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Meeting Transcript The Ritz-Carlton COUNCIL MEMBERS PRESENT Elizabeth Blackburn,
Ph.D. Mary
Ann Glendon, J.D., L.LM. Paul
McHugh, M.D. James
Q. Wilson, Ph.D. INDEX
WELCOME AND OPENING REMARKS CHAIRMAN KASS: Could I ask Council Members to take their seats so that we can get started? Good morning. Welcome Members of the Council to this, our twelfth meeting. Welcome also to members of the public. I'd like to recognize the presence of Dean Clancy, our Executive Director, the Designated Federal Officer, in whose presence we have a legal and proper meeting. And I would also like to take this opportunity on behalf of the Council to express our congratulations to Jim Wilson who yesterday received the Presidential Medal of Freedom. Congratulations to you, Jim. (Applause.) A word of thanks to Council Members for your loyalty and devoted service and especially this time for the heroic amount of material that you have, I would assume, read or will have read before long. I warn you there is more to come, but we are in your debt for your attention and comments, of course. Welcome. The first session of this meeting, "The Research Imperative: Is Research a Moral Obligation?" does double duty in this Council. First, it's part of our ongoing effort at what we call a richer bioethics and second, it does have something to contribute to the on-going discussions of the ethics of stem cell research. It will continue our effort to lift up to view some of the unstated assumptions that lie behind the debates, say about stem cell research or cloning for biomedical research, assumptions that rarely get the attention and scrutiny that they deserve. We've paid some attention to the assumptions about the moral status of the human embryo. At the next meeting we want to look at the ethical and political meaning of funding or not funding ethically controversial research in a pluralistic society. And today, we're going to look at the so-called imperative of research, especially research in biomedical science that could lead to cures for diseases. No one doubts the great value of such research and no one should have anything but admiration and gratitude to the generations of scientists who have pushed back the frontier against ignorance and who provide knowledge and techniques fruitfully used to alleviate human suffering. The question is, rather, what kind of a good is such research and what kind of an obligation do we have to pursue it? Is it an unqualified obligation, a so-called perfect duty that takes precedence over possible objections and concerns, especially ethical ones? Such seem to be, at least the implicit view of at least one scientist who presented to this Council, who in so many words indicated that this Council would be held morally responsible for any lives that were lost should we erect any legal barriers to cloning for biomedical research and similar opinions have been voiced many times in the public debate in recent years. Others have argued that there is no moral or social obligation to medical research at all, even if such research were a social good and good for us, but rather an optional goal to be pursued, one among many and by no means supreme. To help us continue to think about this question, is there an imperative to research and if so, of what sort? We're very fortunate to have with us Daniel Callahan, the co-founder and for 27 years the Director and President of the first bioethics think tank of the United States, The Hastings Center. Dan Callahan has a nose for all the tough big questions in the field, as the titles in his résumé will show. And moreover, the courage to try to make other people face up to them. It is the tough question of the research imperative that is the topic of his forthcoming book, What Price Better Health: Hazards of the Research Imperative and that makes him the perfect person to get us thinking about this today. If I might add a note of personal pleasure, I was a young researcher at NIH almost 35 years ago when Dan Callahan was starting The Hastings Center and he invited me to the first organizing meeting of what would become that center and in an ill-fated writing venture Dan and I were co-editors of a volume called Freedom, Coercion and the Life Sciences for which I had written a chapter on "Freedom, Coercion and Asexual Reproduction" whose arguments I've been cloning ever since. Dan, it's a great pleasure to have you here. We look forward to your presentation and discussion.
SESSION 1: "THE RESEARCH IMPERATIVE": IS RESEARCH A MORAL OBLIGATION? DR. CALLAHAN: Leon and I have worked together for a long time and I can remember my first discussion with you, I think, at my house on Summit Drive, and we talked and you seemed exactly the sort of person I was looking for. You were suggested to me by Paul Ramsey who many of you knew. It's a double pleasure being here then to be with Leon and this particular Council and also because I think I know at least two thirds of the people on the Council and it's so nice to see you collected here. The term research imperative first arose for me with an article that was in The Hastings Center Report and Paul Ramsey used the phrase. He engaged in really a most interesting debate with the Jesuit theologian Richard McCormick on the question of human subject research on children, particularly what's called nontherapeutic research, for the sake of knowledge, rather than direct therapeutic treatment of children. And McCormick argued that children should be available for nontherapeutic research. Their parents should be willing to make them available as a sort of a noble sacrifice for the good of humanity and the advancement of research. Paul Ramsey rejected that notion altogether, felt children should not be used in that way and accused McCormick of falling prey to the research imperative. I had no particular interest in research at that time and it had passed out of my head, but shortly thereafter I did run across Joshua Lederberg, Nobel Laureate, former President of the Rockefeller University who said to me at a meeting, I gather something similar to what Leon quoted at another meeting saying "If we don't carry out research, the blood of those who die will be on our hands." I wondered at the time whether that was true, but again had no particular interest in research and didn't pay much attention to it, so it faded away. But in recent years, all of that sort of came back to me for a variety of reasons. I got interested in the whole enterprise of biomedical research in this country, particularly in this country, although obviously it goes on in other countries as well. And there were a number of things that caught my eye. First of all, the NIH budget is something of a federal marvel. So far as I know it is the only budget that hasevery year without fail gone up rather than down. A researcher went through all the transcripts of hearings of the National Institutes of Health and it has always had complete bipartisan support. There's never been any serious dissent of any kind. There has been some discussion in recent years about the priorities of NIH, but basically no objection to an increased budget and typically the President each year, whether Democrat or Republican, has put in for a certain amount for the budget. Congress has always found that inadequate and forced the NIH to take more money and they were happy enough, of course, to take it. So the NIH budget caught my eye as an interesting phenomenon in American life. I got interested also in the escalation of what I think is escalating history of medical research in this country where research was a worthy cause in the late 19th century when it first was taken seriously in this country, particularly in medical schools. But the kind of shift from a worthy cause to a kind of imperative, necessary cause which really came into play after the Second World War and I suppose nicely symbolized by President Nixon's declaration in 1970 of a "War Against Cancer." And thereafter, language of the imperative of research became stronger and stronger. More recently the stem cell debate caught my eye since many people have argued and you may hear it in your discussion, but a moral duty to pursue such research. Simultaneously, more or less, the pharmaceutical industry, for those of you who follow it you can't help following it a bit these days, pharmaceutical industry has long claimed that they, the main reason they need the high profits is in order to carry out research which is going to save future lives and relieve future suffering. Hence, they have used a very strong research imperative argument in justifying their drug pricing and the like. Now to me, the interesting question is, why has this happened? What has been the reason for this kind of increased interest? It's rather striking, if perhaps unusual, that health care, I suppose - particularly NIH research, but it is a budget that has gone up despite the fact that health is getting better. It seems to me there's some straight line correlation between the better health we have, the more money we spend on health care and particularly the more we think we ought to spend on research and the argument there is, of course, the prospects of new breakthroughs are greater than they've ever been historically and therefore we should go after them. In any case, as health gets better, the budget goes up and spending on health care continues to go up as well. Now I think that there are a number of things culturally that have happened. First of all, I think there's a very strong feeling in this country that illness and disease, which have always been considered human evils have taken a kind of transcendent status as evils in our country. They are seen as among the worse things that can happen to people, one of the most important things we can spend money on, and that there is really nothing better we can do for each other than to invest money in research to promote better health. I think also, as part of that, is that one shift that I think has taken place since the Second World War has been a kind of abolition of fatalism. It's been argued that in the past we reconciled ourselves to aging and death simply because we could nothing. People could do nothing about it and then it had to be rationalized, it had to be given a place in human life, but fatalism, many would, in effect, argue should be put behind us. Now we can do something about the evils of illness and disease. The political scientist, Michael Walzer, I think very perceptively made this point about 20 years ago when he said, "What has happened in the modern world is simply that disease itself, even when it is endemic rather than epidemic, has come to be seen as a plague. And since the plague can be dealt with, it must be dealt with. People will not endure what they no longer believe they have to endure." That was from his book, Spheres of Justice. I think it's also the case that the pursuit of health through research is seen as not only a good in itself, morally and socially, but also of great economic benefit, both in the lives saved and the future productivity of those lives, but also in the jobs and profit that research generates. A strong argument behind the annual NIH budget is that the research is exportable. It's one of America's great products. People need it. They love it. And they will spend money for it. Most importantly, I think, and an issue that's worth a side discussion, but we won't have time to get into today, a strong argument that medical research offers the greatest promise of eventually reducing our escalating health care costs. A number of economists, David Cutler and the new Commissioner of the Food and Drug Administration, Mark McClellan, have argued very strongly that research and biomedical investment is the greatest investment that has been made on anything in this country, that has been worth trillions of dollars to our economy. And both the pharmaceutical industry and from time to time the NIH itself has argued that better research is what will beat the problem of rising health care costs. I would add as a footnote, it hasn't happened yet. It seems to me a wonderful idea, but the historical record is not encouraging. Anyway, the argument has been made. Now I want to really make three basic contentions in this talk. I'm going to make them and let's see if I can defend them and make them quasi-persuasive. First of all, I want to argue that, in general, there is no moral research, no moral imperative or duty to pursue medical research, or in particular, to pursue any specific line of research. Research, I want to argue, is a moral good to be weighed against other human goods, but not an overriding moral obligation. That's the first contention. The second is that in the absence of what I will call a common metric, there is no rationally justifiable or viable way of balancing the moral good of research against other claimed moral goods. And my third contention is that in the legal and ethical policy, international policy now in human subject research that has developed since the Nuremburg Trials in 1947, the principle of informed consent for competent patients has come decisively to overcome any and all claims of research benefits that could come from violating the principle of informed consent. I think this has great historical significance. Let me go to my first contention, why is there, with one exception I will shortly mention, no moral obligation or duty to carry out biomedical research, but at the same time one can say that research is clearly a moral good? I offer you three considerations for that. First of all, this is a point that philosophers sometimes make about the very notion of obligation. Philosophers distinguish between perfect and imperfect obligations. A perfect obligation is one which is based on a specific promise we have made. We're then obliged to keep it. Or an obligation that flows from certain types of roles we take on such as doctor, policeman, lawyer, what have you, obligations that typically are called role obligations and they go with the carrying out of particular professions. So an imperfect obligation by contrast is one where no one in particular has any obligation to carry it out. We talk about it as an obligation, but one cannot say that any given individual has a duty to carry out the obligation. In that sense, it's a very weak kind of obligation. Indeed, it's not clear when you talk about imperfect obligation whether you ought to use it at all, talk about obligation at all, but nonetheless that has typically been done. And here I would want to argue that medical research falls in the category of an imperfect obligation, imperfect in the sense that it's not clear whose duty it is in particular to carry out such research. One can't even claim that of the researcher. If a researcher decides to do basic research with no interest in therapy, one would hardly accuse that researcher of being irresponsible or to say that any given researcher had a particular obligation to pursue this or that line of research. So in that sense, medical research itself would be a classic case of an imperfect obligation. Now it might well be the case that someone in say the field of genetics who took on particular issues pertinent to society or therapy would have some moral obligation to carry through on that if the person had chosen to do that research it would then begin to take on some of the characteristics of a perfect obligation. But there's no obligation in the first place that a person become a particular kind of researcher. Now this may seem like a rather technical, indeed, precious point, the kind of thing philosophers have lots of fun with, but don't persuade many others. I think the question is pertinent because if we're going to talk about a duty to carry out research, and obligation of research, we really then have to ask, in what sense are we supposed to carry out research and what moral sense is there a claim upon us? I simply want to argue that it is perfectly possible to talk about it as a good. It's an ideal of our culture, a very strong ideal. It is based on the notion of a duty of empathy, mercy, of the relief of suffering, the virtue of beneficence, the virtues of mercy. And in that sense, one can make a very strong case that it is a good thing to do, but not necessarily a strict obligation. Now by calling it a good thing to do, it seems to me one then has to raise the question well, how does it compare with other good things we might do? As an economist might say, what are some of the optional ways we might spend a similar amount of money? How do you compare the value and need for man's educational needs, national defense, jobs, all sorts of other things that societies need in order to function well? It seems to me then once one has said it is a good, and simply a good and not necessarily the highest good, then one is in a situation of trying to juggle budgets, juggle moral priorities and make a determination of where we want to locate health over against other things we might do with our money and with our aspirations. I think it is fairly obvious in this country, as at least symbolized by the NIH, that we have given it an uncommonly high status and this is clearly not the case in other countries. The British, the French, the Germans all spend money on medical research, but they don't put nearly the amount of money into it as we do in this country. But I would point out that we don't consider it morally objectionable that they spend less money on research and more money say on other things, since it seems to me once one begins talking about comparative goods for society, this will be determined by the politics, the values, the history, culture and a lot of other things. So basically, I have a very modest kind of goal here, which is simply to use an old fashioned term from theology, demythologize the notion of a research imperative by simply saying sure, it's an absolutely good thing to do, but once we've said it's a good thing to do, then it has to be compared with and compete with other goods in society, whereas to talk about it as a duty seems to act for many as a kind of a trump care which then allows people to not only ask for more money than they might for other things, but also to argue that somehow we have an inescapable duty and I want to argue with that. Now I would make one exception which I think is important in our world. I think one can make a very strong case that there is something pretty close to a duty when you're talking about infectious diseases and particularly disease such as AIDS; diseases that don't simply kill people, but mainly kill younger people and in particular kill those who are responsible for the running of the society. And one of the great problems in sub-Saharan Africa is not simply a high death rate although that, of course, is horrible, but the point is that what we're seeing is the destruction of the health care workers, the police force, government administrators, all the people that make society run, and of course, leaving thousands of children as orphans. So it's very destructive on the family. So it seems to me that plagues and particularly those that affect younger generations and affect the infrastructure of society and not simply the death rate stand out as a particular exception, which is only to say in a way that there is a difference between what was called the endemic diseases, cancer, heart disease and the like and contagious diseases that seem to fall into a different category. Now let me respond to the Lederberg argument. I think when we think about the Lederberg argument, the idea that somehow it's a sin of omission not to support research and therefore we will bear responsibility for the results of failing to support the research, this will certainly be true if we consider a very hard and specific obligation a duty, therefore, we will have seen, failed in our duty and thus to be condemned. But it seems to me one has to really ask about all the other needs of society and ask is it really wrong to decide in a given society, at a given time that education, say, is more important than health care. In this country, we have more or less spent around 6 percent of our gross domestic product on health care for nearly 30 years or so. We now spend about 14 percent on health care and around 3 and 4 percent on defense. Thirty-five years ago we spent about 6 percent on each. So one can really raise the question whether it makes a great deal of sense or there leads to a balanced society to allow one sphere, namely health care to so remarkably outpace all of the others, as if somehow our education system is terrific, we needn't put more money in that, but only health care deserves the constant escalating budget that it typically gets. Now I think in trying to ask the question of research as a good and comparing it with other goods, we really are forced to ask what kind of an evil disease, suffering, and death are. Clearly, they are very important evils. All societies have considered them evils. As I suggested maybe earlier fatalistic societies had to develop rationalizations and ways of making sense of them. Many of these, I believe, still make sense, but we have at least entered a period where there is not much pleasure taken in arguments that seem to have a fatalistic flavor to them. So that pushes us really back to the question of let's take, for instance, the question of death. I think it's very pertinent to ask what kinds of death are comparably more or less evil. There's death by disease. There's death by social violence, war, domestic violence and the like. There's death by accidents. There is death by poverty. Can we rank in some sense, even if very crudely and roughly, can we rank those deaths in terms of evils? I myself would say that the greatest, the worst kinds of deaths are those that come from social violence and deaths that are unexpected, unnecessary and are a function of human evil, rather than biological evil. We can obviously argue about that matter, but it seems to me it's important when we begin thinking about the comparative good that medical research can bring, what are the comparative evils we are trying to overcome and how do we want to understand and rank those evils? To my mind, premature death is something to be worked against. Threats to public health are to be worked against. This would particularly include infectious diseases and threats to sanitation, air and the like, and I suppose anything that threatens the ability, particularly of people in their adult years, to run families and to manage societies. I would want myself to classify the endemic diseases of modern society, particularly those that primarily affect older populations, as comparatively low priority. That is to say they are terribly important. People - it would be a good thing to cure cancer, heart disease and the like, but it seems to me in terms of social priority, I would want to argue that they have a comparatively low priority and it's very difficult, I believe, to say that we have an obligation to overcome cancer and heart disease as much as they cause individuals suffering. I use that as an example because my family has a history of cancer as a cause of death and certainly that brought suffering to our family as to many other families, but I think if one takes a social perspective on, say, death from cancer, one would have to say that while a source of great pain and suffering for individuals, it is not a disease that threatens the very structure of society or the overall functioning of society. I might mention a very interesting quote by Harold Varmus. Harold Varmus, many people will recall, was the Director of the National Institutes of Health, a Nobel Laureate and I think considered a particularly effective Director. He retired - he left that position in the year 2000 and is now president of Memorial Sloan-Kettering in New York. In his last talk he gave to the staff at NIH, he said something very interesting that was not picked up by the press, but I thought was very radical for a Director of NIH. He said first of all, he said I think we pay too much attention to health in our society, an interesting thing for an NIH Director to say; and the second thing he said was he was concerned that too much of the research they were carrying out was going to produce products that Americans would not be able to afford to buy. And it seemed to me that was what I thought was the very first time that anyone in a position like that began to question some of the very basic work that the NIH has been doing. Now let me bring in a third consideration here. It seems to me that if one cannot say that health is an overriding good as I would want to say, but it is one of many goods, then the question is really how do we balance the ensemble of human goods necessary to make up a society? Obviously, a society where you have a very low death rate from the endemic diseases, but is one marked by social violence, corruption and other things will be a lousy society to live in, however healthy physically people may be. And for that society a priority would want to be given to dealing with the social problems of the society. The question always would be, if one wants to say health is a basic necessity for human beings, obviously the same thing can be said for food, clothing and shelter and maybe a slightly less sense of the importance of jobs and other things for society. So the question then is to find a way to decide what priority to give to health compared to the other goods and at the same time to recognize that the aim of a society is to find a way to get a good balance between all the needs and not just one. I am particularly interested in this issue because while the research drive has received an awful lot of money and great attention, we have done less well with the delivery of health care in this country. We've spent a lot of money on research, but we have spent less money doing research on how to better deliver health care and there has been far less public debate, much less agreement on the value of say achieving universal health care in this country. Harold Varmus said something rather radical for somebody in his position. Floyd Bloom, who is the recently retired President of the American Association for the Advancement of Science and before that editor of the journal Science, said very interestingly he thought we should spend less money on medical research and more money on the delivery of health care, because we have a paradoxical problem in this country. Namely, we have a research agenda that's going forward to find cures for disease, but there is by no means any guarantee that all Americans will be able to receive the results of those disease. There are some 41 million uninsured in this country. There are many people who can't afford the drugs that are coming out of the research enterprise, the pharmaceutical industry and yet somehow we can't seem to find unanimity to deal with that problem the way we can in putting money into research itself. Okay, so much for my thoughts on the obligation to do research. Let me turn to the issue of balancing research against other goods and values. Here I mean to talk very generally about balancing research against other human needs and goods, but here I want to particularly look at the language of balancing when, in the moral debate, because it is often said and has been said in many government reports that we must balance various considerations. Let me give you some obvious examples. In the human subject debate, the question has been one of balancing potential, harm to subjects against potential research benefits. I'll come back to that issue. In the stem cell debate, a very common use of balancing language there; namely, the destruction of balancing the destruction of early embryos against the potential benefits of stem cell research. A third area that has received some attention lately, the protection of privacy against the public health benefits that would come from epidemiological and collecting information on people's health behavior and other items concerning their health. In short, in each of those debates, the issue has arisen, how do we balance the potential harms of doing the research and what harms of different kinds over against the potential values. Now I find this very interesting, first of all because it seems to me one can't really use the language of balance in any meaningful way unless one has a kind of common metric, that is to say, it's the old question of sort of comparing apples and oranges. In that case, the issue you can talk about is the fruit, but in many of these other cases, the differences are very great between the values to be pursued. Now it seems to me that unless you have a common metric, you really can't do that in any meaningful way. For instance, by a common metric, I mean if your physician says look, you have a very painful condition, we have some surgery that will relieve the condition, but the surgery is very painful, then, of course, you have a common metric of pain and you can do some serious balancing. But in the cases I've mentioned, the human subject research stem cell debate, protection of privacy, we don't have anything that works in such a tidy manner. Now my own observation is that, lacking this common metric, and despite the language of balancing, the de facto results of efforts to do so have pretty much reflected the ideological, prior ideological commitments of the people doing the balancing. I look at the language of balancing in previous national commissions beginning with the National Commission for the Protection of Human Subjects in the mid-1970s through three other federal commissions and finally this President's Council, I'll leave out this one, but the other ones use the language of balancing, but pretty much the balancing would typically go in the direction of the known policies, attitudes, ideologies of the Commission Members. And it seems to me there's probably no other way of doing it. People will bring to bear on balancing questions their previous commitments. Hopefully, they may have been influenced by arguments and debate they heard, but nonetheless, they are likely to act out some of their deepest values and that will tip the balancing one way or the other. And of course, one way you achieve balancing, there are a variety of ways. One is simply decide that on the balancing of a see-saw, one value really isn't such a high value after all and you get rid of it entirely and thus getting rid of the problem or you find some way to make one of less value than the other, but in point, all I want to argue is I don't think there's any very rational way of doing this. It ends up a matter of politics, maybe in a good sense, but still politics rather than any form of rational calculus. The third issue I'd like to look at is that of human subject research. I think the history of human subject research offers a very interesting perspective on the question of balancing and also on the research imperative. Although the famous physician William Osler, at Johns Hopkins over a century ago insisted on the importance of gaining informed consent from human subjects, and even a German Commission, interestingly, in the early 1930s made it a moral requirement, it was only slowly and fitfully accepted by medical researchers. Their objection over the decades, as one might guess, was that research requires human subjects, that medical progress cannot take progress without the use of medical subjects and that the cure of disease took priority over any claimed rights of subjects to be free of having their bodies invaded by researchers. In short, there was an effort - an effort was made to look at the problem of balancing, but by and large, in earlier decades, probably the Second World War, the balance was always typically in favor of the researcher and again, the arguments are rather familiar ones. You can't do the research unless we go forward without the consent and in any case the saving of lives and the relief of suffering is something that is of higher value than the protection of human subjects. A friend of ours, Leon remembers him well, Robert Morrison, a physician, said of his medical training in the 1930s, it was hard to take the idea of informed consent seriously when so many of our patients were dying all around us, particularly young people. Well, all of that changed with the Nuremburg Trials in 1947, trials of the Nazi doctors accused and correctly indicted for many horrible medical crimes, particularly crimes involving human subject research. Out of that trial came the Nuremburg Code which at its very core had the idea of informed consent as a necessity. Nonetheless, despite the blessing of the Nuremburg Code, it took many years for the report really just to sink in and again the arguments against it were the necessity of the research, the value of the research, and one that became increasingly common, the fact that your average lay person would simply be too incompetent, too ignorant to make informed judgments. In any case, over a period of time, by virtue of the Nuremburg Code, and by other codes that were developed, the principle of informed consent was accepted and accepted in the face of many rationalizations to evade it. And it's very interesting because I think the rule at present, in effect, says competent subjects have a right to make, give informed consent and without their informed consent, no research may go forward, regardless of how many lives might be saved, how much suffering might be relieved. It is a hard and fast rule. We basically get rid of the problem of balancing all together and said this is not an area where balancing is appropriate, patients must be protected. Now this was, I think, a very important precedent. It said something about the research imperative. It said something about the competence of people, even lay people, to make informed judgments and it certainly said something about the necessity to bring in regulation of something very important. A number of people who believed in informed consent such as Henry Veatch, one of the people who blew the whistle in the mid-1960s on the problem, said it would be certainly important that there be a moral requirement for informed consent, but the government ought not to enter in and try to regulate this area. It should be left to the integrity of the researcher. Well, that view was rejected. The institutional review boards were born in the late 1960s and it is now a firm regulatory requirement that research be protected by informed consent. Now I might mention that, of course, as many of you are familiar with earlier Commissions, the issue never gets totally solved. Efforts to this day still go on to evade informed consent. The work of institutional reviews is endlessly being reviewed, criticized. Nonetheless, I think it very striking that this one principle did endure a lot of criticism and particularly criticism from those who argued for a research imperative to do the research. Let me end - I'm not charged to say anything about the stem cell debate, but let me try to make a few applications of what I've said generally to that debate. First of all, if there's anything to what I've said, it is not appropriate to talk about a duty to carry out stem cell research, even if you believe it extraordinarily valuable, even if you believe there aren't any terrible moral objections against it. It seems to me inappropriate to talk about it as a duty. It certainly doesn't meet the standards I've suggested. Now even if we want to say, however, it is not a duty, but simply a high good, then the question is high how a good and how are we to think within that context. The thing that has certainly caught my eye is that it is claimed to be promising research. But I'm struck by the fact that the National Institutes of Health over the past few decades has spent literally hundreds of millions of dollars on other promising research for the very same diseases that stem cell research is supposed to help. In the case of Parkinson's disease, an article a couple of years ago listed 10 different research lines being pursued for the cure of or relief of Parkinson's disease and certainly that's the case with heart disease, spinal cord injuries and lots of other things as well. Therefore, one can hardly argue that stem cell research is the only possible way of - unless someone once said the NIH has been wasting lots of money on everything else over the years, I don't think they would want to say that. One would have to say the stem cell research is promising, but other things are promising as well and that this might be even comparatively more promising, but promising in and of itself is not enough to constitute a duty to carry it out, particularly when there are alternative lines of research. I would notice something else that people haven't noticed which I found at least amusing. Christopher Reeve who has been a great proponent of stem cell research, as you know, there's been a couple of stories about him over the past year, one that he is now able to have some movement in his limbs that he didn't have earlier and this came from recent research on rehabilitation. And secondly, that he is gradually being weaned from a ventilator and this was cited as a sign of research progress on weaning people from ventilators. In short, some of these other alternative lines of research are working on his very condition and bearing some fruit. I think on the question of balancing and here, this is where the balancing issue has come in very strongly, how do you balance the claims of an embryo against the potential of benefits from the research itself? Well, I guess the question is one thing is pretty clear, embryos are killed in order to carry out the research for research that is promising, its hypothetical benefits over against at least some real harm. Now unless one believes that embryos have no moral standing whatever, which some do, of course, one is then left with - or believes that they have such moral standing that they shouldn't be used at all, but if you're like many of us in sort of muddling around in the middle there, then the question is how do you balance off the decisive harm done to embryos against hypothetical benefits? It seems to me that at least from the way I think about the issue, there is one kind of common metric here, that is to say we're talking about the potential value of the life of the embryo over against the lives of future victims of disease. But it seems to me the question is again, it's not a very good metric because it's still a hypothetical benefit. We don't know the stem cell research will, in fact, work. We do know that lots of harm can do lots of harm to embryos to get there. So I suppose I would want to try to think about the matter in terms of how likely are the benefits and even if we don't believe that there's full human life present in embryos, what do we mean when we say, as many former Commissions have, that embryos deserve respect. I think that is a kind of way on the part of the embryos a certain insecurity about the way we talk about embryos, even among those who don't believe embryos should be considered a full human life worthy of full protection. I think the language of respect has been invoked as a kind of middle level term, if you will, to help us say well, we don't think they're nothing, but at the same time we don't think they have quite enough standing to merit their non-use for the sake of research. I suppose I would want to end by saying on this issue and here I will simply end by saying this, I think embryos have a fairly weak moral claim, but on the other hand I think the research claim is even weaker. Thank you. CHAIRMAN KASS: Thank you very much, Dan. Let me just simply throw the floor open for comment. Elizabeth, is that half a hand, Elizabeth Blackburn? PROF.BLACKBURN: I would like to address the points that you raised in the last part of your presentation. With respect to stem cell research, you point out that the NIH has, of course, spent very much more money on different kinds of research avenues from stem cell research. But I think we should acknowledge that the reason for that has been partly because there has not been the possibility to do very much stem cell research because of the situation being so limited right now. So it's not that the stem cell research has been abandoned. It's being sufficiently useful compared with other avenues to pursue it. It's simply that we at this stage haven't had the opportunity, we as a society, to look into it. I think it's early days. And you pointed out that there hasn't been a whole lot of evidence about how useful it can or could not be, but again, the only way to find out that is to gain the knowledge. So I think I was getting from you words somewhat of a sense that you were thinking that extensive research was the inferior mode of research. And I was just going to point out that we really don't know that at this point because we have not had the opportunity. Another quick point I wanted to raise about Christopher Reeve. I think that the news is wonderful that the injuries that he had were in some way not completely irreversible, but I think that what he acknowledges is that he was in a rather unusual position of having a lot of resources. And he could devote enormous resources, financial, into having the very, very intensive sorts of effort put into his rehabilitation, which I think is not commonly the situation for most people. And so if there were alternatives to this route that he was able to take, which was heroic and very encouraging, I think that would be better because these people do not have Christopher Reeve's large amount of resources that he could sink into his rehabilitation. So