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Meeting Transcript
October 17, 2002


Hotel Monaco
700 F Street, NW,
Washington, DC 20002



COUNCIL MEMBERS PRESENT

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

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

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

Francis Fukuyama, Ph.D.
Johns Hopkins University

Michael S. Gazzaniga, Ph.D.
Dartmouth College

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

Alfonso Gómez-Lobo, Dr. phil.
Georgetown University

William B. Hurlbut, M.D.
Stanford University

Charles Krauthammer, M.D.
Syndicated Columnist

William F. May, Ph.D.
Southern Methodist University

Paul McHugh, M.D.
Johns Hopkins University School of Medicine

Gilbert C. Meilaender, Ph.D.
Valparaiso University

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

Michael J. Sandel, D.Phil.
Harvard University


INDEX




WELCOME AND OPENING REMARKS

CHAIRMAN KASS:  Well, welcome to Council members, guests, members of the public to this, the seventh meeting of the President's Council on Bioethics.

I note the presence of Dean Clancy, the designated federal officer whose presence makes this a legal meeting.

I would like to announce that we have at long last added a lawyer to our staff.  Carter Snead from Ropes & Gray will be joining us starting in two weeks.  He will be at the meeting tomorrow.  I will introduce him at that time.

I would also like to announce that we now have at headquarters a members' office so that should you find yourself in town and need a place to sit and work and also to interact with our lively staff, there is a special office set aside fully equipped for your use.

Our cloning report in final version has been produced by the Government Printing Office and Public Affairs has produced the commercial version, copies of which are at your seats.

We have discussions of the report set up in the months ahead, and I know others of you are talking to Diane about arranging things on your campuses.

There will be a book forum at the American Enterprise Institute on the 29th of this month; a session in Baltimore sponsored by the law school of the University of Maryland and Johns Hopkins University on the 21st of November; and there are conversations underway at Georgetown, Princeton, and Chicago for further meetings.

Our next meeting is December 12 and 13 where we will have what's definite for that meeting is a presentation on the use of Ritalin and other stimulants in children; a couple of presentations on aging and longevity research; and Francis Collins of the Human Genome Project will be talking about uses of genetic technologies and the prospects for enhancement.

I would also, since as everybody knows this Council is charged with the monitoring of stem cell research, I would at least like at this point to make a very brief presentation, an update on the subject of the monitoring.

As I think everybody knows, since August 9th of 2001, federal funding has been available for research on embryonic stem cells subject to the particular restrictions announced by the President at that time.  The implementation of that policy which has fallen to NIH has yielded the following information for us.

There is a registry of cell derivations that meet the original criteria and the NIH has identified – 78 cell derivations that meet the original criteria.

The NIH has reviewed 13 grant applications involving human embryonic stem cells at its May 2000 Advisory Council session and 19 grant applications for its October 2002 Advisory Council sessions, and continues to receive applications each receipt date.

The NIH has also made available infrastructure grants to help developers defray the costs of providing cell lines, administrative supplements to encourage expansion of existing projects to produce preliminary data of human cells, and investigator initiated grant awards.

And so far the NIH has granted seven, 37, and eight awards in these respective categories.

Also, six of the NIH intramural labs are conducting research on human embryonic stem cells, and cumulatively there are over 45 researchers representing over 40 different research institutions receiving federal funds for research on human embryonic stem cells.

The NIH has also finalized four material transfer agreements with the commercial companies that have developed these lines.  They are Y Cell, the ESL International, BresaGen, Inc., and the University of California, San Francisco, associated with Geron.

Data on how many of these lines are presently available to be shipped is, however, not easy to get.  At present three developers have lines available for shipment totaling five different cell lines.

Finally, I'd like to mention one recent development that I think is pertinent to our ongoing deliberations.  Since the last meeting, researchers at the National University of Singapore funded by ESL have announced the successful culture of human cells on human feeder cell lines.

This is a newly derived cell line, and therefore under current policy, federal funding could not be used to do research with it.  All of the lines that are in the NIH registry were supported on animal feeder cells so that should human trials be required, these cells would at least at the moment not be available for use under the xenotransplantation regulations.

This new development, I think, will probably be important for us as the pressure might mount for work on these new lines that are potentially usable in clinical trials.

That just by way of an update.  Staff is working ahead on the monitoring of stem cells, and after the beginning of next year, we will have more to do with that at our regular meetings.

Questions or comments on that?

(No response.)

CHAIRMAN KASS:  Well, the two sessions that we have planned for this morning are on the topic of choosing the sex of children, the discussion of current technology and practice, and then a look at the demographics.

Our interest in the topic of sex selection is in part a continuation of questions that we touched on in the cloning report, namely opportunities to select in advance some of the genetic traits of children.

It also represents at least in part a use of biomedical technologies not for therapy, but for the satisfaction of client or patient desires.

This is also an interesting case in which the aggregated effects of choices that might be innocent in themselves might produce results such that even the people who use the technique might be unhappy with the result as a result of its being used by everybody.

And it is also an interesting case for us because there are international implications of biomedical technology where techniques developed for one purpose and one use and one country, say, in the United States, will be used for other purposes and in different ways abroad with consequences that may, in fact, come back to have an influence here at home.

We're very pleased to have with us this morning Dr. Arthur "Cap" Haney, who is the Roy T. Parker PROF. of Obstetrics and Gynecology and Director of the Division of Reproductive Endocrinology and Infertility in the Department of Obstetrics and Gynecology at the Duke University Medical Center.

Dr. Haney is a past President of the American Society for Reproductive Medicine, a researcher, and a leading authority in this area, and I'm very delighted that you could be with us, and especially after all of the travels that were required to make it possible.

We're in your debt, and we look forward to your presentation.

Thank you.



SESSION 1: CHOOSING THE SEX OF CHILDREN:

CURRENT TECHNOLOGY AND PRACTICE


DR. HANEY:  Can everyone hear me?

PARTICIPANTS:  Yes.

DR. HANEY:  Okay.  I appreciate the opportunity to be here.  I'm actually a stand-in for Sandy Carson [President ASRM] who couldn't be here.  She's attending our meeting, and hopefully I can give you something similar to what she would present.

I think I reviewed your briefing booklet, and it has virtually everything I'm going to talk about in it, and so I'll try to do this relatively quickly and then respond to any questions that you have.

So I choose — and this is all personal — I choose to separate two terms:  sex selection from sex determination, and you'll see as we go through this what I mean by that.

Now, by way of indications currently one would define two, a medical and a nonmedical.  There are probably 350 or plus diseases known to be linked to an X chromosome, either autosomal dominant or recessive or X-linked dominant or recessive.  But an X chromosome as a potential carrier of disease.

The Y chromosome to my knowledge — and I'm not a geneticist,  so I apologize if there are some others that are around — the AFG mutations creating severe oligospermia have been well – documented now.  With many of the X-linked recessive diseases, the families who had these children or they're in the families would like to avoid having another child born, and hence, having a female with two X chromosomes and screening — by definition the father doesn't have it — would lead to that outcome.

The Y-linked diseases, we've actually been able to, using ICSI, intracytoplasmic sperm injection, have these very severely oligospermic men father children, but they will automatically pass on to any male offspring, which is going to be 50 percent, the same mutation that created their oligospermia.

And there's two responses to that.  One is I'd like to avoid that and have daughters, and the other response is that if we were successful in 2002, that meant by the time my son is 27 and wants to have children, he'll be that much more successful in 2029.

But in any event, that would be a medical indication for sex selection.

Now, the nonmedical ones, I choose to break into two categories:  primary gender selection, that is to say, the first conception, and the second one would be family or gender balancing, which tries to equilibrate to the social desires of the family, the opposite gender from preceding children.

Now, I don't need to go through the glossary in great detail, but we're all in our business acronym – related. 

IUI means intrauterine insemination with washed sperm, getting rid of the seminal plasma, which contains lots of prostaglandins and being able to put the sperm themselves in the uterine cavity without reaction.

COH is stimulation with — it's supposed to be — I'm a little off on the right-hand side over here —  gonadotropins, but controlled ovarian hyperstimulation, that is to say, inducing multiple ovulatory events in a single cycle.

IVF, pretty traditional, in vitro fertilization and embryo transfer.

ICSI, or intracytoplasmic sperm injection used to inject single sperm into oocytes to create embryos.

Blastomere biopsy, typically done at day three post – fertilization, which is removal of blastomere, typically an eight – cell embryo for some sort of DNA analysis.

Fluorescence – activated flow cytometry, or FACS, which is prominent in this arena here that we are discussing today.

Discontinuous density gradient centrifugation, and this is essentially layering the sperm or the seminal plasma on a gradient and centrifuging the sperm through it trying to separate the weight, subtle weight difference between X and Y bearing sperm to separate them.

DNA analysis, I'm not a geneticist, but there's tremendous numbers of these opportunities, which there will be more.  The ones that are most frequent for us are typical PCR or whole chromosome amplification or FISH, fluorescent in situ hybridization, and those are simply techniques to identify unique DNA, whether it's an X chromosome or a specific gene mutation.

Amniocentesis, removing the cells around a fetus which have the fluid in it and the cells from the fetus are present there.  You then culture them and do genetic analysis on those, and that's typically done by 15 to 18 weeks of gestation.

Chorionic villus sampling is a similar technique, but actually biopsying the trophoblast much earlier in gestation, much more rapidly growing cells.  They are proliferating trophoblast cells.  So in 48 hours you can have information or even shorter time.

And then traditional karyotype, just looking at the actual chromosomes.

Now, this is not a new phenomenon, the attempt to control the gender of offspring.  There have been for basically eternity people attempting this in one way or the other.

There are clearly very unsuccessful methods.  Coital timing, trying to be close to ovulation, there's a whole literature on that.

Changing the environment in the vagina where ejaculation would occur.

Electrophoresis, looking for trying to distinguish the X and Y sperm based on electric charge.

Transferring embryos with the most blastomeres because it's been the observation that the male embryos, genetically male embryos, proliferate.  The blastomeres proliferate a slightly bit faster than the female ones do.

And then density gradients, which I sort of listed as unsuccessful, but it's still practiced and many people in the United States use it, and you have a variety of materials:  albumen,  Percoll,  Ficoll, Sephadex, et cetera, that you could use to do the separation.

Now, possible methods — and I stress the word at the moment "possible" because in the absence of clear randomized clinical trials demonstrating efficacy, I really cannot tell you there is a method that effectively works, but at least these are a step above what was on the preceding slide.

And if you try to do this before fertilization, that focuses on selected sperm, and this is a relatively new phenomenon.  The technology was pioneered by someone in the Department of Agriculture named Johnson, and that's been applied in animal husbandry in a variety of species and simply adapted in the mid-'90s to try to do this to human sperm, and we'll talk a little bit more about what it means.

But when you preselect sperm, you have several options to use them.  You can use them in intrauterine insemination, simply in a natural spontaneous cycle timed reasonably proximate to the ovulatory event.

You can stimulate the patient with gonadotropins to increase the efficiency so that the likelihood of conception goes up, but there is also some hazard of multiple gestation.

In vitro fertilization, simply taking the selected sperm that you have and placing them in the dish with the collected oocyte.

And then trying to preselect the sperm and actually inject it into the oocyte directly with ICSI, and these all basically are the same philosophy with different efficiencies.

And then preimplantation would be not using selected sperm, but simply doing IVF, having embryos developed, and then doing blastomere biopsy and identifying the genes of the embryos to be transferred.

Now, sex determination is certainly not new, and that's a very old technology, and when ultrasound became more sophisticated and the resolution improved sufficiently, then one can identify the gender of a fetus simply by the anatomy of its genitals in utero, and that's probably about 15 weeks to 16 weeks of gestation that can be done.

And then chorionic villus sampling, as I mentioned, is biopsying the trophoblast, and that will be typically done between 11 and 13 weeks of gestation.

And then amniocentesis, which collects the fetal cells, and that would be done closer to 16 to 18 weeks of gestation.

Now, the human sex chromosomes are different than many other animals in that the difference between the amount of DNA is relatively small in the total genome.  So it's 2.8 percent between the X and the Y sperm, and that does leave the possibility at least theoretically of trying to separate it by a centrifugation.

As I alluded, that has not been demonstrated  to be effective, but I'll continue to discuss it a bit because it's being currently used.

And then the X and Y sperm can be differentiated to a degree by the amount of binding of fluorescent dye which allows their separation in a FACS, or fluorescent activated cell sorter.  A difference of 2.8 percent would then bind a greater amount of dye in a Y chromosome.

Now, the typical albumen or the Ericsson method, which has been used for many, many years, or at least propagated for many, many years, is albumen density gradient centrifugation, and it's discontinuous, and this is the various concentrations of human albumen, et cetera, have been more empirically defined, but the method has never been demonstrated to be effective.

And despite claims to the contrary, when objective observers have used it, they cannot see any difference in the offspring resulting.

Now, fluorescence activated flow cytometry is the current one, and it's licensed.  I'm not sure exactly who owns the patent, but it's licensed to Genetics and IVF Institute and under the trade name MicroSort, and essentially sperm are mildly sonicated, stained with a Hoechst vital dye, which reversibly and as best one knows does not alter the DNA, and then this dye fluoresces at 359 nanometer of ultraviolet light, and one can then be using the difference in the amount of dye bound to the two gender specific sperm.  They can be separated by fluorescence activated sorting and trying to simply enrich the fractions of X and Y bearing sperm for subsequent use.

So that's basically the principal involved, and this is just an illustration to show you the stained sperm coming through and then deviated left and right with X and Y.

And there's actually in practicality — they are mostly done not simultaneously, but sorted for X or sorted for Y.  So don't sort them all together for both.

And this is what the proof as has been proposed for the efficiency of that process, and that is that when you extract — this isn't done in the actual treatment procedure, but to demonstrate that they are accurately doing that, they then use FISH, fluorescent in situ hybridization, and look for probes for either X or Y, and this is in an XSort, and you'll see that there's a — it's not so clear here, but these are pink, and that one's green, showing you that there's a substantial shift toward X bearing sperm, and they estimate, based on their FISH numbers with some data that it is 80 to 90 percent effective in separating the two sperm haplotypes.

The FISH analysis with the Y sort is similar, and you see they have the sperm.  An X is marked in red, and the other is green.  This is a little less effective.  Somewhere between 60 and 70 percent shifted to Y bearing sperm with this technology.

And then a case report was forthcoming for the first initial case of a birth that occurred after this procedure in 1996 and consistently the reports have been, except for one, related to female selection.  And this was, I believe, — I believe this is an X-linked hydrocephalus problem in the family.  I'm not sure exactly what it is, but it is a medical problem that this child — they opted for a female offspring.

Now, there are several utilizations or there are several ways of utilizing the sperm that you get, and the number and quality of the sperm selected in this process determines how they can be used.

Now, you have to make the assumption that if you use them, that the selection process did not harm sperm function, how it actually works, and we can't really test sperm function other than the fact that fertilization and embryo development occurs.

So you can look at the number of sperm and accrued semenalysis or a swim-up sample and look for a variety of surrogate markers, capacitation, et cetera, in the sample to see if it had an impact, but function is still difficult.

So if you get what appears to be after your whatever the procedure of sorting that you get normal qualitative and quantitative parameters for this washed sample, then you have the potential for putting it in the uterus, and if you do that in a natural cycle, it turns out to be about an eight percent cycle fecundity, that is, term delivery after one treated cycle.

And the human fecundity at max is probably 20 percent, and people argue between 12 and 18.  That is to say one in every five to six cycles turns into pregnancy.  That's clearly age related, mostly maternal age.

If the selected sample is not in the normal range, but there's more than a million hyper modal sperm, and by that I mean when they're layered in media and allowed to swim out of the pellet with centrifugation.  Those are the most actively modal sperm and the highest quality fraction.

If that is greater than a million, but you're not in the normal range, then you have  the option of doing an IUI with stimulation.  Now, that increases your cycle fecundity slightly, and the reason that's probably true has to do with the estrogen stimulation of the female with higher numbers of oocytes and follicles, and the estrogen in the female genital track facilitates sperm transport into the distal tube where fertilization occurs.

You run the risk of multiple gestation with that.

In vitro fertilization significantly increases your cycle fecundity, but at much significant cost, and we'll talk a little bit about cost at the end, but depending on the circumstances and the quality of sperm, age of the mother, et cetera, you would sort of currently go between 15 and 35, maybe up to a 40 in women below 30 for a per cycle delivery rate.

The conception rate, that is to say, missed period and clinical pregnancy rate, would be slightly higher, but you would see some spontaneous abortions.

And then if the sample is noticeably lower in quality  and the motility in addition may well be abnormal, then instead of traditional IVF where the sperm are simply placed in with the retrieved oocyte, one typically microinjects the sperm or the egg with the sperm, ICSI, and that offers per embryo, which you generally can get the same number of embryos you would if you put healthy sperm in with the standard egg retrieval.  You get the same success rate.

So ICSI, even though it's just a little more manipulation, turns out to be virtually identical to IVF for oligospermic either samples or males.

Now, intrauterine insemination is simply, just to illustrate what we're doing, after you separate the liquid from the sperm and get rid of all of the prostaglandins and the seminal plasma which normally stay in the vagina and never enter the uterus, only the modal sperm actually enter the uterus.  If you can separate the two, you will lose a few sperm in the process, but you then place a small catheter into the uterine cavity and deliver the sperm there.

And the attrition that normally occurs in the vagina to the uterus is on the order of 100-fold loss.  One percent actually get there, maybe two percent.  So tremendous attrition.

So placing them higher, even if you lose a few, will increase the numbers of sperm in the distal tube where fertilization occurs.

So that's the strategy between intrauterine insemination.  You simply have to wash them so seminal plasma is not transferred.

Controlled ovarian hyperstimulation is a more complicated scheme where one injects LH and FSH, the human gonadotropins that are normally made in the pituitary.  Humans are monotocous, that is, we release one oocyte even though a crop of follicles matures every cycle.  Polytocous animals don't have the selection that goes from a crop to a single ovulation that we do.

So the difference between a monotocous species like us and a polytocous species is not the number of follicles you move forward each reproductive cycle, but the selection process to release one.

That's clearly involved with gonadotropins, and when you simply overdose the patient, if you will, with gonadotropins, you can get a larger proportion of that crop to mature and hence you can stimulate more than the single ovulation in a given cycle.

All those follicles appear functionally equal in genetic quality, et cetera.  It's just in monotocous species the metabolic demands of the mother are such that you should have one offspring most of the time.

But that's the way it's done and simply has daily injections in the follicular phase in the first half of the cycle until ovulation. 

And this is what it looks like and how it's controlled.  One stimulates the patient, and then you do standard transvaginal ultrasound exams, and you can very accurately with the technology today measure follicular diameter.

And the stimulation is maturing the follicles and typically human ovulation occurs about 22 millimeters.  We can trigger with HCG ovulation about 18 millimeters, and from a lot of other information with IVF, we get healthy oocytes and mature pre-ovulatory oocytes when you do that.

So this stimulation is then by injection.  We teach husbands how to do it.  They do the shots.  We do the monitoring, and you can measure with the estrogen because each of these follicles makes estrogen as well.

So a combination between ultrasound and estrogen gives you the follicle number and the timing for triggering release of those follicles.

Now, IVF with ICSI using selected sperm, you do the same stimulation with the injectable gonadotropin.  You do the same ultrasound, but at the appropriate — we block the LH surge, blocking the pituitary so the patient cannot mount the terminal 36 hours of that maturation of the oocyte and release of the egg.  We block that so that we're in control of it.

We then do a transvaginal ultrasound guided oocyte retrieval.  It sounds kind of gruesome, but it's very efficient, and it's not very uncomfortable.  We just use contrasedation and retrieve the oocyte, and it's age – related how many you'll get per patient.

And then you have the oocytes in vitro, which you then inject with whichever of the two sperm that you had selected.

The embryos are then transferred via the cervix into the uterine cavity and implantation and all subsequent pregnancy events.

This is what it looks like.  This actually isn't a needle, but this is very accurate.  It's the same picture you saw before, and we simply take our ultrasound probe and put a guide on it and slide the needle through, and you can literally puncture each of these follicles in succession and with minimal suction aspirate the contents, and about 90 percent of the time an oocyte will come with the follicle, the follicular fluid that you've aspirated.

So that's basically the process.  You stimulate with gonadotropins and then do an egg retrieval rather than allow ovulation to occur by itself.

Now, ICSI then to inject the sperm, this is done with micromanipulators in vitro.  There's a cumulus mass.  I should have shown you that, but a cumulus mass is normally present, the zona pellucida.  We strip the cumulus mass, and then with very low pressure fix the oocyte up against a pipette.  This is done with micromanipulators.  So it's not by hand, and then a drawn glass pipette has become very small. 

You can crimp a sperm tail and get a single sperm in the pipette, puncture the zona pellucida and the plasma membrane of the egg, inject the sperm, and then withdraw the pipette, and both the plasma membrane and the egg and the zona pellucida seem to tolerate this reasonably, and fertilization then occurs at the same rate as the normal sperm would penetrate in vitro and have fertilization occur.

So that's used both for oligospermic men, and it was simply adapted here to be able to take sorted sperm and do the same thing.

Now, host fertilization pre-implantation selection is a different phenomenon.  The preceding slide showed you that you injected selected sperm of the gender that you were looking for.  With this process, in vitro fertilization is performed with just the routine semen sample available in the same series of events, except there's no ICSI.  It's standard fertilization in vitro.

And then at about three days, blastomere is removed for determination by one of these analytic methods, FISH, PCR, whatever, to determine the presence of an X or Y, and then one has a series of embryos which are kept in each of their own wells, and you've identified their genetics.

And this is exactly the same technique you would use for pre-implantation genetic diagnosis, except there you do PCR first, with a specific probe for gene defect you're looking for.  Here they're looking for a gender differentiation.

There's a biopsy. You can pull out of a blastomere and then do some sort of DNA analysis.  This is actually on leukocytes, but it looks the same.  FISH is identified with colored probes.  You can do whole chromosomes.  You can do whatever the most efficient analytic technique you have and identify the gender.

Now, here's the clinical data that has been presented for fluorescent activated cell sorting to date, and this is the initial paper in Human Reproduction in 1998, and all of it except for  this one little bit here for the YSort, which I'll tell you about, was last week at ASRM, was on X, selecting for Xes.

  And so they did 208 cycles, and they did a variety of things.  Two hundred and eight cycles of IUI, intrauterine insemination, where they simply got samples and then placed them in the uterine cavity of the wife at the appropriate time.

They had a ten percent cycle fecundity with that.  They then did either IVF or IVF with ICSI, and they did 36 cycles in 27 couples and had an improved success rate, though it's not as high as one typically sees with just straightforward ICSI for oligospermia.

And of those, they ended up with 29 pregnancies.  They had seven losses, one ectopic, nine deliveries, and at the time of the report, 12 ongoing clinical pregnancies, and they have never gone back and validated in the literature what those turned out to be.

But they then claimed that they had 15 of 18, or 88 percent, of fetuses with known gender, and some of these presumably were ultrasonically identified, were of the gender of choice, female, for the selection they had.

Now, that's what existed up until Tuesday, this past Tuesday, as best I can tell in all of the literature, and if you think of all the activity that has gone into this up until Tuesday, it's based on this, and there isn't a single male paper out there demonstrating an equivalent YSort to show that you could actually increase the likelihood of male delivery.

And a comment was made without data in an abstract at ASRM that they thought that the babies born were 78 percent when they did YSorts and 92 percent when they did XSorts, and that didn't have numbers associated with it.  It was just a sentence in the abstract which was actually done for a different reason.  It was there to show that there was no abnormality in the offspring that were generated.

And I tried to deduce based on some issues they had for abortion, spontaneous abortion with that.  They were assessing, and you'll see in a minute, the number of losses that might have occurred and was that different than normal? 

And I think I could deduce 304 total pregnancies in the group, and out of 1,900 sorting procedures.  So that's as best trying to extract from them what's published as to what's actually going to validate that this works.

Now, their current usage, and by that I mean request usage, this is an abstract, two abstracts the group presented, 245 ICSI cycles.  They had roughly two thirds were looking for Xes to select for females and one third for males, and they did note that the goal is to be able to send samples frozen through the mail, get them sorted and send them back, and then do ICSI with them.

And they did note that when they did that, they had a reduced fertilization and cleavage rate, which isn't terribly surprising with the trauma of cryopreservation.  When it works, it works, but the efficiency is going to be declined.

And the other abstract that I mentioned that had 1,900 separation procedures, they separated them without the numbers in each category as family balancing and medical indications and found the same spontaneous loss rate and then noted a 2.5 percent major anomaly rate, which is favorably compared to the three to four percent in the general population.

And importantly, if you look at those sorts of anomalies, there is no pattern.  They're all random and different.

But, again, the fleshing it out to the actual numbers wasn't in the abstract.  It's a little hard to do.

Now, the current availability, if you will, there is no comprehensive place.  ASRM or any other doesn't compile any programs  that offer sex selection, and basically this is an Internet advertised offering.

And I could find six sites, although I'm sure there are more, but there are many locations.  Some of these programs have locations in different states and advertise them in different countries, and the technologies that they advertise  — and sometimes it's very difficult even in the Internet site to figure out what they're doing for sex selection.  So you can't tell if they're doing the Ericsson method of density gradient centrifugation or actually doing the fluorescent activated cell sorting or even PGD.

And some of the sites separate them and say you can do PGD where it's extremely accurate, where you've actually pulled out the blastomere and know the genes to the extent that PCR or FISH would do.

Others — and the couple that would choose that can pick whichever level of security they want for increasing costs to do them.

So they're all over the place, but it's basically an Internet business that's being advertised, and this is the sort of ad that one sees.  This is one of the franchised MicroSort centers, and complete with a full debate about whether it's appropriate or not.

And then if you're really interested, click this button and go further.

These are roughly what the costs are, and they will vary a lot.  New York City is very different than Durham, for example, in IVF costs.  IUI is, with the preparation and insemination, about four to $600; COH, about 2,500, including the drugs and the ultrasound monitoring.  IVF in our institution is ten.  Other places, in more expensive markets, 15, 14, $15,000.

ICSI will be an additional fee with the IVF.  So this fee is the entire thing.  It's a couple thousand dollars more than you traditionally do with IVF. 

Most of the others are not done often enough in enough places to get a good idea what the costs are, but these are estimates for a blastomere biopsy equivalent to ICSI, $1,500 for a manipulation, the same basic sort of technology.

PCR I've seen in several places around $3,000; FISH, a little bit less.  The MicroSort varies, and depending on the franchise place for it, between 2,500 and 5,000.

Ultrasound is relatively inexpensive.  When you look at the three determination as opposed to selection technologies, they're relatively cheap.  Ultrasound exam is very simple, $300, and amino with the karyotype is probably between 1,500 and 2,000, and then a chorionic villus sampling, slightly higher.

And that would be a rough idea, but there is some variation from institution to institution and locale to locale.

Now, the questions that immediately come to mind with fluorescent activating cell sorting, which is the most heavily advertised version, is the relatively small number of reported clinical outcomes, and this is particularly true since the success of the technology is not validated by anyone other than the people who own it, if you will, or who are franchised for it.  So it's not independently done.

It has not been a technology that has been validated by anyone else.  So very small numbers, and I think you have seen what is in the literature.  I could have missed something somewhere, but I scanned everybody's name, whoever was on the MEDLINE and any of those papers and tried to find their name on anything, and that's the only thing I came up with.

So there could be an abstract somewhere else that isn't in MedLine, but other than that, I think that's it.

This is the dye utilized to Hoechst 33342 dye, bisbenzimide, and that's the binding to the sperm that's reversibly binding.  But the question is:  what is the true impact?  Is there any subtle impact in altering the DNA?

And similarly, we're using the wavelength of ultraviolet light to cause it to fluoresce.  So you have the marker to separate the light.  I think there certainly have always been some concerns about the exposure of sperm to that and DNA to that.

And then the relatively small recovery of sperm after you do this process makes the efficiency of doing it with insemination much lower.  So you then, to make it an efficient process after cell sorting, is you see as time has gone on the reports that occur, always focus on doing ICSI and IVF, and certainly those carry their own concerns as well.

Now, future technologies — and this is more free association, and believe me, as you well know, smart people will do things I haven't possibly dreamed of, but future technologies for sex selection would be selective elimination of an  X or Y bearing sperm on the basis of something on the cell surface biochemically or immunologically, and that's been talked about  a lot, but has never come to fruition.

But you can think of it very similar to an assay using complete mediated cell lysis where you lysed sperm of the sort you wanted to remove, and then selection of sperm by some noninjurious DNA analysis rather than simply the density of binding of the fluorescent, something that specifically bound the sperm.

Now, the limitation to date, as you can appreciate, is the sperm is a very condensed DNA package.  It's basically a DNA packet with a tail, and it's very hard to get any probe into this condensed DNA where you could determine anything, but I won't say that isn't possible at some point.

Preimplantation you can potentially look for a gender specific gene expression within an intact embryo analogous to the Fisher dye staining.  So you could potentially without — if you could do it in a noninjurious way, without doing a biopsy, you can potentially look for any genetic trait within an embryo if you can get to the point of not being able to injure an embryo.

You can look in the media and see if there's a differential uptake of one precursor or another.  I don't think that's terribly likely to be profitable just given the undifferentiated state of the early embryos we have, but I can't exclude that.

And then you can do a FISH analysis similar to something like that on cells that remain after you've hatched, an embryo is hatched.  And we've seen something like that happen.  We've transferred just when you get to blastocyst cultures, some of these are beginning to hatch, and you're going to see some cells that are just going to fall away from the embryo and you potentially have those to use as well.

So there's a lot of options, and there are going to be more that come along.

Now, sex determination, that is, having a clinical pregnancy and determining what the gender is, just so that you know if you haven't seen these things before, this is an ultrasound showing a tear shaped uterus with a gestational sac and a fetus in a yoke sac, and the amniotic fluid.

And so one then at a much later stage of gestation can aspirate the fluid from the amniotic or aspirate the amniotic fluid in fetal cells that are in the amniotic fluid, are then available for cell culture.  They use fetal fibroblast and slow to grow.  So it take a long time to culture them.  It's a laborious and difficult process.

The chorionic villus. sampling where you're getting trophoblasts, they're proliferating very actively.  So it's extremely rapid, and you basically place a needle and remove a bit of trophoblast.

And then the fetus itself, you can — I'm sorry.  The red isn't really clear — but you can begin to look at the characteristics of the fetus, such as its yoke sac and other things, by ultra sound and begin to look at gender differentiation.

So the future for sex determination as opposed to sex selection is going to be a variety of things:  a collection of exfoliated trophoblasts which may be present in the vagina.  The membranes of the fetus, there may well be very small numbers of cells shed into the endocervical canal and virtually equivalent to a Pap smear, you could extract those, determine that they were fetal, not maternal, and then have a genome to look at.

Detection of factors in the maternal circulation responsible for gender differentiation in the fetus, and these are primarily related to the duct systems of the two sexes, the Mullerian duct or Musophen [sp?] ducts and Wolffian ducts, and there's some very, very specific hormones involved in female differentiation and male differentiation, and potentially small amounts of those will cross the placenta and be detectable in blood.

There's a phenomenon called 4D ultrasound.  It's 3D with a time element for the fourth, and they're getting extremely sophisticated with high resolution, ten, 12, 11 megahertz to be able to see much more details in the fetus, and that's for a lot of prenatal diagnosis.

And then fetal red blood cells.  Once the fetus begins to make them, they are nucleated so they show up.  And they do show up in very small numbers in the maternal circulation, and you can try to filter them out, and people have for years been trying to find ways of doing that.  It would save you doing an amniocentesis if you could efficiently retrieve them because they have the nucleus, and you could then do a DNA analysis on the fetus by fetal nucleated cells.

CHAIRMAN KASS:  Sorry.  Could I ask?  Could you give the rough age of gestation when these things might be possible?

DR. HANEY:  You're going to stress me there.

CHAIRMAN KASS:  Well, roughly.  What's the earliest?

DR. HANEY:  I don't honestly know.  I would hesitate to say.

