not altogether unrelated to the point raised by Diana, and I'm not sure that the aesthetic objection turns on whether or not this thing is or is not the organismic entity.  But that objection, I think has been overcome by the sense of the real promise of this, and I, myself, am prepared at least in principle to endorse it and eager to see the details worked out scientifically. 

This other proposal, which has also been a long time in gestation, and very, very carefully thought out and very subtly now refined and clear conceptually also strikes me as extremely exciting.  It should not be too hard to do this kind of research, starting in the mice or starting in various kinds of things, and to begin to look for these criteria.  And it seems to me that for this council and the public generally what would be most encouraging, is if, in the course of the next several months, we could begin to receive some kind of information on some specific suggestions on where the science might be or some kind of protocols or suggestions for where the science could go, so that if we indeed mean to endorse this as a morally fruitful possibility for the nation to go, we could also back it up with some kind of practical information on that: "this is not just a nice idea, but might be feasible, if the following kinds of steps are taken."  I think both of you are prepared to do this and have the information.  It didn't — since this was the first airing in this gathering, it wasn't probably the time to get all that scientific detail out there.  

By the way, just accidentally, although one doesn't generally regard the New Scientist or BBC News as a scientific publication, there is this report that human eggs have now been developed parthenogenetically, with the expectation that we will get to the blastocyst stage, using just an enzyme derived from sperm, in which the whole process goes on along.  There are no male chromosomes in this thing and there's an almost certainty that this will not go on — could not go on — to develop into a child, and this might be yet another route, another morally non-problematic route to getting the kinds of — to getting us to the point of getting new embryonic stem cell lines. 

So I want to thank the three of you for — not just for the presentations today but for the enormously serious and careful and thoughtful work that has gone into bringing these proposals forward, the consultations that you've taken and the evolution of these two separate projects which I've known about really since almost the beginning.  And I think the council and the nation are really in your debt for trying to find a way forward that does not involve the — if successful, would not require anybody who's party to this debate to sacrifice anything of great importance.   So thank you very, very much.

Gentlemen, you may be excused but you're also free to sit here.  We have two people who want to make public comment and they might, in fact, be on this, so if you have five to 10 minutes, we have a public comment from Jaydee Hanson of the International Center for Technology Assessment, followed by Richard Doerflinger of the United States Conference of Catholic Bishops.  Do you want to take the microphone there?

SESSION 7: PUBLIC COMMENTS

MR. HANSON:  Well, thank you for the opportunity to comment today.  The Executive Director of the Center wanted me to extend his personal greetings to you, Dr. Kass.  So greetings from Andrew Kimbrell.  I want to say my comments are going to be on the altered nuclear transfer technique and I want to begin by offering my personal words to Bill and how much I appreciate his thoughtful thinking. 

But, we're told that this procedure is intended as a means of avoiding the destruction of embryos in producing embryonic stem cells, but we think this notion is mistaken in that we believe that the technique actually does produce embryos albeit defective ones through a combination of cloning and human germline and genetic engineering.  We think if the proposed experiment were to be conducted on human embryos, it would confront us with an ethical question about whether we produce any human life solely for its commercial value. 

We also think there's a second ethical watershed that would be crossed.  This would be in effect, the first human germline, genetic engineering experiment.  For the first time, we would be engineering human life at its earliest stages.  In fact, it seems to require two engineerings.  We do not believe that society should cross these boundaries without a very full public debate.  We urge the council to support an immediate moratorium on all such experiments with human embryos until a robust public debate has occurred and there is wide public consensus that we have in place safeguards to prevent abuse of this potential technology. 

We go on and list some other concerns we have but those are out two main concerns and I thank you for your time.

CHAIRMAN KASS:  Thank you very much and hold it just a second.  If there is a longer statement either now or soon, I think this would be welcome and we'll see that it's circulated to everybody here.  The genetic modification aspect of this is an issue that so far hasn't been discussed today and whether or not this is or is not an organism or an embryo, there are people who have reason to be concerned about such genetic engineering close to the human and I think the point — it's something we will want to talk about.

MR. HANSON:  We also, just to briefly summarize the longer point, we also have some concerns that this — even if the proponents don't consider this an embryo, they may well want to patent it.  The patent office might consider in embryo-like enough to use it as a precedent.  So we have other concerns as well.