those are the couple of points I just wanted to raise. DR. CALLAHAN: Well, let me first point out I in no sense meant to imply that stem cell research is inferior, in fact, it may be superior to all the others. I was simply making the point that NIH already is pursuing other things that they consider very promising as well. Stem cell would be one more thing added to the list. It might be better than the others, but unless we think they have been wasting money over the years, the NIH has believed that other things are valuable and worth pursuing as well. With Christopher Reeve, you may well be right, but much of that research, the benefits came out of NIH-sponsored research. How it got paid for with him, I haven't the faintest idea. But, again, this gets back to Harold Varmus' point. It may well be that a lot of the research will develop things that only well-positioned, affluent people will be able to afford. But that is a side issue. PROF.BLACKBURN: I think the point was that his current one was such an expensive kind of therapy. And if there were cheaper ones that might be more readily accessible, that would be - DR. CALLAHAN: Sure, sure. CHAIRMAN KASS: At the risk of perhaps deflecting people from where they would like to go, it seems to me the real challenge that Dan's paper and presentation throws out for us is to think really about the large theme, which is the moral imperative to research. And I wonder what people think of the general thesis of the presentation as stated. And the use also of informed consent at least indicates that, if I understand Dan's argument, there were certain kinds of trumping limitations that indicated that the imperative to research, if there were one, or at least the pursuit of research, if there were one, simply wasn't the sort of thing that trumped all other kinds of considerations, including moral considerations. I wondered what people make of the general thesis that has been presented. Frank Fukuyama? PROF. FUKUYAMA: Well, I appreciated that presentation because it really made me think about a lot of things, but it does seem to me that fundamental to your argument is actually not the question of the value of research per se, but the value of biomedicine directed towards basically curing diseases in old people that will add, say, another five years of life expectancy to a population whose life expectancy has already been pushed to a fairly high limit. And the value of that compared to other things because you are willing to say, well, infectious diseases that affect younger people I guess in your mind actually do trump quite a lot of other moral considerations. DR. CALLAHAN: Not informed consent, however. PROF. FUKUYAMA: Not informed consent, but you're willing to concede that. So it seems to me that that is really the focus of the issue, the relative value of biomedical research directed towards that particular population. And that becomes, then, a kind of metric by which you can value one type of research over another. Isn't that the basic - DR. CALLAHAN: I guess to me the fundamental question is, what are appropriate goals of medicine at this stage in history given the fact that we have already made great progress, given the fact that most people now die in old age, rather than as young people. Where ought we to be going? That's the basic question. And at the same time, though, I want to say that I think it's been given an excessively high evaluation. And I would simply want to bring it down a little bit and put it on a par with a lot of other things we could usefully spend money on. CHAIRMAN KASS: Frank, do you want to pursue that? PROF. FUKUYAMA: Yes. I think that that's really in a way a core issue that we ought to discuss much further. I remember once hearing the director of HHS saying that heart disease is down, mortality from heart disease is down, and a number of other diseases, but, unfortunately, mortality from these other diseases is up. Now, it seems to me even the director of HHS should be able to figure out that the total of mortalities from all diseases have to sum to 100. So that if you actually cure some diseases, you will be raising the rates of mortality from other diseases unless you can presume that they are not going to die. So, really, what you are talking about is, in a way, this whole life extension issue and the kind of value that. DR. CALLAHAN: Implicitly, that certainly arises, yes. Well, it's also there's another issue, which I have written about in another case and gotten in trouble for writing about, namely, what is our obligation to the elderly given the fact that the average age of cancer deaths is at age 69 or 70 now. So it is clearly a disease of the aging. Should we continue giving it the high priority it had by virtue of the fact that it's mainly older people who have it, as with spending on money on young people to improve the schools? Which is the greater social contribution? PROF. FUKUYAMA: And I would just point out that among the complexities of that, you get into all of these quality of life issues. One of the reasons that there has been this explosion in rates of Alzheimer's is that you have actually succeeded in other areas of biomedicine, keeping people alive long enough that they can get to an age where they are much more susceptible to that. So it seems to me the total good that is being delivered to society by some of these advances is much more problematic. And I think that's a perfectly reasonable issue to raise. CHAIRMAN KASS: Alfonso Gómez-Lobo and then Bill May. DR.GÓMEZ-LOBO: I have a concern and a question, but I would like to preface that with a broad agreement on your approach. I think there's deep wisdom in placing the question within the ranges of goods. And I totally agree. I seem to see an emphasis on health, which may not be reasonable in the long run. I mean, we are surrounded by other goods. And we may be neglecting lots of other social goods by emphasizing that. Now, what I think is very important is to say there is a limit to the balancing. In other words, that balancing goods is something that is reasonable when the pursuit of those goods is morally permissible. And there I think - and I totally agree with you - the notion of informed consent plays a very important role because that's the nonnegotiable limit, right? You don't balance that in any way. Now, here is my concern and my question. I have seen since I have been on the Council and reading some stuff that informed consent is sometimes extended to the treatment of children and then also to the disposal of, say, frozen embryos. What I am doubtful about here is whether there can be valid informed consent for actions that will not benefit the subject. And I would love to hear some clarification of that. And, of course, that ties into your last remark, the remark about the embryos having a weak moral claim. And I want to ask you, what does that mean? And if it's weak, how does it become stronger and say how strong would that be in an infant? In other words, does the notion of varying moral claim for drastic action, like the action of killing, really make philosophical sense? That's the question I would like to raise. DR. CALLAHAN: Well, your last question bears on the whole discussion, the rest of this meeting. I mean, I could say a lot, but let me say very briefly I think by "weak moral claim," I mean a claim where we are uncertain about the moral status and we are uncertain about how great the harm being done to that moral status might be. By "weak claim," I mean a claim somewhere in between saying embryos are worth nothing and embryos are full of life we claim is one that is somewhere in between. It is something. It has some value, but we are not quite sure how much value. And we may on occasion be willing to say it might be overridden by other considerations. That's all I will say on that. I would just as soon not have to get further into that. I'm sorry. You're first - DR.GÓMEZ-LOBO: The other point was about consenting to an action performed, say, on a child or on an embryo that would not benefit that child in - DR. CALLAHAN: Well, that's a hot area that has been disputed ever since the Nuremburg trials because there are incompetent people doing research and somebody with Alzheimer's disease doing research and children, people who are not in a position. I think it's generally agreed that you may have to indeed do the research, it's valuable research, but there you have to depend upon a surrogate giving you permission, somebody you believe is competent and capable of giving permission for the research to be carried out on that person, the condition being that the person is not able to carry out the research and that the research would be beneficial. Now, on your question of non-therapeutic research, I don't see any reason why a competent person can't agree to be part of research. It is not going to particularly help that person. I was part of a research project on amphetamines myself at one point. It had nothing to do with my health at all. And I think I was able to give informed consent on that subject. So the question of consent for embryos, well, that's a whole totally murky kind of area. I don't think obviously you can give consent for an embryo because you have no idea what that embryo might have wanted, where it's going, or anything else. I am going to put that question aside and not even try to mess my way through that, which would be a confusing business anyway for me. DR.GÓMEZ-LOBO: Yes. I'm a little bit disappointed, because that is exactly the kind of guidance - DR. CALLAHAN: That's not my charge at this meeting. And I will give you references I have written on that, but I can't do it in three or four quick sentences. CHAIRMAN KASS: Bill May? DR. MAY: The paper and the presentation are offered with your characteristic reasonableness. I would simply like to explore the question of the place that you give to research imperative in the setting of a metaphor, a fight against death and understanding of death as a contingent, accidental fact and, therefore, the tension between that research imperative driven by that military metaphor with what you call the clinical imperative, at least the old clinical imperative. You're talking about an imperative directed at doctors. I'm not sure if that is what you mean or patients where the imperative is to accept death as a biological fact. Now, it seems to me what this leaves out, that gives heft to the research imperative, is a further structural characteristic of death, that death is uncertain but uncertain as to time when— Heidegger worked all of that out. And behind that was Kierkegaard. Uncertain as to time when creates a huge opening that allows one to give the impression that one is fighting against death. But one really creates space for the avoidance of death. We send people to hospitals so often because that is where the battleground is located and where we have got people equipped to fight against that. And if they don't have all the resources behind them, it's research so that if it isn't successful with this patient, it will be successful with future patients, all of that. But the other deep response to death is not simply fight but flight or avoidance. And so the military establishment fighting against death offers an important psychological service to patients. Yes, it's certain but in a sense uncertain as to time when this is going to happen. And there are still tricks that the doctor will have and so forth, so that push in the direction of orienting even what goes on in the clinical setting, to if not curative efforts, delaying efforts and so forth. Now, what this leads me to think about is a huge shift in the religious landscape from earlier centuries, a West shaped by a notion of a creative and nurturant God. And purportedly the authentic life was to be open to this deity and then two forms of reaction to this deity, which were defined as sin, fighting against God, Luciferian revolt against God, and avoidance of his presence. That was Philistine flight. So you had a fight and flight response in relationship to the deity. One might argue that the religious landscape of the last couple of hundred years has shifted over that the encompassing reality is not a creative, nurturant God but what James Joyce referred to as dio boia in "Ulysses," the hangman God, or Camus said, "The whole world is organized by death. In the end, we're all done in." And then you get people like Kubler-Ross saying, "Hey, let's be open to this. And, indeed, being open to death, finally we're open to ourselves at our deepest level." And she gave, in a way, Heidegger-on-the-cheap there. But, on the other hand, the terrific attraction of fighting against death and, further, the compounding of that that you set up an apparatus of fighting against death that offers people the sense that we don't get heft to face it. So avoidance, at a deep level, helps drive and give heft to the research imperative. The way you have written this chapter, it seems as though the research imperative is driven by the military metaphor and then spills over into the clinical setting when I think the existential setting is quite the reverse for people, that it is certain but uncertain as to time-when. And there were things to be done in the hospital that I can't do at home. So you put them there and so forth. So it allows one not to have to face it yet. Now, yes, medicine ought to recover that old, old imperative, learning how to accept finitude and death. It was very difficult to do in a setting where one really feels that ultimately one is facing a hangman God. The kind of religious background, it seems to me, would ask one to talk about the drive behind the research imperative. That may be at a deeper level and more complicated level of our attraction to it and the temptation to it. DR. CALLAHAN: Well, just a quick response. It seems to me that, even if one accepts the reality of death, it's seemingly understandable that we would like to stall things a bit, take our time. But this is true of a lot of things that are rather unpleasant. We avoid and we flee. When the doctor says, "Well, you have to have your tooth pulled," we say, "Well, how about next week, rather than tomorrow?" and so forth and so on. I think the question of the research imperative is - the way I like to put it is whether we ultimately believe that death is kind of a biological accident, a contingent event that ultimately can be overcome as distinguished from simply forestalled. And it seems to me that the whole trajectory of modern medical research has been basically to treat it as if it were an accident. As far as I know, there are no fatal diseases that the NIH finds acceptable. The NIH is not in favor of immortality, at least officially, but there are no diseases that kill people that it is prepared to tolerate. And it puts money into research, any and all lethal diseases. So the logic of that whole movement is - DR. MAY: Long before there was modern research, you got Frazer and "The Golden Bough" talking in traditional societies, a tendency to look upon death as an accident; or in Freud, the eagerness to find out the cause of death because it is an accident that befell somebody else and not me or you get the same thing again in Tolstoy's "Death of Ivan Ilych." DR. CALLAHAN: But I think with contemporary medicine, we get a new plausibility to thinking that way. That's the difference. CHAIRMAN KASS: Rebecca Dresser, then Paul. PROF. DRESSER: I share many of your views and concerns. And I think I am so happy that you are writing about this in your usual eloquent and elegant way. I had two questions. One is, you alluded to this but didn't speak to it directly. Something that I think goes on is the equation of provision of proven health care with money for research in the political setting and sort of public ethical debate. I take it you would see those both as goods. And so then the question would be weighing and saying which should have priority, but I wonder if you can comment on how you might weigh those two, the provision of proven health care to more people who don't get access to it, versus money for research that might improve the health care we have available now, but at the same time leaving more people without it. And then my other question was about procedures, sort of at a practical level. If we are to try to make progress toward revising priority-setting in these social programs, any ideas how we might go about doing that and the role of lobbying and all of this? Any thoughts in that direction? DR. CALLAHAN: Well, let me begin with your second question. I like the system used by the British government. Of course, they have the National Health Service. It's financed by the government and run by the government. But I gather that a part of their annual budget-setting is that the different social areas have to compete against each other. They have an open debate: education versus health versus economic development. I would love to see that. Even if done informally, I think it would be terrific if somebody could have a great television program getting people, leaders from the different sectors and say, "Okay. You want more money for education. Are you prepared to say less money for health?" That would really put everybody on the spot. I think if we could get that in open debate, it would be very valuable. I think on your first question, I think one major reform that I am in favor of in the priority-setting area and in support of research is that we really now need to look very carefully at the economic consequences of research. Right now recently Medicare had some hearings to look into new heart technologies that are going to very radically increase the costs of treating heart disease. And the question is, which ones should Medicare cover? Now, typically that is done more informally, rather than as a public debate. I would like to see that done openly. I suppose my most radical suggestion would be that those companies that manufacture new devices and new drugs must, at the same time as they are doing safety studies and efficacy studies, be doing economic studies and saying, "This is our projection of the economic impact of doing this" and before the technology is released. The typical procedure now is technologies are developed. And they're sort of thrown out of the window. And they say, "Okay. You health care administrators sort of deal with it. That's not our problem." And I would want to say we should make it their problem. And I suppose if you want to go really far, you would say no technology or at least to be reimbursed by the government until it has had a very solid economic analysis and debate and some consensus on whether this is economically worth advancing. Now, the typical attitude of researchers is, well, a) that's not really their problem; and, b), after a while, we find ways to pay for things anyway. And this will hold up research. Well, it probably would hold up research, but, an issue that didn't come up at all, I happen to believe that research is one of the main things that drives up costs, that right now we are seeing cost inflation 10 to 15 percent a year. The estimate is 40 to 50 percent. It's coming from new technologies or intensified use of old technologies. If that's the case, then I think we have to very squarely face the problem of the research behind those technologies and learning how better to evaluate the new technologies that come on line. And all of that is set within the larger context of comparing health with other things in society. But I think more generally, it seems to me a really tragic situation when we have — to me, the worst arguments around are those on the part of the pharmaceutical companies that say, "We need these high profits to save future lives" when, by God, if they bring the price down, they could save lots of lives here and now in Africa by making their drugs available. So that this notion of these wonderful lives in the future somehow comes at a discount rate for the future. They're basically saying, "Oh, no. These lives are worth more in the future than the present lives we could save now." And the drug companies simply dodge that issue altogether. CHAIRMAN KASS: Paul McHugh? I have a long queue. I will try to get to everybody before the break. DR. McHUGH: Well, I also want to thank you very much and was looking forward to your presentation because I have read your work for a long time and expected, actually, to find just what I found this time, that I agree with so much I am surprised at what I disagree with. Let me develop my disagreements, at least to the point of talking about them in practical terms. I speak now as a person who has run a laboratory and also a person who has been a director of a clinical academic department. In this arena that you have laid out for us of discussing the value and the value of research in relationship to, is it a moral good, or is it an imperative, you first wanted to talk about it in relationship to cost. And it's that point I want to bring up first, that even if it's a good, just a small good, anyone who has had any experience with research, basic science research or clinical research, knows what the problem for our country is in relationship to its financial support. The growth of investigators and the growth of reimbursement is a Malthusian problem because laboratories grow and replicate themselves with their students in an exponential geometric way. And anyone who has run a laboratory begins to notice that he or she has many of these wonderful postgraduate students. They grow. They become directors of their own departments. And they become steadily more expansive in bringing many more opportunities to our world because of that. But tax money and money from the country can only grow arithmetically. So there is always going to be this problem that you raise. Why is it that the legislature, the things closest to the people, closest to the citizenry, will always overrule the executive, ask for more money because more money is going to be needed for whatever, whether it is an imperative or a good, only to do that to our country? On the other hand as well, it may just be my perspective about your work and your presentation here, and it might be just a prejudice on my part. And so we'll accept that at the beginning, but you've got to begin somewhere with a prejudice. And that is, how would I, who think of research as an obligation, a moral obligation, approach that from my experience? And what is research or why research or how to judge research are the issues before us in relationship to is it a good or a moral obligation? And I would like, of course, as you would, to produce, for example, one piece in this scale, namely the achievements in research over these years. Now, you mentioned the wonderful achievements we have had, at least in recognizing the cause of the AIDS epidemic and developing very effective medications for them. I lived, like any doctor who has lived, with the AIDS epidemic from its earliest beginnings right now, when everyone thought that nothing could be done because it was a viral illness, and now out to a place where I am taking care of a vary large number of people who carry the HIV virus but are protected from the things which were discovered. In my area of work, of course, in psychiatry, the results have equally been remarkable, really, with research that is sometimes developed by accident but sometimes developed out of reason. Those results are not just the reason for wanting to speak about it. I also feel that both attitude and educational communities do not thrive unless there is research going on within them. Again, I ran a clinical department. And the very great importance of mingling investigators with the clinicians was to raise the standards of care offered to the patients and very much raise the standards of discourse amongst the clinicians about what they were doing and why they were doing it. Now, in psychiatry, we have this in vivid terms described to us, demonstrated to us by the neglect of research during the psychoanalytic era, what Ed Shorter has referred to in his book on the history of psychiatry as the great hiatus in psychiatry when during the psychoanalytic era, essentially no research was done because everybody thought they knew the answer. Okay? The result of that era was the neglect of patients, the development of snake pits, the concentrations purely on the worried well, and the loss of opportunities in neuroscience and pharmacological work to do it. And for psychiatrists like myself, I have come to believe that there really is an absolute moral obligation to have this in our discipline and in our departments. And, finally, the very attitude that all of this ultimately produces for us is an attitude of not only optimism for the future but also an attitude of criticism for our views at the moment. So for all of that, I think you have laid out a very interesting point. I have to say that there are some fairly fundamental disagreements that I have with the conclusions you came to draw. I hope you will accept it in — DR. CALLAHAN: Well, I guess if you want to continue to use the word "obligation," fine. But then I would ask you, is the obligation to do research in your field — and it is not a coincidence that you feel it in your field and not my field. I feel an obligation for philosophical research probably as strongly as in psychiatric medicine. DR. McHUGH: Oh, I think that — DR. CALLAHAN: I put that aside. But how do you compare with the obligation better housing, community, national defense, safety nets? I mean, my question is, do you want to give it an overriding priority? Do you say that this is worth far more money than anything else or it ought to be put on the scale and compared with the other obligations? DR. McHUGH: Well, you know, once again, in a democracy, we have issues of competing obligations, competing with values. And my assumptions are going to be that we should be trying to meet all of those obligations as we see them and as we interpret them. That is how I am going to do it. And that is why I am in America, where we can earn the money to do it. CHAIRMAN KASS: Michael Sandel? PROF.SANDEL: Well, this follows, Dan, on your discussion with Paul just now. I think there is something needlessly puzzling, confusing about the pieces you present that obstructs what I think is really a very important insight that you are directing us toward. So let me first say what I take to be one of the really interesting directions that you have given us and then say what I think is puzzling and wrong-headed about the way you have put the thesis. By calling into question the research imperative, you have raised a bigger question lying in the background, which you mentioned at the beginning of your talk, about the inflation of health as a moral and social good in our society. And Bill May gave I thought a fascinating interpretation about the existential landscape that might partly account for this dynamic. There may also be — and this is just a speculation - a shift in the moral and public culture that contributes to this. It might be that the more reluctant we become to pass judgment or publicly to affirm what makes lives worthy or good, the more likely we become to affirm what we take to be all-purpose means to any lives. So the inflation of health may be a reflection of a non-judgmental impulse that has entered into the moral and public culture over the past 40 years, roughly the time that you detect this inflation of health. Health is something we in a pluralist society can agree on because we take it to be necessary to the realization of just about any ends that people might pursue, against the background desire not to affirm any particular ends as aims of lives. And you have directed us to this whole question. That may not be the best or the only explanation. But you have directed us, I think rightly, to this very important phenomenon about the inflation of health as a social and moral good. The thesis, what makes the thesis confusing and puzzling, even to those of us who want to sympathize with it, is that you really, as I understand, are saying two things. First, there is no moral obligation to pursue medical research. That seems to me wrong. There is a moral obligation to pursue medical research. Then you are also saying another thing, which you take to be the same, which is medical research is not an overriding good. It doesn't trump all other goods. It has to be balanced. Well, that is surely right. And I suspect everyone would agree with that, but those two claims aren't the same. It's perfectly possible for something to be a moral obligation and still, as Paul says, for there to be competing moral obligations. Consider other examples outside of medical research. There is an obligation to educate the young, to prevent starvation, to save innocent lives where we can, to oppose injustice, to protect the security of the country. Those are all obligations. But to call them and to recognize them as such isn't to say that any of them is an overriding good in the sense that its pursuit trumps all other considerations. So I think that you could win wide support for your thesis that medical research is not an overriding good. It has to be balanced against other competing goods without making what seems to me a puzzling and unnecessary claim that it is not a moral obligation. DR. CALLAHAN: Well, the reason I was trying to deal exactly with that confusion, which is the difference between a perfect and an imperfect obligation, when people say there is a duty to do stem cell research, they're giving it a very special status. They are saying that somehow: a) we ought to do it; and b) others can make a claim against us that they have a right that the duty be exercised. I would want to say most of these obligations are rather nonspecific. Yes, we have an obligation to raise children well. We have an obligation to our national defense and so forth and so on. But I guess I want to say that you can't use the language. You can't make it a very specific kind of obligation because you then have to say, who is the one who has to carry it out? If you want to say there is an obligation to carry out research, who has the duty to do that research? Do we as citizens have a duty that we must put up the money for it? Does the researcher, young researcher, have a duty that he must go into the field that will deal with XYZ problem? It's narrow and very specifically goal-directed. The imperfect obligation it seems to me is the more general one. So I put it in the category of the imperfect, not the perfect. CHAIRMAN KASS: Very quickly, Michael, we're at the break time. Let me ask the remaining people. Dan, are you okay for another ten minutes? I know you have a plane to catch? DR. CALLAHAN: Yes. Unfortunately, I came from vacation on an island in Maine. You can't get there from here or back to there from here without leaving soon. CHAIRMAN KASS: Seven minutes? DR. CALLAHAN: Yes. CHAIRMAN KASS: We'll ask people not to run over so the people in the queue can speak. I have Gil, Mary Ann, Janet, and Dan Foster. PROF. MEILAENDER: Just quickly, Dan, I wonder if I can get you to think with us just a little bit about the structure of your argument because it seems to me there are a couple of aspects to it. The one aspect that flows out of the language of imperfect obligations is to start from goals, really, aspirations that we seek to realize. And there are many such goals that we think of as goods. And we often, contrary to Paul's American optimism, we can't fulfill all of them. That in some ways becomes a process of political argument, then. And that's, in fact, what you have advocated. You would like to see more overt political argument. There is not necessarily any single answer that has to be given to how we should weigh defense and medicine and education and so forth. It is also true, your talk about informed consent suggests that in terms of the means to those goals, that there are occasions when, even when a clear good could perhaps be realized, one has to forego it simply because the means to it is prohibited. And that's what the principle of informed consent accomplishes. I just wonder if that doesn't need a little more emphasis than you gave it, in a sense. If there is not a research imperative, to use that language, then I don't think the primary reason is that we have a number of goals which we have to weigh and that sometimes health care might come out not at the top. The primary reason is that we have accepted, and I think in some ways the research community has accepted, the fact that there are certain things that ought not be done even to achieve a certain kind of undisputed good. That's where you simply can't claim that there is an imperative to do it because there is some other imperative that really does trump it and is overriding. So, insofar as there is not a research imperative, it seems to me that that fact grows primarily out of prohibited means, rather than simply out of conflicting ends or goals. Doesn't it? DR. CALLAHAN: Well, it seems to me that you can say that informed consent itself is a kind of moral imperative. And it's over against the research imperative. I guess I want to argue that the research imperative is troublesome when it is taken to have the power to overcome those moral obstacles. That's when it seems to me it causes trouble, moral trouble. And it basically says it is such a high goal that the means don't matter, that it is worth achieving because what you are doing is of such ultimate good. PROF. MEILAENDER: But you've actually got a duty of perfect obligation in the requirement that you respect informed consent. DR. CALLAHAN: Well, in that particular case, because you have a trust relationship between a doctor and a researcher and a research subject, in that case, you have a situation of perfect obligation because it is a much more narrow contractual relationship of - PROF. MEILAENDER: Not just because of the narrow relation. Because every human being has a right to claim that over against potential researchers. DR. CALLAHAN: But that's exactly the point. They have a right to claim it against researchers because we agree that there is a particular relationship that ought to obtain between researcher and subject. And we, therefore, have put it into the category of a perfect obligation; whereas, earlier, I think it was not seen that way. That was what the whole debate was about. CHAIRMAN KASS: Mary Ann and Janet. PROF.GLENDON: I want to thank you very much for giving us your expansive vision of bioethics as including, among other things, the ethical dimensions of the choices we make about what social goods to pursue, and I just want to see if I can make a little extension of your argument. You have told us that research is a good to be pursued among other goods and that there are difficult problems of choosing among those goods. The extension I would like to make is that in setting priorities among those goods, if you don't set them thoughtfully, and after deliberation, then they are going to be set by default or by the influence of special interests. Would you accept that as - DR. CALLAHAN: Oh, absolutely. PROF.GLENDON: And so some of the references you made to what happens in other countries suggests that there is more of a process of deliberation and balancing in some other countries than there is here within the democratic forum. Of course, a cynical side of me says, "Well, yes, European countries can, just as they do with defense spending, let us spend the big bucks on medical research. And then they have the luxury of democratic deliberation about education," et cetera. Nevertheless, the question I come to is, why do you think it is that it is so difficult in these discussions to get a public debate or even a legislative debate of the type that you mentioned happens in England, a discussion of the pros and cons of pursuing the various good things in a world of scarcity? DR. CALLAHAN: Well, to me the great difference between Europe and the United States is, at least as far as health is concerned and a lot of welfare programs, the government actually runs everything. They either control the financing or financing and delivery as well. And that means they have to work within a closed budget. And once you're forced to work within a closed budget, you then are forced to deal with priorities. You're then forced to deal with rationing, saying some things are comparatively more or less important. By virtue of our strange mixture of the public and the private, we have no way to have a rational discussion because you have so many different actors with different rules of the game. I mean, the whole private sector can go out and develop all sorts of things medically and technologically, which are absolutely beyond the control of any government or any regulation; e.g., private stem cell research, private human cloning if they want. Under those circumstances, it is very hard to set a budget. It is very hard to have a rational discussion. And it is very hard to have any kind of unified outlook that enables you to set priorities. Now, the National Institutes of Health has set a priority discussion and for a very simple reason. They have to live within a budget. They get a certain amount of money. And they then have to decide how to spend that money. So priorities are forced upon them. But we don't have a country that is run like the National Institutes of Health. So that's why I happen to think government is a good thing in this area because the market does not enforce discipline. The market forces profligacy; whereas, it is the government's and closed budgets for discipline and priority-setting. We don't have it. CHAIRMAN KASS: Janet Rowley and Dan Foster. DR. ROWLEY: Well, I appreciate the thoughtfulness with which you have prepared the material. I have to say that I have very serious reservations, some of which were already expressed in a sense by Paul. To me, the use of research imperative implies that there is some direction of this imperative and an agreement to its goals, even unstated. And it seems to me this does not reflect the real world of science or biomedical science as I have lived it for over 40 years. Your statement just now about who is going to tell a scientist to do stem cell research, that is not the way science is carried out at all. It is true it is carried out that way in companies, but in the academic world, which is where fundamental research is really flourishing, the scientists are the ones who have the intellectual curiosity and the creativity to say, "Isn't this an interesting question?" and to follow up on it. I think Liz Blackburn is a wonderful example of somebody who was studying how the ends of chromosomes in yeast were formed and maintained and discovered the enzyme telomerase. And now this turns out to be a very important enzyme in cancer. But who would have expected research in yeast to then have that kind of applicability? So there is no direction necessarily in medical research. It is what scientists find interesting. Now, it is absolutely true that many of the interests are channeled by research questions that are considered to be very important or research areas that are the hot topics. And if you are a young scientist, that is what you want to do because that is where the action is. But I just don't think that there is a research imperative. So I think that your example of NIH and their following many different ways of Parkinson's, in part, that is because there is no good answer. So you try all of the options, hoping that one or a combination of options will really give you greater insight that will allow you, then, the next step to go beyond. And I realize you have a plane to catch, but I want to come back to Alfonso's question of non-therapeutic research on children. I want to point out that our understanding now of how babies learn, of how infants learn, of how different aspects of the nervous system mature at different stages and allow infants to gradually respond and observe, is all done by research, non-therapeutic research. And it has led to enormous changes on how we look on babies and how we look on intelligence. So you have to put these in the context of what it is that you are doing, what is the goal. It may not benefit that baby, but it sure is going to benefit babies down the line. CHAIRMAN KASS: Dan Foster. Why don't we take both questions, Dan, and then we'll let you comment? DR. FOSTER: Well, I will give it to you that the Council seems to have their loquacious genes fully on this morning. As a consequence, I am going to bring it back towards the mean by depriving the Council of my remarks, which were really of eternal significance, but I am not going to - (Laughter.) CHAIRMAN KASS: Do you want to follow that? Why don't you respond to Janet? DR. CALLAHAN: Okay. I certainly wasn't claiming that the research imperative has goals. The research imperative in its benign sense I simply mean has a very strong sense within the scientific community supported by the American public that research is a good thing that ought to go forward. And we ought to put money into it. And that's what I mean by the imperative, that this is a valuable thing that should be carried out. That's all. The goals are all over the place. People have different goals at different levels and so forth, so on. And, of course, you are someone who spoke for the research imperative. Your scientific colleague said exactly sort of what I was saying. CHAIRMAN KASS: Council members, we have run over. We have a guest waiting to speak. Let's return at five minutes of 11:00. Dan Callahan, thank you very much for being with us. We're adjourned for 15 minutes. (Applause.) (Whereupon, the foregoing matter went off the record at 10:41 a.m.