Sandy [Carson] and Joe Leigh [Simpson] can probably tell you better than I can, but I'm sure it's no earlier than 14 weeks.  I think it's minimum then, but I honestly don't know the exact week.

And then ultrasound guided amnios transvaginally, we aspirate many, many things we never dreamed possible before down to four and five millimeters.  So easily one may well see transvaginal much earlier amniocentesis for fetal material as you saw in the picture.

And just two slides, and I don't want to steal the thunder of the subsequent speaker, but to show you the impact of the sex determination and all of these gender differences, I would tell you are probably related to sex determination, not sex selection, and ultrasound showed up somewhere in the early to mid-'80s that was then capable, sophisticated and with high enough resolution to actually begin to look at genital differentiation in utero, and you began to see that's when the largest change in disparity of male to female ratio by birth occurred.

But this would be both.  Whatever gender selection might have been going on, but I'm going to bet it's all sex selection, but I'll bet it's all sex determination, and this would be for people in this category because they're all parities.  It would be people who selected primarily to get the fetus as opposed to people who had three children of one sex and wanted another.

And then if you look at the impact of gender determination for balancing, that is, in subsequent pregnancies, you can see it's very dramatic; that the further they go in the number of pregnancies, the greater the desire to balance the offspring.

And I think I'll stop at that.

CHAIRMAN KASS:  Dr. Haney, thank you very much.

The floor is open for discussion.  Mike Gazzaniga.

DR. GAZZANIGA::  I'm just curious to know how many cases, if we call it, an event where there's a desire for sex selection or sex determination; how many in the United States per year are seeking this sort of service?

DR. HANEY:  I don't think there's any way whatsoever to determine that.  There's not a record kept anywhere, and the best you have, I think, is an estimate of the total number that are reported in the abstract you saw there, but there's absolutely no way of knowing.

DR. GAZZANIGA::  So say within your own center.  What percent of births do you think would be governed or guided by this technology?

DR. HANEY:  We don't do it at all.  We wouldn't do it.

DR. GAZZANIGA::  Oh, you don't do it?

DR. HANEY:  No, no.

CHAIRMAN KASS:  Bill May.

DR. MAY:  You used the word "franchise."  Are you talking about the ownership of technique and then franchising locations?  Is that what you mean by franchising?

DR. HANEY:  Maybe that's a loose — I don't know all of the financial arrangements of their program, but they do have the label on MicroSort and various programs around the United States, and they have programs hither and yon.  So that's just a loose way of me describing.

They must be related to Genetics and IVF Institute in some fashion.

CHAIRMAN KASS:  Bill.

DR. HURLBUT:  I want to ask you about a couple of the scientific sides of this.  When they use the dye that interpolates into the DNA, is there a way of washing it out before the gametes are mixed with the oocytes?

DR. HANEY:  As best you can read the technology, it's not actually washed out, other than the amount that's washed out in the processing that would occur subsequent to the sorting before you put it in, and it's thought to be noninjurious, and it will begin to — if you wait an interval of time, you get less and less fluorescence.  So the dye is constantly being disassociated with the DNA.

DR. HURLBUT:  What I'm thinking of in asking that is we're coming to appreciate more and more how transcription is affected by large scale operations on the centrosome and around the histones and so forth so that something that interfered, even if it seems to be innocently intercalating, might actually be affecting something.

DR. HANEY:  I think that's the concern.  That's I think what prompted the abstract with the 300 offspring and looking for anomalies, but they're all young and you don't know what's going to be there over time.

DR. HURLBUT:  Other questions on this line.  I know that at least I think it's established that there are often events within a normal embryo where aneuploid cells are produced, for example, or even cells without nucleus in a given eight, ten cell embryo.  There may be a couple of cells that are abnormal.

They normally gravitate into the trophoblast apparently and don't actually make their way into the embryo.  So this isn't a matter of sex selection primarily, but you could have instances in post – implantation or pre-implantation diagnosis where you are actually getting a misimpression from looking at one cell over another, right?

DR. HANEY:  There's no question that when you do pre-implantation genetic diagnosis for anything, you're going to have a limit to the technology because of heterologous, if you will, or heterozygosity of this, the particular agent, and particularly if you have some error in one cell doesn't contain that.

They don't use polar bodies that much for that reason.  Polar bodies could be used, too, for the maternal mutations, and they are less reliable than blastomeres, and you're talking about blastomeres that aren't all the same.  But these are not chimeras.   So it's some other technical abnormality that would have to be there.

But I think that's known inherent with the technique.

DR. HURLBUT:  And finally, the recent evidence seemed to suggest that there is already polarity even in the early embryo, and that there is asymmetric cell division with regard to cytoplasm, which may contain certain determinant factors in the ultimate outcome of the embryo.

This is a rather abstract question, but does it worry you at all that even if you produce a normal, apparently normal pregnancy out of this process that you're actually altering the outcome of the individual life?

DR. HANEY:  By what?

DR. HURLBUT:  By taking —

DR. HANEY:  Blastomere biopsies?

DR. HURLBUT:  — a blastomere out of the developing embryo.

DR. HANEY:  At an eight – cell stage, I mean, the blastocyst is five to six days, and you have a blastocoll cavity and innercell mass, and then the trophectoderm on the outside.  And that's clearly — I don't know if polarity is the right word, but it's clearly differentiated into those compartments.

At the eight cell stage and based on animal models, one would not anticipate that you would alter that blastocyst development by any methodology I'm aware of.  I can never say it couldn't be there, and the more subtle you look, the more reassured you are, but as best I know, when you biopsy that early when there are undifferentiated cells, before that and at an eight cell stage you don't see polarity.  They're just eight cells.

So I think you have to get another day or two out to be able to see that, but I cannot tell you there's some, but not biochemical polarity occurring, if you will, in that process.  And all you can ultimately do is look at the offspring that are born, and hopefully in an animal model under experimental conditions, and determine that as you move forward.

DR. HURLBUT:  There was an article in Nature magazine about four months ago.  Its titled "Your Destiny from Day One," and it tracked the asymmetric cell divisions and certain cytoplasmic factors that were disproportionately assigned between the cells of the embryo, showing that there is a predicted cell fate even at that early stage with disproportions of cytoplasmic factors.

So theoretically at least you  might be getting a different outcome than you would.  The only reason I raise this is because in the thinking about this issue, is the general assumption in the community that you're taking one or two blastomeres out at the six to ten cell stage is not affecting the outcome in any way, or is it accepted that you're affecting the outcome in some way, but not adversely in an abstract sense?

DR. HANEY:  I think that the general, if I had to characterize it, it would be that you're risking that the embryo will not survive, but you're not risking that you're going to have an anomalous embryo.

DR. HURLBUT:  What percent increase of failure to survive do you think you're affecting the embryo with by doing this?

DR. HANEY:  If you looked at IVF success, and I won't say that this is good enough data, but I would guess that you're at least cutting the success rate if you looked at standard IVF without a biopsy at let's just say 35 percent and you do a biopsy, it's probably 20.

DR. HURLBUT:  Thank you.

CHAIRMAN KASS:  Gil and then Michael Sandel.

PROF. MEILAENDER:  I understood you to say you don't do this at your clinic; is that right?

DR. HANEY:  My institution, that's correct.

PROF. MEILAENDER:  Why not?

DR. HANEY:  I wasn't going to talk about ethics and that sort of thing.

CHAIRMAN KASS:  You're free to.  You can take the Fifth if you'd like.

DR. HANEY:  No, we would —

(Laughter.)

DR. HANEY:  We don't philosophically agree with gender selection.

PROF. MEILAENDER:  I mean obviously you don't have to talk about anything you don't want to, but I'd be interested if there's a short version of the philosophy and if you're willing to say a word or two about why you don't agree with it.

DR. HANEY:  I'm fully supportive of pre-implantation genetic diagnosis for medical indications, for medical diseases.  We just don't believe that gender — influencing gender birth by medical manipulation at my institution personally for my division, and all three of us who work there, we're gynecologists.  We think women are good people, too.

PROF. MEILAENDER:  So you engage in client selection?

DR. HANEY:  I'm sorry?

PROF. MEILAENDER:  You engage in client selection.

DR. HANEY:  Define "client selection" for me.

PROF. MEILAENDER:  Well, the purposes for which one wants —

DR. HANEY:  Okay.  Medical indication.

PROF. MEILAENDER:  — medical indication.

DR. HANEY:  Correct.  In that sense, yes.

CHAIRMAN KASS:  Technically speaking, by the way, it is — I think you might agree with me in the suggestion that what you're doing when you're doing pre-implantation and genetic diagnosis that involves the gender of the offspring, as in the cases of the X-linked diseases, if there were a way of finding the presence or absence of that disease marker, you wouldn't be doing sex selection at all.  You would be looking for the marker.

So this is sort of incidentally sex selection as a way of making sure that you do not produce the afflicted child.  I mean, it belongs really with pre-implantation genetic diagnosis for diseases, and it happens that the quick way to screen for the possibility of the disease is to screen for X-Y.

DR. HANEY:  You're exactly right.  If you looked at the — you have two Xes.  One is affected; one is not.  And if you could not only look for the X, but you could look for the specific mutation on the X, then you'd be doing exactly the same thing as any other autosome.

And I think it's just an efficiency, quick and dirty, simple.

CHAIRMAN KASS:  Right.

DR. HANEY:  It's much easier to screen for the X chromosome than it is to be looking for the specific gene mutation.

CHAIRMAN KASS:  Right.  So that technically speaking, I don't think — this is a kind of accidental sex selection as it were.  The intention really is disease prevention.

DR. HANEY:  Correct.

CHAIRMAN KASS:  Could I, Michael, before?  Just to clarify, to see if I can sum up, and I think this is what Mike Gazzaniga's first question was getting at, just sum up where we are technically speaking here.

There is certainly no cheap way of doing this.  There's no do-it-yourself way of selecting in advance.  The best figures right now from MicroSort are if someone were interested, for example, in producing a male child, they could get 70 percent instead of 50, roughly speaking.

So that at the present time it doesn't look like that there is anything that is likely to be used on a wide scale in the way of selecting the sex of children. 

Would that be —

DR. HANEY:  I'm even hesitant to say it's effective until I see randomized clinical trials showing me data.

CHAIRMAN KASS:  Okay.  Then second, on the pre-implantation genetic diagnosis, there the diagnosis is pretty accurate.  There's some questions about the safety of —

DR. HANEY:  An estimate would probably be 90 percent.  You'd be 90 percent accurate with a prenatal — pre-implantation genetic diagnosis using PCR or something like that.

CHAIRMAN KASS:  Only 90 percent?

DR. HANEY:  Un-huh.

CHAIRMAN KASS:  Now, if this technology were used for screening for diseases on an increasingly large scale, in other words, if the future holds much more pre-implantation genetic diagnosis, wouldn't it be — will it be just as easy to simultaneously do the screening for X and Y?  Get the information whether you want it or not?

DR. HANEY:  Not if you're doing specific gene probes.  So if you're looking for Huntington's, you're screening for Huntington's, and you're not doing anything to look at the —

CHAIRMAN KASS:  Okay.

DR. HANEY:  — gender determining chromosome.

CHAIRMAN KASS:  So there's no necessary — if someone were to say, "Look.  If we have a lot more PGD coming, then it will become a lot easier for people who are using PGD also to engage in nonmedical sex selection."

DR. HANEY:  I think you can argue that the better you get a PGD, the less gender you care about.  that's what you were alluding to before, and you're going to use probes —

CHAIRMAN KASS:  No, I —

DR. HANEY:  — that are specific for the mutation, and you'd have to do something additional.

Now, if the lab is working, sure.  I mean, and you had another probe for something on an X or a Y.  If your lab is functioning, that's true, but the more specific you get, the actually less concerned you are about the —

CHAIRMAN KASS:  Well, you're looking for the disease, but I'm thinking now in terms of the client.  The client says, "Look.  I'm going to have PGD anyhow.  By the way, I would like a girl," or, "By the way, I would like a boy.  Can you do it for me, Doc?"

DR. HANEY:  I think it's exactly the same argument that you had if you did it just without a disease.

CHAIRMAN KASS:  Technically, I mean, it's —

DR. HANEY:  It's just a matter of having a functional system.

CHAIRMAN KASS:   Right.

DR. HANEY:  And if you're good at it and you have a lab doing it well and you're looking for a lot of different mutations, I mean, no center is probably going to do everything.  You're going to have some centers that do cystic fibrosis more and Duchenne's muscular dystrophy and all the various ones, and there's going to be some centers that like to do a lot more of it, and they're just good at it, and they have a system that's very efficient.

And so if you said, "Fine.  We had one of those other probes," yes, it will be easier, but it's actually going to be less important from the geneticist's point of view.

CHAIRMAN KASS:  Yeah.  Let me try one last time.  Sorry.  I don't think I'm — what I'm trying to figure out is whether this is a problem we should worry about in the United States or not.

DR. HANEY:  Okay.

CHAIRMAN KASS:  And that was in a way Mike Gazzaniga's question.

DR. HANEY:  One of the most interesting parts about the numbers is you have no idea of where the country are that they came from.

CHAIRMAN KASS:  I'm sorry?

DR. HANEY:  You have no idea where the countries are that they came from.  The data they presented because it isn't even listed in the abstracts as happening in the United States.  So I have absolutely no idea what it is.  It's a very small number.

CHAIRMAN KASS:  Well, it would seem to me that it would not be — I mean, people who want to do sonography and abortion can do that.  I mean, people who want to try to find some way of selecting in advance, either this MicroSorting technique is going to have to be perfected or you're going to find surface specific antigens that will differentiate X and Y carrying sperm and so on, stuff that we don't yet have, or those particular people who offer — there are apparently some 30 or 40 or 50 clinics in the United States that already are offering sex selection.  If more and more people are using PGD for other purposes and they don't have your scruples about doing this for nonmedical reasons, the question is:  could this get to be a sizable phenomenon simply by piggybacking on an increased rate of PGD?

That was the point of the question, and Ó-

DR. HANEY:  There's no question more PGD you do, the more things you can screen for.

CHAIRMAN KASS:  Yeah.  I'm sorry for holding you back, Michael.

PROF. SANDEL:  I have a general question, but this exchange leads me first to a specific one for Dr. Haney.

Did I understand that the thing that you haven't seen, the kind of trials that would persuade you that it works, that's the pre-fertilization sex selection?

DR. HANEY:  I mean, if you're at the FDA, you do a randomized trial.  You're looking for an outcome, and you wouldn't accept something that didn't have that.

PROF. SANDEL:  Right.

DR. HANEY:  And I don't care if you're a surgeon or — it's sometimes harder to do, but you need to look at a more substantial database to be able to do it.

And the disconnect is when you look at FISH related semen or you were talking about 70 percent of the sort being male.  That's not going to translate to 70 percent males born.  It's going to be less than that.

So that it's a fairly inefficient system.  So before I would accept that it's really going to work, if I was simply looking at it, I would want more rigorous testing, and certainly by a variety of different participants, not just the franchisee.

PROF. SANDEL:  So that's the sorting.

DR. HANEY:  That's the sorting business, right.

PROF. SANDEL:  But the thing that works is the pre-implantation.

DR. HANEY:  The PGD works much more — it would be much more highly accurate because you're taking the actual blastomere from the genetics of the embryo you have created and screening for it, and there's very simple whole gene amplification and looking for other epitopes that you could identify, satellites, alpha satellites, and whatnot that you can clearly identify.

So far more expensive, far less efficient, but much more accurate.

PROF. SANDEL:  Well, thank you.

This has been a fascinating account of really what's out there, especially for those of us who are not knowledgeable about this field.  It's of enormous interest.

The general question I had really was for Leon and for the group, and it's a question of what we do with this fascinating overview of the technology.  We could kind of probe Dr. Haney to see, well, just what's the risk of harm and so on and at what stage is this done and what are the technologies that involve destruction of embryos and which ones not and how prevalent.

But is there an opportunity — and maybe this isn't the session for us to take up this question — to address the underlying ethical question itself if there were a way of doing this without harming, without harm and without killing embryos?  Would it be objectionable and on what grounds?

Are we supposed to shoehorn that into this discussion or is this discussion just acquainting us with the technologies so that we can then be in a position to decide whether later we want to take up that ethical question or not?

CHAIRMAN KASS:  Well, I mean, my sense was that we invited Dr. Haney, as we've been inviting other researchers in the field, to get us up to speed as to what's possible and even to — and I'm very grateful to Dr. Haney also for not shying away from suggesting what might be possible, thinking ahead to various at least conceivable techniques so that we have a way of thinking about this — but that we amongst ourselves are free now also to discuss the implications of this and the ethical questions.

The American Society for Reproductive Medicine has — and I think these were distributed with the briefing books — has policy statements both on the use of pre-implantation genetic diagnosis for nonmedical sex selection and also on the sperm sorting, and it seems to me perfectly reasonable for us to discuss amongst ourselves and Dr. Haney insofar as he wishes, I think, to enter into this discussion.

So before we went there, are there any other technical or use questions before we went into that area, just so that we don't leave out?

Janet, did you want to?

DR. ROWLEY:  So as I understand it from particularly one of the slides that you had of oocytes or developing blastomeres in a Petri dish, that particularly if you have super ovulation you may have four or five oocytes that you can do for fertilization.

DR. HANEY:  Typically what's done is all mature oocytes are — I shouldn't say "all" — but almost all.  If you also do ICSI, you practically will do eight or ten or 12.  If you had 15 embryos it gets a little much to do them all, but you do basically all you can.

And then if you're just in standard IVF, you're going to put sperm, hypermotile sperm, with all of them because the fertilization rate probably won't exceed 50, 60 to 65 percent, and then the two pronuclear egg, the pronuclear egg with two pronuclei won't get to a cleaving blastocyst.

So if you started with ten oocytes, you'll probably have six or seven that are fertilized and probably no more than four or five that are cleaving embryos in the process.  So it's a matter of trying to get as many in the beginning so that you can get down to reasonable numbers at the end.

But if you end up with healthy, which occasionally you do, healthy embryos that you're not going to transfer, you freeze them.

DR. ROWLEY:  Okay.  That was actually my question.  So then you have these frozen embryos available either for the couple if they choose to have a second pregnancy or for whatever purposes.

DR. HANEY:  Correct.  In every IVF center in the United States there's large numbers of frozen embryos.

DR. ROWLEY:  Right, because this is one of the issues that we dealt with earlier on, is that at some point some of these developing embryos may actually be discarded, and then if that's the case, what are the acceptable uses of those developing embryos?

And what's the practice at Duke?  Just continuing to accumulate these, or do you have a time after which you discard them?

DR. HANEY:  Every institution has their own  pragmatic and philosophic way of dealing with this.  So you have our attorneys have worked out an agreement.  The patients sign it.  They pay for and store extra embryos, and they're their embryos, and many of them will come back.  If they don't conceive, they'll be back to get their embryos thawed out, much less expensively transferred.

If they conceive, I would say 90-plus percent will be back a year or two later for another transfer.  If you can get both pregnancies out of a single embryo or a single oocyte retrieval, it's much more efficient.

There are people who will get a set of twins and deliver their babies and say, "That was our family size expectation and I have three extra embryos that are still in the incubator or still in the freezer," and then we have legal issues that they have to go through, what to do with those.

I don't know what the actual numbers are, but most of them go through a legal adoption process and put their embryos up for adoption for couples that have no sperm and no oocytes, cancer patients, premature renal failure patients, Turner's Syndrome, people who have no oocytes at all, and they'll adopt embryos.

In our state, we have no embryo adoption law, but we go through an adoption process with an attorney that basically the couple that's going to receive the embryos, before they get them, goes through an adoption process, and the couple that's giving them up goes through a very legal process as if, virtually identical to what they would do if they had a living child doing the same thing.

And then some couples will say, "I want the embryos destroyed."

We haven't destroyed any embryos.  So even the couples that say, "We don't want them," we haven't yet destroyed them.  Our lawyer keeps telling us sooner or later we have to destroy them if the couple says, you know — we haven't had people tell us they want them destroyed.  They have just left them in the freezer, and we're not going to destroy them.

But our lawyer tells us sooner or later couples are going to tell us to destroy them, and we have to.

CHAIRMAN KASS:  Thank you.

Rebecca.

PROF. DRESSER:  These are probably overlapping facts and ethics questions.  I was wondering do you know whether the FDA has tried to regulate this MicroSort process.  It sounded to me as though you personally are concerned about  the objectivity of the data.

And is there concern in the organization about pushing toward more rigorous testing and about inflated claims that might be made and advertising similar to the, quote, success rate of IVF in the past?

DR. HANEY:  Yeah, I think I wouldn't exactly characterize it as objectivity of the information.  I just think it has to be done in a rigorous, scientific design.  And it's not a scientific design that's currently in the literature.  That's number one.

Number two, the FDA is going to exert, I'm sure, regulatory authority over most gamete tissues in the lab comparable to blood banking, and the ASRM has spent some time trying to help educate them.

For example, they wanted us to do the kind of testing we do for semen samples to oocytes, for oocyte donation, and for semen you can freeze a sperm.  You can double check the donor six months later for all of the diseases.  You can take an aliquot of the sample and test it if you choose.  You have a lot of opportunity to do that.

With an oocyte you don't have that opportunity.  You either use it or it's gone.  So they wanted us to freeze oocytes as their preliminary to do donor oocytes, and that just isn't possible.  You might as well ban the procedure because it's not going to be functional.

So they needed some education, and they got it.  I think they're going to be reasonable about what they do and be rational and do it the same way.  They just need a little scientific updating because they're used to blood banking and other kinds of tissue things.

And there are some other issues that they just needed education on, and I think it can be ultimately anything that bothers programs.  We all now have certified CAP, College of American Pathology, or whatever certified programs, and I think that's just going to be one more layer.

PROF. DRESSER:  So you think they probably will start looking at safety and efficacy of this MicroSort procedure?

DR. HANEY:  I suspect they will.

PROF. DRESSER:  The other question I had was I was a member of the ASRM Ethics Committee during a lot of the years when these two statements came out, and I was wondering whether your program's position was at all influenced by those statements.

Because one of the problems is when we think about trying to formulate professional standards or, you know, ethical recommendations and so forth, if they don't have any legal effect or there are no professional consequences to not following them, you  know, in terms of the organization perhaps suspending a member or something, how much influence do they really have?

So I wondered whether you all paid any attention to them or you've just reached your own program's position based on —

DR. HANEY:  I would simply say it's a work in progress.  It's becoming much more influential than it was in the past.  Programs now in SART [Society for Assisted Reproductive Technology], they're going to very seriously look at the average number of embryos you transfer and things like that, that there were ethical comments, and in practice those are translated into practice guidelines.

And you're going to have very specific criteria that you should work under for maternal age related influences  in the number of embryos you transfer, et cetera.

I mean all of that, I think is becoming much more codified, but it started with absolutely nothing, and it has taken some time to get there.

And in the absence of being able to do NIH research on any of this because of no funding, you know, it's difficult.

PROF. DRESSER:  Thanks.

CHAIRMAN KASS:  Michael, did you want to raise a particular question on the ethics of this?

PROF. SANDEL:  Well, I don't know whether — did you want —

CHAIRMAN KASS:  Please.  I think we should get started on it in any case.  So please.

PROF. SANDEL:  Well, rather than advance it, I think there is a widespread sense, though I don't know how widely shared, that there is something ethically troubling even apart from the question of harm and even apart from those technologies that would involve killing embryos in nonmedical sex selection, but it's one thing to have that reaction and it's another to try to articulate the actual reasons and to assess those reasons to see if the initial reaction is correct.

And it seems to me that independent of the harm consideration there are at least two different kinds of reasons that might be operating to explain this and to ground the unease, and this is really just by way of inviting reactions.  It's not a worked out view certainly on my part.

But one kind of ethical worry has to do with the way in which this practice, were it to become widespread, might change the norms that inform the practices of procreation, childbearing and child rearing by changing the relation between the parents and the children in some of the ways that we worried about when we were talking about the designer baby objection to cloning, reproductive cloning.

So that would be one set of objections that we might investigate, and then another set of objections might have to do with a different worry, which is the disposition or the character of the desire to control, to choose the sex of one's offspring.

Independent of the effect on social practices and the effect on childbearing and child rearing, is there something troubling in the stance?  Maybe the short label is the hubris objection, something objectionable in the stance of the person who has the desire and acts on the desire to control the sex, to choose the sex of his or her offspring.

These seem to me different kinds of objections, though they may overlap, and there may be others, and to further question how weighty the two are and how we would make them up, this really would be just by way of inviting discussion on them.

CHAIRMAN KASS:  Someone want to join on this?  Sir, Mike.

DR. GAZZANIGA::  It's sort of a prior question to that.

CHAIRMAN KASS:  Please.

DR. GAZZANIGA::  When hearing about sex selection and seeing the fact that it's sort of being done ad hoc and without any massive government program or monitoring, it raises the question, of course, of how American medicine works.

And how American medicine works, my understanding is that it's sort of monitored locally, monitored by professional groups, monitored by the sociology of a specialist field, and that there isn't a grand monitor somewhere in Washington making sure that all the procedures that go on in a hospital have been given some stamp of approval or being carefully followed up as to their efficacy and so forth.

And if I'm wrong, I would like to —

CHAIRMAN KASS:  That's absolutely right.

DR. GAZZANIGA::  — I'd like to have comment on that so that we all understand that as one thinks about this issue, because it is a red button issue, and if there was any recommendation to somehow monitor this from a government point of view, it would be one of the first because that's not how we do medicine, and I think that's just worth a comment.

CHAIRMAN KASS:  Well, I think the point ties in with the topic we'll be talking about tomorrow with the help of our British visitors, where they have official bodies that in some cases simply advise and in other cases, in fact, regulate.

The question of regulatory activity was part of both sides in the cloning report and something that this Council wants to take up in a serious way.  So the fact that it's unprecedented, while true for the time being, might be an invitation to think through whether we really want that precedent to remain.

But would someone go back and pick up a response and then Robby and then Bill?

DR. GÓMEZ-LOBO:  Yeah.  I'd like to continue along the lines opened by Michael.  I thought it was interesting.

And just to contribute to the conceptualization of the problem, I honestly think about this as questions.  It seems that there is a goal which has to be questioned first, the goal of choosing the sex of the child.  I think that there are various problems there.

And then comes the question of the means, and if I understood correctly, Dr. Haney, there are really two methods:  selection and determination, right?

Now, selection seems to involve the discarding and destroying of sperm.  Now, of course, from a moral point of view that may not be a problem.

On the other hand, determination which can be both pre-implantation and post implantation seems to entail the discarding and destroying of embryos, of human life, human embryos.  And of course, that is very troubling for anyone who tries to think about it.

Now, a last remark on this.  I was very impressed by those charts about three countries, China, South Korea, and Singapore.  Now, the charts about South Korea were really very, very impressive.  They get to, what is it, 130, 140 males per female?

It would seem to me that's a massive discrimination and destruction of females either via abortion or even infanticide.  Is that a possibility?

So that would seem to me to be the extreme to which the acceptance of the goal can take.  Again, these are questions.

CHAIRMAN KASS:  Someone else.   There was Robby and then Bill, yeah.

PROF. GEORGE:  Michael's comment earlier obliquely raised a different question for me, Michael Gazzaniga's comment a minute ago, and it brought me back to thinking about Dr. Haney's comment that his clinic doesn't do this and doesn't do it on ethical grounds.

When Michael was referring to the way in which we practice medicine or the way in which medicine is monitored in this country, it left me with a question.  When it comes to sex selection, Dr. Haney, in thinking about whether your group would do it, is part of your thinking governed by the question whether this is medicine?

What's your own thinking on it?  Let me just ask.  Is sex selection medicine?  Whatever else it is, I mean, is it medicine?

DR. HANEY:  I think that's the question everybody is going to ask themselves.  We would probably at my institution for nonmedical reasons say no.

PROF. GEORGE:  And how do you decide the question of what constitutes medicine and what doesn't, just sort of in a rough and ready way?  I mean, in a borderline case, how do you think about that?

DR. HANEY:  Define a borderline case.

PROF. GEORGE:  Well, someone wants to insure that they don't have a mentally retarded child.  Is that medicine?

DR. HANEY:  I would think that is.

PROF. GEORGE:  Okay.

DR. HANEY:  I would view that, if you knew the process that created the mental deficiency, Tay-Sach's disease, something, not having a child born with Tay-Sach's disease I think is a medical decision, just as it is for Down's Syndrome or other things.

PROF. GEORGE:  How about a borderline case like color blindness?

DR. HANEY:  I'm color blind.

(Laughter.)

DR. HANEY:  And I don't think that's — it's probably not fair to ask me.

(Laughter.)

DR. HANEY:  I'm only mildly color blind.

CHAIRMAN KASS:  Bill?

DR. HURLBUT:  When you try to differentiate this issue of sex selection from what you said was medical, and I assume you mean therapeutic in the sense of healing something or preventing something that has a detrimental implication, buried in your statistics was something that struck me as potentially troubling.

I know this might be pulling too much out of a very limited sample, but I think it was with MicroSort.  One of your statistics showed a decreased rate of congenital abnormalities.  You said half, roughly a third to half of the rate.  It was 2.6.

DR. HANEY:  I don't think that's decreased.  In other words, they found in their sample 2.5 percent of offspring had a major anomaly.  The accepted rate in Washington, North Carolina, wherever, is about three percent.  So three to four at the most, depending a little bit on the definitions and how thorough you are.

Those are not different numbers.  I have no illusions.  That's not a decline.  That's just within the range one would anticipate for a general population.

DR. HURLBUT:  Oh, okay.  I thought you had pointed out that it was somewhat lower than the otherwise noted rate.

DR. HANEY:  In this particular sample it was 2.5 compared to —

DR. HURLBUT:  Okay.

DR. HANEY:  — what most public surveys would be a little higher.

DR. HURLBUT:  Not making too much of that particular sample, I want to ask you a theoretical question then.

Suppose it turned out that this procedure, either sex selection by gamete sorting or pre-implantation genetic diagnosis for something neutral or even IVF just done without some sort of sex selection, actually had a therapeutic effect in the sense that it produced better outcomes than the natural way of doing procreation.  Would that then change your view if the procedure that produced this better outcome actually produced a healthier subset?

Do you see what I'm getting at?  I mean suppose —

DR. HANEY:  Are you asking me if Caesarean section is less traumatic than vaginal delivery would I tell —

DR. HURLBUT:  No, no.

DR. HANEY:  — everybody to get sectioned?

DR. HURLBUT:  Oh, okay.

DR. HANEY:  Is that what you're asking sort of?

DR. HURLBUT:  Maybe.  That's not — that carried a little different atmospherics, but what I'm kind of getting at here is are we heading to the realm where as we understand the biochemistry and then the early development, media into which the blastocyst is sculptured; are we getting to the point in your opinion where we might be able to produce a better than natural outcome?

DR. HANEY:  I would be highly suspicious that's not true.  I can't fathom that's true, but I'd have to face that if it actually had some data to bind it.

DR. HURLBUT:  Well, isn't it true that the implantation of blastocysts at blastocyst transfer actually have a higher success rate than would be statistically implied by normal sexual intercourse?

DR. HANEY:  Oh, I don't think that's true

DR. HURLBUT:  You think 30 percent of successful blastocyst formations go on to —

DR. HANEY:  No, I don't think it's anywhere that high.

DR. HURLBUT:  Isn't that the rough success rate with blastocyst transfer?

DR. HANEY:  Well, all I can tell you is our experience in 1998.  We thought this was blastocyst — in other words, the biggest problem with IVF is your inability to pick out healthy embryos.  We don't understand implantation well.  Human embryos implant very nicely in the fallopian tube.  They don't need endometrium to implant.

If they're healthy and at the right point in time, aggressive — I think humans are the only species that gets ectopics.  So our embryos evolutionary have learned the ability to implant themselves at the appropriate time.  So they don't really need endometrium to do it in.

Then we get to IVF where we're putting embryos a little dissynchronous into the uterus, and we don't know how to pick the good embryos that are going to potentially be developed into humans, and so we compensate by adding more embryos for transfer.

