Sixth Meeting Transcript

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

September 13, 2002


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

Mary Ann Glendon, J.D., L.LM.
Harvard University

Alfonso Gómez-Lobo, Ph.D.
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 Hospital

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

James Q. Wilson, Ph.D.
University of California, Los Angeles


INDEX

Welcome and Introductory Remarks

• Leon R. Kass, M.D., Ph.D., Chairman

Session 1: Toward a "Richer Bioethics" 4: Science and Society Discussion of Hans Jonas' Essay,
"Philosophical Reflections on Experimenting with Human Subjects"

Session 2: Regulation 6: Institutional Review Boards (IRBs)

• Ezekiel J. Emanuel, M.D., Ph.D.,
  Chief, Center for Clinical Bioethics,
  National Institutes of Health

• Peter D. Kramer, M.D., Ph.D.,
  Clinical Professor of Psychiatry and Human Behavior, Brown University

• Carl Elliott, M.D., Ph.D.,
  Director of Graduate Studies, Center for Bioethics, University of Minnesota

WELOCME AND OPENING REMARKS

CHAIRMAN KASS: I would like to welcome members of the Council and our fellow citizens to this, the Sixth Meeting of the President's Council on Bioethics.

I acknowledge the presence of our Designated Federal Officer, Dean Clancy, whose presence makes this meeting legal.

I would like to offer special thanks to the members of the Council who traveled here during this time of solemn remembrance. When we planned the calendar for this meeting, we weren't thinking all that carefully, and however eerie or odd it might have been for you to travel yesterday, the symbolic meaning of your coming to Washington at this time in the nation's service is appreciated here. I want to reiterate my personal thanks for your hard work, loyalty, and devotion over the past eight months.

Just a few announcements before we proceed: There are a few of our members who hope to be joining us at later times during the meeting. Jim Wilson will be here this afternoon. Robby George hopes to be with us tomorrow, and Elizabeth Blackburn, unfortunately, couldn't make it.

It is also with regret that I want to announce publicly that Stephen Carter, for personal reasons, has had to resign his membership on the Council. The letter was received with sadness.

I also want to mention that the cloning report, its final version will be published by the Government Printing Office sometime in October. And as I think I've indicated to you in communication, Public Affairs, an imprint of Perseus Books, is planning to publish the report in its final version, containing only a new foreword written by the Chair. That publication is expedited and should be out in the beginning of October and available, among other things, for teaching.

It is our hope, it is certainly the hope of the commercial publisher, that there might be occasions, from their point of view, to promote the sale of the book; from our point of view, to advance the discussion of these issues. Some of you have responded to my inquiry about your availability and perhaps even willingness to host events on your own campuses where these discussions can continue. If you haven't responded, if you would be willing to join in one or another of these public fora, please let Diane Gianelli know. Diane? There she is in the back, Director of Communications.

The next meetings of the Council will be October 17 and 18 and December 12 and 13. The date that we had reserved in November has been freed up.

CHAIRMAN KASS: At this meeting we continue our discussion of two topics that have been afloat for several months, topics under the general rubric of regulation, topics under the general rubric of enhancement. Neither of those titles are strictly accurate, but you all know what I'm referring to.

As an introduction in a way to the further consideration of both of these topics, I have asked Council members to read for opening discussion Hans Jonas' classic paper on "Philosophical Reflections on Experimenting with Human Subjects."

There are a number of reasons why we thought that this is a good idea. First of all, the ethics of experimentation with human subjects is a critical moral point in which science and ethics intersect and in which one has a look at the relation between the scientific enterprise and the social values.

The goals of medical progress run up against our concern for the inviolability of the human person, and this is a place where society, usually with more-than-willing collaboration of scientists and physicians, erect restrictions, mostly procedural, on what scientists and physicians may freely do to human beings.

Second, those institutional arrangements and procedures for protecting human subjects are also instances of the attempt to put principles into practice. The Institutional Review Boards, which will be the subject of our discussion in the second session, are the places where we try to give effect to the moral concerns that society has, concerns that express themselves in procedures for recruiting subjects, for securing consent, and for monitoring results.

It is well to keep in mind, as we think about current efforts to reform the Institutional Review Boards, what the moral principles and what the human goods are that we are eager to protect and promote. So that the first session today will be largely philosophical; the second one will be largely institutional. It is important, I think, as we think about each, to keep the other in mind.

Third, it does seem to me that both with respect to the ethics of experimentation, but also with respect to all of the things that are of interest to this body, it is important that we try to become self-conscious about what exactly it is that we are trying to protect in these discussions. Of course, we are trying to protect human health and safety. We are trying to promote medical progress. We are interested, of course, in not violating people's freedom, as expressed in our concern for their consent.

But the question is, is that the whole story? Are there other things having to do with human dignity that are of importance here? And that consideration is relevant to the ethical aspects of all of our work, including, for example, things that might concern us in the area of using mood-altering or personality-altering drugs, the topic of our discussions this afternoon.

So it seems to me, for all of those reasons, a look at the kinds of issues raised by Hans Jonas in this essay seems an appropriate way to begin this meeting.

Let me introduce the discussion of the paper with at least one person's formulation of what I think he's about in this paper. It's a dense paper, and it's not the easiest thing to read and follow.

But let me at least state what I take to be the question at issue and something of the way in which Jonas tries to work his way to an answer to this question, and then throw it open for comment and discussion and see where we go.

I think the point of departure is on page 107 in the paper, where Jonas points out that human experimentation, for whatever purpose, is always also a responsible, non-experimental, definitive dealing with the human subject himself, and not even the noblest purpose of such experimentation would abrogate the obligations that this involves.

So he wants to put the conflict in these terms: On principle, it is felt human beings ought not to be dealt with as mere subjects. On the other hand, these dealings are increasingly urged upon us by considerations also appealing to principles that claim to override the objections of treating human beings in this way.

And he goes on to state what is for him the most serious difficulty, down toward the bottom of the page. "What is wrong with making a person an experimental subject is not so much that we make him thereby a means, which happens in social contexts of all kinds, as that we make him a thing, a passive thing merely to be acted on and passive not even for real action, but for token action whose token object he is. His being is reduced to that of a mere token or sample."

And he goes on to distinguish being conscripted as a subject for experiment and being conscripted as a soldier for war, while though you're still subject to someone else's orders and are still a means, nevertheless, are still acting in the way in which you understand yourself to be acting and as an agent.

Now the question of the paper is: What in the world could be of sufficient weight to justify treating human beings in this way? And I won't rehearse much of the analysis except to say that he doesn't find the answer sufficient in the notion of a social contract or even in the notion of health as a public good, because averting a disaster is different from promoting a good, and that medical research, though it falls in between, seems to be closer to the second than the first.

That, to be sure, society has adopted medical progress as its cause, but that the goals, however important they are for the professionals and urgent for the patients, nevertheless, medical progress is societally gratuitous, however noble, and in an interesting move, suggests that even when one goes out to appeal for consent and solicit volunteers for research, one is engaged in something that he calls semi-conscription -- semi-conscription -- in which in fact, and he doesn't elaborate on this, but the moral authority of the physicians, the moral authority of the people in the white coats, and the desire to please those upon whom one is dependent for help makes this not absolutely a free and innocent request, however well-meaning.

And the solution is somewhere to be found in his remarkable discussion where he says, the ideal would be the self-recruitment of scientists and where there would be the maximum motivation, the fullest understanding, the freest and most spontaneous decision, integration of this choice into one's overall life project, and, most important, the identification of the research subject with the purpose of the experimentation. It's that last idea which seems to have gotten lost, speaking now editorially, from the concern purely with consent, which is the granting of permission.

There are things that follow for research, the descending order of who's available and the like; no research on diseases not relevant to the patient. But it points to a kind of ethics of research that goes beyond just calculating benefits and harms, and even beyond merely giving permission and consenting, to something that seeks to do justice to the human person whom one is, nevertheless, inviting into this project as perhaps a co-partner in experimentation.

I wonder, I mean I don't think that's an unfair summary. There's lots of richnesses that have been left out, but I think I take it that's the shape of the discussion. I wonder to what extent we find this paper, written now almost 35 years ago -- it was written in 1968, published in 1969 -- whether this strikes us as sound and whether it offers an adequate ethical foundation for thinking about this subject.

Gil?

PROF. MEILAENDER: Let me just pick up really with what you noted in the paper. I mean, this paper, it is one of those rare papers that at least I think is sort of so profound that one would be glad to die having written it, kind of.

But I want to think about the problem that you highlighted there. I mean, the way he puts it, the difficulty with recruiting research subjects is that it, as it were, "thingafies" the person, which is a little like the concept of alienated labor actually, I think, in the sense that the person is used for an alien cause, not fully one's own, in which he or she is not fully invested, something like that.

Then the question is, how can you make that a human endeavor that fully dignifies the person? And the interesting thing to me, you mentioned it, is that the Holy Grail of consent doesn't seem to be a sufficient answer, as far as Jonas is concerned. Not that it's unimportant, of course. I mean, he doesn't want to suggest that we should ignore it, but it is interesting to ask why it is insufficient.

I think it is, as it were, too negative. It only protects the person against abuse, and that alone doesn't overcome the problem of alienation, the problem of not being fully invested in the undertaking. That is where you get the principle of identification that you pointed to.

If you say, "Why is that so important?", it is because this descending order that he sorts out is a way of trying to see to it that we at least first attempt to recruit those most fully able to identify with the project, which is probably almost the reverse of the way we actually go about doing it most of the time these days.

I think he even says it at one point: that, I mean, really it comes up in the discussion of why you wouldn't use patients as research subjects on something wholly unrelated to their disease. It is because you would be tempted to use them because they're handy in a way. What you are trying to avoid is simply using someone because he's handy, because then that person is in a certain sense alienated from it. Only that principle, which somehow goes beyond just the sort of negative understanding of consent as protection, can deal with the "thingafying" problem.

I think that's, even apart from the context of research, an interesting notion to puzzle over and contemplate a bit. It may relate to a whole variety of other issues, some of which we'll take up, because in a certain sense we might describe Jonas as asking the question: How do we think about the presence of the person in what we do in or to the body, or in what we take into the body?

Overcoming the "thingness" is a way of asking about what it means to be personally present and invested, not alienated from, the action that we undertake. I mean, I don't know how to make all the connections with other questions, and maybe they can't be made necessarily in advance entirely, but that's an issue that has kind of a larger resonance than just questions about experimentation, and in that sense it seems to me we can think about what Jonas says with respect to experimentation, but he's also driving toward something that cuts deeper and will involve or will be involved in lots of other questions.

Thank you.

CHAIRMAN KASS: Paul?

DR. MCHUGH: I can't add a lot to what you've said already, but I want to just give a couple of examples of how at all of our hospitals there are monuments to people who were scientists and who did contribute themselves to this work.

At Hopkins there's a large plaque to Jesse Lazear, who was one of Walter Reed's group in the yellow fever expeditions and died as an experimental subject. He was a young physician from Hopkins.

But perhaps the one that's not known and yet is perhaps the most distinguished human subject at Hopkins was William Halstead, the first surgeon, who in his early career, interested as he was in peripheral anesthesia, did experiments on himself and on others of his colleagues with cocaine as a peripheral anesthetic, ultimately opening up the whole sphere of peripheral anesthesia and dental anesthesia for our benefit, but in the process developing tremendous addiction of himself and on some of his young friends, several of whom died. Halstead was fundamentally carried as an addicted victim throughout the rest of his career by people like William Welch and William Osler.

So the one great advantage of the lineage that Jonas lays out here is that it's been done, and in the process of being done, does show us what can happen to an experimental subject in the most dramatic ways.

We honor them and the plaques for Lazear and our knowledge about William Halstead, of course, encourage us when we're asking other people and ourselves to contribute to similar research.

CHAIRMAN KASS: Janet?

DR. ROWLEY: I'd like to take a somewhat different approach to this, and I'm sure it is because, though I do not myself treat patients, my colleagues do, and the patients they treat are those with cancer and leukemia. Very often, these patients have tried all of the standard treatments for their disease, which seems to continue sort of relentlessly progressing. They are often the main protagonists for what is new: What can you give me that might even give me some remote chance of cure?

So the patient as sort of a partial victim, as is portrayed, I think may be true for some studies, is certainly true for some studies, but I think that it totally loses sight of those cases in which patients are desperate for any straw of hope, and they are more than anxious to participate in experiments that might give them some benefit, but also benefit patients in the future who have the same disease.

Certainly, for the treatment of childhood leukemia and a number of other cancers, the remarkable treatment successes we have now are built on those patients. I think that's totally lacking in this analysis.

CHAIRMAN KASS: Just to this point, Alfonso, go ahead.

DR. GÓMEZ-LOBO: It is my understanding that Hans Jonas does take that into account. For instance, on page 127 he says, "Introduction of an untried therapy into the treatment where the tried ones have failed" -- where the tried ones have failed -- "is not experimentation on the patient." In other words, he excludes that as an instance of experimentation, it seems to me.

CHAIRMAN KASS: Gil, to this?

PROF. MEILAENDER: Yes, right to this. I think we would want to ask a question, Janet, in the kind of circumstances you describe, whether the person is, to use the language I used before, fully invested in this undertaking as a research subject or as a desperate person hoping for a cure.

If the researcher is involved in what he or she thinks is research, and the person is invested in it not simply as a research subject but as a desperate person grasping at a last straw, the researcher's purposes may be somewhat alien from those of the subject. I mean, so we still have to think about that concern that Jonas has.

DR. ROWLEY: But is that really -- I mean, I guess you are in territory where I'm on very weak grounds in terms of trying to think of the concepts, the nuances, and the dividing line between these. I'm not even sure that, for at least some of my colleagues in their work with untried, experimental therapies, but which have some rational basis -- I mean, these aren't just picked off of somebody's shelf; they've all gone through both a fair number of trials in other animals, in animals before you approach patients -- how to separate out the scientists' desire to learn and to see if this is going to be beneficial for the patient and his desire as a physician to do the best for that patient, that's a nuance I think I can't deal with.

PROF. MEILAENDER: Just really quickly, I mean I agree it is very difficult and probably can't be separated out and sorted out sometimes. All I wanted to point out was that nobody is handier than the desperate man.

Insofar as that's Jonas' concern, one would have to continue to worry about the intersection of those two sorts of roles, that's all.

DR. ROWLEY: Yes, but at the same time, if you're not desperate, you're not going to be willing to be a part of something that is experimental and untried, and things come with terrible toxicities, as we all know from any friend who has had cancer and been treated. So I don't know; it's a very gray area, I think.

CHAIRMAN KASS: Rebecca?

PROF. DRESSER: I was just going to comment that there's been some interesting research done actually by the University of Chicago physician researchers on Phase I oncology trials. I think the contemporary concept that people try to use in a formal way to go beyond just permission to be a study subject, it's informed and voluntary consent. I think in the abstract it sounds nice, but there are a lot of studies showing that many subjects don't have the kind of understanding that I certainly would like them to have.

In these Phase I trials, somebody looked at a number of trials and said they have about a 4 to 6 percent chance of directly benefiting the subject, and in terms of direct benefit, that doesn't necessarily mean extended life or even palliation. It's just tumor shrinkage. When they asked people who participate in these studies about possible benefit, many of them cling to that belief, that there's something in there that's going to help them as individuals.

Zeke Emanuel has written on this. So maybe he can comment. But this thing called the therapeutic misconception, where people who are in studies confuse what's going on to advance knowledge with their personal treatment, is a serious problem I think in Phase I trials, at least in actuality.

DR. ROWLEY: I think Chris Daugherty and others have certainly looked at this. See, I think, again, you have to put it in the context in which these studies are done. You're a physician; you treat patients, a very large proportion of whom are going to die. You are trying desperately to advance things. So it's true, you have a personal, psychological, vested interest in trying to come up with something miraculously which will change the situation, so you just don't go in and see one dying patient after another, which when my colleagues come off of the service, they're devastated emotionally for the trauma that they have experienced during the month that they've been on this intensive service.

So these are human activities carried out in very real, desperate circumstances. I think to dissociate the reality from, or to dissociate our dissection from the actual reality, makes this a somewhat unreal exercise.

CHAIRMAN KASS: Let me comment just briefly on that. I would underscore Alfonso's pointing to that place in the text where one acknowledges that desperate people in desperate situations, eager for cure, treated by people profoundly eager and willing to help them, can participate in things that are very risky with very uncertain promise of gain.

But even so, I guess the question is, in what way does one approach these people and what is it that one is -- what of their humanity, in addition to their pain and suffering, is one also trying to respond to? I think that's partly the concern.

If one simply says, "These are the only subjects that are possibly available to advance our knowledge," however true and necessary that is as a condition for using them, the question is whether it's sufficient and whether one doesn't want to try in some kind of honest way to elicit their identification with the enterprise and not simply exploit their desperation.

It's not an objection to proceeding with that research, but the question is: How should they be regarded? How should they be treated? How should they be spoken to?

I think Jonas is suggesting that merely getting the consent form filled out as a permission to subject one's self to the risk is a formal procedure that might point to something else, but by itself isn't sufficient.

DR. ROWLEY: Let me just respond to that because this is a situation where I believe some of his perspectives, at least in some circumstances or some hospitals and teaching centers, has changed. It is certainly true over the last decades that our own informed consent sheet that a patient signs has gone from a simple, one-page form to about a five-page form that you would need a college education to understand. You are dealing with many patients who do not have that level of sophistication.

We have specially-trained nurses who talk with patients, try to explain all of this, but it is not simple. I'm not saying that medicine and physicians and individuals conducting this kind of research should not be even more attentive to patients, but I have to say, as an observer of what goes on in hematology/oncology at the University of Chicago, that I think that the physicians and the nurses bend over backwards to try to make sure that the patient understands the risks. Of course, many patients decide they don't want to do that, and there is no pressure on those patients to participate if they say, "I've been through two years of treatment and here I am, and I accept my fate and will deal with it."

But I am also certain that there are many places where this has not been emphasized as much as it is in some of the teaching hospitals where these concerns are probably much more applicable.

CHAIRMAN KASS: Thank you. Alfonso and then Mary Ann.

DR. GÓMEZ-LOBO: I'm going to step back a little bit in the discussion and try to go back to the basic philosophical framework.

Needless to say, I was delighted when I saw that Leon had included the article by Jonas. I had the good fortune of hearing Professor Jonas deliver a lecture at the University of Turin many years ago, and I was very, very impressed.

Now this is a wonderful paper because here we have someone whose main concerns were really abstract, philosophical thinking, and he's invited to think about the problem of experimenting on human subjects. It's admirable how he carefully sorts out all of the different issues, different possibilities, and at the same time I think is very careful to preserve the genuine interests of promotion of medical knowledge.

Now reading this article in the present times, it seems to me that there are two very important differences in the setting for the paper and the setting in which we find ourselves. Let me just go into two of them: difference in the facts and difference in the ethical approach.

With regard to the facts, of course, we have gone already through the Tuskegee scandal, et cetera, and we all know that there are these very serious efforts to overcome questions of consent, informed consent, that the people know exactly what they are going to be subjected to.

Now this assumes that we are talking about adults as the objects of research in the paper. However, as we know from our previous discussion of cloning, the big problem today is having human subjects, say, at the embryonic stage, who of course would be experimented upon without there being any chance of consent or something of that sort. So that creates a totally new situation, it seems to me.

Now the second difference I think is this: Again, I point back to our previous discussions. All of these trials that Jonas has in mind are, of course, therapeutic, and he insists that there be therapy in the benefit of the sick person herself, and that's what prompts this extension of saying, well, in certain cases, when some therapeutic means have failed, of course, one goes further for some kind of experimental treatment. From a moral point of view, it seems to me that's perfectly reasonable and permissible.

But from the stem cell research issues that we dealt with, there we are in a different situation. The human embryos are being destroyed, which of course is very different from what Jonas had in mind. In other words, there's intentional action there of a sort that he never even imagined, it seems to me, at least from this paper.

Now the second area where I think it is remarkable and what a different situation we find ourselves is, as I said, on the philosophical framework. It seems to me that Jonas takes clearly a Kantian approach. He has the philosopher Kant in the back of his mind, because he assumes that the first principle is that one should not reduce a human being to a thing or mere means, not just means but mere means, and he says, well, in order to violate this, we need very, very, very strong reasons and unusual circumstances, and he adds lots of qualifications. That's why he mentions war and mentions such other things.

Now if we think about our predicament today, it seems that the reverse holds: that what is socially accepted is the goal of promoting health and well-being, and it is the other principle that then needs justification. In other words, how can you justify not using, say, certain human organisms, if or since they are going to lead to all of these benefits? So it seems to me that that is extremely important in order to understand the direction of the moral debate that this article generates. Thank you.

CHAIRMAN KASS: Gil, to this or what? Well, if this is a direct response to Alfonso, yes; otherwise, there was a queue. Okay, Mary Ann, I'll just put you in.

PROF. GLENDON: Okay, this is a somewhat different subject, but this article was written in 1969. So much has happened, not only in terms of scientific and technical advances, but also changes in the culture, that I would be curious to know -- and I think the other non-scientists would be curious to know -- about whether there have been significant shifts in scientific opinion on some of the problem points that Jonas raises.

I mean, to be quite concrete, when you get to be a certain age and you go to a physician, and all of a sudden your physician, she looks like she's 14 years old, but she's probably 30, but, nevertheless, you can't help but wondering, what kind of culture has she picked up in medical school and what does she think about these issues that Jonas discussed in a certain way in 1969?

So I have three points that I would be curious to know whether anyone can enlighten us on, whether there have been significant shifts in scientific opinion. The first is where he mentions, as a somewhat peculiar point of view expressed at a conference, someone said, "Society cannot afford to discard the tissues of the hopelessly unconscious patient." And he raises the question, well, wait a minute, what does that say about who owns these tissues, if you talk in terms of discarding and salvaging?

That put me in mind of the discussion that goes on in my state, Massachusetts, which I realize is somewhat exceptional. We have organ donor cards that we may sign when we get our driver's licenses where we can give consent to have our organs taken, but there's some discussion about whether it wouldn't be better to just have a presumption that people's organs are available unless they sign a card that says they don't want their organs taken. It really reverses this presumption that Jonas is talking about in the area of experimentation. So that's one point about which I'm curious, whether there's some widely-shared view about whose decision this ought to be and what the presumptions ought to be.

Then, secondly, Jonas proposes very strongly that, not only as we have been saying there's an ideal subject for human experimentation, but that there is a category of subjects that are the least morally-justifiably subjects and those are the people who are least informed and least free. I wonder there whether we are seeing an increasing sense that actually that last category is the one that's most available because, well, as Gil said, because they are available.

Then, finally, the definition of death and the warning that he issues that there will be enormous pressure to alter the definition of death, so as to make more subjects available.

CHAIRMAN KASS: Does someone want to join directly these questions? Interestingly, Mary Ann, those are all things that would fit with Alfonso's comment earlier, where Alfonso suggested that his view of the cultural shift is that what is taken as the given is in a way the imperative or the necessity of medical progress or the saving of lives, and that the burden now falls on those who would object in the name of, say, the dignity of the person, something of that sort. I think it would take all three of your examples and make those specific instances of where his claim could be tested.

Does someone want to join, respond to Mary Ann? Paul?

DR. MCHUGH: Yes, I would like to respond to both Alfonso and Mary Ann, but perhaps to begin, to say that I think that there has been an important and, to some extent, a very useful cultural change that has occurred over the last 50 years and that relates a bit to what Jonas is saying but carries it another step.

You see, I agree with you that there's a Kantian thing here, but Jonas is calling for virtues, and virtues, Aristotle said, are tied to practices. The practices have been enhanced. What Dr. Rowley was saying is that we have seen wonderful things happen for our patients and for our world and for ourselves, and in that process a lot of us, patients, citizens, as well as physicians, have said, "We want to join these practices because they do call for virtues." Yes, virtues of the doctor/patient relationship, but also virtues of the subject, and that we want to be part of that.

We want to have this grace or virtue that we'll take part in this great advance that has occurred for our patients, our cancer patients, our endocrine patients, our heart patients, our hypertension patients. I mean these are wonderful things that have come forward, and lots of us have begun to think about how we could be part of that virtuous practice.

In that way, to some extent, we can go too far. I agree with you, we can go so far as to sweep by the people who don't understand what we're doing.

Now in my case in particular, after all, I am often talking about asking patients who are mentally disturbed to help take part, and that's a big problem that Jonas doesn't take into account here. He never mentions it and the like.

I also agree that there is besmirching of this virtue when grants, indirect costs, paying of subjects, and things of that sort come into play as well.

But at an important level, the culture has changed, and changed to advantages, because of the things that we have worked on. We should be talking about the virtues that are implied in the practice of this kind of research and avoiding the pitfalls that are here.

CHAIRMAN KASS: Is it your suggestion, Paul, that for the most part subjects that are recruited or volunteer for research are really entering in the spirit of identification? When you say that they want to join in this virtuous activity, that it's not just they give permission to run certain risks, but that they become, to use Paul Ramsey's phrase, co-partners in the experimentation?

DR. MCHUGH: I think that's far more true now than it was 50 years ago, as people have heard about the things which are potentials and which are happening. I must say they can be greatly taken advantage of. They can be abused. They can be given consent forms that, as Janet said, require a college education.

By the way, I think all IRBs now know that fact and submit the consent forms to these computer techniques that tell you what grade level you have to have to understand it, and show you that, you know, that you can have really impressive ideas that are at the third or fourth grade level. I mean, the Psalms are a good example of just how wonderful they can be, but that's a sideline.

But I do think that the issue of virtue and the acceptance that we have been not only great beneficiaries, but in a sense a common legion to attack the problems of illness in our society, in our world, is a broad theme in the citizenry, and that many patients come forward with that sense of being part of the process with the doctors.

For all the things that Jonas warns us about, I do think that Janet is onto something when she says, gee, you know, talk about this context, and this context is very broad on our society.

DR. ROWLEY: Can I intrude and just ask, Dan, you're probably, along with Paul, a physician who is involved in teaching medical students. If you think of how some of these issues were discussed when you first started as a faculty person and as they're discussed now, I would be very interested in briefly your comments or perspective on this issue. It's not fair for me to put you on the spot, but I think, of all the people besides Paul --

DR. FOSTER: You're always putting me on the spot.

DR. ROWLEY: -- you really have practical experience and can comment.

DR. FOSTER: Well, the culture clearly has changed. When I started in academic medicine, you were either a basic laboratory investigator or you didn't work in a medical school, for example. I mean, there were very few clinical trials with humans which were going on. There were the heroic efforts in yellow fever, and so forth, where many physicians put themselves at risk.

You know, there were things that were going on, but clinical investigation is now a huge operation, both in the private sector for people who develop instruments and drugs, and so forth, but also in the context of teaching in the medical schools. So you find in all medical centers you have to have courses these days in understanding statistics, the consent, and all of those things.

Now do I think that the average -- that that intrudes very much in the four years that they are medical students? I don't think so. I mean, I think that it's those sorts of issues about partnership and consent have been cast more in terms of individual patient care than they have in terms of the larger issue of how one gets consent, and so forth. So the culture has changed.

