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COUNCIL
MEMBERS PRESENT Elizabeth Blackburn,
Ph.D. Daniel
W. Foster, M.D. Michael
S. Gazzaniga, Ph.D. Robert
P. George, D.Phil., J.D. Charles
Krauthammer, M.D.
INDEX
CHAIRMAN KASS: Welcome, Council members, to this, our 13th meeting. Welcome also to members of the public. I will recognize the presence of Dean Clancy, our Executive Director, in whose presence this is a legally constituted meeting. The Council is moving toward completing three of its major projects, two of which are the subject of this meeting: today monitoring stem cell research, tomorrow biotechnology and public policy. The four sessions today are all related to the stem cell project, about which I would like to offer a few general remarks in order to clarify our task and where we are going. As everyone knows, this Council was brought into being in connection with President Bush's August 2001 decision to permit for the first time limited federal funding for human embryonic stem cell research. Although the President's charge to the Council in the executive order that created us was very broad, he also specifically charged us in his national address with "monitoring stem cell research." And monitoring is just what we have been doing for these past 20 months. We have been watching, we have been paying attention to, we have been gathering information about all the relevant happenings, not only the developments in scientific research but also the developments in ethics, law, and policy that have taken place since August 2001 under and in relation to the current federal policy. We have commissioned papers reviewing stem cell research over the past two years, both embryonic and non.embryonic, discussed at the last meeting. We have commissioned a paper on efforts to solve the problem with immune rejection, for now a major obstacle to many potential clinical applications of ESC research. We have commissioned papers on recent ethical writings and discussions as well as on recent changes in state law. We have heard a presentation about and kept abreast of the implementation of the federal stem cell funding policy by the NIH. And later today we will hear more about efforts to move research from the bench to the bedside, both through federally funded research conducted by and administered through the NIH and eventually regulated by the FDA and through privately funded research conducted by industry or supported by private philanthropic organizations. In a word, we have been trying to learn just what is happening as a consequence of or in relation to the current national policy in this area. By the end of today's meeting, we will have completed this round of our monitoring and we will move toward preparing our report provisionally titled "Monitoring Stem Cell Research." In this report, we will convey what we discovered by monitoring all of these fronts as they have developed these past two years under the present policy. We owe the President and the nation an update on how this policy has been implemented and what is happening beneath and around its aegis. Our report, as currently envisioned, will include chapters reviewing the scientific findings and the ethical discussions preceded by an explication of the policy and its moral and legal underpinnings. The review essays that we have commissioned will be included in an appendix, which will also offer a primer on the human embryo. And it is our hope to have drafts of these materials to you soon. To monitor events under the present funding policy, it makes sense to begin by making sure that we understand what that policy is. Although the matter might seem on the surface to be quite simple, public discussions of the policy over the past two years have been anything but clear or accurate with much understanding and not a little misrepresentation on all sides. If we were to do nothing else, clarification of where things stand and why legally and morally would be a significant contribution. The two sessions this morning aim at that goal, the first indirectly by way of discussing in general the meaning of federal funding, the second directly by examining the policy itself. The controversial moral, political issue in the public stem cell debate that was informed by other moral disagreements was about government funding, not as in the cloning debate about a governmen-imposed ban with criminal penalties. In the stem cell case, the issue is about whether or not government funds will be available for a certain area of contested research. In the cloning case, the issue is whether research or reproductive activities should be forbidden or criminalized. Everyone readily understands the meaning of a criminal ban, but the meaning of awarding or withholding government support is less well.known. And no previous bioethics council, to my knowledge, has ever taken up the subject thematically. To enable us to do so, we have commissioned a paper by political theorist Professor Peter Berkowitz of the George Mason University Law School, the Hoover Institution, and happily part.time senior consultant to this Council, the paper on the meaning of federal funding. The discussion we are about to have with Peter's help doubles as a contribution also to a richer bioethics, seeing as it takes up certain important political, philosophical issues of morals and politics in a liberal pluralistic society. We welcome Peter to the meeting, thank him for his paper, and look forward to his presentation and the subsequent discussion. PROF. BERKOWITZ: First, thank you, Leon, for the invitation to discuss the meaning of federal funding with this distinguished group.
SESSION 1: THE MEANING OF FEDERAL FUNDING PROF. BERKOWITZ: I want to say that I come bearing good news. This Council has taken upon itself the responsibility to confront some of the most formidable and excruciating issues of the day, the ethics of cloning, the meaning of enhancement, the moral status of the embryo. But breathe a sigh of relief. The meaning of federal funding is not one of these excruciating issues. To be sure, the meaning of federal funding is a subject that needs to be addressed as part of the effort to understand the President's policy on stem cell research, but the issues it raises by itself are relatively simple and relatively straightforward. What complicates matters, what excites passions is that the decision to grant or withhold federal taxpayer dollars for some undertaking or another is a primary means through which government in a free society expresses enthusiasm, ambivalence, or disapproval, particularly moral disapproval or approval. It's silly to deny the government. I mean, a liberal democracy makes moral judgments. It makes them all the time. In the decision about how much money to spend on national security, in the decision to condition federal funding to higher education on compliance with strict standards of nondiscrimination, on the decision to fund or not fund abortions abroad and at home, on the decision to fund or not fund the arts and the humanities, in the decision to provide benefits to married people that it denies to unmarried couples, in the decision to provide young people with opportunities for public service, to decisions about federal funding, government makes moral judgments right and left. Tocqueville famously said that all political questions in America eventually become legal questions. One may add a corollary pertaining to today's politics. When individuals do not like the moral judgments embodied in government policy, they are prone to try and constitutionalize their objections. But when you get right down to it, the quarrel is usually not with the Constitution but with the majority preferences permitted by the Constitution. In our day, constitutional law has become politics or policy by other means. The basic questions of federal funding are these, how should the government approach the question of federal funding of activities that are deemed controversial by the American people? Is it appropriate to make such determinations on moral grounds? Can moral grounds be avoided? Whose moral views? And which source should govern, with what consequences for those in the majority? Questions of this sort have been discussed frequently in the wake of President Bush's controversial 2001 decision regarding federal funding of embryonic stem cell research. In that decision, as you all know, the President permitted federal funds to be used for the first time to support research on embryonic stem cells but only those already in existence. At the same time, he made it clear that there would be no federal support for any research that involved or depended on any future destruction of human embryos. In so doing, he was upholding both the letter and the spirit of the congressional enactment of the Dickey amendment, which in 1996 prohibited the creation of embryos for use in experiments or the use of embryos in research that led to their destruction. Most scientists and patient advocacy groups believe that President Bush made the wrong decision and that the Dickey amendment was a terrible mistake. Among the objections one commonly hears to the President's policy are these three. First, by withholding federal funding for research that involved the creation of new embryos, the President has effectively banned embryonic stem cell research. Second, the President's decision was wrong because he allowed his personal moral views to govern federal policy or along the same lines, the congressional ban was wrong because it represents the imposition of moral reviews; even worse, religiously based moral views to frustrate beneficial public policy. Third, the President's policy is morally incoherent. If an act is so moral as to deserve the government disapproval implicit in withholding funding, it should be accompanied by efforts to prohibit the activity altogether. But this President Bush has refrained from doing. Whatever the merits of the President's policy, the objections, once examined, these common objections cannot pass muster. The first refuses a refusal to fund with an imposition of a ban or a prohibition. The second wrongly supposes that legislating morals through federal budget decisions is always or in principle wrong. And the third incorrectly assumes that government has an obligation to bring to an end all conduct that it believes immoral. Explaining these errors requires an exploration, a more general exploration, of the meaning of federal funding. So, in quick order, several basic points. First, no one and no activity has a constitutional right to federal funding. There's no government obligation to fund most activities, not even the most worthy, save perhaps for such matters as the Constitution explicitly proclaims to be the responsibility of government, national defense, maintenance of federal courts, the holding of elections, and so on, but even here, considering these constitutional essentials, it is an open question to be decided by the people's representatives of how government will choose to allocate taxpayer dollars. The second basic point, no individual or cause has a right to sit at the government trough. Goods are many and varied. Resources are scarce. And scarce resources are insufficient to support all worthy goods, all worthy activities. People with different causes and interests compete to obtain them. And in order to succeed, they are forced to bring their cases to members of Congress. Funds are distributed only through the political process within limits set by the Constitution; as a result, this all.familiar deliberation, lobbying, deal.making, log.rolling, and the like. Third basic point, in a democracy, people will always have disagreements, in a healthy democracy, I should say, about what activities should receive government funding. Sometimes the disagreements are intense, sometimes not. Sometimes the disagreements include moral disagreements, sometimes not. Sometimes the political process generates a compromise. Sometimes one or the other side prevails decisively. Fourth, people who lose in an effort to obtain federal funding will always feel that they did not get what they need or want, but in the absence of a clear legal entitlement to such funding, they cannot properly complain that the government has thereby denied their rights or interfered with their liberty to exercise them. Fifth, those who lose have several alternatives built into the democratic process. They can try to persuade their representatives to reconsider. They can vote in others more sympathetic to their cause. They