In 1998, the notion of — we were able to then, by media changes and some understanding better of in vitro culture technology, were able to keep embryos on the same growth curve that they would occur in vivo in vitro.  So the opportunity then to grow them further out and do blastocyst transfers and allow developmental selection to pick the best embryos, that idea finally became possible to test, and that started in 1998 or '97-'98, and there was a great enthusiasm for growing embryos out to the point you let the healthy ones continue to grow and transfer those, and you will cut down the multiple gestation rate by being able to maintain a relatively high pregnancy rate with your multiple gestations.

And my reading of the general approach today is that that didn't work out; that it has not been as successful, and there are very few programs exclusively doing blastocyst transfer today and very selected patients who are getting it.

So if anything, I would say it's not, as you allude, a better implantation rate than in vivo.

DR. HURLBUT:  So what you're saying is nature is better and looks to you like will be better in the long term.  It's better not to intervene in nature is —

DR. HANEY:  Well, we're definitely treating disease.

DR. HURLBUT:  Pardon me?

DR. HANEY:  We're treating disease, infertility.

DR. HURLBUT:  Yeah.

DR. HANEY:  Or we're treating patients who can't get pregnant or we're treating patients who in this case if you talk about PGD, of people who have genetic diseases.

But we're not enhancing normality or improving upon it.

CHAIRMAN KASS:  We're going to come up on the break.  I have Gil and then Michael.

PROF. MEILAENDER:  I want to try to just think a little more about the issues that Michael Sandel raised, and if I use Alfonso's distinction between the goal and the means, I want to try to think about the kind of means that would be least problematic presumably, namely, the pre-fertilization, the ones that you don't think are very successful right now.

But if we just keep it to that, then we're not raising the kinds of issues that pre-implantation genetic diagnosis would involve.  Though I have to say, by the way, that on another occasion I'd like to pursue with you the question of exactly in what sense you're treating disease when you do that.  I mean, I'm not actually persuaded by that.

There's a difference between eliminating diseased embryos and treating disease, but let's let that go.

I can understand how you might be worried about problems that would happen with the sex ratio as a result of doing this, and I can understand simply saying we don't want to use medical resources that are scarce in this way.

But what I'm interested in is those ASRM policy statements that we read that Rebecca has claimed some responsibility for here.

No, the interesting thing is that the way the issue is couched is that you shouldn't do this in order to choose nonessential characteristics of human beings, and I'd like to see us figure out what that means in a way.

In certain contexts I would never describe being male or female as being nonessential.  In fact, I'd describe it as much closer to what's essential to a human being than lots of other things.

So I'm not sure what role that language is playing actually there.  I can understand some other things it might mean, but the longer I think about it, the less clear I find myself actually, and so I just put it forward.

If the kind of dis – ease that countless people feel with respect to sex selection is articulated or is to be articulated, is that the right way to articulate it? 

I don't know.

CHAIRMAN KASS:  Paul.

DR. MCHUGH:  I, like Gil, would like to follow up on what Michael was saying, that we should be laying out some of the ideas that are a concern to us, and the one that I think is wrapped up in the issue that Gil mentioned is sex ratio, but probably needs another expression.  Probably an expression felt by PROF. Haney, that is, that you know, when we produce our children, we're not just producing it for our generation.  We are producing it for a community, a community ultimately that goes generation after generation.

And although one can appreciate perhaps that you would like one or the other at this time simply for somebody to be able to use your baseball gloves or somebody to be able to do something else, there is a higher purpose that we all serve from our families to the community at large.

And I feel that one of the things that concerns me about this is that we alter something which is very natural and which we sense only as we move from one generation to the next.

We saw that very interesting data that you showed us from South Korea, and you used interestingly the nonchallenging term "family balancing."  It seemed remarkable that the family balancing all tended towards producing males.  So it seemed to me to the motivation was male specific, and maybe we should talk about this as a growing male hunger in some cultures because, after all, you could have three or four children and they could all be boys, and one would have thought if it was balancing, there would be a balancing out of those.

So I just wanted to make the point that the issues that we're talking about have more to do with just the pleasure of one child or one sex now with all that that relates to the designing of the relationship and that we deal with a community that ultimately has a long term ahead of us.

CHAIRMAN KASS:  Yeah, the practices in other countries is the topic of the next talk, and we'll talk about that then. 

I want to intervene briefly in my own name, too, if I might.  It seems to me that however uncertain are the technologies at the moment, it's also clear that there is an increasing pressure whether created by the people with the licenses to have the techniques used or whether there is a growing demand in the culture for the use of these things.  There's a lot more interest in sex selection now than there was even five or six years ago.

And particularly with PGD there are clinics that are offering this service for non-medical reasons, even though the society has discouraged its practice.  I mean, there are groups that are using this, and we understand from our friends in Britain that they have now to reconsider this question there as well.

So whether we like it or not, it seems to me it's a question that's going to be coming on the table.

And here it does seem to me that a couple of things that have been mentioned are worth our attention.  One is the question of what the arguments are both for and against.  And I guess I have to say that I find the arguments in the ASRM documents puzzling, where, on the one hand, one begins by worrying about contributing to sex bias as if sex doesn't matter at all; on the other hand, arguing that it's probably okay for sex balancing, which suggests that sex matters a great deal, providing that you treat it absolutely equally, that you don't give additional preferences.

And I'm not sure, Paul, whether one could say — I mean, one worries really about what it means not just to pray for a child of a certain sex, which doesn't necessarily produce the result because the Good Lord doesn't necessarily give you what you want, but there's a difference between that and actually having exercised the control over it and have the parents be responsible to the child for the choice made, regardless of what the choice is.

That's a new step, but I'm not sure that we're going to be able to say in this rather libertarian climate of ours that you can't use it for these and these reasons.

And in the Jewish tradition, orthodox tradition, there was a great demand for the son because, among other reasons, there's an obligation that falls on the male child to say the Kaddish for the dead, an obligation that falls on a male child.  Female children can do it.

And people would describe a male child as "now I have my Kaddish."  Now I have the child who is going to actually say the prayer when I die.

I'm not sure that one is going to be able to say to members of those subgroups that's an illegitimate reason for making use of this technology should it be available.

So, I mean, I think that there are a variety of reasons why even if this is practiced on a small scale and when it's practiced on a small scale, by the way, it becomes a question for people to decide do you want to take advantage of it when it now becomes offered.

I think that it's much more complicated than the ethical argumentation that we've seen in those documents indicated, and I think the pressures on this are going to increase, and it might mean that if this is to be left for professional self-regulation, to avert to Rebecca's point earlier, that maybe the society has to think about ways in not simply saying this should be encouraged or this should be discouraged, but these are the guidelines we expect people to follow for these and these kinds of reasons, or perhaps it is for us to recommend other kinds of bodies for at least promulgating such recommendations, subject, of course, to review and reconsideration as time goes by.

DR. MCHUGH:  Yes, Leon.  I was not when making my point saying that this should be go to legal issues.  I just think that we're at the point of raising consciousness about what our problems are or what our difficulties represent when sex selection is brought forth.

We want to just sense is there anything behind our feelings other than the "ugh" factor that we've talked about before.

CHAIRMAN KASS:  Right.

DR. MCHUGH:  And I'm just saying that one of the things that lies behind it is a sense that we all have, believe it or not, even though we never feel it at the time the first child comes along, that we have a generational and community responsibility that comes from bringing up our children well, making sure that they are members of this community, as well as being suitable to go out and find new mates and add to our world.

CHAIRMAN KASS:  let me ask.  Since the general discussion can come back and we've run way over here, let's take a ten minute break.  We'll have the second discussion, and the general questions will come up after Nick Eberstadt's presentation.

(Whereupon, the foregoing matter went off the record at 10:44 a.m. and went back on the record at 10:57 a.m.)

CHAIRMAN KASS:  All right.  In this second session on choosing sex of children, we turn to certain demographic implications of the use of this capacity, and we're very fortunate to have Nick Eberstadt, who is the holder of the Harry Wendt Chair in Political Economy at the American Enterprise Institute, to make a presentation to us this morning.

It was actually a talk that I heard Nick give.  It must be four years ago on this topic that opened my eyes to how things quietly initiated here in the United States for  one reason wind up having very powerful effects across the globe to which we should pay attention.

And when this topic came up, I thought it would be worthwhile for the Council to hear about the uses of sex determination practices.

And, Nick, thanks very much for joining us.  We look forward to your talk.



SESSION 2: CHOOSING THE SEX OF CHILDREN: DEMOGRAPHICS        

DR. EBERSTADT:  Leon, thank you very much.

Ladies and gents, it's an honor to be with you here this morning, and I'm going to start off more or less exactly where Dr. Haney left off in his excellent presentation.

What I'm going to try to do very quickly is provide you with some information about the state of conditions in the world today with respect to the secondary sex ratio, usually called the sex ratio at birth, and also to offer some speculations about some of the implications of trends that are now developing.

Demography is a study about three centuries old, maybe a little bit more than three centuries old at this point.  As soon as students of demography began to look at patterns in human numbers, one of the first things that they recognized was that there was quite a regular pattern with respect to births, slightly more boys born than girls born.

And this was noted and commented upon at the beginning of the study of demography.  I'll read you something that Johann Sussmilch, who was an early demographer, wrote in 1741.  He said, referring to other early demographers, that "Grant, Durham, and others have suggested the Creator has reasons for insuring four to five percent more boys than girls lie in the fact that it compensates for the higher male losses due to the recklessness of boys, to exhaustion, to dangerous occupations, to war, to seafaring and immigration, thus maintaining the balance between the two sexes so that everyone can find a spouse at the appropriate time for marriage."

Well, as you will appreciate, demographers are rather more loath today to talk about divine intent, but they do recognize that there is over time and over space a consistent pattern of somewhat excess male mortality over female mortality.  So that the early surfeit of boys, if you will, more or less evens out by marriageable ages so that cohorts are more equal in numbers.

Now, demographers have noted variations in the secondary sex ratio or the sex ratio at birth associated with a variety of factors.  They have noted variations with respect to ethnicity.   They've noted variations with respect to parity, which is to day birth order, and with the age of parents.

They've noted some variations with respect to the nutritional status of parents.  Nutritional status may have some slight influence upon sex ratio.  Also various sorts of diseases and disabilities.

And there is an ongoing question/discussion, call it a debate, in certain areas of demography about whether there may be an adaptive response with respect to sex ratio at birth, that is to say, it's called the operational sex ratio or the sex ratio of the adult population may have some influence upon the rising cohort's sex ratios.

I have no opinion about this work.  I consider it an unsettled discussion which continues, and I wouldn't suggest that there's any conclusive findings that have been found in this area, but for noting all of these influences upon sex ratios at birth, I think the overwhelming biological fact about sex ratios at birth in large and regularly constituted populations is regularity and the stability of the sorts of numbers one sees produced.

These ratios are almost constant in large populations over time and over space.  Just to give you by way of background some perspective on this, these are the sex ratios at birth by ethnicity for the United States from the early 1980s, and you will see that for the country as a whole, it was about 105 live baby boys born for every 100 live baby girls.  There were differences by ethnicity, but these were not dramatic, let's say.

By the same token, you can see differences in sex ratio at birth with respect to birth order, the parity.  In general the sex ratio at birth is somewhat lower at higher parity or higher birth orders than at lower parity or lower birth orders.

And this result for the United States in 1984 is hardly uncommon.  We could have used data from many other countries, many other times to replicate that.

This was 1984, and we live in 2002 today, and some things have started to change even in the United States itself.  And one of the things we are beginning to see in the U.S. are sex ratios for at least certain groups within the population which would be very hard to explain on the basis of purely random occurrence since we're dealing with large numbers of people.

The odds against some of these sex ratios at birth look very forbidding, very imposing.  Let me show you here.

These numbers compare sex ratios at birth in the United states in 1984 and in the year 2000, which is the latest year for which we have complete birth data, and you'll see that there's not terribly much difference in the sex ratio at birth for the total population or for the so-called white population or the so-called black population.

But when one gets down to Asian Americans, to the Chinese and Japanese ethnicities in the United States, we're seeing some very substantial increases in sex ratio at birth, and those would be very hard to explain on a purely biological basis.

Over the last decade or so, we find, indeed, that there are many places around the world where these sex ratio at birth has started unaccountably or seemingly biologically unaccountably to rise.

Let me show you some data from other countries.  These data were gathered from the United Nations' statistical office which publishes an annual demographic year book.  Of course, it's never up to date, and of course, when it is compiled, the data are from earlier years.  These are the most recent data that the U.N. demographic year book has pulled together on live births in countries and areas where vital registration is nearly complete.

And what I have listed here are simply countries reporting now a sex ratio at birth of 107 baby boys per 100 baby girls or higher.  In ordinarily constituted populations ratios of 103, 104, 105, even slightly over 105 are not things that would look unusual.

One, oh, six starts to need some explanation, and 107 just usually doesn't happen, and that's why I chose 107 as the cutoff there.

And you will see here a number of different regions of the world represented with these unusually high sex ratios at birth:  some Latin American countries, Salvador, Venezuela, most dramatically Cuba, where we have a phenomenal 118 baby boys per 100 baby girls, some of the Maghreb  countries, the North Africa, Tunisia, and  Egypt. 

They represented also some of the post Communist states from the former Soviet Bloc, Belarus, Bulgaria.  I think we have excluded some additional post Communist countries whose birth numbers were rather lower, but whose sex ratios were very high.  I think Moldova, Estonia, Lithuania could also be added into this grouping.

And then, of course, we have a grouping of East Asian countries and regions:  Hong Kong, the Republic of Korea being most prominent there.

One of the problems in tracking changes in sex ratios at birth around the world is that most of the world's population is not found in countries that have complete or nearly complete vital statistical systems, vital registration systems.

By the U.N. Population Division's estimate, in fact, less than one person in 12 in the low income world lives in a region that would be described as a country with complete or near complete vital registration.  So that's a big problem in trying to track trends in sex ratio at birth.

However, we can draw some inferences about changing patterns of sex ratio at birth by looking at the numbers of children at young ages reported in national censuses and other sorts of demographic survey data.  And I will show you this imperfect, but perhaps indicative proxy for a number of other countries.

These data were compiled by the U.S. Census Bureau's International Programs Center.  These are their estimates for 1998 of sex ratios for children under the age of five and for particular countries where the ratio was 107 or higher.  And you'll see, again, a representation of an Islamic society in Tunisia.  You'll find some post Communist representation in the form of Serbia and Macedonia.  For the most part what one's seeing there are East Asian countries:  Singapore, Taiwan, China, Hong Kong, and South Korea.

And the sex ratio in some of those settings for children seem to be very, very unusually high indeed.

There is another smaller area of the world whose imbalances I've just become aware of thanks to a colleague at the Census Bureau. Dennis Donahue kindly supplied me with this table.  But in the Caucasus area of the former Soviet Union, the ratio of children under one year of age — these are not live births, but tabulated infants and through census materials and demographic counts — the ratio of children under one year of age has risen very rapidly and dramatically in Armenia, Azerbaijan, and Georgia.

These Caucasus societies represent a diversity of religions.  Azerbaijan is primarily Islamic.  Armenia and Georgia are not, but as of the year 2001, the sex ratio for infants under one year of age was approaching 120 in each of these three countries.

Let me turn to East Asia which Dr. Haney discussed a little earlier.  This slide, which is put together by Daniel Goodkind at the U.S. Census Bureau shows reported sex ratios at birth for a number of East Asian countries.  You'll see that the sex ratio at birth for Japan, this lower line, falls within the range that would ordinarily be expected of a large human population.

For all the other countries and regions, for Singapore Chinese, for Hong Kong, for Taiwan, for South Korea, in particular for South Korea, some of these ratios have risen really quite extraordinarily.  In the past several years South Korea's sex ratio at birth had declined, but it has declined only to a degree.  It's still in the range of 110 baby boys per 100 baby girls, something like that.

The big enchilada is China, which is the most populous country in the world, and China does not have complete birth registration statistics.  So determining the actual sex ratio at birth requires quite a bit of inference.

As you'll see, there is a discrepancy in China between hospital records, which are certainly not complete with respect to annual births, servicing only a limited fraction of the population, predominantly the urban fraction, and records from vital statistics, limited though they may be.

There is a discrepancy there, and this is a discrepancy which demographers have puzzled over.  It has suggested to some that the imbalance in China may not be as great as some observers have feared.

I think, however, the weight of evidence from demographic records leans towards the more pessimistic rather than, if you will, the more optimistic assessment, and that's a judgment reinforced by the initial data from the November 2000 Chinese census. 

If one attempts to do reconstructions from that and from previous censuses, one sees a sex ratio at birth that has risen perhaps from around 108 20 years ago to something like 117 today, and if one looks at the sex ratio of children under the age of five from this and previous censuses, one gets even more extreme indications of increasing imbalance between young boys and young girls.

As Dr. Haney's presentation indicated previously, the imbalance in these societies is concentrated disproportionately in higher parity births, although as I think I already showed you, in ordinary biologically constituted population, sex ratios at higher birth orders tend actually to decline slightly.

But what we find in many East Asian societies today is an increasing imbalance, increasing sex ratio at birth with higher birth order parities.  This slide presents data collected by two doctors in Hong Kong at St. Margaret's Hospital.  Hong Kong does not ordinarily offer comprehensive data on sex ratios by birth order, although it does have complete vital registration.

St. Margaret's Hospital, I believe, handles about a sixth of the births in Hong Kong, SAR.  So it is by no means comprehensive, but it is indicative, and as you'll see there, Wong and Ho show that for births that were second births, there was quite a significant distinction between sex ratios for parents, for mothers, whose first birth had been a boy and whose first birth had been a girl, and the phenomenon is even more extreme for third order births.  In the cases where the two previous births to a mother had been girls, the sex ratio was 137.

Even with small numbers of births, as in this sort of situation, the odds against this being a natural occurrence become quite astronomical.

Dr. Haney already showed a slide indicating changing sex ratios by birth order.  These are data for Taiwan in 1990 and for China in '89, and as you see, when one gets up to birth order four, fourth births in Taiwan, by 1990 we are talking about sex ratios of 160 boys per 100 girls.

But it gets better than that.  Let me show you South Korea.  In 1992, by the time one is talking about fourth order births, we are above 200 boys for every 100 girls born, and you can see there that blue line is South Korea in 1992.  The red line is South Korea only 12 years earlier, in 1980, for the wide dissemination of technology, making available sex determination and, therefore, sex selective abortion.

In all of these cases, the inference that one would draw, I think, is that sex determination has led to sex selective abortion as a main driver of these biologically unnatural results.  Female infanticide may have played a more pronounced role in China, especially in the late 1970s and early 1980s, but increasingly, I think we can draw the reasonable inference that sex determination and sex selective abortion has been the primary instrument at work here.

Dr. Kass asked me to gather for you some information on gender preference on the parts of parents, and I had assumed this was going to be a very easy task for me, very easy part of my presentation, and was quite surprised to find that it was not.

The reason for the opacity or the difficulty here is that the ordinary or the regular surveys that are circulated through much of the world to determine demographic health fertility patterns, the so-called DHS survey, as a rule now simply do not contain any information to present to respondents with respect to gender preference of children.  Such information was collected in earlier rounds of world fertility surveys, but as it happens, for the most part these are not available now for most low income countries.

It's unfortunate.  As you can see, it's an increasingly unfortunate oversight. 

However, one of the countries that does collect information on gender preference among married women is India, and it's not an inconsiderable portion of humanity.  Roughly one out of six people in the world today live in India.  It's a population of over a billion.

And this shows you results from the national family health survey, second round done about three or four years ago.  Almost everyone, almost all mothers asked to have no children, and most of those who had one child desired more children, and as you'll see below, when asked whether they preferred a boy or a girl, some said no preference.  Some said leave it to God, but of those who expressed a preference, there's an overwhelming preponderance of preference for boys, four to one for the sample overall, and in some cases even higher ratios.

Let me show you data for a particular state in India, the State of Punjab.  Punjab is a smaller sample, and we have asterisks there because in some cases there weren't enough respondents to arrive at statistically significant results, but for the Punjab as a whole, out of the almost 3,000 married women questioned, the preference for an additional child being a boy as opposed to a girl was on the order of ten to one.

Now, let me show you some results from the latest Indian census.  India is another country that has no – that does not yet have complete vital registration of births and deaths for the country as a whole.  So one has to work with census materials and other sorts of large counts to do reconstructions or to draw certain sorts of inferences.

The March 2001 Indian census did account by age for the country as a whole and its various provinces, and what I'll show you now is the sex ratio for children under age seven or children zero to six for different provinces in India.

You will see that there are a number of states and territories in which the sex ratio for surviving children, surviving up to the age of seven, falls within the range that we might call biologically expected, maybe up to about there, but there are a  number of states for the most part in northern India where the ratio is outside of historical biological norms.  Mostly these are states in northern India.

But I'll point out in particular to you the results for Punjab.  In Punjab today for every four girls under the age of seven there are over five boys, and it's probably also worth noting that these newly found differences do not comport with patterns of tradition or with patterns of traditionally construed under development.

These heightened abnormal sex ratios at birth are instead very closely associated with modernization or with some particular variant of modernization.  Punjab, for example, is one of the most prosperous provinces in all of India.  I think we see Delhi.  Delhi at 116 is also one of the most — is an urbanized area with one of the highest income levels in India and one of the higher literacy levels in India.

Thus also Chandigarh, thus also Haryana, and if we go back and review some of those other data that I showed you, I think we'd say that this imbalance in sex ratios at birth has coincided with improved levels of income with higher educational attainment and with heightened interaction with other cultures and other economies, with what we would call globalization.

So far from being traditionally driven, these trends have certainly coincided and comported with some form of modernization.

I will get to that in a moment.

I think it also mentioned that these heightened abnormal sex ratios at birth have been associated with fertility decline, and they're most obviously in low or sub-replacement fertility populations.

As you saw from the East Asian data, all of the East Asian countries that we were discussing are currently at or below replacement levels of overall childbearing, which is to say that if current childbearing patterns continued indefinitely and there were no immigration, no net immigration, population would stabilize and ultimately decline indefinitely.

The phenomenon of choosing higher parity, the sex of higher parity children seems to be more of a pronounced phenomenon in the context of declining or sub-replacement fertility, and it is worth noting that the Punjab area of India has been an area of rapid fertility decline.  It is not the lowest fertility area in India.  There are some sub-replacement areas of southern India that do not exhibit this extreme imbalance between male and female children, but Punjab is an area of rapid fertility decline and is now close to the replacement level.

Dr. Kass asked me if I would draw together some data on sex preference and sex selection in the Arab-Islamic world.  I think I showed you earlier some indications that Tunisia, which is one of the few areas in the Arab-Islamic expanse to have hit replacement or sub-replacement fertility, is now exhibiting unusually high sex ratios at birth or excuse me.  I think it's ratios of children under the age of five, sex ratios of children under the age of five.

And there is precious little information on gender preference from survey and demographic data for this great expanse of humanity, but one of the few surveys that I could find is actually for the Palestinian authority, and it isn't quite as neat as I would like something to present to you, but I think it is indicative nonetheless of what we have here from a demographic survey conducted in the late 1990s, is the preference expressed by I think it was a total of 3,000 married women for an additional child or for an additional son or an additional daughter if one already has a son or daughter, if one already has four-plus sons or four-plus daughters.

And I hope this presentation isn't too confusing, but I think you'll see from these numbers a very strong and pronounced disposition towards son  preference across the board here.

Interestingly enough, the sex ratio at birth for babies within the Palestinian authority area and for Muslims in Israel proper is no different.  It's not appreciably different from that of Israeli Jews.  Both sex ratios for now are in the vicinity of 105, slightly below 105 baby boys per 100 baby girls.

But what we have not yet seen in Palestinian areas or in the rest of the Arab-Islamic expanse is the  dramatic dissemination of relatively inexpensive techniques of gender determination prenatally, and so this is a phenomenon which we may yet experience, although we have not thus far.

What are the consequences of gender imbalances?  One of the most obvious possible consequences of the sorts of gender imbalances we have seen developing around different parts of the world is a later, potentially inevitable, inexorable imbalance in the marriage market.  If there are too many boys to marry off to a given number of young ladies, the market can't clear.

In the past that has not been too much of a problem even in areas where boys in any given age group have tended to outnumber girls in any given age group because for the most part, over the last century certainly world population has been rising, and that has meant that each year slightly more girls were being born in any given birth cohort.  So that matching up or pairing simply would entail an average difference in age at marriage.

You will appreciate, to make a very crude example, if population were growing, if birth numbers were growing by about two percent a year and there was a ten percent imbalance between young men and young women, it would take roughly five years in difference in average age at marriage to make everything square.

But the arithmetic becomes very much less forgiving when one is dealing with sub-replacement populations rather than populations that are at or above replacement level.  And as you will have seen already, the gender imbalances that we have seen developing are most pronounced in societies that are precisely sub-replacement or below replacement fertility contexts.

What I wanted to show you here is some speculative projections for china, and I have to emphasize that these are speculative.  The data on the year 2000 are not really terribly speculative.  We've got those data, but then the question is:  what will China look like, say, 25 years from now?

What I have put together for you here is a Chinese population structure and age-sex structure based on the presumption or the assumption that the 117 to 100 imbalance, implied imbalance, in sex ratio at birth that we've seen from the recent Chinese census is, in fact, real rather than a statistical artifact, and that that imbalance continues from 2000 to 2025.

I think even by eyeballing this, you can see that there are at younger ages an awful lot more greens than blues in this figure.  What does that, what would that hypothetically mean?

Well, let's look at this.  The U.S. Census Bureau takes the cautious and, I think, respectable posture that until there is overwhelmingly persuasive evidence to the contrary, they will be projecting China's future population on the basis of an assumption that the true imbalance, the true sex ratio at birth is 109 to 100 rather than 117 as recently reported.

If one accepts that, by the year 2025, the sex ratio for young men and young women ages 20 to 35 would have risen from about 106 reported roughly today to about 109.  There'd be a deficit; there'd be a shortage in this particular cohort of about 13 million women as opposed to men.

Now, China has been a society, a cultural setting, where near universal marriage has been the expectation.  One takes a look at previous censuses or demographic data on China.  Ninety-six, 97, 98 percent of women report eventually — report having been ever married by the time and heads towards older ages.

But that means that three, four percent of Chinese women do not get married, do not take a husband, and if one deals very crudely here, that would be suggesting that something like ten, 11, 12 percent of the Chinese men in the Census Bureau's projections in this year would have to find wives if they were to find wives from outside of this cohort.

If one takes an assumed sex ratio of 117 and projects that forward, the numbers are even more dramatic.  We would end up with a shortage within these given cohorts of about 16 million potential brides or 16 million excess husbands.

And if one stuck with this same back-of-the-envelope sort of calculation that two, three, four percent of women would end up never marrying, we'd be talking about 13, 14, 15 percent of this cohort having to find wives or partners from outside of this grouping or never marry.

Now, what are the social and economic and political implications of having a large group of men for whom the expectation of never marrying is fairly plausible?  My impression, my very unscientific impression from demographic history is that it very, very much depends.

One can see all sorts of ominous arguments about unsocialized or unsocializable young men causing social strains and perhaps even political problems, and you know, prima facie, I think that argument is inherently plausible.

But it is also true that there have been large regions of the world in which the expectation of never marrying has been quite real for large proportions of the population and where  social fabrics have dealt with this in sort of a regular and non-catastrophic manner.

Pre-industrial Europe, for example, is a setting that comes to mind, although in Europe west of the Danube today a very large proportion of women end up eventually marrying, end up being ever married.  A hundred years ago or so that was not at all the case, and at the end of the 19th Century and earlier, it was not at all uncommon to find birth cohorts of women and of men in which 15 or 20 or 25 percent total never married.

Now, in the western European context, western European culture provided for mechanisms to deal with this phenomenon.  There were mercenary armies.  There's the Catholic church.  There's respectable spinsterhood and bachelorhood, and all of these were social conventions which helped to deal with this demographic phenomenon.

As best I can tell, in East Asian and in Confucian societies, there is no parallel set of mitigating social mechanisms, and rather to the contrary, the expectation seems to be quite strongly to encourage marriage, if possible, in part to continue the family line and to respect ancestors and all of the rest.

Social conventions, I think, would have to change very dramatically and very quickly in large portions of East Asia and perhaps elsewhere to deal with this impending gender imbalance, and it seems to me a very reasonable question to ask whether one can expect this to occur in such a very short period of time.

It's all speculative, but it seems a question worth asking, and I think I'll stop there.

CHAIRMAN KASS:  Thank you very much, Nick, for a very interesting and provocative presentation.

If we could get the lights, we could start our discussion.

Frank Fukuyama.

PROF. FUKUYAMA: Nick, thanks.  I've been reading your stuff for many years, and it has all been extremely useful.  I've got a series of small factual questions and a larger one at the end, but maybe you could just answer them serially.

You know, Amartya Sen wrote this famous book about 100 million missing women, but from your data, it looks like that's actually a very low figure.  Do you  know how he got that or what period corresponds to?

Because it looks like, you know, just China alone over the next decade is going to  —

CHAIRMAN KASS:  Would you turn the mic on?

DR. EBERSTADT:  From the 1980s.  It was based on U.N. Population Division estimates of total world population.

PROF. FUKUYAMA: Okay, and on Korea, the drop that occurred from the early '90s to the late '90s, from about kind of the high teens to, you know, like 110, my understanding is that sex selection was actually illegal there in that the reason that that drop happened is that they actually started enforcing their existing laws.

DR. EBERSTADT:  Yes, it had been illegal.  New legislation had come on the books in the 1980s with the widespread advent of amniocentesis and ultra sound.  The laws were, as you can tell, completely ignored.

Then in the mid to late 1990s, the government started to pay more attention to these practices.  Civil society was also important there.  There were festivals in  South Korea held, "love your daughter" festivals and things like this, and that started to make some sort of more general impact.

PROF. FUKUYAMA: I understand the ratios also varied by province quite substantially.

DR. EBERSTADT:  Yes, yes.  That's right.

PROF. FUKUYAMA: Do we have any historical data on rates of female infanticide in Asia just as a point of comparison for the current sex ratios?

DR. EBERSTADT:  We can only draw inferences about infanticide from, as you will, the missing girls in earlier censuses and very limited registries.

In China, in particular, there's a longstanding imbalance between males and females at almost every given age.  Life expectancy for men at younger ages quite surprisingly is higher than life expectancy for women, and that suggested a whole plethora of discriminatory practices, not only infanticide, but discriminatory practices after those young ages.

PROF. FUKUYAMA: Okay, and then I guess the longer question, you know, there was a book published by Marcia Gutentag and Paul Secord.  I guess it was over a decade ago called Too Many Women, talking about some of the social consequences of, you know, these unbalanced sex ratios, and I guess while the conventional wisdom is having too many men is a problem, they make the point that there may be some compensating advantages, which is that if you have a sex ratio that's tilted towards men, it actually puts women in the driver's seat in marriage markets, and that one of the arguments they made was with the Baby Boom one of the reasons that the sexual revolution happened when it did was that because of this phenomenon of men marrying younger women, they had more choice, and in effect that skewed the sex ratio towards women, which led to, you know, a breakdown of family life and so forth.

DR. EBERSTADT:  Yes.

PROF. FUKUYAMA: And that you could expect the opposite to happen if you had a sex ratio skewed towards men.

Is that a respectable argument?  I mean, what do you make of that?

DR. EBERSTADT:  That's a very reasonable, Economics 101 sort of argument, I think, but not all parts of the world proceed under the sorts of premises that we presume to be in place in an Economics 101 setting.  In China already, the increased value of women, increased scarcity value of women has led anecdotally to distinctly increased reports of woman stealing, of trafficking, of virtual enslavement, and that is, I suppose, a less attractive, but still quite real manifestation of an improved value of women.

DR. FOSTER:   Just a brief comment.  If I remember it correctly, about the last week The New York Times, you know, had an article about single women in the United States, and if I remember the figure correctly, that above the age of 15, about 48 percent of all women are single.

And I don't know where it is in other places, but if a wife of a mature man dies in Dallas, instantly he is assaulted by women who want to have a date or go to dinner or something of that sort.  I mean, there does seem to be in our country a very large group of the excess women, and I don't know what to make of that.  I'm just commenting on it.

PROF. GEORGE:  It depends on what you count as our country, Daniel.