and went back on the record at 10:58 a.m.) SESSION 2: STEM CELL RESEARCH: CURRENT ETHICAL LITERATURE CHAIRMAN KASS: This is the second session, "Stem Cell Research: Current Ethical Literature." As Council members surely recall, the formation of this council was connected to President Bush's decision announced in his address to the nation in August of 2001 to permit for the first time the use of federal funds to support research on human embryonic stem cells, this despite the existence of congressional statute, the Dickey-Wicker Amendment that prohibited the use of federal funds for research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to injury or death, risks of injury or death, greater than that allowed for research on fetuses in utero. Among its other functions, this Council was charged with monitoring stem cell research; that is, following and keep abreast of all developments, scientific, medical, ethical, and legal, in this exciting area of research, embryonic and adult. The rest of today's meeting is given over entirely to helping us fulfill that charge. We are following and monitoring developments in the ethical argumentations on stem cell research, developments in the basic scientific research and clinical application, developments in the state laws, as these have taken place over the past two years under the current federal policy. To aid us in these monitoring tasks, we have commissioned seven review papers: one on recent developments of the discussions of the ethics of stem cell research, five on recent scientific and clinical developments in five separate areas of embryonic and adult stem cell research, one on recent developments in state law regarding stem cell research. The ethics review paper was prepared by our guest for this session, Professor Paul Lauritzen, who is professor of the Department of Religious Studies and the director of the Program of Applied Ethics at John Carroll University in Cleveland. Speaking only for myself, I would note with gratitude that Professor Lauritzen has tried in his paper to expand our horizon of the relevant ethical issues to include matters beyond the one that has so preoccupied us, namely the important issue of the moral status of the embryo. I would like to welcome Professor Lauritzen, who will offer a beginning presentation, after which both the presentation and his paper will be open for our discussion. Thank you very much for joining us. We look forward to hearing from you. DR. LAURITZEN: Thank you. Let me begin by saying I made the mistake of sending the slide show ahead of time and got a call from Dean Clancy last night wondering what the slide show and my presentation had to do with my report because I had decided not to simply summarize my report but to just highlight a few themes in my presentation. And I suspect that Dean is a better and keener observer of human nature because he pointed out that perhaps not everyone would have read the report as carefully as I might have assumed. But I wasn't going to write another presentation at nine o'clock last night. And so I am going to give the one I wrote, which really takes some themes of my report and tries to highlight them by way of some additional data. Mostly I am just going to read this. Several people who have read the draft of my report have commented that for someone who argues that we should move beyond the debates about embryos and the status of the embryo, I spend a lot of time in the report talking about embryos. At the risk of inviting that objection today, I want to begin with of slide that reproduces data reported recently from a study conducted jointly by the Society of Assisted Reproductive Technology and the RAND Corporation on the number and dispositions of frozen embryos in the country. Forgive me if you have already considered this data, but it wasn't clear to me whether you had. As you can see from the slide maybe and based on a survey of 340 of the 430 assisted reproductive technology practices in the United States, the documented number of embryos in frozen storage as of April 11, 2002 is approximately 400,000. Moreover, the study was able to document the use to which these frozen embryos were designated by the IVF couples from whom they came. Indeed, one point of the study was to determine how many frozen embryos are, in fact, available for use in the derivation of stem cell lines. Despite the fact that many advocates of stem cell research call for deriving stem cells from embryos left over from IVF procedures, the authors of the study contend that so-called "spare embryos" are not a ready source of stem cell lines. Of the nearly 400,000 frozen embryos in storage, apparently only 11,000 are available for possible use in deriving stem cells. Although this seems like a large number of embryos, according to the authors, in fact, it is not. And they break down that 11,000 along these lines. Of those 11,000 or approximately 11,000, only 65 percent will survive the thawing process, leaving roughly 7,000 embryos. Only 25 percent of that 7,000 will develop to the blastocyst stage, leaving roughly 2,000 blastocysts. And only 15 percent of those blastocysts will yield viable cell lines, leaving roughly 275 cell lines. According to this study, then, despite the large number of embryos frozen in this country, the number of potential stem cell lines available from their use is relatively small. This is clearly an important study. For one thing, it gives empirical grounding to the claim that we can derive stem cell lines from frozen embryos. It is less likely to be widely cited. My reason for beginning with it, however, is quite different. I wish to highlight not the number of frozen embryos cited in the study but, rather, the date of the study's publication, namely May 2003. As the study points out, the first live birth in this country from a cryo-preserved embryo was in 1986. That means for nearly 20 years, we have had almost no idea of the scope of embryo cryo-preservation in this country. Let me make two observations about this fact. First, I believe it supports my claim that talk about respecting the embryo from conception is frequently more rhetorical than anything else. If the early embryo is really to be treated as a being who deserves serious respect, you would think that we would at least know how many embryos are routinely frozen, discarded, or otherwise lost through IVF. Not to put too sharp a point on it, but if each embryo were equivalent in value to a dollar bill, we would have lost track of nearly half a million dollars. Second, the fact that until recently we knew almost nothing about the numbers or the dispositions of frozen embryos highlights just how unregulated the world of reproductive medicine is. As this Council knows well and as the staff working paper to be discussed tomorrow highlights, the world of reproductive medicine is almost entirely unregulated. Cryo-preservation of embryos is just one of the many developments in reproductive medicine that has been introduced as therapy without any sort of clinical trials and without any real oversight. The significance of this fact in relation to stem cell research is that we have in reproductive medicine a model for what happens when commerce is wedded to desperation, when research is privatized, and when there is essentially no regulation. More than one commentator has invoked the image of the Wild West to capture this scene. The image strikes me as particularly apt, not least because the wild West was notoriously dangerous, at least as it has been conceived in the popular imagination. There are clear dangers in the unregulated world of reproductive medicine. I know there is some controversy about this point, but consider the report in the New England Journal of Medicine last year on the risks of major defects after ICSI and in vitro fertilization. According to this study, infants conceived of reproductive technology were more than twice as likely as naturally conceived infants to have major birth defects diagnosed during the first year of life and were also more likely to have multiple major defects. These were the odds ratios after the numbers were adjusted for maternal age, multiple births, and other factors that might have skewed the data upward. Moreover, the increased risks were not confined to just one organ system. They were found in cardiovascular, urogenital, musculoskeletal, and gastrointestinal systems. Again, my point is not to focus on specific problems with reproductive medicine, as it is currently practiced, but to highlight a pattern. Just as opposition to embryo research has led to the privatization of work on in vitro fertilization, with virtually no oversight or regulation of IVF, so, too, has it led to the privatization of stem cell research with similar results. This is one reason I have noted the relation of IVF and stem cell research in my report. The other is that I do not think we have fully appreciated the deep tensions between the widespread acceptance of IVF and a widespread profession of respect for the early embryos. A foolish consistency may be the hobgoblin of little minds. And Emerson may be right that such a consistency is adored by statesmen, philosophers, and divines. But consistency in ethics is rarely foolish. I have no quarrel with Emerson's advice to speak your mind forcefully today, even if it flatly contradicts what you thought and said yesterday. My concern is that we speak out of both sides of our mouths simultaneously when we say that destroying an embryo is killing a person or that, indeed, the early embryo deserves profound respect and also say or act as if discarding embryos in IVF is non-problematic. I tried to illustrate this point in my report by drawing attention to the cartoon comparing reactions to a stem cell clinic and an abortion clinic and then asking the reader to imagine that an IVF clinic is substituted for the stem cell clinic. Here is the cartoon. As you can see, the cartoon depicts protesters in front of a stem cell research lab, condemning those who worked there as being anti-life. Down the street at the abortion clinic, the workers are noting how quiet things have gotten at the facility since the stem cell lab opened. The point of the cartoon, of course, is that opposition to stem cell research appears to be almost as passionate as opposition to abortion and that there is perhaps an irony in the fact that pro-life advocates, thus, appear to be committed to demonstrating against research being done to find treatments for Alzheimer's, Parkinson's, and other devastating illnesses. Now, try to imagine protesters standing outside an IVF clinic or, even better, outside maternity wings, condemning couples who use IVF as murderers or at least complicit with murder. It is almost impossible to imagine this scene. And it is worth asking why. If the early embryo is fully a person, shouldn't we condemn IVF and work to prohibit it? Is condemning stem cell research but accepting IVF not inconsistent? Of course, one response to this alleged inconsistency would be to say that we should, in fact, be consistent in trying to prohibit both IVF and embryonic stem cell research. I do not subscribe to that position myself, nor do I think it is a politically viable option. But it would at least be consistent. Notice, however, that a ban on embryonic stem cell research will not eliminate the many issues raised by the prospect of regenerative medicine. And that is another theme from my report that I wish to highlight. Although the ethics debate has mostly focused on the status of the early embryo and has, therefore, tended almost exclusively to issues raised by embryonic stem cell research, we need to take a closer look at issues raised by the prospect of adult stem cell research as well. I have discussed some of these issues in my report. And I merely list some of them here. They include issues of social justice; of commodification or of commerce; issues about the conception of nature and what nature might mean; issues about human embodiment; issues raised by the erosion of species boundaries, so-called hybridization; and issues for implications of personal identity and moral responsibility. Worries about eroding the boundaries among species, about destabilizing the concept of nature, and about treating human bodies merely instrumentally are related. I believe that this cluster of issues deserves special attention going forward. And, again, my point is that it's a cluster that is raised for adult stem cell research as well as for embryonic. So that while we ought to continue debating the status of the embryo, we also ought to move beyond that debate to focus on these other issues as well. I also think that we might do well, at least initially, to think about these issues outside of the contested question of human nature. For example, I wonder whether there is some merit in considering the pervasive human manipulation of nonhuman animals. For example, it may be useful to take as more than a curiosity the so-called transgenic art of Eduardo Kac. Several years ago Kac made headlines around the world with his public art intervention that included Alba, the green fluorescent protein bunny. As you may recall, Alba was an albino rabbit that glowed green under certain light because it had been genetically altered and carried a gene from a jellyfish. Kac defined transgenic art as "a new art form based on the use of genetic engineering to transfer natural or synthetic genes to an organism to create new living beings." And here is a slide of Kac with Alba. Many people were outraged at Kac's creation. And many dismissed his work as a publicity stunt. But, in fact, part of the point of the Alba project was to generate a public conversation on the cultural and ethical implications of genetic engineering. According to Kac, "The creation of a chimeric animal forces us to examine notions of normalcy, heterogeneity, purity, hybridity, and otherness." Here is Alba glowing green. The claim that I just read is a bit too jargon-filled for my taste. That he did not use "alterity," instead of "otherness," is astonishing. But Kac's work invites us to reflect on the implications of turning nonhuman animals into artifacts. Of course, we have been doing that for a very long time. Still, it's worth thinking carefully about our reaction to the creation of Alba. It is worth asking whether our reaction to Alba is different from our reaction to, say, the creation of the Harvard oncomouse and if so, why. I began my written report with a passage from C. S. Lewis. And so it's perhaps fitting to draw my presentation to a close with another passage from the "Abolition of Man." Lewis writes, "Now, I take it when we understand a thing analytically and then dominate it and use it for our own convenience, we reduce it to the level of 'nature' in the sense that we suspend our judgments of value about it; ignore its final cause, if any; and treat it in terms of quantity. The repression of elements in what would otherwise be our total reaction to it is sometimes very noticeable and even painful. Something has to be overcome before we can cut up a dead man or a live animal in a dissecting room." Although it is perhaps justifiable to reduce the world of nature to mere nature, as Lewis puts it, I am inclined to agree with him that something is lost when we do so. When I reread the "Abolition of Man" in working on this presentation, I was struck by the fact that the sort of dynamic Lewis describes here is very close to that recorded in Jonathan Glover's impressive work "Humanity, A Moral History of the 20th Century." Glover writes, "Human responses are the core of the humanity which contracts within humanity. They are widely distributed. But to identify them with humanity is only partly an empirical claim. It remains also partly an aspiration." As Glover powerfully argues, morality must be rooted in human needs and values. And these needs and values are both rooted in human nature and grounded in human aspiration. As we move forward to wrestle with issues of stem cell research, we ought to be conscious of what is at stake in the possibility of redefining either our natures or our aspirations, for, as Glover makes clear, the inhumanity of humans is a frightening and all too familiar thing. Thank you. CHAIRMAN KASS: Thank you very much. I assume, Professor Lauritzen, that both the presentation and the paper are fair game in the discussion. DR. LAURITZEN: Sure, absolutely. CHAIRMAN KASS: Does someone want to start? Jim Wilson, please? PROF. WILSON: I wanted to be clear, Professor Lauritzen, in your views. You displayed the differences in the cumulative prevalence of diagnosed major birth defects singled in infants resulting either from natural conception or IVF and pointed out that the data suggest that that incidence is roughly twice as high with IVF as it is with natural conception. Do you conclude from that that we should be opposed to IVF? DR. LAURITZEN: No. I mean, first let me say that data is somewhat controversial, I gather, in that there are other studies that don't show that kind of risk. Rather, my point is that we don't have the data. I mean, that is part of the issue here. I have to go back and look, but I think that data actually came from western Australia. So it doesn't even reflect data in this country. I think that is right. I would have to go back and look. The point is we are not tracking the potential health consequences of in vitro fertilization in anything like the way we should. And it seems to me part of the reason is that this is an area, reproductive medicine is, which has almost no oversight. And it obviously also has almost no federal funding. Had there been federal funding, there might have been more oversight. But even apart from the issue of federal funding, it is an issue of one area of medicine where the move from a novel idea, like intracytoplasmic sperm injection, moves very quickly into clinical practice when it is really a therapeutic modality that has been largely untested. And then it is offered as a therapy when it is really, in fact, experimental and not tracked in any significant way. So we don't know, long term, what the genuine health risks have been. So that one of the issues here I think a staff working paper - the Council may have flagged that. The little regulation there is tends to be sort of consumer protection regulation so that prospective couples using IVF should be protected in some way, get adequate information about success rates of clinics and things of that sort when, in fact, there may be larger public health issues about the long-term implications for women and children, for the women undergoing high-dose hormones to induce hyperovulation and for the children to see if there are long-term health consequences or, for that matter, short-term ones. PROF. WILSON: Could I make one follow-up? DR. LAURITZEN: Please? PROF. WILSON: I certainly agree with you about the unfortunate lack of longitudinal research that will track babies from these processes. My view is that we should encourage this. But let's suppose there is this longitudinal research to the extent that we can. And let's suppose, in effect, it replicates the data you have presented for the United States over the long term. Would such data lead you to question the value of IVF? DR. LAURITZEN: Well, I think it raises certainly issues about which there is a significant literature in the philosophical side of things about so-called harm to future children. And there are folks like John Robertson who have argued a variation of the point that essentially you can't harm by bringing that into existence because without the technology, this child would not exist or the adults that might come from the child. So that even if it turned out that there were significant health risks, much higher rates of cancer in children, in vitro fertilization procedures, that you haven't, in fact, harmed those children because they wouldn't have existed otherwise. My own view is that that is not the right approach to frame it entirely in terms of harm to the specific child and compare that to nonexistence, which obviously is a difficult comparison. So I'm dodging your specific question, I think, a bit except to say we ought to sort through it. I mean, obviously there is no regulation preventing couples to reproduce who are carriers of known genetic effects with a certain percentage likelihood of problems for their children. So I am not saying necessarily that that would mean we should shut down IVF programs, but it's information we need. It's, frankly, information that ought to be a kind of obviously a fairly detailed part of the informed consent process for couples considering using IVF. And I don't think that any of those things are true now. PROF.WILSON: Thank you. CHAIRMAN KASS: Janet Rowley? DR. ROWLEY: I would like to follow up on both your comment and then Jim's question because I think that it is extraordinarily important that we emphasize, as we have in previous Council meetings and in the document we have under consideration, the lack of reliable long-term data on the outcome of IVF and ICSI and other procedures. I think we have to emphasize that that is because there has been no money available to gather such data. And such data is going to be very, very costly to obtain. I know just in terms of our own research projects of tracking down cancer patients and what's the long-term outcome of their treatment, that to try to find these individuals is extremely difficult. The laws have just been changed, the Privacy Act. So I would think that before you can contact any individual, you have to go to the clinic. The clinic has to go to that patient and say that they're trying to collect information and would the patient be willing to provide that information before you can even begin the collection process. So this is no small task that we have set and that apparently CDC is embarking on because it is a two or a three-stage process before you get it. And you say research is privatized. This is the only area of medicine in which research is privatized. And, again, that leads to the problems that we are currently facing. CHAIRMAN KASS: Thank you. DR. LAURITZEN: Can I just make one observation on that? CHAIRMAN KASS: Please? DR. LAURITZEN: I think there is going to be that difficulty of getting consent. There is also I think in the case of reproductive medicine the additional difficulty that the prospective parents in giving that consent would have to be acknowledging in a way that is different from cancer, where the expectation is that there is going to be certain morbidity and mortality. Well, the assumption that most infertile couples have is that if we go forward with this, we are going to have a healthy child and there aren't going to be long-term problems. So I think to some degree, reproductive docs are going to be a bit reluctant to raise the specter of potential long-term harms going in. DR. ROWLEY: Can I make two comments? One, my impression is that most infertile couples who live in states where there is no insurance and, therefore, they are paying 30 to 50 thousand dollars for this procedure are pretty sophisticated and, as a consequence, know the risks that they face. What we are trying to get is data on children 5 or 10 years old or older now and what is their status so that the individuals involved in IVF 5, 10, or 15 years ago gave no such consent for this follow-up information. And that is the first step of running a survey, to get their permission to even contact them to get the information. CHAIRMAN KASS: Thank you. Just as one fact, I understand that the NIH is gearing up for a massive study on children, a prospective study. And it might be of interest to us to explore the ways in which some of the things that we would be interested in might be incorporated in the planning of this study as it goes forward. But that's for a later discussion. I had myself in the queue. Let me deal with things in the paper, rather than in the presentation. A couple of comments and then a question. First, I guess it's fair to say you criticize what you take to be the excessively individualistic treatment of the ethical questions, especially as they are concerned with the matters of the embryo or even the language of rights in this area. I would simply observe that in questions of life and death, which, after all, are things that befall individuals, a certain individualistic focus ought not to be pejorative but is somehow necessary, that there might be other kinds of goods that are here that don't concern individuals, but the people who care about whether or not embryonic life is destroyed will, in fact, care about the death of individuals. And that can't be avoided. Whenever you are dealing with a question of death, you can't sort of avoid that. That would be an observation. I don't imagine you would dissent from it. I would take that as a friendly amendment. Second, on the questions of economics and commerce, it seems to me there are three things potentially that are bothering you here. One is the notion of commerce in the body altogether. Second are questions having to do with distributive justice and unequal access to the benefits that are available. And third is a kind of faint whiff of a dislike of profit, although it doesn't come out very strongly. These are questions that have come up around the table before. And I am sometimes sympathetic to these arguments, but reading your paper made me less so for these reasons. It seemed to me that the mere assertion of inequality is not ipso facto a demonstration of injustice, though the question of equal access is important. The remarks about the truck company said, after all, why should they be able to profit from the embryos when the people whose embryos they were don't? The answer to that is they have mixed their labor with it extracting the stem cells. The embryos as such are not by themselves valuable until somebody has done something to them. So at least there is a prima facie case for saying that there is some claim for profit. And then on the question of commerce in the body, I am not so sure whether it is the money changing hands that bothers us as much as it is sort of the free alienation of body parts. We don't object to people selling their labor, although people have done so. And, therefore, I wonder whether what might bother us is even - if there was something that was somehow disquieting simply about the giving of an embryo for research, we would be bothered by the fact that someone might be paid for it. I think the commercial aspect of this is a sign that there is something beneath the commerce that is troubling to us. I have got more, but that is too much. Let me stop. I would be interested in your comment, really, on this nest of the economic questions. It's not the first time that we have taken them up, but we haven't taken up in the stem cell context. And I think it would be useful to spend a few minutes on that. DR. LAURITZEN: Sure. Well, my first reaction is to say that I'm not sure your nose for the smell of the concern about profit is on target. I would be happy to accept a larger stipend for my work here. So we can talk about that afterwards. CHAIRMAN KASS: People make exceptions to their own case. DR. LAURITZEN: I mean, I do think it's a fair observation. And it depends, I suppose. One point about the embryo, the difference between the researcher who mixes his or her labor to produce the product and the embryo is going to depend, of course, what stage we're talking about with embryo research. And, arguably, women have mixed the labor of their body in producing either the eggs and going through the hormone regimens to generate the embryos or if we're talking about an embryo then subsequently brought to term, obviously there is the work of gestation, though I don't like that kind of language particularly. And that may just be my anti-profit convictions of some sort. As you were talking, I was trying to think of some comparisons. Here I am just trying to mine an intuition in a way that as I thought about surrogacy, for example, in the past, I have always found the prospect of surrogacy more troubling in a case where there is a paid surrogate than in a case where there might be a family member who has stepped forward to carry a child. So I am not sure quite how you put the point, but there is something about the commercial aspect of paying the surrogate that seems problematic in a way that a sister or a cousin or something who might offer to gestate a child doesn't invoke. So I am not sure - CHAIRMAN KASS: Why is that? DR. LAURITZEN: Yes. I think it is a good question. In part - well, I'm not sure. Let me say that my inclination at this point is to draw on the story of the minister who had gone to seminary and had training in doing sermons, which I haven't had the benefit of. This guy was giving a talk at the university. And he had a written text. I went up afterwards. In the margin throughout, there were a couple of marginal notes that were "PP." So I was puzzled by this. And I asked him what they referred to. And he said, "Pound the pulpit." So he always pounded the pulpit at the weakest point in his argument. And I'm inclined to pound the pulpit here. I'm not sure that's the best response, but it may be all I can come up with right now. CHAIRMAN KASS: Gil Meilaender and Alfonso. PROF. MEILAENDER: At the risk of dismaying our chairman, although perhaps not to your surprise, I want to come to a question about the structure of your paper, the way you work it out, where you suggest that there has been too much attention paid to the embryo status question and not enough to this other range of things. Leon congratulated you on that, and I want to worry about that a little bit. Well, okay, Leon, I am just having a little fun with you. I haven't at the moment come up with a great analogy, but if in the instance of warfare, for instance, we were using all sorts of very large, powerful weapons with very little concern about the collateral damage that came to people apart from the military targets themselves and I was worried about that and you said, "Well, yeah, but let's don't focus too much on that. Let's worry about the fact that we are probably stereotyping our enemies when we think we can do this to them," that we may coarsen our sensibilities in pursuing warfare in this way, that acquiescing too quickly in this may keep us from developing other better kinds of weapons and those are the things that we really ought to worry about while proceeding to bombing the living daylights out of them in this way, it would strike me that - and you will recognize that this is a version of a different formulation - that would be an argument for sort of unlimited casualties always with tears. We should always feel bad about these casualties because of all of these other reasons involved while we continue to inflict them. It seems to me that that is sort of the structure of your argument. And while I don't wish to deny that one or another of the issues that you raise might be important to think about, indeed, that they are all important and that taken as a package, they bear considerable weight, I can't imagine that we would worry so much about them if we had entirely set aside the issue that you say we have worried too much about, namely what we ought to think about the embryo. And so I guess what I want to know is, will you accept my description of the structure of your argument as sort of unlimited stem cell research always with tears? And if you will, are you really prepared to defend that kind of moral argument? DR. LAURITZEN: What you need to know is that Gil has accused me of this once before. I think I denied it in that context and will probably deny it again here. It seems to me that in urging in some way the expansion of the moral discussion, I don't want to suggest that we not attend to the status of the embryo. There may be a way in which I put my point too rhetorically sharply to try to suggest that. So I don't want to suggest that we stop talking about the embryos, the status of the embryo. We are going to have sharp disagreements around the room. And there is a sense in which what I said in the report was suggestive of the fact that, look, it's hopeless. We're never going to make any progress on this. So let's just stop talking about it. And I may have come close to saying something like that. I didn't mean to. After all, we have made progress on moral status questions in the past. I mean, we certainly in this country have made progress with regard to African American status and the status of women historically. I think there is some reason to suggest that we have made at least some progress with regard to thinking about the status of nonhuman animals. So I think their status questions are important and we should continue to talk about them. But my point, instead - and I suppose this is something of a structural issue. My point is to say, why don't we bracket for a moment that which divides us and focus on that about which we are united? There may not be universal agreement about those thing we're united about, but I think we would find more commonality around the table if we started focusing on some of the issues that I identified that apply to both embryonic stem cell research and adult stem cell research, which might, in fact, lead us to hesitate to do embryonic stem cell research, not because we share the conviction that their early embryo is a person with a full moral status but because we agree on a cluster of other values. So that I don't think I am necessarily suggesting that we continue doing, necessarily doing, embryonic stem cell research and just wringing our hands about it, though I do say in the end, just to try to weigh my own position out, in fairness, that I think it is justified to go forward with both embryonic stem cell research and adult stem cell research in a carefully regulated way. PROF. MEILAENDER: As long as we're haunted by it. Is that the language? DR. LAURITZEN: Yes, that we will be haunted by it, we will be wringing our hands about it and I will be crying and tearful. But I could easily be persuaded that part of the regulation would be, for example, moratorium on embryonic stem cell research until we do more adult stem cell work but, even there, be awfully careful about how we are doing it. So I don't entirely