can seek to influence public opinion or they can seek nongovernment private funding for their activities. All of this, as I said, is straightforward and sensible. It suggests the legitimacy, even the routine character of the President's policy, might be regarded as the end of the story. Yet, many regard the withholding of support for selected aspects of biomedical research as a special case, an exception that demands a different approach. It is, I want to emphasize, understandable, why stem cell research seems to be a special case. The most important reason that the President's policy looks like a special case is that it involves the head.on collision of genuine goods and competing policies. The nation strongly and overwhelmingly backs biomedical research. It is one reflection, this devotion to biomedical research, of our respect for human life. And we generally leave the mapping of research strategies to scientists and those who administer the institutions in which they work. The entire biomedical enterprise in the United States, including also the training of the next generation of scientific researchers, has come to rely heavily on government support. The public generally favors this arrangement, has come to rely on government.funded research for the treatment and for the cure of all still.untreatable diseases, such as cancer and Alzheimer's disease. All of this creates a strong presumption in the public's eye in favor of funding for biomedical research. Consequently, the decision to withhold public funds from any particular piece of the biomedical research portfolio looks both to scientists and to the public like an intrusion of government into a place where it does not belong and it prompts harsh accusations the government is engaging in censorship or even outright prohibition of medically necessary scientific research. To be sure, the FDA regularly imposes restrictions on research but mainly on grounds of safety. When, however, government's objection to research is moral in nature, it strikes scientists as a deprivation, a restriction of freedom to inquire, a thwarting of worthy community goals, an imposition of morals. And it looks to those members of the public who disagree with the decision as a failure by the government to abide by its moral obligation, to use its resources to explore all fruitful areas of research in search of cures for dreaded diseases. However, those who generally make these objections forget that their support of government funding of biomedical research is also moral in nature. as I suggested. It springs from, it reflects our commitment to the dignity of human life. And they forget as well that those who oppose the destruction of embryos believe that permitting it would involve government in a failure to abide by another moral obligation; that is, the moral obligation to protect human life. In other words, stem cell research involves a decision about federal funding where powerful moral principles are at loggerheads and the nation is deeply and passionately divided. It poses a confrontation between our commitment, our real, genuine, admirable commitment, to unfettered scientific inquiry and to the fight against debilitating and deadly disease and between our respect for human life, in this case nascent human life. Moreover, it presents a clash between those who hold that the moral status of the embryo is no different from that of a fully developed human being and those who believe that the embryo is a clump of cells, utterly devoid of moral worth. I want to emphasize this. The challenge here is formidable, not merely because of the sociological fact of intense disagreement - this one cannot debate - but also for the philosophical reason that genuine moral goods are at stake on both sides of the question. There's genuine and intense debate in the country - that's a sociological fact - and real moral goods and stake. Nevertheless, controversy over federal funding of stem cell research does not really present a special case, not in principle at least. It looks like one because of the powerful presumption in favor of federal funding in biomedical research, one; two, because both sides to the debate view the moral stakes as exceedingly high; and, three, because both sides are correct the moral stakes are high. But this doesn't make it a special case in principle. Typically the question of whether government will or will not fund an activity is about more than mere distribution. It's about shaping choices among various and competing goods or undertakings. The child tax credit, for example, reduces the financial costs of child.rearing. In so doing, it strengthens family in not one but two ways. It enables families to save money. And it conveys a judgment, a powerful judgment, about the political importance of the well.being of the family. All law requires, forbids, or permits, but as a reflection on the meeting of funding suggests, government may adopt a range of attitudes toward that which it permits. It strongly endorses charity and higher education. It looks favorably on national service in the arts. It prefers marriage to cohabitation, frowns upon smoking. It is the distinction between permitting or tolerating an activity and actively promoting it through governmental funding that is crucial to understanding the debate over the President's policy on stem cell research. Here I do want to emphasize the distinction between permitting or tolerating an activity and promoting it through federal funding is crucial, not only to the stem cell controversy. The question of federal funding routinely implicates questions about the nation's moral priorities among permissible activities. And the question of moral priorities is not so simple as the questions of good and bad. It is a question of better and worse. This is true to an extraordinary degree in the stem cell controversy. Both sides are defending moral principles. Both sides are defending admirable moral principles. To make matters more difficult, both sides are tending to defend these admirable principles in their absolute form. Because moral principles are frequently at stake in the fight for federal taxpayer dollars, decisions like the stem cell debate can be bitter. Truer still, when the moral principles are wielded in their absolute form, both sides make moral claims. And one or another will have to live with the fact that their moral principles are being rejected, if not assaulted, by the government in their own name and with their own taxpayer dollars. Why should those who lose the political struggle put up with this, what amounts to a rejection or at least the belittlement of their moral principles? Well, the answer again here is simple, straightforward. Living in a democracy means sometimes being in a minority, even on questions of the utmost importance. And so long as the laws which one opposes are consistent with the Constitution and enacted according to legally appropriate procedures, one has an obligation to obey them. But is it really a legitimate aim of a liberal democracy to adopt laws and take actions to shape the moral beliefs of its citizens? Doesn't government in a liberal democracy have an obligation to remain neutral toward competing conceptions of a good life? And so we refrain from enacting morals into law. Otherwise, doesn't it impermissibly infringe on the people's right to choose how they ought to live? Well, to be blunt, the answer is no. Neutrality is a chimera. It's impossible for any government to remain neutral about morality in the nature of a well.lived life since public policy for "What purpose is the state permitted to classify citizens by race? What is the meaning of marriage? What medical procedures and what biomedical research should government fund?"; these always or almost always draw upon, reinforce, or suppress a view about what is deserving, proper, and good. Of course, it's possible and desirable as a matter of public policy in a liberal democracy to tolerate a wide variety of choices and forms of life, but toleration itself is a moral principle based on a certain interpretation of how to secure freedom and based on a certain interpretation of the requirements of respecting the dignity of the individual. Law and public policy in a liberal democracy rightly seek to create conditions in which citizens can make responsible and informed choices. This is accomplished in a variety of ways. The first and most taken for granted is through the securing of public order, also to establishing a system of public schools, promoting research in the sciences and humanities, supporting the arts, enacting a wide array of social and economic legislation, and all of this, in part, with a view toward forming a citizenry that is incapable of taking advantage of enjoying the blessings of freedom. Laws designed to respect and encourage respect for nascent human life can reasonably be seen as contributing to the conditions under which individuals learn to respect humanity in others and in themselves. To be sure, even within the limits provided by law, government's encouragement of informed and responsible choice can easily become a tool for the ill.conceived circumscribing or corrupting of choice. Well.meaning government efforts to prepare citizens for liberty and toleration can undermine both. Governmental funding of education can be, government.funded education can be dogmatic and ideological. Government.supported arts may disseminate tawdry or jingoistic sentiments and images. Government.funded programs directed at the family may fail to adapt or adapt slavishly to changing times. These familiar abuses, though, are not arguments against government promoting the conditions that enable citizens to take advantage of the freedom. Rather, they are reasons for proceeding with care and with an appreciation of the complexities of contemporary moral and political life. American politics furnishes many examples of funding decisions that effectively inevitably take sides on divisive moral questions. Here are a few. Consider first the battle over abortion, which involves a longstanding struggle over the question of government funding for lawful constitutionally protected conduct. Shortly after entering office, President Bush ordered the withholding of funding from international organizations that performed abortions. The decision was neither required of him nor forbidden to him, but within his discretion, the principle behind this policy is common to his position on stem cell research. Government funds should not be used to destroy nascent human life. At home, a line of Supreme Court decisions stretching from 1977 to 1991 dealing with abortion and government funding established the principle that the Constitution does not require government to fund even those activities that the Constitution singles out for special protection. Another example. This comes from higher education. Title VI of the Civil Rights Act of 1964 provides that no person in the United States shall on the ground of race, color, or national origin be excluded from participation in, be denied the benefits of, or be subjected to discrimination under any program or activity receiving federal financial assistance. It is this provision that requires private universities to avoid those racial classifications in admissions and hiring that would violate the prohibitions imposed on state action by the equal protection clause of the Fourteenth Amendment. Title VI is far.reaching because most private universities rely heavily on government funding to support basic research. And it provides a way for the federal government to shape the moral contours of what is largely private conduct and bring that private conduct in line with fundamental constitutional principles. Of course, private colleges and universities are free to continue to practice activities to disqualify them from federal funding. Close in form to federal policy on stem cell research are Social Security regulations regarding marriage and survivor benefits. Although cohabitation without matrimony is not illegal; indeed, it's quite common, the federal government refuses to pay Social Security survivor benefits to all but legal spouses. This is a way for government to provide financial incentives for marriage and for government to take sides on the good of marriage, proclaiming the union marked by it is good for individuals and good for the polity or, from a different angle, consider the question of elementary level and high school education. In 1923 in a landmark decision, Mayer v. Nebraska, the Supreme Court ruled that