I think I want to say that the sort of conversation we're having today does not intrude on the real world. I mean, one of the dangers is, I mean these sort of sophistications that we're talking about here are not real-world problems.

I once heard somebody in a counseling session say, if you're worried about what people are thinking about you, don't worry, they ain't thinking about you. That's sort of the situation here.

The issue of literacy has to do with just reading of prescriptions, and so forth. I mean, you really do have to cast these things in terms of just consents that are understandable. Many times the corporations, if you're doing a trial, the lawyers put in these things that nobody can understand. Most of the time -- we just had a grand rounds on this -- you have to communicate the level of the fifth or sixth grade for most things, just the instructions on it. So this kind of conversation doesn't have anything.

So I don't think that -- I mean, I think it's important to do because there have been terrible abuses of humans, and I think we need to focus on that. But I think that the effort -- I mean, I thought this was a very scholarly paper, sort of ethereal in some sense for most average people. They wouldn't really understand it.

But there seems to be, and I certainly don't want to say -- this is a warning -- I don't want to go back to the discussions that we had about embryos, and so forth. I mean, we've already been through that in great detail. I think we ought to talk about the real practical problems that we have here.

There seems to be built in a view that I kind of hear that anything that you want to do in terms with humans, regardless of the virtue, is either dangerous or shouldn't be done. I mean, it's very carefully said here, well, okay, if it's a desperate situation, a patient is dying from cancer, you're worthy of trying to do something.

But to find out about a drug that just shrinks a tumor, in the first place, everybody I've taken care of in an experimental drug, if they have a tumor, that gives them at least a month or two of joy. I mean it does, and that's part of the foundation to build up -- you know, it took 15 or 18 years to get Gleevec, or something like that. You know, you've got to get these small advances.

So I'm sort of rambling to say that I don't think that this enters into medical education in detail about consent until you get into start doing clinical trials.

As long as I'm here, I might make one other point. We began with talking about Kant and this issue of "thingifying" humans. That seems to be, for all the ethicists, sort of a holy grail about what we should do. But there is an element where in just clinical care the physician is more, or the scientist is more, than just an equal partner.

I want to illustrate that by a real-world case and then I'm through. I think that most people are happy to have somebody that they think they can trust to be working on things for their disease individually or for the long run.

The long-term editor of The New England Journal of Medicine, Franz Ingelfinger, as many of you know, was probably the most influential person during his lifetime about things. When he was a scientist, he had worked on esophageal cancer, and he got esophageal cancer.

He wrote an article in The New England Journal called, "Arrogance." That is the arrogance of the view that a physician should be not co-equal in terms of the care of the patient. Because he knew everybody in the world, he was besieged by: Should he have radiation first? Should he have surgery first? Not only that, he had kids who were physicians, and everybody -- he said he was just torn to pieces.

Finally, somebody said to him, "Franz, what you need is a doctor." And he said, "I followed that advice and turned to my internist and was at ease that he would take care of me, and then I got back to my usual activities of editing this Journal and giving talks," and so forth and so on.

In other words, his learning, his plea was not for -- I mean, he wouldn't consider himself a thing, but he certainly considered himself to be cared for by somebody that he trusted, and so forth.

So the bottom-line answer: The culture has changed, but it has changed mostly not in the undergraduate work in the medical school, but subsequently I think that there are very marked abuses that we have to limit. In the practical world, I think that consent is not simply a negative thing. I think it is a very important thing.

I am very worried continually about a subtle sense that medicine and medical science, which I consider to be a high and noble virtue, becomes cast in terms that it is automatically in some sense negative for those who are participating in it or those who do it. I would say that's not real world in this country. I think people who are sick want to do it.

If I had been prepared to say something, I would have said it a little better, but, anyway, I'm trying to answer your question.

DR. KRAUTHAMMER: Could I make a point on that, a response to that?

CHAIRMAN KASS: Charles.

DR. KRAUTHAMMER: Dan, I don't think that the issue is that we're casting advances or the noble or wonderful things that medicine has done as negative. I think what we're trying to do is to point out certain inherent difficulties and contradictions.

That is that when you do medical experimentation on humans, you necessarily introduce "thingness." That, in and of itself, is inevitable, and that, in and of itself, is a problem. It does not mean that you don't carry on that research, but it means that you have to be very careful and think about it.

We know what extremes of "thingness" can do. We saw it at Auschwitz. We saw it at Tuskegee. Those are the seminal examples which warn us that, however noble and beneficial medicine is and can be, the very nature of experimentation, which is to treat a person as a thing because we are studying it as a thing, is inherently dangerous. All that we're saying is, let's examine the dangers and ask what kinds of protections one has to introduce.

I was struck, incidentally, by the "thingness" of it. It always strikes me in blind experiments. We all read a few weeks ago about this new discovery that a certain kind of surgery for arthritic knees is useless, and it was discovered by having two sets of subjects, one-half of whom received sham knee surgery. It was shown that there was no difference in outcome between those who had the real and those who had the sham.

I always ask myself, how would you feel if you were the one who had that sham surgery? I mean, it's rather remarkable.

There's a more famous case, I think about 30 years ago, where that was done with heart disease. Also made a wonderful discovery of the uselessness of a certain kind of invasive surgery, right, with the mammary artery transplants which were useless. But it was discovered by doing sham surgeries on half of the patients, actually opening their chest, sewing it up, and doing nothing.

So we have here an inherent problem. That was a great discovery, that the mammary artery surgery was useless. On the other hand, we had real people who were wheeled in, anaesthetized, chest opened and closed, and nothing happened to them.

If I could make just one other point in response to what Paul had said about participation, being part of a great enterprise, I agree entirely that is the ideal. I think it's exemplified most dramatically when the physician himself engages and becomes a patient.

But consent is a separate issue, and it introduces itself here. There are three categories of patients in whom you can never really get true consent. That's children, the mentally disabled, and prisoners. Those are the classic cases.

Even if you exclude those cases, you have patients, adults, who are sentient and who are not in prison; you always have the questions of desperation and naivete. Those always contaminate, and I would contend that it is almost impossible to get a true consent.

Again, this doesn't mean that you don't engage in the therapy, in the experimentation, but it has to be a real caution.

DR. FOSTER: Let me just respond to that. I would be absolutely first in line to preclude the sort of issues that give interesting data but are totally unacceptable. I could probably spend a lot of time today, which I'm not going to do, giving you examples of things that have been done that I think are absolutely wrong. So count me as first in line for that.

I think that if we can bring some insight into that, but I just don't want to go over so far -- I mean apart from the dialogue, which I think, as I say, is ethereal for the average person. I mean the illiteracy in this country may be as much as 23 percent. I mean in the West you can't talk like this.

I think everybody understands about protecting subjects and getting them to do that, but I don't think that most people are going to be involved in the Kantian thing. I would rather us concentrate on how we improve the process.

CHAIRMAN KASS: Bill May?

DR. MAY: On this question of recruitment and depths of identification, I suppose the most obvious analogy is recruiting for armed services. There used to be the practice, as we say, of shanghaiing people for service in the Navy, and so forth. Informed consent or signing on was a protection against dragooning people into military service.

But there's the next category of, if one especially went after those folks who would be highly motivated, let's say immigrants or convicts maybe destined for execution, those folks that you would hope could recoup significance for a life in danger of losing or rapidly losing the capacity to recoup or signify, and, look, you can't become a citizen of this country, but join the armed services and you'll find your way into citizenship, and so forth. So you're offering not the inevitability of it, but the possibility of it. Then the question is, what degree of possibility?

The final level that Hans Jonas is talking about, and that Gil highlighted for us, is a kind of patriotic investment. I mean people who join the Army and the Navy for reasons of patriotism. But what lies behind that, it's a conception of the country. I mean, if they are disposed to sacrifice, it's not simply because just out of nothing they're disposed to sacrifice, but they belong to something; they're participating in something that in a sense they're joining a history of sacrifice.

This was talked about in terms of some idealistic physicians who felt themselves belonging to a tradition of sacrifice that precedes them. That tradition may not be very alive amongst us now.

The problem is, the larger problem is, we live in a setting of a society where we do not think of the society itself as founded in sacrifice. Its origin was a deal where you surrender something and you get something, and then the terms of that deal is, what allows the State to do things? It is the fact that it gives you something. In order to be able to give you something, it, of course, has to stay alive. So a fundamental warrant granted to the State is its capacity to conscript if its survival is at issue, and that's where Hans Jonas takes that.

But there are, of course, other old traditions of the origin of the State where the State was founded not on a deal, 17th and 18th century, but is founded on sacrifice, the sacrifice of the gods or magnitude of investments on the part of individuals, and so forth.

There's an echo of that, I guess, in immigrant folks who weren't dragooned to come to this country, but whose parents made great sacrifices to bring them here. In a sense one belongs to a tradition of sacrifice, so that what you do is simply your mode of participating in it.

It seems to me that is what is largely lacking in the particulars of professions or the kind of warrants that we can present to people. So we have to suppress that speech. Hans Jonas gives us an illustration of that speech, almost mockingly, because you know it will chill people. They will not act, because the ordinary terms of relating through such an undertaking, such an enterprise, is signing on. Then the question is, what will I get out of it? That's understandable.

CHAIRMAN KASS: I have Rebecca and then Bill Hurlbut.

PROF. DRESSER: One interesting thing about that sham surgery study was that, as part of it, they made people write down, "I understand that I am going to go through surgery and they might not do anything to me." They lost a lot of people after they said, "Yes, I want to do this," but then they had to write this in their own words, and people said, a certain percentage said, "No thanks."

I think this paper is brilliant and timely, and it really forces us to step back from something that we accept so much as a society today, this idea that progress is not optional, but it's nearly mandatory and this kind of sense that we are in a war against disease and we must go forward with research.

So progress is almost mandatory, and progress of a certain sort, progress in the form of advancing knowledge to produce miracles or unknown effective treatments, as opposed to progress in providing measures that we have available today to more people, such as established health care and even more basic things, like decent housing and education, and so forth. So it's we must make progress and we must make progress in a certain way and not another way.

Then it becomes interesting, why do we see it this way? Why is our culture at that point? You know, I don't know; I think we've gotten more that way than we were when Jonas wrote partly because of the patient advocacy movement, which started with HIV/AIDS activists where they started presenting research not as something to be afraid of, but something that we will demand. "You must do research on our disease." Then women and other groups got involved in saying you must study women because we want to know whether to take an aspirin, and all this sort of health advice that's being given to men.

So research is seen as a benefit, and that view is really, I think, promoted through patient advocacy groups and also through journalism. I really think the way that research is reported on reinforces that image.

But I'm not sure if those are cause or effect. So I would be interested in hearing if anyone else has thoughts on that.

CHAIRMAN KASS: Bill and then Gil.

DR. HURLBUT: What interests me about this essay most strikingly is the way Jonas puts the ethical, foundational, central significance and progress as contingent upon the preservation of the ethical.

Central to the essay is a dignified and exalted view of human beings and a recognition that the ongoing existence of society and the progress of science depend on this view of humanity as the source of something that can't be legislated or enforced.

The progress -- it seems to me in his essay he says it plainly -- progress is not the highest concern, that progress flows forth out of a society where you preserve humanity's central core of individual dignity and its commitment to personal devotion, what he calls authenticity and spontaneity.

In an interesting way, this places the essay as a hinge-point between our previous six months and where we're heading next, because our disagreements and discussions at least hinge to a large extent in the first half of the year on the question of how to preserve this humanity that we're trying to promote, nourish, and heal.

The thing that strikes me about this essay so strongly is how Jonas acknowledges the central concern for all of the other benefits of society of the preservation of the crucial qualities at the core of humanity. In that sense, as we go forward now, we talk about enhancements. The issue is, how do we preserve this crucial, ethical quality within human beings, this central core on which all things depend, both meaningful individual existence and social cohesion?

He speaks of a sphere outside the sphere of social contract, of public rights and duties, of a trans-social upwelling of personal idealism, the noble of grace, not decree, and intangibles even of a religious order, and what Bill was saying of self-sacrifice.

It strikes me as an interesting place to start our discussions of where we are heading with our progress, that we need to preserve these qualities as central. Just to give a couple of his own words, he says, "The ethical dimension far exceeds that of the moral law and reaches into the sublime solitude of dedication and ultimate commitment, away from all reckoning and rule, and shored into the sphere of the holy."

And he says, "A society cannot prosper without this. It must draw on them, but not command them."

And then he goes on to say how this source is powerful and wells up from natural humanity. All we have to do is be sure not to preclude or quench it. He says, "We have laid down what must seem a forbidding rule to the number-hungry research industry" -- in his essay, that is -- "having faith in the transcendent potential of man. I do not fear that the source will ever fail a society that does not destroy it, and only such a one is worthy of the blessings of progress."

I found this a very striking essay for that because it called me back to that commitment to the central significance of the ethical in not just the individual, but the whole outplay of social process; that we need to be concerned not just with what we preempt, but what we promote as well and what we preserve, perhaps more centrally.

CHAIRMAN KASS: Thank you. Gil.

PROF. MEILAENDER: I want to go back to Mary Ann's comment quite a while ago and make my way from that to Dan's, in order to try to persuade Dan that this really is the real world here.

At least as long as some of your fellow human beings seated around here obstinately intend to talk about it, Dan, it's going to have a certain kind of reality. We're just going to keep beating you over the head with it.

DR. FOSTER: I wouldn't have been in this discussion if it was not for Janet. Okay?

(Laughter.)

PROF. MEILAENDER: It's her fault, that's right.

(Laughter.)

The interesting thing, in terms of the three kinds of issues that Mary Ann raised and just inquired sort of how things had or had not shifted in the roughly 30-year period, say, since Jonas wrote, is that in fact I think I'm right to say that a lot of people worried about those questions, and that the increasing attention to consent, you know, free and informed consent, the increasing kind of codification and requirement of consent was precisely designed in many cases to deal with some of those issues that you raise, and does deal with it in many ways. I mean this was Paul's sense that something good has happened.

The peculiar thing is, though, that I think if you took those three, you would see that they all remain quite contested areas actually. Indeed, for a while we thought consent solved the problem, and I think you would say that many aren't so sure that consent has solved the problem, partly for reasons Rebecca referred to in her comments.

See, that brings me back to the, to me, interesting thing about the Jonas article, is that you somehow have to dig a little deeper than just consent. Just a notion of consent won't turn out to satisfy us in terms of the sorts of issues, and the enormous amount of attention that's been paid to it in the past 30 years and real concern about those issues and progress in certain ways still doesn't turn out to solve it entirely.

That brings me to Dan's comment. I think part of what Jonas is getting at, and part of the reason for that, is this is not just a concern about researchers out there, Dan. We love them all, though they are, of course, subject to all the vices and temptations that the rest of humanity is.

The concern is not just that they might misuse their research subjects or their patients or those desperate people, or whatever. The concern is that we might being using the researchers as our instruments.

I mean, we do all, to some degree, live off of each other, of course. But we don't just want to live off other people. Insofar as we all benefit from what medical research does, we do need to think about whether what that really means is that some of us benefit by living what others have largely done.

What Jonas forces us to ask is, to what degree those people off whom we are living really thought of themselves as sharing with us in some kind of undertaking or to what degree we're simply living off them with nothing more? So it's really not just a question about what researchers are doing, though if their consciences bother them, you know, that's good and they should worry about it, but he is really getting at kind of what all of us do in benefiting from research.

I will say, I mean, if you go to a teaching hospital and you look around at the people who are there, it ought to lead you sometimes to worry about whether you are living off some other people who are very unlikely to have some sense of sharing in a joint venture.

So that's where I think Jonas ought to point us. If that's not a real-world problem, then I wouldn't know what an important real-world problem would be.

CHAIRMAN KASS: Dan?

DR. FOSTER: Just one quick comment: I mean, I think your concern about living off others is not limited to biomedical research. I would wonder about the stock market and everything else. I mean it seems to be sort of a systematic desire for a few to live off others.

I mean, I think that one cannot eliminate the human need or evil, or whatever you want to say, to live off others in that sense. I accept your comments, and I love bioethicists, too, even though they are often ethereal, as I say.

(Laughter.)

CHAIRMAN KASS: Alfonso?

DR. GÓMEZ-LOBO: Just a little clarification for Paul, if I may, on the question of virtues. But let me start from what Charles said because Charles -- it happens to me very often -- expresses with great clarity what I would have liked to express, but never managed to do.

What we are talking about here is a question of caution, of being very careful with what we're doing when there's research with human subjects. Now that can be expressed either in terms of respect for the dignity of persons, but it can also be expressed in terms of virtues.

One of the key and fundamental areas to deal in virtues is, of course, the virtue of justice. One could say the endeavor here is this: that in the overwhelming majority of cases there are no violations of justice, I presume, but we should be very careful in these very special cases that justice is being done. So I don't see it as mutually-exclusive. By the way, Kant does have a very strong theory of virtues as well.

A further remark is this: We hear in the paper and in Bill May's remark the constant parallel with conscription. I find it a little bit unsatisfactory myself because I'm not sure that all instances of conscription are morally justifiable. I think that a case can be made that in certain instances it's morally wrong to conscript young people.

Now the extreme case would be, of course, the conscription of young Austrians to fight for Hitler in World War II. Some young Austrians drew that conclusion, and they were duly shot, of course.

CHAIRMAN KASS: Paul, and then I'll have a comment, and we'll break.

DR. MCHUGH: I'm always in your debt, Alfonso, to explain to me these differences amongst the philosophers.

But I think we're all at least talking in similar ways about what we want to do as practitioners. I want to get away from this idea that it is ethereal, Dan -- I have to speak as the psychiatrist here -- that it's ethereal to work in a full and expanding consciousness. That's really what I want to do as a doctor, and I think that's what you want to do.

All of the activities that I do every day I want to have in full consciousness and appreciating my place in this community, because it's the community issue that I believe the virtues ultimately emerge in, in the practitioners who are fully conscious of what they're doing all the time and who are listening to people like Jonas and others about how they should think.

But I still want to come back to the idea that the full consciousness of a community does come in advance and does advance along with things which a community accomplishes. The tremendous accomplishments of things in medical science, along with, as Gil said, refinement of our research procedures, has been a tremendous uplift to what we can accomplish as members of a community, whether we are subjects or whether we are investigators.

I also agree that we haven't ever completely answered all of the issues that Mary Ann raised, because these are always vexed questions, and there's, to some extent, an asymptotic approach to the justices in them in which we can't be completely satisfied that we have an absolute forum.

Now Charles wonderfully explained that there are three groups of people in whom research is -- well, he said it shouldn't be done: children, the mentally disturbed, and prisoners. I want to salute that. I want to get up and say, "Right, I'm all for that."

But then, gosh, wait a minute, I want at some time to be able to talk about why I might want to persuade people who have mental disturbances to work with me and to be pa

I'm also losing it a bit, but it was this idea that this is too ethereal. It is not ethereal, I think, to anyone who believes that he should, or she should, be acting in his practice in full and advancing consciousness of what is happening and finding the words that deal with the feelings that he has, or she has, when he asks patients and subjects to commit to being in part a "thing" in this work.

DR. KRAUTHAMMER: Leon, I must make a clarification here. I didn't say that you should never experiment on them. I simply said that you could inherently never have informed consent --

DR. MCHUGH: Right.

DR. KRAUTHAMMER: -- which is why you have a difficult problem of delegated or implied consent or proxy consent, and there are all kinds of regulations which, in fact, in a previous life, a quarter of a century ago, as a psychiatrist working in the Carter Administration, I worked on those regulations.

But these are three categories of people which make the problem of informed consent very, very clear, since it is impossible to get that kind of consent out of them. So you have to devise a mechanism to get around it. It is not as if you can never have experimentation. I would never argue that you can't have experimentation on children.

DR. MCHUGH: Yes, fine, thanks. Thanks, Charles.

I think my point continues just in the same way, that that kind of discussion, that kind of interaction, that kind of explanation of and misunderstanding makes my life and my practice more enriched. That is the whole reason why I want to do it.

CHAIRMAN KASS: Okay, we're coming up on break. Let me make a couple of comments. A lot of people stirred me up, but I will just be very, very brief.

It does seem to me that, however abstract the text is and however philosophical, and, therefore, seemingly remote from everyday practice the article is, and certainly can be a big jump from this to talk about the regulations and the IRBs, it does behoove us, I think, to think very hard about what it is we are trying to protect and preserve in all of these arrangements with our patients, not just as experimental subjects, mind you, but in all the human encounters.

If it turns out that the attempt to protect these things produces documents of five pages long, which one needs not just a college education, but a legal education, to understand, and it is in fact the lawyers who have seen to it that it looks like that because they're interested primarily in protecting the institution, and not necessarily protecting the things that we are interested in, then it seems to me one might have gone off the road.

It ought to be possible to explain to someone with a fifth grade education but with a human heart what it is that one is trying to do here in the same way as one could explain to them what one is trying to do in all other kinds of human relations.

Jonas is, I think, trying to get at something which lies beneath and ought to inform the procedures and the human interactions, and I think not just in the experimentation, in the area of human experimentation, using human subjects for research.

It seems to me both Gil and Bill Hurlbut in their own way called attention to the fact that the principles that are operative here will be relevant for the discussions that we are going to have this afternoon, and they ought to at least be in our mind -- I'm not sure we've clarified them yet -- but ought to be in our mind when one thinks about trying to adjust the procedures that are, in fact, meant not just to encourage the research to go forward, which we all want, but in fact to protect, whether it's human dignity or human virtue or the sense of community or the notion of paying one's price for the benefits of having a community and the sacrificial norm that Bill spoke about.

Those abstract things are, nevertheless, tacitly present, and we probably, at least the presupposition of this conversation is that we would be better off making them not just tacitly present, but, as Paul says, matters of consciousness, when we try to fiddle with various things.

We have gone over a few minutes, not too bad. Why don't we reconvene at 10 minutes before the hour, and Dr. Emanuel will join us?

CHAIRMAN KASS: In this session the Council returns to the general topic of oversight and regulation of development and uses of biotechnologies, a subject of interest to us in general and also, I remind you, in relation to our work on cloning and stem cells, in which many of the people on both sides of the aisle on the cloning debate were interested in exploring the prospects for and the principles of regulation.

In previous meetings we have been looking both at what other countries are doing and also learning about the current regulatory activities in the United States. So far, we've had an overview of what is happening around the world with Lori Knowles and a report on the Canadian practices in reproductive technologies with Patricia Baird. We've had three sessions domestically on the patenting of living organisms.

Tomorrow morning we will hear from Professor Simitis on Germany's practices and policies, and today we will be looking at the Institutional Review Boards, those local bodies that are now charged with oversight and approval of all federally-funded research involving human subjects.

We are very fortunate to have as our presenter this morning Dr. Ezekiel Emanuel, physician, oncologist, Doctor of Political Philosophy, Chair of the Department of Clinical Bioethics at the NIH. His paper he wrote with co-workers, Ann Wood and Christine Grady, entitled, "The Crisis in Human Participants Research: Identifying the Problems and Proposing Solutions," was distributed to Council members in advance.

I remind everyone present that the opinions expressed in this paper and in this presentation are those of the authors. They do not reflect any official position or policy of NIH, the Public Health Service, or the Department of Health and Human Services.

It's a special privilege for me to welcome Zeke Emanuel here who I first met when -- I shudder to think when -- he was still a student, a senior at Amherst, and I was a much younger fellow.

Zeke, welcome and thanks for being with us.

DR. EMANUEL: My speech coach always tells me to stand and never sit. So I hope the Council will indulge me in that.

It's very wonderful to be invited here, and many of the Council members have been my mentors, many are my current colleagues, and many are people whose writings and work and research I have admired over the years.

I think it's fair to say that everyone seems dissatisfied with the current system of protecting human research participants. Many of our researchers find the system onerous and more of a hurdle to get over than something that is value-added.

IRB members who serve on the oversight bodies -- IRB stands for Institutional Review Boards -- find the regulations quite opaque, feel in a bind between federal oversight and what they're supposed to do for their institution. The pharmaceutical and biotechnology industry finds the process very time-consuming, very inefficient, and very resistant to innovative and novel approaches in research.

Regulators feel frustrated. They get criticized by the federal government and the public for not doing enough. They get criticized by institutions for being too intrusive.

And the public is afraid, uncertain. They believe greatly in biomedical research, but recent polls have certainly shown them to be much more concerned than they ever were. I think the cover of Time magazine over the summer that showed a human subject in a guinea pig cage attests to this concern.

I don't think it is misplaced. Since 1999, the federal government oversight body, OHRP -- that is the Office for Human Research Protection -- has stopped or suspended research at 13 major research institutions. This includes two of the top ten medical centers in this country, and a third of the top ten medical centers in this country had a major scandal involving the death of a patient, but was not actually closed.

Now that dissatisfaction has led to tremendous activity to respond to the problems. You can see all those acronyms up there. You know you're in Washington; it's alphabet soup time.

Recently, there was the creation of this Office for Human Research Protections during the end days of the Clinton Administration that reports directly to the Secretary of the Department of Health and Human Services.

At the FDA there was the creation of the Office for Good Clinical Practice to oversee all their ethical issues. The NIH, my employer, has issued requirements on training and education of investigators and one-time grants to improve the function of IRBs. There are new initiatives for accrediting IRBs, which I'll talk about in a moment. And there's introduction at least of two bills by Senator Kennedy and Representatives DeGette and Greenwood in Congress for reforming the system. This attests to a huge amount of activity.

I think there's a problem, though, and a lot of this activity really tends to address specific problems without stepping back and assessing the whole system. In the next few minutes I really want to sort of systematically delineate what I take to be the problems of the system, evaluate how the various proposed reforms address or don't address those problems, and then I want to float for you a more comprehensive solution.

It is at this point which I want to just reiterate Dr. Kass' disclaimer for me, which being a federal government employee I always do at every talk, which is that these are my opinions and the opinions of my colleagues, Ann Wood and Christine Grady, and our Department, and these are not the official opinions of anyone else.

I can tell you, having circulated the manuscript you saw inside the NIH, many people certainly disagree with, but they also thought it was important that these issues be aired and discussed. I greatly appreciate their commitment to free inquiry.

For those of you who aren't sort of up, as it were, on human subjects research and the regulations, I thought a brief historical digression would be helpful. From basically the mid-sixties to 1972, there were a series of research scandals in this country that really began in 1966, where Henry Beecher, a Professor of Anesthesia Research at Harvard Medical School and the Mass. General Hospital, published a very important paper in The New England Journal of Medicine that delineated 22 violations of research ethics at major research institutions.

He said he culled these 22 from a further 50 cases which he couldn't produce because of reasons of space, and that was from a further 100 cases. He made very clear that these events were occurring at the premier research institutions in the United States: Memorial Sloan-Kettering, NYU, Harvard, the NIH.

For the next six years a series of scandals happened in the country, culminating in the Tuskegee syphilis study, which was stopped in 1972 by the then-Department of Health, Education and Welfare after it was revealed in the press, although it is important to emphasize Tuskegee was not hidden; it was not done surreptitiously. Papers were coming out annually from that. As recently as 1969, just three years before it was stopped, it had been reauthorized by the Public Health Service.

Tuskegee led directly to the appointment of a National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in 1974. That was chaired by Dr. Ken Ryan, an obstetrician and gynecologist at the Boston Lying-In Hospital.