DR. FOSTER:  Well, I believe — I don't know, Robby, whether I'm following you or not, but I believe that Texas did join the Union some time ago.

(Laughter.)

CHAIRMAN KASS:  Rebecca.

PROF. DRESSER:  These are questions for you to comment on, but as for the group as well to think about.

I guess one issue this raises for me is how should we as a Council look at patterns and practices in other nations.  Certainly it would have an impact on U.S. medicine when people from other cultural backgrounds come here and want particular interventions that are more popular in other nations, but should we go beyond that?  And how should we think about that?

And then the second is provoked, I guess, a little bit by Leon's point about orthodox Jewish preferences for sons.  I think we're looking at sex selection as part of our, quote, enhancement project, I think.  Is that right?

CHAIRMAN KASS:  Go ahead.

PROF. DRESSER:  Maybe it's related to some other project I don't know about, but anyway, if we're to think about sex selection as being done for non-health related purposes, putting aside defining what falls under health related purposes, but if we're just to say, okay, for other reasons, is it possible to make arguments that would say certain reasons deserve more weight than others?

So a religious tradition, a cultural tradition, family balancing; is it possible to really discriminate or differentiate between preferences, saying some are unjustified gender or sex discrimination and others are not, or should they all be treated equivalently, whether that is to say they're all okay or they're all not okay?

CHAIRMAN KASS:  Nick, do you want a word on this or not?

Let me say something about the first question.  I mean one could argue that what goes on in other countries with the use of these technologies is a curiosity and we should pay attention, but finally not of concern to this body, and that might be closer to the truth than not.

On the other hand, as has been pointed out in previous discussions, what goes on in other countries has an impact on what happens here, either where precedents set elsewhere come to be argued for here.  I mean if the British are doing embryo research, why shouldn't we, or conversely, they would say, "Look.  If the United States isn't doing sex selection, you know, maybe we shouldn't either."

But there's also these — there are sort of social and political ramifications of these technologies, and Nick, in his characteristic understatement, just alluded I think.  The numbers are by themselves interesting, but what they actually mean socially and what they mean internationally in an age of globalization is, it seems to me, of importance and, at the very least, it might be worth our while to call attention to what goes on with the use of these technologies and perhaps even recommend nothing so radical, nothing more radical than the need to monitor and pay attention to what is happening and where in ways which we are not at the moment doing.

That would be at least the minimum suggestion as to why that kind of conversation — I mean, the material that Nick has raised is, I think, of importance to us.

And if I might simply respond just to open up the other question, yeah, there is a question here as to whether or not — I mean, whether sex selection is an enhancement or not could be discussed.  That it is a non-medical or nontherapeutic use of medical technique is part of what makes this of interest.

And I think one of the reasons it's part of this conversation is that it's one of a whole series of developments produced for medically related purposes, but which will yield individuals, unless there are regulations, but will yield the desire, will support the desire for individuals to use new technical power to achieve their desires either for self-enhancement or for the control of their offspring or for the control of behavior of others.

The question is whether if those things are worrisome, what, if anything, can and should be done about it.  I think that's the context, and what are the reasonable reasons for using this thing, except for the prevention of disease is, it seems to me, interesting.

And does one sit in judgment of the people in Punjab or is this one of those occasions where who are we to judge the cultural preferences of other people or, for example, the cultural preferences of American subcultures, the first slide that Nick showed about beginning to see changes in the United States in the East Asian populations where the sex ratio begins to approach 110.

DR. EBERSTADT:  I think the ones I showed were 107.  The Philippine Americans, it's almost 110.

CHAIRMAN KASS:  Yeah.

Janet.

DR. ROWLEY:  Well, I'd like to go back.  Just some of the techniques that are used to achieve these changing ratios, and one of them obviously is sex selection before implantation, and the other is selective abortion, and it's sort of surprising to me, say, in countries that I assumed had  restricted availability of some of these technologies, that there are changes.

For instance, you had the statistic about American Indians going from 101 in 1984 to 103.5 in 2000.  I'm not sure whether that's within the range of variation because one thinks of American Indians as not having access necessarily to fairly sophisticated technologies.

And then you also quoted countries like El Salvador with 107, the Philippines, 108.7, Egypt, 108.7, and Pakistan, 110.9.  It would seem to me it's a small portion of the population within those countries that would have access to more sophisticated technologies.

But the implication of all of this is that it's really some kind of sophisticated technology and access to it that is causing these changes because these are birth ratios.  These aren't zero to four where you can think of infanticide.

So what is going on actually in these countries that may be associated with these changes?

DR. EBERSTADT:  I would not myself become at least yet too alarmed by the data reported there for the American Indian population even though the reported ratio, sex ratio at birth in the years that I chose had increased.  103 is still well within the range of ordinarily reported biological variability.

I think one starts to ask questions to be arbitrary at about 106, and one starts to have alarm bells go off at about 107.

With respect to Pakistan, the data there for Pakistan were from their vital registration system, which I don't think is complete.  I would guess in the case of Pakistan — I would have to go back and double check, but I would guess that those are hospital deliveries, and hospital deliveries are going to have the enhanced techniques that you asked about.

With the case of El Salvador or Egypt, medical services are presumably much more limited than for native American population in the United States.  I'm only speculating, and I have no basis in fact for this, but just to speculate about this, if a relatively small proportion of parents felt rather strongly about some preference issues, it would be possible to alter to some degree the national sex ratio at birth without having comprehensive medical services and availability, but I don't know.  That's a speculation.

DR. ROWLEY:  Well, if I can just follow on with this, and again, toward the end you also tied this in with more sophisticated family planning, if you will.  So if you only want to have two or, say, three children and you already have one or two children of a certain sex and you're going to have just one more child, then may well pay much more attention, and your data has suggested if you already had two females and you were going to have only one more child, it was very important to you that you have a boy.

I happen to have four sons and only four children.  So —

DR. EBERSTADT:  And I have three daughters.

DR. ROWLEY:  So, you know, years ago I'm not sure if really effective sex selection had been available whether I might have taken advantage of it for family balance.  It wasn't available.  It's not clear that it is even yet available unless you to go really extraordinary lengths.

But I think that these are intellectually interesting issues.  Again, the question whether it's a matter for us to consider and pursue, I think, is the kind of discussion that Michael was suggesting that we have.

CHAIRMAN KASS:  Michael, and then Bill May, and then Gil.

PROF. SANDEL:  Well, these were two such fascinating presentations, and I'd like to go back to the ethical questions that they raise.

First, a comment that occurred to me at the end of our first session, or thought rather.  There are lots of reasons to worry about sex selection, but I think that our greatest contribution can be to resist the reflect or the tendency to translate what troubles us into overly familiar terms.

And that comes out if we say, well, it must be the means.  And so people have views one way or the other about certainly infanticide, about abortion, and for that matter, about embryos.  So there's a tendency to translate it into that aspect or, on the other hand — and in this report, Leon, that you referred to we have in our binder, to translate it to different kind of familiar terms.

Well, it's going to lead to gender discrimination.  We're familiar in our society arguing about those two things, about the status of embryos, on the one hand, and about gender discrimination, on the other.

But what's distinctive about this question of sex selection — and this connects to the broader issue of enhancement — is that there are reasons to worry that go beyond those two familiar reasons, which isn't to diminish those familiar ones, but this question is philosophically interesting and challenging because not everything that's objectionable about it can be translated either into worries about embryos, on the one hand, or about discrimination, on the other.

And that takes us to the goals or the goods or the ends to reflect on, and looking at the data, the demographic data, we all shudder at the numbers, but trying to make sense of the shuddering is what's interesting.

There are worries obviously about the social consequences, and here we enter into the kind of speculation in the exchange between Frank and Nick about, you know, will all of those extra men in  China create instability, make China more warlike.  Will it make the situation with women better?  Will it make it worse?  There's that set of worries.

But beyond the worries, there's something also chilling about this, quite apart from speculating about the social consequences for China or for the world or for war or for instability or for all of these extra men rattling around there.  And that's what we should try to get at.

Is it chilling?  Well, one thing is, oh, it's chilling because we know lying behind there, you know, is some infanticide or abortion  or the killing of embryos.

But there's another dimension to what makes it chilling, and that has to do with — well, I'm not sure, but here's a speculation or a question just to invite us to direct some of our energy anyhow in our reflection to this other set of issues.

Is it that we see in those ratios, rising ratios, is it that we see here's what happens when we have the technology to actually implement the things that for various reasons we might desire?

And is the danger — is what's chilling the power that the technology give us?  And may shrink before the consequence of that technology when we see it here, or is what's chilling that the technology being available just reveals to us vividly desires, things that people want, that themselves — we think people shouldn't want that sort of thing.

And suddenly the technology lays bare desires that  we haven't been able to act upon in other times.  So here's one way of testing that independent of the technology.

Is it wrong  or not wrong, but is there something morally troubling or questionable about praying for a boy rather than a girl?  And is the problem with the technology that it answers the prayer that's independently objectionable or it enables us to answer the prayer, to perhaps obviate the need for the prayer?  But is that the underlying desire; is it the prayer?  Would that be objectionable?

And if it's not, then we have to look elsewhere, but if it is, then that leads us to some difficult moral terrain, but at least it's the kind of terrain that may kind of get at this issue of enhancement.

CHAIRMAN KASS:  Could I as Chair ask members in the queue if they would waive the queue and address the question?  Because I think it's a nice — if we could at least response to Michael's challenge, if people would like to address it rather than just run away from it?

Gil, do you want to speak to it?  Both you and Bill were in there.

PROF. MEILAENDER:  I do want to speak to it.

CHAIRMAN KASS:  Please.

PROF. MEILAENDER:  Maybe he does.

DR. MAY: But go ahead.

PROF. MEILAENDER:  Well, yeah, I want to pick up on that actually relate to where it was Rebecca who sort of started us down this road to some degree by thinking about kind of how this fit with our larger concerns.

And let's assume an unobjectionable means for the time being, you know, whatever that means.  It probably means different things to different people, but let's assume an unobjectionable means so that we're talking about just the goal of getting a child of the desired sex.

I don't myself think there's anything wrong with the desire, and if somebody said, "I'm praying to have a boy," that's all right.

If I may just kind of switch issues for a moment, St. Paul prays to die and be with Christ.  He doesn't act on that, however.

So that, I mean, I don't think there's necessarily anything wrong with the desire.  So that's not — if we're looking for kind of a deeper concern, I don't think that's it, that it reveals to us some desire that's suspect.  I don't think there's anything wrong with wanting a boy or wanting a girl.  I don't think there's anything wrong with not caring either, but it doesn't matter in that sense.

I think the issue is when desire turns to action, it's control, and I think to me at least the issue is or one of the issues anyway is the kind of control of offspring that is set up there in the sense that means a less than unconditional affirmation of somebody who turns out to be other than one desired.

That to me would be the problem, not just having a desire. 

I think there's a second kind of issue that probably moves beyond —

PROF. SANDEL:  Could I just add quickly?  But you don't think the desire could ever condition the affirmation?

PROF. MEILAENDER:  I think it could, but I think it's much more likely that the availability of the technology is what brings the conditions rather than just having the desires.  Because technology turns out not just to free us and give us new options, but to shape us and constrain us in various ways.

So that, in fact, is what I think generally happens.  Now, if I may make one more point that kind of in a way relates a little more to where Rebecca had started us, but I think an additional question here — I mean I think you're right, Michael that it's important to ask, you know.  Get out the means and everything.  Is there any reason to just object to choosing the sex and can we articulate what it is?

But relates to the demography stuff is if there are undesirable larger consequences, one of the issues that we're raising then is if my desire is innocuous, if there's nothing wrong with it, whether I have to suffer for the larger good, whether my desire should be thwarted, whether we should regulate it.

And that is a question I think at least in a society like ours that also needs to be faced.

CHAIRMAN KASS:  Bill, Bill May.

DR. MAY: Partly a response to yours, but also to return to the issue you were raising.  As I listened to you, I couldn't help but think about how studying comparative information of this kind accentuates for us the difficulties of anticipating consequences.

As I think about India, just a passing word.  The fact that towards the third and fourth child, one even more intensely wanted a boy does relate to economic circumstances there.  The dowry that has to accompany the girl into a marriage, and I know farmers there who have gone into major debt and wanted a boy.

Terrific pressure on boys later on.  If they don't happen to hold to that system of a dowry and coming to this country and working on computer work to be able to send money back at home to help out the father to escape from the economic bag or trap he was in.

So there are lots of pressures of that kind that haven't surfaced in this discussion, but at the same time it was very interesting you mentioned that at Punjab modernization tended to move us in this direction.  I wondered to what degree that related to the fact that the boys in those provinces or regions, modernization meant to move to the city, and there is more mobility in the boys and girls, and so there might be more reason, again.

But all of this traffics in the question of micro controlling as opposed to macro controlling, and you say the problem of micro controlling is acute only if it's going to produce macro problems, and that may be the wrong way of looking at it, and that I think is what you, Michael, are forcing us to consider.

The deeper problem as it relates to parenting for me is the whole question of how parenting relates us to the question of the unbidden and the unelected in life.

I mean, we elect a mate in our kind of culture, but we pick up with that a lot of things that we haven't elected:  the in-laws, and the genetic load, and so forth.  There's a whole unelected, and the testing out of a relationship very much depends on our capacity to rise to what has been unbidding and unelected.

And that's certainly also true of children.  In that very delicate issue is it okay to desire something else because is that going to hamper your ability to be open to what is unelected is the exchange I see between the two of you.

You happened to mention prayer, and it's a very interesting issue, intercessory prayer in the setting of the Christian tradition.  Is intercession the way in which we, absent of technology, look to God to provide us with the deus ex machina response?

Within the machine we don't have the technology.  So we need this cosmic bellhop who will do certain things to fulfill our wants and our desires.

And there's another way of looking at intercessory prayer, is that circumstance under which we now temper our desires.  We express them, but we temper them.  "Let this cup pass from me, but not my will, but thine be done," and suggests a way in which one hands over into the hands of another, and that other is not defined as the cosmic bellhop.

But the way in which I am sustained and supported to be open to the unbidden in life, the unelected in life, which nevertheless to which I have to rise.

So I see you, Michael, have raised a very important issue for us in your opening statement here.  In addition to harm and so forth or long range impacts and so forth, what are the impacts in our whole understanding of the relationship of parents to children, mates to one another, is the issue to which we return here.

CHAIRMAN KASS:  Frank and then Robby. Oh, sorry.  Bill and Robby.

PROF. FUKUYAMA: Well, this may not answer Michael's question of why this is chilling, but I have my own take on why this is important as an issue, which is that this is a textbook case of a negative externality where you have a decision based on medical technology that is individually rational for the parents, but has a negative social cost and has a population level effect.

This is not a moral.  You know, this is, I think, a good answer to people who say, you know — use this libertarian argument that says, "Well, the only thing wrong with eugenics was that it was state sponsored, and as long as it's individual parents that are doing it, we don't have to worry because, you know, they love their children and they know what's best, and so forth."

And so this just seems to be — and this may not be the most important issue, but it does seem to me it's a model for other decisions that will be possible in the future where you could have perfectly individual, rational decisions that will lead to population level effects that will be bad for society as a whole, which then, you know, I think even for the most libertarian economist, I mean, you know, is grounds for some kind of social regulation.

Now, the troubling desire, you know, I have this mental exercise of a different case of this kind of selection that would be a lot more troubling to a lot of people.  Let's say that there is a gauging or, you know, you can actually in the privacy of your doctor's office, in effect, select the sexual orientation of your child and speculate as to what the population level effects of that kind of power would be

And my private, you know, privately held opinion is that even the most tolerant, you know, person with plenty of gay friends, and so forth, in the privacy of their doctor's office is very likely to, all other things being equal, you know, if they had that choice available, you know, they would avoid having a child with a proclivity to gayness, and it doesn't have to be genetic.  You  know, it could be just, you know, done through drugs or some other thing.

If you had that kind of technology cheap and relatively simple, I would think that you'd get population level effects, you know, that would seriously affect the number of, you know, distribution of gays within the society.  It could happen, you know, within a generation.

So the importance is really not the sex selection issues per se, but just the fact that this does demonstrate that there are new technologies that can have, you know, larger social consequences on the basis of individual choice.  So that eugenics is not troublesome simply because it's state sponsored, but can be quite troublesome as a result of disbursed, decentralized individual parental choices.

CHAIRMAN KASS:  Bill Hurlbut and then Robby, and then I think we'll have to break.

DR. HURLBUT:  I want to ask you a quick question, and then I want to make a comment.

Are there statistics on the gender realities of abortion in America?

DR. EBERSTADT:  Not that I'm aware of.  There may be some data of some sort kept.  Dr. Haney, you may know this better than I, but since the total estimates for the number of terminated pregnancies or abortions in any given year aren't exactly fixed, there correspondingly are other sorts of data one might want to get.

DR. HURLBUT:  I mean, it seems apparent if you add up the huge numbers of lost females in your international statistics that that must be driving the abortion rate strongly in certain countries.

I've read statistics concerning India, certain hospitals where 99 percent of the abortions are female fetuses.

DR. EBERSTADT:  I've read the same sorts of accounts.

DR. HURLBUT:  The second question I want to ask you:  is there a correlation with being noted with crime rates as there are disproportions of males to females?

DR. EBERSTADT:  Internationally?

DR. HURLBUT:  I know it's a hard one to weigh.

DR. EBERSTADT:  Not that I am aware of.  Everyone has — in all societies one always has impressions about the way things worked in the good old days and the way that things are, you know, falling apart now.

And certainly in most of the places in East Asia that we describe, they're not seen as high crime settings.  I wouldn't have the data to support that sort of generalization right now.

DR. HURLBUT:  It seems to me that one likely consequence of this in the regions of the world where there's a strong disproportion maybe 18 years later is going to be a high rate of prostitution and maybe increased rates of sexually transmitted diseases, which may be local to some extent, but has international implications.

DR. EBERSTADT:  I think that's a very good question to ask.

DR. HURLBUT:  What strikes me about this is if you add some of this up, you might actually say that there could be a social advantage overall.  This is the individual versus the state.  There might be a social advantage by governmentally imposed sex ratio of the opposite dimension, that at least in our country crime rates correlate with the number of young males more than they do with anything else.

They've tried to correlate this with drugs and post war and so forth.  It always comes out that it's the number of young males, and so you could theoretically hypothesize a better society by doing something like sex ratio engineering.

That leaves certain questions unanswered like who's going to marry whom, but I just bring it up because when I think about Michael's very deep and important questions, it seems to me that there's something going on under the surface about nature, and we somehow relate this question of God and prayer and nature all together as a single unit.

You start out with the interesting and ironic comment about God's provision for the balancing of the sexes because of male recklessness and death and war and so forth.  And it was kind of funny; it seemed an anachronism.

Nevertheless, underneath the surface that assumption seems to be holding in a broader way for both religious and nonreligious people; that there's something about the way nature does things that seems to be better, wiser, more balanced.  Even if we could produce a better society by decreasing the number of males, therefore decreasing crime or something like this, that it wouldn't be right even then and that, therefore, when we pray for one particular sex or another, there's the element that Bill May was suggesting, that there is a humility in our prayer.  Whereas in our technologies the humility seems to be lost.

DR. EBERSTADT:  I think that Sussmilch did not intend his comment about the Creator at all to be ironic.  I think he was completely serious in his description.

It sounds a little antique to some people today, but I think he was completely serious in his description.

And as for speculating about young males, if there were a technology which could cryogenically freeze our children at the beginning of adolescence and unfreeze them at the end of adolescence, people might pay a lot for that.  I don't know what the ethical implications of that would be.

CHAIRMAN KASS: Robby, and then we'll break.

PROF. GEORGE:  Dr. Eberstadt, a quick question of clarification, and then I want to discuss the matter that Michael Sandel raised.

In the charts that gave us information about the expressed preferences of women in various countries with regard to additional children or having children or additional children, the question was put to married women or was it married women of childbearing age?

DR. EBERSTADT:  It was married women of childbearing age.

PROF. GEORGE:  Of childbearing age.  Okay.

DR. EBERSTADT:  Yes.

PROF. GEORGE:  I didn't think that was indicated.  Thanks.

I'm sorry Michael is not here.  I thought Michael was right or is right to warn us not to assimilate concerns we may have about sex selection entirely to familiar concerns that have been expressed in other domains, and the two that he mentioned were discrimination and abortion and infanticide.

But I wonder if that means we need to find that when we think the thing through we'll find a new set of concerns, a new set of concerns laying somewhere deep in our consciousness or whether it might not be yet another familiar concern, but not one of the two.

And the concern I have in mind, particularly in listening to Bill and Gil is the concern that Leon expressed many years ago and influenced some of us.  I realize not all of us accept this, and that is the concern about turning procreation into production or manufacture.

It was a concern that was voiced by some of us, including Leon, at the very beginning of our deliberations about human cloning and, of course, has been expressed by critics of IVF and other reproductive technologies.

And it does sound to me when I hear Bill and Gill, and their points sound very persuasive to me, that there is something about sex selection which seems incompatible with a posture toward a child, a posture toward the coming to be of a new child that really does treat that child not as a product of manufacture, but as a gift to be received.

And I think that if that distinction holds, and if we  can also distinguish, as I think Christians and Jews would want to do — and I'm not saying that other religious traditions would think about this differently,  I just don't know enough about them to say — but if we would do what Christians and Jews do about distinguishing prayer from magic so that we're not trying to use prayer as an efficient means.  It's just the best one we happen to have to this productive end.

Then I think we can begin to understand that there really is a distinction between praying to have a boy or praying to have a girl and an act of the will, a choice, the use of a technology, and in the process willing that we're going to have a boy or going to have a girl such that the lack of success in that enterprise would constitute a failure of our effort in a way that a Christian or Jew would never say our prayers were a failure.  They didn't produce the result that we aimed to produce.

CHAIRMAN KASS:  Thank you.

Dr. Haney, Dr. Eberstadt, any final comments that you'd like to make?

I want to thank you both for a really very informative and instructive and interesting morning.  We've run over, as is our habit.  We were supposed to start at 1:45.  It gives members an hour and 15 minutes for lunch.

(Whereupon, at 12:27 p.m., the meeting was recessed for lunch, to reconvene at 1:45 p.m., the same day.)

 

 AFTERNOON SESSION

CHAIRMAN KASS:  Let me just remind Council members that we are in the midst of a three month inquiry into various uses of biomedical technology, present and projected, for purposes that go beyond the treatment of individuals with known diseases and disorders or that have uses that could go beyond those purposes, and we are doing so because we were, by executive order, encouraged to undertake some fundamental inquiry into the human and ethical significance of developments in biomedical technology and to contribute to the public understanding of these questions.

And that meant at least that we have the opportunity, but also the liberty to step back from some hot button topics and to try to take a look at the field as a whole and to discover whether there are certain kinds of questions that cut across the uses of this or that technology.

And as I suggested in the memo that was circulated to you before, the prospect of these kinds of uses of biomedical technology really do raise for us some of the weightiest questions in bioethics, as we saw this morning, already touching on not just the means that are to be used, but also the ends that we wish to pursue and touching very often on certain fundamental features of human life.

We've been looking at technologies that affect the body, whether in terms of muscle enhancement or blood doping for athletics.  We will be talking in December about research on aging and the human life span, and we have been looking now — this will be the second of three sessions in which we will be looking at technologies that offer the possibility of influencing certain features of the human psyche, mood and affect the last time; next time, attention and conduct and the discussions of Ritalin and the use of stimulants; and this time things that affect memory and cognition.

And we are very, very fortunate to have with us today two of the leading researchers in the field of human memory.  Dr. James McGaugh, since the 1950s, has been a pioneer in the neurobiology of learning and memory.  He's PROF. in the Departments of Neurology and Behavioral Science, Psychiatry, Pharmacology, the School of Social Sciences, and the Director of the Center for Neurobiology of Learning and Memory at the University of California at Irvine.

And we have PROF. Daniel Schacter, who has written very widely and for a broad, nonspecialist audience wonderful books on the psychology of memory.  He's the William R. Keenan PROF. and Chair of the Department of Psychology at Harvard.

We're delighted to have both of you with us, and by prior arrangement Dr. McGaugh will go first.  We'll then take our break after about an hour and a half, and then we'll have Prof. Schacter's presentation.

But the conversation can flow with all of you present.  Please, Dr. McGaugh, thank you for being with us.

 

SESSION 3:  REMEMBERING AND FORGETTING: 

PHYSIOLOGICAL AND PHARMACOLOGICAL ASPECTS

DR. MCGAUGH:  Well, thank you very much for inviting me.  It's nice to come here and speak about a topic that I have been interested in for over four decades and which serves as my current interest, deep current interest, at the present time.

I'm going to talk about memory, and I think we can all agree that memory is a good thing to have.  You'll hear later on this afternoon that it comes in different forms and provides different advantages and different disadvantages.

But I'm going to focus on only one aspect of it, and that is the experimental or other treatments that will make long lasting memories longer lasting and stronger, and the general assumption underlying this, which certainly can be questioned, is that if it's good for us to have memories that enable us to get along during the day, to remember where we parked our car, to remember our motor skills, and so on, then maybe it's a good idea to have a little bit more of that.  That's an underlying assumption that's been made.  I'm even going to question that assumption.

Now, there are several reasons for investigating memory enhancement which I'll start with later.  I'll talk about memory blocking and start with memory enhancement.

First is just the basic research on brain memory, and that's what drives my research.  I use drugs and other treatments to enhance memory in order to understand how the brain ordinarily works when memories are made.  That's the purpose of it.

If we take drugs, in particular, if we know something about the mechanism of actions of drugs, let's suppose we give a drug which is a GABA receptor antagonist, and we find that this drug does something to memory in a very precise way.  Then we can conclude that GABA receptors located in some places of the brain are very important in the making of the memory process.

Beyond that, if we focus on those places in the brain, we can learn much more about not only the receptors of a particular kind, but a receptor in a particular location.

And out of this is unraveling little by little more and more understanding of the key neurochemical systems and the key anatomical systems that are involved in making and preserving memory.  So that's a fundamental line of inquiry that drives this research, where memory enhancement is a way of inducing the brain to behave in a different way so that you can learn something about it.

Another more obvious reason is the question for finding treatments for memory disorders, such as Alzheimer's disease.  I probably shouldn't say "such as Alzheimer's disease" because the research is almost restricted to that.

There isn't any research on the drug effects for the mentally retarded or it's just minuscule research.  There isn't any research for drug effects on people who have brain damage that prevent them from learning and remembering.  That's a nascent field.  It really doesn't exist.

The focus has been on progressive disorders of learning and memory and cognition that are progressive, such as Alzheimer's disease, because as you know, the incidence is estimated to be at least 25 percent, if not 30 percent, in people over the age of 85.

So we're all looking at something that can happen to us.  So it drives our attention.

Now, there are other interests of the pharmaceutical companies and the biotech companies that overlap, but differ somewhat from the two categories that I've given you, and one is looking for treatments for a new disease, which is age related memory decline.

Now, that's a new disease because drugs can be found to treat it.  It was new to me that it was a disease.  I thought normal aging was normal aging, and we have known for at least a couple of decades that there is, on average, a slow decline over the decades starting at the age of 30 in cognitive processing on memory tasks, in particular, memory tasks that use speed as a criterion.

For example, if you ever watch "Jeopardy," you don't see many 80 year old people on "Jeopardy" because of speed of response is such a high priority, but those of us who are over 50 or well over 50 know that we curse the television because we know, but we can't respond as quickly as the folks that are there.

I'm also concerned about that because while there is age related memory decline, without question, on average there are plenty of people who show absolutely no age related memory decline, and there are others who show rapid age related memory decline.

And underlying all of that, by the way, is a countervailing influence which is an increase in knowledge and wisdom and ability to deal with the environment, which readily compensates for the speed driven responses.  But that is a new target for drug development.

Another target for drug development which sometimes is said explicitly, but most of the time it's implicitly, is just drug improvement for everybody else, and why not?  And why not?

If you look at the health stores or even your drugstores or your supermarkets, you can find dozens, if not hundreds, of bottles and packages on the shelf which are entitled something like "memory boosters" or "brain busters" or something of that kind, and they're not on the shelves because people want to fill up the shelves and make them look pretty.  They're on the shelves because they're being sold.

Ginkgo biloba, which is now the latest study shows has no effect at all in age related memory decline, still sells, makes millions and millions of euros in Germany and, I suppose, somewhat less than that here, but nonetheless, I get more questions about ginkgo biloba than anything else appearing on my E-mail screen.

But that's a target you can see.  That is, as soon as you see there is a market, you can see that there's a target for it, and so there is a slippery slide from disorders of memory to the new disease of age related memory decline, which is in normals, to just having a drug to improve memory in normal subjects.

Now, I have done a nonscientific sample of this by just asking lots of people I know.  I've asked if there were a drug that was safe and effective and would improve your memory for such things as where I parked my car yesterday or, you know, things of that kind.  I have yet to find anyone who said, "No, I wouldn't be interested in it."

And I would have thought that most people would say, "No, you'd have to convince me to take it."  But even people whose judgment I trust and have trusted and maybe no longer trust have said, yes, they would take it.

And then I had another question.  I said, "Well, let's ask how eager you are.  Would you do it if it was free?  How about a penny a day?  How about ten dollars a day?  How about a hundred dollars a day?"

Well, they drop off, of course.  Now, the drop-off doesn't occur for family members of people who have memory disorders.  The drop-off is not really quite so steep because they will do anything to try to keep their family members more cognitively competent for a longer period of time.

But what this nonscientific study tells me is that this is almost a frivolous kind of thing for most people.  Yes, if we're there, and, yes, if it were cheap, and if it would give me a slight edge, yes, I would do it. 

And don't misunderstand.  The pharmaceutical companies and biotech companies are listening to that by looking at the sales of ginkgo biloba and other ones.

ow, there are other reasons you have to come that are implicit, unstated.  One of them is memory enhancement in children, that is, school children, just regular school children.  I'm not talking about children with disorders. 

I was driving to a concert with a neighbor, and our families went, and she said, "Oh, Jim, I'd like to have a drug for my daughter to make her more competitive in school.  Could you give me the name of one?"

It wasn't "do you know anything about it," "are there any things that are safe and effective."  It was "can you give me the name of one," and the model that she had in mind was Ritalin because some of her children friends take Ritalin.  So there must be something else that her child could take so that she wouldn't have to study very hard, you know, just to make up the difference.

But I think that that's coming down the road, and it's something I think appropriate for this group because that's part of the slippery slope.  If there is a drug which is safe and effective and not too expensive for enhancing memory in normal adults, why not normal children?  After all, they're going to school, and what's more important than education of the young?  And what would be more important then than to give them a little chemical edge in getting a better education if it didn't do damage, and so on?

So I see that that's there.

Now, we also have genetic manipulation, which I'll talk about perhaps a little bit more later down the line.  Many of you, I'm sure, saw the cover of Time magazine and read the article after the report of a genetic manipulation which increased the number of a certain kind of receptors, glutamate receptors in the brain, and the mice that had that genetic manipulation, those mice were better at a couple of memory tasks than were other mice.

And so all of a sudden Time magazine began talking about designer babies, I think, which would fit in with your topic of discussion this morning.  If you think selecting for sex is a problem, think about selecting for learning or selecting for intelligence using genetic manipulation, gene transfer or knockouts or something of that kind.  I think that is an incredible morass.

Now, as we consider these latter, however, in children and even for adults, there's an important confusion to clear up that was not cleared up by Time magazine, on the contrary, and that is the distinction between intelligence and memory.

All these things do — all of these things do, including all of the drugs that I work with, is make animals and humans remember a little better information that they have been presented.  That's all they do.

Now, intelligence is quite another matter, whether you think of it conceptually or whether you think of it the way it's tested in an intelligence test.  Memory is a very small component and memory tests are small components of intelligence tests.  They have to do with reasoning.  They have to do with judgment.  They have to do with all kind of things, and there's no evidence that inserting a gene or taking a gene away from a mouse imparts it with greater ability to make better judgment, better reasoning or anything of that kind.

So I think that these experiments, however interesting, do not lead to the conclusions that were jumped on by Time magazine, that all of a sudden we can do genetic engineering, and we have to be worried about intelligence.