parents have a right to educate their children in a foreign language. In 1925 in another famous case, a companion case, Pierce v. Society of Sisters, the Supreme Court ruled that parents have a right to educate their children in private schools. But nobody or very few argue that these cases prohibit states from policy decisions encouraging public education. And nobody claims that the right of parents to privately educate their children creates an entitlement to have that private education funded by government. To conclude, the controversy over stem cell should be seen as one among many political battles over the allocation of limited federal funds. The controversy is distinguished not by the presence of moral principles or the presence of moral principles on both sides but by the peculiar, by the particular, moral principles at stake and the peculiar intensity of the compassions their defense provokes. When the question of federal funding is placed in perspective, it can be seen that the common objections to the President's policy on stem cells are misplaced. A failure to fund is not a ban. Funding decisions typically involve a moral dimension. And the complexities of a free society frequently create situations in which it makes sense for government to express doubt, anxiety, ambivalence, disapproval, or approval, and enthusiasm for a permitted activity. None of this, of course, is to deny that the President's policy on stem cell research is open to criticism on the merits. It is only to claim that this policy reflects a perfectly appropriate exercise of governmental powers. But what if you still think that this conclusion is incorrect? What if you think that the President's policy does represent still a special case and an inappropriate exercise of governmental powers? Then it seems to me it's incumbent upon you to craft an argument that accomplishes the following. First, you need to distinguish the President's policy in principle from the other cases: abortion funding, federal funding in higher education, arts funding, subsidies for marriage, refusal to subsidize private education, and so on. And, second, you must articulate a more satisfactory resolution of the contest between competing goods or, alternatively, you must be prepared to show why the controversy over stem cell research is anomalous in the sense that unlike all of the other important political controversies that we face, it does not involve competing goods on the other side of the question. I should stop there. CHAIRMAN KASS: Peter, thank you very much. Your paper and formal presentation are open to discussion. Professor Sandel calls on Professor Meilaender - (Laughter.) CHAIRMAN KASS: - because he wants to go second. Would you like to lead off? PROF. MEILAENDER: Sure. It's a very clear and useful paper, Peter, maybe too clear. That's the problem. And I don't disagree with the basic thrust of it. I wonder if you would say a word about what sort of word we should use to describe this general tendency that you have characterized in so many cases of the circumstances in which we permit but do not necessarily promote and avoiding in a certain sense a substantive decision on the matter, we handle it procedurally. Is this the best way to deal with such questions, at least in a liberal democracy, or is it a compromise, a kind of a second best, or I just wonder what you think on that question? Is it desirable and good that we find ourselves in circumstances like this regularly or are we sort of stuck and, therefore, rightly fall back? It makes a little difference, I think, how we describe it. PROF. BERKOWITZ: Right. I think we should take some solace. First, we should recognize that liberal democracy is itself a compromise. If we knew somebody who knew all the answers to all the tough questions, we could make him king or president for life and he or she could decide matters for us. So liberal democracy is, in part, a response to an appreciation; in part, a response to an appreciation, that on the tough questions we don't have access to all we need to know personally to make the right decisions. Second, I would say that in such a situation, the situation that we find ourselves in as citizens in a liberal democracy, there is a natural frustration when you feel strongly, believe strongly, believe your arguments are compelling, and you can't get them, you don't get them enacted into policy. It's not surprising that when people fail to persuade a majority, we look to other means to get our preferences and our principles enacted. Recourse to the courts is one of the solutions both sides adopt in different circumstances. So I'm inclined to say that what we have here is one of the frustrations that naturally arises in a complex free pluralistic society. And what we have to do is learn to live with it better and manage it better. It is not a reflection of some kind of pathology in American liberal democracy that an intense debate has arisen about stem cell research, and people are bitterly divided. I myself regard this as a sign of health in our liberal democracy. CHAIRMAN KASS: Gil would like to follow. PROF. MEILAENDER: Yes. You have to wait, Michael. So it makes perfectly good sense, then, for someone to think that according to his lights, the best solution would be some solution other than just the permitting but not promoting and to continue to try to argue for and press for that while, nevertheless, supporting these sorts of decisions in all of the different areas that you have outlined? PROF. BERKOWITZ: Yes. And, of course, I don't mean to suggest that every controversial issue, every issue that becomes controversial for us either is deeply imbued with moral significance or is subject to resolution through statesman.like compromise. There are familiar examples when one has no choice but to man the barricades. And there are other debates in which it is difficult to get overly excited, even if there is a moral dimension to the debate. So I am suggesting it is my own opinion that the debate over stem cell research is one which does not involve, at least certainly not at this stage, a need to man the barricades. And it does involve competing moral goods on both sides of the question. I can well imagine a policy controversy where the moral question is remote. And I can well imagine our history furnishes familiar examples in which the time for debate runs out. But I don't think either of those two extreme situations represents the situation we now find ourselves in. CHAIRMAN KASS: Michael Sandel? PROF. SANDEL: Well, first of all, thank you, Peter, for, really, a thoughtful and judicious and subtle paper. I want to add that I think the Council is fortunate to have enlisted your efforts in its work. This paper really is enormously helpful to thinking about this question. What I would like to do is to bring out what I take to be an assumption implicit in your defense of President Bush's decision. Bringing this assumption out may also help explain why my colleague Gil is antsy in the questions that he was asking. You deal with three familiar objections to the President's policy. It seems to me that your answers to those objections are entirely correct. The first one is that withholding funding is not the same as banning. And that's an important point that you stress. Secondly, there is nothing wrong with the President or public officials embodying in federal policy moral judgments. We do that all the time. I think that is certainly persuasive. What I would like to focus on is the third. The third objection is that the decision is morally incoherent for if an act is so immoral as to deserve the federal disapproval implicit in withholding funding, it should be accompanied by efforts to prohibit the activity altogether. You show that this isn't the case. And the way you show that this isn't the case is you point out there are degrees of moral disapproval. Their government can express doubt or anxiety or ambivalence or outright condemnation, in which case we man the barricades. But not every moral judgment that federal policy expresses is of that last kind, the manning the barricades outright condemnation kind. So there may be some acts that are so immoral that they should be accompanied by efforts to prohibit the activity altogether, but there may well be a range of other acts that while we may morally disprove of them, we don't want to encourage them, they aren't so immoral that we should man the barricades or ban them. And we can register that lesser moral disapproval or ambivalence or doubt in withholding federal funding. Now, the question, of course, is whether embryonic stem cell research falls into the first category or the second. You have given us some examples of activities that fall into the category of things that are morally questionable that we, nonetheless, don't ban, like cohabitation without matrimony. So we don't ban it because we don't think that the federal government needs to condemn it outright. It's not that grave a sin. On the other hand, neither do we want to encourage it. And so we discriminate against those who cohabit in the case of Social Security survivor benefits. And it's a legitimate discrimination because it registers this moral disapproval or anxiety. We want to encourage marriage, but we're not going to go out and ban people who live together outside of marriage. And then there are other cases. You mentioned our history. Slavery would be one where it would seem odd to say, "Well, we're going to deny federal funding or tax breaks to slave holders, but we're not going to ban it" or, to take another hypothetical example, if there were a practice of killing children to take their organs for transplant, that would be like slavery, not like the marital cohabitation. We wouldn't say we're going to deny funding for those organ transplants because we want to register moral disapproval, but we're not going to ban it. It would make no sense. That would be morally incoherent to take that position in the case of the practice of killing children for organ transplants. So the implication of your analysis is that for the President's position to avoid the charge of moral incoherence, it must be more like cohabitation without marriage than like killing children for organ transplantation. So the President's position can be defended on a principled basis as being morally coherent if it presupposes that the activity in question is not morally comparable to killing children for organ transplants but only if there is some doubt or anxiety about the sacrifice of nascent human life. Would you agree? CHAIRMAN KASS: Your lawyers are ready to help you out, too. PROF. BERKOWITZ: I understand. I would agree, yes, that the more one adopts the extreme position or at least the - I should say the absolute position that there is no fundamental moral distinction between embryos, any stages, and a human being, fully developed, grown human being. The President's policy becomes less coherent in the way I have described. So in other words, the presupposition of my analysis exactly as you have identified it is that the President's policy supposes that the moral status of an embryo is an open and difficult question. In that vein, I want to remind everybody of what the President said when he announced his decision. He said in his speech in August of 2001, "On the first issue, are these embryos human life? Well, one researcher told me that he believes that this five.day.old cluster of cells is not an embryo, not yet an individual, but a pre.embryo. He argued that it has the potential for life but it is not a life because it cannot develop on its own. An ethicist dismissed that as a callous attempt at rationalization. 