Over five years, the National Commission issued some very major reports, including reports on research with prisoners that has already been mentioned and many other topics. Its probably most enduring report is so-called The Belmont Report, which established the sort of framework, ethical framework, for research ethics.

Soon thereafter, the federal regulations on research -- that should say, "on research" -- 45 CFR 46, were enacted in 1981. In 1991, they became what's called the Common Rule, when 17 federal departments and agencies adopted them, although it is important to mention that there are some federal departments that still don't adhere to these rules, notably the Department of Labor.

What's cut off (referring to the viewgraph) should say that the FDA maintains similar but slightly different rules regarding research that is being applied for approval as a drug or a device.

All right, the Common Rule focuses predominantly on local institution-based IRB review of research protocols and continuing review, at least annual review, of those protocols. It is also relies on informed consent of individual research participants, and there are special rules that have been in place for research with children, prisoners, and pregnant women.

With that brief historical background, I want to try to systematically and coherently look at the problems of the system, because I think a large part of the debate, certainly inside the Beltway, focused on one or another of the problems, but not on a sort of overall structure to the problems.

I think the problems can be divided into sort of three domains: structural, the whole system is laid out in the regulations; the IRB review process itself, and assessing the performance of both clinical research and that process.

Before I proceed, I would need to insert two caveats. The first is that there's a serious paucity of data documenting these problems. We just don't have a lot of studies of the whole system and of clinical research and how it is performed. So my claims here that there are problems is born of my experience as a clinical researcher and as an IRB member, discussion with lots of clinical researchers and IRB members, collection of the limited available data that's been published, and we'll look at the actions by the federal oversight institutions.

I also personally think -- and I'll get back to this at the end -- that the absence of performance data on the system is also an indication of serious defects. If Ford didn't know how many defects there were in its cars, you would think there was something wrong with their production system.

Second, while the review of the problems here is systematic, I don't by any means suggest it is comprehensive. There are lots of other problems I'm not going to talk about, such as the application of the regulations which were originally created for biomedical research to things like social and behavioral research and whether they fit or don't fit very well.

So with all of those caveats and hesitations, I want to talk about some structural problems. The first structural problem is that it may strike you and the public as ironic, but not all research, biomedical research, in this country is actually covered by the federal regulations. Research that's not funded by the NIH, research that's not seeking FDA approval doesn't have to get, isn't covered by oversight. This covers some very important research.

A lot of reproductive research falls into this category, and, in addition, research such as on dietary supplements isn't covered by federal regulation. Research on surgical procedures that aren't looking for approval as drugs or using devices is not covered.

Second, currently in the system there's no mechanism in a systematic way for addressing major ethical issues in research or for assessing the social value of research. There was a national commission; there was a President's commission; there was NBAC; there is this Council; there is another group called NHRPAC, which has just been disbanded -- for occasionally looking at major ethical issues in research, but these are stop-and-start events. They're not systematically organized.

Importantly, assessing the social value of research -- Is it really going to contribute that much? What are the down sides of research? Is it designed so that it will affect the most citizens? -- is not systematically evaluated in the system, and to some degree is discouraged from being evaluated.

The third problem: We rely on local institutional-based IRBs. When this was developed 25 years ago, that might have been reasonable when a lot of the research happened at our major academic settings like Johns Hopkins, the NIH, Harvard, UCSF, but in fact a lot of research, or maybe even today a majority of research, has now filtered out into private practices, clinics, and a lot of other organizations. There is a mismatch, many people feel, between the fact that we have institution-based IRBs, but a lot of the research isn't even occurring anymore at institutions.

Fourth, even within institutions there's no dedicated funds for IRBs. When the NIH gives out grants for research, there is no extra money for the IRB function. It comes out of what's called indirect money, and there's not even a line item in there.

Many IRBs, certainly before these recent scandals, were resource-starved, I think is an accurate way to put it. Now the scandals have gotten the attention of many institutions, especially if you can close down Johns Hopkins, and Johns Hopkins has announced or indicated that they have doubled the amount of money they devote to their IRB. But I think in general there's still a lot of lack of resources there, and, importantly, IRBs have to compete with all the other demands for medical institutions that are under increasing price pressure.

Fifth, there's a lack of attention to institutional conflicts of interest. One of the problems of having your IRB be institution-bound is that the IRB is actually regulating the research within the institution that is paying the IRB. That is an inherent conflict of interest. I, myself, have twice experienced some of the pressures that can be brought to bear by reviewing research done at the institution and people, powerful people, in the institution having some interest in getting that research going.

Sixth, there's a very poorly defined mechanism for investigator conflict-of-interest rules and the IRB's role in enforcing those rules. An investigator in this country can be subject to as many as five different conflict-of-interest rules: one from the institution where they work; one from the NIH; one from the FDA; one maybe from their professional society, and if they work at a state institution, there's frequently state conflict-of-interest rules.

They all differ. It is very unclear how to follow them, and it is very unclear how that is matched with submitting a protocol. The IRBs also don't know what they are supposed to do.

Seven, there has been inadequate education of clinical investigators and IRB members. The NIH has recently mandated that for its grantees there be education and training, although there's no curricula requirement; no one knows what the content is supposed to do, and, importantly, therefore, no one knows what the sort of core material they're supposed to understand and any way of assessing whether it works or not. This, by the way, is in marked contrast to animal research.

Eight, the system is replete with repetitive reviews. So, for example, if I do a research study, which I once did at Harvard, involving five other cities and hospitals in all those other cities, and ultimately there were 40 different hospitals, I actually had to get that protocol reviewed at 42 different places to do the research, all of them looking at the exact same thing over and over again. Sometimes this process can take a year and involve a lot of people's attention and energy. I know that another project I am currently involved on, we have one person who is full-time, worked for a year, just in getting all the paperwork together.

Those are structural problems. Now I want to shift to the IRB process problems. I think it is fair to say that a lot of the attention that we have today is really focused on these IRB process problems. A lot of the legislation, the accreditation process, really take these as key. I, myself, think they're important, but I don't think they're the whole story, and that is one of the reasons -- and the previous eight problems are a large part of that reason.

Getting your research approved is a time-consuming process. It has become longer and longer. I will say that most investigators are increasingly frustrated. Six months from submission to approval is not unusual. You often have to go through scientific review, which can take several months. Then the IRB frequently meets only monthly, and if you don't get on the schedule, the IRB frequently has corrections or modifications they want made. You then have to go back in front of the IRB. It is a very lengthy process.

Ten, there's poor quality control of the IRB reviews. One of the things we learned from the Johns Hopkins episode is that the investigator submitted information about the drug being used, but it wasn't complete or comprehensive information. The IRB relied on that information, did not proactively investigate further. This happens frequently.

Sometimes the IRB will get a protocol in an area. There's no one on the IRB who's an expert. Well, IRBs always could get ad hoc members, could actively investigate. That requires time, resources, and it is frequently not done.

Eleven, there's is excessive focus on the informed consent process at IRBs and excessive focus within that just on the document and what is, I think, derisively but not inaccurately called "wordsmithing" of the document. Now some of that wordsmithing is important to make sure that the language and the level of comprehensibility is correct, although we don't always get it right, but a large part of it is just altering words for preferences without any real focus on its importance.

There is good reason why this is true. Frequently, IRBs have been criticized by federal regulators for leaving out something when a scandal happens. This happened at Johns Hopkins. But a large part of the deliberations are about the document and really ignore many, many other important aspects of the research.

Twelve, there's substantial deficiency on how IRBs monitor research and conduct these continuing or annual reviews. It's frequently said, and very accurately said, it seems to me, that IRBs see the research protocol at the start, and then the ball rolls down the hill. They have no idea whether the research is actually being implemented as stated, and continuing review, the annual review, is a very perfunctory thing, done frequently in just a handful of minutes for very complicated studies. This is a very, very serious problem.

I think one of the most serious problems personally is we have a very inefficient and ineffective adverse event reporting system. Adverse events are those problems that arise in the course of a trial, people having reactions to drugs or complications that need to be reported.

It is now required that every IRB get informed. The FDA has a very strict timeline, a strict rating criteria. The NIH is a much more loose, very undefined system.

More importantly, if you have a large trial with lots of centers, you have to send the same information to all the IRBs and they have to make a decision, each individually, what to do, frequently without knowing how many people have been enrolled, are these three cases a large number of cases, a small number of cases, how serious. It is a very time-consuming process, but doesn't do a lot to protect the people on research studies.

The last two problems I want to talk about -- cut off at the top, unfortunately (talking about viewgraph) -- are what I call performance assessment problems. I think these are extremely important and not very well-appreciated.

We have almost no data about IRB function and how well they do their function, and whether, in fact, they actually protect patients. We don't know a lot about what goes on, where they spend their time. Is there a relationship between bad continuing review and harm to patients?

Fifteen, probably more serious is no one in this country, not the Director of the NIH, no one at Pharma or at Bio, and not the commissioner of the FDA, can tell you how many research trials are going on today in the United States, how many people are enrolled in research trials, how many people experience serious toxicities, and, indeed, how many people die on research trials. We don't record that information anywhere.

Again, it seems to me it is hard to know whether the system is better, worse, going in the right direction, going in the wrong direction, if you don't systematically, regularly, routinely even know how many people are on research trials. We don't even know how much we spend on it. I might say we don't even know exactly how many IRBs there are. I am sure General Motors knows exactly to the number how many dealerships it has. We know that there's somewhere between 4,000 and 6,000 IRBs in this country.

Let's talk about the reform proposals now. There are a number of reform proposals: accreditation of IRBs, which I'll talk about in-depth; credentialing of IRB professionals, which I won't talk about because I think it addresses a very small number of these problems; some of these legislative proposals, which I'll talk about. OHRP, again, that federal oversight body has some quality improvement initiatives and conflict-of-interest initiatives. There's been an effort at the National Cancer Institute to create a central IRB, which is in a pilot phase, and I won't say more about that. In a few months we think the Institute of Medicine is to report on its view of how to change the oversight system.

So I want to say a few words about accreditation of IRBs. There are two accreditation processes, again the alphabet soup here. NCQA, the National Committee for Quality Assurance, was hired by the Veterans' Administration to reform and look into and to accredit veterans' IRB programs, and AAHRPP -- and I can never even remember what all the initials stand for -- is an independent group that is doing voluntary accreditation of institutions and research hospitals.

There's some overlap in what they are evaluating. They are looking at the educational programs of these institutions. They are looking at the specification of IRB membership qualifications, how they're trained, how they're kept current. They are looking at policies on conflict of interest in other areas that the IRB has to deal with, and they are developing guidelines and assessing how many resources are provided to IRBs.

At the request of the Department of Health and Human Services, the Institute of Medicine, as the first part of its oversight, examination of the oversight system, reviewed these projects on accreditation. Basically, they said that the standards being developed do not apply to all types of research in all types of settings, that they really focus on biomedical research in the academic setting.

They argue that neither set of standards is tested or ready, as it were, for prime time. They said that accreditation is really best viewed as a pilot project, to be evaluated over a substantial period of time.

I would say -- and this is my summary; they didn't put it in this language -- at best, the IOM gave what I would call tepid support for the accreditation initiatives. It was certainly not wholehearted.

Importantly, which we can confess to you we just learned yesterday, as of April 17th, the Veterans' Administration suspended the NCQA accreditation process because of concerns about the standards and the process itself. It is anticipated they will resume in January, from what we have heard.

Part of what is happening is that the number of standards is being decreased from 130 to 100, and the revised process is supposed to be more VA-friendly. It was felt that the accreditors were not, in fact, very sympathetic to the institutions and that any deficiency on any one of those standards flunked people.

Now accreditation might affect a number of the concerns and problems I raise, such as resources for IRBs, some of the conflict-of-interest issues by forcing policies, some education issues, quality control, but they, by and large, concentrate on the reforms about the IRB process. They cannot affect the structural issues and do absolutely nothing regarding collecting performance data.

I want to talk a little bit about legislative proposals, and those of you who know about these things are much wiser than I about these. But these are proposals. They're clearly going to get reformed as they work their way through Congress. They may never get passed. We know how these things happen.

But both Senator Kennedy and Representatives DeGette and Greenwood have introduced bills into Congress, and they overlap in many ways. They have some individual characteristics. All the proposals want to apply the federal regulations to all of human research regardless of the funding or the location of the research. All mandate investigator education. Both of the bills mandate disclosure of investigator conflicts of interest. They permit central IRB review for these multi-center trials, so that you don't have the repetitive review process, and they mandate collection of some basic performance data.

Senator Kennedy's bill would require accreditation of IRB six years after passage, and the DeGette-Greenwood bill talks a little bit about requiring institutions to provide some money for the IRBs and funding, although it doesn't actually say where the money is supposed to come from.

Now, again, these legislative proposals I'm sure are going to change as they evolve, but they do some important things, but they obviously have some deficiencies, again, when we look at all of the problems we have in the system. While they will cover all research regulations and they will shift slightly away from reliance on local IRB review, they do at least nod towards providing some resources for IRBs, address issues of conflict of interest and repetitive review process. There are still many issues they don't address, such as the larger ethical problems that IRBs are going to confront and need to confront.

Finally, OHRP, the federal oversight body, has undertaken several initiatives, including a quality improvement program and to get conflict-of-interest rules. As I understand that, the conflict-of-interest rules are awaiting the Department of Health and Human Services' final approval.

The quality improvement programs are an important self-assessment program for institutions where they provide a survey that institutions can do for themselves and see where they are deficient. This at the moment is sitting at the Office of Management and Budget and, as I understand it, hopefully, by the end of the month, will be approved.

They also offer some site visits to particular institutions to address particular problems, and they are beginning a program on continuous quality improvement, which I think is quite innovative. But this is really their form of accreditation.

The conflict-of-interest rules, at least as gone up to the Department, apply to institutions, investigators, and IRB members. Again, at best, many of these initiatives will concentrate on the process problems, not really on the structural, and certainly not on the performance assessment.

So those of you who know me as always being bold, a little reckless, I thought I might offer a more comprehensive reform proposal for this Council to consider and to enliven the debate. I, again, hasten to add that many of my colleagues at the NIH don't agree with me, but they think it is important to elevate the debate and to begin to consider all possibilities.

So I want to suggest an alternative reform of the current system that would have these qualities: It would extend federal oversight regulation to all research. It would abandon local IRB review. It would create Regional Ethics Board to conduct all independent review of research studies, monitor research, train investigators, and formulate ethical policies and assess the value of research studies. It would entrust to a federal agency coordination of these Regional Ethics Boards.

We imagine that the Regional Ethics Boards would be geography-based in this country, that there would be 10 to 20 to cover the whole country. They would have something like this structure:

Each Regional Ethics Board would have a number of Regional Review Committees. It would have a liaison between the Board and particular institutions. It would have ombudspersons to interact with research subjects, and it would have an Ethics Policies Committee that would develop comprehensive policies.

There would be a federal oversight body, as I said, that would coordinate and monitor the function of these Regional Ethics Boards. The federal oversight body would collect data, publish performance data, and I give you some suggestions as to what I think that data should include, so that sometime someone in this country can actually say something authoritative about the clinical research landscape.

Importantly, it would also coordinate the Regional Ethics Boards to share best practices, to share operating procedures and, I think importantly, share ethical policy reports, which we really don't have today.

At the heart of these Regional Ethics Boards I think would be Regional Review Committees. There would be multiple Regional Review Committees per Ethics Board, I think possibly specialized and focused, so you would have one on cancer, one on heart disease, one on eye diseases, one on infectious diseases.

At least a quarter of their membership should be lay people. They should meet very frequently, weekly, not monthly, and they should conduct all prospective reviews of research studies in the geographic region.

Importantly, I think each research study should be submitted to one, and only one, Research Ethics Board. The Research Ethics Board in the geographic region of the Chief Investigator should review the study, and approval by that should be sufficient for doing research anywhere in this country.

Importantly, I think one of the things we don't have, and I didn't mention this as a problem but I think it is an important problem, is we need an appeals process for any adverse rulings by a Regional Review Committee. If you are going to concentrate power, you need an examination of that decision.

So I would suggest that if a Regional Research Committee rejects a study, the investigators should have the option of appealing, and that the federal oversight body should assign that research study to another group.

Importantly, I think the Regional Ethics Boards would collect data from investigators and report the number of people approached to enroll in research studies stratified by key variables like race, sex, age, diseases, number of people who actually enroll, number of participants removed from research and the reasons why they were removed, number of people who stopped participating in research, number of people who experienced what we in the industry call grade IV and V toxicities -- that's serious, serious toxicities, usually accounting for removal, but not always -- number of participants who died in research.

I also think that these Boards would be responsible for developing educational material and educating all the investigators in their Region.

I think all of the Regional Ethics Boards should have to establish a Regional Ethics Policy Committee that would create a forum to examine major ethical issues arising in research. Again, right now we do that haphazardly. We do it on a national level, very distant from people.

The kind of problems or issues I have in mind are: Should we pay children to be on research studies? A lot of studies do, probably unbeknownst to you. What are the ethics of it?

What about xenotransplantation, transplanting tissues from animals to people? What about having children to provide therapies for a sibling, conceiving and having a child? These are big issues that we really don't have a sort of systematic forum for addressing.

These Regional Ethics Policy Committees should engage the public in thoughtful discussion of the issues and develop coherent, consistent policies. Again, part of the issue is to educate the public and elicit their views. They could convene public deliberations, develop a draft report that could be the focus of public discussion, revise the report, establish a policy, and begin sharing the policies. This is a way of bringing the public into these discussions, educating the public, but also developing policies in areas where we have no policies today.

We also think that institution liaison is important. If you remove this review process from institutions, you need to connect with them. So we think each Regional Ethics Board would appoint individuals to serve as liaisons with major research institutions and probably liaison with smaller research institutions and physicians who individually in their practices conduct research.

Their responsibilities would include coordinating submission of protocols, clarification of policies, feedback, alerting the Regional Ethics Boards about problems and deficiencies.

Finally, I think an ombudsperson is very important. Right now if you get a research trial, if you have a problem, the number on the research form given to you to contact is the principal investigator. That's the person who you contact. We think there should be an ombudsperson who provides an independent view, so people who participate in research can contact them about any concerns they have about a research study.

Now any reform is going to have a lot of problems. I, by no means, catalog all of them. But I think it is very important to keep some in mind.

Again, I have mentioned the distance from and resentment by investigators is possible. At least if it is in the institution, the people you resent are your colleagues. If it is 100 or 200 miles away, it is some bureaucrat. I think that can cause a lot of resentment.

The concentration of power, I don't have to tell this Committee, can lead easily to the abuse of power. That is definitely a potential problem.

Uniformity of policies among 20 Regional Ethics Boards can certainly lead to rigidity, and that I think is also a problem.

Finally, no doubt, some people are going to worry about the high cost of having multiple Regional Ethics Boards. Cost is always a problem. Clinical research in this country is estimated to be a $40-billion-a-year industry. That is the research part of it. It seems to me a few hundred million dollars is not too much to pay for protection, and that is probably what we're paying now, although it is very hidden.

I thank you for your time and attention and welcome discussion.

(Applause.)

CHAIRMAN KASS: Thank you very much.

The floor is open for discussion. Michael Sandel.

PROF. SANDEL: I would first like to ask one or two naive factual questions, and I may be the only one who doesn't know the answer to these questions, except maybe my friend Gil. I hope maybe he doesn't either.

(Laughter.)

The IRBs, as they currently exist, that's only for federally-funded research?

DR. EMANUEL: It is a little more complicated than that. It is for federally-funded research and research that is seeking to get FDA approval for device or drug.

Now the federal oversight body has used its authority to mandate, to create agreements, for example, with Harvard that any research done at Harvard, even if it is not NIH-funded or if it is not seeking FDA approval, will still abide by the rules. But those are voluntary agreements. There's no law that requires them.

Furthermore, there is a lot of research, research that's not seeking FDA approval, like on dietary supplements; research that is not NIH-funded, such as many reproductive research studies, that don't have to abide by those regulations.

PROF. SANDEL: If there's a private company that doesn't take federal money, they don't have --

DR. EMANUEL: And not seeking FDA approval.

PROF. SANDEL: They don't have any IRB?

DR. EMANUEL: They might.

PROF. SANDEL: They might?

DR. EMANUEL: They might, but, again, the issue is whether they are legally required to.

PROF. SANDEL: And the people, let's say there's some biotech company someplace that has an IRB. Can they just appoint employees or do they have to appoint certain people to it?

DR. EMANUEL: Usually companies don't appoint or have their own IRBs. What they do is they contract out with proprietary or for-profit IRBs, some of which are probably the best IRBs in this country actually. So there is a private IRB market out there, as it were.

PROF. SANDEL: And it only applies to research on human subjects? IRBs don't deal with ethical questions of research apart from research on human subjects?

DR. EMANUEL: Right, and human subjects are defined in the regulations. They, for example, don't include dead people, are not human subjects.

PROF. SANDEL: And just one last question: This is no longer now in the category of the naive factual questions, but about your proposal. The thing you're proposing, that would apply, that would look at ethical questions beyond necessarily human subject research?

DR. EMANUEL: That would depend on what's crafted, but it seems to me one of the -- it would certainly be more than enough ethical questions regarding human subjects research. Importantly, how human subject research interfaces with many other aspects of clinical care and society are important issues that we haven't looked at.

The inclusion, in our view, of the importance of examining what we call social value of research, that's widely considered to be part of the ethical requirements of research. It would be wrong to do research that has no social value. It's now currently not systematically looked at at all.

PROF. SANDEL: And for your setup, are you only interested in the ethics of research, human subject or otherwise, or are you interested in the ethics of biomedical practice, and is there a clear distinction between the two? The reason I ask is that you gave the example of people conceiving a child for a blood match or a bone marrow match, or conceivably, as we'll discuss later, sex selection.

Suppose an IVF clinic wants to engage in various practices like those, not research practices but clinical practices. Would your proposal cover those, too?

DR. EMANUEL: You're getting to the issue of what distinguishes research from practice --

PROF. SANDEL: Right.

DR. EMANUEL: -- and there's not a -- I mean there's some stipulative definitions, but it's an open question as to exactly what the criteria are.

Certainly the early cases of conceiving a child for therapy were done on research studies. My current conception is that this is related, ought to be related to research, but, obviously, the considerations and the rules that you set down and the research setting would have some moral force, it seems to me, to extend beyond.

One isn't going to engage necessarily in some of these things in the clinical setting before you do it in the research setting. So it's very frequently, it seems to me, that you will address or at least confront the issue in the research setting before you get to the clinical practice setting. Certainly you ought to.

CHAIRMAN KASS: Let me follow on this, too, Zeke. I mean, I'm mindful of the fact that the talk is about the reform of existing institutions that are problem-ridden, and much of what you say in the proposal and the summary makes sense to me. But what's missing in the discussion, and what is somehow tacitly assumed, is some notion of what the goal of the IRBs or of your Regional Ethics Boards would be. If they remain defined as the protection of individual human subjects of research, then it seems to me you have -- I don't mean inappropriately, but you've limited only one piece, you've limited off only one piece of the larger ethical issues that, for example, concern this body. Point one.

There is for many people a sense that the crucial ethical issues in biomedical technologies are, in fact, the research ethical questions, and one will try to force almost all of the other questions into that model, and we had our hand at that actually earlier this year.

But if you then go on to say, as the statute does, that what you mean, what you're looking at, the protection of individual human subjects, that you will consider risk-benefit analysis, that you will consider questions of subject selection, and that you will see to it that there is informed consent, that is a further narrowing even perhaps of what it is you want to consider when you're taking account of individual research subjects.

So the large question is, the largest way to put the question is, assuming you wanted to design a system that would in fact protect the individual subjects of research in as rich a way as you can, would such an institution devoted to those goals be reasonably expected to address some of the larger social and ethical questions or do we need something different to do that?

DR. EMANUEL: I don't think I said anywhere that these groups should limit themselves in the way that current -- that we simply should take the way current IRBs limit themselves to individual research subjects and simply protecting them as necessarily the paradigm. I don't think I meant that, and I certainly don't take that to be the case. I'm very much on record in getting at, among other things, concerns about how research affects communities. It's very important and underplayed.

Second of all, it seems to me that many of the questions that ought to be taken up do go beyond a narrow conception of either risk or subject selection. Let me just point out the way I conceive it, and maybe we're talking here a little orthogonally.

If you take the question of, should we pay kids to participate in research, now you can conceive it very narrowly, but you can also conceive it much more broadly. How does it express how we value children in our society? How do we understand the relationship between kids and their parents, if you pay the child independent of the adults? What kind of payments communicate different things? What's their both material and symbolic value?

It seems to me you can't answer those questions in any narrow way, and part of my alluding to the kinds of things that I think are on, or would have to be on the agenda, this is a burning question for lots of IRBs, I take it, I know, in this country.

I would tell you that there are probably only two things written on paying kids in research. We've written one of them, and the American Academy of Pediatrics has written another. Actually, the European Union has a third. But that's it. I think discussing the underlying values of what you are trying to achieve in policies is absolutely critical. That's part of the reason for having an ongoing body.

Similarly, other topics that would have to be taken up that are burning issues today have broad social meaning. For example, what are the obligations of researchers from this country who are going overseas to developing countries to provide medical care beyond the end of their research for the people who have been involved in their research studies? And maybe not just on the disease that they've looked at, but on other diseases. How long does that occur? Who is supposed to shoulder the financial obligations? You cannot answer that kind of question in a very narrow frame of just protecting subjects.

Third, it seems to me that when you include the notion of assessing the value of research, the social value of research, you go to the heart of the question: Why are we doing this? One of the things we have certainly learned over the last decade or 15 years, and I think was alluded to by Professor Dresser, was a lot of the research we had structured was very narrow, you know, assessed only white males between the age of 50 and 59, and had no greater social implication, or couldn't be extrapolated without significant danger.

How we understand the research we're doing, make sure that it is maximally valuable to society, I think is very important. Again, it is widely recognized as an ethical requirement for research and simultaneously widely ignored in any review of research. It seems to me that's exceedingly important for us to examine.

So I think it is hard to see how, if you take one of these issues seriously, if these Ethics Policy Committees took it seriously, how they would stick to the narrow question of just protecting individuals. Almost all these questions open up larger questions of social values.

CHAIRMAN KASS: Just a very brief followup: It does, then, seem to me that you've got enough trouble, I suppose, peddling this proposal as it stands, but I think it would be enriched if it began really with an articulation of the kinds of things you're now saying, where you somehow talk about your perception of what it actually means to call something a Research Ethics Board as opposed to saying Institutional Review Board, and to make some of these tacit goals explicit and call attention to what might be different in the overall ethical and social intent of this, I mean if you mean it.

DR. EMANUEL: Yes.

CHAIRMAN KASS: So that it becomes -- people will see really what's at issue. They may not like it. The individualistic focus is very prominent in the society; communitarian perspectives have an uphill battle. But, nevertheless, it does seem to me that the proposal itself could be enriched upfront with some kind of discussion that doesn't begin just that there are dissatisfactions with the way the system works, but to talk in a more positive way about what one is trying to accomplish.

PROF. SANDEL: Okay.