accept your characterization, but it's not entirely unfair either. CHAIRMAN KASS: I have Alfonso. Bill, do you want on this point or - DR. MAY: Not directly. CHAIRMAN KASS: Okay. Then I'll put you on the queue. Alfonso? DR.GÓMEZ-LOBO: I'm going to refer to the paper as well, but I'll preface that by saying that, unfortunately, it seems to me on certain moral issues, we just have to have sharp disagreements, the idea focusing on what we have in common. That papers over the deeper question, will it not serve the American public? I read your paper over a couple of times because I don't see in the paper the presentation of the arguments. I see descriptions. I see appeals. But, for instance, to put embryonic stem cell research and adult stem cell research as closely connected it seems to be obscures an argument that some of us have against one and in favor of the other. That's why, for instance, I would say I am all for stem cell research. My only concern, my single concern is that we not use, destroy, or instrumentalize human beings to do that. That is why, for instance, one of the great challenges I see for the scientist is just try to figure out how to get those stem cells without destroying the organisms. It's a challenge from someone who is viewing this from the point of view of moral philosophy. And that's why I am very interested in your arguments for your final statement that you think that an embryo is not a person. And just to go out on a limb, let me give you an argument. And you please try to refute it. I would say the following. I have a twin brother. I was conceived 64 years ago. I got my genetic inheritance from my father presumably at the time. Genetically I am the same individual I was back then. And spatio-temporally also, I have the relationship of saying this with that early embryo. If you pursue me in time and space, it turns out that I am the same individual. And then my second premise, well, I am a person now. I am a human being now, and I should be respected now. Why should I not have been respected then? DR. LAURITZEN: Well, a couple of things, first about your earlier point. I guess what I want to press you on is why your only concern about stem cell research, adult or embryonic, is that it may destroy human beings. I think there is certainly a range of issues that I think have come up in other Council deliberations that I would urge you to take up going forward about the social implications of profoundly enhancing human characteristics in various ways, perhaps radically increasing the human life span. Whether that is realistic or not is another matter. But if, in fact, it is, it seems to me to raise important moral issues. Already this morning we have had some discussion. Dan talked about Harold Varmus' concern about access to therapies. All of those issues are I think terribly pressing moral ones. And they don't have anything at all to do with destroying embryos or necessarily destroying human persons. So in a way, that's what I mean to say. I think we would have a very interesting conversation about that when we didn't talk about embryos at all. The second part has to do with embryos. There is some material in the report that I think is at least intriguing to talk about the developmental potential of that early embryo as if it was, in effect, a kind of little homunculus that just is going to develop in a set way is just biologically inaccurate, that it's the interaction of a complex set of systems that in your case, in fact, led to an arc that 64 years later is you. And you can trace back that arc. But that doesn't mean that there was the potential in that early embryo or only one natural kind of teleology that leads to you. In a different environment, it would have led to some other. Well, if we derive stem cells and then grow an organ from them, say, well, we say that heart, we can trace back to that embryo that was then disaggregated to produce the stem cells. I didn't jot down everything you said but genetic relation, spatio-temporal relations, you could trace the same arc backwards if the environment were such that it produced something else. This is a fairly common argument, but I don't find it compelling. CHAIRMAN KASS: I'll give you one more round briefly. You see the incorrigibility of this. One more shot. DR.GÓMEZ-LOBO: I'll follow the rules. A heart is a part of an organism. It's not a complete organism. And what matters, really, is the entity through time of the complete organism, it seems to me. CHAIRMAN KASS: Michael Sandel, Bill May, and then Rebecca is what I have. PROF.SANDEL: I liked your paper very much. I was just going to offer a brief reply that you might offer to Leon, but while I'm at it, I could also offer you a brief reply to Alfonso. DR. LAURITZEN: That would be great. PROF.SANDEL: That would be that it's also true that every oak tree was once an acorn, but it doesn't follow that acorns are oak trees or that we should regard the loss of an oak tree as the same as the loss of an acorn. The reply to Leon, do you want to hear that now? DR. LAURITZEN: Absolutely, and anybody else. PROF.SANDEL: The reply to Leon might be that the reason that commerce in the body is objectionable in a way that is independent from the giving, as in your surrogacy case, the reason there may be a difference is that to support your intuition that there is something objectionable to commercial surrogacy that might not be the case with gifted surrogacy, say, of a sister, for example, that the ground for that intuition might be that the body isn't private property, open to any use that we may desire or devise, but, instead, is a gift with a certain telos. This should appeal to Leon, in fact, a natural telos, which means that it's not open to use for other lesser purposes, like making money. So that in the case of commercial surrogacy, this would be a case of using the body or selling oocytes, for example. This would be a case of using the body for a purpose at odds with its telos, namely making money. But to donate or to gift without any commercial transaction for one's sister, say, to carry her child wouldn't be objectionable in the same way. It would still be in accord with the natural telos of the body. CHAIRMAN KASS: I won't say more than it's an odd natural telos to say that one woman's uterus is to carry the child of someone else, even out of love. I mean, that's a new kind of natural teleology. We would have to argue about it. PROF.SANDEL: But you would agree, wouldn't you, that it's in line with the natural purpose in a way that selling it to make money clearly isn't? CHAIRMAN KASS: No. It's a nice try. But I think that if there weren't something disquieting about the thing itself, the fact that money changed hands wouldn't even occur. The same thing is true about prostitution. The same thing is true about a whole range of things. I am not saying it is wrong, but we are not, most of us are not, upset with the fact that people sell their labor. And the money changes hands. And it may distort human relations profoundly, but we don't regard that somehow as a deep violation in the same way as a lot of people seem to regard the selling of body parts as a violation. And that must mean it has something to do with the alienation of one's body from one's self to begin with. PROF.SANDEL: It's use, rather than alienation. The intuition at odds with this is kidney fails, a lot of people that object to a market in kidneys who wouldn't necessarily consider that our position requires you to say that there is something objectionable to a kidney transplant as such. CHAIRMAN KASS: I said, "disquieting." I didn't say, "objectionable." PROF.SANDEL: Well, even disquieting. CHAIRMAN KASS: There is. There is something to begin with disquieting about taking an organ from one body and putting it in another. I think it's terrific that we do it. It's not a question of an objection. But it's odd. I'm sorry. I'm not on trial here. It is Bill May. DR. MAY: I hadn't planned to say anything on surrogacy, but it seems to me not simply the question of the telos of the body, but it's different. Gestating is different from manufacturing, where you can distinguish the process from the product. But in gestation, there is a kind of bonding to what is within you. And the releasing of that child to another because it's a bond ought not simply to be based on commerce. The early court case on this said they tried to distinguish process from product, you know. And merely buying the process misses what is going on for the woman and bonding and why it should not be an enforceable contract. It can only be a gift because a kind of bonding has gone on. I was interested in another issue, and I will take advantage of my opportunity here to say you and Dan Callahan have brought up front the issue of access to benefits in a way that it seems to me we have not as frontally discussed that topic. It has come up from time to time, but it really hasn't been as openly discussed across a couple of sessions. And I wanted to deal with that issue. There might be a way of talking about the status of the embryo but relate that issue to the import for access to product. Some of us in this group did not agree with the idea of a total ban on cloning for research purposes. We talked about the intermediate status of the embryo, that it is not fully there with the claim of the human. And, therefore, we were not ready to talk about a ban. On the other hand, it is not nothing. It is not yard-lot materials. It has a kind of intermediate status. And that has implications. Most of our time was spent on the issue of how you do the research and respect for this pre-implanted embryo. Most of the discussion was in that area. But it seems to me if you use the pre-implanted embryo in research, one has to talk about regulations that not only constrain how you conduct that research, let's say the 14 days before the neural streak an all of that, but if you are using this human source and you are removing it from life, you are not removing it from the circle of human indebtedness. And that is a consideration that is not simply individualism. It's that you are conducting research on something that doesn't have the full claim of urgent human needs of extant human beings. But, on the other hand - and I would not want to use the word "resource." I would call it "source," a human source. And if you are conducting this research and removing it from life, you are not removing it from the circle of human indebtedness. And that has consequences not only in how you conduct the research, but you structure the results in such a way that all of those who are in need have access to the benefits of that research. Otherwise one creates I think a lack of respect for what one has used. And that doesn't mean you don't pay researchers and so forth, but you think through the problem of the health care system. I think Dan this morning talked about and you yourself talked about expanding the issues. We're concerned to talk about are we going to produce a lot of products that would be available only to the few and not to all of those in need. And it may be the status of the embryo, this intermediate status, is not simply individualistic reflection but forces us to think about the communal significance of what we have done and the necessity of honoring it in such a way to make sure that it reaches not just the few privileged but the many. CHAIRMAN KASS: Gil, do you want - PROF. MEILAENDER: Yes, just really quickly. Bill, this is a question for you. We're letting Paul off the hook. I know you have made this argument before. And I am sort of afraid I may be asking the kind of question where I am just asking you to repeat yourself, but I really don't understand that argument; that is to say, the "circle of indebtedness" language. So that if we use some embryos and distribute the knowledge gained unequally, we have somehow not honored those embryos that we used; whereas, if we distribute the knowledge equally, we have honored them. Now, I just don't understand. I am prepared to grant that it would be better to distribute the knowledge equally than unequally. I just don't see what in the world this has got to do with whether we have honored the embryo as a human source. Can you help me? DR. MAY: I'm not sure that I can do it in a form that doesn't realize your fears. It just seems to me that in making use of this to produce this benefit, one has to insist that it reach the many. And that is not simply some principle out there separate from, indeed, what has been done. PROF. MEILAENDER: May I try once more? CHAIRMAN KASS: Briefly, yes. PROF. MEILAENDER: So we honor the slave better if we distribute the cotton garments equally than if we distribute them unequally. DR. MAY: Well, you have assumed that I have equated the pre-implanted embryo with an extant human being. PROF. MEILAENDER: Well, it was a human source. That's all. DR. MAY: That sets me up for an equation that I am not prepared to assert. I already began with the notion of the intermediate status. And the slave does not have an intermediate status. CHAIRMAN KASS: Mr. Lauritzen, do you want to respond to the original comment? DR. LAURITZEN: I was hoping Michael would do that for me, but let me say just a couple of things. In the past, I have tried to weigh out a position that tries to avoid understanding the early embryo as a person with a full set of rights and to use language that is common and controversial about respecting this as a source or whatever precise language we use and that one way to do that would be, in fact, to do the research on adult stem cell first, see what we can learn there as a last resort and perhaps invoking fairly explicitly just war theory to do this deterrence of using embryonic research if we hit dead ends. There are some issues about scientifically whether that is a viable strategy, I understand. But over time, I have come to be a little concerned that - and this is I think reflected to some degree in the report. I have become somewhat suspicious of the language of respecting the early embryo. And this I think partly goes to Gil's point, while, nevertheless, destroying itregularly, et cetera. Perhaps the better way to proceed here would be to talk about a slightly different frame for thinking about this, the way in which we have increasingly kind of instrumentalized everything about our world. I mentioned before the instrumentalization of non-human animals so that they're simply now artifacts that we create with different traits without any concern for their value as independent organisms. And I think we see the same dynamic with in vitro fertilization, frankly, with regard to embryos. Whatever we happen to think about their status, I think there is little question that in vitro fertilization has led to the kind of instrumentalization of embryos that ought to give us real pause so that we get some new idea about how to create an embryo. Somebody dreams up ICSI. Oh, I know. We can do that this week. And we don't hesitate. So I think the danger here is a danger that is difficult to appreciate when you throw it into a certain context where the frame of the debate is largely about protecting individual rights and individual autonomy. So a John Robertson is going to say, "Who is harmed?" Well, unless you give some account of the early embryo as capable of experiencing harm, there doesn't seem to be a good answer, at least in terms of the objects or subjects direction. But it may be that we are harmed when we so approach the world around us as something that we ought to be utterly controlling in every aspect so that everything turns into a human artifact, including humans. So that's a very different tact on the issue that to some degree could remain agnostic about embryo status, I think. CHAIRMAN KASS: Let's see. Rebecca? PROF. DRESSER: I liked the way that you are trying to bring in other issues because I do think this is a complicated area. And I think, especially when we are talking about a topic that has public policy implications in a pluralistic country like ours, we should think more broadly. So I wanted to mention a couple of other points that maybe you might want to think about that I have talked about and that bother me about the stem cell debate. One is the area of what I would call truth-telling and the way that both adult and embryonic stem and all other kinds of stem cell research is being discussed in terms of the exaggeration I think of promise. I don't know about exaggeration of promise but exaggeration of speed with which this is likely to develop into therapies, the likely success of any therapies, degree and percentage of people it is likely to help, all of those kinds of things. I think in bioethics, we started with informed consent and we went along with a focus on truth-telling to patients about a serious prognosis and terminal prognosis. And now in the United States, at least, there is a strong belief that physicians should be honest with patients about a prognosis that may not be very optimistic. So I think that we need to talk about research of all sorts in those terms. And I really see a violation of that in this area. So that is something that I think might be worth mentioning. The other is, is it worthwhile to think about an ethical value of deliberation, accommodation, and compromise when we are talking about issues like this that, as I said, have public policy implications. And knowing that we live in this nation where people have very strong beliefs on different sides, how should we think about the problem and the activity of coming together to try to work out policies, of course, in different areas? But should we give ethical weight to the idea that perhaps I will give a little on my favorite outcome in order to reach an accommodation that might be acceptable to more people? And, again, that's something I have personally felt in working with this issue and something that might be worth separating out and talking about on its own terms. Thanks. CHAIRMAN KASS: Thank you. Shall we collect a few or do you want to respond? DR. LAURITZEN: That's fine. CHAIRMAN KASS: Let me collect a couple of others and see. I have Bill Hurlbut and then Mary Ann. DR. HURLBUT: I want to return to the idea of commodification. I think it's very helpful to what you said earlier about reflecting back on the embryo in light of these other categories of consideration. When I think about the issue of commodification, I am naturally drawn to thinking about, well, what is it that you are commodifying or selling, commercializing even. And when I think about the body parts or associated body realities that could be commercialized, I think of people selling their hair for people to make wigs. That doesn't bother me very much at all, maybe none. Blood, that's a little more something there, but that seems okay to me. Sperm or ova, that troubles me a little. There's more going on there, and maybe troubles me a lot. Selling a kidney definitely bothers me. And then selling your whole life really bothers me if you know what I mean; in other words, "I'll give up my life. I'll sell you my life." Okay? Somebody might sell their life so that their children got money, for example, to survive. That bothers me a lot. So there is a spectrum going on there. On the one hand, something seems simple, trivial, and okay. On the other, it requires highly significant justification to even give up your life or to give up a significant part of it. What is it that bothers me at the far end of that spectrum? What is the key here? I think it has to do with something that you would call integrated organismal integrity, identity, or continuity that we can give up something that doesn't challenge those three, but if we give up something that does, we have to have a really good moral reason for doing it. So commodification of an expendable part is completely different than commodification of a whole human life. And then when I reflect on it, what bothers me about sperm, for example, is not just that it's giving up a part of the being. In this case when you give it up, it doesn't hurt the static reality of the organism. It's that you're giving up a part of what you might say is the dynamic of an integrated identity and continuity. You're giving up a relational dimension of being. There is no significant disruption of a relationship to sell hair, but selling a sperm or a womb, use of a womb, is not just part of the static being but parts of dynamic relational being. So it seems to me that the key here is that the moral meaning is in identity with the integrated organismal integrity and the integrated of dynamic process or continuity or overall purposefulness. This brings me back to the point that Michael Sandel and I think it was William May and Leon were in a few minutes ago. What is the difference between selling and giving? Well, it seems to me that giving can sometimes be justified, even at the loss of something, integrity, identity, and continuity, because it is an adult form of voluntariness. You are doing something that is a very high order act of hopefully consciousness, which preserves the fullness of being of the individual as a moral entity. This, in turn, brings me back downstream to your comments that these larger issues of commodification and so forth can inform our understanding, not just of the absolute total landscape but can actually focus back down on the status of the embryo. For me, as I read your paper, I thought yes, yes as I went all along. And I got to the end. And I thought, every one of these categories makes me more concerned about the moral status of the embryo. Obviously commodification of the embryo violates the things I have been talking about; whereas, selling or giving a body part, let's say giving, is a high order of self-donation. Relegating an embryo to research is exactly at the opposite end. It really is commodification. It doesn't have the voluntariness of giving in it at all. It's a violation of something that is fundamentally human in the process. So what seems to me is going on here, at least from my perspective as I looked at all of this, is all of your categories, commodification or, worse, at the level of the embryo, justice, giving something its due, is worse at the level of the embryo because it's not taking something from anything that has a choice. The idea of natural embodiment, the embryo, everything we are is deeply, inextricably in continuity with that embryo. The erosion of species boundaries raises a specialized dilemma here, violation of integrity, which is at the concern of that ethical consideration. And, finally, the implications for personal identity and a deeply rooted thing that it is. So I don't know if this at all makes the point, but what I would like to say is that I think these issues are of one piece and that organismal integrity and identity and continuity seem to focus all of your higher concerns right back down again, I mean, both directions, of course, but there is a whole package here that is inextricably related. CHAIRMAN KASS: Do you want to take both of these together? I mean Rebecca Dresser's earlier comment. Please respond if you wish. DR. LAURITZEN: Well, let me just respond to the last part. CHAIRMAN KASS: Okay. DR. LAURITZEN: Then I can go back to Rebecca's. It just suggested some friendly directions in which it might be pursued. I actually think that is a very interesting observation. And I want to think fairly carefully about that because I think that you may be right about this. It may provide some language for actually teasing out some of the concerns I want to articulate about adult stem cell research and then rethink their implications for embryonic stem cell research. I forget the exact language you used. What did you say, the organismal integrity? I wonder if that isn't threatened in some significant ways, not by selling parts of our bodies but purchasing new possibilities for our bodies in a way that might fundamentally change who we are. I have thought about this a little bit. I got married when I was 24 and have been faithfully married to my wife now for quite a few years. And at 24, I promised to be faithful until death do us part, but that was a commitment of about 50 years. And if we doubled the life span, I am making that commitment for 100 years or something. What would that commitment look like and whether it would fundamentally change how we thought about an institution like marriage and things of that sort? I think it would have implications for personal identity and responsibility over a very extended period of time. So there would be questions about purchasing as well as selling. My initial reaction, going back to the embryo, is mixed. On the one hand, I want to think more carefully about this notion of eroding the sense of a kind of natural trajectory because if there isn't that kind of natural trajectory, then I don't think what is threatened with the embryo early on is that unity that you describe because it has got multiple possible trajectories depending on the environment, the interaction, et cetera. But I want to think about that more because I think it is a very interesting observation. DR. HURLBUT: One little brief follow-up on that. I think that, actually, what you said has a power to it, but I see it at the other end of life. I think the embryo is not as contingent as the full human being who has a sense of real opened determinacy and contingency. I mean, sure, environment is going to affect things a lot for sure, the final trajectory. I think it is more determined early and less determined later. And so if the criterion of expendability is in determinacy, it wouldn't be the embryo. It would be the up and breathing, bubbling human beings. CHAIRMAN KASS: Mary Ann? We will break in about three minutes. PROF.GLENDON: I'm going to follow Dan Foster's illustrious example except just to say that Dr. Lauritzen I think has responded in his last remarks to the concern I was going to raise that what I think we're getting at when we use terms like "instrumentalization," "commodification" is really a deep concern about what kind of people we are becoming when we make certain decisions. And so I think this has been a really fruitful discussion. CHAIRMAN KASS: Yes. I would like to take at least one minute to add one thing to underline something that I thought was fairly good in the paper. It ties in with things that we didn't talk very much about in Dan Callahan's presentation. I found the two papers very nicely complementary. That really has to do with the questions of the goal of stem cell research, combining both the embryonic and the adult and thinking through the purposes for which these are used, purposes which I think all of us at first glance will simply endorse what we endorse for generative medicine. But the question about the limits of that and whether or not that really isn't also using things at the beginning of life to transform not just the trajectory but also the question of whether there really ought to be an end or a completion I think is a very important issue here. I've got sort of half-baked notes for an essay called "The Old Man and the Embryo," in which it's at least paradoxical that one comes to look upon these cells, which are in some ways part of the seed of the next generation, to come to see them as the salvation for those of us who are getting close to the end. And if you want to present yourself with a kind of parable in stock terms, imagine Abraham, the biblical Abraham, and Sarah in a desolate world except for an IVF clinic. And they manage themselves. I guess I've got to make two embryos. They manage a couple of embryos. And the question is whether the embryo ought to be Isaac or ought to be the cure for Abraham's Parkinson's disease. Then you take that and universalize the matter, and I think you see something of the difficulty here. This is not an objection to stem cell research. I want to underscore that. But there is something going on here about the way in which we think about the things at the beginning of life in relation to things at the end of life. And they're becoming somewhat unmoored. I think your paper I think highlights the importance of thinking about those things and the powers, what we're going to use these powers for, as well as the questions of the ethics and the means upon which we for the most part so exercised ourselves. So I'm in your debt for that and for much else as well. CHAIRMAN KASS: Council members, show up at five of. Thank you very much. (Whereupon, at 12:25 p.m., the foregoing matter was recessed
for lunch, to reconvene at 2:00 p.m. the same day.) SESSION 3: STEM CELL RESEARCH: RECENT
SCIENTIFIC AND CLINICAL DEVELOPMENTS CHAIRMAN KASS: Could we come to order, please? The third session of this meeting is on "Stem Cell Research: Recent Scientific and Clinical Developments." The most challenging aspect of trying to fulfill our charge of monitoring stem cell research is the monitoring of the scientific research itself. There is so much of it, it's very diverse with many sources and types of stem cells, and many types of research. Things are changing amazingly rapidly, and we are trying to monitor a moving target. The material is highly technical and hard, even for scientists outside of the field, let alone a layman, to evaluate carefully. "The Isolation of Human Embryonic Stem Cells," and, "Human Embryonic Germinal Cells," by James Thomson and John Gearhart respectively was reported only five years ago. The obvious promise of these cells both for gaining knowledge of development, both normal and abnormal, and eventually for regenerative therapies with hundreds of thousands of patients with degenerative diseases or injuries has produced great excitement, much fine work, and to be frank, more than a little hype. At the same time, reports of previously unknown and unexpected multipotent or stem cells in various tissues of children and adults has produced enormous interest also in so-called adult stem cells, with similar promise, and to be frank, also more than a little hype. By almost all accounts we stand today in the infancy, not to say embryonic, stage of these researches, and it is surely too early to answer the questions that the layman wants answered. How soon, for which of our diseases, from what sort of cells, at what cost, and at what risk will the cure be available? Yet it is not too early to learn where we are in fact in this rapidly growing field, to try to separate fact from fiction, true promise from hype. And to do this we have gone to the experts, commissioning review essays, essays that would review for us the published literature over the past two years since the August 2001 decision, covering work in five areas according to the origin of the cells. "Human Embryonic Stem Cells," a paper by Tenneille Ludwig and James Thomson, "Human Embryonic Germinal Cells," a paper from John Gearhart, a paper on cloned embryonic stem cells, a paper by Rudolph Jaenisch, a review of the adult stem cell research, a paper from David Prentice, and an update on the work with her own multipotent adult progenitor cells from Catherine Verfaillie. The papers have been sent out with the briefing books, and I assume that they've been read. We are thinking about another paper on mesenchymal stem cells. We're very fortunate and grateful to have with us this afternoon three of the authors, Dr. John Gearhart, Dr. Rudolph Jaenisch, and Dr. David Prentice, who will, in brief presentations, highlight their own papers, after which we will have questions and discussion. I would remind Council members that the purpose of this session is wholly scientific. We want to learn as much as we can about the current and projected state of this research. This isn't the time for ongoing ethical arguments about the moral status of the embryo, the research imperative, or equal access for the current funding policy, important though these issues are. And I will simply say I'll use the authority of the Chair to see to it that we try to stay on the topic. Dr. Gearhart has kindly agreed, by the way, to field questions pertinent to the review essay submitted by Drs. Ludwig and Thomson. Gentlemen, welcome to you all. Thank you for your papers, your presence, and in advance for your presentation and participation. And we will proceed in alphabetical order with John Gearhart first. DR. GEARHART: Well, I can't say I'm delighted to be back, but I'm happy to be back. And to not really dwell on the research that's going on specifically in our laboratory, but to give you a bit of a general overview of where the work is in this field, and I think there will be ample opportunity from some of the things that I say that you can ask questions about it. I think the first question, and judging from some of the morning topics, that I would like to address is the one before you now, which is, why study these cells? And what we have heard most frequently are the issues, well, this is going to be the most versatile source of cells for promised cell-based interventions for various therapies. But I came at this at a different angle. I am an embryologist by training. I've been a student of human embryology for 28 years. And I'm extremely interested in knowing how we are put together. What are the events, what are the mechanisms that lead to the formation of the human being? And over time, as you can imagine, we've studied fruit flies, we've studied mice, we've studied rhesus monkeys. And I think one of the major, and perhaps the most important bit of information that we're going to get out of embryonic stem cells are going to be the issue of how we are formed. And this is going to involve cell biology, genetics, on and on and on. But this is what is going to enable us. And I think with this information, which at the moment is under the heading of Fundamental Science, or Fundamental Discovery in Basic Science, this, I think, is going to be the lasting contribution of studies from embryonic stem cells. They're going to have applications, obviously, with that information, and the sources of cells. And we're going to apply those to birth defects. We're going to apply it to injuries and disease, because many of the processes are similar. And we're going to be able to draw on that information in trying to correct diseases and injuries. True, I think out of this we're going to get sources of cells which, in the short term, are