'Make no mistake,' he told me, 'that cluster of cells is the same way you and I and all the rest of us started our lives. One goes with a heavy heart if we use these,' he said, 'because we are dealing with the seeds of the next generation.'" So I mention this to say in theoretical point, I think you are right. To the extent that one regards embryos as absolutely indistinguishable, one cannot defend the President, the policy in the way I have, but I also want to emphasize that is not the way the President defended his policy. The President in announcing it emphasized the difficulty of the question, what he found after consulting for a couple of months, the intractability of the issue, the presence of good arguments on both sides of the question and, therefore, the need for further debate. So while that approach may be foreclosed to some people, I think it wasn't the presupposition, as a matter of fact, of the administration. That is, the premise that you suggest would be inconsistent with my third point. CHAIRMAN KASS: There are people in the queue, but there are also I think some who want to join on this particular question, rather than letting it come back to it later. So if someone wants to just on this last exchange between Michael Sandel and Peter. Robby? PROF. GEORGE: Yes. Peter, my colleague Michael I think assumed that the distinction that you were trying to draw or implicit in what you were trying to draw was a distinction that turned on the matter of degree of immorality, that it was the degree of immorality of an act or judgments about the degree of immorality of an act that determined where it was reasonable to come down as a matter of policy. But there is another possibility, and it is consistent with everything you say. Now, you can choose between them or there may be a way to have some combination. It's certainly logically possible and consistent with what you say to make the matter turn not on degree of immorality but on something distinct, which is degree of confidence in one's judgments of the immorality of the act. One may think that a certain act may be very, very wicked indeed, but one may have only limited confidence in one's judgment about it. What you said a moment ago in responding to Michael was that the President's own judgment seemed to be that this was an open and difficult question, but one can believe that entirely consistent with the belief that one's judgment to the extent that one has confidence in it is a judgment that the act is indeed a very wicked thing, in this case perhaps a judgment that the embryo is not of lesser value, at least in respect to the right not to be killed, than more developed human beings. One might make the judgment from a statesman's point of view, in part, based on one's view about the extent of reasonable disagreement among people of good will. One thing that has to be said I think by anybody on any side of this debate is it is a debate on which we have very substantial disagreement among reasonable people who are people of good will. And there is no reason, again, in principle, why that shouldn't factor into a statesman's judgment of the matter and, indeed, into any particular individual and particularly a statesman's judgment as to whether it is, in fact, an open and difficult question. And it seems to me it ought to affect one's judgment about the degree of confidence one can have given one's own knowledge of one's own fallibility. PROF. BERKOWITZ: I agree with Robby. And I take it as a refinement of the exchange between Michael and me that one can put at issue or what we have to take into consideration is not only the content of the moral judgment but the degree of confidence we have about that judgment and, moreover, the fact of how deep disagreement is in the society. This is partly what I was gesturing at when in the presentation I distinguished between the sociological fact of deep disagreement in the country. One can count up. One can count, measure, and weigh that. One can look at the polls. People disagree strongly. That's a fact about what is. I distinguish that from the philosophical claim that there are moral goods on both sides. And one might then refine that point by saying the arguments that we have available to support our moral judgments are less strong than we would like them to be. And we think one day as we think through a puzzle, that could not have presented itself to us before relatively recent developments in science and biotechnology. As we think through it more carefully, the arguments may become clearer to us. CHAIRMAN KASS: Still on this point, Frank Fukuyama? PROF. FUKUYAMA: I think there is a simpler defense, which is just pragmatism. I mean, until the Battle of Gettysburg, Lincoln was not willing to press for the abolition of slavery. And I believe that he believed that it was a very serious moral wrong. Prior to that, he was only willing to press for its banning, banning it in its extension into the territories. And that was based on a pragmatic judgment of what was politically possible at the time. And so you can believe that something is a severe wrong but still refrain from doing things you know will not work politically. CHAIRMAN KASS: Still on this point, Gil? PROF. MEILAENDER: I wasn't at all antsy. I liked what I heard and wanted to draw it out a bit. It suggests to me that commitment to this sort of resting place isn't commitment to some final position, but, rather, it's precisely a way of allowing an argument to continue. And if we forget the stem cell research thing, just think about another of Peter's examples, the abortion case, where we do have that whole string of court decisions, making clear that a right to something is not an entitlement to have it funded, people on both sides of that issue don't have to regard that as the best place for the argument finally to end. You are entitled to argue that it would be a good thing that if government were, in fact, to fund it. You're entitled to argue that it would be better were we to prohibit more abortions. But the argument continues in a way - and this is a way we find to permit that to happen - in a way that shows a decent amount of respect for the competing positions involved. That seems to me to be a good thing. It simply doesn't mean that you, as it were, adopted a new principle. You found an additional principle that allows democratic argument to continue. That was my thought anyway. CHAIRMAN KASS: I have - DR. KRAUTHAMMER: One more point on this still. CHAIRMAN KASS: Yes, please, Charles? DR. KRAUTHAMMER: I just want to add one other consideration on Michael's question about how you can have moral compromise or policy compromise on issues where you feel, then, a deep moral wrong is being committed. And that is, to follow up on Frank's point, which is he calls it pragmatism, there's also a question of settle social practice. I mean, some people may believe that the disruption of embryos at IVF clinics is equivalent. It's a very, very great moral wrong. I think you can make a reasonable argument that when you have an already accepted social practice widely supported, you are required to make a pragmatic political judgment about overturning that kind of practice. I think that also enters into stem cells and into the compromise that the President has arrived at. It's not just a question of the valence, the moral valence, of the activity. I think it has to do, as Rob indicated, with a question of the confidence one has in one's judgment, which is related to the depth of the opposition and the respect one would have for that opposition. CHAIRMAN KASS: Michael? PROF. SANDEL: First, I don't think that Peter was defending this as a compromise, nor does the other discussion paper defend this as a political compromise. So that might be a way of defending the decision. I thought here we were discussing whether this could be justified as a principal decision, not just as a political compromise. And so I was taking seriously Peter's attempt to do this. As for Frank's example of pragmatism in the case of Lincoln's position on slavery, that was in the face of Lincoln's fear that to try to ban slavery where it already existed would bring civil war. And he was right in his judgment that it would bring civil war. I don't think that banning embryonic stem cell research would run anything like that kind of risk. I mean, it's less, rather than more contentious, than the abortion question. And so I don't think that the stakes, the political stakes, are anything comparable. I think that if a president really did believe that embryonic stem cell research were morally equivalent to killing children for organ transplantation, that that president could perfectly well politically and morally call for a ban on the activity. And the fact that the President doesn't support a ban on the activity implies, it seems to me, - and following Peter's analysis reinforces this - that he doesn't consider it morally equivalent to killing children for organ transplant. And as for Robby's suggestion that it's possible, there's a difference. Of course, Robby's right that there's a difference between how bad you think something is and how confident you are that it's bad. But at a certain point, that distinction becomes difficult to sustain. I was tempted to ask Robby, can he give me an example of one thing that he believes, really believes, is very, very wicked, in his phrase, and, yet, he's not sure he's right about. I think in the case of if we really did believe, - he can offer an example later if he wants to; I won't put him on the spot - if a president really believed that embryonic stem cell research were morally equivalent to killing children for organ transplantation, it seems to me the moral thing to do would be to ban it. CHAIRMAN KASS: But, Michael, may I suggest to my learned colleague that there is something in between something like cohabitation and murder and that one might not have to regard this as the equivalent of killing a two.year.old child for transplant, to think that it is, nevertheless, of sufficient moral gravity, quite apart from the confidence in one's own opinion? PROF. SANDEL: Yes. I am agreeing with that. I am saying that the President's position presupposes some version of what we here have been calling the special respect view of nascent human life. DR. KRAUTHAMMER: But, Michael, there's hardly a greater social sin or offense than racial discrimination. We ban it in just about every area that we can. But when it's practiced in a purely private club like Augusta National, we don't say the President, therefore, has an obligation to pass a law that bans it in a purely private arena. We do have limits on what the state does, even with great moral issues. PROF. SANDEL: Even that doesn't involve murder. CHAIRMAN KASS: Peter. Then I'm going to go to the queue. I have Bill, Mary Ann, and I'm also there. PROF. BERKOWITZ: I think we should avoid distinguishing too sharply between sticking to principle and achieving a compromise. Sometimes it's the best way to defend a principle to compromise on its basis. Moreover, I think we should distinguish the sense in which the President's policy can be seen as principled and a sense in which it can be seen as a compromise. The principle is, as I understand it, - Yuval Levin will speak more about this in the next session - that government money should not be used in the creation and in the destruction of nascent human life, but the goods in conflict have to do with the moral status of the embryo as against scientific research. It seems to me you can adhere to the principle which has a relationship to these goods, the principle being no use of government, the principle being no use of government, federal taxpayer dollars for the destruction of human life. And the compromise, the balancing between these goods, one's opinions about the moral status of the embryo, and one's respect for free inquiry, and one's desire to promote free inquiry. And, again, just to pick up on something that Robby and Frank said in different ways, every compromise is not a tarnishing of principle. Some compromises are the best kind of defense in the principle in the social and political circumstances. CHAIRMAN KASS: Bill May? DR. MAY: A comment about your last paragraph. None of this is to deny that the President's and stem cell research is open to criticism on the merits. It is only to claim that this policy reflects a perfectly appropriate exercise of governmental powers. A word about your choice of phrase in the last sentence. To say "perfectly appropriate" kind of moves in the direction of having almost dealt with the merits of the case. Why not simply "constitutionally permissible," leaving room for stating there are other constitutionally permissible exercises of government powers? And you don't deal with the question of the merits of the case. Maybe as a professor of law, you feel you are not obliged to think about that. But do you have any comments to make about the merits of the case, particularly since you have left that undiscussed, the impacts of a practical surrender to the marketplace and the whole question of regulation of the marketplace? PROF. BERKOWITZ: First, I should say if you were my editor, I would not man the barricades on the question of whether "perfectly" should modify "appropriate." I would fight different battles but not that one. "Perfect" can go. But what I meant to emphasize, though, was appropriate in the