CHAIRMAN KASS: I'm sorry. Charles and then Michael.

DR. KRAUTHAMMER: Michael Sandel said he was asking a naive practical question. My job is to ask the naive philosophical questions.

Why regional and not national? I know that obscenity is defined locally and regionally in this country. Is ethics also defined that way?

DR. EMANUEL: Well, I think moving to a national body would be, for practical reasons, unwieldy, just sheer volume and considerations of that. I think many of the standards are universal and aren't particular to a region. So part of the regional focus is a practical focus.

It is also an attempt to try to avoid the rigidity problem. While I think having 4,000 to 6,000 IRBs is probably more akin to chaos, having 10 or 20 think through some of these problems and some of the implications is probably a good way to keep the pot stirring and keep innovative ideas.

I think in this country I don't have to tell you, a better historian of American culture than I, national things obtain a lot more resistance than even local things.

One of my colleagues did ask a similar question, which is, well, then, let's look at the Ethics Policy Committees, why are they regional and why that could be national. I would consent to that.

DR. KRAUTHAMMER: Am I overinterpreting you to say that this is more of a political, practical, what-is-feasible consideration rather than philosophical? If you were creating a system from scratch and had no political constraints, would you have any -- is there any reason in principle, other than the idea of the laboratory of democracy, different regions learning things and teaching each other, other than that, which I think is a consideration?

It would seem to me more logical, if you were going to have a set of ethical regulations and people applying them, that it would make sense to have one system or at most one or two or three regionally. But I don't quite understand, other than what you're saying, that it is politically impossible to go the other way. In principle, would it not be desirable to have as few as possible?

DR. EMANUEL: I guess I am somewhat of a student of political history. Concentration in one place I think does tend to ossify. I think that is not a trivial concern here, especially as research progresses in some areas. I am not a big believer that it raises, you know, the argument that it raises new questions, but it certainly puts them in different lights and makes different kinds of challenges.

I think in that light, having everyone having to troop to Washington or Chicago or something, it is probably a much better idea to have different places looking at things.

DR. KRAUTHAMMER: Could I just have one quick followup? So, in practice, if you have an investigator who's headquartered, say, in Boston, under your proposal he goes to the regional one there, but he might involve a hospital in San Francisco that is operating under a different set of rules. Yet, that protocol, as practiced in San Francisco, would have to adhere to the Boston rules rather than the local rules. Wouldn't that lead to all kinds of jurisdictional problems?

DR. EMANUEL: It might lead to jurisdictional problems, but I think I don't see the different rules per se; there might be different interpretations of some rules. But, again, I think that's possible, but it is a problem that is better lived with than either the current system or one system.

PROF. SANDEL: I hadn't thought about this before Zeke's presentation, but one argument in favor of having Regional Ethics Boards might be to allow not just a laboratory of democracy, diversity for that reason, but different arguments to be developed and positions taken on ethical questions, analogous to the way it works with federal district courts and courts of appeals.

Now there is a Supreme Court. And one question you might have put to Zeke was, why not have a Supreme Ethics Review Board to handle the appeals rather than some other regional one, which is what I thought you were going to ask?

But there is currently the law now, as a result of regionally-based federal courts of appeals, that you are allowed to count race in admissions to law schools in Michigan but not in Texas, because the courts of appeals have come out with different positions on affirmative action. The Supreme Court could take those cases up to resolve it, but so far they haven't.

There is something to be said -- I don't know if it is enough to be said -- for having debatable questions like these medical ethics questions and like affirmative action be reasoned and debated differently by different regional courts.

DR. KRAUTHAMMER: But, Michael, that structure really only makes sense because you ultimately do have a Supreme Court which will in the end adjudicate on the critical issues. If you didn't have that, you, I think would agree, that having a system, a legal system in America of circuit courts and no Supreme Court would be incoherent and ultimately hard to defend.

PROF. SANDEL: Well, incoherent I'm not sure. There are those who defended the federalist system who would say there's something to be said for that degree of decentralization.

But you could add to Zeke's thing a Supreme Ethics Review Board.

DR. KRAUTHAMMER: But you would have to find a better name.

(Laughter.)

CHAIRMAN KASS: Mike Gazzaniga.

DR. GAZZANIGA: There are efforts going on, or about to go on, to address some of these things. I know that Dartmouth just received a large grant to start a database of all the IRBs that are funneled through the NIH. So some of these coordination efforts are started.

But I have three questions for you. One, are you knowledgeable about any cross-cultural models that might help us think about this?

Two, have you really thought about the time to study? I'm the clinical investigator who uses the current system, and I'm about to inherent your system. Have you thought it through to what's involved there?

Three, a little more thought, apparently, you're in total agreement on this, but the monolithic problem of an agency with an ethic. If I have learned anything in the last six months, there's no one ethic; there's all kinds.

The ossification you talk about I think is a huge problem. Science, for example, if it only had one vendor, one source for all money, the beauty of the process would come to a screeching halt.

Lastly, I don't think that local control is all bad. I see in our IRB process that people learn quickly who is responsible, who are good. Whereas, if we mailed this off to somebody in Manchester, New Hampshire, or to Boston, or whatever, it sounds like a nightmare.

So, as a friendly skeptic, maybe you could comment on some of those.

DR. EMANUEL: First, in the cross-cultural models, all through Europe there's different models. Some countries have a national system, like Denmark. Some countries have a regional system like this. I think it is fair to say that there is a European directive now; they want to facilitate review, and review is in a few years going to be required to be 60 days, no longer than 60 days.

Places like The Netherlands are fulfilling that review by basically getting rid of all IRBs at the bottom end, that don't deal with a lot of protocols, don't have a lot of experience, don't have a lot of standard operating procedures. They've acknowledged that essentially it is going to be a regional system.

Second, I think we actually have home-grown examples of how this might work. The proprietary IRBs are, in fact, a model of a regional IRB system. At least in this country, as I alluded to, they are quite good.

Now those people who are at academic centers I know are quite skeptical of this, but, in fact, we have some good data about that, because every time the federal government closes down a major research institution like Hopkins, they don't send their protocols from Hopkins to Harvard; they send them to Western IRB out in Olympia, which is a for-profit, proprietary IRB, which they think is good not just to review them, but also to give Hopkins and other institutions ideas about how to reform their system and remodel it.

Now if you look at the Western IRB, unlike most institutions, they actually keep track of how long between submission of a full protocol and actual action occurs. Their time on average is 10 days.

I worked at the Dana-Farber Cancer Institute in Boston. We couldn't get the 10 days to even get in front of the IRB, and I'm sure at your institution it's no different.

So if you want to know, could it be more efficient, could a regional system actually work, and would it be better than what I live with, the answer is we actually have models that suggest it is true. Now one of the virtues of these big regional models is the Western IRB has 210 employees doing all the background, you know, the back-room work, as it were. I don't know what yours at Dartmouth has, but most IRBs have two-three people even that are considering a thousand protocols a year. So that can be a substantial big difference. I think, yes, they are going to be distant from you, but, on the other, they are also going to be -- they might be more efficient.

As far as the single ethic versus multiple ethics, I think it partially does draw into the discussion back and forth between Charles and Michael. The fact of the matter is I am sympathetic to your view. I don't think there is going to be disagreement on some of these very, very tough issues.

I think one of the things we don't have in the current system is an established, systematic way for addressing these issues and discussing them. So you raise the issue of paying kids for participating in research. You get a lot of gut reactions, and I can tell you what the gut reactions are. Absolutely no, it's wrong.

But you don't have a lot of reasoned thought about it and reasoned argument. Is it wrong because you're exploiting the kid? Is it wrong because it symbolically suggests that kids are to be used? Is it perverting their incentive structures, et cetera, et cetera?

It seems to me that part of what we do need in the system are much deeper ways of thinking and developing those arguments and considerations, laying them out, and seeing how we think about it.

One of my other hopes, which I actually didn't emphasize, is, you know, some of this actually is not just theoretical arguments. It actually might depend upon data; you know, what does the practice lead to? Are people more callous?

I mean, I heard earlier when someone asked the question, well, you know, in the current research, if people don't identify, do we get a lot more poor and ignorant on research? Well, it might be good to know the answer to that question.

We don't even know the answer to the question that the Council was debating in the morning: Do people identify with the research studies they're on or not? We assume somehow that they don't. Well, there's at least some evidence that they do, but it's not great evidence.

Anyway, I think a large part of -- I mean, there are multiple considerations. In a pluralistic society we are going to have debates, but on some things I think we might actually come to some good consensus, and on other things at least we could come to some greater clarity about what is at stake. Again, I guess Charles' fear is different places might do different things. To some extent, that might be good, and we might see the consequences of that.

DR. GAZZANIGA: You wouldn't be opposed to this being run by the private sector then, from your lionizing of the Western --

DR. EMANUEL: Well, let me step back. I do think Western is a great model actually, and I ought to say here that I started out being a skeptic, went out there, and its president now is a colleague and a friend of mine. I think she has a great thing going, and partially because she has been quite dedicated single-mindedly to it.

I'm not sure turning it over to the private sector is necessarily the way to go. I do think the private sector ought to contribute, since pharmaceutical and biotech companies do a lot of research, but so does the federal government. Like everything else, it is likely to be a public-private partnership because it's got virtues on both sides.

CHAIRMAN KASS: Janet, please.

DR. ROWLEY: I just wanted to say that at the University of Chicago we've gone from having a single IRB with 15 members to three IRBs. They do meet monthly, but now we have 45 of our faculty plus lay members involved in this. I just wanted to add that because you mentioned that one or two or three, or some such, as a number of IRB individuals involved at some institutions. Rebecca was saying, I guess, at WashU they've got four IRBs going simultaneously to meet the increased demands.

DR. EMANUEL: Let me just clarify what I was commenting on. It wasn't just two or three people on the IRB. Yes, most IRB panels are good size. Especially at major research institutions, 15 is not an unusual number. It's the back room that I'm talking about, the people who are actually monitoring, say, the regulations and trying to understand how they apply or monitoring the literature to try to understand how new thinking might apply to research, or actually getting the protocol together and overseeing and collecting data like adverse events. Those tend to be starved areas, areas that don't get a lot of resources and I think actually are quite important for protection, for actually thinking through the system.

Because, let's face it, most IRB members have lots of other jobs; this isn't their primary function. They're not bioethicists. When an issue of, you know, this protocol says they're going to pay children $1400, you know, they're going to make a gut reaction without having thought it through for very good reasons. No one at the IRB or in the institution, might I say, and dare I might say even in most of the country, has really thought it through.

DR. ROWLEY: And I just follow up on that in terms of the back room, which I have no way of knowing right now how many we have. But these are costs that are actually borne either by the medical school or the hospital, which you alluded to, and you're saying, well, you get a certain amount of indirect costs and so some portion of your indirect cost is allocated to trying to compensate for this. But as these costs increase dramatically, it does make it extremely difficult to do this with the funds available.

DR. EMANUEL: Right. I agree with you 100 percent. The current system isn't made to support it.

DR. KASS: I have Rebecca Dresser, then Gil, Bill May, and Paul.

PROF. DRESSER: I think on this issue of how much diversity among regions or localities we would want, it would get stickier the higher up we go with sort of broad policy issues and value judgments, such as if one region says, "Well, xenografts the risk is worth the percent of benefit," but another one doesn't. I think that could be problematic. Or say, getting to this afternoon, one region says, "Well, any more new drugs on sort of cosmetic psychopharmacology, those aren't justified," you know, that could create some difficulties. But that was just a sidebar.

One thing I would add, which you talk about publishing policies, and so forth, I think we also need kind of a common law system. We need IRBs who wrestle with difficult cases to then publish them, and I think that would be excellent. Because there really are a lot of these conflicts that can't simply be resolved at the legislative level. I think IRBs need to see how different ones handle these things.

I guess the final comment I would have is, I really agree that the way the human subjects' protection system has been applied has left out a lot of the more crucial values conflicts, which I think underlie a lot of things. Belmont actually gets to a fair number of them, but then they sort of were left aside.

For example, I think so many judgments, say on the value of studies, the regulations say the risks have to be reasonable in relation to the benefit in terms of the knowledge that will be advanced and any direct benefit, if there is one. That is such a value judgment.

When we talk about reasonableness, in law we are talking about the jury system, you know. They also refer in there about, when you're talking about how well-informed should people be in making a decision to be in a study, well, we could talk about the standard of the reasonable subject. These reasonableness judgments are throughout.

You talk about 25 percent lay people on your Regional Boards. I don't think that fully gets to this problem of, how do we inject the democratic element and input from people who are not part of the scientific enterprise or the academic enterprise?

Robert Veatch wrote a really good article back in the seventies alluding to some of these things. He said, basically, everyone in universities is convinced that advancing knowledge is valuable. As somebody who works at a university, I certainly buy into that.

However, not everyone in this country takes that point of view. If we are talking about a democratic process, we ought to have that point of view.

So I think it is not just a matter of what percent of public representatives, lay people, you have on; it is also a matter of: How do those people get educated? How do we get people on there who are not intimidated and who don't learn everything from the people who are part of the establishment, which I think is often the case now, and really can represent an independent point of view?

I actually think there are good patient advocates out there who are knowledgeable enough, who are skeptical in ways that I think are healthy, who might be able to help out here. But I think that is something that is not so much addressed in your proposal.

DR. EMANUEL: Let me first go to the point about case law, which I think is absolutely a great point: that if you are making lots of ethical choices, and there are hundreds to be made in this process, you need some way of sort of recording them, being consistent, having some institutional memory. That is impossible, it seems to me, with 4,000 to 6,000 IRBs running around the country, all basically on a starvation financial diet.

It becomes much more reasonable when you have 20 or something and you have a coordination system. Coordinating 20 is a lot different than coordinating 4,000 or 6,000. Part of that coordination is sharing things like policies and practices and decisions.

Second, I'm not sure -- and I would love to have your ideas on it, and everyone else on the Council -- I agree with you it's very important to have people who have some independent thinking and can think who aren't necessarily wedded to the research enterprise or don't get their daily bread from it, but are thoughtful about it. Other than specifying numbers, it is hard for me to figure out what you do to engender that democratic process.

Now we have tried, one, to increase the numbers so they are not isolated and they are not intimidated necessarily. Another element that we have tried to include is to try to think through how an Ethics Policy Committee might actually involve the public and create focus for discussion.

I think my at least peripheral or cursory look at the way Britain handled much about the cloning and stem cell issue is, you know, there over the course of about 15 years they had a report. They had a lot of public discussion about the report. They had a second commission looking at things.

First of all, it was an expanded period of time, but also there was a focus for discussion. I mean, if we just talk about some of these ideas without a focus and without someone presenting a paper, I mean, it seems to me one of the -- I don't want to speak for Dr. Kass, but one of the reason to have a paper at the start of a discussion is to provide a focus for thoughts on the matter at hand, but we don't have that system currently.

We have commissions coming and going, reports sort of collecting dust because they haven't really -- there's no ongoing continuity. There's no actual implementation to test out the ideas, see what the problems are, revision process.

So while I am sympathetic to your concern about having a more open process and having people who thoughtfully engage, it seems to me very hard to figure out, other than the sort of structural and procedural elements, how you actually guarantee that.

CHAIRMAN KASS: Gil?

PROF. MEILAENDER: Just a question for a little more information about -- and I suddenly find myself blanking on the name. Did you call them proprietary IRBs?

DR. EMANUEL: Yes.

PROF. MEILAENDER: You said we have several illustrated examples of these that are really very good, although you only mentioned one. But what makes them good? The only thing I've gotten so far is it sounds like a resources issue; namely, that they hire a bunch of people who do the kind of legwork that is required. But is there something more than that? That is one thing I want to know.

Then kind of where do their ethical principles come from? Do they just tell you how to apply the Common Rule? I mean, are they doing independent ethical thinking? So tell me a little bit more about what makes you think they are so good, and especially ways that extend simply beyond resources, although maybe that is the answer; I don't know.

DR. EMANUEL: Like almost everything else, I think there's a lot of reasons that make Western and a few of the others very good. One is certainly leadership and dedication to doing the right thing, and believing that by doing the right thing, you'll be successful, and in their case profitable.

I do happen to know the, I guess, presidents -- I don't know exactly what their titles are -- of several of them. They really are dedicated to doing the right thing, and they actually created their proprietary ones because many of them started out in institutions and found that there were limits.

Now some of it is resources. If I did have a criticism of these places, I think one of the criticisms is that they don't do enough sort of independent ethics thinking.

At Western, which is by far the big gorilla in this area -- I mean they are the dominant player -- they have, I think, four to six people dedicated to their regulatory office, which isn't just looking at regulations, but does scan the literature, read articles, try to understand the impact of articles for the protocols they are reviewing.

For one thing, that I think is admirable. It is certainly more than the several IRBs I have been on do. But I think it is inadequate. I have sort of chided the president there about they have a wealth of information and knowledge and experience, and maybe they ought to be developing their own ethical guidance. I mean, they do have many standard operating procedures which embody some ethical values on these complicated issues.

But I think that the final thing I would say is they actually may have an advantage in being institution-independent. This might sound a little heretical. They don't have to kowtow to any one place. As long as most of their money doesn't come from one pharmaceutical company or one organization or something, they can think independently of how things go.

Actually, an institution-based, you know, part of what they think about is, how is this going to affect the institution? You know, if I keep turning down those studies from Merck, they're not coming back to us. If we keep turning down the research of one of our investigators, it is hard for him to get NIH grants or her to get career advancement. There are those considerations. It seems to me you don't have any of that in an independent IRB.

So there may be some structural things. There are certainly some leadership things. There are certainly resource things. But are they perfect? No. Do they provide a model for some of what I have suggested? I think so.

But I do agree with you; I think if you are going to investigate big ethical questions that have large social ramifications, many of these places are hesitant under the current system because they don't think they have the imprimatur to do it. Certainly our regulations don't encourage it. If anything, they discourage it.

I quote in the paper some of the language that says, you know, limit very carefully what you're allowed to consider, which I don't think is quite proper and certainly it limits how you can really ethically evaluate the protocols.

CHAIRMAN KASS: Bill and then Paul, and we're coming up to a break.

DR. MAY: It sounds like a budgetary question. You have mentioned $200 million to mount this Regional Board system. But I am interested in what kind of people you would be calling on here. You said they would meet every week, and if it is regional, it doesn't mean you slide into another office in the hospital; you may have to go out of town, come back into town.

DR. EMANUEL: Uh-hum.

DR. MAY: Institutional Review Boards I have been a part of were largely pro bono. Now you are talking about an amount of time invested. Are you really thinking about a shift from pro bono work over to paid staff and some kind of mix of ethicists and people out of institutions? The regional problem is it is more convenient to get people still in the city, where your regional office is located.

But I think the basic problem here is not whether we go with, one were to go with, for-profit institutions, but the whole shift over from volunteer to paid staff seems to me to be a fundamental issue. There are two ways of conceiving it.

One is a staff that has preset standards and then efficiently applies these standards. We know about that even in academic institutions, which have committees, which are largely janitorial and custodial.

(Laughter.)

I mean they apply what is already preset, and even curriculum committees in universities like this, they process that material.

The other way of looking at a Regional Ethics Board is to think of a deliberative body. That is a very different kind of activity. I am wondering how you build that in, especially since it seems to me you are moving in the direction of a paid staff of specialists as you move toward a regional solution to his problem.

DR. EMANUEL: Let me take the first part.

DR. MAY: May I add just one point? The local problem is conflict of interest. What you may end up with is flagging of interest. That is another kind of problem that leads to inadvertent inattention to issues until you get a public crisis that comes along, and then people get very excited about it. That flagging of interest seems to me to be another dimension or problem that one has to think about.

DR. EMANUEL: You are describing Washington, I take it.

(Laughter.)

DR. MAY: Well, I am thinking of some corporations as well, their boards of directors.

DR. EMANUEL: Let's take the first problem. It certainly seems to me that we are going to have to have more professional staff, but I would not want the Review Committees to be professionalized and bureaucratized. I think that would be a disaster.

DR. MAY: So they would be a staff serving the Board?

DR. EMANUEL: Yes. I think, again, in most academic institutions I have been a part of, they undervalue that, minimize its importance in proper and efficient functioning.

Nonetheless, I think if these Boards do meet weekly, the question is, could you maintain a voluntary or at least nominally-paid group? Again, institutions now are having to go to pay their faculty to serve on these things because they are a big-time commitment. So it is not even voluntary there.

Second of all, if you do look at the Western model, which I have suggested here might be very instructive, they actually get people for $150 a day. They meet four hours for the day, separate from reading the protocols, which is at least another four to eight hours. They re-evaluate these people each year. They are not making money, these people, by participating in this.

They have a number of physicians who want to do this to stay intellectually active. They have a number of scientists who want to do this. They have a number of just interested people in the community.

We haven't experimented or seen how big an interest there might be in doing this, and we assume that the options are voluntary or a full-paid staff. I think that this is a very rich country, and volunteerism, even for nominal pay, is something that people do, and for adults who want to stay intellectually active this may be very interesting.

I think, again, I don't like the model -- we are trying to create a hybrid model. There's clearly some things these groups are going to have to do efficiently.

I have estimated that there's something like 40,000 research protocols per year in this country. It seems you can't grind the system to a halt; we're going to think deeply about every single thing. Some of it has to just be applying rules.

On the other hand, we do need a system where we do confront serious issues or we confront issues repeatedly that raise deep ethical questions. We need a system for figuring out how to reason about those. That is why we suggested sort of differentiating those kind of functions into different kinds of committees but having them under one rubric, so that there is a lot of cross-talk. That is our view of how it would go.

I am under no illusion that any single Regional Ethics Board with a regional sort of Ethics Policy Committee could address all the issues that come up. I mean, there are just an unbelievable number of serious issues and new issues or issues again coming to the fore or we are being alerted to all the time.

But it does seem to me it needs to be systematic and ongoing rather than sort of what we have had for the last 25 years: start-stop; cancel that commission; put its findings on hold; get another one. They are going to take up a different set of issues. No continuity, no way of implementing in policy/practice any of the decisions.

CHAIRMAN KASS: Paul McHugh?

DR. MCHUGH: I was very interested in what you said and the series of problems that you think your proposal will address. But what I haven't heard is how you think some form of institutional review is going to coordinate with the responsibilities of NIH study sections, which are, after all, peer-reviewed and protocol-focused.

You, quite rightly, criticized the Johns Hopkins issue of having overlooked a piece of important results and research prior to the submission to the IRB, but I also want to point out, as you should, that the peer review study section also had passed that and the like.

If the issue that these organizations need is a better back room where they can study the literature and back it up, well, isn't that what the NIH study sections are supposed to do with their peer review, protocol focus groups?

DR. EMANUEL: Well, I can safely say that I have never received an NIH grant, and that entire process is a complete labyrinth, of which I don't understand anything.

(Laughter.)

DR. MCHUGH: It is a terrific group. Having been a chairman of one of the study sections, I am very proud of it. I think it is a great achievement for the United States.

(Laughter.)

DR. EMANUEL: I wasn't criticizing it. It is just I don't understand it. It is a little different. And I don't understand --

DR. MCHUGH: Well, you should. You should understand it.

(Laughter.)

DR. EMANUEL: -- how exactly it should interface with this. I think that is probably another whole area where the current system is just as opaque as our suggestion and probably needs a little more thinking. But there is re-review of science there, and that is obviously a very important element of good research, but it is far from the only element.

DR. FOSTER: Just one quick question: We have talked about the changing culture. I also chaired a study section, sat on the Council, and so forth, but that culture has drastically changed. So that now study sections do not look just at the science. They look at the priorities. It is a very different system. I don't know of a better system, but it is drastically different from your glory days than what it is now.

So even the time for the number of protocols is greatly enlarged. You are worrying about budgets. You are doing all those things. So that would take back-room people there, too.

CHAIRMAN KASS: Well, I want to thank you, Zeke, for a very stimulating talk. I would hope that we might down the road call on your help as we continue to talk about this regulatory question, and in particular the kinds of questions, not just the mechanical things which were the subject of very interesting discussion, but also the large issue, for example, that Michael Sandel and I tried to raise with you at the beginning: To what extent this can be, for this Council, a source of practical hope for the kinds of questions that we have been addressing?

Perhaps as this paper evolves, if you might see fit to try to address that, or maybe we can have you down to the office for further conversation, it would be very welcome.

But thank you very much.

We are adjourned until -- what is it? -- until 1:45, when we will meet to have some discussion of happiness and sadness and pharmacology -- if that's not the wrong way to characterize that.

(Whereupon, the foregoing matter went off the record for lunch at 12:20 p.m. and went back on the record at 1:50 p.m.)

CHAIRMAN KASS: All right, the two sessions this afternoon are sessions on a particular case study under the general heading of our inquiry into what goes by the wrong name of "enhancement," defined for now as possibly non-therapeutic uses of biotechnical power to alter by direct intervention the, quote/unquote, "normal" workings of the human body and psyche, whether by drugs or genetic engineering or other manners.

Our interest in this stems from the fact that we sense that these uses of these powers may raise some of the weightiest questions of bioethics, touching on the ends and goals, on the nature and meaning of human flourishing, and, at bottom, questions of humanization, super-humanization, de-humanization, and the like.

It has been a rather neglected topic in public bioethics, and yet it is, some of us think, one of the deepest sources of the disquiet that people feel about these new capacities, represented in remarks about man playing God or "Brave New World" or post-human future.

While this topic is hard to get a hold of, especially if you look at it across the board, we have decided at least to have a go at it, because if not us, who? It has not yet been taken up by any of the previous councils. It has been a subject of interest in the bioethics literature. We do have the freedom and the opportunity to step back from some of the potboiler questions of the sort we just finished to have a look at this field as a whole and see if we can develop some useful means of talking about it.

Nevertheless, rather than go at this in the abstract, we have decided to proceed case by case and look at a series of areas where these kinds of questions might come up. Over the next several months we will be inviting people in who have worked in these various areas to tell us what the new powers can do, how they are now being used, what the reasonable and unreasonable uses might be, and what we might expect in the future.

We have in October already lined up people to come talk about pharmacological modifications of memory, both to enhance and to erase. We have Francis Collins coming in December to talk on the possible enhancement uses of new genetic technology. We have people coming to talk about Ritalin, and we are in the process of getting people to talk about work going on in the biology of aging, as well as in choosing sex of children.

So looking both at the genetic and the pharmacological end, we will over the next three months try to educate ourselves as to what is going on and what this might mean. In the course of doing that, staff will try to develop some of the analytical tools.

One of the great difficulties in this area is to learn how to talk about them, and especially when you are dealing with things like the so-called higher human functions, it's especially difficult. It is for that reason that we are really very fortunate to have with us this afternoon two people who not only know the science and the clinical practice, but who have given a lot of careful thought precisely to this question of: How do you really begin to talk about this topic?

We are delighted to welcome Dr. Peter Kramer, who is Clinical Professor of Psychiatry and Human Behavior at Brown University and the author of Listening to Prozac, and Dr. Carl Elliott, who is Professor in Philosophy and in Pediatrics as well as the Director of Graduate Study at the Center for Bioethics at the University of Minnesota and author of a forthcoming book, Better Than Well: American Medicine Meets the American Dream.