going to be used directly for the cell-based interventions. And I think through the use of these cells, we're going to discover other important things about these cells, and some in our research we've learned, which we can apply in therapies. But I want to emphasize one point, and this is my belief, that this period of time that we're going through in studying embryonic stem cells is going to be transient. And I want to emphasize that I believe it's the information we're going to get out of these cells that are going to be used in the longer term to restore function, to regenerate tissues within the bodies of patients, without the use of these cells. And that to me, as I look downstream, is going to be the most important outcome of this research. Now I realize that this quote is taken out of context for these essays that were written, and what was being questioned here. But I want to make some comments which are important when we consider the use of human embryonic stem cells directly. And that is, we are finding enormous differences between mouse embryonic stem cells and human embryonic stem cells, not only in practical issues within the laboratory from the standpoint of cell cycle times, et cetera, but also, as we begin to differentiate these cells in a dish, we find some very subtle and some very not so subtle differences between the mouse cells and the human cells to get us to the differentiated functional tissue that we need. So I do believe it's time that we work directly on the human embryonic stem cells if we want to gain this information on embryogenesis, and if we want to move forward with developing cell-based interventions. So, the sources that we're going to talk about in general deal with this very early stage here derived from the IVF-donated embryos, and from tissues collected within the early stage of fetal development, the germ cells. These cells have many things in common, and we've published on this. You've seen this, probably. And so we look at them as a group. There's a third member of this group, which is embryonal carcinoma cell, depicted here on the right, which has very similar properties to these two other cell types. In fact, it's the only cell type from which any cell has been derived that's being used in a pre-clinical trial. And this is on stroke patients at the University of Pittsburgh. I want to spend time now, or my brief time, on three slides to give you an indication of where the human work is on this class of cells. What are the questions that are being asked, where are we on some of this stuff, et cetera? So here now are issues around human embryonic stem cells, or embryonic germ cells. One of the first questions that's being asked about the stem cell itself is what is meant by "stemness"? And obviously this, at the molecular level, gets us into genomics, proteomics. And so there is a major effort around the world at trying to determine the genetic basis of a stem cell. And the human cells are being used extensively for this purpose. How many genes are involved, what genes are involved, what signaling pathways, on and on and on. So stemness is an important issue within this research. Now, it's a comparative thing. We can do it also with mouse cells. We can do it with adult cells as well, trying to find commonality. What is it that makes a cell a stem cell? That information will be vital, I believe, in the future, in converting virtually any cell to a stem cell, if we want to go that route. The second major issue currently are characterizations of existing lines. As you may know, there's no standardization within the field as to what constitutes a human embryonic stem cell. We talk about developmental potential. We talk about molecular markers, biochemical/antigenic markers, this is now being taken up by an international committee under the auspices of the MRC in London to try to get an agreement on these issues from stem cells around the world, human embryonic stem cells around the world. There's also the issue now of whether or not we should be deriving new stem cell lines. And in many countries, this is indeed happening. There are a number of new cell lines coming online. And what is the importance of this? Now, many of you have heard at least from what the Europeans refer to as the presidential cell lines, those that are eligible for funding in this country. Should we have cells that are only grown on human feeder layers? Most of the cell lines that have been derived are on mouse feeder layers, and there is a concern about infectious agents passing into the human cells. I think there's a misconception out there that these lines will be ineligible for any kind of therapeutic use. I think the FDA has made it very clear that they're certainly willing to consider those grown on mouse feeder layers if they meet certain criteria to also be eligible for use in the clinic. But there are a number of lines now that have been derived on human feeder layers, and there are lines being derived that are feeder layer independent, which means it makes it much easier to work with in the laboratory. You don't have to worry about these other cells that are present in your cultures. And there's an attempt now being made to derive these lines in defined media, which means there are no other animal products, no serum, that you can control very carefully the differentiation of these cells by adding specific growth factors in a sequential fashion. The most important element to this, though, is this top line here. Many of you may not realize it, but when we say that routinely three or four different mouse embryonic stem cell lines have been used for the last 20-some years, what's the problem here, why can't we use just a few of the human. Those lines have been selected from a hundred and some cell lines that were made as to being the best cell lines to use for those purposes. And so I think we're still in this phase of trying to determine what are really the good cell lines, human embryonic stem cell lines that are available. And thus the issue of generating more. For the use of these lines, emphasis in the lab now is in the following area. We're trying to work up high-efficiency differentiation protocols that result in homogenous cell populations of functional cell types. That is, can we in the laboratory come up with protocols, growth conditions, that are going to get us 10 million dopaminergic neurons, and only dopaminergic neurons? Most of the protocols we have now result in a mixture of cell types within a dish, and we go in and select out the ones we want. So there's concern about the heterogeneity of the cells, and the fact that we can't at this point have a high efficiency in getting the cell types we need. We manipulate the growth environments, and we manipulate the cells genetically to accomplish this goal. Once we differentiate these cells, and we've had some success in certain pathways which we can talk about, we are very concerned about what we refer to as the authenticity of the derived cells. That is, is the dopaminergic neuron you've formed, the insulin-producing cell you've formed, the cholinergic neuron, the cardiac muscle, are these actually functional cells that are the equivalent of those that you normally find in the adult? So a great deal of effort, both in the dish, in vitro, is being made in different parameters to measure whether or not these are authentic cells. There are many protocols, as you can imagine, that lead to cells that look like something, but they're not functional. And this is a major concern. The other side of this is, the golden test is can you transplant these cells into an animal model of some kind and see that they assume the function that you're hoping that they would. But again, these are human cells going into rodents, primarily. Do we have every reason to believe that they're going to function appropriately? We don't know that yet. We're also putting cells into non-human primates to get that kind of a measure as well. We are in the laboratory contrasting and comparing among various sources of stem cells. In our laboratory, we work on human ES, human EG, umbilical cord blood, et cetera. And the importance of this is that you are able to compare and contrast in the same paradigms the sources of these cells to see which ones are going to be appropriate for which tasks. And I think this is extremely important. We're also very concerned, as you know, if these cells are going to be continuously grown in the laboratory, there's a finite possibility that you're going to get genetic mutations. We're interested in the frequencies of this, and the types of the mutations that occur in these cells. It's a safety issue. But with our genomic and proteomic studies, we can get a good handle on this at this point in time. When we get into the grafting issues, which is obviously a desirable endpoint, both in the basic science side, to say you have a functional cell, and then transitioning into any use of these cells in cell-based therapy, we have a number of issues here. The first, and I think you have to realize this. There is virtually no appropriate animal model for any human condition. That's the fact. We approximate it. We do the best we can. But under those limitations, we do the best we can. And you have to be aware of this. There's a concern about what animal models you're using for what test. The issue of what stage of cell differentiation in any of these cells do you use for a specific graft? We are finding that many things within the central nervous system, you want to use something that is fairly undifferentiated so that the cells can interestingly migrate to where they're supposed to go, set up the appropriate connectivity. And so if you are working with a motor neuron, you'd like to use a motor neuron precursor. If you put in a fully differentiated motor neuron, nothing works. I mean, when you think about the nervous system, it's not surprising. With insulin-producing cells, we find that you want the terminal cell, at least in the experiments that we are doing. But for each of the cell types you're working with, we've got to determine this, as well as how do you want to deliver it to those animal models. The last two are extremely important. What are the fates of these cells that you've grown in a dish, selected for in a dish, once you graft it into an animal paradigm? We know these cells like to migrate. Do they differentiate appropriately? Do they form tumors? I remember a few years ago when I was all puffed up that our cells were working so wonderfully, and I went to the FDA for this meeting I thought was going to be one-on-one with members of that group. And it turned out that there were 40 of them and one of me. All their questions were about safety issues. We now spend as much time on these safety issues as we do at looking at differentiations of these cells in a dish. Why? Well, what have we found? Indeed, in the early mouse work with embryonic stem cells the rates of tumors were extremely high. Formation of teratocarcinomas, mixed germ cell tumors. We have at this point, though, grafted well over 3,000 animals with our human cells, and we haven't seen a tumor yet. And maybe we're just lucky, maybe there's a difference between mouse and human cells. We don't know that. But these experiments are extremely expensive because you've got to serial section through the whole central nervous system if you're putting cells in there. You're putting them in IP, et cetera. It's a lot of work. The FDA, ideally, would like to know if you're putting 300,000 cells into an animal, they want to know where all 300,000 cells went. This has gotten us into extremely expensive experiments in labeling cells, developing labels for cells that you could follow for a year or more later. You could go back and find those cells. So we've employed radiologists, and chemists, et cetera, to help us with these kinds of things. So it is a major issue. And in all of our experiments, we look at this. The last issue, on immune response graft rejection, is obviously to some extent the Achilles' heel of this work. If we can't provide tissue that's going to be accepted in a graft, then all this work has gone for naught. So there are issues of active experiments now going on in tolerance, in genetic alterations of cells, the consideration of cell banks, how many different stem cell lines would you need to cover certain populations of people, and something you'll hear about probably from Rudy on nuclear and cell reprogramming, so-called therapeutic cloning. Is this one of the avenues that we can approach? So all of these are very active research elements going on with respect to the human embryonic germ cells and stem cells. We can't divorce them. Now, in this cartoon, what I've depicted here is one of the more difficult scientific aspects of the research. And that is that you have in a dish - now this is a bit of a repeat, but it's important to mention - you have in a dish these cells that are capable of forming any cell type that's present in the body. The major problem here is how do you get them only to form hepatocytes, dopaminergic neurons, heart muscle, blood cells, pancreatic islet cells, solely. How do you do that? This is where the real issues are within the laboratory. And we try to recapitulate, as I showed you this before - oh, and finally, the issue of - I put this little thing down here to remind me. Some of you have seen this report earlier this year from Hans Schuler's lab at Penn, that he's been able to find oocytes within embryonic stem cells derived from the mouse. Now, he did not - now keep this in mind, he did not purposefully differentiate these cells into oocytes. He came up with a neat little trick of identifying them once they were present in the plate. Okay, so it's not that he's worked up a condition to differentiate them only to oocytes, it's that they're there. You can use that technology to pull the cells out, and then further try to mature them, see if they are actually functional oocytes, et cetera. So we rely in the lab on trying to recapitulate what has occurred to some extent in the embryo by providing growth factors that these cells normally see to get them to enhance, or try to direct their differentiation into the product that we want. We use selection techniques in the laboratory after getting these mixtures of cell types by different avenues in the dish. We then come back using genetically selected markers, different growth media, cell sorting, which is a fancy way of sending cells through a beam of light, and if they have a certain antigen on the surface, you tag it in a way that will put them into different pots. And this works fairly effectively for a number of cell types. But it's highly inefficient, and we've got to improve this technology. So what have we done? What have we been able to do? We've been able to identify many, many different cell types in a dish. We've been able to expand many different cell types, whether they're insulin-producing cells, dopaminergic neurons, heart muscle cells, smooth muscle cells, hepatocytes, we're able to do that. Human. And we've been able, in many cases, to show that they are functional within the parameters that we like. And in a few cases we've studied extensively we've been able to graft them into animal models to show that they will work, and can ameliorate a condition in the animal, whether it's, to some degree, whether it's a diabetic animal, or one with motor neuron loss, mouse models of Parkinson's disease, we can do that at this point. To reiterate, we are concerned about safety issues. They go hand in hand with all that we do in the laboratory. It adds, again, expense and time, but we want to make sure we get it right. Here's another issue of safety. We find that in many of these cell lines, if you're not careful - now human embryonic stem cells are much more difficult to grow in the laboratory than mouse, and if you're not careful, this can overwhelm your cultures very quickly. This is an example of a tetrasomy 12p, and also of a trisomy 17, which appear to be fairly common coming out of the human cell lines for whatever reason. We don't know. But you have to constantly monitor these cell lines to make sure that they are remaining normal as far as the karyotype is concerned. Not an unusual circumstance. Rudy, I'm sure, will deal with this. But we got highly involved with the issue of somatic cell nuclear transfer, mainly coming in from the desire to have matched tissue for a patient. But I want to point out two other issues here that I think, in my way of thinking, are perhaps more important. Rudy will probably disagree. Number two on this list, to increase the diversity of stem cell lines. Number three, to facilitate the study of inherited genetic diseases and somatic mutations. Now, there's been a lot of talk about, with the justice issues, of diversity of cell lines. We now know how many cell lines we need to cover the population of the United States. How are we going to get these lines? We're not going to get them, if we wanted them, by going out and matching up people to get embryos, okay, or even assaying embryos in banks. The easiest way to do it is you identify a person that has the haplotypes of class I and class II genes, and take a nucleus out of their cell. And generate stem cells through somatic cell nuclear transfer. No question about it, easiest fast way of doing it. The issue of the studying of inherited genetic mutations and somatic mutations. It means that we can take cells from a patient with a disease, some of them not expressing very much from the standpoint of the pathogenesis of the disease, to others that are full-blown, to try to figure out why some patients have one form of the disease, another has the mild form of the disease. We can take this directly, and generate stem cells for those studies. Somatic mutations, breast cancer mutations. We can generate cell lines - it's the only way we can do it - through somatic cell nuclear transfer. And then the issue of being able to determine mechanisms of nuclear reprogramming. We would hope that they would approach normalcy from the standpoint that we may be able to use that information to convert somatic cells into stem cells at some point downstream. This is why I think somatic cell nuclear transfer into a human are reasons that are quite important. Well, I think with the issue of the human embryonic stem cells, I think they have uniqueness in certain areas, and I think that what we're going to learn out of these studies is going to be extremely important in the future, not only for deriving cell-based therapies, but in getting information that we're going to be able to begin to instruct our own genes. And this is something which hasn't been paid a lot of attention, but I think even within this Council, it may be a good idea, that we're on the verge, I believe, of being able to instruct our own cells. And I think the ramifications of this are enormous. I mean, talk about enhancement. One could go on the Internet and get a kit for enhancing any part of your body to a certain degree. And this is all going to be done, I think, from information that we get out of learning about cell differentiation, how these cells function. So I think we've got to keep our eye on this for the future as well. Just in closing, the greatest impetus that I can think of for making advancement in this field is funding through the National Institutes of Health. This is the only information that I could get my hands on. It's available. It's for the fiscal year 2002. You see how much money is being spent on stem cell research in toto, how much on human adult stem cell research, how much on animal adult. And up to this point, $11 million. On the human embryonic stem cell research, I think this year it's going to be more, and we would hope in the future, as the bottleneck for cell lines and more applications come in to the NIH, that these numbers will become robust. And I think this will be the key to the dreams that we have, anyway, of learning more about how humans are built, and cell differentiation of human cells on their way to therapy. So I hope I've given you enough to think about. Thanks. CHAIRMAN KASS: Thank you very much. Why don't we simply proceed in order. Dr. Jaenisch. DR. JAENISCH: Well, thank you very much for inviting me here. And I will right away get to the cont roversy. I'm not going to agree with much you said. So I want to try to develop two arguments. One is reproductive cloning faces principle biological problems that may not be solvable for the foreseeable future. And the other one is therapeutic cloning poses no principle biological obstacles, only technical problems. And this, I think, in my opinion has implications for the status of the fertilized and the cloned embryo. So you need one piece of data. When we do nuclear transfer, then it's clear that the donor cell, the donor matters. So if we use a somatic donor nucleus, cumulus cells, fibroblasts, Sertoli cells, the result to get cloned adults is really low, a few percent. If you use B or T cells, or neurons, it is very low. Only with tricks we were able to get animals. However, when one uses embryonic stem cells as donors, it's an order of magnitude more efficient. So the conclusion is an embryonic cell is easier to reprogram to support life than a somatic one. I will come back to this later when I make an argument. So, let me first come to cloned animals. If you have an animal born, if you looked at this carefully, you find that approximately four to five percent of all genes, as done in percentile, are not correctly expressed. Still, the animal develops to birth. If you look at imprinted genes, it's even worse. Thirty to fifty percent are not correctly expressed, regardless what the donor cell nucleus is. So from this we would argue that it's amazing that these defective embryos can develop to birth and beyond. But you pay for that. You pay with abnormalities. So my argument would be, and I will develop this more, that there may be no normal clones. Of course, we have the problem to define what we mean with "normal". But let me then say that faulty reprogramming seems to me is a biological barrier that may preclude the generation of normal cloned individuals, at least for the foreseeable future. Let me come to therapeutic cloning. So, as we heard, cloning would involve taking from a patient a somatic nucleus and derive an isogenic embryonic stem cell by nuclear transfer. This could be used, then, to correct the genetic defect if it was present. One has to differentiate these cells in vitro, and then transplant it back into the individual and see whether it could improve the condition. So we have made such an experiment. I just want to briefly outline the steps we went through. As a patient we used a mouse, which was totally immune-incompetent. Due to the Rag2 defect, it did not have any B and T cells. So that was our patient. From this, skin cells were removed from this animal. They were transferred. A blastocyst was derived. And from this blastocyst, an embryonic stem cell, which of course is mutant, as the donor. And then we used just simple homologous recombination to repair one or two alleles to make a functional Rag2 gene, and then differentiate these cells which had problems into hematopoietic stem cells, put them back into the animal, and the result was that these cells could colonize the embryo and repair, in part, the defect. So some have argued that this experiment really didn't work. It really only showed that when you have - I think Dr. Prentice argued that it only showed that one has to use a cloned newborn as a source. And this, of course, is not therapeutic cloning. I think that is a misrepresentation of those data. I would argue that from this experiment we know that somatic nuclear transfer and therapeutic cloning will work because it has worked in the mouse. So only technical, not principle, barriers exist to adapt it to human use, although these technical ones may be daunting. Technical, in contrast to principle ones, which we see in reproductive cloning. So, if I look at the two ways we can think about cell therapy, then we have the nuclear cloning approach as I just outlined, which in the mouse we know works, at least for hematopoietic cells, and I believe will work for other cells. The alternative is somatic adult stem cells. We'll hear later from this. And I believe here there are many, many question marks. It is a very young field, very interesting, but we really don't understand how to really handle these stem cells, how to propagate those. And there's really, with the exception of bone marrow stem cells, not really any proof of therapeutic potential at this point. So I think we need much more to learn here, but this we know will work. So I want to come to really two key questions. One is can reproductive cloning be made as safe as in vitro fertilization? And the other one: Does faulty reprogramming after nuclear transfer, does it pose a problem for the therapeutic application of this technology? I think these are the key questions in my mind. So, can reproductive cloning be made safe? I believe in addition to the technical problems, which are solvable, there are serious biological barriers. And the main one is this one. The two parental genomes in all of our cells are differentially modified depending on where the genome came through the egg or through the sperm. They're epigenetically distinct in the adult. If you want to recreate that situation, you would have to physically separate the two genomes and treat them independently in an oocyte- or sperm-specific way. So let me point that out in this very complicated-appearing diagram, but it's very simple. So let me just go through briefly what's happening during normal fertilization. In normal fertilization, the egg genome and the oocyte genome are combined. And they are differentially modified during gametogenesis. And this is what these lollipops here show. So they're different in the zygote. But now something very curious happens. Within hours of fertilization, the sperm genome is stripped of all methylation. The oocyte is resistant to this not-well-understood demethylation activity because the oocyte genome has been, of course, together with this activity throughout oogenesis. So then cleavage proceeds. And the point I'm making now is that the cells of the genomes in the adult are different, different because of their history. It's not only for imprinted genes, but also for non-imprinted genes. Now what happens in cloning? In cloning, one removes, of course, the egg nucleus and replaces it now with one of the somatic nuclei. Now, both of these genomes are now exposed to the egg cytoplasm. So both become really - they're in identical chromatin state. So they'll be both modified, and the difference will be equalized. So the difference you see in a normal adult cell will be equalized, tends to be equalized in cloning. I think that is a problem among those which we call epigenetic problems. So in order to solve that, I think one would have to separate the two genomes physically and treat one in an egg-specific appropriate manner, and the other one in a sperm-specific manner. I think if we could do that, then I think we would have a way to solve that problem. So the phenotypes of clones, I would argue, is a continuum without defined stages. So we know the most important stages are implantation and birth, and indeed, most clones are lost at implantation, and then at birth again many are lost. You end up with very few which develop to late age. And we know from most experiments, even animals which are one year of age, 80 percent of those die very early with major problems. These experiments could only be done so far in the mouse because the mouse is the only organism we have old cloned animals. So I think the problem here is, yes, you might get - because our criteria are not very good here - you might get quasi-normal or maybe a normal individual with a certain frequency. It's very difficult in animals to test, really, because our tests are limited. But we cannot predict ever at any of these stages who will be among those outliers, and who will not be. There's no way to select good healthy from non-healthy clones. I think that's very important to emphasize. There's no way we can think of to do that. So there's no predictability whatsoever. So from my point of view, this doesn't matter, really, whether one or two percent of potentially normal animals which survive for a long time. You can't predict who this will be. So, therapeutic cloning. So, as I said, cloned animals are abnormal due to faulty reprogramming. Why is normalcy of differentiated cells derived from ES cells not affected by this problem? There are two reasons. One is that we don't involve a generation of a fetus. And the other one is that the embryonic stem cells lose what I'm going to call epigenetic memory of the nucleus they came from. So let me develop these two ideas. So first, it's simple. In contrast to reproductive cloning, there's no embryogenesis required to derive functional cells in vitro. So it's totally irrelevant, for example, whether imprinted genes are reprogrammed or not. Imprinted genes have a function only during fetal development, not in the adult. So it doesn't matter. There is one or two exceptions, and those would have to look at. Very importantly is the cells themselves select themselves in vitro for the cell type you are selecting for. There's no selection possible in vivo after implantation in a cloned animal. And then we know that cloned ES cells form normal chimeras, as do any other ES cells. So biologically there is no difference. Let me come to the memory question on this slide here. So we know we can make blastocysts from a zygote from a fertilized egg, or by nuclear transfer from these various donor cells. Now I would argue the blastocyst remembers exactly where it came from. And we know that because we implant this blastocyst, derived from a zygote, into the uterus, it will with a high efficiency develop to birth, and will make a normal animal. If you derive - take a blastocyst derived from an ES cell, and implant it, it will develop with a high efficiency to the newborn stage, but it will make an abnormal animal. If it came from a cumulus cell, it would be very low efficiency - I showed you this on the second slide - low efficiency to the newborn stage. It will be abnormal. If the nucleus comes from B-, T-cells, or neurons, it will be very low. And it will be, of course, abnormal, if you get it. So these blastocysts know exactly where they came from. And we know this, actually, when we look at gene expression patterns in clones derived from ES cells, or from human cells, they're different. So they remember at birth where they came from. That's why cloning doesn't work. That's why these cloned ones develop abnormally, too, in the great majority. So what about ES cells? In ES cells, it's a very different thing. I would argue you erase the epigenetic memory of your donor nucleus. And the argument is the following. We know that if you take such a blastocyst, the ES cells are derived from the inner cell mast cells. These inner cell mast cells express certain set of genes, one of those called the Oct-4 gene, one of the key genes, but another 70. You put this blastocyst in culture. All these genes, all these cells array - silence, Oct-4. This has been published. And they don't divide. They sit there. But over the next days or week or so, some of these cells, one or the other, begins to re-express Oct-4 and another set of 70 genes. And these are the cells which would proliferate. And we call them ES cells. It's a total tissue culture artifact of those cells which can survive under the harsh tissue culture conditions. So I would argue ES cells have no counterpart in the normal animal model. They are a real tissue culture artifact, although a very useful one. Now the same occurs, of course, with these blastocysts. The efficiency is lower. But once you go to the selection for the survivors, they're exactly - I think in order to survive, they have to express the set of 70 genes which we call the embryonic genes, which are important for the early developmental stages. So the point of this slide is really that this selection process, which selects just for the fastest growing cell, erases the memory to where the ES cell came from. And indeed, when you transplant these cells derived from a B- or T-cell or from a neuron or from a zygote, they have identical properties. They form normal chimeras, and they in vitro differentiate indistinguishably. I want to summarize this. An ES cell derivation selects for survivors. And I would argue survival depends on an ES default epigenetic state which needs these Oct-4 like genes being on. Selection process erases the epigenetic memory of the donor nucleus, and the cloned and the fertilized cells form normal chimeras. So the potential of ES cells derived from an in vitro fertilized embryo and from a cloned embryo is identical by all measures we can do. So I would conclude, then, it's unlikely, if not impossible, to create a normal individual by nuclear cloning. The problem of reprogramming may not be solvable for the foreseeable future because of these principle barriers, but ES cells derived from clone embryos have the same potential for tissue repair as those from the fertilized embryo. So I think one of the key concerns I can see of this committee is that the derivation of embryonic stem cells by nuclear cloning necessitates the destruction of potential human life. I think that's a major concern. And if I just compare now, to my opinion, the difference between a fertilized and a cloned embryo. The fertilized embryo is created by conception. It's genetically unique. There's a high potential it will develop to a normal baby. The cloned embryo of course has no conception, no new genetic combination. It is really the product of a laboratory-assisted technique. Sloppily, we could say it's a laboratory artifact. But most importantly, it has little or no potential to ever develop to a normal baby. So I think the embryo, the cloned embryo, lacks essential qualities of the normal embryo, which on this sort of maybe summarizing my thoughts is on this slide where I think there are really three possible fates for a cloned or for fertilized embryo. We