sense of its formality. What I wanted to say was from the merits. DR. MAY: And, therefore, permissible. PROF. BERKOWITZ: And, therefore, permissible. As far as the policy, as far as the merits of it go, - and this harkens a bit to what Michael Sandel was saying - surely on the merits of the case, to the extent that in looking upon an embryo, you can see nothing of moral worth. You will find the President's policy extremely objectionable. I can understand that. I myself am torn about the issue. And so I regard it as a salutary compromise on the merits. But I am not an expert on matters. I haven't come here to discuss that. But it is I imagine implicit in my paper in the way I bring it out that I actually do think this is an issue in which there are serious and profound arguments on both sides of the question, as the President said in August of 2001. CHAIRMAN KASS: To this or do you want to get in the queue? Okay. Mary Ann? PROF. GLENDON: I want to join the chorus of people who thought this was a wonderful paper and very helpful to us. If I were your editor, on page 5, the last paragraph, I would want to submit for your consideration where say, "our liberal democracy," the words "one version of liberal democracy." I don't make that suggestion in a nitpicking way at all but, rather, because it seems to me the goods in conflict that we are discussing, the hard questions that you have identified do, in fact, involve another hard question that your definition of liberal democracy sort of glosses over. And that is what kind of liberal democracy are we, a subject that Michael Sandel has written about a great deal. Michael will say whether I am right, but, Michael, I don't think you would agree with the statement that our liberal democracy privileges the autonomous or freely choosing life. As I understand Michael Sandel's writings on this subject, there is an ongoing tension in the United States between the version of liberalism that does privilege autonomy and free choice of individual understood in a certain way and another version of liberal democracy that I think I understand you to favor that is more complex and gets into questions that are intimately related with the stem cell debate, such as what do we mean by an individual. Do we think of an individual as really radically autonomous or do we think of an individual as constituted, in part, by relations with others and then the other range of questions about present and future? So I would have expected - this really is maybe a question more directed to my colleague Michael than to Peter. I would expect Michael Sandel to support the President's policy on the basis of Michael's understanding of a rich and complex liberalism that has to attend to preserving the conditions for its own survival. PROF. GEORGE: What should Michael say to that? PROF. BERKOWITZ: Michael should say sort of. We both should be so lucky to have you as an editor. I hope you will not regard this as mealymouthed, but, just as I wanted to suggest we shouldn't draw too sharp a distinction between decisions based on principle and compromise, my own view is that we should not draw too sharp a distinction between the liberal democracy that celebrates or privileges the autonomous individual and the strands of our political tradition that Michael has written at length about and educated us about. My own view is that one discovers in our country - and, by the way, I take this to be consistent with Michael's view, although I may not put it in a way that he finds congenial - I take it that our country is, in large measure, constituted by this running debate over the meaning of freedom. But freedom and individual freedom, how much attention to put to the individual as self.reliant, how much attention to give, how much weight to give to the individual as he or she flourishes, grows up and flourishes in family, neighborhood, house of worship, state, and the various communities that constitute us. Again, what that is is a debate about the meaning of freedom. It is not a debate about something else. So the larger point is, once again, the thinking in terms of public policy's role in securing the conditions for the enjoyment of freedom is not an alternative to taking into account considerations of attachment, community, to borrow one of Michael's phrases, duties we don't give ourselves but are given to us and to which we are born. It is not an alternative to that. That is part of the larger ambition and larger public policy struggle. What are the conditions that promote and enhance individual freedom? CHAIRMAN KASS: Mary Ann, follow-up? PROF. GLENDON: Yes. Well, I would just like to clarify that what I was suggesting is that the President's decision involved, among other things, a position in that ongoing debate about what kind of society we are bringing into being. CHAIRMAN KASS: Thank you. I have myself next, Peter. The details of the President's policy will be part of the discussion really more in the second session. So let me try to formulate this in more general terms. Actually, the staff working paper for the second session also has some discussion of federal funding and its meaning. And it makes an argument that you haven't made or at least if you have made it, I haven't heard it. I heard it emphasized. And that has something to do with the fact that a decision to fund is not just a financial encouragement, but it is also an expression of the seal of governmental approval and that one might say that the existence of this intense debate as regarding the moral meaning of embryonic destruction in the service of medical good is something on which the very fact that the nation is divided might be an argument for withholding official national approval. And a person might, in fact, think that the embryo might not be worth very much but, nevertheless, say, "I understand that lots of my fellow citizens think otherwise." And it would somehow be a mistake for a polity on a question so hotly contested for my side to prevail if prevailing means the national approval. I quote two sentences, "While embryo destruction may be something that some Americans support and engage in, it is not something that America as a nation has officially supported or engaged in. And one has in the background the congressional legislation, which is, in fact, the constraint here." So the question, I guess, to generalize it, not to add to the polity, couldn't one make an argument that because federal funding is an expression of national approval, there might be grounds for arguing that that approval should be withheld, even if you are on the side that would benefit from the award of funds? That would be question one. Let me just add the second. I think I would add a kind of small asterisk to the way you formulated the controversy. This is now into the substance, where you say that you have got a genuine moral goods at stake, powerful principles at loggerheads, and defended in absolute terms. Well, as a description of the way the debate has gone, I think that is true, but there is a certain complication in that if this is simply a matter of moral goods at stake, those sorts of things tend to be handled by compromise. But what do you do if the contest is between what might be called right and good; in other words, where on one side, you have a principle that something should never be done because it is a moral evil and, on the other side, you have something that this is good to be preserved but that it is not the same kind of moral imperative. We had this discussion last time about what kind of an imperative research is. In other words, does the fact that we are dealing here with an issue that isn't like the usual funding questions, where there are competing goods simply but where one side at least claims to uphold some kind of absolute moral principle, which they're not only defending in absolute terms but they regard as a moral absolute; whereas, while others might defend it in absolute terms, it's very hard to say that the case for doing medical research has the same kind of moral absolute status. PROF. BERKOWITZ: Difficult questions. First, on let's call it the moral meaning of division in the country, here I do want to go back to something I did say in the presentation. It seems to me that in characterizing the division in the country, one does have to distinguish the fact of division from the reasons that people give in support of their opinions. So in my view, it's very important in stem cell debate that when I read the arguments that are put forward on both sides, I find what I regard as serious moral arguments on both sides. The fact of division in the country would have less weight if one side were clearly right and one side were clearly wrong. It could still have pragmatic weight. Law is still designed and crafted and implemented and adjudicated for real people to live under. You can't have laws under which people cannot live. But these two features of the debate are very important, what I call the sociological fact of it and the philosophical features of it. There are good reasons on both sides. Second, as far as your suggestion that there is a kind of asymmetry in the debate, where there is a good on one side, a good we all affirm, scientific research, free inquiry, and an absolute principle on the other side, actually, I don't quite see it that way. Again, referring to the President's August 2001, the principle is actually, as I see it, embodied in the policy. It's not an absolute principle. The principle, it may actually be something the President holds, people on this Council hold, people in the country hold, but one certainly could defend it in these terms. The principle is that we don't use government taxpayer dollars to destroy nascent human life. One need not subscribe to that principle based upon the absolute, inalterable, extraordinarily confident opinion that a two.week.old embryo is of the same moral status and dignity as a fully developed human being. One may adhere to that principle because one is still uncertain. One believes that the embryo is different from clumps, different from collections of cells, but because it's a kind of new problem, we didn't have access. We could not manipulate two.week.old cells. So there is a way at least of seeing the debate as not quite as imbalanced as you put it, although I wouldn't deny that some people do view it as you suggest. CHAIRMAN KASS: I wasn't speaking about the President's decision. I should make the more general point. What happens if you've got a contest, not between things that people acknowledge as competing goods simply but in which at least the key partisans in the debate - and I am thinking more about Congress - regard this as a contest between the right and the good, between something which would be a right or a wrong in more absolute terms and an optional good, however powerful optional good or is this just the sort of thing that you see in the rough and tumble of politics and it gets worked out in the usual way? PROF. BERKOWITZ: Well, I wouldn't quite put it only that way. I do not see a philosophy or a moral philosophy providing us a formula or algorithm for figuring out what happens when a right clashes with a good. But I like the phrase "rough and tumble of politics." And I would like to apply it also to moral and political philosophy. The clash between the right and the good in this case involves the rough and tumble of thinking, thinking rigorously about the problem and figuring out the kinds of the moral weights we attach in this case to the right and the good. There's a rough and tumble of serious thought, too, but, again, I haven't gotten and I don't believe there is an algorithm or formula that tells you what to do when an important right clashes with a good. CHAIRMAN KASS: Thank you. Rebecca, Rebecca Dresser? PROF. DRESSER: A suggestion and a question. If you would like to flesh this out more, you might want to follow up on the fetal tissue transplant research history because there was a similar acrimonious longstanding debate over federal funding. And then eventually the Congress got into it and established a policy. And then a new administration came in. So it might be a nice way to illustrate some of the points you are making. The question I had was, had you thought about - and maybe I am just being a law professor and being procedural - principles for responding to situations like this? How should we deliberate when there is controversy over funding policy? How should the different sides engage each other? It seems to me that some of the animosity around stem