Welcome to both of you. We are delighted to have you here.

We will divide the sections up as scheduled with Dr. Kramer going first. Dr. Elliott will speak in the second half, but in the discussion of each other's papers we would like to invite both of you to feel full members of the panel and join in the discussion.

DR. KRAMER: I am honored by this invitation, not a little daunted to speak before such an accomplished group of people. I got a phone call from Dr. Kass only four or five weeks ago about whether I would come down here, and I thought it might be an advantage rather than a disadvantage to prepare quickly.

I am an academic only in a marginal sense. I do sometimes write academic papers. But it was a relief to know that I didn't have time to prepare a full paper with footnotes, and so on.

The call found me at a particular spot in my thinking about issues related to enhancement in depression. I had written about those in a book that came out in 1993, Listening to Prozac, which then led me into a number of subsequent discussions, including some hosted by Carl Elliott.

But really in the interim, in order not to be trapped by the success of that book, I had written two very different books, one about intimacy in couple relationships and the other most recent one, a novel, which is also a novel of social commentary.

So I had just come back to this issue. While I am going to be very comfortable reviewing with you some of the thoughts that I raised in Listening to Prozac, the overview of what has happened in the eight or ten years since is more in the nature of a work-in-progress. I hope you will allow me that, to have that sort of uncertain status.

I want, as regards to enhancement, to consider with you the case of depression or, rather, conditions that are not depression but resemble it and might respond to interventions developed to treat depression. For convenience, I am going to call those conditions, the ones that aren't illness, minor depression or melancholy, but I mean for those words to extend to very solid degrees of health, where people have complaints that relate to depression but no one would consider to be ailments.

I want almost to warn you off this topic; I think that minor depression is uniquely problematic among the indications for enhancement that you are likely to consider. We had mentioned ordinary muscle mass or ordinary forgetfulness, and certainly ordinary shortness has been considered for enhancement or ordinary states of declining sexual functioning.

I think that minor depression differs from these in a way which I will call a problem of value. That is to say that we can value minor depression, whereas I think no one is likely to value forgetfulness, or one is at least less likely to value forgetfulness than one is to value the traits that make up depression.

But before we turn to that special problem of value, I want to begin with a question of method. This is the topic that in Listening to Prozac I call "cosmetic psychopharmacology."

Now to step back half a second, that book is built around a sort of core vignette that involves what I call recursion. That is, a person who, say, had a legitimate medical problem, was depressed, or had a serious anxiety problem, is treated with a medication, gets better, comes off the medication, and comes back to the physician, say, months or years later and says, "I'm not depressed again. I don't have that legitimate medical indication for which I first came to you, but when I was on the medication I was a better parent" or "I negotiated better at work" or "I had some benefit," that is the kind of benefit that people do in fact claim to experience on medications. "Will you put me on the medication again?"

Later, in discussing this issue at some of these ethics and philosophy conferences, I extended this sort of thought experiment, which actually occurs in offices, to one where somebody was never ill at all. So that say a woman comes into the office and says, "I have all the characteristics of the melancholic temperament. I'm a little timid. I have low energy. I am easily derailed from my purposes. And I have an identical twin sister. We were raised in the same family, had very similar childhood experiences, and where we diverged is that she had an unfortunate love affair and fell into a deep depression, was put on medication, and not only recovered from the depression, but had these other benefits of appearing, feeling more sanguine and less melancholic. Would you put me on medication? Would you prescribe for me based on the likelihood that I might have a similar response to the one she had?"

Now in considering dilemmas of this sort, these dilemmas are answered often in terms of medication side effects or long-term effects of medication. There's a general belief as regards mood that what goes up must come down.

One of my teachers, who was also a mentor of Dr. Krauthammer, labeled this sort of belief "pharmacological Calvinism" or "Puritanism." It may actually be that the opposite is the case, that depression is so damaging an ailment that what goes down goes down, and that intervening quickly allows, raising the level of mood, allows for future good mood.

But, in any case, there is general resistance to medication under the belief that it will incur some kind of doom and is morally weak or wrong in any case. To me, those are interesting considerations. Certainly, if you think about enhancement, you will have to think about those concerns, but they beg the question of the inherent morality of enhancement.

To that end, I framed this definition of "cosmetic psychopharmacology" that is also a sort of thought experiment. I defined "cosmesis" as using medication to take a person from one normal state to another equally normal state that is more desired or better socially rewarded.

I stipulated that the imagined medication is not addictive and not even directly hedonic; that is, taking the medication is not enjoyable, though the results of medication may allow a person better to enjoy ordinary pleasures in the manner that other normal people already enjoy them, and that the medication has no side effects or only such ones as a rational person would accept in exchange for the expected benefit.

I wanted to ask, in that case, what are the moral issues attendant on offering the medication? I think the same considerations would inform a discussion of electronic interventions or genetic interventions, although this is cosmetic psychopharmacology because I began with the example of Prozac, which is a medication.

I wanted, through this definition, through this term, to eliminate most frivolous uses of medication. So, in other words, this is not people that want to get high or to enter a radically-altered state of consciousness, and to eliminate concerns of safety, matters where we would say the doctor knows best, and even some issues of evolutionary fitness or unfitness by the constraint of changing from normal to normal, so both conditions have passed the test of generations, and to clear the field for the very issue at the core of your current considerations: What are the most basic moral considerations attendant on enhancement?

Now I didn't frame this issue in a vacuum, but the inspiration was, frankly and openly, the introduction of the first selective serotonin reuptake inhibitor, or SSRI, in this country, Prozac. Patients reported on that medication that they felt better than they had ever before felt, that is, better than before they had taken the medication at all, perhaps better than before they had fallen ill. They use this expression that Carl adopted for his book, Better Than Well, which I take to be the same as this term "enhancement."

The manner of this improvement was different in different instances, but a shorthand description for what patients reported was that medication for them was like Garrison Keillor's powder milk biscuits, that the SSRIs lent them courage. They made patients less sensitive to rejection or loss. They occasionally lent them energy, allowed for greater optimism and social assertiveness.

In those patients who had suffered psychic injuries early in life, it seemed that they were more the way they had imagined they might be before the injury occurred. To use a political term, the medication was empowering, but it was worrisome on a different level because it was empowering in precisely the direction that the culture values.

The medication could be called conformity-inducing as regards a favored personality style for the modern woman, in particular, although that style includes a measure of assertiveness and potential for rebellion. That is, it was a model of the way we want them, a modern woman might be when she was admirable, but wasn't conformity-inducing in the sense that her behavior, her choices, would then be conformist or subject to influence.

This change was in response to a medication which, whatever its substantial negatives, had a side effect profile that was more acceptable than that of medications that had come before. Most patients didn't feel drugged or aware that they were on medication.

In Listening to Prozac, I detailed the reasons I had for suspecting that such effects might occur, that is, to give credence to these reports. In brief, at the first level the SSRIs worked through serotonergic pathways in the brain, and in other mammalian species serotonergic pathways appear critical not so much in the maintenance of mood as in the regulation of status hierarchy.

Again to simplify, alpha males have high serotonin levels, and in times of turmoil within the troop, animals premedicated with SSRIs are more likely to assume dominance. This is a very antique mechanism. If you look at lobsters that are closer to the food supply, apparently, they have a better serotonergic transmission than lobsters not near the food supply.

It seems to be both from clinical observations and from pre-clinical research literature that SSRIs' major effect might be in inducing an overall sensation of social well-being. As you know, some of these medications subsequently have gotten indications for the treatment of social phobia.

Whether it is true that in humans these medications have the effects I have suggested is a question that has never been properly tested, but there is one detailed study that appeared in 1998 that did find that normal people given Paxil were more socially adept when confronting a test challenge. They were given a very-difficult-to-solve problem, put in pairs, and the observers saw who was the leader in the pair and how they got help in solving sort of a tangram problem. Academic articles citing the experiment said that the effects that this experiment found were the ones that I had predicted.

Although we can imagine quite varied instances of cosmetic psychopharmacology, the test case I considered was this one that had to do with a movement along the personality spectrum from self-doubt to a sense of belonging or insider status or from melancholy to sanguinity.

I knew that observers might be troubled by such use of medication, and the question was, why? In fact, I was troubled by it. Was this expectable response psychopharmacologic Puritanism or Calvinism or did it have some inherent moral justification?

In considering this question, I began with the observation that for many years we have had an intervention that meets all but one of these standards of cosmetic psychopharmacology, and that intervention is psychotherapy. The standard that it fails to meet is that it is not a medication, although some recent research does suggest that in gross terms psychotherapy may work through brain mechanisms similar to those of pharmacotherapy.

That is, there are these studies looking at complicated brain imaging of people who have had either psychotherapy or medication, and after a few doses of each, the changes in the brain in people who successfully respond look similar.

We have no objection to a physician's conducting that intervention, that is, to giving psychotherapy for making a melancholic person, say, more sanguine. Indeed, part of what seems eery or uncanny about the new medications is that they resemble psychotherapy. This is so both as regards psychotherapy's ends and its processes or intervening effects. That is, patients in studies report that antidepressants can connect memory to affect or make painful memories more bearable or accessible, and so forth.

That is to say, we have lived comfortably for 50 or 100 years with the goal of enhancement within the medical profession. In truth, we might say that, as a society, we have lived with this goal much longer if we accept that people have tried to make themselves less melancholy through a variety of means that in Listening to Prozac I call "quest," methods such as religion, friendship, work, self-inquiry, and so forth.

An interesting book for the Council to look at is Martha Nussbaum's "Therapy of Desire," which frames the schools of Hellenistic philosophy, the Stoics and Cynics and Epicureans and Aristotelians, in terms of their efforts to create relative invulnerability to the pain of loss. In this sense, enhancement is at the base of the Western cultural enterprise.

By this analysis, the new issues as regards psychopharmacology will ignore the questions of ends altogether and will cluster around means. Although in sentiment Listening to Prozac was on the side of those who feel unease at these potential new uses of medication, the challenge it set was to specify the cause of that unease on the basis of differences between the new technology and the old.

I would venture to recommend this method to the Council in general when framing its response to the challenges of enhancement. In a given instant, is it the goal of enhancement that raises ethical challenges or the means? I think the method behind cosmetic psychopharmacology as a thought experiment is a useful probe in this clarification.

For any given proposed enhancement, if there were a purely harmless means of achieving it, would the ends still be ethically troubling? If not, we're down to the issue of risk and benefit, broadly taken, which is a manageable topic.

If I can be allowed a parenthetical digression on the risk-benefit question, the automatic assumption might be that we would require a lower ratio of risk-to-benefit for enhancement than for treatment. We hesitate to put the healthy at any risk, and the ill are already at risk. For them, the question is not whether to play the game, but how. The paper you read this morning made some remarks in that direction, that ill people are in some ways more suitable for taking on certain risks.

But if we add in the element of judgment, our perspective may change. After all, if risk and benefit are properly calculated, those terms of the equation include the differing starting points of the players. What the equation lacks is an assessment of an element we might call freedom or coercion or leisure.

The healthy actor is fully able to make an unpressured judgment. His vantage begins with a self as it is ordinarily. His decision is truly his own. On this basis, he might ask to be permitted to assume a greater level of risk than he would demand were he ill.

The example of depression is illustrative. Who has the less impaired judgment in terms of informed consent, the person when he is free of depression or the person who is merited or diagnosed because of impaired memory and concentration, suicidality, low self-esteem, and the like.

To be sure, there are meta-considerations beyond the perspective of the individual seeking enhancement or even a physician supervising the intervention. I mean effects on the culture and effects mediated by culture.

One difference between medication and psychotherapy might be their differing effects on the social atmosphere. For example, if harmless medications were available that could reliably make people more assertive, then social coercion might come into play. A boss might say to a salesman, "Don't come back until your medication level is adequate," or words to that effect.

In such an atmosphere or such a workplace, those who are not characteristically assertive off medication would be at a disadvantage relative to those on. The analogy to steroids in sports is evident.

This coercion might apply all the more for medications less benign than those imagined by the strictures of the thought experiment I have labeled cosmetic psychopharmacology, say addictive medications or those with insidious harmful effects. We might fear medications because of the influences of their manufacturers, the pharmaceutical houses.

It does seem that the risks for distortions in informed consent differ as between medication and psychotherapy. As regards decisionmaking, the pressures brought to bear by therapists would tend to be more intimate but less organized and less global.

Regarding considerations of evolutionary psychology, I have said the ground rules of our thought experiment, normal to normal, make certain concerns disappear. True, melancholic traits may have conferred fitness in the hunter/gatherer environment, but then so did sanguine ones. At the level of the individual nothing is lost, but at the level of the culture we might fear the effects of too much uniformity, everyone a top banana.

The same worry could conceivably result from psychotherapy or religion, but our experience is that quest has never so far worked in this overly-effective way. This is the challenge I posed with cosmetic pharmacology as a variant of enhancement.

I would like in our remaining time to update you on my thoughts of the following eight or ten years and to say something about progress and prospects for progress in biological psychiatry.

This may be going on too long. Are we comfortable?

The first set of thoughts have to do with my own experience. You will recall that I had made a division between ends and means, saying that since we accept ends of enhancement when quite mechanical forms of psychotherapy are applied, the principal issues must be those attached to the new technology.

But something strange happened. When medical ethicists took up the challenge, for the most part they continued to talk about ends. You will hear from Carl Elliott, and may have seen his work referenced in my monograph and his own in the Hastings Center Report in your materials. I don't intend today to address that material in detail, as I do in my own written reply. But I can say that Dr. Elliott makes a series of cases for alienation as a valuable human trait.

But by way of precis, let me propose a quick thought experiment. A patient in one of the recursive vignettes returns and says, "I'm not depressed again, but I noticed on the medication I felt more comfortable in conventional social groups. I had less sense that I was an outsider. People found me less awkward. I was less troubled by absurdities and contradictions. I was less finicky. And I have been proposed for membership in a conventional business leadership group. Acceptance would help my career. For the probationary period, I would like to resume taking the medication."

If this request sounds unlikely, I should remind you of that study by Knutson and Wolkowitz in 1998 demonstrating that an increased ease in affiliative behavior and leadership behavior in response to serotonergic medication. I take this request as invoking the sort of possible objections made by Dr. Elliott when he writes memorably that, "To address alienation as a psychiatric issue is like treating Holy Communion as a dietary issue. It's a category mistake."

I think that the question of alienation is an open one. Alienation is very much an element in some psychiatric conditions, and even where it is not, it might legitimately engage the psychiatric enterprise and all of its aspects, including the pharmacological.

But at the same time, I want to say that the recursive vignette is an example of a request for enhancement, not a treatment of an illness, and it does raise questions of value, in this case the value of alienation, which is a trait philosophers have valued on a variety of grounds, for example, placing it at the core of existentialism.

I should add that, in the wake of Listening to Prozac, ethicists have written in praise of rejection sensitivity and self-doubt. However painful, these traits are aspects of self-awareness and awareness of circumstance. Value can be attached to almost any of the personality traits that are also symptoms of depression.

And there are other problems here. I saw this article by Stephen Braun also in the advance material, where he talks about having these mini-storms in his life where he would feel depressed for a short while, maybe not rising to the level of illness, and wondered whether there was something behind them, although apparently there was not, whether there was some problem in the marriage, or so on.

Of course, psychoanalysis has taught us not to trust our own testimony. So it might be that someone would think something is random, where some adequate explanation or adequate inquiry would show that there was some particular human value in having that symptom. He concludes in that article that there is not, that this is just some kind of mental glitch, and is happier being on medication.

This circumstance makes depression and its neighboring conditions special, if not unique, among the examples you are likely to consider. I think I have said this.

I have come to think that the matter is yet more difficult, that ethicists might value depression itself, not just the neighboring conditions, call it illness though we may. One provocative test of this assertion is this question: Would we want to eradicate depression the way we eradicated smallpox, so that no human being experiences depression ever again? This question might elicit different answers, presumably a wider range of answers than a comparable question asked of cancer or diabetes or arthritis or some other illness.

Now think of the objection to this provocative test. It displays and conceals verbal ambiguity packed into the word "depression." That is to say, some people might be content to eradicate or entirely prevent the severe condition depression if its boundaries could be well-demarcated.

It is the minor conditions that make the question sound troubling, but that objection is a demonstration of the problem of value of minor depression. That is, the reason people make that objection is that, while they are quite happy to get rid of major depression, even those who are, they want to hold onto minor depression. That is why they think it is a trick question. I hope that was clear. If not, we can forget about it or discuss it.

I mention this possible exercise as a quick proxy for a longer discussion of the premise that, when it comes to minor depression as regards enhancement, some possible objection attaches to the goal.

In recent years I have come to think that the argument from psychotherapy deals with these concerns too easily because of unspoken beliefs about the test intervention. Ethicists seem to think that psychotherapy does not work or does not work thoroughly or acts only through a limited sort of means, such as insight. It is only in the face of interventions we imagine to be ruthlessly effective, such as medication, that the issue of value emerges.

I want to mention a second issue that makes depression special, although not unique, which is that it is a true spectrum disorder. Your materials also list how psychiatrists diagnose depression. It is based on having a depressive episode, and to have an episode you think about nine symptoms. You need to have five of these symptoms continuously for 14 days and they have to rise to an adequate level of severity, and if so, you have a depressive episode, and then from there you might have different kinds of depression.

This is the sort of sharp-edged definition that allows for enhancement paradoxes. Shortly after the publication of Listening to Prozac, when colleagues challenged the assertion that SSRIs could affect people who had never been depressed, and I mounted variants of the identical twin challenge proposed earlier, if the, quote, "unafflicted" twin had only experienced four symptoms, would she, nevertheless, respond to treatment?

A similar question might serve to indicate the difficulty of defining enhancement. If a person has never suffered more than four symptoms, but those four are chronic and disabling, does addressing them constitute enhancement or treatment? What of those who have experienced only three symptoms? Will a single symptom suffice? Is this sufficient?

In reality, in a doctor's office people do come in with just one symptom. You know, they are only suicidal, say, or they only have low self-esteem. We are often happy to treat those.

These questions are made more complicated because of the results of recent research. It turns out that the accepted definition is arbitrary on every axis: the number of symptoms, the duration, and the severity. In other words, if you looked at people with only four symptoms or have five symptoms for ten days or, you know, have a lower level of severity of symptoms, they all have a degree of risk for future bad outcomes that is very similar to those who meet the definition. This is a true spectrum.

The same is true if you try to raise the bar, that is, if you try to look at really core symptoms of depression like suicidality, you know, you start losing some people whom everyone would say are truly depressed and you still include people who turn out to do very well in the future.

In fact, only half of people who meet the initial definition of depression ever have another depressive episode. I think psychiatry is much more interested in this term of illness, in this sort of career of depression over a lifetime.

This doesn't make the definition of depression a bad one. It has proved very useful for research and public policy purposes, but it limits its applicability to ethical conundrums. Clearly, we would not consider a culture immoral that had a differing definition of depression, slightly above or below ours in terms of the severity demanded.

The matter is all the more problematic because of recent research that emphasizes the physical deterioration implicit in depression. There are studies that show brain nuclei to be atrophied or perhaps small in the first place in patients who have been depressed, and the size, the loss of tissue appears to be correlated with the length, lifetime length of depression, the number of days of depression. There are also post-mortem studies that show cellular disorganization, glial cell atrophy. So this looks like a condition that doctors legitimately might want to prevent on the basis of anatomical findings.

In addition, there is research on what is called sub-syndromal symptomatic depression that looks as if it leads to all sorts of bad outcomes, like worse results in heart disease, and so on.

The result is that many of the areas that ten years ago we would have thought about as the realm of enhancement have probably been subsumed into the medical enterprise. I warned about this tendency under a phrase I called "diagnostic bracket creep," the tendency of diagnosis to expand to meet the medication available.

Although that designation contains a measure of sarcasm, the movement is not necessarily for the worse. What happens is, if you have an effective medication, you start doing research on ever more minor conditions, and you may find legitimately that they are as fully medical under the concerns you had as the ones you had started treating when you needed a more uniform population to do your research.

So I have proposed two sets of problems: Do we grant legitimacy to the concern over enhancement based on valuation of the target ailment, or lack of ailment, and can we define a territory that is outside the legitimate medical enterprise? It would be interesting to see what would happen if worlds collide.

Imagine an ethical determination, say by a commission such as this one, that the culture values a trait related to depression and considers its diminution to be problematic unless certain conditions are fulfilled. So say we value alienation and say really medication ought not to be used to treat alienation.

Then imagine that research defines a cause and set of biological markers of a subtype of depression, and that subtype turns out to include some of the cases where we have said it is morally preferable for people to live with the trait. Could we stand fast against the suasion of biological evidence?

The same argument might apply to prevention. To create an extreme example, say that depression in offspring is caused by maternal exposure to a pathogen. So say it is like toxoplasmosis, where if the pregnant woman is exposed to feces of cats carrying toxoplasmosis, the child is at risk in life for certain ailments.

And let us say that if you didn't handle cats, your child is much less likely to be depressed. Would you sincerely -- would you take seriously the worry that your child also might not be alienated? That is, do we so value these traits that, if they thoroughly entered the medical enterprise, we would continue to value them, and someone would say, "No, women ought to go on handling cats because otherwise the human race would lose this valuable problem of melancholy"?

One response is that we don't think depression or melancholy personality are like that, but of course there have been surprises in medicine before. Well, what do we think depression is like?

There are a number of speculative models now, some of them built on a neurobiological analog of what we see in the behavioral phenotype; namely, problems and resilience. In other words, that the brain in depressed people does not produce reparative chemicals. So that when there is stress, whatever damage is done remains more in the brains of depressive people than other people.

A fuller model, worked out in rodents, involves stress, increases in stress hormones in the brain and then difficult-to-reverse brain damage. A yet fuller model sees depression as maybe 35 or 40 percent based on genetic vulnerability, where that vulnerability merely takes you further down that road of the results, the effects on the brain of repeated stresses.

And a yet fuller model sees subtypes that may be tied to particular stressors, such as, for example, declines in vascular sufficiency. If this is so, and I know that was a quick runthrough but just accept perhaps this conclusion, then prevention may be a better strategy than treatment for depression.

Now no one objects to prevention for depression. There are all sorts of interventions with high-risk mothers, say, to prevent depression in children. But, again, this may be a false counter-example because it seems so natural and because it is not thorough.

I haven't spoken to you about developments in psychopharmacology, and the reason I haven't done that is that I don't think there have been ones that present dramatic new ethical problems beyond those that I talked about ten years ago in terms of what has come to market.

But there have been medications that haven't come to market because they have had side effects on the liver, and so on, that involve interrupting the effect of stress on the brain. These include CRF inhibitors intended to block receptors for corticotropin-releasing factor. In lower mammals these compounds prevent even the effects of prenatal stress on offspring. So that you can imagine someone undergoing a stress, taking these medicines, and not suffering the deleterious anatomical presumed effects of stress on the brain. These do, I think, present new ethical problems.

For instance, if a child lost his or her parent, lost a mother, would you want to give such a medication to prevent the future liability for depression, and if you did so, would you feel that you were preventing certain normal responses to the loss of a parent, such as development of, say, melancholic personality traits? Or taking away this kind of proxy problem that children present, would you want a spouse to take it upon the death of a pre-deceasing spouse?

And at the next level of science fiction we can consider genetic interventions. Robert Sapolsky and colleagues have done lower animal experiments in terms of introducing genetic material to prevent cascades of stress hormones that follow upon strokes, so strokes don't generalize. So that if an animal has a stroke, it won't have the permanent elaborator effects of that stroke on the brain.

Sapolsky has talked about the possibility that one could in theory create genetic interventions that would have the same effect as regards depression. That is to say, when a person who is liable to become depressed in response to stress would have such an intervention, that person would then be less liable. Are we concerned that such interventions also would prevent alienation, moodiness, sensitivity, and the like?

This forecast, which is also in the way of a thought experiment, raises questions about agency. Ought we to allow or encourage mood enhancement, perhaps under the name of resilience, as a boon to public health or economic productivity, or would you prohibit or discourage or attempt to minimize enhancement, perhaps even when it occurs as a side effect of clearly legitimate or mainstream medical projects? Is depression a special case? Ought it to be a special case?

Our own current interest is in a topic, my own current interest is in a topic, I'm sorry, that bears directly on this last question. What is the origin of this sentiment for minor depressive symptoms? Is a "faute de mieux" a result of millennia where men and women could not prevent these traits and so had to live with them, or did the human race develop strengths out of handicaps, so that we entail some risk, individual or societal, when we mitigate melancholy?

I am, frankly, suspicious of much of the sentiment in favor of melancholy. If we accept the medical model of depression, then we may imagine that some years hence that sentiment will resemble the romanticization of tuberculosis in the 19th century. Although the role of depression in the culture is yet more substantial, it informs our very notion of romance and has for centuries. If that is confusing, I can say more about that as well.

I want to end, as psychiatrists often do, by showing the other side of the coin. I have said that depression and its lesser relations may be an unfavorable area to tackle because of the unique medical and cultural qualities of the core disease and the sentiment or valuation attaching to associated traits.

But I might also want to say the opposite, that these questions are timely. It seems to me important to say what we want to say about melancholy now before we are unduly influenced by the facts. The valuation, say, of alienation is a cultural question and best assessed at the end of millennia in which it gains its status, millennia during which its causation remained unclear. Once we know more about the causes of depression, this debate will be that much harder to engage, so prone are we to give biological dissections priority.

I see that I have taken an odd tact in outlining issues arising from concerns about enhancement. In the end, any wider opinion you issue will focus on informed consent, implicit coercion, social conformity, the natural and unnatural, risks of addiction or other forms of seduction, modes of balancing risk and benefit, and the like.

My only justification for the path I have taken is to say that it is my interest, the one that has captured my interest, and that it serves to underscore the question that I think should come first in considering enhancement, since it properly informs all the others, questions of value.

So why don't I stop there? I am happy, you know, in the course of the discussion to say more about my own opinions on this issue, whether if we discovered tomorrow that a combination of vitamins actually prevented minor depressive traits, people ought to be encouraged to take those vitamins or not, but I think I should hear from you first. Thank you.

CHAIRMAN KASS: Thank you very, very much for a very rich and stimulating presentation.

Let me just open the floor for discussion and hold my own comments. Gil?

PROF. MEILAENDER: This is very interesting and very puzzling. I would like to get you to think a little bit for me not just about kind of reporting on what people think, but react yourself with respect to one of the kinds of issues you raised especially near the end.

I mean, we often think, I often think at least, that to love anyone is to make yourself vulnerable because you might be hurt if the person is lost. I would like to think about your case of the person being widowed, say. What would be an appropriate reaction to losing the person to whom you had been married for 25 years, say, or something like that? I want you just to reflect normatively on it for me now.

If I lost my wife after 25 years, and it wasn't that I just soldiered on kind of, you know, because there were things that had to be done, but I just carried on kind of happily, readjusted, and so forth, and seemed positively buoyant, in fact, on many occasions, would you judge there to be -- I mean, am I defective as a human being in some way? Has something gone wrong? Or if not, then maybe it would be desirable for you to help anybody who lost his or her spouse after 25 years to just carry on buoyantly.