If that is something of concern, then I think those people who are interested in it have to be better educated about what it is that memory is and what can be expected from such manipulations.

And finally on this, there's a huge caveat.  I'm now going to question the assumption that I made at the very beginning, that if memory is good, then more is better.

Well, more is not better.  At the extreme more is worse.  There are two famous cases, one a fictional case of "Funes de Memorias" by Borges, a short story in which Funes was capable of memorizing everything that was presented to him, and he remembered everything that he encountered such that towards the end of it he said, "Sir, my mind is like a garbage heap.  It's all there."

And over 100 years ago the famous psychologist William James, in whose hall Dr. Schacter lives, said that to remember everything is as valuable as to remember nothing because it's all there and needs to be sorted out.

Now, there's also the case written in Luria's book, The Mind of a Mnemonist, which you can get at your local Border's bookstore, a subject that he studied for many, many years.  This was a subject who could memorize very well.  He memorized by using synesthesia, by mixing the senses which enabled him to remember better, and he could remember very detailed information for 15 years, very precise knowledge of what numbers were given to him in what order over a 15 year period of time.  He had a very unhappy life and ended up a failure.

I also had a subject.  Up popped on my E-mail one day as the Director of the center, "I have a memory problem.  Would you talk with me?"

And I sent back, "This is not a memory disorders clinic.  I can direct you to one."

"No, I have a kind of a problem you might be interested in.  Would you at least talk with me?"

And this was a young woman who claimed that she had such a powerful memory that it interfered with her daily life, and could I at least listen to her and direct her to someone who might help her, and I had trouble at first understanding what she meant by that.

So I got out the two books that were published at the millennia about all of the things that happened in the last hundred years and just randomly opened pages, and I couldn't stump her.  I just randomly opened pages, and several times she said, "Well, you have the date wrong."

And I said, "No, no, it's written right here.  It's a date line out of a newspaper."

"No, no.  That's the date in which they wrote it.  The date of the occurrence was three days before that," and so on.

And I said, "Well, how did you do in college?"

She was a C student in college, barely made it through, and I said, "Well, why couldn't you put this extraordinary capacity of being able to remember to good use?"

She said she never could because it's disorganizing.  "I'd begin to do something and somebody would say, 'Well, it's Thursday,' and I'd begin to go backwards, Thursday last week, the week before, the month before, the month — five years before, and it's just like going through a Rollodex, flip, flip, flip, flip, flip, flip, like that," and she was distracted from what she was to do because she had such a powerful memory.

Now, lest you think I'm making this up, we also have her diaries, which she kept over all these years, and with the help of an assistant, we are able to check information that she said that she has by going through her diaries, and we have yet failed to find any error or any mistake.

Here's a failed person in life who has an extraordinarily strong memory for events that occurred in her life.  She's unable to use that, and the only way she used it productively was she worked for a while with a very well known trial attorney, and she was the assistant standing there or sitting there so that when some claim was made about something happening on a certain day and it rained that day and so on, this trial attorney could turn to her and say, "Did it rain on that day?"  And she could say yes or no without having to go to the records and see.  That's all that she was good for.

So a little, maybe a little is good, but I don't think any of us would want to have the memory of Mr. S, Mr. Luria's patient, or Funes, the Memorias, the fictional character, or the subject that I've worked with.

Now, let me turn a little bit to the research on drug enhancement of memory, which is my special interest.  This was all started in 1917 by a study by Karl Lashley, a very famous neuropsychologist, in which he gave a drug, strychnine sulfate, which many of you know to be a rat poison, to rats each day shortly before they were trained on a simple, little maze, and he found that they learned the maze faster.

Now, this was of interest to me many years ago because we thought we knew something about the mechanisms of strychnine.  So in the mid-'50s, with a colleague I replicated and extended this study and found that, yes, strychnine did what Lashley said it did.

But we couldn't draw the conclusions that we'd like to draw, which has to do with the drug making memory stronger, because we're confronted immediately with what we know is a classic learning performance problem.  The animals learn better.  The drug influenced the learning, but did it influence the learning because the animals could smell better, because they were more attentive, because they were more reluctant to enter alleys and so they were more selective?  All kinds of performance factors.

Now, if one is only interested in having human performance better, then one doesn't care about this distinction.  That is, if you just want to get humans to perform better, you don't care whether they remember better, whether they're more attentive, or whether they're more highly motivated or whatever.

But if you're interested in mechanism, it's very important.   So I introduced the procedure of injecting drugs not before learning, but immediately after learning, and the reason I did that is because it had already been established or already been suggested that when you make a new memory, there's a period of consolidation in which the formation of the memory is susceptible to influence.

This was first seen with electroconvulsive shock so that humans and animals that are given electroconvulsive shock treatments remember less well those things that happened just before the treatment, and this and other things led to the view that memories consolidate over time.

Now, if that's the case, I said it should be possible to give a drug after the animals are trained and find the same effect, and, lo and behold, I did.

Now, that led me and many others down a path of using this post training drug injection procedure to find out which drugs would enhance memory, which would not, where they acted in the brain, and what mechanisms they used in acting in the brain to produce these effects.

And I won't bore you with all of the details.  Suffice to say that we know that there are several brain regions that are very important, and for those of you who are interested in neuroanatomy, they include primarily the basolateral amygdala. They include the hippocampus, the entorhinal cortex, and the medial part of the prefrontal cortex, in particular, but there are some other regions as well.

We can enhance memory in laboratory animals by microinfusing microquantities of the same drugs that we would inject peripherally into specific regions of the brain and get exactly the same results or we can put antagonists of those drugs directly into those brain regions and completely block the memory enhancing effects induced by peripheral drug injections.  So this is a way of learning about the anatomy of memory, the pharmacology of memory, and the neuromodulatory systems that are involved in memory.

Now, interestingly many of these drugs converge on promoting the release of noradrenalin, norepinephrine or acting on the receptors that adrenalin and noradrenalin use because if we use blockers of those compounds or of those neuromodulatory influences, we can prevent the memory enhancing effects.

Now, we asked then a number of years ago why is it that we have a brain that's organized in such a way as to be labile to influences that happen after learning.  Why is it your and my brain is made that way?

Because I can skip ahead and say some of the same drugs have been studied in humans.  Amphetamine, for example, given post training to humans will enhance memory just as it does in laboratory animals.  Well, why are our organs organized this way?

We came up with the idea that this might be part of the selection process that enables us to keep things that are important to us and not clog up our brain like Mr. S in Funes, the Memorias with things that don't happen.  It's a way of allowing a period of time for selection.

So you have an experience, and a decision has to be made.  Is this memory to be kept or not?

Well, we ask what is it that ordinarily would act in the body that does the same things that drugs do?  Well, what happens when you get excited?  You release stress hormones to yourself.  We all do that. 

When you are aroused, when you are insulted, when you're frightened, you release adrenalin into the blood stream from the middle part of the adrenal gland, and you release cortisol from the outer part of the adrenal gland.  They go into the blood stream.  Both of these stress hormones are released.

So we ask the question then:  do the stress hormones do the same things as the drugs?  And the short answer is, yes, they do exactly the same thing, and they work exactly in the same places in the brain, and they use the same mechanisms that I describe for the other drugs that work on GABA systems and noradrenurgic systems, and so on.

So here's a built in system that does the job, and our conclusion is that what happens with this release is that a correlation is then created between the significance of an event and the subsequent remembrance of the event, and I'll come back to that a little bit later.

Finally, there's a caveat in all of this research, which is very important to think about whether it's drug manipulation or whether it's genetic manipulation, and that is if there is simply a tradeoff between a drug and additional training.  We have found nothing that a drug can do that additional training won't do.

So it's not as though the drugs turn the animals into super animals.  It just means that they get there a little faster.  That is, it gives them a little edge in how they get to that point.  That's very important to think about because if you're thinking about outcome, then there's lots of ways to get that outcome.  You don't have to give a drug to get the outcome.

If you have a child that's not learning well, you don't need to give it a drug.  Give it more training to get to the same outcome.  Now, if you want to use a drug as an aid to get to that outcome, then that's a decision that you have to make, but it's not going to get you someplace that you otherwise wouldn't get.

For example, Mr. S could do all of these marvelous feats of memorizing.  Well, we know perfectly ordinary people who have been trained to memorize a telephone book.  You can do that.  I mean if you want to spend your time learning a telephone book, you can do that.  I wouldn't particularly advise that unless you had some special reason for doing so.

All right.  Let me turn now more specifically for a moment to the effects of drugs used in the treatment of memory disorders, and here we have a sad story. 

Despite many millions and millions and millions of dollars that have been spent by pharmaceutical companies and biotech companies, and despite a lot of academic research, we only have one class of drugs that is useful in treating Alzheimer's disease.  It's all the same class.  They're all acetylcholinesterase inhibitors, which means that they inhibit the enzyme that destroys acetylcholine when it's released.  If you inhibit that enzyme, then this neurotransmitter, neuromodulator is around at the synapse for a longer period of time.

And the drug such as Tacrine, Aricept, Exelon, and so on, they're all "me, too" drugs.  They're all acetylcholinesterase inhibitors, and the further development is to try to get rid of the gastric distress, all of the cholinergic side effects that one would not want to have, and they are more or less effective in doing that, but they are not horrendously effective drugs.

As a matter of fact, they're modestly effective.  The underlying problem is that Alzheimer's disease is a progressive disease.  Subjects are going to get worse and worse and worse no matter what you do, and all you can do is squeeze a little bit more effectiveness out of a patient for some period of time.  It is no cure.

And — and this is a tough one — no new or novel drugs have been produced.  So there isn't any drug out there which is a novel drug, which has been found to be effective, and there have been a lot of them that were this close to being effective and didn't make it all the way through for one reason or another.

There are lots of them that have been developed by pharmaceutical companies that are very effective in animal models, and then they drop out along the way because of side effects.  I'll just give you one odd ball side effect.  There was a company that I was consulting with that had a very powerful memory enhancing drug in laboratory animals, which means they could learn much faster, not ever better, but much faster, and it was yanked out because in Phase 1 it caused nosebleeds in humans.  So it was kicked out because of that, and others have liver damage and they have other things.

They just haven't made it through for whatever variety of reasons.  And I was wrong because a dozen or so years ago because so much money was being put into it, I bet that we'd have three or four by this time working on different classes, that are different classes of drugs working on different systems, but they don't exist.

What's really needed when you look at it carefully in disorders such as Alzheimer's disease is not the palliative types of drugs we're talking about that squeeze a little bit more out of a deteriorating brain, but we need drugs that will or some treatments which will prevent the disorder from occurring in the first place or restoring cellular function through some other means if that's possible to do so.

And there is an awful lot of effort going on at the present time, and now I switched my bet, and my bet is that these are going to pay off.  Let's say, in the next ten to 15 years we'll have some treatments which might — particularly because so much more is known about the etiology of Alzheimer's disease that it's a good bet that something will happen in that area.

All right.  Now, let me say a few words about blocking memory formation.  Can we block the formation of memory?  The answer is, yes, we can do that.

I already mentioned that electroconvulsive shock will do that.  That's been known since 1949 approximately, and it's known both for humans and animals that if you give such a treatment, there will be a selective forgetting of things that have just been learned.

But there are also a lot of drugs that are in common use  that are antagonists of memory that impair or block memory, and I'll mention some of them.  Anti-cholinergic drugs will do that, drugs like atropine and scopolamine will prevent memory formation.   There's not much danger of that happening because these drugs are not used in high doses ordinarily, and they're not anything that's subject to abuse, by the way.  These drugs have  such unpleasant side effects that you wouldn't find many people abusing them.

But there are others that are abused.  Benzodiazepines are memory impairing drugs, drugs like Valium, Halcyon, clonazopam.   All of these drugs induce anterograde amnesia, in both humans and in animals, if these drugs are taken in high doses.  Performance can be reasonably normal without registering the information acquired while under the drug.  This is anterograde amnesia.

And these drugs certainly will weaken the formation of memory, and in some cases they will have very powerful effects, and these are drugs that are commonly taken by many of us.  They were anti-anxiety drugs originally, but  we apparently have lots of anxiety because they are sold in vast amounts throughout the world, much vaster, I think, than the extent of anxiety.

So benzodiazepines are there, and interestingly they work in the same place in the brain that I talked about.  They induced their amnesia by acting specifically in the basolateral amygdala.  So there's something about that region of the brain that's integrating an awful lot of neuromodulatory influences coming in, including those for the benzodiazepines.

In the last category are the beta blockers, which are commonly used for the treatment of heart disease, and I'll say a little bit more about those.

This work came out of the work in my laboratory with laboratory animals in which we found that a common effect of many drugs that enhance memory had to do with the activation of the noradrenergic system within the brain and then this particular region of the brain and some other regions as well.

So it looked as though with that information and the information that we had from the stress hormones that it might be that ordinary emotionally aroused memory, the memory of emotionally arousing experiences might involve the systems in humans.

So Larry Cahill, a colleague of mine in the laboratory, set out to do this.  We did the following study, which is now well known in the literature.

He told human subjects a story about a boy, and it had two versions.  One is an emotionally arousing story, and the other is a boring story.  And then he measured the memory in a surprise memory test three weeks later, and the subjects selectively remembered better the information presented to them during the exciting part of the story.

So let me run through it for you.  A boy and a mother leave home and they cross the street and there's a slide.  There are 12 slide that are shown.  Cross the street.  They see a damaged — I'm giving you the boring story — they see a damaged automobile.  They visit father who works in the hospital.  They're having disaster prepared in the demonstration that day.

They see people with make-up on to make them look like they've been injured.  The mother makes a telephone call and goes to the bus and goes home, and that's the story.

And you can divide it into three parts.  Early stages, leaving home, in the hospital, and then the denouement at the end.

On the surprise memory test three weeks later, the subjects remembered all three parts equally well.

Now, other subjects, exactly like those, were told a different story, same 12 slides, and the test is on what's in the slide.  Told the same story.

The boy and a mother leave home.  They cross the street.  The boy is hit by the car.  He's seriously injured.  They rush him to the hospital.

Surgeons work frantically to save his life and reattach his severed legs.  A distraught mother makes a telephone call, goes to the bus and goes home.

So here it is.  Same pictures, and then the surprise memory test is:  tell us what you saw in the picture.  Don't tell us about the story.  What was in the pictures?

And there is a significant increase in the information remembered in the pictures in this subjects that had the exciting story told.

So then Larry and I did the same experiment, except we gave the subjects a beta blocker, Propranolol or Endurol, in clinically used dose, in a clinically used dose, and told them the story, and then tested them three weeks later, and those subjects were — their memory was just like that of subjects that had received the boring story.

So here's a blocking of emotionally influenced memory by Propranolol.  Now, this turns out to be important, we think because it has some implications for the etiology of post traumatic stress disorder, and as you may know, about 25 percent of the Vietnam veterans had or have post traumatic stress disorder, and any time there is  crisis, traumatic event, there can be a significant amount of this disorder, which in many cases will never go away.

In some cases it will go away in a few months, and what Roger Pitman did was to get hold of human subjects that had been traumatized in an accident or in some way and put them on beta blockers as quickly as possible afterwards and maintained them on for several weeks and then looked to see symptoms of PTSD several months down the line.

And a first study that was just published showed that there is a significant decrease in the expression of PTSD several months down the line, and subjects were put on the beta blockers.

Well, what is the logic of this?  After all, the exciting event is over. 

The logic is based on the evidence from studies of post traumatic patients, that the events will flash into the mind after  they're over the next day and the day afterward, and you consider each one of these as a rehearsal.

So every time they relive the experience of being mugged or being raped or being almost killed in a car or whatever, every time that comes up again, there's the same emotional reaction again.  It's like a rehearsal with the autonomic concomitance of this, and the effect of the propranolol is to allow this inadvertent rehearsal, but without the stress hormone consequences of that, which would lead to a strengthening of the memory.

There's another study in press that shows the same results.  So there now will soon be two studies showing the effects on PTSD.  Whether this will hold up in the long run we don't know.  This is very early in this research.

Now, let me bring up very quickly some issues.  You asked me to, some issues that might be worth discussing, and one is the blocking memory.  I'll start with that because that's where we just finished discussing, and there is some concern that it might be a bad thing to reduce the strength of memory for people who have had a traumatic event for lots of reasons.

Maybe we need to remember trauma in order to deal with life or maybe we need to remember the trauma in order to testify in court, and so on. 

So one could make an argument that it is certainly a judgment to be made as to whether if this really does work, as it appears to, but we're not sure at this point; if it really does work, then one would have to make a judgment.  Is it better to reduce the probability of development of PTSD and forego a strong memory, or is it better to save strong memories, complete with the suffering, and forego the opportunity to decrease the suffering?

That's a judgment call that each individual would have to make if what I have told you turns out to be validated and substantiated.

Here's another one that's of deep concern to me, and this is, by the way — we've had several conferences on this topic, including one at the Ciba Foundation in London a few years ago, and so we've discussed these issues many times in small conferences.

This one concerns me.  Arresting neurodegeneration, I said that there were likely to be such drugs.  I'm worried about that because I could anticipate a situation in which Alzheimer's disease was identified, let's say, because a person is becoming demented.  Now there's a drug which will prevent any further deterioration, and now you have an arrested dementia, which means that people will be in this arrested state for a longer period of time.

It is not necessarily the case that you would want to stop deterioration if the deterioration is far along.  Once, again, that would be a judgment call.

The next one I touched on, drugs for children.  If we go down that slippery slope from Alzheimer's disease to age related declines in memory to drugs for normal people who would like to have an edge, well, children can be normal people who would like to have the edge.  They would be on that slope, and so the question would, in the subjunctive, or will, if things have a certain way, come up; should drugs be given to children as an ancillary treatment for learning?  Why?  Which children?  Is this going to be another economic divide?  The rich kids get the pill in the lunch box and the poor kids don't, if it's readily available.

I mean, I can certainly foresee that happening.  I can't predict that it would happen, but I can foresee that happening.  And is this yet another cost that we're going to have to bear in society in treating the walking well?

We already spent a lot of money on treating the walking well.  Here's yet another example of it.

And finally, the worst one of this is the designer baby and what I call the Time magazine issue.  Time magazine, based on this study that was published in a very reputable journal took unfortunately a word that was used in the paper, both in the abstract and in the introduction of the paper, "intelligence."

That PET study did not study intelligence.  That study asked does a mouse freeze when you put it in a place where it had received a shock.  Does a mouse swim more rapidly to a platform where it could escape from cold water?

The genetic manipulation produced mice that both of those did better than their controls.  That's what they did.

Now, there's nothing in there that 100 other people haven't already done with drugs.  Those are the same studies that have been done literally hundreds of times with drugs, enhancing memory of this kind.  So there's nothing conceptually new.

What's new is the permanence of it and the use of molecular genetics to produce it, which leads people to think, and Time magazine certainly thought that and the author of the paper implicitly suggested that by using the word "intelligence" rather than "memory" or "performance," that it might be possible with right consultation of the right people to have designer babies in which you insert particular genes which are guaranteed to make them learn better.

Well, there's no guarantee, but my guess is that we would have, if they worked, we'd have more Mr. Ses and more Mr. Funes de Memoriases and not necessarily more thoughtful, intelligent human beings that will help to make this place a better world.

Thank you.

CHAIRMAN KASS:  Thank you very much.

We should just open the floor for discussion.  Mike Gazzaniga, please.

DR. GAZZANIGA::  Thanks, Jim.  That's terrific.

It might be helpful though for us to have you distinguish between memory as sort of a unitary event and memory as you and I know it to be, which is this complex system of information and coding, retrieval and all of the rest.

The reason I say that is that one of the benchmark observations in the clinical and neuropsychology  is that the memory quotient score correlates perfectly with the IQ score.  And so when we have these enhancing devices that allow for, quote, increased memory, probably what we mean by that is increased sort of lexical entries or something.  It isn't enhancing the entire memory system that allows the intelligent encoding and retrieval of all that information for use.

And if that pill came along there might well be an impact, it would seem to me, on these matters.  What do you think?

DR. MCGAUGH:  Well, starting way back when I first began working on the drug enhancement, I tried to ask the question are there limits to the kind of information that, let's say, post training drug injections will influence.  And the answer so far is no.  That is, I found memory enhancement with post training administration of a variety of drugs in every task that I could think of that would tap different kinds of information that the animals were acquiring.

So it appeared to be general over a very broad range.  Now, we're going to hear more about different forms of memory in the human this afternoon, but as far as different kinds of things that animals are capable of being taught, I haven't found any constraint on that, nor has anyone else.

Now, with respect to the memory and the IQ, however, wouldn't you agree that if the memory test was a perfect predictor, then you wouldn't need the IQ test, and the IQ test covers things besides just the memory subtest, correct?

DR. GAZZANIGA::  Oh, yes, yes.  The fact is though that if you take a look of somebody with an IQ of 100 versus an IQ of 125, the memory subtest goes right up with it.

DR. MCGAUGH:  Sure, sure, and it would have to because that's the way it was built.

DR. GAZZANIGA::  Well, no, in separate, totally different, independent memory tests, too.  But anyway, you know my point.

But one final point.  Beta blockers and Baghdad.  So let's say you're going to send troops into harm's way.  Is in some sense modern neuropharmacology suggesting in order to prevent post traumatic syndrome you ought to give them a beta blocker before they go in for their dirty work?

DR. MCGAUGH:  Well, first let's assume that what has been found will be replicated.  Let's make that case.  I don't want to make that too strongly because this is an early stage in the human application.

But once again, that's your tradeoff question, isn't it.  Let's suppose they really were to prevent or to attenuate the development of post traumatic stress syndrome, and actually the number from Vietnam, I think was 29 percent of the veterans of the Vietnam War had post traumatic stress syndrome, from which many never recovered, and then they filled up the veterans hospitals.  That's just a fact of life.

Would it be worth using pharmacology to prevent that from happening, if it didn't do anything which would harm the person?  That's the judgment to be made.  Somebody would have to make that.

DR. GAZZANIGA::  That's right.

DR. MCGAUGH:  Now, stimulants have been given to soldiers for years to make them implicitly, and I think explicitly in some cases, to make them better soldiers.  Nicotine is a memory enhancing compound in laboratory animals.  Post training injections of nicotine enhance memory.  It just does.  It's been known for many years.

One doesn't do those studies in humans because of the taint from the tobacco industry so that one just wouldn't do that research.  You don't want to be tagged as somebody who's going to increase tobacco sales, but my guess is it's probably is memory enhancing in humans as well, and caffeine as well.

Soldiers are routinely given cigarettes, and that came in with their K rations.  Amphetamines were used by the Germans, given all the time to their soldiers.

So the use of pharmacological enhancement of human performance is not new to the military.  So the question is if you think that they're going to survive and they have a quarter percent, a 25 percent chance of being debilitated even if they win, would you want to do something to prevent that from happening?  That's a judgment that would have to be made.

CHAIRMAN KASS:  Gil and then Dan.

PROF. MEILAENDER:  I don't know I even know enough to know how to ask my questions here, but I have two sorts of questions.  One is — and this is really a naive layman's question — but in some of the things you talked about with respect to — actually it was particularly with respect to sort of blocking memory formation, which it seemed to involve controlling various kinds of emotional responses that one might have in various ways.

In what sense is that — in what sense were you doing something that specifically touches memory when you do that?

I mean, I don't know.  As I say, this may just be too naive, but is it really memory that one's dealing with at that point?  That's my one question.

Let me just ask my other and you can do what you want with both of them.

Is it conceivable just in terms of the mechanisms one's working on that one could go to work on Alzheimer's, on trying to find ways to stop that kind of degeneration, that would not also be applicable to, you know, possible memory enhancement in school children, say, or something like that?  Are these separable categories?

So those are my two questions.

DR. MCGAUGH:  Well, those are both very good questions, but I do think they are completely separable from my perspective.  Let me take the first one.

The answer is no.  We're not only affecting memory.  The question is are we affecting memory, and the answer to that is yes.  We can show that it's not due to some other side effect of it.

We are affecting memory, but we're also affecting — I mean, after all, these beta blockers are going to affect the action of the heart.  I mean, that's what — think of all the things that adrenalin are required for.  They're required for releasing glucose from the liver and so on.

So that when we give a beta blocker, lots of systems are going to be affected.  The body is going to be changed in lots of different ways, but we've been able to sort out with our experiments the question is it specifically, no matter what else it's doing, is it working on memory, and the answer is, yes, it's working on memory while it's doing all of these other things.

Does that answer that part of it?

All right.  The second one is that I think that they're really quite different questions.  Let's take the Alzheimer's disease, and let's assume for the moment that the cause of it is the anatomical sequelae that lead to these plaques and tangles in the brain.  Let's just assume that for a moment, and that's still a little contentious in the field.

The kinds of drugs that one would use for that would be the ones that would interfere with the cellular processes that lead to that kind of neuronal damage, and they may have no other effects.  They may have no other effects at all.  They just may prevent that sequelae from taking place.

Whereas the drugs that are currently given for Alzheimer's disease, the acetylcholinesterase inhibitors, make better use of a declining brain system that uses acetylcholine as part of its communication mechanism, makes better use of that, but it doesn't do anything that we know of to stop the degenerative process.

So the degeneration is continuing, and it's sort of like trying to squeeze a little bit more lemon juice out of the lemon juice that's been squeezed.  You can always find a little bit more.

It's like the economists who say that we are never going to run out of oil, and their reason is because there will always be some oil.  Now, we'll never run out of coal because there will always be some coal.

Well, there will always be some acetylcholine.  Can you make it work better with a declining brain?

But the drugs that are used to make the acetylcholine work better or whatever neurotransmitter may do nothing at all to deal with the underlying cause of the disease, whatever that may be.

So I see them as going in different mechanisms.  To put it in another way, I don't think that there's any danger that normal human beings will run out and buy Exelon or Cylert or one of the other Alzheimer's disease to try to make them a better sales manager.  That's not going to happen, and those drugs are not going to be given to children.  I mean, nobody in their even quasi right mind would think of doing that, nor if there were drugs that would prevent neurodegeneration would a normal person take them unless they thought they were at risk for the degeneration, which brings up another question.

If we were able to make those predictions, would there be drugs to deal with that?

CHAIRMAN KASS:  Dan Foster.

DR. FOSTER:  Just a comment and then my question.

Of course, the Alzheimer syndrome or disease is sad, but the sadness and pity is not so much for the patient, who doesn't remember anything, but for the caregivers. The caregivers are continually stressed and presumably releasing epinephrine and norepinephrine all the time. Maybe that is what keeps them going. It is not a bad disease for the patient when fully developed because memory is gone, but one wants to prevent it if at all possible.

Now, you just made a statement which I was going to follow up.  You said that even if you knew that there was a drug that was going to be preventive, let's say, of the Alzheimer's dementia, as an example, would I take it or would you take it, and the answer might be if that were solely an effect of the drug that you would not.  You don't have a family history of Alzheimer and so forth.

But one of the things that there's an increasing interest in in medicine, I believe, is where a drug which is used for one reason has powerful effects in others.  For example, probably the cheapest and safest chemopreventive drug that you can take with the rare exception that you're going to bleed is an aspirin.  It's going to cut colon cancer 50 percent, probably going to diminish, slow down Alzheimer dementia.  You know, it's got a variety of things that are additional.

Now, one of the drugs, and I'd be interested in your comments, that's been very much of interest lately in terms of chemoprevention of the Alzheimer dementia are the statins, the drugs that are used to lower blood cholesterol. I mean, at least in terms of retrospective studies, if you've ever taken them, you may be as much as 70 percent in large populations.  The veterans population study is the one I know best.

It also is very helpful, it turns out in odd ways of preventing osteopenia in women, bone loss, and of course, the people who really work on cholesterol, we have two guys that are Nobel Laureates for cholesterol at our place.  They believe that, you  know, to take a target of a cholesterol of 100, let's say, even if you've got diabetes and so forth.  The NIH says 130 LDL, the bad cholesterol.

They clearly show a linear progression back to the 60s and so forth.  In other words, if your LDL is 100, that's great, but if it's 60, it's better if you want to prevent atherosclerosis and so forth.

So the question would be:  would you have the same anxiety about a single prevention for something like dementia if at the same time you could handle — and this is before they get a disease.  So you're in prevention and not treatment.  Would that change your thought about the approach to this fairly common problem?

I guess I don't know whether I'm saying this very well, but if you get several effects from a drug that's relatively cheap and seems to be — and I don't want to confirm that it's really stopped.   It's not due to the cholesterol.  That's clear.  It's not due to the cholesterol even though E4 — I mean apolipoprotein, E4, E4 is one of the genetic risks for early Alzheimer's and so forth, and that also gives you lipid disease, as well.

But if you could do that, would you have the same concern about it?

DR. MCGAUGH:  Well, let me shift diseases to Huntington's.

DR. FOSTER:  Okay.

DR. MCGAUGH:  There it's clear.  If there was neuroprotection for Huntington's disease or for multiplesclerosis, I don't think there would be any question at all because they're well understood or pretty well understood.

DR. FOSTER:  Sure.

DR. MCGAUGH:  But at the present time, in the case of Alzheimer's disease, it's etiology is not well understood even though we know that there are genetic predictors of it, and so it's not clear what one should do.

You know, take ten times the amount of Vitamin E and take more aspirin and all the rest, statins, whatever.  If I had three of the genetic markers for Alzheimer's disease, I probably would look for all of the above in order to keep that from happening, just as I would if I were destined to have Huntington's disease do everything I could to find out how I could be neuroprotected.

Now, let's think about it more broadly, about the general public where they're not going to have genetic information about this.  Already people are taking Vitamin E.  People are taking aspirin, I mean, much more than they used to.  So there are people who are trying to be neuroprotective just to cover the odds.

Now, let's suppose it costs $100 a day to be neuroprotected.  What do you think would happen to the Vitamin E sales and the aspirin sales and so on?  They'd go down to the floor because people would say getting that new car today is more important than what happens to me when I'm 70 years old or 80 or whatever.

So there are huge economic consequences that have to be factored into this, just as there are economic factors for dealing with AIDS, for example, or the cost of the medication influences how well it's point to be accepted and used in different countries and so on.

So the same thing would apply in the United States.  The cost of these things, even if you knew their effectiveness, would have a big influence.

DR. FOSTER:   I was just really trying to get to the issue that sometimes there are surfaces, and we've heard a little bit of it today, that if you do anything to alter the natural development of nature, that is to say if you — I'm not talking about acute disease or, you know, a kid who gets zapped by a sniper or something like that — but if you alter it, that that is both — it should not be done.  The playing God syndrome.

And I just want to be sure that your worry about the issue of the side effects and so forth of dementia did not imply in some sense that if scientific investigation could give us prevention against some of these major things and at a reasonable cost, which also has to be taken that you — I just wanted to be sure I understood your philosophy about that, and you've just answered it, but I wanted to bring that to the floor.

DR. MCGAUGH:  And I think in the case of neuroprotection that that's likely to happen.  I mean, that's the greatest effort that's being made at the present time on finding neuroprotection, even some thinking that it might be possible to make the cells behave better and behave the way they're supposed to after they have started to degenerate.

So not only protection, but recovery are two targets that are being actively pursued at the present time.

What I was trying to say though is that this is quite apart from the other reasons for having drug enhancement of memory, quite separate.

Thank you.

CHAIRMAN KASS:  Could I clarify?  I was in the queue.  I've also got Janet and Paul.

I would like to clarify just the bottom line on what is currently available or likely to be available in terms of interventions both for enhancement and for blockage.

I think I heard you say that notwithstanding the huge amount of effort, we have nothing really available with respect to the already existing degenerations of Alzheimer's disease. 

Nevertheless we do have in animal models various kinds of things that can enhance memory at least as testified, the performance of certain kinds of tests, but that the attempt to use these things in human beings have run afoul because of side effects in most cases.

Let me add one additional fact that you alluded to at the beginning, but stayed away from.  As I understand it, the main interest in the biotech companies or the others who are pursuing this is less Alzheimer's disease, but much more the memory enhancement —

DR. MCGAUGH:  Yes.

CHAIRMAN KASS:  — of — I can't find the keys.

DR. MCGAUGH:  That's where the market is.