CHAIRMAN KASS:  Thank you very much.

MR. HANSON:  I do have copies of the statement I'll leave with whoever.

CHAIRMAN KASS:  If you'd just leave it with Diane Gianelli, she'll see that all of us get sent this.  Thank you very much.

MR. HANSON:  Thank you very much.

CHAIRMAN KASS:  Richard Doerflinger.

MR. DOERFLINGER:  I also want to talk about altered nuclear transfer.  I have — as many on the council know — have been skeptical and remain skeptical of many claims for the unique benefits of embryonic stem cells, including those derived from nuclear transfer.  That being said, I know many scientists believe in those unique benefits, and some of them share my moral convictions against destroying human life at any stage. 

If, and this is a big if, a procedure can be found to provide embryonic stem cells without creating or destroying embryos, that would address the Catholic Church's most fundamental moral objection to embryonic stem cell research as now pursued.  Clearly, such a procedure would not be prohibited by the cloning bans the Catholic bishops have supported at the state or federal level, which routinely exempt the use of nuclear transfer or any other cloning procedure to produce tissues, organs or cells other than human embryos. 

I, therefore, see no moral reason at this time to oppose the further exploration of this theory in an animal model so its feasibility can better be assessed.  This would give scientists an opportunity to show their real commitment is to scientific progress, not to the exploitation of embryos, and gives organizations like mine an opportunity to show that our concern is respect for life, not a fear of scientific research or scientific progress.

Regarding one particular technique for pursuing this, the deletion of the cdx2 gene, I for one am not convinced it fulfills my criterion for saying the resulting entity is never an embryo.  Surely, it is not enough to say the genetic defect preventing organismal development was introduced into the genome from the very beginning.  Any adult who develops Huntington's disease at the age of 40 had the genetic defect ab initio.  But it also matters what development has taken place in the meantime. 

If that gene is expressed only after the 16 to 32-cell stage, it seems to me this would be an embryo that undergoes normal development as a human organism to a certain point and then dies.  Surely the entity has to depart from organic human development from the beginning to fulfill what I would see as the correct goal for altered nuclear transfer.

If no procedure can be found that truly produces embryonic stem cells but not an embryo, my objections would certainly be equal to some of those raised by Mr. Hanson. 

Finally, the problem of using human eggs and the potential of exploiting women for their eggs will ultimately have to be addressed once this is attempted in humans.  Perhaps animal eggs will turn out to be sufficient.  Those have proved very disappointing to researchers trying to use cloning to make normal human embryos using animal eggs, but here we are not trying to make normal human embryos.

Perhaps very few eggs of any kind will be needed, because this technique will be used chiefly to make a few cell lines as disease models or for drug testing.  Increasingly, proponents of cloning for research are admitting that large scale use of nuclear transfer to make cells for direct therapeutic use in patients is doomed to practical and economic failure.  I would only note that it would have been nice for them to admit that before they managed to convince the voters of California to approve the $3 billion give-away for cloning last month. Or perhaps other ways to achieve complete or partial reprogramming of a body cell nucleus without using an egg will be further refined and replace the use of eggs for this technique. 

I do simply want to offer the caveat that this problem ultimately must be addressed as well, the problem of use of human eggs, if this approach is to achieve moral consensus. But at this time, I certainly appreciate the conceptual model that Dr. Hurlbut has presented, and I think exploration in animal models is well worth at least pursuing at this time.  Thank you. 

CHAIRMAN KASS:  Since you have the floor and since you are really one of the most meticulous and thoughtful and careful people about such things and even though you didn't come prepared to speak about it, do you have any reaction to the other proposal of developing criteria for death in embryos follow — only following which would the removal of embryos be attempted?  Does that strike you as morally acceptable, questionable?  Do you have — or would you rather think about it and let me know privately?

MR. DOERFLINGER:  I would rather think about it.  I came in late and was not here for the presentation and have not read the materials, and I will certainly study that as well.  Anything that achieves the promised scientific benefits without exploiting or destroying human life is something that the Church wants to have an open mind to, so I will certainly study that as well.

CHAIRMAN KASS:  Thank you very much.  I think we've done everything that we hoped to do at this meeting and more.  I thank our guests especially.  Thanks to council members.  Thanks to the members of the public and the meeting is adjourned.

(Whereupon, at 12:13 p.m. the above entitled matter concluded.)