Just think about the case a little bit more for me. I am really interested in what you, yourself, want to think normatively about it.

DR. KRAMER: I am very much within the culture. So my answer is likely to be an answer from within the culture, and I certainly would think you had missed some of the richness of life if you didn't mourn or grieve to some extent.

But that is more one vote.

PROF. MEILAENDER: Are there different cultures on that matter?

DR. KRAMER: Yes. Yes, there are. One of the things I wrote about in Listening to Prozac was a particular case that was initially admired of mourning in rural Greece. In rural Greece I guess women wear black after the death of a pre-deceasing child or husband, and they are given a long period of mourning during which they are very much supported by the rest of the community and allowed not to do certain tasks that ordinarily a woman would be required to do, and so on. And this was held up as sort of a model for the mourning process.

But someone who looked more closely at that culture found that some women were very antsy and grumpy about this, that they recovered much faster than this ideal period required, and that they were just too resilient for that culture. It didn't fit them well.

I think there is a range of naturalistic responses to loss. But my question is more for the philosophers, which is, forgetting what I think is natural or normal, where does the value attach? In other words, do we more admire the women who take a year or the women who after a couple of months want to be back at work?

And is the value in thinking about the person constantly or being forced to think about the person constantly? That is, let's say you could take a medicine that after a couple of months would relieve you in some way. You certainly could go on thinking about your lost loved one as much as you wanted, but you wouldn't be forced to.

So I think ordinarily when we think about morality, something is more admirable when it is done without coercion than when it is done merely because there is no other choice. So I think it is an interesting question.

More broadly, I want to say something about suffering because I think we value suffering altogether. The question is, do we value suffering because we learn from it and it is morally somehow enhancing -- that's probably the wrong word -- or do we value it almost because we can't avoid it in this manner that I called "faute de mieux"?

I had an interesting -- I am just going to tell a story, which is I was in Denmark, and through various storms and things I was forced not to go where I wanted to go and ended up at Isak Dinesen's house, Rungstadlund, with a Danish pharmacologist. We had been talking about these sorts of issues that we are talking about today, about the amelioration of depression.

People always say, what if Prozac had been available in van Gogh's time or in Denmark what if Prozac had been available in Kierkegaard's time? So I said jokingly, "What if penicillin had been available in Isak Dinesen's time?" because the story on Dinesen was that she suffered from syphilis given to her by her Baron Bror Blixen, the bad husband in this movie "Out of Africa". And the chronic pain that she had from the syphilis made her a darker writer, and so on.

And no one objects to treating syphilis. There is no moral objection or richness of human experience objection to treating syphilis in a woman infected by a feckless husband. I mean it is just not something we consider at all.

This pharmacologist said to me, "You know, she probably did not have late-stage syphilis. Probably she was cured of the syphilis early by arsenicals. There was no trace of this ailment in her later life. She was on phenothiazines and barbiturates, and probably what she had was depression."

So why is there a Prozac question and not a penicillin question? Just as an interesting -- this is not, I know, it doesn't have to do with mourning in particular, but why is it that we ask questions? And I think the answer to that question, in my mind, having thought about it, is that depression is sort of a proxy for suffering altogether, whereas these other illnesses are all individual forms of suffering. What we don't want to lose is something that relates to the capacity to suffer, although any given instance of suffering we would be happy to free the human race of.

I know that was not a good answer to the question, but --

PROF. MEILAENDER: Just a brief followup: I mean your distinction between any given instance of suffering and the capacity is a good one. I was just going to say, I'm not particularly big on suffering, but let me try to put the question, or at least a version of the question, once more in a way that doesn't make it a question about medicating at all.

I don't know how you would get this information. It would be a difficult question. But if you were to die and then you were to find out that your wife, having given you a dignified burial, just carried on, you know, we're not talking about five years or anything, just carried on --

DR. KRAMER: I got the question.

(Laughter.)

PROF. MEILAENDER: -- didn't seem to matter at all, and you somehow could get this information and evaluate it, would you think yourself to have been loved?

DR. KRAMER: Yes. Well, you know, an interesting question is, was I loved? You know, that is, I think that you are asking the question that anybody -- I mean it is the right question. This is the right first question.

On the other hand, imagine a science fiction future in which someone looks back and says, "Do you remember primitive days when attachment was guaranteed by the pain that followed upon loss, whereas now we love because we love and we are free to love. We would be free to withdraw our love, but we love because we really love."

You know, it is like what parents say to adopted children, "I had you because I wanted to have you. We had you because we wanted to have you. We chose to have you."

So that one might say that a more noble form of love would be one that wasn't predicated on pain of loss, although, yes, that certainly would seem unnatural to us.

I mean, I suppose one reason it would seem unnatural to us is that we would have further beliefs about what the nature of that love was. The availability of a medication that erases those assumptions, that is, you assume a fully normal, loving person would have been able to abbreviate the mourning process through those, whereas today we would think that wasn't love at all, and we would be right.

CHAIRMAN KASS: Are you satisfied for now?

Michael Sandel, Mary Ann. There's going to be a queue here.

You've started us all up. Thank you.

PROF. SANDEL: Well, I found this very provocative and suggestive. Not having thought this through fully at all before hearing your talk, it strikes me that the issue or the thing that troubles us isn't the medication at all, but the mode of being that the medication induces or promotes. Let me say why what you said suggests that to me.

You identified certain traits or dispositions associated with cosmetic pharmacology, traits that people might want, even if they are not clinically depressed. Then you mentioned some other means of acquiring those traits, traits like optimism, social assertiveness, a sense of the sanguine, ways of acquiring those traits other than medication that we regard as acceptable or unproblematic: psychotherapy, even religion.

Your suggestion there, as I understood it, was, well, if we accept those ways of acquiring these traits, then why not accept the medication, too? By the way, I would add to the list of other means of acquiring those traits of optimism, social assertiveness, a kind of blithe optimism, and sense of being sanguine, maybe even a blithe vacancy -- I would add to the drugs, the psychotherapy, and the religion spending too long in Southern California.

(Laughter.)

In fact, before I knew about Prozac or what traits it promoted, I was struck at a party once by a woman, a friend of my wife's, who seemed to be more than usual displaying these traits, and I wondered about that and then later learned that she was taking Prozac.

Now in reflecting on the traits, what struck me about them was I can understand why someone might want them rather than to be, say, fraught with self-doubt or something like that, and yet there is something associated with those traits, however desirable given the alternative, that seems shallow or a kind of vacancy, a kind of unreflective self-possession that goes with them.

I would say, having spent some years of my life in Southern California, that that's true of people there in general, even ones who aren't on Prozac. That's actually one of the reasons that I wasn't eager to go back or to raise a family in Southern California, and it had nothing to do with drugs.

But it did have to do with a certain way of being that I thought was promoted or made more likely or induced by living in Southern California that I didn't really want my kids to grow up having, nor would I really be happy if I found that they joined a religion, stoic or otherwise, that promoted those kinds of qualities, even though I would want them to be assertive in other kinds of ways.

But the package of dispositions that we are talking about here that seem to be associated with Prozac -- and I don't know how uniformly that's the case -- but it seems to me that to possess those traits too fully is to lack, never mind alienation and melancholy, maybe that overstates the alternative, but it is to lack a certain kind of depth of character or a quality of reflectiveness, even short of being plagued with kind of clinical melancholy, if there is such a thing.

Then when we consider that there are risks and side effects to acquiring this morally-dubious package of dispositions, then you really wonder about the character of someone who would aim at that mode of being, knowing that it carries certain risks. I mean it is bad enough just to come into the possession of that mix of traits with the superficiality and kind of vacancy that sometimes attends it, at least around the edges, but then --

CHAIRMAN KASS: Some of us "resemble" those remarks.

(Laughter.)

PROF. SANDEL: But then to actually undergo risks and side effects for the sake of that really might lead to further worries about the character of the person who would go in for it. So that makes me think that really the issue isn't enhancement, because here on reflection the making better the enhancement isn't really fully an enhancement.

After all, if you take this account of the package of dispositions -- and so maybe we can accept all of the analogies that you propose and say that any of those means to this mode of being would be troubling and for the same sort of reasons, though the side effects might differ in the case of religion, psychotherapy.

In Southern California, the side effects might be more or less grave. It would depend, but the graver they are, the more we would worry, but in any case, we worry for the same kind of reason about all of them.

DR. KRAMER: I wish I had taken notes because I think there are about five issues, you know, in that, and I hope that this council doesn't end up forbidding people to move to Southern California.

(Laughter.)

DR. KRAMER: Because I think that is almost ?- let me tell you what --

CHAIRMAN KASS: We're only advisory.

DR. KRAMER: I am raising my children in New England for this same reason.

I think there are some problems. One has to do with what's in the package, and it does happen that almost any psychotropic medications we know about sometimes cause apathy, and almost any antidepressant we know about sometimes causes mania. So I think that part of my normal to normal requirement would meant to get rid of what very likely are side effects or negative effects of actual antidepressants in actual people with mood instability.

So that, you know, I think some of what one sees actually on antidepressants is apathy or silliness, disinhibition, and so on, and that I would want to exclude those cases. So it's not clear exactly what the package is.

But I think that the Southern California example, it troubles me, and I think it contains a judgment on a lot of normal people. That is, we admire and think to be intellectual people who have trouble making decisions or are, you know, very reflective, are prone toward pessimism and worry.

And the question is: to what extent are we just admiring ourselves and to what extent do we want to sign our name to that as a moral position.

I encountered this when I was asked to write a preface to a new edition of a book by Carl Rogers, the Midwestern American psychologist, who I knew largely through being considered not to be intellectual, and I thought very seriously about why he wasn't an intellectual, because he was someone who had written a number of research papers at a time when people in the mental health field rarely did, and had been innovative in certain research methodologies and was in dialogue with some of the great people of his era.

And I think the answer was that he was an optimist; that, you know, a Midwestern American optimist could not be an intellectual. And even though when his ideas were stolen by, you know, sort of Viennese depressives, they took on a different cast.

But that is the nature of my answer, which is I'm asking us to rethink this denigration of optimism on the assumption that it comes with blandness and so on.

The question you point to is exactly the question that troubles me, whether we're not too quick to value depressive traits exactly on those grounds, and you know, what do we make of Southern California? I think it's an interesting question.

PROF. SANDEL: Could I give just a quick reply? Which is I entirely agree that what I've said contains a judgment on normal people, but the whole tradition of moral philosophy and moral reflection consists precisely in that, containing and engaging in reflective judgments on normal people, including ourselves.

What is moral reflection if not precisely that?

DR. KRAMER: Let me actually make a second answer to that because I think there is another answer to it, which is to think about William James' first and second born religious joy. That is, some people just seem to be born, you know, able to believe in God and to believe that the world is good, and that we somehow consider those people less morally worthy than people who have to struggle and go through suffering and come to, you know, essentially what James claimed was essentially the same state of religious optimism.

You know, the moral enterprise, it is true, values troubled people more than untroubled people, but it's also true if you think about these Stoics and Cynics and Aristotelians that the apparent goal is to live a life less troubled by loss and pain or, you know, in the case of a religious person, to get to the state of faith.

And then the question is: why is it that just having it naturally or having it through some automatic means is less valuable than having it through some other means?

I mean, I think there would be an answer along those lines, as well.

CHAIRMAN KASS: I have Mary Ann and then Rebecca and then Paul.

PROF. GLENDON: Well, first of all, thank you for such an interesting paper and discussion. There's so many things one would like to ask.

I'm going to start with some little questions that a number of us were wondering about this morning and then come back to this discussion between you and Michael Sandel.

In something we read it was said that Prozac is the fourth most commonly prescribed drug in the United States in the year 2000. Would that be approximately right?

DR. KRAMER: I don't know the answer to that, but let's say it is.

PROF. GLENDON: Okay, and so one thing we were wondering about about the top three, would any of those be psychopharmacological?

DR. KRAMER: My memory is that the top ones, you know -- that the top one or two always have to do with high blood pressure and esophageal reflux, but certainly if you throw together Prozac and Zoloft and so on you get pretty high up on the list.

PROF. GLENDON: So this is the last of the little questions. Would you want to take a stab at guessing what proportion of the American population at any given time is on some kind of mood altering drug?

DR. KRAMER: I don't know the answer to that, and someone does know the answer to that. I just don't know.

But you know, an implicit question behind this is: how does the prescribing relate to the burden of illness? And the data I've read is that you could still double the number of antidepressants, maybe more than double before you would reach the number of people who at any one moment are thought to be depressed by those criteria that I mentioned.

Now, we could discuss whether those criteria really include some things that aren't depression, and it also is the case that those medicines aren't only used for depression. They're used adjunctively in other mental illnesses or directly in some other mental illnesses and for some other purposes altogether.

But you know, also if you had gone back ten or 15 years, there would have been much less prescribing of antidepressants. I forget again what the numbers of it are. It certainly has gone up by one and a half times, you know, in the short period of time.

PROF. GLENDON: Well, one reflection is the one that is prompted by the thought. Those of us who are learning about this for the first time, I suppose, now the next time we walk into any social gathering, you're going to look around the room and say, "I wonder how many people here am I experiencing in some kind of pharmacologically altered state."

Of course, we all go to cocktail parties. So we're sort of --

DR. KRAMER: All there.

PROF. GLENDON: -- to that, but more seriously, if this is a mass phenomenon and if the effects or Prozac are as you describe them, then how are we to think about the effect of that on our political and civic culture? That's one question.

And the other is whether you've changed your mind over the years since you wrote this book about the way you feel about Walker Percy. You seem to be, on the one hand, powerfully attracted by him, but ultimately, am I right that you're in disagreement with him? You think maybe -- well, specifically his idea that it's very bad to be a castaway. I think he gets that from Heidegger, the "Geworfenheit."

It's very bad to be a castaway, but the one thing that's worse than that is not to know you are a castaway. He's thinking of that more in existential terms, but for those of us who operate at a more political level, it's somewhat alarming.

There are times in the history of a country when you think that there are things that people ought to be worried about and not going around what may worry.

So I wonder if you think that this mass use of these mood altering drugs has an effect on our political and civic culture.

DR. KRAMER: I think that the -- I'm sort of a clearing house for Prozac complaints and information and crackpot schemes and so on. So that, you know, just by monitoring my answering machine and email I have some odd overview. And I don't mostly think these drugs are used trivially. I guess that might be a first step towards this social -- I haven't seen these examples that people worry about.

And, of course, it may be that you run into someone and they say they're on it to be more creative, but you know, if you really interview them, they're not on it to be more creative. They're on it -- they were put on it for some very substantial reason usually.

And there are effects. I mean, I read something twice in The New York Times, once in the education section and once in some other article, where the health services at universities are complaining that they're getting sicker children, sicker young people because the people who otherwise would have been handicapped or hamstrung by depression in high school are on these medications which, say, work for them for a year, a year and a half, whatever, and they do well enough to get into a higher level college, and then the health service has more children who, you know, started out more depressed to begin with.

And I think we would say that is a good thing, you know. That is assuming that we don't have some other concerns about the medication and their long-term effects and so on, but merely that more depressed young people are entering into ordinary productive behaviors more successfully we would say is a good thing.

And I suspect that that is the major effect, and I think one reason we're hearing about things like accommodation in the work place for the mentally ill is that there are more depressive people successfully in the work place, and then they're having whatever trouble they have on top of it and, you know, what is the right accommodation for them?

So that on the whole, I think, you know, on a public health basis the first thing to say is recognizing depression, treating depression is probably much more important a problem even where we are now than worries about overuse of medication.

I think I'm very prone to ambivalence myself, and I don't know if I'm much changed with regard to Walker Percy. I've thought a lot about, you know, what I value in myself. You know, do I value my ambivalence and so on?

And I think a lot of my work comes out of worry and empathy with depression and so on, although at the same time I think any time I've had a chance to cast some of that aside, I have done so quite willingly.

And I think, you know, if we had the opposite, if we had a medicine or a procedure that made people less confident and more troubled and so on, there would be very few takers for it, you know.

I think depression is one of the things we value very much in others or in this "faute de mieux" way where people write memoirs of depression and they say, you know, "But there were all of these things I got out of the depression."

And you say, "Yeah, right." I mean, that's true. In every life one gets things out of what it is one experienced, but you know, they really have worked very hard and the same is true in earlier eras. I mean, you know, what if van Gogh had antidepressants? Well, you know, van Gogh was on, I guess -- was it arsenicals? He was on digitalis. He was on high dose digitalis as a sort of antidepressant, anti-epileptic on the general sense that if you slowed things down, these people with manic depression would do better, and there's this story about whether one of his yellow paintings is related to medication side effect.

I mean, there hasn't really been a time where people haven't wanted to very vigorously diminish those traits. I don't know if that -- oh, let me give the real Percy answer, which is I think it's the same answer about freedom.

That is, yes, I want to be troubled by things that are legitimately troublesome, and no, I don't want to solve all of my problems by going to the Gap and buying another pair of clothes to feel that I'm being rewarded as a consumer.

But at the same time, it doesn't seem to me that there's a lot of inherent nobility in suffering that is mere biological happenstance.

PROF. GLENDON: I have one short question about the effects of Prozac. Does it affect people's ability to conceive and plan long-term projects, to think about the future?

DR. KRAMER: I mean, I think it may, but you know, I think it may be one of these sort of parabolic curves, if I have the right shape, where, you know, if you're depressed and now you're less depressed, you can certainly plan where you couldn't before. Whereas if you're manic, you know, you're sort of throwing off all sorts of things without choosing well among them.

It may be that that's one of the -- in terms of main effects, I think that's the spectrum. I think in terms of the side effects of apathy or failing to care adequately, you know, that that is just a problem on a number of dimensions which would include planning.

CHAIRMAN KASS: The queue is longer than we have time for. So let me call on a few people now. We'll take a break and we'll hear from Carl Elliott, and then we'll continue.

I have Rebecca and then Paul McHugh. We'll see where we are when those two are done.

PROF. DRESSER: I wonder if you think about a different kind of group of social effects, I suppose economic. So does it bother you if drug companies are focusing a lot of resources on, you know, the next Prozac or after the next whatever, the next thing in this so-called cosmetic area, as opposed to, you know, all the many others, even if you limited it to mental illness, the needs that are out there?

You know, its effect on priorities, either drug companies or, say, federal funding or what's covered by health insurance, given, you know, increasing pressure to cut cost and people are losing insurance.

I mean in the real world, these are the questions that bother me, sort of allocation of resources and priority questions.

DR. KRAMER: Yes, yes. I'm very worried about that. I mean, I think we could have started the worries earlier. I actually think that, you know, doctors who go into cosmetic surgery where that is not plastic surgery for cleft lip and palate and burn victims, but for taking normal people and making them look more attractive, should have to at least pay back the subsidized costs of medical school, to the medical school that I went to medical school.

I mean, I think, you know, that really there is a distinction between treatment and enhancement, you know, that we want to be able to make, and that treatment really is the priority. There's no doubt that treatment is a humane consideration, and there is doubt about enhancement.

I do think that most drug companies are working on treating mental illness, and there's an enormously long distance to go in treating mental illness, but because of the way brain pathways work, because you're really working on developing things that attach to receptors or, you know, all of those methodologies, it seems to me are going inevitably to produce substances that are as likely to change temperament as they are to treat mental illness.

CHAIRMAN KASS: Paul.

DR. MCHUGH: Peter, it is wonderful of you to come and to talk with us in this way, and I wanted to begin by telling you that, while I like you because of your gifts and your generosity, your handsomeness, your height --

(Laughter.)

DR. MCHUGH: -- what I value in you, why I think you are a remarkable psychiatrist in America, and I've said this to many people, is that you're one of the few psychotherapists that really listens to his patients and drew from what the patients said not a conclusion about their particular insights that you delivered, but that maybe the pill that you were giving them was doing something quite remarkable, and it took a lot of other people a much longer time to recognize what you did and, therefore, you advanced the field tremendously, and I value that.

And in the questions I want to ask you now is I want to know if I can get you to move along a little bit further along the same directions, of course, that you went.

First of all, you are talking in DSM-IV and DSM-III terms a bit, and you and I know, and certainly Charles knows better than anyone else, that that's a very poor lead for us to know what we're talking about really because DSM-IV is a nomenclature. It's a dictionary. It's not even a classification like we have.

And, therefore, the terms that we get to use may be too loose for us to carry the kind of weight that you want to carry in ethical terms. For example, because we don't have yet a solid foundation on the biology of depression, we cannot tell whether we're dealing with one subject that is a spectrum or whether we're dealing with the fact that there may be a particular disease in which something broken, just like tabes dorsalis is a broken thing. Epilepsy is a broken thing, and that there are other conditions that both of them are affected by Prozac, but they might be different.

So, for example, bipolar disorder, of which depression is one and which you haven't talked about as specific depression, that might be clearly a broken part, and if we could find out what that broken part would be, we might want everybody to get fixed up just like we did before we discovered things about epilepsy.

We're very confused about the range of epileptic phenomena, out to fainting and things of that sort. We're quite clear about what epilepsy is now and how different it is from swooning.

Now, to bring that around to what we're talking about, but just as an aside, by the way, you talk about what we want. "We" might be a very special group, we guys that grew up in New England and all, because there are lots of people, you know, following Michael's view, that were not terribly pleased with psychoanalysis not just because of the theories, but because of the kind of being that it promoted.

I mean, the idea was that you signed out, and there were plenty of people that said, "Well, gee, what would have happened to van Gogh if somebody psychoanalyzed him?"

You know that. I'm telling you things that you're perfectly aware of. So what we're coming down to and what's concerning lots of us in this conversation and, I think, concerning you is whether the things that we're driving for are really what Aristotle would call, you know, "eudaimonia" or whether we're talking about Joe Campbell's bliss. Is that really the pursuit of happiness, is to chase a bliss, and if we get a drug for bliss, is that really what we want?

And, secondly, are you talking about wanting to support and find value in -- value by the way that I don't share -- in issues that are common and are called depression, but really are the state of mind of fundamentally unstable introverts? You know, unstable introverts are okay, but they don't necessarily --

DR. KRAMER: Paul, I want to go back at some point and ask you how you ever became a psychiatrist.

(Laughter.)

DR. KRAMER: Because they only let unstable introverts in.

DR. MCHUGH: Spoken like a psychotherapist. An interpretation.

But what do you think, Peter? Do you think -- these are all tremendously important questions that you've raised, and I've loved listening to you, but do you think they're going to shape up and fall out? When we start instead of using the word "depression" and even your word "melancholia," we're going to start using words like demoralization in a certain situation, the common state of mind of unstable introverts, the mode of being that is more aggressive and assertive rather than more accepting. And in that way we might be able to get to a point where we could agree or disagree about what we're doing instead of bringing this medical stuff all in with it. Okay?

DR. KRAMER: All right. Well, thank you for the lead-in. I really appreciate the lead-in, and you know, as usual, you've gotten the exact issues, which I am probably not going to answer well.

Right. I think it's very hard to discuss these issues without knowing what depression is, and we really don't know very well. A psychiatrist in the office throws away the DSM, and as I say, if you have a patient who has one or two symptoms, but they really look like career symptoms, you might think this person really is depressed. This is the real thing.

Whereas if you have someone who comes in and meets every bit of those criteria, but you see a lot of resilience behind that, and there's not much history going in and not much family history, you might treat that person very differently than the first one and really assume that although it looks on a phenotypic basis exactly like depression, you're just going to assume this person is going to get better on his own or on her own or with just a little support.

So that we are looking for some core ailment, and it may be that we're going to be able to pick off pieces of it. So let's say late life depression really is a vascular phenomenon. Well, we would all sign on to say we'd eradicate that. No one needs, you know, vascular problems in the brain late, late in life.

And so that maybe we'll pick things off, but my sense is that in the end a lot of depression is just going to look like what goes wrong when things go wrong in a certain direction, and some people are going to be more vulnerable to that and some less vulnerable.

And it's true that the hints of who is more vulnerable is going to be something like neuroticism. This might be a private discussion. I don't know, but I mean, that we can forecast who's going to have a lot of trouble, and the way that looks like is going to look like emotional reactivity in general.

So that's sort of how it looks now anyway, and I think that's what psychiatrists, you know, maybe not a lot of psychiatrists, but I think the psychiatrists who have thought well about this, or researchers think.

Then we are going to be stuck with problems like the ones I've talked about because it's going to look to the Darwinists as if those problems are really a way of getting mothers to attach strongly to their infants, by punishing them for loss of attachment or so. It's going to look like part of the normal human condition to be emotionally vulnerable in certain ways.

And the question is: there's going to be, you know, a very profound question, which is how much we want to play the hand that's dealt us, and how much we want to be free to do something which, yes, the medical profession could treat it as a predisposition to depression, but being really honest about it, what we're doing is freeing people from constraints that have been necessary human constraints or useful for the troop.

And you know, whether we want to do that is going to be a very serious question, and that's why at the end of that, everybody said maybe it's better to decide these questions now than when we know more because we're very much in touch with the whole tradition of caring about alienation or caring about approaching troubles with a great deal of ambivalence and doubt and worry and so on, and that maybe we ought to decide how we value those before it turns out, you know, that we can sort of pick them off piece by piece, attaching them to things that medicine calls ailments.

I may have said two opposite things there, but you know, that might be a fuller description of what I'm imagining.

CHAIRMAN KASS: Look. I'm somewhat arbitrarily -- I've still got five of us in the queue, and there are probably others who would like to get in. Let's take a break, and let's make the break a little shorter, say, ten minutes instead of 15.

We'll have Carl's paper. Dr. Kramer will stay with us, and we'll continue this discussion once again.

(Whereupon, the foregoing matter went off the record at 3:20 p.m. and went back on the record at 3:36 p.m.)

CHAIRMAN KASS: Would people please return to the table so we can start?

Let me just turn the floor over to Carl Elliott, and thank you.

DR. ELLIOTT: All right. Well, thank you. Thank you very much.

I've enjoyed this so far.

Leon Kass called me and asked if I would talk about SSRIs and our souls and if possible, in less than half an hour. I'm going to give it a try.

I should probably start by at least mentioning, if I'm going to talk about psychiatry and souls, Walker Percy, the Southern doctor-novelist, and particularly his 1971 satire Love in the Ruins. Peter talked about the Thanatos Syndrome in his book. I liked Love in the Ruins a lot better.

And those of you who know the book know that its hero, my inspiration, is an alcoholic, lapsed Catholic psychiatrist and ex-mental patient named Thomas More, a descendent of the famous Englishman who invents an instrument called the ontological lapsometer, or as he calls it "a stethoscope of the human soul."

And the lapsometer is basically a medical instrument with which More can diagnose and treat existential illnesses. So his patients are generally these lonely, alienated, well to do Southerners who play golf and bridge and mow the lawn on the weekends, and then suddenly they wake up and look in the mirror and say to themselves, "Jesus Christ, is this all there is? You know, golf on Saturdays and shopping at the mall?"

And what Tom More finds is that he can actually treat these people with his lapsometer. He gives them a sort of quick, temporal lobe massage, and in no time these alienated folks are back to their old selves. They're self-fulfilled; they're self-realized; they're happy in their work, and at home in the world. What's wrong with that?

Something, More thinks, but it's not clear exactly what it is.