CHAIRMAN KASS:  That's where the market is and enhanced probably further by the market of the people who want their kids to do better on the SATs or as you have it.

With respect to those things, is there likely to be something — if you leave aside the treatment of the degenerations, but talk about possible things that would be coming in the area of the potentiation of more or less normal memory or this new age related; is this 20 years, 30 years or —

DR. MCGAUGH:  Well, we always think it's right around the corner because so much money is being spent doing exactly that.

I did send in a tape [to the Council Staff] of a BBC program that is about ten years old.  It's available from somebody here, and in it I was interviewed, and I said that my belief was that the real target of this drug development was not for the memory impaired, but it was for the normal because that's where the market is, but nobody will say that.

I'll be damned if they didn't find the Director of Marketing of a major pharmaceutical company that they put right after my statement who said, "Yeah, that's what we're going after.  That's where the market is."

I mean, he just said what I said that nobody would say in public.  I mean just opening.

Well, their compound failed.  They put a lot of money into a compound, and it just didn't work.

Now, let me back up here and say there are things that work, but they have no interest because there's no money in them.  Paul Gold has shown that glucose enhances memory, not only in normal people, but in elderly people and in Alzheimer's patients.  You get a little improvement with glucose, but there's no money to be made in that.

Amphetamine is a very potent memory enhancing drug, as I mentioned, both in humans and in animals, and it works even when injected in humans or given to humans after they've learned something.  It strengthens consolidation.

But there's no money to be made in amphetamine, and besides that, it's a nasty drug, and people get dependent on it and they get addicted to amphetamines.

So there are things right now that people could take that will enhance memory, but pharmaceutical companies are not very interested.

Now, one major company, Abbott Laboratories, certainly knew about nicotine.  So they decided to modify the nicotine molecule and, once again, the count was millions of dollars to make a drug that is like nicotine, but for which they could get a patent, and it didn't work all the way through Phase 3.  So that was a big loss of financial investment.

Now, nicotine probably works, but it's also addicting.  So there are these side things, the things that might do something for memory that we know of or that companies have tried to develop.  All have some kind of a restriction.  They just — there's no free memory enhancement that isn't going to do something else.

It's sort of like looking for a nonaddicting opiate.  You remember in the early part of this — well, right at the turn of the last century when heroin was introduced by Bayer.  It was called Heroin because it was heroic.  That's why they called it that, as the nonaddicting opiate for children, and it was in children's cough medicine for probably 20 years.

And after the discovery of the opiate receptor, there was a huge increase in looking for nonaddicting opiates.  If we could only take that drug which is analgesic and modify it, you know, pull off a methyl group here, add another group over there; we'll find an opiate that is nonaddicting.

Well, the less analgesic it is, the less addicting it is.  So memory enhancing compounds, let's say, our own memory enhancing compounds are adrenalin and cortisol, and they do all kinds of things.  I mean, you wouldn't want to give adrenalin to a heart patient, for example, but we know that if we give adrenalin to a rat or a mouse, we can make it learn a lot faster or if we give a drug that will activate those receptors it will happen.

But there are always going to be these side effects, and I don't see them disappearing, but that's what the pharmaceutical companies are looking for.  They're looking for the pure memory enhancing drug that doesn't do these other nasty things.

And is that around the corner?  Maybe it will be in the paper tomorrow.  I don't know.

CHAIRMAN KASS:  On the parallel side now on the memory blocking, the same answer?

DR. MCGAUGH:  Well, that can be done right now.  I don't think —

CHAIRMAN KASS:  But also with drugs that have systemic effects, right?

DR. MCGAUGH:  Yes.

CHAIRMAN KASS:  I mean blockers are also not innocent —

DR. MCGAUGH:  You pay for it, but let's put the emphasis.  You want to reduce the anxiety, and so you take a benzodiazepine.  Well, the sufferance there is that you are also likely to induce anterograde amnesia.  It was discovered after it was approved for anxiolytic effect.

So now you take, let's say, benzodiazepine to produce anterograde amnesia.  The payoff is you're going to be less anxious.  I mean, you don't have to remember.

(Laughter.)

DR. MCGAUGH:  I mean, the way this — many of you here probably know that it was discovered by psychiatrists and psychologists after the benzodiazepines were introduced.  People would come back after having been on a trip, and they were very anxious about going, and they would come back in the report, "I don't remember what happened on this trip," and so that's what stimulated the research on it.

And then it was discovered in animal models as well as in humans it's a very strong anterograde amnesia, which of course is dose dependent.  So that you can certainly take a benzodiazepine and get an anxiolytic effect without having severe anterograde amnesia, but you can also take a high dose, and you think you're okay, and then have anterograde amnesia.

CHAIRMAN KASS:  Thank you.

I have Janet and then Paul.

DR. ROWLEY:  Well, I want to follow up.  My question is in a sense related to what you just said because many, many individuals are taking beta blockers, particularly older individuals, and the question then is — and I don't even know what doses are generally used for beta blockers, but what is the relationship of the dose that would be used clinically and that which causes retrograde amnesia?

DR. MCGAUGH:  The clinically used doses, let's say, propranolol, 20 milligrams, is not going to induce any retrograde amnesia.  What it does in a study so far is simply prevent the added memory that is induced by emotional arousal.  So we have not found in human subjects any memory impairment in these doses, but we have found complete blockage of the effect of this emotional arousal on subsequent memory. So in that sense I don't think there's any danger.

This, by the way, independently in the same year, an experiment was done in a very different way by Rob Jenson and his colleagues in southern Illinois, but in place of emotional arousal what they — these were now with elderly people who are on beta blockers or on other drugs for controlling heart disease, and they taught them standard psychological verbal material.

And then after that they had them squeeze what's called the hand dynamometer in which you squeeze it, and you can see how much pressure is induced by squeezing it, and this is well known to release catecholamines, including adrenalin.  You do this.

And they found that the memory, squeezing this thing, enhanced memory in the elderly subjects who were on other drugs for treatment of heart disease, but did not enhance memory in subjects who were taking beta blockers.

In normal subjects now, Larry Cahill has used another technique which is standard procedure in cardiology studies, and that is just thrusting one's hand into a bucket of ice water.  I know that doesn't sound very sophisticated, but it will certainly get the heart going, and it releases adrenalin massively right at that time, and Larry Cahill has now found that memory for ordinary verbal material is significantly enhanced.  Subjects learn something and put their hand in this tub of ice water.

So it doesn't have to be an emotionally arousing response, but we think in our nature that's probably what ordinarily controls it because we don't go around putting our hands in buckets of ice water to release catacholamines.  We get catacholamines release when people say, "You're dumb, you're ugly, you're stupid.  You did a good job.  You won the lottery.  You got a Nobel Prize.  You're going to be executed.  Things like that tend to get epinephrine or adrenalin released.

CHAIRMAN KASS:  Paul McHugh.

DR. MCHUGH:  Well, we could talk all afternoon after that wonderful talk, Dr. McGaugh.  I had two comments and then one question.

The first comment was in your deep wisdom you reinforced what my father told me when I first went off and recognized that there were a lot of people in schools that were smarter than I was.  He said, "Don't worry.  You can out work them."

DR. MCGAUGH:  That's right.

DR. MCHUGH:  And it's the truth.  You're backing that up.

DR. MCGAUGH:  That's a missed point.  My neighbor, who wanted the drug for her child, I don't think had asked the child to work a little harder.  I think she was just saying she's not doing well.  Let's make up for that..

DR. MCHUGH:  That's right.  That was my father's idea.  Just work harder.  You can do it.

DR. MCGAUGH:  Well, he was right.

DR. MCHUGH:  He was right in many things.

The other thing was, of course, in relationship to treatments for the conditions, the deteriorating conditions like Huntington's disease or Alzheimer's disease and the like, which are devastating when they occur and which have their beginnings before, if we understood not just the risk factors, but the mechanisms, it probably would be that everybody who had those mechanisms in play would probably take the treatments even no matter what they cost.

The real problem now is not for Huntington's, but something like Alzheimer's disease.  We only know that there are risk factors that are tied to it.

DR. MCGAUGH:  Think of all the people who are taking Vitamin E and aspirin at the present time.

DR. MCHUGH:  Oh, I'm well aware of that.  Aren't you?

DR. MCGAUGH:  So that there is at least among people who pay attention to these things — we try to reduce our risk.  I mean, if we knew more about it, we could do more selective things to reduce that risk.

DR. MCHUGH:  That's right.  So the mechanisms would help us to know more things.

DR. MCGAUGH:  Absolutely.

DR. MCHUGH:  I had one real question I wanted because it was very interesting what you were saying about the effects of beta blockers on consolidation of memory.  But as you know, lots of people use beta blockers who are performers, particularly artistic performers.

DR. MCGAUGH:  Absolutely.

DR. MCHUGH:  Stringed instrument players and the like, and they discovered in their performance that they can do much better if their hands aren't trembling and the like.

And I wondered about you making the point that beta blockers inhibit consolidation.  Do they have any effect on retrieval, on memory retrieval, which would both affect the piano player who was following the Schuman approach of doing it by memory, but also might affect us otherwise negatively?

DR. MCGAUGH:  I had a whole section on that that I didn't include because of lack of time, but may I just say something about that?

First of all, it is the case that beta blockers are the drug of choice for stage fright, speech fright, and also for controlling trembling and things of that kind.

But in the case of the violin player who is up there performing, that is so over rehearsed that the memory is not going to be affected for that.  That's on automatic drive at that point.  So that's not an issue.

But these same hormones that I told you enhance memory consolidation on other circumstances, on other conditions, will impair the retrieval of memory, and we have studied that fairly carefully using cortisol in the human or corticosterone in the rat, and the experiments are as follows, and we try to make them as parallel as we could for the two.

The subjects learned something on one day to some criterion, and then the next day they are tested on it, and then we check to make sure it's not interfering with their performance or anything of that kind.

And it turns out that a glucocorticoid, a cortisol, has an impairing effect for about one hour after it is either released or after it is injected, and we know that it is the cortisol because if we give a drug that blocks the release of cortisol, then there is no memory impairing effect of the treatment or  in a rats it can be a shock, an electric shock to its feet.

And this is an effect that lasts for about an hour, an impaired retrieval selectively induced by that.  So we think that all of the things that we have learned from our undergraduates over the year about how they knew the information very well and they just panicked on a test and couldn't remember it.  We now think that at least some of that may have been honest, that there was an over excitement and there was a temporary depression of selectivity of memory retrieval lasting for about an hour, and this we found both in rats and in human subjects.

And we are now doing experiments at the moment to find out the involvement of beta receptors, beta adrenergic receptors in that mechanism.  We had experiments in place right now doing that.  So I can't answer the question.

But in everything else I said it had to do with getting information in and getting it stored.  It all had to do with making a memory, and now we're shifting it.  That's why I left it out of my main talk here.  We're shifting to something else and saying are there things that affect our ability to utilize information that we have, and stress hormones do affect that.

DR. FOSTER:  Just one quick question.  Does epi/norepi also do the same thing, that one hour impairment of retrieval?

DR. MCGAUGH:  No, we haven't examined that yet.

DR. FOSTER:  Because oftentimes they're almost always up together.

DR. MCGAUGH:  Yes.

DR. FOSTER:  And you know that cortisol has a permissive effect on that.

DR. MCGAUGH:  And we're looking specifically once again in the basolateral nucleus of the amygdala because that was critical for our consolidation effect, and I can say our first experiments indicate that activation of beta adrenergic receptors within this same region of the brain plays a role in this memory retrieval effect that I just described.

But that's not published.  That's the only thing I've told you that's not published yet.

CHAIRMAN KASS:  Frank Fukuyama.

PROF. FUKUYAMA: Are you born with a certain natural memory capacity?

And when you talk about memory enhancement, you're talking about the ability to move information in and out of that fixed capacity or can the capacity itself be affected by environmental factors?

DR. MCGAUGH:  You're probably going to hear a lot of that, something about that from  Dan Schacter, but let me just touch it briefly. 

The answer is no because there are lots of ways in which as we go through life we improve our memory capacities.  Let's say in areas that are your hobbies or things that you deal with an awful lot, you just get better and better because you have more information that's related to other information, and it's not stored as an isolated packet, but it becomes integrated.

So that I have two hobbies.  I play jazz clarinet and saxophone, and I do woodworking.  So I have lots of things that are very easy for me to learn because they are related to that, but if somebody starts talking to me about their hobby which is something I don't know anything about, I would have trouble remembering it just because I don't have the contextual connections formed to do that.

Now, also, if you take very specific domains, memory can be trained.  So that if you want to be able to memorize digits, let's say for some reason you have a zip code which is 2,000 numbers long.  You could do that.  You could do that.  And you would be better then for a while in memorizing of digits.  So that this specific domain can actually be improved. 

So you're not born with a capacity.  What we're born with is without any extra effort to get seven digits plus or minus one, and that's one reason we had seven digit telephone numbers and the area code was kept separate, because you can remember seven digits at least long enough to write them down.

That's probably the native thing that most people have, but  you can have a digit span of 15 if you'd like to have it for some reason.  You can get special training to do that.

CHAIRMAN KASS:  Bill and then —

DR. MCGAUGH:  And, Dan, I hope that you'll elaborate on that because that's more in your domain.

Excuse me.

CHAIRMAN KASS:  Bill.

DR. HURLBUT:  I want to ask you about something you touched on briefly, the engagement of possible memory enhancing agents in education.  If you say that, as you more or less said or at least implied strongly, that memories related to life significant issues because the body itself produces through at least the adrenal gland, and probably in many other ways, agents that modulate memory retention.  It then implies from that that if you enhance one component of that system artificially that you might be disrupting the psychophysical unity of your identity or your normal life processes.

In other words, you'd be forcing on your system memory of things that your other normal process wasn't encoding.

DR. MCGAUGH:  Absolutely.

DR. HURLBUT:  So in other words, we have a therapeutic model of memory enhancement where we think there's a deficit.  That makes sense, and just as it's easier to fix a broken link in a chain than it is to strengthen the whole chain, we can comprehend how that might work where there was a problem.

But would you really improve life overall is a large question I hear going on in the background of what you said.  In fact, you started at the beginning in saying if memory enhancement were a simple good, then evolution probably would have done it.  Didn't you say something like that?

DR. MCGAUGH:  Somebody.

DR. HURLBUT:  Okay.  Here's my question.  The work that Mike Merzenich is doing with enhancing Ó- going back to basic neural processing, things like dyslexia and reworking very fundamental things in the way a person takes information where they have a learning deficit or, for that matter, any strategy of approaching life tasks.

He suggests that maybe you could combine what he's doing now with computers with drug enhancement to reinforce or make more powerful that basic neural revision.  You're familiar with —

DR. MCGAUGH:  Sure.

DR. HURLBUT:  Do you think this is something that is coming?  Is it realistic?  Would it be profoundly disruptive?

And what do you see as the ethical questions associated with that?

DR. MCGAUGH:  Well, I hope it's not coming because I think that the ramifications are really very broad.

The reason I hope it's not coming is because you picked a particular case, but I could pick many others.   Let's just say the school teacher who is teaching the number facts to the children, and number facts are not very exciting, but you need to know how to multiply at least 12 times 12 and how to do the division, and that's not any different than dealing with dyslexics.  You're trying to correct here a disorder.

The disorder is that they don't know the number facts, and they have to know them or that they have to know the grammar.  And so why not a little chemical aid to do that?

So if you start with something as narrow as that and say:  folks, this is a very special case.  We're going to do this for the dyslexics under this condition because we think we can give a drug to enhance this particular thing.  All right?  Then we'll expand it.  What about English literature?  You  know, how about the sonnet?  You know, memorization of the sonnet is due tomorrow, or how about language?  I have to learn German, as I did in graduate school in four months in order to pass the exam.  Wouldn't that have been nice?

Well, we did have amphetamine in those days.  So that was helpful.  Amphetamine and caffeine, as you know, were not — amphetamine was not controlled when I was a graduate student, and it was commonly taken.  Would keep you awake, but probably helped a little bit.

No, I think that you've given a very special case, but it's easy to make an argument for a large number of cases.  I don't know how you would constrain it after that.  I mean, that just happens to be his interest in what he's doing, but other people are interested in other things, and they say, "Fine.  What we need is a little pharmacological help."

And now remember the basic thing I said is that whether it's hormones, our own pharmacological agents or the ones that we manipulate, we have never been able to do anything that we can't do by just more training, never.

Now, in the case of Alzheimer's patient, that isn't the case.  With some subjects, particularly with Exelon, which appears to be a little bit better than some of the others, they can get them to do some things that they couldn't otherwise do.  So there's some help for a degenerating brain to make it work a little better so that it can finally do something that it couldn't do.  That data on that are weak, but that's another case.

So I guess what I was trying to do is present things here, which were tailor made for this group, and so in this context I would say this is not immune from my criticism.  It falls into, let's say, my concern.  It falls into my bag of concerns because it is a very short step from there to giving the drug to my neighbor to give her child because she's not going to tall the child to work harder, but it's just a little bit easier to do.

It's sort of like taking a valium when you're anxious rather than to use the anxiety to help cope with the problem.

DR. HURLBUT:  I hear a strong preference, if not prejudice, for the natural in what you're saying because one could argue, well, so what if it enhances one thing even at the expense of the other.

DR. MCGAUGH:  No.  I'm neutral.  I'm bringing it to your attention.  I'm neutral on this.

What I was trying to say is that I don't think that that special case solves the problem for us.  If that works, then I don't see any reason not to do it for any learning condition.

I do favor the natural circumstance.  I think I would go back and say how can you become a better teacher to use the naturally occurring devices that children have rather than to use some ancillary treatment, which we know we're probably going to have to do for the deteriorating brain, but that kid has all of the machinery.  The machinery is there.  How can you make that machinery work better would be the first approach that I think should be taken.

DR. HURLBUT:  Well, you've convinced me that I should be scaring my students more.  A little more adrenalin would help them learn better, but really —

DR. MCGAUGH:  Let me — let me — I don't think you're entirely wrong in the statement that you just made.  It's nice to be nice to people, but I just had to write something about my earlier experiences recently, and the two teachers that I singled out as having the biggest impact on my life were two of the sternest teachers that I had.

I mean it just didn't dawn on me that until I've thought about it pretty systematically.  These were not touchy-feely people.  These were the most demanding teachers I ever had in my life.  One of them was my band and orchestra instructor whose aim was to embarrass you in front of everybody else.

And so we knew that at any moment during rehearsal he would stop it and point at somebody and say, "Play the next 16 bars.  Stand up and play the next 16 bars."  At any moment.  Now, that kept our attention.  It really did.

So if you want to get learning to take place and have an impact, I don't think that roughness is necessarily bad.  I mean, it's better if they could do it in a nice way and say, "Gee, Jim, would you do the next 16 bars?  We'd sure love to hear you do it in a nice way for the group." 

You know, that would be helpful, but that's not the way it was.

CHAIRMAN KASS:  Rebecca and then we'll take a break.

PROF. DRESSER:  This is in line with some of the other comments.  I think at one point you said there is no memory enhancing free lunch or something like that.  I mean, the tone of your presentation seems to me to be a good corrective to the media, kind of public image about a lot of these prospects, which is there are always going to be costs, financial costs, adverse effect costs, as well as your great problem of what if we could arrest neurodegeneration in the early stages of Alzheimer's disease.  Would that be a good thing or not?

I mean that's a very complicated question socially.  So thank you for the really, I think, balanced point of view and perspective.

DR. MCGAUGH:  Well, let me comment on that.  I do memory enhancement as a living, and that's what I do for a living.  So that's what my research is all about.  So I wouldn't want you to let me get out of here saying that I have dissed memory enhancement.

But I think there is a role for it, and I think it has been excessively over-hyped by pharmaceutical companies, biotech companies, and by the press because it requires the kind of thoughtful thinking that you people as a group have as your mission in order to evaluate these things and find out what is the proper place.

I think that there may well be — just as I believe some children need Ritalin, all hyperactive children do not need Ritalin.  All right?  I think there may be some children who need memory enhancing drugs because they can't do it.  They don't have the machinery to do it in the same way that the deeply disturbed hyperactive child does not have the machinery which enables normal behavior.

So some children's brains will need this, but once again, I come back to the slippery slope.  Which ones do and which ones don't and under what conditions  and so on?  And that's a tough one.  That's a tough one.

CHAIRMAN KASS:  Let's take a break.  the conversation will continue.  Let's take 15 minutes.

(Whereupon, the foregoing matter went off the record at 3:24 p.m. and went back on the record at 3:44 p.m.)

CHAIRMAN KASS:  I'd like to turn this session over to PROF. Daniel Schacter.

Gentlemen, please.

Professor Schacter, the floor is yours.

DR. SCHACTER:  Thank you.  Thanks for having me here today.

CHAIRMAN KASS:  Push the button for your mike.




SESSION 4:  REMEMBERING AND FORGETTING: PSYCHOLOGICAL ASPECTS

DR. SCHACTER:  Am I on now?  Okay, great.

I think a lot of what I'm going to say today will hopefully amplify some of the points that came up in Jim McGaugh's interesting presentation.

First, let me just say a few general words about the perspective that I'm coming from.  In the program it listed my talk as "Remembering and Forgetting Psychological Aspects," and that is true, but I substituted a cognitive neuroscience perspective, which is probably a little bit closer to the general approach that I take to research, which is one that combines analysis of psychological aspects of memory with analysis of brain systems underlying those aspects.  It's the kind of approach that Mike Gazzaniga, among others, has advocated and has, I think, become very influential as a way of studying memory and many other aspects of cognitive function recently.

And this interface takes place at a relatively high level.  We're interested in the level of brain systems, how different regions of the brain interact, how different regions of the brain together underlie the various manifestations of memory.

So that's the perspective I want to illustration, although fundamentally I am a psychologist and will focus more on those aspects.

Second, I want to just pick up on a point that came up a few times in Jim's talk, which is that memory, and we refer glibly to memory as if it might be one thing, but as we heard mentioned a couple of times, it's not.  It's much more complicated than that.

And there are various ways in which we can divide up memory so that we're clear in our own minds about which particular kind or form of memory we're talking about.

For example, one way of looking at it is through the idea that there are fundamentally different memory systems operating within the brain, and this is an idea that has received a lot of support in the last 20 years in cognitive neuroscience, and there are many ways of making these distinctions.

One distinction I think widely accepted would be between a short term or working memory, the kind of memory that's capacity limited, as Jim mentioned earlier, holds roughly seven plus or minus two bits of information, and typically lasts for a few seconds; the kind of memory that you rely on looking up a phone number in the phone book and then running to the phone before you lose that memory.

That sort of memory seems to differ fundamentally from a longer term memory that is the kind of memory that Jim focused on.  It's the kind of memory that most people are referring to when they're talking about memory improvement.  That's the kind of memory that we really want to target with drugs or other approaches.

Other distinctions have mainly been drawn within the domain of long term memory, and there are many of them partially overlapping, but just to give an example of what I'm talking about, one distinction that we have found useful in our work is between explicit and implicit memory.

So explicit memory is our kind of conscious recollection of everyday events and facts of our lives, the kind of thing that we ordinarily think of as memory.  When we use the term "memory," we're talking about our ability to recall our past, personal episodes and experiences to access general knowledge.  That's all within the realm of explicit memory.

The whole other domain of memory that usually doesn't come up in these discussions, which we call implicit memory – others have called nondeclarative memory in opposition to declarative memory – and this is a type of memory that operates largely outside the realm of consciousness.  It's the kind of memory that might be involved in acquiring skills, how to ride a bicycle.

And interestingly, and there are many different manifestations of implicit memory, nondeclarative memory, but interestingly this type of memory can proceed pretty much independently of the explicit form.

So one type of patient who people have studied intensively over the last 20 or 30 years, and I'll talk about a little bit later in a different context, amnesic patients who have a devastating inability to acquire new memories, but this seems largely restricted to new explicit memories.  They can learn new skills just fine and show other manifestations of implicit memory even though they have no explicit conscious recollection of the experiences that gave rise to those implicit memories.

So we could do the whole talk just on this topic, but I just wanted to mention that at the beginning because I think it's useful to frame one's thinking about what exactly is it we're trying to improve.

Another way to divide up different aspects of memory or forms of memory is really the one I'm going to take today, and that is looking at the various ways in which memory can fail or various kinds of imperfections in memory.

So when we talk about trying to improve memory with drugs, what precise aspect of memory is it that we want to improve?  What imperfection in memory is it?

And some of the background readings go into this, but in a couple of recent articles in a book I published last year, I've argued that if you look at the wide expanse of literature on the topic of memory and you ask the question, which to my surprise few people have really asked, what are the difference ways in which memory can fail?  What are the different kinds of memory imperfections?

I've proposed that there are seven fundamental categories of these imperfections, and by analogy to the seven ancient deadly sins, I've called them the seven sins of memory.

I'm going to have to apologize if you're looking at the slides.  There is a slight glitch in some of the Power Point translation from Mac to PC.  So I don't ordinarily use these arcane symbols here on the left in my slides, but somehow they turn up when you E-mail a Mac Power —

DR. MCGAUGH:  The yen. 

DR. SCHACTER:  Well, maybe that's it.

DR. MCGAUGH:  You've used the yen for all of them.

DR. SCHACTER:  Hey, you've given me a new idea for the next book.  That's right.  The seven yens.

So there are a few glitches that will appear from time to time, the result of Mac to PC Power Point Translation.

Well, let's just walk through these quickly, and then I'm going to focus on a few that I think are particularly relevant to your concerns.  The first three of these so-called sins are different kinds of forgetting, and it's really forgetting that we are focused on for the most part in Jim McGaugh's talk.

So transience I refer to as the decreasing accessibility of memory over time, the fact that all other things being equal, memories will tend to fade over time unless reinforced through rehearsal or other means.  This is probably the basic fact of memory, and I think for most of us when we think of improving memory, we are really thinking in terms of improving this particular feature of memory.  We want to stop information from fading out of memory.

That's not the only kind of forgetting.  Absent-mindedness refers to lapses of attention that are associated with forgetting to do things.  Here it's not so much a question of information fading over time as the information either never getting into the system to begin with, operating on automatic and you put your keys or glasses down.  It's those kinds of everyday episodes that fall under the rubric of absent-mindedness, or failing to remember to carry out an action at the time that it needs to be carried out, and I'll come back to that with some everyday examples in a few minutes.

Sin number three I call blocking.  This refers to the temporary accessibility of storing information so that information hasn't faded out of memory.  You're paying attention, but you can't get to the information at the moment you need it.  A slightly different sense of blocking than Jim McGaugh talked about, and we'll talk about one common manifestation of this.

The tip of the tongue phenomenon we all know, and when information is on the tip of our tongue, we can't get at it, and then it comes to us some time later.

The next three of the sins I think are as important as the first three, but they all refer to situations in which memory is present but wrong.  It's not forgetting, but rather memory distortion, which we know is a fascinating and very important feature of our memories; that when we remember, we don't always remember accurately.

What I call misattribution occurs when we remember some aspect of a past event, but we attribute that memory to the incorrect source.  Perhaps we think we really did something when we only imagined it.  We know what that is, but we get the source wrong.  We think we did it.  In fact, we only imagined it.

Maybe we hear something from a friend, but we think we heard it on the radio last week.  We misattribute our knowledge.  This can have very important implications that we'll trace out in a few minutes, sometimes leading to a phenomenon (cut off here in that unfortunate Mac to PC translation) known as false recognition that I'll elaborate on.

Suggestibility refers to situations in which implanted memories arise as a result of leading questions or leading suggestions, the kind of work associated with Elizabeth Loftus, now a colleague of Jim's at UC-Irvine, and as we know, this is not only a theoretically interesting foible of memory, but something that can have grave consequences in the real world.

We know from the controversies that have existed over the reality of suggested memories of childhood trauma and childhood abuse. Paul McHugh has been a voice of reason in that very emotional debate.

Bias refers to I think an under-appreciated aspect of memory that we all give lipservice to, but has really only recently been studied systematically by psychologists, and this refers to retrospective distortions produced by current knowledge and beliefs, when what we know, believe and feel in the present skews our reconstruction of the past.

I won't get into that in much detail today, but I think it's pervasive in memory.  There's some elegant demonstrations of it.  I think it as much as any of these sins emphasizes the crucial point that memory is not a tape recorder, a playback, a video recorder, but it's a reconstruction that uses bits of information from the past and combines that with what we currently know and believe.

And then the final of the seven sins I call persistence.  This is a little bit different from the other six, and these refer to unwanted recollections that people can't forget.  We covered this, I think, in Jim's talk under the rubric of PTSD, the kinds of traumatic experiences that result in repetitive, intrusive memories that are associated with some of the neurobiology that we heard about earlier.

So for the purposes of today's talk, what I want to do is walk through some examples both from the laboratory of everyday life, primarily of transience, absent-mindedness, and blocking because when we talk about memory drugs, I think these are the kinds of things that we're really concerned about, and I also want to talk a little bit about misattribution because I think there's some interesting issues there that relate to concerns of a bioethical nature.

Okay.  Let's talk about transience.  Probably the best known experimental finding coming from psychology that bears on transience goes back 100 years to the German psychologist Herman Ebbinghaus, and it was Ebbinghaus who for the first time was able to document quantitatively the fact that memory, all other things being equal, memory tends to get worse with time, which people of course know from everyday experience in a casual manner, but what Ebbinghaus did was to show that the curve of forgetting has a particular shape.

So he did a sort of unique study.  He was his own subject.  He just memorized thousands of nonsense syllables and would test himself at various times after learning and measure how much of his earlier learning he was able to save at a later time.

So you could see when tested very soon, within a third of an hour after learning, he showed 100 percent savings.  Everything that he had learned he had retained shortly thereafter, but as time goes by, within the first hour there's a very steep fall-off in forgetting, and then the rate of forgetting slows down as more time passes.

Now, what's interesting about this curve is that although it was by today's standards somewhat idiosyncratic, it would be hard to get a study published when you're the only subject and you're the experimenter and you have hypotheses and so on, but this transience curve, as I would call it, the basic properties turn out basically to hold up across a wide variety of situations.  You get variations in how quick the fall-off is, and so on, but the basic idea that the rate of forgetting slows down as time passes, I think, holds over a remarkable variety of situations.

So one way you could think about attempts to improve memory through drugs or other means would be, you know, moving people around on this forgetting curve.  We start off here.  You know, is there a drug that will keep us there?  We don't want to go down there.  At least that's one perspective on it.

Of course the risk is if we stay up here, we're going to become like those unfortunate souls that Jim talked about, Funes and the Borges story, Shereshevskii and the patient he saw, which is perhaps we're going to have access to too much information, which is a point that applies to each of these memory's sins.  I try to argue, and we may get into a little bit later, I see them as kind of costs we pay for benefits in memory that make the system work as well as it does most of the time.

Maybe we don't want to be up here for every bit of trivial information that we take in for the reasons you heard about earlier.  So you can think about transience with respect — you can think about attempts to improve memory with respect to this curve we're forgetting.

Now, what are the variables that affect where you are on this curve?  Well, we heard about one earlier consolidation. Events that occur after an experience has been encoded can have a very large effect on whether that experience holds up over time or whether it's lost.

What I want to focus on, and this picks up on some of the points that Jim was making in response to questions, has to do with what goes on in the very first seconds when a new memory is formed, when a new memory is born, the state of memory process that psychologists refer to as the encoding stage.

As it turns out, what goes on in the second or two or three when an experience is encoded through the senses, taken in related to things you already know, has a surprisingly large impact on the subsequent durability of that memory, and it has a lot to say about how quickly you're going to fall down this curve.

Now, to give you an idea what I mean by encoding and how psychologists have studied it and then more recently how we've been able to look at it from a cognitive neuroscience perspective, let me tell you about an old experiment, but I think an important one, that was published some 25, 27 years ago by Craik and Tulving, a couple of my old mentors at the University of Toronto, who were interested in trying to get a handle on  how people encode new experiences and whether the nature of encoding operations, the nature of the mental operations that transform incoming sensory information into mental representations, whether and to what extent those operations have an impact on later memory.