fertilize one of these leftover embryos, hundreds of thousands in the clinics. They can be disposed of, they can be implanted to form a normal baby with a high probability, or they can generate normal ES cells. The cloned embryo, three fates. It can be disposed of. It can make normal ES cells, as I have argued, but it cannot make with any acceptability efficiency a baby, not even a normal one. So if this is accepted, instead of disposing these leftover embryos and use them for normal ES cells, which could be used for research, as we heard. This, of course, to my opinion generates an ethical problem because you destroy potential human life. I think this - so if this is acceptable to some, I think it should be ethically less problematic, because in this case I think you don't have the potential to form, within acceptable possibility, a normal baby. So from the biological point of view, I think the derivation of embryonic stem cells by nuclear cloning develops the structure of an embryo that lacks the potential to develop into a normal being with any acceptable efficiency or predictability. I was asked - and I want to close with my final slide, which really follows what John said - what are the potential applications of cloned embryonic stem cells derived from a cloned embryo. I think we talked about therapy. Clearly, I don't have to dwell on this. I'm not sure whether this will be really generally available technology. It maybe too expensive. I don't know. And I don't know how fast we could solve the technical problems of adapting this to human medicine. However, I think this is the more important point, which I think John emphasized. I think it allows us to derive genetically identical cells from patients with multigenic diseases, such as Parkinson's, Alzheimer's, ALS, diabetes. And we can now use this system in vitro to validate the cellular defects of these complex diseases. So compare ES cells derived from a healthy individual with those from such a patient. I think there's enormous potential here if we find a difference, to find out why that is so, and is it a screen for potential therapeutics, just in the culture dish. And as John emphasized, such diseases cannot be studied in animal models, because there are no animal models for those diseases. But you can really make those in the culture if you just use a cell of the patients. So I think this is a very important, maybe the most important driving issue, to my opinion, to use this technology. Thank you. CHAIRMAN KASS: Thank you very much. Dr. Prentice. While we're waiting, Dr. Jaenisch, would you mind just taking one question of just factual information so that we don't lose a lot of time. This last point about the models for multigenetic diseases. If someone were to say the same kind of models might be available through, for example, the multipotent progenitor cells that Dr. Verfaillie has, where you could go into the patient and get out progenitor cells. You might not get all the tissues, but if those cells could reliably be differentiated into islet cells, couldn't you do the studies on the pathogenesis of - in other words, couldn't one, if one had stable and reliable adult stem cell populations, wouldn't you have the same access to the cells from the multigenetic diseases? DR. JAENISCH: Yes. I think if this would work, if this would efficiently work, I think absolutely I agree with you. I think the problem as I see it now is that, indeed, working with adult stem cells is very difficult. And the major problem is that we lack the ability in most cases to, for example, propagate them in the undifferentiated state. For example, with bone marrow stem cells, although they're known for 30 years, this has not been accomplished. They are very useful for therapeutic applications because they select themselves in the patient, but not easily for this type of research, what you want to do. So I think there might, at some point, if we learn that in this young field, I agree with you. Then I think these cells would, if you could differentiate them to dopaminergic neurons in a way that we can do for now from ES cells, as Ron McKay has shown, yes I think that would be useful. CHAIRMAN KASS: Thank you. Dr. Prentice, you're all right? DR. PRENTICE: Yes. CHAIRMAN KASS: Good. DR. PRENTICE: I think we're ready to roll. Thank you, Mr. Chairman. I apologize for the delay up here. I was fighting off a fever from a respiratory virus, so I probably was in a time warp. One of the main goals of stem cell research, as you're all aware, is the idea of regenerative medicine with stem cells, the idea that you might be able to take a stem cell from some source, for example here from bone marrow, inject that into an area of damaged tissue in the patient and regenerate or replace the damaged tissue. Now, the interesting, confusing thing about adult stem cells has been that it defies what for years we have thought of as the normal developmental paradigm, that as we develop from the blastocyst stage here, that cells follow one of these main developmental trees. And as a cell would become more and more developed and more and more differentiated, they would end up out here on the tip of a branch and not be able to back away from that particular tip; not be able to back down and take a separate branch, whether it were a nearby branch or one of these main branches. A lot of evidence now suggests, however, that adult stem cells, at least some of them, can actually move from branch to branch. Now exactly how they're doing that, the mechanism involved in these types of differentiation or different branches of tissues, is still unknown. There's several questions related to adult stem cells, and in fact many of these have to do with the same questions related to embryonic cells. What is their actual identity? How could you identify a particular adult stem cell? What is their actual tissue source? How do they form these other cell and tissue types? Do they form actual functional cell and tissue types, as we look at these organs and tissues? And what's the specific mechanism of differentiation? They do seem to have some unique characteristics, such as a homing phenomenon, where they tend to home in on damaged tissue. And most of the results that have been seen in terms of an adult stem cell differentiating into another cell type or tissue type seem to be tied primarily with injury to a tissue or organ. Usually you do not see these types of changes in the experiments taking place unless there is some sort of damage. The other thing would be what type of cellular interactions and signalling within the target tissue might trigger some of these differentiative events. Now, one way to try and identify a stem cell is with various markers, and I discuss this at some length in the paper. Typically what people have tried to do is eliminate what are termed "lineage markers" for particular blood cells. Some people pick a particular marker called CD34, which has been associated with bone marrow. But others tend to eschew that type of marker. And I mentioned other markers in the paper that might indicate that an adult cell is a stem cell. The CD133 marker, or the c-kit marker. Several people have begun to undertake studies of the gene expression within adult stem cells, and compare them to embryonic cells to see if there is a commonality in terms of all of the various genes that might be expressed that identify a cell as a stem cell. One of the problems that's been faced, though, is that these markers tend to change over time. This has been seen in several studies where actually a marker such as CD34, that might have been a chosen marker to identify a stem cell, actually might not be expressed at a later time with that cell. And then expression of that gene would re-occur, even within the same cell. So it may be difficult to actually identify one particular stem cell based on some of these markers, simply because of changes in gene expressions as the cells undergo changes in environment, as they may undergo changes in their isolation conditions, and what Theise and Krause simply have called the uncertainty principle, equivalent to the Heisenberg uncertainty principle. You might at one point be able to isolate a cell with a particular set of markers or milieu of gene expression and say this is a stem cell, but then as you would try to put it into different conditions, or isolate it from different tissues, those particular markers might change, or might be different. So it may actually be very difficult with adult stem cells to particularly isolate a particular cell and say, yes, this is an adult stem cell. It may be more a matter of the particular context of the cell: the tissue they're derived from, the isolation conditions used, or the tissues that they're put back into that may determine their functionality. In terms of differentiation mechanisms, cell fusion appears to be one particular mechanism by which an adult stem cell may change into another tissue type. Now there were some in vitro experiments done approximately a year and a half ago that indicated this possibility, but the in vitro experiments were unable to verify whether this was actually a particular mechanism that might be used by an adult stem cell. More recently, two papers have verified in mouse systems that bone marrow stem cells, at least in these experiments, did fuse with hepatocytes and take on that differentiated morphology and function, even in terms of repairing liver damage. So this is obviously one possible mechanism with some experimental evidence. Another possibility might be that a cell would de-differentiate, actually back down one of those branches and go up another branch. This would involve changes in gene expression to an earlier state, or more primitive type of cell, and then re-expressing specific genes particular to the tissue into which the cell was placed. Another possibility is what's termed "trans-differentiation" in which the cell apparently is not backing down a branch, but instead simply changing its gene expression so that it now conforms to whatever tissue or cell population that it's within. In terms of sources of adult stem cells, not just tissues, but how did they get there? How did an adult stem cell get into bone marrow, or brain, or liver? One theory is that some of these cells may be leftover primitive stem cells, perhaps embryonic stem cells, a few that are kept around, maintained in a state so that then they can differentiate into various types of tissues. Another proposal is that there may be a universal stem cell, an adult stem cell, not a primitive cell, but one more geared towards maintenance and repair functions in the adult body. It may arise in one or more tissues, and then may disperse into other tissues. Other possibilities are that there are particular tissue stem cells, multipotent, not able to perhaps form all tissues of the adult body, but a limited subset, and that they would be resident within a few of these tissues. And then I mentioned here transient stem cells, cells that are just sort of passing through. And there is the possibility that, especially if we're looking at this idea of a universal stem cell, or even a tissue stem cell that can migrate in some cases, that it may end up passing through a tissue, so you will isolate what appears to be a stem cell from a particular tissue. But it didn't arise there. It just happened to be passing through via the circulatory system. I might mention, too, that some of the other challenges for adult stem cells are very similar to some of the challenges for embryonic cells. For example, standardization. There essentially is no standardization in terms of adult stem cell isolation, propagation, differentiation into other tissues at this point. Long term culture, with a few exceptions, has not been attained. Catherine Verfaillie's MAPC cells from bone marrow do appear capable of long-term proliferation in culture. And there are a few other examples, very limited, that I point out in the paper. But being able to keep these cells growing in culture for a long period of time has been difficult up to this point. The idea of safety, of course, is always an issue when we're going to be dealing with patients. Do these cells form tumors? Do they differentiate abnormally so that you don't get the correct differentiation in the place, in the time, in the tissue that you need? So all of these need to be faced. Now this idea of a potential universal or at least tissue stem cell that can migrate primarily has been put forth by Helen Blau of Stanford, the idea being that perhaps the cell is in the bone marrow, but then can go into the circulation and then exit the circulation into another tissue. Again, most of the studies have seen this type of phenomenon in response to an injury, not in response to the normal physiological systems. How would we then define a stem cell, especially an adult stem cell, if we have all of this problem with changeability of markers, and lack of standardization? Moore and Quesenberry have proposed a couple of simple guidelines. Now obviously, any stem cell has the ability to continue to replicate and maintain a population of cells. And then in response to some signal, to differentiate into one or more potential tissue types. An initial first cut at how to identify a stem cell in the adult would be, can it take on a different morphology in a tissue in which you place it? Can it take on some of the differentiated cell markers that you would see in that tissue? Now this is a bare minimum, and it doesn't really mean necessarily that the cell is functional, that it can participate in tissue repair, or perhaps even that it has truly differentiated into that specific cell type. Supplementing that, if you could demonstrate functional activity, and actual integration into a tissue, this would be a much better marker of a cell as a stem cell. And certainly, if in an injury situation, in animal model or even in human, you could demonstrate a physiological improvement. That would be a good indication that you were seeing this sort of stem cell differentiation and repair. Now, the next set of slides, what I've tried to do is just condense from that rather difficult mass to read of all of these various tissue sources, and cell types that they can turn into, and so on. I won't spend a great deal of time on these. I'll just try and point out some particular points on each slide. With mesenchymal or stromal stem cells from the bone marrow, we need to keep in mind that bone marrow is a mixed population. We've known about hematopoietic stem cells from bone marrow since the 1960s. These are well-studied and used clinically. The hematopoietic stem cell is differentiating primarily, at least, into blood cells. Another stem cell that's in the bone marrow is this mesenchymal, or stromal, cell. As I mentioned in the paper, one way that this type of cell is actually isolated is perhaps first by markers, but then also simply by its ability to form attached adherent layers in the culture dish, once you're putting them into the dish in the lab. Now, there have been various studies, and I've just tried to collect a number of them here, showing potential differentiation into different tissue types, either in the lab dish, or in the animal. Again, the way they're following this in the animal is primarily to use a genetic or a fluorescent marker, follow the cell, see what tissue it ends up in, and look at its morphology, and then also potentially try to analyze functionality and integration into the tissue. In various disease models, some of these cells have been used. For example, in models of stroke. And I want to point out again what Dr. Gearhart said. Animal models are only an approximation. This does not tell us the actual situation that we might encounter in human beings. But at this point, it's the best we can do. We can see if these cells might participate in cell and tissue repair. Using rat or human cells, there has been some therapeutic benefit in some of these disease models in stroke with animals. With demyelinated spinal cord. Intravenous injection, interestingly enough, of mesenchymal stem cells in the mouse has shown some remyelinization in spinal cord injury. Adult stem cells are not alone in terms of this ability. Other cell types have shown this. And this does not necessarily mean that you've totally corrected the condition. It simply means that you're able to provide some sort of functional recovering of a bare nerve. Another interesting point about this particular study was that they did not see a large incorporation of these cells into the spinal cord tissue. So what benefit they did see did not appear to be due primarily to the adult stem cells actually differentiating into the myelinating cells here. Instead, what appeared to be happening was the presence of those cells caused a signal for the endogenous cells to start to re-grow and repair the damage. In fact, Dr. Gearhart's lab just recently published a paper showing that embryonic germ cells showed in a particular mouse model the same type of repair phenomena. The mice did show therapeutic benefit. But what they found was that the cells did not, to a large extent, integrate in and participate in the repair. Instead, it seemed to be a signalling phenomenon. And I'll point this out in a couple of other examples along the way. There has been one clinical trial that I could find in the literature where 11 patients were treated for Hurler syndrome, or metachromatic leukodystrophy using allogeneic, and not from the original patient, but from donor mesenchymal cells. Now, the study noted that four out of those eleven patients showed a small increase in nerve conductance. One of the problems with these diseases is a decrease in nerve conductance. There are other neurological effects, and so on. So small increase. And in terms of loss of bone mass, all 11 patients seemed to maintain, at least for a certain time. But in terms of any of the other symptoms in these patients, there was no effect of the adult stem cells. Very early study. Using mixed population of bone marrow stem cells. So in this case, and again, this lack of identifiability for a particular adult stem cell. What many people have done is simply take raw bone marrow and either in culture try to get various differentiations, or putting back into the animal in various disease models. And they've been tried in quite a number of disease models showing some therapeutic benefit. In this particular case, again in stroke, intravenous injection of this mixed population of cells. Again, no attempt to purify the cells, or identify the particular cell that's being used for the treatment of the animal model. But the cells in this case did home in on the damage. Again, this interesting phenomenon that we've seen. Various other conditions. There was an interesting study relating to cardiac damage, where cells from mice were actually put into rats. And what they noticed was over a fairly extended period of time there did not appear to be immune rejection of these transplanted cells, even though they were even from a different species. Now, it's only one study. Does that mean that these particular cells might be immune privileged and not subject to rejection? Only more experiments will tell. Recent study indicated that with diabetes, in a mouse model again, where the pancreas was damaged to induce loss of insulin secretion, bone marrow stem cells injected into the animal could regenerate insulin-secreting cells. As in the other example I mentioned before, there was very low incorporation of the actual bone marrow stem cells identified as forming insulin-secreting cells. Instead, what they seemed to be doing in this instance was again secreting particular growth or stimulatory factors to stimulate the endogenous cells to re-form insulin-secreting cells. And there have been several clinical trials and publications, peer reviewed publications, from those trials, primarily with cardiac damage. There have been several groups in Germany and a group in Japan that have published their results. Again, very, very limited numbers of patients, we must keep in mind. And what they're seeing, though, is some physiological improvement in the ejection fraction from the heart, and when they actually examine some of the damage that seems to be being repaired. One Japanese group has reported growth of blood vessels in limbs that were threatened to be lost by gangrene. Peripheral blood. Probably we should just skip this category, in a sense, because they seem to be very similar to the bone marrow stem cells. And it makes a lot of sense that bone marrow stem cells could actually enter the circulation. The interesting thing is that two groups recently have isolated peripheral blood stem cells from human blood. One group in particular noticed that the cells that they isolated showed high levels of Oct-4 expression, this gene that's associated with pluripotent status of a stem cell. In a couple of animal disease models for stroke and cardiac damage, and I put this under peripheral blood because what the workers did was not remove adult stem cells and then re-implant them in the animal. They injected growth factors to stimulate mobilization of the stem cells, most likely from bone marrow. And these cells appeared to provide a therapeutic benefit in these conditions. And we'll come back and talk a little bit more about mobilization later. Neural stem cells. I certainly was taught in graduate school that you start with as many brain cells as you're ever going to have and it's downhill from there. And on my campus, it's downhill even faster on a good Friday or Saturday night. But within the last decade or so, the discovery that there are these stem cells within neural tissue that can at least regenerate all three main neuronal types, and perhaps some other tissue types as well. Interestingly enough, they have been used in some animal disease models to show some therapeutic benefit. And there have been some clinical trials, very early. There is one Parkinson's patient who was treated with his own neuronal stem cells. The cells were removed, grown in culture for awhile, and placed back just into one side of the brain. He did see a benefit. He did see improvement. In terms of spinal cord injury, there are no peer reviewed publications in terms of actual human treatment. But there have been reports that at least one group in Portugal are beginning these types of treatments on patients for spinal cord injury. Dr. Gearhart mentioned the embryonic carcinoma cells. And there's one group of this cell termed usually "hNT" that you might say has been tamed in culture. This particular line that they've come across primarily forms neuronal-type cells in culture, and, as he mentioned, it's being used in a beginning clinical trial on stroke. Muscle stem cell can regenerate itself. It has its own stem cell, primarily dedicated to forming more muscle. But there's indication that it does have, perhaps, another stem cell present in that population. Debate as to whether those cells can actually form blood, or if that was one of these so-called transient cells moving through. The potential though, perhaps, to form bone from this type of cell, and these muscle stem cells have been used in some disease models, primarily directed back towards muscle. Very interesting one that I came across was to re-form bladder muscle, or at least reinforce bladder muscle, in a rat model of incontinence. And there's been one published paper regarding a clinical trial using muscle stem cells, one patient, in France, where the patient did seem to receive some therapeutic benefit from the muscle stem cells. Liver stem cells and pancreatic stem cells. Pancreas and the liver derive from the same embryonic primordia. And so it might not be surprising that you tend to see liver able to form pancreas, or pancreas able to form liver. The interesting thing here is that genetically engineered liver stem cells, simply by adding and activating a gene, have helped an animal model induce diabetes in these animals. The pancreatic stem cells, likewise, have shown the similar ability. Corneal limbal stem cells are a very limited subset. And what we might in one sense call a unipotent stem cell, at least for the most part, other than one or two little reports, so that they would re-form only the tissue in which they're located. They have been used, however, in corneal transplants in a number of countries. And there are several published reports on this. In vitro, one group was able to get them to form neuronal cells in culture, or what looked like neuronal cells. Cartilage, again, a very limited sort of application, but clinical trials for articular cartilage transplants. And one group has used them in an attempt to treat children with osteogenesis imperfecta. Umbilical cord blood, not a great deal of research has been done, but there are a growing number of publications. The interesting thing here is, in terms of the disease models, stroke, spinal cord injury, and one particular model of ALS, the cells are delivered intravenously. So again, this potential to home in on areas of damage. And then just a list of a number of other tissues here where some type of adult stem cell has been identified, or potentially identified. And I want to point out the adipose, or fat-derived stem cells. And I use "derived" because it's very likely this is one of those transient stem cells moving through via the circulatory system. Interestingly enough, though, it provides a reliable, readily available source, you might say, from liposuction fat. And one group has been able to see neuronal differentiation in the lab; not in any animal models yet. Now, in terms of activation and mobilizing these adult stem cells, this may be actually one of the best directions to go in terms of potential clinical treatments. Simply because it may not be the stem cells themselves that participate in the repair of the damage. And in that case, maybe what we need to do is simply activate the cells so that they can deliver the signal to the damaged tissue. And again, there may be various states within the bone marrow as an example of a tissue where you might activate, where the cell could be activated and then mobilized into the circulatory system, and then reach the particular tissue to differentiate. Again, there were two animal models that had been used, one for cardiac damage, and one for stroke, where there was an indication that this might be a potential avenue of research. Rather than removing the cells, having to culture them, isolate them, identify them, put them back, simply being able to mobilize the cells within the body. Another possibility is genetic engineering. And in terms of actual animal models of disease, genetically engineered adult stem cells have been used in a few examples in the publications. In lung, that one particular reference indicated that there was a large contribution of the adult cells to lung tissue. Again, a damaged tissue system. Clinical trials, not directly, you might say, repairing a damaged tissue. But in Severe Combined Immuno-Deficiency Syndrome, bubble boy syndrome, several infants have been treated using genetically modified bone marrow stem cells from the patient. They seem to have been, quote, "cured," and I use that word advisedly, of the disease. There have been reports that at least two, and potentially a third infant, has come down with leukemia as a result of that treatment, most likely due to the viral vector that was used to insert the gene into those cells. Because the gene is not targeted in those instances. Instead, it may go into an area where it can activate oncogenic genes within the cells. In terms of delivering the signal, this might be an even better use of genetic engineering in adult stem cells. And there have been a few published examples, potentially for use in animal models with tumor therapy, to alleviate some of the symptoms in the model of Niemann-Pick disease for increasing bone healing, and in a Parkinson's model, where the cells were not participating to any great extent in repair of the tissue. Instead, they're delivering a signal to the endogenous cells there, and stimulating them. And in terms of that then, perhaps the best avenue eventually to pursue might be trying to isolate what these factors are, so that no stem cells would be needed at all. Instead, if you can identify those factors to stimulate regeneration within the tissue, they could be delivered directly. And there are a few published examples of this, one in which there was some axon regrowth, some, in a rat spinal cord injury model by injecting a couple of different factors. One mouse Parkinson's model study infused directly a factor into the brain of the mouse model and saw a therapeutic benefit. Another publication lists a different factor in terms of a model of chronic kidney damage. And one clinical trial where five patients, five Parkinson's patients were treated with infusion of this glial-derived neurotrophic factor, they did see some improvement. Not a cure, and it may be that that's not the sole signal that's needed, or the correct signal. But it did seem to stimulate some physiological improvement in the patients. Thank you. CHAIRMAN KASS: For a young field, there's a lot going on. And we have also talked our way late into the hour. Let me make a suggestion, if I might. Technically, this session was to run till 3:30, with the next to start at a quarter of 4:00. I'm going to take the liberty of suggesting we spend a half an hour here at least with our visitors to get some of our questions asked. And if Lori Andrews will forgive us, we'll be pushing back the start of the next session, just so we can get the questions asked. Michael Sandel, then Jim Wilson. DR. SANDEL: I learned a great deal from all of these presentations, as I suspect we all did. I was especially struck by one feature of Dr. Jaenisch's presentation, and I'd like to put this as an observation which actually will end with a question. The subtitle of the paper and of the talk, Dr. Jaenisch, and my Council colleagues will appreciate this perhaps more than our visitors. The subtitle could well have been, "The Vindication of Paul McHugh." Because when we were discussing the biology of cloning, almost everyone here shared an assumption, regardless of the positions that we took on the ethical issues. Almost everyone took it for granted that biologically the fertilized embryos and cloned embryos were essentially the same, and the moral argument proceeded from that assumption. With the exception of one person, Paul McHugh. And he introduced a distinction, a distinction, as he put it, between a zygote and a "clonote", by which he meant the cloned embryo, the product of cloning. And for insisting on this distinction, poor Paul suffered heaps of ridicule and abuse, and, at best, a kind of bemused chuckling, by those of us around the table. And he argued that there's a difference, a biological difference, with a possible ethical significance between a zygote and a clonote, between a fertilized embryo and an artifact created in the lab. And he was told that this is an eccentric position. He was told that this is an off the wall distinction, that it had no basis in biology or science. And in a memorable exchange with our colleague Charles, who unfortunately isn't here for the benefit of this discussion, he was asked, "Well, but what if a cloned embryo actually came to term? Isn't Dolly a sheep?" And Paul's answer was, "Well, a sick sheep." And then we read, Dr. Jaenisch, in your paper that a cloned human embryo would have little, if any, potential to develop into a normal human being, that it lacks essential attributes that characterize the beginning of normal human life. And you explained that it has to do with faulty reprogramming after nuclear transfer. Now, I don't know whether that's true, whether it's generally accepted, or controversial in the scientific community. But whatever the case, it seems that what we regarded here as an eccentric, off the wall suggestion, that there is a biologically significant difference between a fertilized embryo and a cloned embryo, now, if I understand you correctly and here's my question, now, you're telling us that far from being eccentric or off the wall, Paul's position may be true. DR. JAENISCH: Well, I think that was the whole purpose of going through these arguments for me. To argue from a biological point of view, it is a continuum. We have to struggle with that. And we have, for the early, most abnormal stage, we have good markers. Death is a terrific marker. Then we have molecular markers after birth, or we have aging as another marker. So these are concrete markers, and we know these animals are not normal. So when it is claimed that cows on the field are normal, which has been published by ACT. They looked at their one- to four-year-old cows sit on the fields and eat and give milk. They argued, well, they must be normal. So they checked that. And they checked it by checking if it had a heart. Yes, it had a heart. A liver, yes they had a liver, and that serum, even. So they concluded they must be normal and publish this in "Science". Now, this of course is a very superficial way of looking at it. And very interesting. Once this paper came out, six months later, two of these healthy cows, one got multiple tumors, the other one generalized seizures. Now this is not normal. You wait, and these things come out. The point I was trying to make is that these are stochastic problems. There is not a key master gene which, if this is right then the embryo's right. No. The whole genome is stochastically, correctly reprogrammed or not. And what's amazing to me is that mammalian development is so regulative that it can tolerate so much gene disregulation and still get an animal to birth and beyond. But you pay for that. You pay with subtle or less subtle, more or less subtle problems. And of course, because it's stochastic, you will arrive at the end at some animals which live a normal life span. And by all our available tests they might be normal, or you might not see it. If you look at the primate, or in the human, we might see this because we could look at some much more subtle phenotypes. So I think the point I was trying to make is if you want to use this as a technique to generate human beings, there's no