So when the psychopharm boom and panic began in the early '90s, Love in the Ruins was the first thing I thought about Prozac as the ontological lapsometer. Now, of course, America has been going through these psychopharm booms and panics for at least 50 years now. In the '50s it was Miltown. In the '60s and '70s, it was Valium and Ritalin. Ritalin set off one boom and panic in the '70s, another one in the '90s.

And it seemed to me that one common thread that was running through these panics was the notion that the drugs were somehow changing people, that they were somehow turning people into something or someone other than who they really were or who they ought to be, sort of this Stepford Wives' syndrome.

And so what seemed different in the '90s though was a strand that emerged especially in Peter's book Listening to Prozac, which I thought was very smart, a very smart book and very observant, that seemed to turn that old worry on its head. With the SSRIs, people were saying things like, "I feel like myself on Prozac," or, "This is who I really am," or stop taking Prozac and, "I don't feel like myself anymore."

And that seemed like a striking difference to me, as it did to Peter. I mean, it's one thing to use drugs as a kind of emotional numbing device. That's a familiar story. But what does it mean to find ourself, find your true self on Prozac?

Now, the answer that industry has pushed, of course, is a story that's told in the language of pathology and treatment, that we are being restored to mental health. The reason we don't feel like ourselves is that we're sick. Sick people don't feel like themselves. We have a dysfunction in brain chemistry, and once our serotonin levels are fixed, we'll feel like ourselves again.

In fact, GlaxoSmithKline even uses that line. They must have taken it from your book, Peter. You know, "I feel like myself again" in their TV ads for Paxil. But the Walker Percy in me wanted to resist that explanation.

Now, about the same time, as a result of a Canadian project that I started when I was teaching at McGill, I started to look at other kinds of so-called enhancement technologies, things like plastic surgery steroids, Ritalin, Botox, extreme body modification, sort of the works.

And the more I read and the more I talked to people using those technologies, the more I started to hear that same kind of language, that language of identity and fulfillment; you know, transsexuals who talked about becoming themselves with sex change surgery; body builders saying they use steroids to make themselves look on the outside the way they feel on the inside; shy people getting ETS surgery to prevent them from blushing so that they can be the same people in public that they are in private.

Even people who wanted their healthy limbs amputated because they're convinced that they'll only feel really at home in their bodies if they're missing a leg.

And the more I heard, the more I started to believe that I ought to rethink the way I had initially approached these patients who say they feel like themselves on SSRIs, and I started to think that that language that people are using is not so much a result of anything radically different about the SSRIs, but simply because that vocabulary, that vocabulary of identity and fulfillment and authenticity, that's the vocabulary that comes naturally to us now. It's everywhere.

You know, you find it on Web sites, chat rooms, interviews, ethnographies, TV advertisements, movies. You hear it in pop music. This is just the way we talk now. This is the way we think. This is the way we picture our lives.

And it seems natural to me now that it should be the way that people talk about psychopathology and medical treatment. So that even when people describe these radical self-transformations, when they've changed things that you would think are, you know, at the very core of their identities, you know, men into women, 90 pound weaklings into Schwartzenegger look-alikes, even healthy bodied people into amputees. They find it natural and fitting to describe that as becoming who they really are.

So when I gave this book that I've been working on, the subtitle American Medicine Meets the American Dream, that's what I had in mind, the way that the tools of medicine have been enlisted in that search for self-fulfillment and psychic well-being.

And it seemed to me that there must be a reason why that's happening here and now, and part of that reason, I suspect, is that when we retreat into ourselves, when we focus solely on the self, we lose our sense of how to measure the success or the failure on the life of any yardstick other than psychic well-being, and psychic well-being, I think, is something that can easily be bought and sold in a consumer economy.

Now, that said, the more I've given these sorts of talks about Prozac and I'm starting to teach classes using Peter's book, the more I've found a kind of striking contrast between private conversation about SSRIs and the broader public discussion.

It seems like in public everybody is officially anti-Prozac. All right? Feminists want to know why doctors prescribe Prozac more often for women than for men. Undergraduates worry that Prozac is going to give their classmates a competitive edge. Philosophy professors argue that Prozac will make people shallow.

My German friends will object that Prozac is not a natural substance. Americans say Prozac is a crutch, and most people seem to feel that Prozac is creating some version of what David Rothman called, in a New Republic cover story, "shiny, happy people."

In private though, people seek me out and tell me their Prozac stories. I think they have tried Prozac and they hated it. They tried Prozac and it changed their life. They tried Prozac and can't see what the big deal is. And it's starting to seem as if everybody I know is on Prozac or has been on Prozac or is considering Prozac, and all of them want my opinion.

And most of all, they want me to try Prozac myself. They say, "How can you write about it if you've never even tried it?"

And I can see their point. They're right, but still it strikes me as a very strange way to talk about a prescription drug. I mean, these people are oddly insistent. It's like we're back in high school, and they're trying to get me to smoke a joint.

Now, back in the '60s, I quoted Richard Nixon saying back in the '60s that Americans have come to expect happiness in a handful of tablets. I don't think that's right. I don't think that's quite right. That doesn't quite get at what's going on.

I think Peter is right, that the drugs are not being prescribed in a trivial way. I think we take the tablets, but we brood about it. We try to hide them from our friends. We worry that taking them is a sign of weakness, and we try to convince our friends to take them, too.

We fret that if we don't take them, others will outshine us, and we take the tablets, but they leave a kind of bitter taste in our mouths.

Now, why do they leave that bitter taste, you might ask. That's the question that I'm interested in, and I think it's a legitimate question. What actually is wrong with a psychoactive drug that not only relieves human suffering, as the SSRIs do, but can also move us from one normal state to the other?

That's the way that Peter framed the issue in Listening to Prozac, you know, as a drug that can move people along that spectrum from shy to outgoing, from melancholy to upbeat, from obsessive to laid back, and from a clinical point of view, I think that's a perfectly adequate description.

People have a variety of different personalities, a variety of different personal styles, and if a person makes an uncoerced decision to move from one style to another, then why should anyone else have the right to get in their way. I'll concede that point.

I think what we shouldn't lose sight of, though, is what that way of framing the issue misses, and I think what it misses is any sense of a person's relationship to frameworks of meaning outside the soul. If all you pay attention to is a person's inner psychic well-being, then you can't say anything about the appropriateness of that psychic well-being, whether it's the right kind of response to a predicament.

I think that's why I appreciated Gil Meilander's thought experiment.

Now, psychiatrists know this, of course, and psychiatry tries to finesse the issue somewhat successfully, not completely, by talking about how the patient functions, you know, how they get on at work, how they get on with their families, how they perform these various social roles, and so on.

But I think that function is only going to take you so far because it's not just a matter of how well you function in your job or with your family. I think what we want to say is that some jobs are demeaning; some families are dysfunctional; and some ways of living are spiritually empty.

And if your worry is about the spiritual emptiness of life as an American consumer, then it's the happy consumers that you're going to be worried about, the people who don't feel any sense of alienation from that kind of life.

I have to say I feel a little bad that Peter was sort of put on the defensive about Prozac, and I think his actual writings show much more ambivalence, and especially his novel, which I highly recommend to you, and I think in some ways gets at some of the same worries that I have about the SSRIs.

Now, Walker Percy, I think, talks about this very same thing, The Delta Factor. Percy says given two men living in Short Hills, New Jersey, each having satisfied his needs working at rewarding jobs, participating in meaningful relationships with other people, et cetera, et cetera, et cetera, one feels good; the other feels bad. One feels at home; the other feels homeless.

Which one is sick? Which one is better off?

Now, from a clinical point of view, the answer is clear. If you're a psychiatrist measuring depression using the Beck depression inventory, there's no question which man is better off. It's better to feel good than to feel bad. It's better to feel at home than to feel homeless.

And I think it's perfectly reasonable for the man who feels bad and feels homeless to want a medication that's going to make him feel better.

For Percy though, the answer is not so clear. Percy wants to say sometimes it's not better to feel good than to feel bad. Some situations call for a kind of alienation. Some people ought to feel guilty. Some people ought to feel ashamed. Some things call for fear and trembling.

So when the psychiatrist looks at the unhappy American consumer, she sees somebody in need of treatment, somebody who could function better on Zoloft or Prozac or Paxil. When Percy looks at the same unhappy American consumer he sees something very different. He doesn't see a patient with a problem, but a person in a predicament.

And part of that person's predicament, Percy thinks, is that he's come to see himself as nothing more than a consumer of experiences the success of whose life can be measured in terms of his mental hygiene, his sexual happiness, and the state of his body and his bank account.

That's his real predicament, and that's not a patient in need of treatment. That's a wayfarer who has lost his way, a castaway.

Now, Percy is the first to say it's not great thing to be lost, of course. It's a problem. It's just not a medical problem. All right? And this is not a criticism of medicine. It's a plea to keep medicine in its proper place.

The problem, I think, is the tyranny of a world view that presents all unhappy psychological states as medical problems defined by the languages and techniques of psychiatry rather than, say, as existential problems defined by our predicament as mortal beings who will die.

Within that medical world view, suffering becomes a problem of brain chemistry. A drug that fixes the chemistry solves the problem of suffering, and so death, loss, grief, fear, anxiety, shame, all become medical problems that can be addressed by experts with prescription pads.

Now, I take it that it's an open question whether, in fact, SSRIs do, in fact, blunt people's sense of alienation. Some people have argued that they may even help Percy's alienated consumer take charge of his own life and change it.

I'll have to defer to the clinicians here for that, but there is a literature that suggests that at least in some patients, the opposite is true, that the SSRIs do take that edge off of alienation, that they do cause a kind emotional blunting, that they do cause a certain apathy, help people get rid of their shame, and that literature seems to fit with, you know, what I hear from friends and colleagues who are taking SSRIs or prescribing them.

Now, the impulse here if you're worried about what some people will call the medicalization of unhappiness is to try to draw some lines, to try to drop a few anchors, to try to come up with some hard definitions of mental illness so that we know who really has major depression and social phobia and generalized anxiety disorder, and so on.

Now, I can understand the impulse, but dropping those kind of anchors is very difficult. It's not nearly as easy as it looks. I mean, we talk about mental illness, but the fact is mental illness doesn't stand on all fours with physical illness. One of our project meetings, Peter was there. The philosopher Jim Edwards made a sort of offhand comment that he felt as if the word "depression" has a lot more in common with a word like "suffering" than it does with a word like "diabetes."

And I think that's right, and I think it gets at something important about the grammar of psychological experience, and the words that we are drawn to use when we're trying to describe those psychological states.

I have a sort of thought experiment here that I want to repeat to you. It comes from Wittgenstein. Whenever I say the word "Wittgenstein" people's eyes tend to glaze over. So I'll make it short.

PROF. SANDEL:: Here they brighten.

(Laughter.)

DR. ELLIOTT: One. I'll look at you when I -- okay.

There's a famous passage in the Philosophical Investigations, the so-called beetle box game where Wittgenstein says imagine a game. Suppose everybody has a box. Something is in it. We call it a beetle, "beetle" in scare quotes here, a beetle. Nobody else can look into anyone else's box.

Everyone says he knows what a beetle is only by looking at his beetle. Right? Now, Wittgenstein says, look. It would be quite possible for each person to have something different in his box. In fact, it would even be possible for the contents of the boxes to be constantly changing. In fact, it would even be possible for all of the boxes to be empty. Yet still the players could still use that term "beetle" to refer to the contents of their boxes. There don't have to be any actual beetles in the boxes for the game to be played.

Now, what's the point, you're asking yourself. Well, the point is that the words that we use to describe our inner lives, our psychological states, words like "depression" or "anxiety" or "fulfillment," those words get their meanings not by referring and pointing to intermental states, things in our heads. They get their meaning from the rules of the game, the social context in which they're used.

They're like the word "beetle" in Wittgenstein's game. We learn how to use the words not by looking inward and naming what we see there. We learn how to use the words by playing the game. The players don't all need to be experiencing the same thing in order for the words to make sense.

I say I am fulfilled. You say you're fulfilled. We both understand what the other means. Yet that doesn't mean that our inner psychic states are the same. Right?

We can all talk about our beetles, yet still have different things in our boxes.

Now, I hasten to say none of that means that psychological suffering isn't real. I surely don't want to say anything to demean the experience of psychiatric patients.

The point is about the grammar of psychological language. Generally speaking, there are no independent, objective tests for mental disorders. There's no blood work; there's no imaging devices; there's no ontological lapsometer.

Psychiatrists usually don't listen to heart sounds and percussed chests. They can't open up the box and look at the beetle.

The diagnoses that they give to patients are determined not by what they see in the box. They're determined by the rules of the game, and psychiatrists don't write the rules. They try. That's why you have manuals like the DSM, but even if they could, the rules would still be indeterminate because of the grammar of psychological experience.

Everybody can have something different in his box and still play the game. Now, what that means is that no matter how rigidly you define psychiatric disorders, no matter how many criteria you list in the DSM, there's always going to be that kind of indeterminacy, and that indeterminacy can be exploited.

And you know, I guess in the end that is what I worry about, the way that that kind of fuzziness around the edges, what Peter called "diagnostic bracket creep," the way that can be exploited and it will be.

Antidepressants are now the most profitable class of drugs on the market. The pharmaceutical industry is now the most profitable industry in America. According to Fortune magazine, the drug industry has had the highest profit margins of any industry in America for the past ten years, over 18 percent.

The study that you referred to, Professor Glendon, it was the one I referred to. It came from the National Institutes of Health Care Management, and it said in the year 2000 Prozac was the fourth most prescribed drug in America. Zoloft was the seventh most prescribed drug, and Paxil was the eighth.

GlaxoSmithKline spent over $91 million that year in direct consumer advertising for Paxil, mostly TV ads. That's more money spent advertising Paxil than NIKE spent advertising its top shoes.

Now, that is a remarkable change over the past -- really over the past five years, but especially over the last ten years.

We've been talking about antidepressants, and you've got a background paper on depression, but in fact, the term "antidepressant" is starting to sound more and more old fashioned all the time because the SSRIs are now approved by the FDA not just for depression, but for social phobia, obsessive-compulsive disorder, post traumatic stress disorder, generalized anxiety disorder, and premenstrual dysphoric disorder, and they're likely used off label for a whole range of other conditions, from eating disorders to sexual compulsions.

And that expansion in use corresponds with an expansion of mental disorder. It's diagnostic bracket creep.

Now, that's not to say that drug companies are in any way making up diseases. Nobody doubts, or at least I don't, that some people genuinely do suffer from depression or social phobia or that the right medications will make them better. But around the core of those disorders is this wide zone of ambiguity that can be chiseled out and expanded.

And the industry has a very powerful financial interest in doing just that because doctors are gatekeepers to prescription drugs. It's only when a condition is recognized as a proper disorder that it can be treated with prescription drugs. The bigger the category, the more patients who fit in it and the more psychoactive drugs that will be prescribed.

Now, to me in some ways that's potentially the most dangerous part of the SSRI story. I mean, in Love in the Ruins, Walker Percy, I think, saw this coming. When Tom More is tempted by the devil, the devil looks like a drug rep, a detail man as they were called back then.

I think that's unfair to drug reps, actually, who are just doing their jobs after all, but I don't think it's unfair to psychiatrists. Since we have at least three psychiatrists around the table, I say this with some trepidation, but I don't think psychiatrists have been exactly iron-willed in resisting this particular temptation.

Here you've got the most profitable class of drugs in America being produced and marketed by the most profit industry in America. Yet psychiatrists apparently see no conflict of interest in being on that industry payroll. You have psychiatrists doing clinical trials for industry, recruiting patients for industry, clinical trials, signing patent and royalty agreements with industry, taking gifts and honoraria from industry, signing their name to ghost written articles for industry, even holding industry stock.

Two years ago, the editor of the New England Journal, Marcia Angell, who was then the editor, wrote that when the journal published an article on the antidepressants, the ties of its authors to the drug industry were so extensive that the journal didn't have sufficient space to list them all in print. They had to run them on the journal's Web site instead.

And when she tried to commission an editorial on the antidepressant, she could find very few academic psychiatrists who didn't have financial ties to the makers.

Now, that makes me very nervous. I mean, it makes me nervous about how much I can trust the drug approval process which relies on academic psychiatrists as outside experts.

It makes me worry how much I can trust psychiatrist expert witnesses in litigation. It makes me worry about how much I can trust what I read in psychiatric journals.

But mostly it makes me worry about patients. Psychiatrists, like other doctors, have this extraordinary responsibility over vulnerable patients. Yet they're assuming a position where they have financial ties to corporations with an interest in having them write more and more prescriptions.

That's not just a conflict of interest. It's a microcosm of what's happening with enhancement technologies more generally: a medicine has moved to become more and more like an industry run by large corporations, managed care forums, for profit hospitals, insurance companies, the drug industry, the biotech industry. The sale of psychic well-being has become big business, and mental health as a result is becoming just another commodity to be bought and sold in a market economy.

I think I'll stop there. It's a sort of polemical tone to stop on, but I tend to get worked up when I talk about the pharmaceutical industry. I'll stop.

DR. KRAUTHAMMER: I'd like to take up two points. One, the social construction of disease, which is what I think you were getting at, Dr. Elliott, and secondly, try to get us back to the issue of enhancement.

I have no conflict of interest in talking about these issues because I'm a psychiatrist in remission.

(Laughter.)

DR. KRAUTHAMMER: I haven't had a relapse in 25 years.

It's clear to me that when we talk about the diagnoses, psychiatric diagnoses, there is an enormous amount of arbitrariness in those definitions. I know that from personal experience because I worked in the '70s on the depression inventory with Gerry Klerman. I worked with him on DSM on the depressive illnesses in DSM-III, and I have the unique experience of having written a paper identifying a psychiatric syndrome, a depressive syndrome actually, a manic syndrome, and inventing the criteria for it and then discovering over the last quarter century that every year a dozen or 20 papers are published, discovering new cases of this illness that I had described using the criteria that I had chosen.

And I know that I chose them reasonably, but also arbitrarily. I could have chosen in my Chinese menu three from Column A instead of four.

So there's an enormous amount of arbitrariness that goes into these definitions, but I think that does not mean that the illnesses are necessarily socially constructed.

I think Paul is absolutely right that when you see a psychotically depressed patient, you know that something in his world is cracked. This is clearly something medical. It is not a question of just excessive suffering. There is something here that is not arbitrarily -- Thomas Szasz is wrong. It is not something that is imposed on the patient by us.

But once you get closer to the norm, then that is where the arbitrariness kicks in. I think we would say that similarly with the question of intelligence and retardation. If we have a person with an IQ of 30, you would say that something here is cracked. If you have somebody with an IQ of 90, you would say this is just a variation off the norm, which I think brings us to the issue of enhancement, which is to go from one position, one normal state to another.

I think that's a good definition that Peter offered.

If you have a pill that would cure retardation, take a person with a 30 IQ and give them a 100, nobody here, I believe, would object. The question is: do you take people with 80 IQ, give them a pill which puts them at 90?

In this analogy of depression, I don't think anybody has a problem with giving ECT or drugs to cure a person with psychotic depression. We're always amazed and gratified when it works, as it generally does.

Our question is: do you give a person who is melancholic a pill that will bring them to a different, otherwise normal state, which they feel more comfortable with?

So in answering that, I think that we have to go to what Mary Ellen spoke about, which is what are the larger social, societal costs.

Now, I'm just throwing this out as a possible answer to this question. I'm not sure that if an individual came to me and said, "I'm melancholic. I'm not depressed. I'm not mentally ill, but I want to feel better," will I deny them Prozac?

As an individual I think my answer would be no. As a prescriber, I think I would say I would have qualms. We've discussed what are the drawbacks in terms of that person's soul, if you like, in doing that, but I wouldn't deny them.

The question is that if you have the whole society on that what happens. It's almost a question of externalities. What is the cumulative effect of having a society that does that?

I was thinking of this question that was raised earlier by Gil about grief, normal grief and loss. I was thinking of yesterday, September 11th, and how necessary, how moving, how human was that sort of tidal wave of sorry and grief that we saw, and what -- and I imagined for a moment what our society would be like if we could have had a pill to eradicate that.

Yes, in the cases of one or two individuals and even ourselves, our loved ones, we might even want to have that pill and administer it. But how catastrophic would be the results if that was how we dealt with grief and loss as a society.

So I'm throwing out a very crude way to look at our question of enhancement (a) to say that there are real diseases that I don't think anybody would have a problem dealing with. They bleed into the normal. That's where we have our problem.

On the individual level I'm not that troubled, and I'm not sure as society we would be with allowing a person to go from, say, a depressive scale that was equivalent to an IQ scale of 80 to 110, but if you did that as a matter of course in society, I think it would have terrible societal effects, and that, I think, is the paradox and dilemma of enhancement.

CHAIRMAN KASS: Jim Wilson.

PROF. WILSON: Since I'm from Southern California and was raised there, I am naturally a buoyant spirit as my remarks are about to indicate.

Thirty-four years ago, in May of 1969, I sat in a room at Harvard College where a couple of people much younger than I said that corporate greed and the profit motive of industry was preventing young people from feeling authentic and was instead instilling in them a deep sense of alienation, of which Harvard University was the witting or unwitting tool.

Now, 34 years later, I sit in a room and young people tell me that corporate greed is encouraging authenticity and preventing alienation. The pendulum has swung. I'm not particularly interested at either end of the pendulum swing. I'm more interested in what is generally true.

And if you look at the human temperament, as Charles suggested, you might look at IQ. You would see that many traits are normally distributed. Some people, some men at the death of their wife immediately become suicidal and may, in fact, kill themselves. They may represent just a tiny fraction of the population.

At the other end there probably are some men who at the death of their wife go buoyantly off chasing the next skirt in town. I doubt, however, that the second group is as large as the first because unless the wife had been seriously abused, she would long since have left this husband because she would have realized he was incapable of love.

But in between are 96 percent of the population, and so the question I'm raising is: what are we talking about here? Are we moving toward some understanding of how most people ought to be treated by most physicians or rules should be set governing how patients are treated by most physicians or are we simply trying to stake out the territory at the ends of the cyclical swings?

CHAIRMAN KASS: That's a question which Dr. Elliott or Dr. Kramer could be invited to respond.

DR. ELLIOTT: I'm curious about why this council is discussing psychopharmacology. I mean, when Peter and I talk about it in our project meetings, it's fairly clear that we're not looking for any sort of policy results. We're sort of doing philosophy or literature, whatever.

And I don't think we've had any conversations in our group about regulating.

CHAIRMAN KASS: The intention here is not a regulatory one or not immediately a policy one. As I indicated in the introductory remarks, which I kept fairly short, I think that among the concerns that people have for biotechnical powers are those uses that go beyond the obviously intelligible use of treating known individuals with recognizable diseases or acknowledged disabilities or suffering, ranging from the mere satisfaction of desires, however reasonable, to the uses for social control, to the possibility of improvement bordering ultimately on making changes in what at least people who are still friendly to this notion would regard as changes in human nature, and that we have the luxury here of being able to step back from some of the burning questions to have a survey of these powers now present and on the horizon and to try to figure out what do they actually do to us. What do those actions mean? Why, if at all, should we be bothered?

Is our disquiet simply a function of their novelty or are there really questions that touch deeply the character of our humanity as individuals and as a community that we should worry about?

And one of the reasons I think we chose to begin -- and we've had something on the use of genetic technology for the enhancement of athletic performance, and we will tomorrow be talking about muscling up with the aid of genetic technology. This is the first venture really into the technologies that affect the psyche.

And one of the reasons for starting with Prozac is not that anybody here is envisioning new regulatory mechanisms, but here is one of these drugs which has a whole spectrum of uses in which, as has been indicated, the indications are fuzzy. The diagnostic categories are to some extent arbitrary, where it's not really clear what the character of the moral disquiet is, and we've got an opportunity to learn from something which is here, which we've had some time to think about, maybe pick up some pointers about how we should think about the things which are on the horizon.

And I think Jim Wilson's question is -- I mean, the question is what is the source of our disquiet and our concern. I don't think, Jim, you meant to say that the economic interests in this area are irrelevant to our concerns. I mean, I don't think that was --

PROF. WILSON: I'm prepared to open that up as a hypothesis to be discussed. I have no views one way or the other on it.

CHAIRMAN KASS: Right. But, I mean, partly there are the questions, it seems to me, of -- well, let me have a stab at it, and maybe this will provoke some other things.

For the people who have been waiting, let me apologize. I was somewhere in the queue, in fact, just about now.

It seems to me part of the difficulty with this subject is it's not clear on whose turf, which is to say in whose universe of discourse, conversation properly belongs. If Mike Gazzaniga will get into the conversation, I suspect we would start much closer to neuroscience than to the question of the pharmacological industrial complex and its medical complicity.

When Peter Kramer starts, he starts with patients who come to see him with what to begin with looked like depression, but then who come with various other existential conditions which they would perhaps like to see altered.

One can enter this in a variety of ways. You could begin to talk really about personal self-discontent without regard to clinical definition of depression. I mean, there are people who don't like something about themselves, and one happens to have here, thanks to neuropharmacology, something that enables them to do something about it.

And the question is: is there any reason why that is somehow different than people who are in some other ways handicapped by things which are perfectly acceptable to us as a result of their being familiar?

So partly there's a question of what's the proper terminology for talking about what this is, and I think there are lots of possibilities, and all of them have a certain kind of plausibility, at least at the start.

Second, it seems to me there are the questions about the end results that are being aimed at and whether or not and the costs of their success, whether an individual or, as Charles and Mary Ann are talking about, in terms of the community. And there it's not necessarily obvious to me that what we're talking about is the virtue of melancholy and alienation rather than something else.

I mean, everyone is talking about flattening of souls or a decline of aspiration or a certain complacency or whether one's talking about freeing people from certain demons or goblins or just impediments that would enable them to pursue their human ends in the way in which people who don't feel these impediments do.

And then there is, it seems to me, also the further question about what you really mean by happiness or well-being and to what extent that is a mood or a temperament or whether that is somehow connected with human activities the realization or fulfillment of which produces a kind of flourishing, which is a different account of happiness than Paul alludes to.

And then there is, finally, the question which Peter Kramer raised in passing, but we didn't discuss so far, and that really has to do with the question of the peculiarity of pharmacology as a means and whether part of our disquiet has to do with the fact that these drugs bring about changes from the patient's point of view like magic. That is to say one can feel their result, but what has happened to oneself is unintelligible because the means of change are not the usual means of self-improvement, which are through speech or symbolic deed or things which are at least in principle intelligible to us, even if we are being coerced by people we can somehow see what they're trying to do to us.

It seems to me these are a family of questions which somehow are responsible for why there is a disquiet here. No one is talking about legislating about these things. One's trying to understand what does this mean. Is it important? What does this bode for things that might be more powerful and that affect other aspects of our being, you know, from memory and alertness to various kinds of dispositions in the world?

DR. KRAMER: I'm just trying to be quiet for a minute, but I actually think I do want to say a little, tiny something.

And I'm in agreement with all of the last number of speakers. I think Carl has done the favor of being somewhat practical where I have been impractical by bringing, you know, drug companies into the mix more openly.