cells, the stem cell funding debate, is related to how the debate is being conducted. And it's generating perhaps unnecessary animosity. PROF. BERKOWITZ: Well, first, thank you for the suggestion, and I'll have a look. And, second, once again, just as I didn't have an algorithm or formula, I am afraid I haven't gotten principles ready at hand. But I can say this. Just as hard cases make bad law, I would be reluctant to generalize overly much from this particular controversy, again, not because I think that in formal structure, it represents something anomalous but because I think in content, it represents an issue that is very difficult, goods or right and the good, serious ones on both sides of the question, excites high passions. And the kind of problem that history and the history of moral and political philosophy doesn't help us as much as it does in other areas because the amazing advance of science has enabled us to do something that we couldn't do before. Actually, we have created a moral problem for ourselves. So I am inclined to say that as far as my limited imagination will take me, that this was not a bad idea to deal with. The Council on Bioethics was not a bad idea to deal with this vexing moral question. Congress passed a law. The President conferred. His speech suggested that he had not come to a firm resolution. It suggested that the reason that he had not come to a firm resolution was because he was confronting extremely difficult issues on which the country was divided and on which the country was divided for good reasons. And one response to that is to gather a diverse and distinguished group of people to engage in both the rough and tumble of politics and the rough and tumble of serious inquiry and conversation. I fear that's not very satisfying, but I say without too much fear that I think it is the best we can do. CHAIRMAN KASS: Elizabeth? Elizabeth Blackburn? PROF. BLACKBURN: Well, I wanted to address the issue of the consequences of when federal funding is not granted. And you say to go chapter and verse, page 8. Of course, private institutions are free to continue to practice activities that disqualify them from federal funding. All they have to do is refuse to take federal funds. I think what I didn't get from the chapter, which would have been nice, - it was very clarifying in many ways - in different contexts, the consequence of not granting funding is so very different and, as somebody rightly pointed out, people can cohabitate and refuse and they don't have federal funding and that doesn't prevent a common practice, for example. But in the case of this particular activity, because of its nature, not granting federal funding is very effectively a ban. And you could say, "Oh, wait a minute. This could be done in the private sector." But I think that is to misunderstand the nature of basic biomedical research at the stage before it is really commercially viable in a realistic sort of fashion. And so I think that because this, in effect, was a ban on such research taking place in ways that are known to be the way that scientific research can proceed best with the proper peer review and proper open exchange of public information and publicly funded information and all of those things that are held to be the right way to do biomedical research, then it has a somewhat different effect from what you rather lightheartedly talked about at the end of this paragraph on page 8. Of course, they can just refuse to do it. PROF. BERKOWITZ: Right. PROF. BLACKBURN: And I think that is a distinction we should really face up to - PROF. BERKOWITZ: Yes. PROF. BLACKBURN: - because you are technically right, of course, that, in effect, it didn't work out that way. PROF. BERKOWITZ: There are others who are much more able than I am to speak to the consequences. In fact, I understand that the next session will be, in part, devoted to that issue. So I both don't want to encroach and, even if I wanted to, couldn't very effectively. So I will just make one or two small points. Supposing you are right. An effective ban is still different from an actual ban. And, second, - and I don't mean for a moment to underestimate, although I understand it is a subject also of intense debate and controversy, what actually are the effects on scientific research of the ban on creating embryos today or creating stem cell lines from existing embryos. I understand that that, too, is a subject of debate. There is - and this is the sense in which I address this question in the presentation - a ready.at.hand expedient for scientists and for those in the public who think that the President's policy is wrong and should be changed. It's the democratic expedient. It's to gather a majority of fellow citizens and persuade your congressman. So in that sense, it's, once again, the sort of thing that happens in a liberal democracy, our liberal democracy, which gives fairly wide latitude, fairly wide latitude, to majorities. And no doubt on some individuals, especially individuals whose livelihood is devoted to such research, this policy falls with a special heaviness. PROF. BLACKBURN: Nobody has devoted their life to this research yet because - PROF. BERKOWITZ: Those who wish to. CHAIRMAN KASS: The record really should show, Elizabeth, that this is not a ban. In fact, this was the first awarding of federal funds. PROF. BERKOWITZ: Yes. CHAIRMAN KASS: I mean, let's be clear about that. And we will this afternoon from Dr. Zerhouni about research that goes forward now for the first time with federal support. Whether it is sufficient encouragement for the field, to take off is another matter, but it would be simply a mistake to let the record say that - PROF. BLACKBURN: Right. I think my point was that technically this is all correct, but I think it is worth pointing out that how it works is so very context.dependent, how not granting federal funding is extremely context.dependent. And in one case, there is a ready recourse to the private sector. In other cases, there aren't. PROF. BERKOWITZ: Even though I am aware that there is a debate, even among scientists, about the promise of stem cell research, nothing I said should be understood as suggesting that the President's policy is not a significant obstacle to conducting scientific inquiry. What I meant to say is that it struck me as both a constitutional and reasonable obstacle. CHAIRMAN KASS: We are near the break. Robby, are you in the queue? You are? PROF. GEORGE: Yes, but if there's anybody who hasn't spoken yet - CHAIRMAN KASS: The only two I have left are you and Michael. So if we can make it brief? PROF. GEORGE: Michael, would you? Well, you might get back to Michael quickly here. Peter, I'm curious about your own view. Do you think that we know enough based on what the President himself has said and the content of the position that he adopted and put in place? Do we know enough to be able to say whether the President's position logically entails either of the two competing views of the moral status of the embryo that are on the table here, either what Michael calls the special respect view or what might be called the full moral respect view? PROF. BERKOWITZ: As it was put on the table in August 2001, I certainly don't think it entails the - how did you describe the latter, the full - PROF. GEORGE: The full moral respect. PROF. BERKOWITZ: The full moral respect. PROF. GEORGE: Well, I don't either. PROF. BERKOWITZ: It certainly doesn't entail. It's obviously not - well, I shouldn't say "obviously not." I don't believe it's inconsistent with that view. PROF. GEORGE: So it doesn't entail either. If it's not inconsistent with the first view, then it can't entail - PROF. BERKOWITZ: I'm sorry. I meant that it's not inconsistent with the full moral respect view. PROF. GEORGE: Right. But if you believe that, then you also must believe that it doesn't logically entail the special respect. PROF. BERKOWITZ: I suppose it could still. It could have flowed if we're speaking strictly logically here. It could have flowed from a genuine uncertainty, confronting both arguments and saying, you know, "Special moral respect, to what extent and what quality, sounds like there's something to it. I'm not sure. Scientific research should proceed, nevertheless. Not sure. Let's inquire and let's for the time being adhere to the principle that the federal government doesn't support the destruction of nascent human life" because one could give a perfectly respectful argument that it has to those of you who spend your lives doing such things, it will have echoes of Kant. But it's also essential to respecting your fellow human being in a liberal society could believe that this principle, no federal taxpayer dollars, is necessary to creating a society in which individuals respect humanity in themselves and others. CHAIRMAN KASS: Michael? PROF. SANDEL: I just wanted to reiterate my agreement with Peter's analysis and the way in which it highlights this important implication, which is that the President's position of denying funding but not banning can be saved from the charge of moral incoherence but only if you assume that he is agnostic or unsure about the moral status of the embryo or if he accepts an intermediate view of the embryo, that it's not merely a clump of cells but neither is it morally equivalent of a fully developed human being because if a person held that view, if embryonic stem cell research were a merger or infanticide for the sake of saving other people, then there would be no good principled reason not to ban it short of averting civil war if civil war were really the consequence. But since the President didn't ban it, then either he must be unsure about who is right in the debate about the embryo or he must hold some version of the intermediate view. PROF. BERKOWITZ: Well, I need to say there is one other possibility, which is the President could have concluded that the attempt to implement what Robby George calls the fuller view would be impossible or have destructive consequences. And so one morally could conclude, it seems to me, that it is both saner and wiser to attempt to implement the principle and to refrain from implementing the principle in its maximal and absolute form. PROF. SANDEL: That would be like Frank's civil war worked, - PROF. BERKOWITZ: Yes, that's right. PROF. SANDEL: - Lincoln's Civil War. Something like the civil war will loom if you try to ban the infanticide. DR. FOSTER: Can I say one sentence? CHAIRMAN KASS: Dan Foster, please? DR. FOSTER: One sentence. If my memory has not failed me, at the time the President met with this Council at its initiation, he seemed to make clear his interest in finding out more about embryonic stem cells with a clear conclusion on my part that he was in the position that has been articulated here this morning of not being certain about what to do. Unless my memory completely fails me, that was a major thrust of the meeting that day. CHAIRMAN KASS: Yes. Very briefly, Bill, because we're going to break. Briefly. DR. HURLBUT: Michael, I just want to understand what you are saying. When the President issued his statement in August, he was speaking about federal funding. And he was upholding the Dickey amendment, right, the Dickey clause, whatever you call that. And so he wasn't even addressing the question of a total ban on anything. He was addressing the issue of federal funding. Isn't this right? So why would we conclude from that one way or another about his larger position? CHAIRMAN KASS: It would have been my question, too. I mean, you misframed I think the situation. There is a law on the books. The question is, is there a legal loophole against the spirit of the law but within the letter? And that was a loaded question. You can say you can fault them for not at the very same time calling for a congressional ban on all embryo research, but that was not the question at issue. PROF. SANDEL: Why would you look for a legal loophole in a law that banned infanticide if you really considered infanticide an evil? CHAIRMAN KASS: I'm saying he wasn't looking for a legal loophole. It was - PROF. SANDEL: Sorry. I was just using the phrase that you had. CHAIRMAN KASS: I think this will come up in the next. The way the question is formulated is I think terribly important. Let's thank Peter very much for a very clear and lucid paper and for discussion. (Applause.) CHAIRMAN KASS: We are not very late, 15 minutes. We will convene at ten minutes of the hour. (Whereupon, the foregoing matter went off the record at 10:38 a.m. and went back on the record at 10:57 a.m.)