predictability. You cannot do this. And for me, it doesn't matter with one percent or two maybe something normal, because you can't predict it before. So I totally agree with what your thought was. CHAIRMAN KASS: Jim Wilson. PROF. WILSON: Michael asked the same question I was going to ask using virtually the same words. I guess it's the Harvard affliction. But I want to just press a bit more. An oocyte is not potential human life because it's an unfertilized egg. You can enucleate it and put in a new nucleus, and now it is a clone. But according to your account, a cloned embryo has little, if any, potential to ever develop into a normal human being. If you would step back, then, from your biological role and adopt a somewhat more philosophical role, would you say that a clone, therefore, is not potential human life? DR. JAENISCH: I would argue it's not potential normal human life. PROF. WILSON: Thank you. DR. JAENISCH: I think that's the only thing I can say. CHAIRMAN KASS: And Dolly still is a sheep? DR. JAENISCH: Still was a sick sheep, was a very sick sheep, and which died, of course, predictably very early. CHAIRMAN KASS: Janet Rowley. DR. ROWLEY: Well, I, too, learned a great deal this afternoon. I want to make two comments, and then I have a question for Rudy. The first comment is that I think it is most unfortunate that we're prevented from asking our experts, and particularly John Gearhart, about the status of funding that supports this very critical area of science. The second comment is also directed to John. And I was struck by the specific chromosome abnormalities that you identified in your human embryonic cells, because you probably know that an isochromosome for 12p is the most common abnormality in human testicular carcinoma. So it's astonishing that this is the abnormality that you see in these cells, and I'm sure it is extraordinarily important. The question that I have for Rudy - I was surprised when you said that imprinted genes are only important in embryogenesis, because clearly there are a number of human conditions. Now, you could say, well, human condition and the malformations occur because of embryogenesis, but there is also this whole question of imprinting and its relationship to carcinogenesis. So I'd like you to expand on that. DR. JAENISCH: This is a very important point you're bringing up, so I was probably a little bit generalized. So I think most imprinting, as we know, have - so that could be among these things that could be the most interesting, because it's IGF-2, which is a loose cannon. IGF-2 is a tumor, an oncogene essentially, so this would be available for cloning, because IGF-2 is very easily dysregulated. And I would worry if you have both copies active, because that's pretumor status. So you want to screen for this. But the other genes - for all of the other genes, for example, an Angelman Syndrome probably really is - there are really problems of fetal development. So these genes and fetal development - I could go further into this, because it's really growth of the fetus, where these genes appear to play the most important role. And there's really no evidence, with the exception of IGF-2, maybe KIP-257, which is a tumor suppressor gene, those are the ones you would worry about. So I think we know only two of those, and those you would test for I think. So I agree, which makes this a little bit more restrictive when I say it. DR. ROWLEY: Right. And there probably are others that we don't know about, but - DR. JAENISCH: There might be others which we don't know - DR. ROWLEY: - you're saying that they would - DR. JAENISCH: Yes. DR. ROWLEY: - just all be tested for. DR. JAENISCH: Those two we know for sure, but others we know they don't play a role. CHAIRMAN KASS: I have myself next, if I might. A question for Dr. Prentice, and then for the group as a whole. In Dr. Gearhart's presentation, he gave a great deal of emphasis to the importance of the characterization of these cells, the reproducibility, all of these various things. You had to cover an enormous amount of material in the number of papers, and you also in your presentation alluded to the problem of characterization, though I gather many of these studies seem to be one-shot efforts of throwing some things in and trying to see what their clinical effect might be. And as I've read the debates, a lot of people wonder, are these really stem cells? How well characterized are they? So could you say something about what criteria should be used for these stem cell preparations? What criteria would they have to meet before you could satisfy the critics that these are, in fact, fit to be called human stem cells, and fit, therefore, for controlled studies on the kinds of things that you're talking about here? And kind of a subordinate question, what's the best characterized of, and the most versatile of, these adult stem cell preparations? Are there any that at the moment meet the criteria that you yourself would advance? DR. PRENTICE: In answer to your first question, it's difficult, obviously, because as you point out many of these studies have been sort of one-shot, especially if you look at the mixed bone marrow population studies where they are simply taking a preparation, putting it back into a diseased animal or a diseased model, and trying to come up with some therapeutic benefit. You know, obviously, what you'd like to be able to do is to isolate the cell or the population, keeping in mind that caveat that the population dynamics may be an important facet of this. But let's say there's one particular stem cell that you're after. Supposedly, if you saw that sort of therapeutic benefit from the mixed population, you should be able to go in and simply take cuts and eventually isolate that one cell, and then be able to grow it in culture. In terms of the overall markers, that's been very difficult, and there have been a few studies looking at the gene expression common to neural stem cells, bone marrow stem cells, embryonic stem cells. And there are a subset of those genes that are common to all of those cells. Now, what you would hope to be able to do, then, is to go look at each of those genes and start using those as guides to come up with a marker for any stem cell that would be targeted for the types of differentiation models that we'd like to see, and eventually clinical applications. CHAIRMAN KASS: And with respect to the second question, what is the best characterized and most versatile adult stem cell preparation at the moment? I mean, can you - is there - DR. PRENTICE: Probably Dr. Verfaillie's MAPC cells, and I can't speak for her, but those do show many of these characteristics that ideally you would like - long-term growth in culture, clonogenic growth, and then differentiation. They've been used in a couple of different animal models of disease to see some sort of benefit. One of the mesenchymal cell - stem cell lines, if I remember correctly - and there are a lot of things to sort back through there - had been kept in culture, I believe, for about two years. There was another cell line that - I think it was also a bone marrow derived cell line, but it had been genetically engineered to contain telomerase or additional telomerase gene. And that had been kept in long-term culture. I believe also one of the neural stem cell lines has been kept in long-term culture, and actually Dr. Gearhart might be able to comment more on that. CHAIRMAN KASS: Okay. Thank you. And I have a general question to all of you, if I might. Since we sent you some general questions that we were hoping to get some help on, to go from where we are now to actually having reliable tissue grafting therapeutic applications in humans, since there's a fair amount of speculation out there - and, Dr. Gearhart, you did emphasize how early we are in the process and the emphasis, really, on learning of the basic biology. But the public out there is more - much more interested in, you know, where are the cures? Could you address that particular question of the various sort of stages, and where we are, and what kind of - how one should talk about these things responsibly in relation to the widespread hopes for remedies for which the patient groups are, quite understandably, clamoring? DR. GEARHART: The answer to that question is a very complex one for me. I could run through a number of cell lineages with respect to the human embryonic and stem cell and germ cell lines, where we are in the process, but it's the other end that I want to address. The most difficult talks that I give anymore are those before patient-based groups where the hopes are high. They come with expectations that far exceed, I think, where we are. And this is the result that I think that early on in the field, as you mentioned, the hype was there when circumspection should have been there. And I don't think circumspection is a retreat from promise. The reality is when you get into the laboratory, and you are working on cell lines, it seems the more progress you make, the further away the goal is as we learn. And we can show I think remarkable things in our animal models of putting in cells, and these are almost - they bear some resemblance to the adult stem cell story where you try a lot of things empirically, you get a response of some kind, and you're trying to figure out what it is, why. But when you superimpose on top of the biology issues of trying to control these cells in a dish, and trying to expand them in a dish to characterize them, to show that they're authentic, that they do work, the issues of safety, which I think we all are in agreement have to be foremost in this, that the time frame is years away before I think any of this will be realized in a clinic. I think there's misunderstanding, that if all of a sudden you have an insulin-producing cell in a laboratory, which we do, and we're - as other labs have as well - that most people think this is the answer. You just put insulin-producing cells into a diabetic. And as you know, this doesn't solve the underlying problem. We can - so I don't know how to answer the question that you ask. I mean, I'm certainly optimistic. I think it's going to be a direct function, and I'll come back to Janet's question that she can't ask or isn't supposed to ask, and that is that obviously more funding into this area - and I know that this isn't a congressional committee of any kind, where we're seeking funding, but obviously the progress is directly proportional to the number of good investigators you have working on projects. And in this field, we've had a bottleneck, first from the number of lines that could be used, now the NIH funding I'm sure is going to be more robust over time, but this remains not only I think a financial issue but also almost a psychological one - for students getting involved, for post-docs getting involved, for young faculty getting involved in the field, where we don't know what the future will be, to be honest with you, in this country. We see our colleagues around the world in different laboratories I think making really substantial progress here. And so I'll get off this part of it, but I think this is an important issue, at least with the embryonic and fetal sources of cells. And I hope we'd get over that. CHAIRMAN KASS: Thank you. I have Gil Meilaender, Bill Hurlbut, Janet. Gil. PROF. MEILAENDER: Yes. Dr. Jaenisch, I want to come back to where Michael Sandel started us, because I'm just not certain that I'm clear on something. And what I want to know is, you know, it's always hard to know when one's speaking as a scientist and when one's speaking as something else. But as a scientist, there are various kinds of chromosomal or genetic defects that a fetus might have, the result of which would be that it might die immediately after birth or very soon after that. How would you scientifically describe those fetuses? Would you say that they have - that they also do not have the potential to be a normal human being? I'm trying to get away from the stem cell issue for a moment. Would the same characterization be the appropriate one there? DR. JAENISCH: This a really a question which is not a scientific question, then, right? An embryo which has a trisomy number, whatever, large chromosomes will die very early, maybe before implantation. So that has this embryo which is afflicted with this genetic alteration. Has that a normal potential development to a human being? No. PROF. MEILAENDER: So it falls into the same - so, in other words, this is a rather large category of embryos and fetuses that - about which we would say this. We're not only talking about cloned embryos. DR. JAENISCH: Well, I think that - PROF. MEILAENDER: The same characterization - DR. JAENISCH: Yes, I - PROF. MEILAENDER: - would fit. DR. JAENISCH: I think the difference, from my point of view, if a chromosomal abnormality occurs after normal fertilization, something which is totally unpredictable and is assessed, that is what fate is to genetic game. With cloning, I think it's predictable, and that's the difference. It is predictable to a large extent, so I think that would make the difference. One is spontaneous, unpredictable, it's a risk of normal reproduction. The other one is predictable. Otherwise, I really can't - I think this for me is a major difference. You predictably generate a human being which has no chance to become normal with any acceptable efficiency. PROF. MEILAENDER: I think I'll stop there. CHAIRMAN KASS: Bill Hurlbut, and then Janet. DR. HURLBUT: Did I hear you correctly say you find destruction of IVF embryos morally troubling, but cloned embryos for embryonic stem cell use less troubling? DR. JAENISCH: No. Well, I said that if you accept that instead of throwing away an in vitro fertilized embryo which cannot be implanted because nobody wants it, instead of throwing this embryo away generating to an embryonic stem cell, I mean, people accept this. I find this acceptable. But it does pose an ethical problem, because you do destroy potential normal human life. There's no talking around it. So if you accept that, then I would argue that a cloned embryo is less of an ethical problem. That's all that I want to say. So the potential is not there. DR. HURLBUT: And from hearing you and talking with you at lunch, I had the sense that you feel like nuclear transfer actually offers us more versatility and more promise than using IVF embryos, because we can use the genotypes we want and control various things. Is this fair? DR. JAENISCH: Yes, I would think so. DR. HURLBUT: So I have to admit I'm troubled by your comment, and not convinced by Michael Sandel's comment. As much as I like my colleague Paul McHugh, I'm not - I'm troubled by the notion that what you called not potentially normal human life does not have a moral standing. And the reason I'm troubled by that is - was just alluded to by Gil, that I would not say that a potentially abnormal trajectory of embryogenesis is not a human life necessarily. Now, I have a handicapped child myself, and she does not have a problem of development, but she had brain damage at birth. But she's not what you would call a normal human life in that specifically all-healthy sense. But she's very human, as human as I am. I'll let somebody make the joke on that one, if you want. But the question is this. I feel for what you're saying. I feel for what Michael said, and I feel - have been with Paul to some extent on this all along. But if we say that natural - the natural meaning of the definition of a human life is not normal, but some meaningful process of integrated - of integration of identity, of continuity, then it seems to me that the clones that have been produced at least with animal studies have to qualify as entities of their species. So even though, as you said to me even a year ago, a cow standing on a green hill chewing its cud isn't - doesn't make it a normal cow. I agree. But I think it's still a cow. And likewise, the human trajectory of whatever the clone could be is troublingly human-like. I personally wouldn't feel comfortable saying, for example, as was implied by John Gearhart in his talk, that we could use it to harvest out later tissues for more difficult differentiations. Well, let me back that up. All of my colleagues, and my own reading on this, confirms to me that going from embryonic stem cells to useful cells, tissues, and organs, is a long journey, maybe short for Parkinson's Disease, but longer for more complex tissues, and very long for - what we really want is organs and - for transplant, like kidneys, and so forth. I think there will be a temptation in our civilization to move the trajectory of something that's designated non-human on to further stages of gestation. Now maybe not gestation in a human womb. Maybe it'll be in an artificial endometrium or something that can coax it just 30, 60 days longer for good use. It starts to be troubling, even if you accept your premises. Let me back it up, then. I think in principle what you're saying has something to it, and Paul and I have been trying to talk about this, and I've had dialogues with my colleagues on this. I put forward in my personal statement on the President's Council Report on Cloning what I called a speculative proposal, where I suggested that - drawing on what Paul had said, that this is an artifact, not a human being, a clonal artifact. Why don't we go to the bottom of the problem? Why don't we say that something that does not have a human potential in any meaningful way, not an abnormal human potential, but no meaningful human potential, might supply us with the essential way to get around the moral problem, at least to get us to stem cells? And we can deal with the next issues later. And I want to stay two things before I conclude. One is in making this proposal, I was very aware that the first issue of what you might call the inviolability of the human life is only the beginning of the questions about the moral use of human process or human tissues or anything. But what I had in mind was this - that just as we've come to see that a cell does not define the locus of human dignity, nor does a gene, of course - let's start at the smallest. A gene - a human gene can be put into a bacterium, grown, used to make insulin. A cell - we do blood cell transplants. Tissues - we do skin transplants. Organs - we do transplants and even organ systems. None of those are the locus of human dignity, human moral standing. Likewise, in this age of developmental biology, we will learn that partial generative potentials are not the locus of human moral standing. We will harness these partial generative potentials in such a way that we can do wonderful things with them without violating the integrity, identity, and continuity of human life. So this is my question to you. Could we find a scientific way to meet the challenge of our President and our nation and the imperative of our civilization to go forward with the science? Could we define the danger as we never want to interrupt a normal human life in process, or even one that is remotely normal? Could we meet that moral objection while at the same time opening the positive future of our science? And here the suggestion I would have is using something so fundamental, like short, interfering RNA, to preclude the very possibility of anything but the most minimal and genetic mammalian process to the blastocysts from which we could then take embryonic stem cells. What do you think? DR. JAENISCH: Yes. I think we talked about this before. I think it's a really interesting possibility. So what we need to - for a human being to develop two major lineages, which is a trophoblast lineage and the epiblast lineage. The trophoblast lineage will support the embryo from the placenta. So certainly there are genes which are only needed, as far as we know from experiments, that are only needed for placental development. They are not needed for the epiblast lineage or for the embryo. So one would modify a donor cell - let's say a skin cell that you want to transplant - with inactivating such a gene - I can give you examples of those - and expressing, for example, using the SI RNA technology, which now really becomes - seems to become a routine procedure to inactive genes. And, indeed, an embryo - a cloned embryo derived from such a nucleus would not be able to form a trophoblast lineage which would be functional. So, therefore, if this embryo would be implanted, it would definitely fail. You could predict it would fail much earlier than this continuum, which I outlined for the cloned embryos which are not modified. So I think, in principle, this is a doable - potentially doable manipulation which would prevent what you are interested in and what you are raising, prevent the development very far in utero. DR. HURLBUT: In your opinion, could we reasonably call that not in any sense a human life in process, abnormal or normal, but call it a clonal artifact, a laboratory production for the procurement of cells with a potential for something, but not what we would have to call embryonic cells? DR. JAENISCH: Yes, because you would argue this embryo - I mean, the definition of an early embryonic cell, like a two-cell or a four-cell embryo, the blastomere, is totipotent. These cells can make the placental lineage and the epiblast lineage. This embryo would not be able to make the trophoblast lineage, so, therefore, it would not be totipotent. So I think you could argue this would be a real biological difference. CHAIRMAN KASS: We do want to go to the next session shortly, but I've got Janet and Elizabeth, and then I'm going to call a halt for this session. DR. ROWLEY: I come back to John Gearhart. And, first, I want to take you to task for comments at the very end of your talk, and then I have a question. And what I want to take you to task for are your comments, all related to enhancement and how easy it's going to be to just get genetic enhancement of all sorts of features. And I think - well, you could expand on that or explain what you meant by that. But this has been such a critical issue for this particular Council - the likelihood of enhancement - that I think that it shouldn't just be left unchallenged. And the question that I have is, with regard to characterization of current lines, you indicated that that's under the auspices of the MRC in London. And I'm just curious, are they looking at both so-called presidential lines as well as lines available elsewhere? Or are they only lines available elsewhere? And what kinds of characterization are they proceeding with? DR. GEARHART: Let me answer the non-controversial question first. This is a relatively - this panel - there has been, over the last nine months or so, an international consortium that has been meeting on human embryonic stem cells. The outcome of this was the appointment of a panel headed by Peter Andrews at Sheffield University, who will be - that panel will be setting up the standardizations, if you will, or the criteria for the embryonic stem cell lines. They will - I think some of this work will be done in the equivalent of what's the FDA in the United Kingdom. But they will take any cell line that's submitted to them, whether it's a presidential one or one from anywhere else. They are not a - they are not distributing cells. They are just testing them for these different parameters. And, obviously, there will be a number of transcription factors, a number of surface antigens. This kind of thing will be in that mix. DR. ROWLEY: Will they do karyotypes? DR. GEARHART: Oh, yes, karyotype is - yes, it's absolutely essential to have a normal karyotype, and one that's stable over a number of cell passages is critical. The comment I made about enhancements, I just - it may have been out of order here, but I am concerned, I mean, as a biologist I'm concerned. I'm concerned about a number of issues. It makes it sound as if most of the time that scientists aren't concerned, that we're just going along in a fashion that, you know, science for science sake. And I only have to remind you over the last few months to see the use of human embryonic stem cells in mouse chimeras, the use of chimeric human embryos that has been done, that you say there's no reason that these things should have been done. I mean, there's no scientific basis for this. And we have to have some degree - and I'm not going to call it regulation, I don't like that term, obviously, but there has to be some consensus as to what should be permitted and shouldn't be permitted in almost a global way. And I realize that this is very, very difficult. I've been to two G-6/G-7 meetings in which we have tried to get some kind of consensus even on human cloning among countries. I mean, let alone the use of embryos for research, and things like this. And as you can imagine, nothing much happens. Everyone has their own opinions, and we go away. When we have the capability - if this work is successful - I'll be frank with you. If this work is successful, and by success that we are learning mechanisms around differentiation and the development of cell types, we are going to have an awful power that we can instruct ourselves. Now, we're not necessarily going to be talking about germ line cells or germ line modifications. Maybe. Because, obviously, if we can grow oocytes from these cells - there are reports that we can grow spermatogonia and sperm cells out of these - maybe the possibility exists for that at this point. But I'm just hoping that people are thinking ahead a bit, that, you know, this is something that's going to be on the table in a number of years, and that we should give it some thought - where we're going to go with this. That's all. And so I made a comment about, you know, getting it off the internet or something to do it. Maybe that's an overstatement. Maybe that's just crying wolf, and I apologize for that. But I think it's something that we have to be aware is out there. It's going to be out there. Not out there now, but will be out there, and we should be thinking ahead. So I apologize to the Council for making that kind of a comment. DR. ROWLEY: Well, I don't think an apology is necessary. I think what I'm trying to say is - my own personal view is that the Council should be especially concerned about things that are relatively near term. And by "near term," in such a rapidly-moving field I think a few years is near term. And if you're saying, well, in 10 years' time we'll be able to do this, we can't see that far ahead. DR. GEARHART: Right. Right. DR. ROWLEY: And so that - so what kind of terms are you talking about in terms of time? DR. GEARHART: Oh, I'm talking not about 10 years. I'm talking about a shorter time interval. DR. ROWLEY: Okay. DR. GEARHART: You know, Janet, I think to be honest with you, the number of federal Blue Ribbon Panels that have been set up, at the NIH level, the National Academy, to discuss issues that seem to be 10 years away, recommendations were made by our leading scientists, our leading scholars, only to be ignored. And then, we find ourselves in a pot once these things happen. And it's just, I mean, frustrating as a scientist. It's frustrating almost as a citizen to do this, where it seems that the scientific community, to a certain degree, is marginalized when it comes to making recommendations as to how we should proceed. And we are left, then, every time something comes up in this area everything is thrown up in the area as to where we're going, etcetera. So that's the nature of the comment. Or, I'm sorry, that's the basis of the comment that I made. CHAIRMAN KASS: Last comment. Elizabeth, if you - did you still want to say something? You were on the queue. PROF.BLACKBURN: I'll return to the science, and I don't know who would like to answer this question. But it was picking up on the point that I think Leon did raise about asking about the sources of adult stem cells. And you mentioned that there's really only one good one, or the best one, is that right. Dr. Verfaillie's. And - DR. PRENTICE: I think Dr. Verfaillie's is the best characterized - PROF.BLACKBURN: Yes, best characterized. DR. PRENTICE: - in terms of all of these various traits. PROF.BLACKBURN: Yes. So, you know, we're struck - and I think Leon pointed this out, too - by the fact that there's a great deal of research that's been ongoing in the last, you know, couple of years - DR. PRENTICE: Yes. PROF.BLACKBURN: - on adults. And yet it seems to me there's a real problem. And, you know, what's the problem? Why is there so little known? To put it bluntly. You know, here's 192 publications that you cite, and why is it so difficult? Are these just inherently really difficult things to work with? Is this what it comes down to, that people who work with adult stem cells don't really like to say that, or - sorry to cut to the point, but I know time is of the essence. DR. PRENTICE: I think one of the reasons comes back to this difficulty in identifying which one is actually the stem cell, how to actually purify it, isolate it. Some of the cells seem rather easy to isolate. Certainly, peripheral blood is quite easier, or the adipose-derived cells would be easy to isolate. But then, how do you really know that one is the stem cell? And, again, most of the results - the best results seem to come primarily from these mixed populations of the bone marrow stem cells, where they have not intentionally in many cases isolated the particular stem cell. Instead, they've been geared towards some sort of physiological endpoint. My assumption would be, then, working back from that, once they could achieve that end point, then they might be able to derive the particular cell. But I think it also brings up a point I tried to raise before in that it may not be possible, or it may not be preferable, to try to get a particular cell. It may be the context of these cells with the population and their interactions, exchanging growth factors, altering their own gene expression, and then - in the tissue milieu - that really gives them this ability to somehow cause the repair. And I use that term because, again, I think in many of the instances the research is showing that it's not direct integration and taking on the function. It's somehow stimulating endogenous cells. PROF.BLACKBURN: So it may - are you hinting that it might be qualitatively different from what is going on with embryonic stem cells, when those were tried to be used? DR. PRENTICE: Well, I - PROF.BLACKBURN: I don't want to get too much into this, but I'm just trying to understand the science here. DR. PRENTICE: Yes, I think that might be a good way to put it. It may be qualitatively different. You know, it's interesting Dr. Jaenisch mentioned that embryonic stem cells, in a sense, are a tissue culture artifact. He might just as well, by the same definition, call Dr. Verfaillie's MAPC cells a tissue culture artifact. And it may be that putting these cells into culture, now changing their context, gives them some of these characteristics that are so sought after. Our target might be better put in terms of, what is the physiological endpoint that we want? Not a particular starting cell, but how do we achieve the repair of the tissue damage? And, again, as I mentioned in the talk and in the paper, it may be that it's not a particular cell that we really need. Short term, cellular regeneration may be our best goal. But long term, figuring out the particular molecular and cellular signals - and, again, it may be a context-type signal - cell-cell context or cell-matrix context - that actually can give us that physiological endpoint, and so eventually going to a non-cell-based system, but a signal-based system if you will. CHAIRMAN KASS: Paul McHugh insists on a very brief comment, and then we're - DR. McHUGH: I have just two - CHAIRMAN KASS: - going to break. DR. McHUGH: - little tiny scientific questions, but because they are important science that we're discussed here. The first one really relates to Dr. Jaenisch, and that is, I wanted to know, sir, now whether you could say that the genetic alterations and the problematic genetic status of the fully cloned animal, whether those genetic abnormalities would then pass on to their offspring, and so, therefore, be a contaminant to the whole human genome legacy from then on? That's the one question. DR. JAENISCH: Let me first clarify there are no genetic alterations which are important. They are all epigenetic. DR. McHUGH: Right, yes. DR. JAENISCH: So the experiment has been done. You can take two animals afflicted with large offspring syndrome and mate them. The offspring will be all (risk?) normal, because you send the genome through the process of gametogenesis, which reprograms everything in a normal way, everything is reset. Of course, there might be some genetic alterations which are acquired during somatic life. DR. McHUGH: Right. DR. JAENISCH: Those would not be - they cannot explain the phenotype. They would be recessive, and so they haven't shown up yet. DR. McHUGH: Right. DR. JAENISCH: So we don't know if they would show up. DR. McHUGH: They might show up later. DR. JAENISCH: Right. DR. McHUGH: And secondly, to John Gearhart - John, you whine a lot about how troublesome it is to be a scientist nowadays. I just want to know this. The President made a very good Solomonic decision and produced the cell lines for you scientists to work, putting the ball in your court. Are you saying to us now you've used up all of the potential in those cell lines, and now, because of the President's decision, are restricted in your progress? CHAIRMAN KASS: You don't have to answer, and he's over time. But if you'd like to - DR. GEARHART: I have to answer Paul. CHAIRMAN KASS: - 15 seconds. DR. GEARHART: Being a scientist is the greatest thing in the world, and I wouldn't trade it for anything, Paul. And so I don't - DR. McHUGH: I know that, John. Me, too. DR. GEARHART: Okay. And I'm not here to whine. The funding issues are improving, and they are improving nicely here. Okay? And, clearly, we can learn a lot through the lines that are approved. CHAIRMAN KASS: Gentlemen, thank you very much. Look, we have a guest we've kept waiting for quite a long time. Would the Council, please, 10 minutes. Thank you all very much. (Applause.) (Whereupon, the proceedings in the foregoing matter went off the record at 4:10 p.m. and went back on the record at 4:23 p.m.)