And I think that I am torn two ways about what categories are and what category mistakes are. And one practical thing to say -- I know this Commission isn't going to do this -- is that there is some risk of taking this medical model, which is built on things like there being genetic contributors and there being changes in the brain and there being standard courses of the ailment and so on. That's how we construct illnesses.

There's some risk of taking that and extending it further and further because as we get better at genetics, as we get better at brain imaging, it's going to turn out that lots of very minor things are going to turn out to have those qualities.

There's going to be genetics fighting a lot with your spouse, and there's going to be brain damage from that stress and so on if we get subtle enough.

And one question is who controls those boundaries. Are the boundaries more or less like what the boundaries of health and illness have been for a millennia, for centuries anyway, or do we allow those to be expanded in some way so that the medical enterprise takes on more and more legitimately?

And one question is a lot like the IRB question, which is: who controls the data that contribute to that decision? Who makes the decisions?

And I've said many times I would be much more comfortable, say, if drug companies were taxed based on the success of their drugs or, you know, "tax" may be a bad word, but where in some ways contributed to a pot of money where some independent agency then tested the after market risks of the drugs or even tested efficacy of the drugs.

And it would be good to take that out of commercial hands. You'd still want this vastly successful enterprise of drug development to continue, but you'd like some greater independence for this enormous amount of money so that the psychiatry professors and all do not have conflicts of interest and so on.

That would seem to me a good thing, and it relates to this question of enhancement in the sense that the boundary between illness and wellness would be somehow controlled by public discussions that weren't overly commercially influenced. So that seems to me that's one practical result.

The other thing I want to say though is back on the impractical sphere, which is that as regards these category changes and category mistakes, in the past our failures have largely been in the other direction than the one we're fearing here. That is, there was a period that Charlie referred to where people said schizophrenia was really the result of bad parenting or mixed messages within the family and so on, and where, you know, the claim was that what medicine called an illness really was an existential dilemma for a troubled soul.

And really, I think, one would have to believe just very strange things to believe that today. I think schizophrenia really looks a lot like an illness on every ground, and it may be that on quite legitimate grounds we will expand the definition of illness as regards things like minor depression because we -- you know, it really just turns out that some things that have seemed like normal levels of melancholy and so on really are caused by a virus, you know, and it's clear that people that don't have that virus, you know, do much better and they make beautiful paintings and write poetry as well.

So I think that, you know, those seem to me, anyway, two aspects of it.

CHAIRMAN KASS: Let me go in the queue. I have Bill Hurlbut, Dan, Frank and Bill May, Paul and Janet.

DR. HURLBUT: The issue you just raised about expanding the borders of definition of illness, that seems to me something we could reasonably endorse. The question is: where does it get over into just normal human variation? And where does it end up relating in some way to something that shouldn't be called a disease at all?

That wasn't very insightful, but let me go on, and I'll show you where I'm circling back.

Leon said a few minutes ago that -- mentioned the notion of alienating -- I guess he didn't use quite this word -- but alienating ourselves from our own self-understanding by taking a drug that doesn't allow the continuity of comprehensible change or intelligible change, and so in a way it alienates us from ourselves, making us not just unable to understand, but inadequate and in a sense turns us over to -- turns our problems over to the matter of being understood by an expert.

And I think one of the weird things about these new drugs is that you see people saying to themselves, "Do I need this?" who never even thought they were sick in the first place. It's expanding the question in everybody's mind as to what do I need to be optimal.

And that's what I want to get back to. I want to ask each of you a question and make a comment, but premising this, when you said, Charles, that you can imagine people going from 30 to 80 and then from 80 to 110, but what about from 110 to 160 or 140 to 180? I think that's the real issue.

And so I want to ask you each a question, one, and then I want to make a comment about them because I think there's a coherence.

If we look to this whole question of enhancement that moves us off center, not just to center, then the question of values and goals comes up. Peter when you were saying -- when you were speaking earlier, we pretty much all dismissed the notion of -- well, there were two dimensions that were dangerous with regard to goals. One was that we might become frivolous, have frivolous, meaningless lives, what you spoke of, alienation, the Los Angeles syndrome, what Nietzsche called pitiable comfort.

But the other thing, and this is what I want to ask you, you implied earlier that serotonin was genetically and socially a drug related to hierarchy and, therefore, evolutionary competition or at least social competition and evolutionary success.

To what extent is this well-being feeling that we're getting actually just the feeling that we're winning? And is this really, in fact, a form of competition?

DR. KRAMER: I think that these serotonergic drugs give a feeling of well-being, and I'm not a great believer in evolutionary or Darwinian explanations. They seem to me so unfalsifiable and so much in accord with what just happens to be the case.

But one of the more attractive views of what depression is on a Darwinian basis is its discouragement in foraging activity at a time of scarcity. I mean, there could be a million different theories like this, but let's think about this one.

Let's say food is scarce and it makes sense on the basis of energy expenditure to sit in the cave for a while. So the body does that to you by making you depressed.

And then when things look a little more likely, you spend the energy and go out and forage for food. And now, we don't think on the basis of human good that we should necessarily be subject to those signals, except when they're adequate signals. Maybe we're far enough from the hunter-gatherer domain that we oughtn't to experience even minor versions of those feelings because they're actually not accurate signals. They're accurate only in a sort of metaphoric or analogical way, and we have other ways, less painful ways of gathering that information and making choices about action.

So I think, you know, that's sort of a partial answer. That is, I don't think that it necessarily is the case that the medications are making everybody feel like, you know, the top male or that they're winning, but taking people who sort of characteristically are prone to be the first ones to feel this sense of unlikeliness that things will succeed and, you know, bringing them probably into a more adaptive relationship with their current environment.

That was not even grammatically clear, but you know, I think that's sort of a partial answer to one way of thinking about the question you asked.

DR. HURLBUT: I mean, I don't endorse evolutionary psychology wholeheartedly either, but I think it's a reasonable premise that the mind would have been shaped just like the anatomy and the physiology for functions that had real significance of evolutionary import, and in that sense our sense of well-being ought to coordinate with that which is in our evolutionary best interest.

Does that make sense?

DR. KRAMER: Well, I think the issue is, you know, is it now a misleading signal where it once was a leading signal and is there enough other development, you know. Are we enough different from mice and so on that we could do with less of it?

I mean, I think that is one question. That is, when we talk about the natural, this is a particular area where the natural is very much related to the social environment, you know, both when we think in gloomy ways and when we think in optimistic ways about making those changes.

That is, you know, it seems to me a person might rationally say, "Yeah, this may have been a useful signal for a hunter-gatherer, you know, but I've got to punch the clock at nine in the morning."

And then we could take that statement seriously and say it's not adaptive for this person to be depressed even in a minor way, and then we could ask whether there are social distortions that then enter in, if people who otherwise are depressed are enabled or whether there are benefits to the individual, what level of analysis we want to apply.

But I think we don't necessarily have to say because it developed on some evolutionary basis we want to saddle people with it or discourage them from altering it in any fashion.

DR. KRAUTHAMMER: Leon, could I give just a quick answer to Bill's question about the extremes? You asked about the 110 and the 160.

I think the reason that we're talking about the middle range is because the extremes are easy. If you're taking either an intelligence, retardation or if you wanted some arbitrary or fictional scale of well-being or happiness, someone who's at 30 and you bring them to 100, everybody would say that's okay. If you start at 110 and you go to 160 and create a genius or someone with an excessive sense of well-being, we'd be troubled by it, and I think consensually so.

The difficult problem is the 80 to 90 to 100, and I throw out again an example from September 11th. We have a drug that treats grief, demoralization, unhappiness, disgust with oneself. It's called alcohol. The problem is it wears off.

So assume that we had one that didn't. Would we administer it? I think that that's a difficult question.

DR. HURLBUT: Well, I'm not sure I agree with you. I mean, I think I see this as intuitively more difficult as you get toward the norm, but why shouldn't the goal of enhancement or maybe put it this way.

The reason it seems to me that we find the 160 to 180 easier to say is not because it isn't better to be smarter. It's because we see the competitive motive in it. We see it as disordering society somehow.

But why shouldn't it be go for everybody to be enhanced?

DR. KRAUTHAMMER: Well, I think that is what I raised earlier about the cumulative societal effects. If you do this on a widespread basis, what would our society look like if everybody had 160, I think?

CHAIRMAN KASS: But probably that depends, Charles, on having an accurate description of what it is that these various measures do to us, and that's not altogether clear.

I mean, are we sort of turning people into things that -- well, by Peter's hypothesis, it's moving the individuals who would like to from one kind of normal condition to another, and it's not absolutely obvious that if a sizable fraction of the population moved over that the world would be a worse place.

DR. KRAUTHAMMER: It would be different, and because it would be different in ways that are obscure to us, it's the difficult question. I think the other ones are a lot easier.

DR. HURLBUT: Can I follow this a little further?

CHAIRMAN KASS: Briefly because there are others.

DR. HURLBUT: That's okay.

CHAIRMAN KASS: Frank.

PROF. FUKUYAMA: I'd like to take a stab at answering Jim Wilson's question about what's really at stake here. I mean, I agree with the things that Leon said, but I think there's an easier way of describing the problem.

I regard a lot of this discussion as part of the broader discussion that's been going on way before neuropharmacology about the expansion of the domain of the therapeutic medicalization of a whole series of behaviors, and what's wrong with that? What's wrong with that is that it undercuts the notion of individual moral agency, which is a public good.

It's important that people believe that they are responsible for important domains of their lives and to the extent that you tell them that what they have is a disease that is caused by an external, that there's an external etiology for that, then you relieve them of that responsibility of taking care of themselves, and I think that's exactly what happens with a lot of these pharmacological agents.

I mean, one of the popular books written on Ritalin in the 1990s was titled It's Nobody's Fault, and you know, the authors begin by saying, well, there's something like -- I don't know -- 20 million people that have ADHD, and they just don't know it. And if you have trouble concentrating, it's because you've got this disease and no one has told you about it.

And there's a drug, and you shouldn't have to worry about, you know, your interior motives because it's really not your fault.

So I think the problem is really that. Everyone would agree that the popular belief in individual moral agency is an important public good that ought to be preserved, and it's threatened by this constantly expanding domain of the therapeutic, and I would say that the threats are very much as Dr. Elliott described.

I mean, the drug companies -- well, okay. There's three parties really that are pushing this. The drug companies, you know, Prozac goes off patent, and so they've got to figure out new disorders that this thing treats.

The psychiatrists, you know, want the business, but it's also the patients. I mean, every participant on Oprah wants to be told that it's not their fault, you know, that they're feeling sad or that, you know, they can't get their lives together, and everybody would like to be told that, in fact, no, you got this disease. It is treatable and get your own, you know, individual moral self out of it.

And so without the cooperation of all of those groups, you know, together, I don't think you would have this problem. I do think that it is, you know, something that requires more rules.

This doesn't happen in somatic medicine nearly so much because, you know, there's fairly accepted standards for what's the pathology, and you need a pathogen and so forth.

But as Paul and Charles and we have discussed this in earlier sessions of this, I mean the DSM is a mess. I mean, it's driven by politics. There's not a clear consensus as to what's a disease, what's a disorder, which means that basically it becomes this grab bag, that anyone with an interest in putting something in there can put it in and cumulatively that has the effect of medicalizing, you know, virtually everything.

And I think that's really what's problematic about that. And so I think, you know, it is worth thinking a little bit whether there's a way. I mean, given these very powerful interests on the part of these three communities that are pushing us in this direction, whether there are ways of, you know, breaking that a little bit.

I mean, one suggestion is, you know, there are cases where something, as Paul was saying, cases where things are definitely broken, and if you could actually use better science, you know, to figure out, you know, where that point comes and where you can actually say that something is broken, then, you know, that might be a contribution to breaking this broader process.

CHAIRMAN KASS: Jim.

PROF. WILSON: I certainly agree with Frank's view about the importance of individual moral agency. I certainly agree that maintaining standards of guilt and shame and innocence and guilt are extremely important.

I wrote a slender book which three people read, two of them quite critically, about how moral agency is maintained in the court system, in the criminal court system, where you see brought out the full panoply of alleged expert opinion, much of it produced by so-called scientists who are testifiers for hire, some produced by psychiatrists and physicians who should know better.

And what's striking about it is that people reject it. There are conspicuous exceptions, and we can all name a few where people have been let off for what strikes us as absurd, over medicalized reasons.

But in general society doesn't tolerate the medicalization of deviants. They are very stern at least with respect to the criminal code regarding individual accountability.

Now, the reason I mention that is not to confront Frank with an alternative view or to dismiss the importance of what he says, but simply to highlight the following question. Before we discuss this much longer, we have to have some idea of what the problem is.

Now, when I tried to find the problem in the criminal courts, does the abuse excuse work, does chemical agents cause behavior to be modified in ways that juries will let up, I couldn't find it. Now, maybe we can find that on Oprah, though unlike Frank, I have not watched Oprah. So I will have to check it out.

But in Southern California we have more important things to do than watch television.

(Laughter.)

PROF. WILSON: But unless we get a sense of what the problem is, not at the conceptual level, that we want to be concerned about the human soul, but at the level that we can embrace in the 18 months in which this council has yet to live, it's hard for me to understand what we're talking about.

CHAIRMAN KASS: Does someone want to tell him?

DR. MCHUGH: Well, yeah. I think this is an important point that Jim is raising and it's the one that I want to come back to, and that is that whenever you start talking about the realm of psychiatry, you very often don't know what you're talking about.

That came very clear to me when I was made a chairman of a Department of Psychiatry in 1975 and had before me the task of developing the careers of people who wanted to be treaters, people who wanted to do research, how to go to the dean and speak to him about what the department needed and the like, and I looked around and I looked for a model department.

There is none or there was none. I looked at what constituted psychiatric disorders. Everybody was at that time fussing about whether it was biological or dynamic. What should be a treatment? Nobody knew. This was even before Prozac.

And I decided that the crucial thing then, and I still think the crucial thing now, is to speak about what we mean by the nature of the disorders psychiatrists take care of. And when you look at them, in point of fact, and if you define them simply as conditions that people come to you with problems in their mental life or behavior, in fact, some of them are on all fours with any physical disease.

I mean, for example, delirium is on all fours with any other neurological condition. Alzheimer's disease. You remember Alzheimer was a psychiatrist. It's hard to believe that, but Korsakoff syndrome, all of those.

The real problem for psychiatry and for our conversation here has been not the medicalization of unhappiness, but the neurologicalizing of unhappiness and the neurologicalizing of psychiatry. That's really what's happened.

I happen to be both a neurologist and a psychiatrist, and was fundamentally disappointed that there were things that the neurological system didn't take in.

Now, the person who really called this to my attention early and in some of his writings was, in fact, Walker Percy, not just in his novels, but in his interest in child psychology, and Percy wrote several interesting essays on the distinction between what he called dyadic disorders, of which the neurological ones are the kind we are talking about, that one gene, one disorder, one problem, from triadic disorders, which human beings can have as well as dyadic, namely, how they symbolize the world, what assumptions they take about the world, and how those assumptions can get them into trouble.

And I believe that psychiatry in DSM-4 has not only screwed itself up completely in this terrible nomenclature, but it has given up on the idea that we have responsibilities, both the conditions which are dyadic and other conditions which are triadic in the sense of taking responsibility for them, changing our assumptions about them, finding our way out of the troubles, out of our predicaments because of what we're in.

And I think I tried to lead a Department of Psychiatry that took all of those into account.

I was not only prompted thinking in these terms by Walker Percy, but an early person prompted me to this, Augustine when he said, "Give me chastity, but not yet," and made you realize that he thought that at some point he needed a gift to get out of the troubles that he was in.

And sometimes a doctor or psychiatrist appropriately would work in that arena. But what do you think about that, Dr. Elliott? Do you think -- by the way, I also want to announce to you that I am an academic psychiatrist. I take not one nickel and never have from any drug company. I have no -- the only monies I ever got outside of the Johns Hopkins was from the NIH.

And I agree with you that it has certainly poisoned the wells of our confidence in this field when we discover that there are essentially people making millions of dollars a year from drug companies and claiming to be advocates for particular disorders.

But what do you think about that? Do you think really there's a problem, the problem that's being raised by Jim and everything, is that we have forgotten the fact that psychiatrists take care of both conditions which have clear neurological issues and things which are also quite clearly of human origin and the human capacity to symbolize, to assume, to take up positions far and beyond what rats and mice and other things can do?

DR. ELLIOTT: I think I agree with virtually everything you've said actually. It seems to me that the problem is that it's so easy to neurologize ordinary life. I mean, because of the fact -- I mean, you're absolutely right. Some illnesses that are taken care of by psychiatrists are on all fours with physical illnesses certainly. Schizophrenia, probably.

The problem is that even for many of those the pathophysiology is unclear, and so you rely solely on what you see the patient doing and saying for diagnosis, and once you have a diagnostic system that's built solely on that, that kind of arbitrariness is going to be built into the diagnostic categories from the start.

And then if you -- yet because psychiatry is medicine, it's wedded to a medical model where you have diseases and you have treatments and you match them up and, you know, that's the way medicine works.

But you have these drugs being produced that don't quite fit into that model, and so the model has to be made to fit them. And so it seems to me that what you've had with the SSRIs, you know, has been, you know, a gradual expansion of things. You sort of look at what they do to people, and then you come up with, you know, an illness to fit it or you expand an illness that was there before.

I mean, social anxiety disorder is one, you know.

DR. MCHUGH: Well, as Charles says, we don't come up with the illness, things which alcohol can take care of when we discover that we can feel more cheerful with alcohol. We don't try to fit a disease to that.

DR. ELLIOTT: But if you had to have a prescription from a psychiatrist every time you went into a bar, you probably would.

DR. MCHUGH: Well, I don't know. Not necessarily. A psychiatrist could well say, "I mean, look" -- I mean a psychiatrist really does study mental life, not simply follow a neurological point, but studies mental life.

He could well say, "Look. There is grief," Gil's point, "and panic-like grief that Jacqueline Kennedy suffered down in November 22nd, down in Dallas." She was given a drink to just calm her down. We didn't think that she had a neurological disease. We thought she was a person who had just seen and witnessed something that was, you know, devastating.

We psychiatrists, I think, do this all the time or at least I hope the psychiatrists that I train do. They might discover, and all of us might agree, that your neuroticism came down with an SSRI, and that if you are severely unstable, we could kind of help you for a little bit. But we wouldn't say that neuroticism was a disease any more than we say a low IQ necessarily is a disease.

DR. ELLIOTT: What if your a managed care organization said --

DR. MCHUGH: Oh, yeah, well --

DR. ELLIOTT: -- to be reimbursed you have to have a reimbursement code?

DR. MCHUGH: Managed care would not be here without DSM-III, let me tell you. DSM-III opened the door to managed care by making it clear that we psychiatrists could only think in these categorical terms.

CHAIRMAN KASS: I've got a few people in the queue, and we're coming close to closing. I have Bill May; I have Dan Foster, Janet.

Bill.

DR. MAY: I'm not disposed to think of the conversation for this particular group a waste of time. I mean, if one is talking about the problem of medicating away something that's valuable, then that's worth our considering.

I would like to begin by offering two cheers for sadness. Dr. Kramer, you talked about the way in which we can sentimentalize the traditional society that provides structured forms of appropriating a major event like death and pointed out to us there are perky Greek widows who are restless under the discipline of this social structure, and of course, there's the modern widow who may be not permitted to grieve, not because we force her to pop Prozac, but we don't have adequately developed social forms for framing the grief that people have to go through.

And we're not talking here simply about bundles of dispositions, but we're talking about the way in which people negotiate the passages of life, and that fundamental negotiation is not simply the final event of death, but death as it besets us in the course of life over and over again, and not simply because others die, but because we're going through redefinitions of the self.

We are giving up and taking on in a variety of ways. You may recall, Jeffrey Gore in his book Death, Grief and Mourning did talk about society that maybe doesn't have adequate social forms for accommodating, condemns too many people to limitless grief.

And the prior problem may be that we haven't developed the social forms that make us excessively dependent upon the medication to solve the problem in private settings.

The stamp of grief is even there on the most celebratory of occasions, the Jewish wedding and the breaking of the glass, the traditional society puberty rights, which included the whipping, the tattooing, the pulling of a tooth.

I was very impressed by one traditional society which had a rite for parents following the rite where the child now, death to childhood, now enters adult life, and then a rite for parents called crossing the fence.

And I've often thought if I were doing a commencement address, it would be interesting to have the ceremony, commencement ceremony, and then a following rite for parents called "over the hill and crossing the fence." There's a redefinition not simply of the child, but also of those who are close to him or her who are going through redefinitions themselves.

On this whole business of alienation, which appears in the articles that we've read, and then the association of alienation with pessimism, and the unalienated with optimism, and I don't think that's what is at issue in the literature on alienation.

Alienation, as I understood it, in "Geworfenheit," the Heideggerian literature and so forth, is the whole problem of how are we thrown outside of an absorption in the world, and of course, Heidegger did, of course, identify this in the being towards death and so forth, but even Heidegger had the sense that there's a kind of cognitive significance to feelings other than the feeling of anxiety.

Boredom throws us outside of our absorption with the world. Joy can also do it, the element of ecstasy, of standing outside of our normal forms of absorption.

And that very much relates to human transcendence, a kind of openness. Now, that's very different from both pessimism and optimism. I mean, the optimist is absorbed in the world, the unimpeded flow of the shallow mind. And we've had lots of descriptions of the surfer in this afternoon's discussion.

But there's also the question of the absorption of the pessimist, choked with worry, preoccupied, anxious. And it may very well be that Prozac and other such drugs are very important in establishing a little bit of that clearing, that openness to the self and openness to others, and so forth which that person is not able to achieve on his or her own.

The last comment on healing. We have tended in this discussion to associate healing with curing us of the negative, but in Leon's earlier work when he defined health as the well working of the organism as a whole, there was the connection to the positive, which was very important and the way in which you develop that.

And of course, in traditional societies, the traditional healer, there were two different narratives for illness, one as the invasion of the negative, in which case the healer treats to overcome the negative, or the removal from the positive and the way of reconnecting with the positive.

Now, it's that latter activity that has some difficulties in establishing boundaries because shouldn't we be drawn to ever increasing possibilities for participating in the enhancement, better working of the organism of the whole? And, hey, we've got something further that will help that well working of the organism as a whole even more.

And it is this latter understanding of healing that we can't dismiss. It's important, but tends to create all of these problems of boundary that are not so obvious when healing is defined as fighting against the invasion of the negative.

CHAIRMAN KASS: Very, very nice. Let's see. Dan.

DR. FOSTER: Mr. Chairman, in view of the fact that we've gone past the time, I'm going to pass.

CHAIRMAN KASS: Janet. You don't have to follow his example.

PROF. ROWLEY: Well, I was thinking about that earlier, but there are two comments I want to make. One is sort of following on some of the discussion, and that is as an optimistic Midwesterner, I object to the equation of optimism as shallow and insubstantial.

The second is that -- and partly in response to your question to us as to what are we doing here or why are we looking at this question -- as you can see, we are a democratic group with very disparate views of almost all parts of the world, and there are at least some of us or I, speaking for myself, am not really very concerned about enhancement, and I think that some aspects that we're talking about do have some issues of concern, but I think that from my view, this is not one of the more major problems of ethics and bioethics that face either our society or the world.

And I will repeat what I've said before, that when we know, Charles, how to take somebody with an IQ of 100 and make them 160 or 180, the world will probably have already come to an end because this is just not something that is even within the realm of possibility, and we are spending time and effort on -- we talk about etherial things and elusive things. This is just not going to come to pass.

And so I am concerned --

DR. KRAUTHAMMER: Janet, you --

DR. KRAUTHAMMER: You entirely misconstrued my point on intelligence. I was using it entirely analogously.

What I'm saying is that in depression, we have the drug that can take you from 30 to 100. ECT can do it. Antidepressants can do it, and they can do it -- ECT can do it in one day.

And what we have with Prozac, as Dr. Kramer has outlined, is we have another technology which can draw you from -- and I use these numbers. I was using IQ only as analogous -- as a way to be able to draw a scale.

Prozac will take you from, say, 80 to 100 or 110, from a normal state to another normal state. I was not talking about our ability to create a genius. I was talking about a real problem today of having a drug which can cure clinical serious depression, which we would all agree is a good thing and having drugs which at the same time can change your normal state, which is what we're discussing here. Is that a good thing for individuals and for society?

And I think that's a real issue and real problem.

CHAIRMAN KASS: Yeah, and I think the discussion has indicated that for a variety of reasons these come through the path of medicine because these are prescription drugs which we tend to think require some diagnosable indication, but the more -- I mean we didn't talk about this particular very much, this selection from Stephen Braun. Kramer alluded to it ?- but the more one finds out about the workings of the brain and the more one develops various kinds of agents that can produce, by the way, not just transient relief from some acute episode of grief, but that can bring about certain transformations of the psyche.

The pressure will not be from people who say, "I have this disease," but there is an efficacious way of making me different than I am and the way that I would like to be, and it's not clear, given the fuzzy boundaries of nosology and psychiatry, that self-discontent doesn't count as a perfectly legitimate reason for coming to ask for some kind of help unless, of course, there are some kinds of arguments that can be offered either in the individual case or in a communal case for why this doesn't really make a lot of sense.

The incidence of use of these things above and beyond the treatment of clear and severe disease already is, I think, an indication of the fact that lots of us -- and I'll speak for myself -- reading your stuff made me wonder to what extent is my outlook simply in the Middle Ages. Melancholy was an excess of black bile. Now you guys have got new names for this stuff, and to what extent is my outlook a certain kind of funny humoral balance of these neurotransmitters rather than a correct response, a correct feeling, affective response to a correct perception of the world?

And the more and more that question comes up, the more and more it seems to me lots of people are going to be interested in experimenting with this to see if they can't get themselves to a kind of psychic condition which they like themselves better or the people around them like them better or they're going to function better.

And that's got nothing to do with clinical disease because the boundary, it seems to me is very fluid, and I think you've already eight years ago or nine years ago did an enormous service by calling attention to the fluidity of this, and it does seem to me, I mean, it's not necessarily a public policy question for us, and it may not be the most burning question, but these are now powers to do things to where we really live and fit with certain cultural understandings of what's desirable, fueled by certain kinds of economic forces and the reconception, the neurological reconception or the neurobiological reconception of who we are.

But once those concepts begin to change and you have powerful means for doing something, people are going to want this whether the drug companies are pushing it or not.

So it does seem to me whether it's the right case study for us, it seems to me something that's already here with large implications for what it means to be whole and how you go about pursuing it.

CHAIRMAN KASS: I believe that this was time set aside for public comment. By my report at the break, no one had signed up wishing to make a public comment, but the floor is open for anyone who would like to address the council.

The rules are no more than five minutes if anyone would like to speak.

(No response.)

CHAIRMAN KASS: All right. Council members, dinner, for those of you who are joining us, will be at -- sorry. Does someone have the sheet in front of them? I seem to have lost mine -- at 801 Pennsylvania, Signatures Restaurant, 801 Pennsylvania Avenue.

We meet tomorrow morning at 8:30. Professor Spiro Simitis will be presenting.

Thank you, and thanks very much to both of you for a wonderful afternoon.