Now, prior to the time of these experiments, psychologists had not made much headway in this problem.  The way they typically studied memory is they brought people into the laboratory.  They gave them a bunch of words or nonsense syllables or pictures or other material and said, "Here.  Try to remember this," and they'd give them a test later on.

Now, that kind of an experiment can't really tell us very much about how encoding processes influence memory because I have no idea what you're doing with the material.  You could be repeating it.  You could be making up images, making up a story.  I have no idea how you're encoding it.

So this is an early attempt to get control over the encoding operations and to look at their influence on subsequent memory.  To do that people in this experiment didn't know that they were in a memory experiment.  They were just told, "We're going to ask you some questions about words," and they had no idea their memory would later be tested.

So at what we call the structural level of encoding, they're shown a word.  It could be in capital or in small letters.  You'd be shown words one at a time, and you'd be asked the question is the word in capital letters.

So if you saw this word, you'd say yes.  If you saw this word, you'd say no.  So now the level of encoding is focused on the kind of perceptual level.  What does this word look like?  That's what you're focusing on.  That's what you're encoding from the word on that particular occasion.

When they wanted to focus people on the phonemic level, they would ask them a question like does the word rhyme with "wait."  So that's kind of the sound level.

So if I showed you "crate," you'd say yes, and it wouldn't matter if it's in capital or in small letters, and if I showed you "market," you'd say no, and it wouldn't matter if it's in capital or small letters.  So now we've got you encoding at a phonemic, phonological or sound level.

The final level of encoding was what they call the semantic level.  Would the word fit in the following sentence:  he met a, blank, in the street?  So if I show you the word "friend," you'd say, yeah, that fits.  It doesn't matter whether it's upper or lower case.  "Cloud," you'd say, no, that doesn't fit.  In either case, you have to think about the semantic properties of the word to determine whether it fits in that sentence frame.

So the subjects are sent away.  They come back at a later time and they say, "Oh, by the way, we didn't tell you earlier, but we're actually interested in your memory for the words that you saw earlier.  I'm going to show you these words now, and I want you to tell me was it one of the words that you saw earlier when you were answering those questions?"

And they'd mix in some words that hadn't been presented previously in order to keep the subjects honest.

The question is:  does the way that you encode the information at study have an impact on your later ability to recognize whether the word occurred earlier in the study list?

And the answer as you might guess is, yeah, it has a huge effect.  So here's the proportion of words recognized on the memory test as a function of whether they earlier appeared in the structural, phonemic or semantic condition, and every word appears equally often in each condition.  They're counterbalanced in the way that psychologists usually do these experiments, and you can see there's a huge effect on level of encoding.

So if all you did was answer questions about upper and lower case, you'd hardly remember any of those words later on.  You'd do somewhat better with the words when you thought about sound, and then it's only with the semantic level that you really get the robust level of memory.

So this speaks to the point that Jim made earlier that a lot of what influences memory has to do with interrelating new information with old information.  Here you're interrelating, in the case of semantic information, the word with lots of semantic associations, things you know about the word, and that provides you with a good basis for later memory.

There are more extreme demonstrations of this.  Perhaps you were thinking of this earlier.  There's an interesting study of a college student that was carried out at Carnegie Mellon a number of years ago in which they were interested in the question of whether you could increase memory span beyond seven plus or minus two.  So they want to see if you could just do this with practice with an ordinary person.

So they brought a student into the lab, and they started giving him strings of digits to remember, and he'd have to repeat them right away, and most of the time he would just give back seven plus or minus two, and they kept doing it and doing it.  Nothing much happened for a couple of weeks.  He would average seven as you would expect.

Then he started to show some improvements.  He could do 11 digits.  He could do 15.  He could do 25.  He could do 40.  I don't mean repeated digits.  I mean random strings repeated back right away.

After six months of practice, he could do 80 at once, and what was going on here?  Had they just increased some kind of memory muscle or increased his memory capacity in some general sense?

The answer is no.  Basically he had latched onto a very effective form of semantic encoding.  At the moment that he started to show this improvement, the student was a runner on the Carnegie Mellon track team, and he started to devise a semantic encoding strategy in which he encoded these digit strings with respect to his semantic knowledge of running, and so if a string came along, you know, four, one, four, five, he'd think to himself, "Oh, that would be a pretty good mile if I had the wind at my back," and build it, you know, starting very simple things like that.  He'd build a very complex semantic encoding network that he used in order to achieve this remarkable memory performance.

And, you know, to really prove the point, they did a test at the time when he was able to do 80 digits from one hearing.  They gave him a test of letter span memory, and for that he can only do seven plus or minus two because he didn't have this semantic encoding strategy developed.

So I think that shows (a) the power of this kind of semantic encoding.  You know, I'm not sure that you can get that much of a boost from, you know, any of the drug agents that we now know of, and (b) the specificity of it.

Okay.  So that's some points about the psychological aspects of encoding.  One of the exciting things now about being in the field of memory is that we're able to relate some of these psychological and cognitive processes that have been very carefully and thoroughly studied by cognitive psychologists over the past 25 years, such as semantic encoding, to brain activity.

And one of the ways in which we were able to do this in the case of human beings is by using new neuroimaging techniques, and there are a couple of these, really one now, that is pretty much standing alone as the main way of doing these studies:  positron emission tomography, or PET, scanning and functional magnetic imaging, or FMRI, which is really the technique of choice nowadays.

In both cases basically what we're doing is measuring hemodynamic or changes in blood flow or blood volume in the brain, and the basic idea is that when a part of the brain becomes very active, there's more blood rushing into that area of the brain.  So that if you can measure the blood flow into a particular area of the brain and localize it very precisely, which both PET and FMRI can do within a few millimeters, then the inference would be that you could say something about the neural activity in that region during a particular cognitive act because that is associated with, related with, correlated with the blood flow in that region.

So making that assumption that blood flow and these hemodynamic factors associated with neural activity, a lot of people now over the past ten years or more have been using imaging techniques to look at a whole variety of cognitive processes, including memory and including encoding.

So I just want to give you one example of an experiment.  This is one of several that show a similar result.  One I was involved in a few years ago with Anthony Wagner, Randy Buckner, and a few other colleagues at Harvard and Mass. General Hospital in which we adapted the Craik and Tulving type paradigm to neuroimaging.

So people would be in the scanner.  They'd be looking on a screen, and they'd be seeing a long series of words.  They would either make a semantic judgment about the words:  does the word refer to an abstract or concrete concept? 

So if it was "democracy," they'd say abstract.  If it was "garden," they'd say concrete.  On some trials there's a semantic encoding trials, and then on other trials they'd be asked the upper/lower case judgment, the low level structural judgment.

The question is:  what's going on in the brain in the semantic condition relative to the non-semantic condition?  Can we isolate particular brain regions that are active and related to these semantic encoding effects that we know have such a big effect on transience?

And the answer was yes.  Here are a couple of images from that study.  Let me just make a couple of points.  What I'm showing you here is a slice of the brain.  If you can imagine that you're taking a slice through the brain, you're looking in from the top down, and we're going about halfway down and making a cut, and that's the left side of the brain or actually a little lower than halfway down.  That's the left and that's the right.

And these colors here, as I'm sure some of you know, are basically a statistical map showing parts of the brain that are activated in the condition of interest compared to a controlled condition.

So in this upper strip what we're showing are brain regions that in the semantic encoding condition, the abstract/concrete task, plus the non-semantic encoding condition, the upper case/lower case task, are showing activity relative to a low level condition where you just fixate on an X and don't do anything.

The most notable thing here is this huge activity in the back of the brain.  That's the visual cortex showing a large activation.  There's also a big activation here in part of the frontal lobe on the left, the lower left frontal lobe.

Now, if you move down, this lower strip is the more interesting slide because now you're comparing directly activation during that semantic encoding task to the non-semantic encoding task.  So now you're seeing words in both conditions.  All that varies are the mental operations, the encoding operations they're carrying out.

You'll notice now that big yellow blotch in the back is gone because that's occurring in both the semantic and non-semantic conditions, that visual activation.  So when you compare the two together, it cancels out.  There's nothing there.

What's left over at this point is something that's going to tell us something specifically about semantic processing, and what we see here is that left frontal lobe activation remains, and there's also an activation at the very front of this visual activation near a part of the brain known as the hippocampus, which we know is very important for explicit memory.  It's actually in the parahippocampal gyrus. 

Those two regions seem to selectively activate more for semantic than non-semantic encoding, implying that these regions are playing some role in, and we don't yet understand exactly what that role is, in carrying out these semantic encoding operations that are associated with good subsequent memory.

Now, we and others have pushed this a little bit further, tried to link up the brain activation and the memory effect even more strongly and asked the question:  suppose I put you in the scanner right now.  All right?  You're listening to me, and presumably if I tested your memory tomorrow, you'll remember some of the things I said, and you're going to forget others.

Could I tell from your brain activity right now, could I get any insight into whether you're more or less likely to remember or forget a particular word or sentence that I say?

And that was basically the question we asked in a follow-up study to this and more precisely was:  would these two brain regions that we saw activate more for semantic than non-semantic encoding activate more when you're encoding some information at the time of study that you're going to remember later on as opposed to forget?

So in this study they were just shown hundreds of words, and they made abstract concrete judgments about all the words.  It's semantic encoding for all of them, but we know if I give you a test later on, you're going to remember some and forget others.  Maybe for some words you can hook it up to what you know about the word or you get a better image or something of that nature.

So the question is:  can I tell now from the scanning patterns and encoding whether you're going to remember or forget the word later?

And the answer was yeah, and it turns out to be the same brain regions again.  What I'm showing here is that left frontal, a few different views of the activation in the left frontal lobe, the same slice I showed you before, and this is looking in from the back of the brain.

And down here on these graphs what we're plotting is the strength of the FMRI signal at encoding for words that you would later remember.  That's in red, and the stronger signal versus for those you would later forget, and you can see in all three cases these different regions within the left frontal lobe are showing a stronger signal at encoding for the words.

It turns out that, you know, a couple of hours later you would remember compared to those it turns out that you would forget.  So this provides an even nicer link between the brain activity and the neural activity, and this also shows up in that region near the hippocampus, the parahippocampal gyrus that I was telling you about, and those are the only two regions in the brain that show the effect.

It's not just that on the trials where they forget the subject falls asleep and they close their eyes and there's no signal in the brain.  Other brain regions show equal signal for words you'd later remember and forget.

So this kind of work and a lot of other work like it, I think, is starting to give us some clues now into the neural processes underlying this very fundamental encoding process that I think is central to any discussion of memory improvement through drugs or other means.

Okay.  Let me move from transience, some ethical questions I was going to raise that I think we've already heard a little bit of discussion about and we can get to in discussion later, and say a couple of words about absent-mindedness, lapses of attention that involve forgetting to do things.

Let me just give you a couple of everyday examples and throw out a couple of points for your consideration.  Here's a picture of Yo-Yo Ma, the famous cellist, who a couple of years ago had a kind of unnerving encounter with memory where he put his cello in a taxicab, took a ten minute cab ride, got out of the cab, and then walked away without his cello.

Fortunately for him, this episode of forgetting was nullified.  The New York City police got right on the case, and later that day here he's shown reunited with his $2.5 million cello.

Now, this would not appear on the face to be an example of transience.  Presumably the information hadn't faded out of his memory within minutes that he put the cello in the trunk.  Rather, he wasn't reminded at the time he needed to carry out the action that he needed some cueing to remind him that the cello was in the trunk.

Presumably had he said, "Where's your cello, Yo-Yo?" he would have immediately said, "Oh, it's in the trunk."

So the forgetting here, I would argue, is based on totally different mechanisms than is the forgetting in the case of transience, and one thing we know about this kind of absent-minded forgetting is that it can take extraordinary forms when people (a) are operating on automatic and (b) are not cued to carry out an action at the moment they need to cue.  So with memory for doing things in the future, it doesn't help very much to remind yourself, "Oh, I've got to pick up" — or it may not help very much — "I've got to pick up bread and milk on the way home," if you're not reminded later on at the moment you need to carry out the action.  And there's a lot of interesting research that backs up that point.

Just an extreme case with, I think, some interesting ethical implications, so I couldn't resist talking about it with you today, briefly was that of a — and there have been several cases like that around the country in the last couple of years — a woman by the name of Carie Engholm, a high level hospital administrator who drove her son and her daughter to work one morning, her seven month old daughter who she put in the back of a van, dropped the son off as she did every day.  She was not accustomed to taking her daughter; drove on to work, forgot about the existence of her daughter, and unfortunately the daughter died in the van and was found later that day.

Now, there's a lot of discussion, you know, how could Mom forget that baby.  How is it possible for someone to forget something of this nature?

I personally would argue that it's an extension of the Yo-Yo Ma principle, that without cueing at the moment you need to carry out an action and operating on automatic, it is astonishing how far forgetting can do.

Eventually she was found not guilty because there was the question of is someone responsible for their memory system.  Do you take responsibility for the fact that one of the foibles of memory is that if you go on automatic and are not cued, you can forget extraordinary things?  Are you, therefore, responsible for setting things up in advance to make sure something like that never happens?

The judge eventually decided that she was not guilty.  There were various reasons for that, some having to do with the exact nature of the charge which required proof that Engholm knew she left her child in the van when she clearly didn't, but he then concluded that forgetting is an involuntary process that can't be knowingly or recklessly done.   A person either forgets or remembers.

So I throw that out to you in terms of maybe another angle on some of the ethics of forgetting.  When are we responsible for our memories?

If I show you a 20 word word list and I give you a test and you only remember five words, I don't accuse you of being, you know, a flawed moral agent because you can't remember them all.  Does that logic apply here?

I think that's better for you guys to decide than me.

Memory sin number three, I want to say just a little bit about blocking and then conclude with a few words about misattribution.

Blocking is the kind of memory failure that occurs when we haven't lost anything from memory and we know the information is there, and it's not a matter of paying attention.  There's an example of this, again, a flawed Power Point slide of British Deputy Prime Minister John Prescott, who was at a press conference a couple of years ago where he was forced to justify the cost of the Millennium Dome, this extremely expensive stadium that was built in London.  I think it is now being taken down.

And he was asked, "Well, where did the money for this come from?" in his overrun budget so much.

And he said that money came from the — you know, what do they call it?  He just couldn't come up with this word, and then he said, "Oh, was it the raffles?  No, it wasn't the raffles.  What was it?" and then finally someone came up and whispered to him, "the lottery."  It was the lottery.

So that's kind of a classic tip of the tongue blocking phenomenon.  Clearly he knew the word.  It hadn't fallen out of his memory, and this tip of the tongue state is quite pervasive.  It's something that is known in virtually all cultures.

There's an interesting article published by the psychologist Bennett Schwartz who noted that 88 percent of the languages that he surveyed used the tongue metaphor to describe this kind of temporary retrieval block, "on the tip of the tongue," "on the tongue," "on the top of the tongue," "on the front of the tongue," my favorite, "sparkling at the end of the tongue," "in the mouth and throat," all aspects of the TOT.

One thing we know about the TOT state, this blocking type of forgetting, is that it's a very active state.  One comes up with incorrect items like raffles.  You've got to make decisions about whether those items are correct or not.  Are they just leading you down the garden path?

William James — being in William James Hall I have to have one William James slide for any talk I give, and he always has something interesting to say about something in psychology — describes it well.  "Suppose we try to recall a forgotten name.  The state of consciousness is peculiar.  There's a gap therein, but no mere gap.  It's a gap that's intensely active, a sort of wraith of the name is in it beckoning us in a given direction, making us at moments tingle with the sense of our closeness and letting us sink back without the longed for term.  If wrong names are proposed to us, this singularly definite gap acts immediately as to negate them.  They do not fit its mould."

So that really captures the phenomenology of the TOT state.  It's as if there's some cognitive monitor in there that knows what we don't know.  We're not quite sure how that works, but, again, we've been starting to get some insight into some of the brain activity during blocking through neuroimaging studies.

We recently did an imaging study of blocking, of tip of the tongue blocking, where we induced TOT states while people were in the scanner by giving a cue such as War and Peace plus author, London plus river, Aida plus composer.  Those may seem obvious to some.  Can you think of the answers for each one?  Obvious to some, maybe not obvious to others, but about ten to 15 percent of the time you'll get a TOT state for Tolstoy or for Thames or for Verdi.

So we put them in the scanner.  We run hundreds of these by them, and interestingly what we find is that there are certain parts of the brain that activate selectively specifically during the TOT state, and by and large, these are regions that in other studies have been implicated  in kind of cognitive monitoring processes.  They're parts of the brain that get going when there's conflict, when we've got to make cognitive decisions between conflicting alternatives.

One was a region of the brain in the middle of the right frontal lobe, and the other is in an interesting part of the brain tucked away in the middle of the brain called the anterior cingulate that gets activated in all kinds of imaging studies and seems to be related to this monitoring of cognitive conflicts.

And in this study these brain regions were activated only during the blocking state.  They didn't show significant activation when people knew the answer or didn't know it.

So there's some initial insights into some of the neural activity associated with blocking.  It's an interesting question as to whether this kind of blocking is something that merits attention and attempts at memory improvement.  Certainly it is one of the most common subjective complaints of memory loss as we get older, is blocking particularly on the name of familiar people.  There are cognitive ways this can be approached, and as far as I know it's really never been looked at through drugs and, you know, maybe shouldn't be looked at.

Finally, I just want to say a few words about misattribution because I think the whole realm of memory distortion, though it's really not a big issue when it comes to memory improvement – people are, whether they should be or shouldn't be, people are generally not looking for ways to make their memory less distorted.  They're looking to remember more, and I think people often take accuracy for granted when perhaps they shouldn't.

Let's just say a few words about misattribution.  We'll go through those paintings and go directly to misattribution.

A number of you may remember — probably all of you remember — that when the Oklahoma City bombing occurred back in 1995, there was a search for two suspects, John Doe No. 1 and Joe Doe No. 2.  John Doe No. 1, of course, was Timothy McVeigh.  John Doe No. 2 was never found, although there were bulletins issued by the FBI shortly after the shooting in a search for a person who looked like this.

Well, it turned out he wasn't found because he didn't exist.  At least he didn't exist as a suspect in the case.  He existed as the figment of the memory of a guy by the name of Tom Kessinger, who was a mechanic who worked in the body shop where McVeigh rented the van that he used to carry out the bombing.  And he distinctly remembered McVeigh coming in with this guy.

Well, it turned out he was also there the next day when somebody, who the FBI later discovered looked like McVeigh, entered the body shop with a guy who fit this description.  He was an innocent Army private by the name of Todd Bunting.

What had happened here was a classic memory misattribution error.  Kessinger was right.  He had seen that face before, but he misattributed his memory in this case to the wrong time.  He mixed up the time that he had seen the two and thereby committed this error.

Now, this sort of memory error can have very serious implications for eyewitness testimony.  It is the kind of thing that is often involved in eyewitness misidentification as, as we know from studies of people who have been wrongfully convicted and exonerated on the basis of DNA evidence.

Approximately 90 percent of these individuals who have been studied were put in prison wrongfully, largely or entirely on the basis of eyewitness identifications, often involving this kind of memory misattribution.  So it's certainly something that we need to pay a lot of attention to.

One way psychologists have studied this recently is through a very simple but effective paradigm that came originally from the 1950s and then more recently in the 1990s, rediscovered by Roediger and McDermott where if we had time we could easily induce this phenomenon in most everybody here.

You present people with a bunch of words that are related to one another, such as candy, sour, sugar, bitter, good, taste, tooth, nice, honey, soda, chocolate, heart, cake, eat, pie, and then you later give them a memory test where you present words that were on the list like "taste," and most people will correctly say that "taste" was on the list; unrelated words that weren't presented like "point"; and then the interesting case which is associatively related theme words or critical words like "sweet."

"Sweet" wasn't on that list, but if you do this experiment, if we had time to do it here, what you find is that most people swear up and down that they heard the word "sweet," and Paul knows this because he's had this done to him.

DR. MCHUGH:  Exactly.

DR. SCHACTER:  Here's an example from one study we carried out, Ken Norman and I carried out, a few years ago with college students and old people who were exposed to a bunch of associate lists like this, and this shows you that both the young group and the older group in their 70s about 75, 80 percent of the time are correctly saying that words like "taste," which were on the list, really were on the list.

The problem is they're also claiming with high confidence that words like "sweet" that weren't there were also there, and as you can see, the older group shows an increased susceptibility to this.  I'm sure that it had nothing to do with you showing the effect.

(Laughter.)

DR. SCHACTER:  And which we thought was an interesting discovery at the time, and I can't resist just giving you this quick quote that shows that we were scooped by 100 years by none other than Mark Twain who said, "When I was younger, I could remember anything whether it had happened or not, but my faculties are decaying now, and soon I shall be so I cannot remember any but the things that have never happened.  It's sad to go to pieces like this, but we all have to do it."

What's going on here is this, again, illustrates the fact that memory is not just a tape recorder or computer or whatever; that what we're doing is we're kind of constructing a mental representation of the general sense or the gist of that list, and "sweet" really fits in well with everything you heard.

So later on when you reconstruct what you heard, that seems to fit so well that you're absolutely sure that you heard it.

Now, we've been interested in this for a number of reasons.  In part, we've been interested in what is going on in the brain when people make this sort of memory error.

And through a number of approaches, we've gathered evidence that the hippocampus, the region of the brain that I told you about earlier that we know is so important for remembering things that really did happen, also seems to be involved in this memory illusion.

For example, patients who have damage to the hippocampus and music patients that have great difficulty remembering what really happened also how less of the memory illusion than healthy people do.  They show about half of the memory illusion.  They're not fooled like you and I are.

Why?  Because we think the hippocampus has something to do with it.

We've also done brain imaging studies that I wanted to get to and conclude on because I think they raise some issues that might be within the purview of this group, namely, about the ability to use brain imaging to tell whether someone is reporting an accurate memory of the past or a false memory.

So this is a study we published last year with Roberto Cabeza, where we scan people while they were making judgments about whether words were on the list they heard earlier.  They had been given a whole series of these associate lists, and they false alarmed to words like "sweet" that really weren't there.

What's interesting here is that you can see these are the FMRI signals, that there's just as much FMRI signal for the false words like "sweet" in the hippocampus as there is for the words that were really there like "true."  There's a nice increase in signal compared to words that had nothing to do with what were on the list and people easily say no to.

So in both of these cases the hippocampus is lighting up roughly equally.  It's fooled into thinking that "sweet" was on the list perhaps because it's remembering the semantic gist of what was there.

But there's another part of the brain in this study, that parahippocampal region we just talked to posterior to the hippocampus that shows activity only for the true words, not for the sweet words.  We're not quite sure.  We have some hypotheses about why that occurred, and we've seen similar things in a couple of other studies.

Now, the interesting — the broader societal question here is if you want to know whether someone is remembering accurately, can you just put them in the FMRI scanner and tell?   And the short answer to that would be no.  This is data that comes from a group study.  You have to average across many people in order to get these effects.  If you look at any one individual, you're not going to see very much, but I think it is a technology about which we'll be hearing more, the use of these imaging devices for distinguishing between truth and deception in the context of lie detection, perhaps between true and false memories, and although we're certainly not at a stage we're even close to being able to use this for practical purposes, it is something, I think that at the interface of technology and memory that you might want to consider.

I'll stop there.

CHAIRMAN KASS:  Thank you very much.

Someone gets us the lights.  Thank you.

Questions for Prof. Schacter?  Robby George.

PROF. GEORGE: Yes, just very quickly, PROF..  On that false memory with the "sweet" are the Paul McHughs of the world claiming to remember seeing the word or are they simply reasoning that it must have been?  Have you somehow tested for that, controlled for that?

DR. SCHACTER:Yes, that's a good question.  There's a lot of data that speak to that and indicate that they're not just reasoning and guessing that it was there or just saying, well, probably it was there because it fits with everything.

There are a number of studies that various people have done and some of our own work that show how it really is for whatever reason people are having this subjective experience of memory.

There's a lot of debate in the literature about what the mechanism is, but they will claim if you give them a choice of saying one of the two things, one of the following two responses:  you're saying, yes, this word was in the list because you have the specific recollection of having seen or heard it, depending on whether the presentation was auditory or visual, or you're saying, yeah, it was on the list because you just know it was there, and you don't have a specific recollection.

And sometimes people will say, "Oh, I just know it."  They give the remember response just as much to these words as they do to the words that were really there.

So in other words, they say, "No, I have a specific recollection of it," just as much to the sweet words that weren't there as to the words that really were there.

If you do an experiment where you have half of the words presented by a man and half of the words presented by a woman and you say to people, you say to the subjects, "Okay.  Tell me if you remember the word, and then if you really remember who told you, a man or a woman, tell me man or woman.  If you don't really remember the source of the word, don't write down anything," they'll write down man or woman with high confidence just as often to these false words as they will to the ones that were there.

So it really seems to be subjectively they're absolutely convinced that it was there.  That's my reading of the literature.

CHAIRMAN KASS:  Charles.

DR. KRAUTHAMMER: I just had a question on intrinsic and extrinsic memories that you mentioned earlier.  Can a Korsakoffian learn to ride a bicycle?

DR. SCHACTER:  We don't know the answer to that exact question, but by implication the answer would be probably yes, barring — yeah, barring any general cognitive deterioration.  They can learn a whole variety of motor skills and laboratory tasks that, you know, for example, if you have people trace a moving stylus they get better at keeping time on target with practice, and these patients will show that same kind of improvement.

We've even done experiments years ago where we have shown that they're able to learn some basic computer programming skills.  Even though they come back to the lab, they have no idea that they've done it.  They don't realize that they've ever worked on a computer, but if you get them going on a test, they'll start to do it, and they're kind of amazed that they can.

DR. KRAUTHAMMER: And have you studied brain injured people whose injuries happen to be in the two areas that you identified with encoding, that left temporal —

DR. SCHACTER:  The left frontal and the temporal lobe.

DR. KRAUTHAMMER: Left frontal, right.

DR. SCHACTER:  Parahippocampal.  You know, there's a little bit of literature on the left frontals that suggest an encoding deficit.  It's hard to find people that have a specific parahippocampal deficit.  You just don't see those patients very often.  So I'm not aware of any literature on them.

But that's one of the tasks in this general area, is to try to map the brain imaging work onto the lesion work, and they don't always go together.  I wish I could say that they did.  They often do, but they don't always.

DR. KRAUTHAMMER: Because if I could just add, because most of the knowledge and until this new technologies, this stuff I learned 25 leap years ago from Normal Geshwin was based entirely on pathology.

DR. SCHACTER:  That's right.

DR. KRAUTHAMMER: The patient was missing an area, and then you deduce what that area was doing.  Now you can see it in vivo.  I'm just wondering if they correlate.  I mean, there's the whole entity you'd want to be correlating with now.

DR. SCHACTER:  Right.

DR. KRAUTHAMMER: Active areas versus pathology.

DR. SCHACTER:  Yeah, they don't always correlate.  They correlate often enough in important ways, I think, both, you know, to validate the technique and, you know, give us some confidence that, you know, we're looking at some of the same things that the earlier neurology types looked at.

But I think they're very different kinds of evidence, and you probably need them both, and in the sense with bright imaging we're looking at areas that are active during a task, but it doesn't tell us that they're necessary.  They'd just be coming along for the ride or they may have something to do with the subject's reaction to the test where monitoring is in the case of blocking, whereas the neuropsychological patients tell us, you know, more what areas are necessary.

So I think, you know, each one adds to the other.

CHAIRMAN KASS:  Could I ask about — this may be perverse of me to ask about something you chose not to talk about today, but if I'm remembering rightly, persistence was the last of the sins —

DR. SCHACTER:  Right.

CHAIRMAN KASS:  — is not somehow a fault either of failure, kind of forgetting, or of distortion, but it's rather a dismaying accuracy that we remember things we would rather not remember.

First of all, am I right about that?

DR. SCHACTER:  Yeah.

CHAIRMAN KASS:  Is that what you meant by it?

DR. SCHACTER:  Yeah, that's what I meant, and I thought we'd touch on it a little bit earlier on, but that's exactly right.  Persistence, as with the other sins, I wouldn't see as some fundamental shortcoming in memory.  It's the price we pay for having a memory system that, you know, responds to emotionally arousing situations in the way that Jim McGaugh described earlier and in a way that presumably works to our advantage most of the time, and then it's good to remember, you know, these terrifying events and, therefore, avoid them in the future.

The down side is, you know, you can be plagued by such events.

CHAIRMAN KASS:  Let me see if I could Ó- and this would be to invite Jim McGaugh back into the conversation as well to tie up this discussion with the earlier one.

As I think about the possibilities for altering memory, the enhancement of memory whether it's as good as just working harder or not, there are lots of our fellow countrymen who would want it if it were easily available.  It doesn't bother me a whole lot.

But the thought that you could selectively block and erase memories and particularly not just for the prevention of post traumatic stress syndrome, but for what when Paul McHugh's colleagues finish with the DSM-5 or 6 will include painful memory disorder, shameful memory disorder, because we can do something about that, and there will be reimbursement for it, and therefore, it will be in the book.

And it's not just the really horrible things, but you know, within the last week I'm sure all of us have probably some things, you know, embarrassments, sorrows.  The temptation will be to have some kind of amnesia for these things or, as we were talking about it at the break, amongst the young, one could lose one's inhibitions for shameful behavior and not have to remember it afterward.  It's a kind of win-win situation.

So I'm wondering —

PARTICIPANT:  It's called alcohol.

(Laughter.)

CHAIRMAN KASS:  It's called alcohol, but it comes with disturbance.

In any case, I'm wondering about how you would sort of talk through that aspect of memory and whether we could, in principle, distinguish those things that persist which say as a therapist one would be happy to somehow extirpate if one could from the temptation that all of us would have to our peril and, in fact, to our detriment, somehow wipe out the things which we would rather not remember and make us wince years and year after.

DR. SCHACTER:  I think there's one distinction that needs to be drawn between some of the work that Jim was talking about with propranolol and alcohol in that in the former case it's not a question of wiping out the memory because people can remember what happened.  It's taking the sting, the extra emotional edge off of the memory so that you remember it, but you don't —

CHAIRMAN KASS:  It doesn't bother you.

DR. SCHACTER:  You're not overwhelmed by it, right.

So that line of work as far as I know has not really gotten into memory erasure, which as he points out, you know, I guess we already have alcohol and we can make our judgments about the effectiveness of that strategy.

I'll turn that one over to Jim, but I don't see that as a new issue that is suddenly being driven by new drugs or new developments.

DR. MCGAUGH:  No.  I think I may have overstated the ease of doing it in the first instance.  That is, recall that the only experiment with humans was not erasure with propranolol, but it was dampening the development of PTSD so that the subjects could still remember the event, but they didn't have the emotional outflow, and it didn't take over their lives.

Now, that takes a long time to do.  So it isn't as though I did something horribly embarrassing yesterday and I can pop a pill and that's going to be gone.  If it was really so horrible, it's going to flash into my head, recur and recur and recur so that it begins to take over my life; then that would be a case, I think, in which a little propranolol, if the studies bear out, might be of value.

But there's something else that I didn't emphasize, and I should put in the equation.  This thing works equally well for good things that happen, as well as for bad things.  So I think when we think of the strong memory's persistence, I'm sure that Nobel Prize winners remember what they were doing — well, in the U.S. most of them were sleeping, but where they were and what they were doing when they got the call of winners and prizes.  Anything as much coveted, you remember birthdays and weddings and all of these kinds of things; they stand out.

So the pleasant side of this works just as well as the unpleasant, but there's never a quick fix.  It's not as though — well, there would be.  You walk around with an ECT machine in your backpack and something terrible happens.  Deliver yourself an ECT.  That's the only thing I can think of that would do the job.

Short of that, it's all going to be a dampening.  Would you agree with that?

DR. SCHACTER:  Un-huh, yeah, I would agree with that.

And you know, it's an interesting point to consider, you know, when you consider some of the adaptive role of some of these intrusive memories.  Actually I was running out of time, but had it in my last slide in case I had time to get to the persistence issue a picture of a Holocaust survivor from a real interesting series of art works that's been done on this topic by an artist by the name of Jeffrey Wollman, who interviews Holocaust survivors about their stories and then takes the picture and does it in interesting ways.