SESSION 4: STEM CELL RESEARCH: CURRENT LAW AND POLICY WITH EMPHASIS ON THE STATES CHAIRMAN KASS: The last session of the day, also on stem cell research, recent developments in law and policy, with emphasis on the states. Federal policy governing human stem cell research is well known to the Council. It has been formed basically of two elements — a legislative prohibition on the use of federal funds for destructive embryo research, and President Bush's funding decision to support work on the already-existing human ES lines, with some 70 lines eligible but only 11 lines available for use. Funding for research on adult human stem cells is unrestricted, as is research on human embryonic stem cells in the private sector. The Europeans, who have similar national policies, don't understand either American federalism or the traditional distinction over here between public and privately funded activities. And they are surprised to learn, say, the difference between what California and Louisiana are doing in these matters. But to Americans, the separate laboratories of the several states are nothing new. And to help us monitor developments in this area we've commissioned a paper by Lori Andrews, Professor of Law at the Chicago-Kent College of Law, Director of the Institute of Science, Law, and Technology at IIT, who is the country's leading authority on this subject and a prolific writer also in the area of law and bioethics, especially in relation to ART. It's a very great pleasure to welcome Lori Andrews for this presentation to the Council. We thank you for your paper. We look forward to the presentation and the discussion. Thank you for coming, and thank you for indulging us this extra time. MS. ANDREWS: When you were having your earlier discussion this morning about commodities and body tissue, it made me think of a newspaper article I had read growing up saying the chemicals in the body were worth 89 cents. Well, obviously, with the tens of thousands of dollars being paid for eggs and a human gene, like the erythropoietin gene being worth a billion dollars a year, we've entered an age of a market in human tissue. And coming after the scientific panel, talking about the many, many uses, you can see that market could be burgeoning around embryo stem cells. Immediately after the potential for these cells was announced in 1998, every NIH institute put on their website what they planned with those cells. The Heart, Blood, and Lung Institute said it would repair failing hearts and grow new heart chambers. General Medicine said it wanted to grow artificial skin. And even the Environmental Sciences Group wanted to get in the act, proposing to use embryo stem cells to "test the toxic effects of biological chemicals and drugs." Now, obviously, this is not without controversy, and both pro choice and pro life advocates have particularly centered on some of the commercial aspects of this. About a week after the announcement in '98, I got a call from an in vitro fertilization clinic, and the head of the clinic said to me, "We have about 300 embryos that nobody has asked about recently. Can we sell them to a biotech company?" And I think this kind of goes against Dr. Kass' idea that the people who aren't the individuals but who are making the profits out of it have mixed their labor into it. Since obviously this in vitro clinic had charged people to do the in vitro, were charging them for storing it, and so they would just clear a sheer profit on it. But imagine the heartache of a couple who later showed up wanting their embryo for a second child and learned that it had been sold, and what if - you know, even if a couple had checked "research" on their in vitro form, they may have had in mind at the time research dealing with fertility and not something that would turn their embryo into a set of nerve cells that was sold to the highest bidder. And we've also seen instances where the couples now disagree about the fate of the embryo. In one case, there was a divorce. The woman wanted to use the embryo for creation of a child. Her husband did not. But they had checked "research" on their form, so after seven years of litigation the court agreed that research could be done. And as we've heard from Dr. Gearhart, there's no guarantee necessarily that these stem cell lines will be used to cure serious diseases. It might turn out that the cardiac cells would be used not only to repair damaged heart chambers, but to enhance athletic ability. Geron Corporation touts the artificial skin it's developing as a treatment not just for burn victims but for people with sun damage and other age-related conditions. And, indeed, one older Senator might have let slip his real interest in embryo stem cells when he referred to them as "a veritable fountain of youth." So what perspective is the law, particularly state law, taking on all of this? I've been asked to address how existing laws apply and affect this work, what kind of legal research might be permissible, who should oversee it, and who, if anyone, should own rights to the processes and the products of embryo stem cell research. I'll just briefly go through several approaches, and then the meat of the laws themselves. Now, one approach that we could take, and some states do take it, is to ban embryo stem cell research altogether and focus more effort on the exploration of the potential of adult stem cells. We saw from the budget put up by Dr. Gearhart that more money is being distributed in the adult area. A second approach — the opposite extreme could be to allow any type of stem cell research. There have been bills proposed on that, including the creation of embryos for research purposes, as was done at the Jones Institute where they paid an egg donor and a sperm donor and created an embryo for research purposes, or at Advanced Cell Technologies, creating that six-cell embryo through cloning. In China, such research is also proceeding, with a study of . apparently transferring a human cell, nuclei from a seven year-old boy into a rabbit egg. A third approach might be to use excess in vitro fertilization embryos. There are, as the papers show, over 400,000 such frozen embryos, and studies show that 10 to 30 percent of them are . could be made available based on couples interested in participating in research. Again, though, there's a question about whether there actually ever is such a thing as an excess embryo, if there are couples willing to adopt such embryos, and also, you know, given, you know, other, you know, concerns about the couples' interests. Now, the states as well as the Federal Government have a role in setting policy in this area, and 26 states have laws that govern research on fetuses and embryos. They are enormously different, and they vary widely on things such as whether they only apply in situations where there's been an abortion. For example, 12 of the states only apply if the research subject was the subject of a planned abortion. So there's more leeway in those states to do research on a miscarried fetus, but there are medical reasons to think that might be less than optimal, since most stem cell research will not take place on miscarried conceptuses but on in vitro embryos. In that situation, we currently have nine states that banned research on IVF embryos altogether. And what that means, though, is that it doesn't really get to the heart of the activity. For example, if Dr. Gearhart found that a certain type of destructive embryo research produced a safe and effective therapy, once it passed the experimental stage it could be done in those states. It only applies when the activity is at the research stage. And it has created a kind of funny situation across time where . for example, one of those laws is in Massachusetts, and so researchers at Harvard couldn't do certain research on embryos and fetuses, like chorionic villae sampling research in the early stages. They had to wait until their colleagues at Yale in Connecticut, which doesn't have such a law, got it to the stage where it was clinical and then it would be okay to do it in Massachusetts as well. There are also, at least in one state, in California, a law that permits human embryonic and adult stem cell research from any source, including somatic cell nuclear transfer. Now, in that state, there's only a little bit of regulation on this being done. The research has to go through an institutional review board, and the research can't be undertaken unless there's a written informed consent of the embryo donor. Now, I'm intrigued because they don't say donors, you know, and an embryo, of course, has a male and female, you know, part to its creation. And so it would appear that the female patient of infertility services, the woman, and not her husband, is the sole source of consent under the California law. Now, if it goes forward in California, I think they need lots more attention to issues around informed consent for some of the reasons I mentioned earlier. Some couples who would consent to research generally may not feel comfortable with that commercialization. And I've seen that in another area that I work where there are people who are willing to participate in certain types of genetics research, but for religious or other reasons oppose gene patents, and so are troubled with that application. In addition, neither the California law or any of the proposed laws give any attention to the recipient and the level of informed consent you might need from someone who would use a therapy based on human embryonic stem cells. Some people may not want treatment that uses cells derived from human embryos, just as Jehovah's Witnesses will turn down treatment involving blood transfusions. And it won't always be necessarily clear. I mean, there was an issue in Germany, for example, where there was a product called Lyrodura, which people used, and it wasn't explained to them it was made out of human brain matter - dura. And so not only did they not understand that, but they weren't prepared for the medical problems that happened when some of them started having negative effects from infections passed on by it. And I think there are other issues around informed consent and CGD which have to do with what you tell the person you're going to do in terms of the screening. I mean, you generally asked about the characterization of these lines. Okay. And so if my embryo is used for research purposes, and I'm not told that they're going to do infectious disease screening and karyotyping and a lot of things that might have implications for my future health insurance, or even my future liability- I recall when Jose Cibelli was first using purportedly a cheek scraping to create an embryo at U. Mass. It went through their institutional review board, and the IRB said, "Oh, of course it doesn't apply to researchers who do scientific studies on themselves," without thinking about what happens if he creates a heart cell line that has some defect in it. He'd be open to a products liability case for - potentially for that. And so there are ways in which the donor needs information about what's going to be done. So Dr. Kass had mentioned that this is an area that I've studied for a long time. In fact, the past 25 years — 25 years ago this week I took the bar exam on the day that Louise Brown, the first in vitro child was born, and so I've looked at, you know, what has happened in state legislatures around embryo research, around in vitro around fetal tissue transfer, around germ line gene therapy, all of these things. And I see something different emerging now. I mean, one thing that I see emerging is this real inflated hype in kind of both directions, in the preambles to these bills, and so forth, either promising the moon, you know, we can do all of these treatments now, we're going to cure every disease, to be skeptical of, or this is all really horrible and a kind of misstatement of the science that I point out in my paper. I'm a little . and then, another difference I see is that in the earlier generations of laws dealing with embryo research, the issue was only, is it permissible, or not? Now, though, what I'm seeing is that both states that want to discourage and states that want to encourage put forth all of these provisions about what also applies to contracts and liability. You know, for example, states that don't like cloning sometimes have in their laws liability provisions that say if anything's wrong with the clone, they can sue, you know, their parents, the doctor, everybody else. And states that like embryo stem cell research actually already have liability provisions being suggested and in place that would make it harder for someone who does have a real problem with the stem cell research to sue. So in terms of the restrictions that are in place . that are being proposed as opposed to the ones that are in place, 22 states have bills currently being considered that would ban therapeutic cloning, and nine states have bills that would allow it. And some of those bills that would allow it . I mentioned Kentucky in my paper. You know, you just give $50 to register that you're doing this, and kind of that's the oversight as opposed to some sort of regulatory structure that might deal with the safety of it. In addition, four states have bills that would prohibit acts where the human fetus or embryo is destroyed or subject to injury. So a parallel to the federal law and would ban embryo stem cell research as a subset of that. Ten states have bills that would allow embryo stem cell research from any source, and they often say human embryonic stem cells, human embryonic germ cells, human adult stem cells, somatic cell nuclear transplantation. And those that want to encourage it, there's a small subset of about five that have thought through at least a few of the issues. How would this work kind of on an industry-wide basis? And they have proposed provisions in these bills that talk about what the responsibilities of physicians are to inform couples in in vitro clinics of this possibility. Some have . five states talk about institutional review board approval. One would have all proposed research assessed by a state committee. And 11 states have bills that really are more study bills. They would establish a subcommittee to think about these issues much as you're doing at this moment. Now, my paper also points out that not all of these laws are necessarily constitutional, if you ended up going to court as a scientist or other individual who was limited. And remember the state laws that are in place, like the nine states that ban embryo research, apply no matter what the source of funding is. So it's very different than the federal law hinging on federally-funded research. And some of these laws have been challenged. In Arizona, Illinois, Louisiana, and Utah, there used to be embryo research bans that got knocked out. And why did they get knocked out? Because they are criminal laws, and under criminal law you have a right to notice . a sufficient notice about what behaviors you're supposed to avoid. And something that just says it's a crime to do embryo research doesn't give sufficient notice. I mean, think about it. If I'm an obstetrician and I'm treating a pregnant woman for asthma, and I don't know the impact on her fetus, that could be viewed as, you know, criminal experimentation on a fetus. Or if I'm an in vitro physician, and I use a different medium in the petri dish, that could be research on the embryo. So it's just too vague. Now, you can get around that in some of the new generation of bills that are being proposed that specifically say you cannot do somatic cell nuclear transfer to create a human organism and use it for stem cell purposes. Now, policy obviously can tremendously affect what science is taking place, the scope of research, access to research results, and the rights of the participants. And I think the law can play an important role in this area in terms of creating a sense of trust in people, no matter what your decision is. And I don't see that any of the proposed laws going either way have the ability to do that. And I think of all the in vitro physicians who have said to me across time, "Oh, I'm so glad I'm not in the United Kingdom, because they have all those horrible rules about review, and they have that Human Fertilisation and Embryology Authority, and it's just too cumbersome and clumsy." But then, what happened was that I think that system in place created a sense of trust where when the embryo stem cell research issue came along there was more of a willingness to go forward, because the public at large there didn't feel it was, you know, in such a state of laissez-faire as in the in vitro situation in the United States. So we're hearing this brain drain to actually a culture where science is more restricted, but I think has created a sense that at least someone is watching over it. And I don't see that any of the proposed bills are sufficiently detailed in either direction to give that, you know, sense of trust. So I'll open it up for questions. CHAIRMAN KASS: Thank you very much. The floor is open for discussion. Michael Sandel. PROF. SANDEL: Well, this is a question for our speaker as well as the other lawyers in the room. Would a federal ban on cloning - put aside even the debate about reproductive versus therapeutic cloning, but a federal ban on reproductive cloning even, would that be constitutional? Is that a federal function? MS. ANDREWS: I think it is, and I would say that when . I'd say 10 years ago there would be more hesitation to my answer. But looking at how courts are ruling on things like the Americans With Disabilities Act, and whether it applies . and natural law, whether it applies, for example, to a dentist who only practices in his own state, and so potentially there's no interstate commerce to it. And in decisions like that, the federal courts have said, you know, if you're in an area where it's . it deals with people coming from other states to get the services, it deals with doctors who go to seminars in other parts of the country or are trained in other parts of the country, there's enough of an interstate commerce issue to make it an area of federal reach. Then, the second question would be: does it interfere with reproductive liberty if you ban my right to clone myself? And I would argue that reproductive liberty does not cover it, much as the argument was made by Dr. Kass earlier that it's hard to think of natural law covering carrying someone else's child. But even if it did cover it, and certainly in California right now there's someone who wants to challenge the California ban on reproductive cloning on the idea that it interferes with his reproductive liberty, you can nonetheless still sustain a ban if you show that it furthers the compelling state interests in the least restrictive manner possible. And I think the dangers physically are high enough that you would meet that, so I see no problem with a federal ban. PROF. SANDEL: I wasn't thinking of the reproductive liberty issue, which I agree could be raised. But strictly on federalism grounds, Mary Ann, Rebecca, do you agree with that, that it wouldn't be a controversial constitutionally . no, I mean, it wouldn't be a live case. PROF. GLENDON: That's a different question, whether there would be a case, whether it would be controversial. But I think Lori's analysis is correct. MS. ANDREWS: You know, the same way the Food and Drug Administration can regulate . I mean, if you look at some of those decisions, and lots of times drug makers in individual states try to challenge it, and they say, "We only have used things from within our state." And the court decisions say, "Listen, you know, you're using a glass vial or the adhesive on the back of your label comes from another state," and so in that sense I think you could regulate. CHAIRMAN KASS: Mary Ann Glendon. PROF. GLENDON: On the vagueness argument, the constitutional argument based on vagueness, were those old statutes that were struck down in those four states? And are there examples of statutes banning certain kinds of embryonic research that are drafted so as to resist that kind of challenge? MS. ANDREWS: They are exactly the same language that was struck down as exists currently in the nine states that banned embryo research, you know, because they basically . those statutes just talk about it in those terms - embryo or fetal experimentation. So these are states where it hasn't been challenged. And where it has been challenged they were - it was struck down as too vague. I think if you described more what process you choose to ban, as some of the states do with the reproductive cloning bans, one of the problems with that, though, is you sometimes get too narrow, that people can invent around it. You know, so like the statutes that say, oh, you can't put, you know, somatic nuclear material into a human egg, then if someone comes along and puts it into another mammalian egg, it - the law doesn't apply. CHAIRMAN KASS: I have Gil, Rebecca, and Frank, in that order. Gil Meilaender. PROF. MEILAENDER: Lori, can you say a little bit about what you think the significance of these proposed laws might be? And at least one thing I mean by that is this: if we look at your chart, in relatively few cases are there laws actually that have been enacted. Mostly what we have are laws that are proposed. It wouldn't be that - it's not that hard to propose a law. In a way, that can happen, and it can have no chance of going anywhere in one or another state legislature. So do you - I mean, do you sense any trends, for instance? Is there anything that you would conclude from what you've put on the chart, other than that, you know, quite a few states are - in quite a few states there is at least somebody who is interested in the question. You know, I don't know quite what we should conclude from this, and probably nobody can know for sure. But anything you could say about it I would be interested in hearing. MS. ANDREWS: Yes. I mean, I think the more interesting things are just to assess what the motivations might be behind these laws. And, you know, if we're concerned about an ultimately important interesting legal outcome, how to deal with those motivations. And I think that, you know, there are a number of states that are just saying, "We want to be a biotech haven." And so unless you take on straight away, you know, kind of what fundamentally do we want out of our technologies, and so forth, you're just going to see a sort of crazy quilt of proposals that are saying, "Biotech, come to us." You know, on the other hand, on the other side, there are laws being proposed that are, you know, part of a packet of a pro life agenda. And so it's really - it's about that, and it's really not so much about this particular technology - embryo stem cell research. I mean, I see the same thing going on at an international level. When I'm in other countries, you know, like France they'll say, "Oh, we hate, you know, what you're doing in the United States, and we think you're getting us down to the least common ethical denominator about gene patents and stem cells, because of the GATT treaty." At the same time, these same people are, you know, wanting not to lose any chance for the biotech dollar. CHAIRMAN KASS: Rebecca. PROF. DRESSER: Two questions. One is, I wonder if any of the bills that are in California - I looked for this a little bit, the law that was passed that wants to permit research cloning, if any of them have anything in there about the oocyte providers, and who is going to be deciding how that should be arranged, and the payment issue, and so forth. And the second question was: have you seen any groups or individuals trying to work on, say, a model statute approach with alternatives? You know, if you like X, don't like Y, here's what you could do, similar to what I think it was the ABA did with surrogacy. MS. ANDREWS: I haven't seen that approach in model laws, although I've seen it a lot with reproductive technologies. And maybe if I go back over those, I'll - I think all they say about research is giving people the choice to donate to research or to have their embryos terminated or to give them to another couple. There is a lot of law on the banning of payments to the egg donors or providers of embryonic or fetal tissue. There is less concern for quality of consent or monitoring. You know, if you made a market in this, monitoring the effects of Lupron or other fertility drugs, and so forth, and I think that that's an intriguing problem, even at the federal level with the Food and Drug Administration. Once it gets into this therapeutic model, this whole area of embryonic stem cell and embryonic tissue is treated as if these were drugs. So the whole focus is kind of on the safety of the recipient, if you look at proposed FDA guidelines. Are infectious diseases going to be passed on? And so forth. There's very little attention paid to safety issues around the donor, or even disclosure issues, and so forth. So I think that's a big - perhaps because we're uncomfortable with the human source of it, you know, we're just pretending this is like any other pharmaceutical product, without looking at, you know, the implications on the donor. CHAIRMAN KASS: Frank Fukuyama. I'll follow you, Frank. PROF. FUKUYAMA: Professor Andrews, could you say something about the ability of the FDA to accomplish what the state laws are trying to do, given its existing statutory authority? Because we've heard from a number of fairly authoritative sources that, in fact, the existing statute would allow them to do that. For example, although they typically don't regulate procedures, they do regulate medical products, and there's no IVF clinic in the world that doesn't use medical products of various sorts. And so if they interpreted their statute in a certain way, they could in fact, you know, extend those regulatory powers. And the primary reason they don't is just a prudential political judgment that the country doesn't want them to do that. But, you know, in terms of their legal authority, that's - you know, that would be perfectly possible. MS. ANDREWS: Well, one of the difficulties is that their focus is on safety and efficacy, so they have pretty - you know, they have a really broad range. I mean, they could use - do more with the authority they have under certain of the public health laws. You know, but certainly this is an area where people have concerns far beyond safety and efficacy, and that's where the FDA is not going to provide guidance either by its temperament in having talked to people there, you know, and asked, you know, for guidance, and also by their mandate. And so to the extent that society wants to make a decision that says, you know, we don't potentially think the benefits of this particular - you know, some aspect of this technology are worth running roughshod over other values, it's not going to be the FDA that can say that. They can just tell us, you know, if you go ahead, what would the implications be for human health. PROF. FUKUYAMA: If I could just follow up. But if they wanted to, for example, ban reproductive cloning in effect on safety grounds, I mean, wouldn't they be able to do that? MS. ANDREWS: In part it depends whether a medical organization, like the American Society of Reproductive Medicine, argued that it was a procedure. You know, they can't regulate medical procedures, and so a lot of unsafe surgery is going on, and sometimes for years on end. But the FDA can't step in. And so that has been part of the problem. I mean, in fact, when the FDA first said, "Oh, we have the power to regulate human cloning because it could be - you know, there could be genetic problems in the offspring, and, you know, there's this manipulation at the lab," everybody said, "Well, why haven't you been regulating IVF," which has those same problems. And there was considerable, you know, concern that this exception for medical practice, which they can't regulate, could be used in a way to swallow it up. So, I mean, I think they have more power than they've traditionally exercised, but that's where the conflict would come up. CHAIRMAN KASS: We've given you a narrower assignment than you could manage. That is to say, we've asked you to talk about the legislation on stem cell research, and, of course, it is in some cases tied up with cloning, both for producing children and for biomedical research. And to tie this in with the Council's own inquiry, which we will visit again tomorrow, on the aspects of oversight monitoring and regulation and the whole area of the confluence of ART and the growing genomic knowledge, we've in a way been trying to think about this area as a whole rather than piecemeal, cloning here, stem cells there, though it looks like in most of the state laws that we have either on the books or proposed they are responses to the latest threat that's perceived by somebody either to their interest in going forward with the research or to the embryonic life that they seek to protect. And I guess one question is: is it at all feasible to think that the states might be laboratories for more comprehensive treatment of what the people are now starting to call reprogenetics? Or this whole area of which stem cell research is but a piece, ART is a piece, PGD is a piece, and things of that sort. Or is that something which, if to be considered at all, is something to be considered federally? That would be one question. And the other - and I think we can figure out why the current new state laws - people being frustrated at the prospects of enacting something federally are going into those states where they have the best chance of winning and pushing through either Louisiana or California, or everything in between. So it might very well be that these are the kinds of issues, precisely because of the issue of the embryo in the middle, that are not easily amenable to compromise. You don't balance if one side holds something as a matter of inviolate principle and right. It doesn't enter into a balance. On the other hand, comments that you made about you don't see any place where the people interested in protecting human dignity, and the people interested in having the research go forward, sit down together in some state and try to work out some kind of a package that is the best possible arrangement here in Kansas, or some other place, do you think that because of the intractability of the embryo question it's out of - it's unlikely to try to develop some kind of collaborative efforts in which industry and the people who are worried about where this is going could collaborate on some kind of state regulatory activity? Or is that just a pipedream? That was really two questions, rather long-winded. MS. ANDREWS: No. I think that is a possibility, because I do think there is more consensus if you start, you know, in some other area. Even if you start from a question like, what do you do in a divorce with frozen embryos, and, you know, something that hasn't been as - you know, where sides have built up the sort of animosity that they have around the abortion question. And I think that there are some states - and I'm trying to think - maybe Virginia, Florida - on reproductive technologies generally where they've created more detailed laws. They've tried to think about all of the different, you know, possibilities of, you know, diagnostics and of different combinations of parents, and kind of work it out a little bit in advance. One of the problems at the state level, though, is that even well-meaning lawmakers who have gone into that sort of approach find out this is unlike, you know, regulating the roads or insurance, because everybody has an opinion about how the next generation should come into the world. And there's no political gain from ever taking a position on this. So I think that's, you know, one observation of legislation-watching for a long time on these issues. The other observation is that it takes some huge public event to really push an issue. For example, there are lots of states that had really interesting, very comprehensive surrogate motherhood legislation working through the pipeline before the Baby M case. But nothing got adopted, and then, you know, this case came to the fore of a surrogate changing her mind, and then quickly states adopted laws that just dealt with that situation. So when other situations came up where nobody wanted the baby, instead of everybody, they didn't have anything to cover it. And so I really think - and I fear for our biomedical policy in that sense, because I know that the policy we get on, say, you know, certain gene therapies is going to be based on whether we have some horrible case in the media or some wonderful case in the media. And that's not really the way to think these things through. But, I mean, I do think that the part we have - I guess what we've talked about is a bioethics fire drill. A new technology comes around, and we all run around and try to deal with it, rather than thinking through the various possibilities and trying to do this collaborative effort to deal with it. CHAIRMAN KASS: Could I follow on just briefly? As I listened to your answer, it makes me think that it's even more unreasonable to expect such collaborative and far-sighted and thoughtful effort in the states. MS. ANDREWS: I think - CHAIRMAN KASS: What's the incentive there for people in the states to sit down and figure out, you know, what the state policy overall in reprogenetics ought to be? Aren't they likely to react only when something like this happens? Think some kind of piecemeal - MS. ANDREWS: It's hard. They don't have the staff - staffing available. But that's the perfect situation for the sort of - CHAIRMAN KASS: The models. MS. ANDREWS: - model - CHAIRMAN KASS: Yes. MS. ANDREWS: - law to come along to say, okay, we've thought about all of these things. And I certainly think in the overall issue of different biotechnologies that are on the table, there is getting to be a growing interaction between people who have previously identified themselves as pro life and pro choice, who are waking up and saying, you know, let's put abortion off the table, because we're going to lose a lot of ground with human dignity and human life if we just let the people who are commercially benefitting make all the laws, while we're busy, you know, shooting across the barricades on this other issue. So I see big movement there. CHAIRMAN KASS: Janet Rowley. DR. ROWLEY: It's my impression that you were on one of the panels, if that's the proper term, at NIH over the past decade that was looking at the issues about embryo research. Is that - MS. ANDREWS: No, I was on one dealing with the Human Genome Project, actually. DR. ROWLEY: Okay. Because what I was - the question - and it's been alluded to - that we are trying to figure out where to go next on this issue. And there are some of us who feel that - I think everybody agrees that there needs to be some sort of oversight body in addition to the IRBs. And then, the struggle is, would this body be best housed, say, at NIH? Should it be a higher level Health and Human Services issue? Or is this the kind of thing that you need a Presidential commission looking at? And so I was just wondering whether in your experience in considering some of these issues whether you have any advice for us. MS. ANDREWS: My advice would be not to put it at NIH, you know, just because of the potential conflict of interest when you've got sort of every institute there saying, "Well, we'd like to, you know, do all of these techniques. You know, we'd like to do gene therapy. We'd like to do embryo stem cell research." There shouldn't be any constraints on what we do. I mean, it is sort of, you know, the fox guarding the chicken coop, so I would suggest that, you know, at either at the higher level, at the Secretary's office. And it is an important, you know, issue, much as we were talking about with the Food and Drug Administration. You've got these regulations that apply to federally-funded research that specifically say that IRBs are not to consider the long-range effect of the research. And so you do need some other body potentially saying, you know, is germ line genetic engineering on embryos, is sex selection of embryos appropriate or not, because that's precluded from consideration in part under the existing - you know, from consideration by institutional review boards. DR. ROWLEY: Can I follow up on that? Because some of us, myself included, have thought that the Recombinant Advisory Committee, the RAC, was a potential model, and that's an NIH committee. So you're saying that isn't the model that you think might be wise to - MS. ANDREWS: You know, I don't think so - I mean, the RAC occurred before NIH itself started adopting, you know, based on the 1980 laws that said NIH researchers can patent their findings and make an additional $150,000 a year based on their patents, and they could form biotech companies, and so forth. So there are ways in which the NIH itself - you know, unlike in the early days when the RAC was formed, now our - you know, have some of the same commercial motivations in a way. DR. ROWLEY: Well, but I was thinking that though the - such an oversight body might be within the purview of NIH, I wasn't thinking that any NIH members would actually be part of that. It would be more, as the RAC is, external scientists and lawyers, ethicists, etcetera. MS. ANDREWS: In part, it just I think makes sense as an institutional structure to make sure it's, you know, staffed elsewhere, though. You know, if you staff it by NIH people, you know, volunteers that meet once a month or, you know, so forth, I mean, they ultimately, you know, may not have the last, you know, say in it if the day-to-day recommendations, and so forth, come out of an entity that really wants to go - you know, would not like to be encumbered by problematic regulations. But that's just my personal experience - DR. ROWLEY: Okay. MS. ANDREWS: - from my own, you know, experience at NIH. CHAIRMAN KASS: Comments? Questions? I want to ask - some of us attended a meeting a week ago, a seminar that Frank Fukuyama is running on this whole area, and the professor of law at a local university was in fact - the question was: what are the constitutional obstacles to regulation in this area? I'm going to revisit the question that Michael Sandel asked you earlier, where he was dealing with the question of Congress's power to enact legislation, not so much the constitutional protections that such legislation might violate. You alluded to the possible claims in reproductive rights. This lawyer, who was practicing creative legal thinking to see what might be done, suggested that there might be, in an expansive understanding of the protection of freedom of speech, understood as expression and understood as fatly as you'd like, some kind of claim that scientists might bring under the First Amendment a complaint that laws restricting research in any area, for whatever reason, was a violation of what? MS. ANDREWS: Of the First Amendment. CHAIRMAN KASS: Yes, the First Amendment. MS. ANDREWS: Sure. CHAIRMAN KASS: Very broadly conceived. MS. ANDREWS: Yes. I can comment on that. CHAIRMAN KASS: I don't want to encourage such thinking, but do you have an opinion? MS. ANDREWS: Yes. You know, we are under the First Amendment, freedom of speech, there is the idea that it not only protects speech itself, but the precursors of speech, so the funding, you know, of - and the gathering of news, whether you go into prisons, or whether you - you know, that sort of thing, or campaign funding, and so forth. So you could make the argument that doing science is a precursor to having a marketplace of ideas. How can we talk about things if we don't generate the research to do it? And there are some cases that talk about it. The most prominent one has to do with whether the Kinsey Institute at Indiana University can - researchers there can look at pornography, you know, things that are considered obscene, or whatever, or does that interfere with their right to research. And it was held that they could, you know, look at this, because, you know, and so there's some - there's even some low-level case law in addition to the theory. Now, people have tried that argument with respect to fetal research, for example, and courts have, you know, sort of slapped them down in terms of saying, you know, freedom of research is one thing, but there's also the need to protect the subjects of research. And so, you know, virtually any regulation that you can come up with that promotes safety, for example, would not run afoul of freedom of research. CHAIRMAN KASS: Okay. MS. ANDREWS: And so it's basically been interpreted to be allowing people access to existing materials, and so forth, not cutting off what's there, but in terms of generating new knowledge in a way that might be risky, it doesn't apply. CHAIRMAN KASS: All right. Anyone else? MS. ANDREWS: May I add another legal comment that we haven't - CHAIRMAN KASS: Please. MS. ANDREWS: - addressed? And this has to do with the sort of fruits of the research in the sense of the issue of patenting. And I think that is going to play an important role ultimately in what happens in the embryo stem cell area and touch on all of the issues you were dealing with this morning, in terms of access, and so forth. The approach of the President of allowing access to existing stem cell lines obviously has an impact on accessibility in terms of the fact that most of those stem cell lines are owned and patented, and so forth, by particular entities. And even though there has been access allowed to some of them for, you know, not horrendously high fees, there are still these intellectual property reach-through rights. So what's happening is that, okay, I'm percolating along, maybe I'm a scientist who is, you know, trying to develop, you know, nerve cells. And I might come up with something really, really fabulous. But the owner of the - you know, depending on the reach-through agreement, that original owner can then say, "Well, you have no right to make it; we kind of own what you've ultimately done." And I think that's problematic. I think there's not only the issue of sort of taxpayers paying, you know, what some have estimated as, you know, 40 percent of the costs for the intellectual property rights to use stem cell lines, that's a cost that you wouldn't have if people could generate new ones. But, you know, there's also a real issue - and it resounds with me, because I'm seeing it play out in the gene patent area, where you're not supposed to be able to have patents on products of nature or formulas, and a genetic code seems to be both. And now we're seeing researchers being prevented from looking at a gene sequence because some other company or institution owns that gene sequence, or people being detoured entirely from going into a field because the idea is, why should I spend all of this time when I'm not secure that I - you know, when an ultimate pharmaceutical product, which clearly should be covered by a patent, comes out, you know, it's unclear I'll have rights to it. So I would say significant problems are developing in the gene patent area in terms of access to diagnostics and in terms of research. I would - you know, you're a little earlier on in the embryo stem cell area, but I would alert you to those. I mean, that's a legal issue that will have an enormous, enormous impact. CHAIRMAN KASS: Thank you. Frank, and then I think we'll probably wind up. PROF. FUKUYAMA: Well, okay. I just want to go back to Leon's earlier question and follow up. It's not - the lawyer in question was Steve Goldberg at Georgetown who was talking about these constitutional issues. I don't think that he was so much advocating that you could declare, you know, that there was this constitutional issue, he was just trying to - he's like a lawyer. He's trying to make the best legal case you could. But one thing that he said on the other side is that the interest of the people - you know, the power of the interest of the people that are trying to ban cloning, in this case the House bill, also has to be taken in account. And the law was written in a very narrow way, such that the primary objection was essentially a moral objection rather than the health of, you know, a child or, you know, other kinds of - or safety or efficacy, other kinds of issues that they could have picked. And that the trend in court decisions - and he thought that this recent Texas - you know, the striking down of the law, the Texas sodomy - homosexual sodomy law, was important in that regard. And I guess Justice Kennedy has played a big role in this, is in saying that although we take seriously moral claims, you know, these purely moral claims made in the community, that those by themselves, you know, cannot be written into these laws. And that was the reason - and he thought that this is a broader trend in I guess a kind of enshrining of a certain kind of moral relativism, you know, into American constitutional law. And that given that, if that's the only basis on which the law is being enacted, then that's not a very powerful counterweight to whatever potential, you know, constitutional claims, First Amendment claims are being made on the other side. Could you comment on that? MS. ANDREWS: Sure. Well, you have two things going on. I mean, first, unless you're protected by some fundamental right, and so that would occur if you're dealing with a particular category we protect, a category based on race or religion, and so forth, or a particular sort of activity we protect - speech, you know, reproductive liberty, and so forth - and I don't really see an indication there's enough court cases that don't find scientific inquiry to be one of those that probably wouldn't find human reproductive cloning to be one of those. You know, and if you don't - if you're not in one of those fundamental categories, then states can enact laws even if it just is for a moral, you know, reason, or they can enact zoning laws that say I can't paint my mailbox purple or, you know, whatever. And so you'd have to make - you'd have to first get in that category. I think you're right, once you're in that category, if we had societal accord, and we had a Supreme Court who might say reproductive cloning is a fundamental right, then if we got to the stage that - where you didn't have the physical or psychological problems - and it doesn't matter if the law itself said it, because lots of time legislatures, when they get into constitutional fights, say, "Oh, we really meant this to do this for protective purposes." So it doesn't have to be on the face of the law. You know, if you got to that - that stage where it was a fundamental right, maybe we all became infertile, it was the only way to, you know, carry on, and it was all of a sudden safe, really safe, then moral arguments wouldn't be enough. So once you're protected, you know, you're right. Thank you all for letting me attend. CHAIRMAN KASS: Thank you very much. Thanks very much, Lori, for your work on the presentation and the discussion. Tomorrow morning we will meet at 8:30. We have two sessions tomorrow, and then a public session. We should wind up not long after 12:00. We're adjourned. Thank you very much. (Applause.) (Whereupon, at 5:17 p.m., the proceedings in the foregoing matter were adjourned, to reconvene at 8:30 a.m., the following day.)
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