SESSION 2: STEM CELLS: THE ADMINISTRATION'S FUNDING POLICY: LEGAL AND MORAL FOUNDATIONS CHAIRMAN KASS: All right. We move from the general question of the meaning of federal funding, to a session entitled "Stem Cells: The Administration's Funding Policy: Legal and Moral Foundations." The basis for the discussion is a very fine and lucid Staff Working Paper on the topic, one which, if I might be allowed a personal rather than official opinion, is the clearest and best explication of this matter that I, at least, have seen anywhere. The paper provides a brief background history of the embryo funding debate, leading up to the Dickey Amendment, and the different approaches taken by the Clinton and Bush Administrations in executing that law, that law still setting the background for all of the discussions that follow. The Staff Working Paper then explicates the present funding policy, and clearly articulates the moral legs on which it rests. Among its most important contribution, in my view, this part of the working paper points out that the President's policy rests, at least in part, on moral principle, not a political compromise or a cost benefit calculation, and draws from this fact the following conclusion. And I'm reading from page 7 of the Staff Working Paper. Well, let me read the whole paragraph. "This character of the decision, namely, that it's been based on moral principle, has been overlooked by both its opponents and by many of its defenders. As a result, the debate has tended to focus on the precise balance of benefits and harms resulting from the combination of the Administration's policy and the state of the relevant science. It is focused on whether there are enough cell lines, or whether the science is advancing as quickly as it could, and has proceeded as though this Administration sought simply the same end as the previous one; that is, to allow for maximal progress in embryonic stem cell research within the limit of the law. Had the decision been based on that desire, then claims or evidence of slowed progress alone might constitute an argument against it in its own terms. But since the decision was grounded firmly in a clearly discernible, if controversial principle, it does not appear simply to be overturnable on its face by a shift in the ratio of harms and benefits. Judgments made in matters of calculation and weighing of competing goods and bads are, of course, altered decisively by the changing weights of what is placed on the scales. But judgments made as matters of principle of right versus wrong, rather than better versus worse, can only be altered on the level of principle. To argue with the President's decision on its own terms, one would need to argue with its moral and political premises; namely, its view that a human embryo ought not to be violated. Its view, therefore, this is indeed a matter of principle rather than a balancing, and its assessment of the significance of government funding of the contested activity. All of these are, of course, appropriate subjects for public debate." Finally, the Working Paper also treats the issue of federal funding and its significance, the topic of our last session, and offers its own take on what kind of a decision, the decision to withhold or offer federal funding, really is. I think it's perfectly compatible with Peter's paper, though there are some interesting different nuances. The paper is now open for discussion, and let me suggest that we begin with questions of clarification, or questions that go to the accuracy of the explication offered in the Working Paper. Once again, before we move into an argument about the issues, we should try to be clear and reach agreement on what it is that we're arguing about. So if we could begin with those kinds of questions and comments, and then we can move to a more substantive discussion. I should say, this paper is largely the work of Yuval Levin, who's had critical comments from others, but it's his very fine handy work, and if I get stuck in any places, I will feel it appropriate to call on him for assistance. Robby George. PROF. GEORGE: Would it be possible for you or Yuval to give us a little more detail about the change in policy toward the end of the Clinton Administration, and when the Bush Administration took over. There's a nice short summary of that in the paper, but I wonder if there's more detail that could be given. CHAIRMAN KASS: Let me try. I'm not sure that this is much more than what's here, but the language of the Dickey Amendment says "no federal funds may be used for the creation of a human embryo or embryos for research purposes, or research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury, et cetera." Reading strictly according to the letter, and reading, I think, in the spirit of what the paper identifies correctly as the basic sort of thrust of the Clinton Administration's view of the matter, the political question there was how can embryonic stem cell research be maximally aided within the limits of this law as written? Well, the law as written says you can't fund research in which the embryos - an embryo or embryos are destroyed, discarded or subjected to risk, but it doesn't say that you may not fund research on cells derived from prior destruction. So the argument would be if the stem cells were - stem cell lines were derived from embryos destroyed not with federal funds, and no further embryo destruction is now entailed in the further use of those cells, then those cells could be - research on those cells could be funded without violation of the Dickey Amendment. That was the reading of the law by Council within HHS in the latter part of the Clinton Administration. Rebecca, am I so far okay? PROF. DRESSER: Yes. I was just wondering if Robby was interested in the proposed guidelines that NIH was going to adopt with Secretary Shalala. PROF. GEORGE: Yes, Rebecca, I was. That's what I was interested in learning more about, because it was the - where it wasn't - what wasn't clear to me from the paper is what happened as far as implementation once the administration had decided upon this reading. I know at the end it was kind of left hanging because there was a change of administrations, but how far did things go? PROF. DRESSER: Well, this is my recollection. The NIH put together a committee which proposed guidelines for federal funding. And I believe they went through a comment process, and then I think they were formally published in the Federal Register, but they hadn't taken effect before the election. And they did have some substantive provisions; such as - one which I think is of interest here is that no funding for stem cells from embryos created through cloning. And they did have some other limitations, so it might be helpful to include some of the substance of them in this document. CHAIRMAN KASS: Thank you. Janet. DR. ROWLEY: Yeah, because Shirley Tilghman was the Chairman of that committee, and they met for quite some time before the recommendations were made. And they were subject to federal comment. And it's my impression that the members of that review board, which would review all of the research proposed to be done under this new permitted research was going to be reviewed by a committee that would be housed at NIH, just like the RAC is. But it was so close to the election that, in fact, that review committee never met. CHAIRMAN KASS: Well, I think it would be important for us to get that information and make it part of the historical background of this chapter. Rebecca, please continue. PROF. DRESSER: I had another question just about the term "loophole". Is that something that was intentionally used, and do we really want to use it? Let's see. I think it was on the top of page 4, about the middle of the first full paragraph. And it's been referred to earlier in this discussion as a loophole. I mean, it seems a pejorative term. Perhaps an exception in the area where the application did not - I don't - I'm just throwing it out for discussion. PROF. SANDEL: A lacuna. CHAIRMAN KASS: Yeah, it will be altered. I think it's certainly fair to say that it was an attempt to use the statutory - to find openings in the statutory language that would permit activity against the spirit of the law itself. I think that's not controversial, but I don't think we will strike anything that suggests that there's something improper about that. PROF. DRESSER: Well, I mean if it is a loophole, it's a loophole that the current policy also, to some extent, rests on. Isn't that correct? Because the current policy is a way of funding stem cell research consistently with the Dickey Amendment. CHAIRMAN KASS: Well taken. Jim Wilson. PROF. WILSON: I think the text suggests for reasons it does not make explicit, and I emphasize the word "suggest", there was a difference in motivation between the Clinton and Bush Administrations, but it doesn't make explicit what the text suggests. And as Rebecca just pointed out, however we may characterize Mr. Clinton's personal motives or Mr. Bush's personal motives, that the present policy is consistent with prior policy in the Clinton Administration; that is to say, a private funding led to the destruction of an embryo. Then the cells from that embryo could be analyzed using federal funds. And is there a difference? And if so, it should be made explicit. CHAIRMAN KASS: Does someone want to comment on this? Gil Meilaender. PROF. MEILAENDER: Well, I think there is this difference, that the policy in place now in the Bush Administration does not reckon with the possibility that newly derived embryonic stem cell lines could become the subject of research; that is to say, the derivation/use distinction doesn't continue indefinitely. Whereas, presumably with the policy of the previous administration, it could have - there could