And in this particular slide, if you can read the small writing about the woman's story, I mean, she talks about how, however painful it was, however critical it was for them, you know, to keep that memory alive and, you know, the whole issue from an adaptive perspective of how, you know, dealing with a memory helps you adapt to the traumatic event.

And then the question of whether it's better or worse, you know, to be dealing with it with the sting or less of the sting, it's hard to address, but I think that's one of the issues.

DR. MCGAUGH:  Yeah, I think the critical case is that of when it becomes incapacitating.

DR. SCHACTER:  Right.

DR. MCGAUGH:  That's the issue because certainly I think in most cases having a very strong memory of a horrible event has adaptive consequences.  You want to stay awake.  You want to be on guard.  You want to know what to do, what not to do, and so on.

And as a matter of fact, they had a hell of a time getting post traumatic stress syndrome classified as a psychiatric disorder because it was matched up against malingering.  You know, it's not really true; it's not debilitating.  What you want to do is just take advantage of the VA system and take all of the benefits, and so on.

And it took a long time for them to get to recognize that in a certain percentage of the cases, their lives were really debilitated by it, whereas in most cases it's not.  So that they have now matched cases of people who have severe automobile accidents.  All right?   Twelve to 15 percent of those cases, as my reading of the literature, will develop some PTSD.  All right?  Some will have none even though they've had the same experience.  They certainly will remember a lot about it.

Now, what do you do about those 12?  Well, in most of those cases or over half of those cases, those will resolve in about eight months, and then you're left with a residuum of a very small number of people whose lives have been damaged over the long term.  Now, that would be the focus group, I think, right there.

CHAIRMAN KASS:  Thank you.

I have Bill May, Alfonso, Rebecca, and Mike Gazzaniga.

DR. MAY: Well, in these last two sessions we verge ruminatively on topics that in so many ways move beyond the reach of medicine, but no less interesting for that.

I think about the two responses to the past and remembering of nostalgia and remorse.  I've just gone through a 50th reunion, and so you ride down the moonbeams of nostalgia.  There is a faculty member who is now in his mid-80s who wrote a lovely letter saying, "Affection grows as memory fades."

Laughter.)

DR. MAY: That's a very nice comment.

Another PROF. on another occasion talked about the sickness of nostalgia, that living in a lost world.  That's a very interesting human problem, and it's not just ideological bias in that case.  It's a kind of disconnect with the present that afflicts people in the course of time.

And remorse, your category persistence very much relates to that.  We're not now talking about the medical danger of eliminating past memories, but in fact, as I recall, the Catholic Church in its sacrament of penance vividly understood that remorse is very dangerous because it is that relationship to a past which stings and you bite yourself all over again in remembering it.  So it's unavailing, and there's no way of moving beyond it and moving forward into the present.

And perhaps just as dangerous as writing out memory is the reliving of a past event that is so wincing in memory that one engages in a kind of suffering all over again, which is unproductive of a future.

And I guess it remains to us, sir, as to how any of this relates to the questions before us in bioethics.  Fascinating issues though.

CHAIRMAN KASS:  Thank you, Bill.

Alfonso, please.

DR. GÓMEZ-LOBO:  This is on a slightly different topic, I think, but I'm really delighted that I have a chance to ask you these questions.

The topic of memory, of course, fascinated the ancients.  There's a lot of memory in the Platonic dialogues and in Aristotle, and I'm thinking about — and I'm going to formulate a question — the following.

When we talk about the blocking of memory, if I understand it correctly, there is a question of retrieving something, and if we retrieve it wrongly, if for, say, War and Peace we say Dostoevski, we can do that because there's something that we have not forgotten, right?  So there is an actual belief held by reference to which we match whether the memory was correct or not.

Now, this is independent of whether it is factually correct.  So memory seems to entail this matching or making coherent two beliefs of some sort.

Now, my question, what I'm really intrigued with is this.  In the contemporary study of memory, is there such a thing as remembering something which we did not first acquire, for instance, through a sensible experience?

I've noticed that memory and the response is not restricted to the sensory experience.

Now, the example I have in mind is this.  Is it correct to speak of memory, for instance, in the retrieval of the set of natural numbers, for instance?  We've had no encounter with that, and yet somehow that seems to be stored in our minds.

DR. MCGAUGH:  What was the word?  What did you say?  The retrieval of what?

DR. GÓMEZ-LOBO:  The series of natural numbers.

DR. MCGAUGH:  Yeah.

DR. SCHACTER:  Well, I think this partly gets into the realm of the distortion and false memory, that you could say we know from experiments that people can be induced to remember episodes from their past that by all objective accounts did not occur.  College students, you just ask them about it several times, and a certain proportion of college students will claim to recover a memory of spilling punch on the groom or bridge at a wedding when they're five years old, and as far as we can tell, this event never occurred.

So, you know, it doesn't make sense to talk about that as a false memory.  Well, if you define memory or part of memory as the subjective experience of what occurs at the time of report or retrieval for whatever reason it's there, then, yeah, that makes a lot of sense.

If you define it with respect to tying it to an event that occurred in the past, then it would be an oxymoron of sorts.

DR. GÓMEZ-LOBO:  Yeah, I think I was taking care of that.  What I'm curious about is the kind of knowledge that in philosophy we call a priori knowledge.

In other words, the fact that we can say a lot and handle a lot of problems in this series of natural numbers, which we have never learned, and in the standard sense, never stored in our minds, but maybe this question is a question in epistemology or metaphysics.

DR. MCGAUGH:  Yeah, we wouldn't refer to that as memory even in the same way that we wouldn't refer to our extraordinary capacity to learn language as memory.  It's a capacity that we have, but it's not memory until we've learned something.

CHAIRMAN KASS:  Rebecca.

PROF. DRESSER:  A couple of comments.  With regard to the ability to reduce the distress associated with an embarrassing experience or a traumatic experience, obviously as with many of these things we're discussing the problem is line drawing because, I mean, we don't want to remove that distress for social reasons in some circumstances. 

For example, I think that's where a lot of empathy comes from.  That is, when we have an embarrassing experience, we develop empathy for others who have a similar experience.

Also, shame or feeling of responsibility for consequences, I mean, once you do something stupid or sloppy or, you know, that's a lot of growing up, development.  So we want some of that sting.  So the question is:  what is dysfunctional sting?

There probably is some sting that we would rather not have as individuals, but it's good for the rest of us that others have it in determining, you know, when sting ought to be removed.  This is, I think, a big problem.

The other point that I thought of in response to your presentation was I think we've been discussing the use of these things in situations where individuals might want to use them or parents might want to use them and other people might have reservations about whether that should happen.

But here with the question about whether something is an actual memory, there might be cases where it would be in the interest of society to force someone to have an FMRI or a PET scan or some other intervention in order to discover whether it's a false memory or not.

And the person might say, "Well, I don't want that."  And so there could be a coercive potential use of that, and we would have to think about how should, you know, autonomous choice fit into the situation.

DR. SCHACTER:  I think you have all of these same issues that surround lie detection today, you know, from that sort of issue, but also the whole question of efficacy and just how good the technique is.

PROF. DRESSER:  Right, yes.

DR. SCHACTER:  That's why lie detectors are not admissible.  They're just not good enough, and brain imaging is nowhere near the level even of lie detection.

So I think one would end up revisiting pretty much the whole range of issues that has come up with lie detection.

DR. MCGAUGH:  Could I comment on the first part of that?

I think that this sort of was the view of the Veterans Administration on the complaints of the GIs who were suffering so terribly, you know.  "Suck up your guts.  Come on.  Everybody has problems."

But there's a difference between the level, the intensity of this disorder in those people who really present as opposed to people who just said, "I had a very bad deal in Vietnam," or on the road the other day or whatever it is.

But there's some point you can draw a line and say, "You can cope with this and for some reason you can't."  And there is no treatment for long lasting post traumatic stress disorder.  I mean, it just sits there.

While you were talking, I was thinking about the case of anxiety.  It's good for us to be anxious about things.  It's good because it helps us prepare.  We have to anticipate the consequences.

And yet there are people who are so anxious that they can't anticipate the consequences in an adequate way.  And so benzodiazepines are a drug of choice to deal with that end of the distribution.  People will become incapacitated because of the anxiety, but they're not drugs, in my opinion, aside from Viagra that's a most widely used drug.  There isn't any rationality for an ordinary person taking a benzodiazepine just because they think they might be a little upset.

And yet that is the draw.  That's what we see all the time now on TV stations where they're now advertising medicines.  They're saying there's a pill for everything.

Of course, call your doctor, as though the doctor is going to be standing by the telephone waiting for your call, right?

There's a pill for everything, and I think that — I don't know what you can do about that with your committee here, but that to me is a major concern, is the marketing of drugs to the general public that are really initially developed for and efficacious for a very small set of the public.

And it's the drugification of the society as a consequence of that.

CHAIRMAN KASS:  I have Mike Gazzaniga.

DR. GAZZANIGA::  I just wanted a point of information from the two, Jim and Dan here.  About a year ago from Joseph LeDoux Lab there was this report of memory erasure by bringing up an animal that's reminded of something and then a protein synthesis inhibitor is injected, and then the memory seems to be Ó-

CHAIRMAN KASS:  Mike, could you speak up a bit?

DR. GAZZANIGA::  — the memory seems to be erased, and this was an animal model repeat of the classic ECT work that Jim was mentioning.

I know that talking to LeDoux that he was inundated with phone calls from humans, not the rats he studied, who wanted a pill because they wanted to get rid of certain memories in their life.

Has that folded?  Is there any biotech work on that?  Is that a viable concept still?

DR. SCHACTER:  Well, they're continuing with it in their lab, and I was actually at a conference a few weeks ago, that Self Conference in New York.  I was talking to Karim Nader, who was one of the authors on that paper, who claimed that there is some obscure clinical paper published 20 years ago where actually some form of this was done with people.  I haven't seen it yet.  He gave me the —

DR. MCGAUGH:  Larry Squire did that.

DR. SCHACTER:  Larry Squire tried and couldn't get the effect.

DR. MCGAUGH:  Yeah, he did the —

DR. SCHACTER:  With ECT.

DR. MCGAUGH:  With ECT, did the right experiment.

DR. SCHACTER:  Right.

DR. MCGAUGH:  He gave subjects new material to learn or material that they learned a long time ago or material they learned, I think, just the day before, gave them an ECT, and the only thing that they forgot was material that they had just learned.

And so reactivating, that is, just doesn't do the job.

DR. SCHACTER:  I guess the question would be it's not clear whether it's this new research that would be pointing toward a possible new avenue for this, but given now that there's reawakened interest in this because of what it might tell us about some of the basic, you know, mechanisms of memory, might that point the way towards some other way of approaching this than ECT?

You can comment on that.

DR. MCGAUGH:  But even then it has constraints.  I was one of the first people to publish on this many years ago, and it didn't work in 1970.  We now have another paper in which we did the same thing, but to the hippocampus rather than the amygdala, no effect.

The effect is supposed to be that if you bring up information, you retrieve information that you know pretty well, that makes it susceptible to erasure by some treatment, and now I know of several other studies that have completely failed to do it.

So I think the phenomenon itself is in serious question.  I wouldn't get too upset about its applicability because in my view it doesn't exist, but we'll just have to wait and see.

DR. KRAUTHAMMER: But what about application to immediate erasure?

DR. MCGAUGH:  To which?

DR. KRAUTHAMMER: Immediate erasure you say happens —

DR. MCGAUGH:  On immediate erasure.

DR. KRAUTHAMMER: Right.

DR. MCGAUGH:  We've known about that for 50 years.

DR. KRAUTHAMMER: Right.  But the question as I understood it was other than ECT, are there any other agents that can do it?

DR. MCGAUGH:  Sure.

DR. KRAUTHAMMER: Erasing?

DR. MCGAUGH:  Sure.  Protease synthesis inhibitors can do that.

DR. KRAUTHAMMER: And these have been tested in humans?

DR. MCGAUGH:  No, but scopolamine can do it and atropine, and that's been tested in humans.

DR. KRAUTHAMMER: So you have an experience.  You get atropine.  The memory is erased.

DR. MCGAUGH:  It's not formed.  It's not formed.

DR. KRAUTHAMMER: Right.  I mean, right, it never Ó-

DR. MCGAUGH:  Yes.

DR. KRAUTHAMMER: — it never takes.

DR. SCHACTER:  It's not fully formed and consolidated.

DR. MCGAUGH:  Yeah.

DR. KRAUTHAMMER: And what's the lag between the experience and the administration?

DR. MCGAUGH:  It would have to be for something like that probably minutes.

DR. KRAUTHAMMER: So you have a memory for a minute or two, right?  I mean, until it's —

DR. MCGAUGH:  No, no.  You can have that memory for a longer period of time because that memory is based on a different system than the memory that you use the next day.

This is what he talked about in the first instance, the difference between this immediate memory and the long term memory.  It's not the same brain mechanism at all.  Underline that.

So what's happening with these treatments that are affecting long term memory is that they're leaving short term memory alone.  You can have that memory for hours, let's say, and then it will finally disappear, but what's happened is you haven't made another stage of memory.

Maybe that's something to bear in mind, that not only are we talking about information for different kinds of things that are learned, like the motor skills, but we're talking about information that's in a different temporal domain having a different substrate.

DR. KRAUTHAMMER: I guess my question is:  if I could just follow up, I mean, is it conceivable that you could market something that would tell people if you take this immediately after a terrible experience, you'll wipe it out and you won't suffer from it?

DR. MCGAUGH:   Yes, that's conceivable.  That's more doable than the other side of it.

DR. KRAUTHAMMER: Right, and that would seem to me to be a rather interesting question as to whether you'd want to market a drug you carry around in your wallet to be administered upon extreme shame.

DR. MCGAUGH:  Well, let me give you an example of that from the 1978 PSA crash in San Diego where they made the horrible mistake of sending out desk people and baggage handlers to clean up body parts after the crash, and then there was a report in I believe it was the L.A. Times maybe five years ago, a follow-up, and a very high percentage of those people were never able to work again.  They had been permanently disabled because of the trauma.

Now, that's PTSD to the nth degree, and it probably for them, I would make a guess, was worse than a soldier.  These things are happening all the time in the battlefield, but imagine you as a baggage handler and for the first time you have to pick up body parts and put them in bags.

Now, there would be a case in which something like that I think would be of value.  I don't think that you could say, "Well, you know, it's really adaptive to be able to know how to handle body parts.  So it's a good idea to keep that memory strong because you may have to do that again and know how to cope with it."

I think that's a low probability.  So that would be a case in which — a clear-cut case — in which it would be nice to say, "Take this.  Weaken your memory of that."

DR. KRAUTHAMMER: I would agree with you, and I would say that this is not just an odd event like a crash of an airplane, but in Israel they're experiencing that every week, and there's  huge reports of post traumatic stress syndrome.  So in a society like that, you might want people walking around with that in their wallets.

DR. MCGAUGH:  Yeah.  I just gave the other one as a, you know, clear-cut stand-alone case.

DR. KRAUTHAMMER: Right.

DR. MCGAUGH:  But the situation in Israel and Palestine are just unbelievable.  I mean it's just hard to imagine living.  I mean if we think it's bad enough to worry about whether we should cross the street in Washington or Maryland or Virginia, where we should be thinking the odds are very high that we're going to get hit by a car, the probabilities are just vastly different, the sniper versus dying of food poisoning, for example.

CHAIRMAN KASS:  Frank, we've got a few people on the list, and then we are going to move to wind up shortly.

Please, Frank, Gil, and the two Bills.

PROF. FUKUYAMA: This is just a question on a somewhat different subject, but both of you have talked about fairly low level cognitive processes like, you know, memorizing a seven digit string of numbers and so forth, but there seems to be another much higher cognitive level that involves memory that's also quite socially and politically important, which is that, you know, you develop a paradigmatic way of understanding the world at a certain point in your life cycle, and usually that stops happening past — I don't know — the age of 25, 30 or so, and once you've got that paradigmatic way of looking at the world, you know, no amount of disconfirmatory experience then can shake you from it, which is why politics, you know, proceeds in generational cycles.

So if you lived through the Depression, you know, you think that big government is the solution to, you know, out of control markets, and you think that you've got to save, you know, and saving is a great virtue because a rainy day may come back, and so forth.

Whereas if you grew up, you know, in the '60s and '70s or through the sexual revolution, I mean, you have just very — you know, so you get these cohorts, age cohorts that have basically imprinted memories on them, and basically until they die they're never going to be shaken, you know, from these paradigms.

I mean, do we know anything about the physiology of this kind of, you know, memory at this cognitive level?  Because it seems to me it's actually quite, you know, politically relevant and important.  But it seems to be at such a higher level than the kinds of issues that you're dealing with.

DR. SCHACTER:  I think within the realm of memory discussions what you're referring to would probably fit under the rubric of what's called semantic memory at another subdivision, semantic and episodic.  Semantic is kind of general knowledge of the world.  Episodic memory for personal experiences.

And you know, we do know something about semantic memory, albeit studies in the laboratory context and, you know, in a more modest way than full flown political beliefs and whatnot, but we know something about the structure of semantic memory and some very interesting work on how it may be organized categorically.  You know, you have patients who can lose access to one category of knowledge and not another, you know, fruits and vegetables versus living things versus tools, and there's new imaging work on that.

So there's nothing that I'm aware of that directly speaks to your point, but there's certainly a lot of cognitive literature on what I would assume would be the basic building block processes that would be relevant in your case.

DR. MCGAUGH:  Well, I would add that the assumption that is made in the neuroscience of memory is that the building blocks may be the same for many kinds of memory, but they build into different systems, and then they can build into higher order systems, such as concepts.

There was a very famous book by Donald Hebb from McGill University, Organization of Behavior, which you dealt with.  How do you get a concept?  And his notion was you get a concept out of individual small units which then interact, interface with each other, and you get a concept because these things hook up.

Now, once those things are built up from a neurological point of view, they're all the same.  That is, this one is like this one over there, but the content of it is different.

But one thing is sure.  You're never going to build that for somebody.  That is, you're not going to put a gene in and say, "I believe in globalism," or put a gene in and something else.  These are all slowly developed over a long period of time.

PROF. FUKUYAMA: But if I could just say, I mean, but there does seem to be an age related ability to put those concepts together and then to deconstruct them and replace them with other concepts that would seem to have to —  I mean that just intuitively would have to have some genetic basis because, you know, that ability to reconceptualize things in very fundamental ways does seem to decline with age.

DR. MCGAUGH:  Well, I'm not sure.  I'm not sure.  Let's put in the motor skills.  All right?  You can learn to ski at any age, at any age, and even if you have been an ice skater, which is very different motor skills involved, you can still learn to ski.

So you're not prevented from doing that.  I would make the counter argument that you get comfortable and then avoid changes.  It's not that it's genetically fixed in that you're going to be stuck here for a while and then stuck here.

I think that rather it's a consequence of what you're doing, what you're surrounded by, what opportunities there are that provide that.  Because we even see people shifting political parties and saying, "All the time I was wrong."  And we see Lula in Brazil having an epiphany about world economics that he didn't have a few weeks before.

So the constraints that are put on one can cause one to see the world in a different way.  And then we use the same mechanism to make a change.

Another thing that happens, I think, because I am growing old, is that you can see the stages in your own life.  I grew up in the Depression.  So I am one of the people that you talked about, but you can then as you get more information, you can put that phase of your life in a very different context.

So I'm not tied to what I learned and did during the bad old Depression days, but I can use that information in a flexible way to change my views about what our relations are with Mexico, for example, and what our relation to Canada and whether Schroeder is a nut or whether Schroeder is onto something good.

Because we learn more.  We incorporate more information, and I think that's one of the great things about the human brain is we're not fixed in developmental stages, but rather we retain a large flexibility.  That would be my take on it.

It's just artificially that we get forced into it and you see we respond to our own stereotypes, and this certainly is the case in the political arena.

CHAIRMAN KASS:  Gil.

PROF. MEILAENDER:  This is really just a factual question though depending on the answer there might be sort of more to be made of it, and it probably relates to transience.

Different people at least as they age, the effect of aging on their memory is different, more pronounced in some than in others, and so forth.  What I want to know, if this isn't a silly question, is do people in the very early years, the early years of childhood, do some people just form less transient, more vivid memories than others?

And I ask it because anecdotally, it seems to me to be the case that they do.  In other words, just among my friends and acquaintances, some people remember a great deal more, claim at least, seem to remember a great deal more about when they were four years old than others do.

Are there differences at the beginning of life the way there are at the end?  And if so, do we know anything about why?

DR. SCHACTER:  Yeah, well, presumably, I mean, there are individual differences in memory though they're quite poorly understood throughout, you know, life, and you know, for the early stages I'm not aware of anything that would really speak to an understanding of (a) the nature of the difference and (b) whether one can really localize it, as it were, to transience, to the actual forgetting over time process.

There might be many possible subprocesses that are responsible for a difference between one individual and another in memory.  Some of those might have to do with basic processes operating within the memory system or it just might be different contents being operated on by those processes.

I suspect that a lot of time when people compare their memories, and you have a good memory for this and I have a good memory for that, that it's less about the basic process and more about the particular contents of the memory.

But I'm not aware of anything on the very early stages that would speak to that.

DR. MCGAUGH:  But you also have to be concerned about confounds in that.  How much did the family talk about it?  How many photo albums are there around?  How many times were they reminded of it in various things?  And these would play into that.

PROF. MEILAENDER:  I even have in mind rather pronounced differences among siblings in this matter.  I mean, I know of cases like that and so I was just curious.

DR. SCHACTER:  I would suspect that post event rehearsal is probably playing a bigger role there than people realize, and you know, why it is that one person talks about and thinks about and is reminded of, you know, an event than another is, for example, within families where you'll get siblings, you know, one claiming to have no memory for the same event that the other remembers in detail is unclear, but I would think of that, you know, in some sense as a confounder and in come sense as part of what's interesting about individual differences in memory, just the big role of post event processes.

CHAIRMAN KASS:  I have two people left, and I ask them to be brief, and we have as a procedural matter, we have one person who wants to make public comment.  So if you'd be willing, we'll not take a break and go straight to that and we should be done probably in ten to 15 minutes.

I have Bill Hurlbut and then Bill May.  And then we'll go to the public comment.

Charles?

DR. KRAUTHAMMER:  I just want to ask a question.

CHAIRMAN KASS:  Why don't you wait at the end then.  Thank you.

Please, Bill Hurlbut.

DR. HURLBUT:  Returning to the question of forgetting, to Frank's question about the political convictions and affiliations, there's an interesting relationship between learning, memory, and our larger sense of place within our affiliations.

There was a flood in Leningrad after Pavlov had conditioned his dogs, and the dogs were floated up and almost drowned, and afterwards their learning, their conditioning had been erased.  Do you know about that?

DR. SCHACTER:  No.

DR. HURLBUT:  And this was picked up on and used as some of the basis for the Soviet ideas on brainwashing, and I think this is called transmarginal inhibition.  Have I got that right?

Anyway, here's the interesting —

DR. SCHACTER:  Outside of my domain.

DR. HURLBUT:  Here's the interesting question.  How do we and how does memory relate to the dissolution and resolidification of the self in these very crucial domains of affiliation?

And this comes back to William May's comment that affection grows as memory fades.  What I'm really getting at — and there's a question in here — it seems to me at least looking at animal models that certain types of memory and certain types of structuring of the self are tied in not just with memory in the broad sense, but with very specific systems, and here I'm thinking of things like oxytocin where the memory of the sheep, for example, for its nursing offspring, is with the second offspring completely erased.  It doesn't recognize or acknowledge at least its first offspring.

And there have been suggestions that maybe oxytocin plays this same role in solidifying and bonding.  It's a kind of a memory conviction state.

Do you know anything about this?  And what I'm getting at here is are there any systems you know of that suggest that there might be ways to specifically enhance certain kinds of memories and, therefore, certain kinds of affectionate structures or convictions of personal identity?

One of the suggestions, for example, has been that oxytocin be used in marriage therapy to make the marriage bond stronger.  Do you see what I'm saying?

DR. SCHACTER:  I think I see it.  I don't know anything relevant to it.  Do you?

DR. MCGAUGH:  The only thing that I know is mother-child attachment is associated with the release of oxytocin by the mother.  That's all I know.

DR. HURLBUT:  And this kind of bonds a memory relationship?

DR. MCGAUGH:  It is proposed that it plays a role in the bonding.  What we have is a correlation, but no one has done any critical experiments on that.

Now, oxytocin has been studied in Holland and DeWied's laboratory as a memory enhancing drug, if you like, peptide about 20 years ago, but it faded from fashion.  So I don't know of anyone who's working on it now.

CHAIRMAN KASS:  Bill May.

DR. MAY:  In thinking about the medical — the warrants for use of medicine, I guess an old distinction would be between existence and developed existence, being and well-being, survival and flourishing.  And in some of your writings there's some suggestion, well, memory is very important to survival.  You know, we need it to survive, and obviously medical warrants for doing something for those who are impaired.

We get a little bit more nervous if what it seems to be used for is economic survival, I mean, to help SAT scores and so forth.  On that level the medical warrants, other than helping the impaired, the basic argument is no longer survival, but flourishing.

The problem of impoverishment and the Alzheimer's patient, we've got various social ways of keeping them going and so forth, but the human impoverishment is huge.  It's the flourishing of the human which is our concern there, and we see objective warrants for trying to solve that problem it seems to me.

Now, Frank is now gone, but he worried about was there any application whatsoever at the level of politics or the level of flourishing of the society at large, and there it seems to me we may move beyond medicine and so forth because really we happen into the arena where we are talking about ritual retrieval of the past and the retrieval of decisive and defining events.

And that's a dimension of education which is very important, but gets lost where education is justified simply in terms of what it will give you by way of economic survival.  The problem of safeguarding the treasures from the past operates at the level of politics and religion, and through education, the transmission of tradition.

CHAIRMAN KASS:  Thank you.

Charles, do you want a brief comment and then we will —

DR. KRAUTHAMMER:  Well, before your question, I would like to ask Dr. Schacter.  I was intrigued by the hints that you were giving about possibilities of using these technologies to distinguish real memory from misattributed memory, and I was just wondering since we are talking about enhancement and thinking about whether we should worry about enhancement in this area, if you could just speculate on what the field would look like in 20 years and whether there's anything about the direction of the field and the power it's acquiring that ever troubles you.

DR. SCHACTER:  It's an interesting question.  So far I would say I'm not too troubled mainly because I'm all too familiar with the ins and outs of data and how far away we are in this realm from really having anything that works at an individual level.

So as a practical matter right now, I'm not particularly troubled.  You know, where it might be in 20 years it's not clear.  It's interesting to look back on, for example, lie detection, again, as an example, something that is related to this even though we're talking about people who were doing their best to tell the truth in a memory situation.  I'm not a careful student of that literature, but it seems to me that pretty much the issues have been the same at least as practical legal issues, you know, for the last 30 years.

We may make faster progress in brain imaging that will bring these things onto the front burner more quickly than they have in lie detection, where you know I think if you turn the clock back 20 or 30 years, I don't think you would have — I don't think we've advanced all that much in that amount of time.

Now, whether, you know, the same applies to this kind of work is not clear to me.  Most people, for example, our group and others who are doing this are doing this not with any pragmatic aim in mind.  We're interested in basic memory processes, and so you know, I think from the perspective of the field, people who are working on this stuff in the field aren't by and large doing it from a practical viewpoint.

Whether the advances, you know, in the name of basic science in the next 20 years would be sufficient to where we have to start worrying, I just don't know.  It's just hard to guess.

CHAIRMAN KASS:  Well, thank you both very much.

This is one of those occasions, I think Mike Gazzaniga commented at the break, this is one of those occasions where in addition to learning some interesting and wonderful things about memory, memory research, that a certain kind of reassurance has been provided with respect to at least the immediate concerns that some people have, and it's good to be able to report things like that, as well, and to a culture that's rather nervous about just about everything that's coming.

If you would kindly stay at your seats while we have a public comment from the one person who has signed up, it's Wrye Sententia, who is the Director for the Center of Cognitive Liberty and Ethics.  I believe that's California; is that right?

MS. SENTENTIA:  Yes.

CHAIRMAN KASS:  And you've come a long way and most welcome to you.  We look forward to your comment.

 

PUBLIC COMMENT

MS. SENTENTIA:  Thank you.

I just have a few brief comments that emphasize two main points, and I'd like to start by saying that any discussion of the ethics of treating or manipulating the mind or what some people are now calling neuroethics must begin by protecting the interiority of individuals' minds.

So our twofold principles are that, first, no one should be forced to use drugs or mind technologies against their will, and second, that no one should be denied access or criminalized for their use.

The Center for Cognitive Liberty and Ethics is a nonprofit, education, law, and policy center working in the public interest to foster cognitive liberty, which we defined as the right of individuals to think independently and autonomously, to use the full spectrum of their mind, and to engage in multiple modes of consciousness.

So in essence, we're working to protect the full potential of the human intellect.

Cognitive liberty is an essential human right.  The United Nations' universal declaration of human rights and the U.S. Constitution's Bill of Rights both support a basic human right to cognitive liberty or freedom of thought.

The complexity of our social fabric conspires to make any assignation of transcendent values difficult, particularly when, as in the case of bio or neuroethics, the issues span such elementary yet malleable values as individual and collective good or quality of life.

The CCLE recognizes — that's the Center for Cognitive Liberty and Ethics — recognizes, as does the Council, that the complexity of many of the issues involving brain enhancement are not easily resolvable.

However, we hope that by introducing the principle of cognitive liberty into the discussion, the Council will find useful distinctions in making its recommendations.

To the CCLE and our supporters, the question of mind enhancement is fundamentally a question of cognitive self-determination interwoven with an ethics of reciprocal autonomy, autonomy not as arbitrary legislation created for oneself, but rather as laws that permit whenever possible successful interaction with others based on respect and tolerance for each other's core values and freedoms.

I'd like to read a quote from Laurence Tribe of Harvard Law School.

"In a society whose whole constitutional heritage rebels at the thought of giving government the power to control men's minds, the governing institutions and especially the courts must not only reject direct attempts to exercise forbidden domination over mental processes.  They must strictly examine as well oblique intrusions likely to produce or designed to produce the same result."

Decisions about as intimate a freedom as cognitive liberty should be allocated to the individual rather than the government.  The CCLE works from the premise that the role of the state, criminal law, science, and ethics, should be guided by principles that enhance opportunities for each individual to self-actualize.

Public policy decisions should be framed by principles of legal liberalism, not by moralism or paternalism.  This is not to say that morals or safety precautions have no place in determining appropriate uses of drugs or mind technologies, but that the role of the state should not be to determine what is or isn't moral, what are or are not acceptable personal risks.

In our opinion, public policy for psychotropic drugs and/or brain technologies should stem from our democratic government's responsibility for preserving individual autonomy and choice to the maximum extent possible.

While neuroethical issues are complex and often deeply philosophical, the Center for Cognitive Liberty and Ethics maintains that a solid starting point for practical discussion begins with these two fundamental recognitions.

First, as long as their behavior doesn't endanger others, individuals should not be compelled against their will to use technologies that directly interact with the brain or be forced to take certain psychoactive drugs.

Second, as long as they do not subsequently engage in behavior that harms others, individuals should not be prohibited from or criminalized for using new mind enhancing drugs or technologies.

Simply put, the freedom and right to control one's own consciousness is the necessary foundation on which virtually every other freedom stands.

Thank you.

My written comments also have been submitted to the Council which are extended.

CHAIRMAN KASS:  Thank you very much.

Is there any other member of the public that would like to make a comment before we adjourn?

(No response.)

CHAIRMAN KASS:  If not, thanks to our guests for stimulating presentations.  Thanks to the Council members for your attention during the long day.

You should have at your seat the directions for where we are meeting at dinner, which will be, I believe, at seven o'clock; is that correct?  Let me have it.  Six thirty for the reception, seven o'clock the dinner.

I remind you that tomorrow morning we start at 8:30, and we will be joined by two distinguished guests from the U.K. to talk about regulation in Britain.

The meeting is adjourned.

(Whereupon, at 5:33 p.m., the meeting in the above-entitled matter was adjourned, to reconvene at 8:30 a.m., Friday, October 18, 2002.)


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