have been an indefinite number of stem cell lines derived without federal funding, but then the use of federal funds to do research with them. And in that sense, there's a clear distinction. PROF. ROWLEY: But I think that's a point of specific information, that as we get more details about what the precise language was of the committee that Shirley Tilghman was chair of, we'll see whether, in fact, what you just said is correct or not. PROF. MEILAENDER: I'm perfectly happy to have us see that. PROF. BLACKBURN: Just a clarification. I thought it said at the end of that first full paragraph on page 4, it said, "Because such research would require no new embryo destruction", it seems as if the previous administration's did have that provision in it. PROF. WILSON: That's exactly what I'm trying to clarify. That phrase put me off. It was my understanding from my memory of the time, quite shaky at best, that it would have allowed continued destruction of embryos by private funding. If that's the case, then this sentence is in error. That's what I wanted to have clarified. Yes. DR. KRAUTHAMMER: I think it might be just amended to read, "Because such research would require no new embryo destruction by federally supported research", and that would cure the problem. PROF. BLACKBURN: It needs to be clarified what it was. CHAIRMAN KASS: Someone was in the queue. Mike, why don't you just - Mike Gazzaniga. DR. GAZZANIGA: Well, just a point of clarification. The principle that you're referring to that must be changed in order for the President to change his position; namely, that the human embryo ought not to be violated, I was wondering if Michael Sandel would comment on that, given his argument this morning. Does this argument force upon him a - force upon us a different way the President should have stated his principle? CHAIRMAN KASS: Do you want a clarification of the question that's put to you? PROF. SANDEL: I didn't quite catch the first part. DR. GAZZANIGA: Well, just the discussion we had this morning about, in order for the policy of his to be morally coherent, there had to be this assumption of the fact that he was not yet decided on the moral status of the embryo. That seems to me, if that is true, if that argument is valid, then the principle that you're referring to in the paragraph you just read should be amended. PROF. SANDEL: Well, we're going to, I assume, get into this. It seems to me that the whole issue here rests on the complicity issue, what is complicity, and in what kind of moral evil is there complicity if you use the fruits of the morally evil act for good ends? And then the question is, well, just how morally evil can the act be for you to use the fruits of it, and not be morally complicit in the wrong? But I think the issue of complicity is, that's the heart of the moral position here. And we need to get into that, but I don't know that - CHAIRMAN KASS: Let's hold that - I'm sorry. PROF. SANDEL: But I think we're going to come to that, I assume. CHAIRMAN KASS: We will come to that. Let's see if there's still questions of clarification. Jim Wilson, sorry. PROF. WILSON: On page 5, there is an effort to distinguish the Clinton position from the Bush position. And we assert President Clinton, like many Americans, did not believe that the destruction of an in vitro human embryo is inherently or necessarily a moral evil. And in the next paragraph, President Bush had a very different question in mind. Like many Americans, he does believe that these are - these are statements. It would be better if they were quotations of the Presidents so we'd know what, in fact, they said, if they said anything. CHAIRMAN KASS: Point taken. Janet. DR. ROWLEY: Because to follow on, but skip to the conclusions under number 2, the conviction held by the President that nascent moral human life should be deemed inviolable, and we spent the earlier part of today saying that in fact we - it was our impression that he hadn't come to a decision on that. CHAIRMAN KASS: Yeah, I'm not - by the way, Jim Wilson's counsel is, of course, as it often is wise, and if we attribute opinions to various people, we should find the text. I don't think, by the way, that - and I think we can find it. I don't think that the argument that agnosticism - the argument that the President is agnostic on the question can be settled by the quotation that Peter gave from the fact that he heard two different opinions, and cited those opinions in the Address of August, 2001. And he has, on other occasions, said things that are very much like this in public speeches, but we will find - we will get the evidence. Rebecca. PROF. DRESSER: A question of clarification, that this first paragraph at the top of page 5, the very last sentence. I wondered if that should say "nascent human life ought not be violated for research", because, I mean, that seemed rather broad. And if I remember correctly, isn't there federal funding available for abortion under certain circumstances? Say if the mother's life is in danger, so that seemed rather absolute. CHAIRMAN KASS: Point taken. Robby George. PROF. GEORGE: Leon, a bit more if you know more, back to my original question, about the source of the cell lines funding on which was authorized by the President in his August 9th, 2001 Address. Do we know the circumstances under which those cell lines were created? Presumably, they were created - the destruction of the embryos to generate the cells to begin the lines was privately funded. Is that right? CHAIRMAN KASS: That's my understanding, yes. All those lines were checked out under Whitehouse direction, but by people at the NIH. PROF. GEORGE: And do we know when? CHAIRMAN KASS: When were they checked? PROF. GEORGE: No, when were they created? CHAIRMAN KASS: I think at various times in the preceding years. PROF. GEORGE: Going back five years, ten years? CHAIRMAN KASS: The first stem cell lines were derived and reported on anyhow in 1998. That's the first publication. Whether they existed prior to publication for a short period of time, I don't know. Yeah, we have one of the pioneers here. Elizabeth. PROF. BLACKBURN: And should we add some of the lines counted in the original 76 I believe were from foreign sources too, and those might have been from - PROF. GEORGE: Yeah. I was wondering about that. PROF. BLACKBURN: Those might have been from those countries' equivalent of federal funding. I'm not sure line by line about that, but that's a possibility. CHAIRMAN KASS: Yeah. No, I mean what was - while speaking just about that question, and we need to get more information in here because I think it's going to be relevant to the document. A certain kind of confusion was created by failure to observe the distinction between eligible and available. Some 60, and then eventually it grew to some 70 lines were eligible, eligible in the sense that they met the criteria of having been derived prior to the date of the policy by informed consent, et cetera, et cetera, and not derived with government funds. Available meant, in fact, that they were characterized that there were no commercial or other impediments to their being shared, so that there was a certain amount of confusion. When people said there were some 70 lines available, what they meant really was that there were 70, 71, I've forgotten, eligible for funding. I believe the number now actually available to the NIH is 12, so that of the 70 original available lines, most of them from international sources, in fact, they are now a dozen of them that are actually available for use. And we'll get some more information about - to fill in that part of the history. Janet. DR. ROWLEY: And I think that's a very important distinction because when one uses the term "characterized", that means a different level of real scientific analysis to different people. But that was one of the issues, that many of the so.called lines are not lines and that they cannot be grown indefinitely. Secondly, their karyotype was not established, and so many of them may be abnormal and, therefore, not suitable, so that this is why you go from 77 down to 12. And this is part of the concern about the availability. CHAIRMAN KASS: Okay. Still a clarification, Jim? Please go ahead. PROF. WILSON: Yes. Janet raises a question that I thought will be answered in the document, possibly it should be answered in this document; namely, very practical questions. How long, and under what circumstances does a cell line endure? To what extent do we know the physiological origin of the cell line? At some point obviously we may summarize information about what has been done, what has been accomplished with these cell lines, but just practical terms. Where do they come from, and how long do they last? And will at some point, some President, if not this one, the next one, have to consider re.authorizing other cell lines to make up for a deficiency? CHAIRMAN KASS: All right. Then if this exhausts the matters of clarification, I think we can now sort of get into discussion of the more substantive questions. And maybe we should go back to this question of complicity. Michael, do you want to proceed, or do you want to have the question put to you again? PROF. SANDEL: Well, the moral heart of the issue seems to be this question of complicity, and the paper brings this out at the bottom of page 5, and on page 6. And it suggests an answer in the third paragraph on page 6. The question is "whether one can benefit from the results of an immoral act without becoming complicit in the act." That's the heart of the moral test of this position, and the discussion paper says that one may make use of such benefits if, and only if three conditions are met; one doesn't cooperate or actively involve oneself in the commission of the act, and does nothing to abet or encourage the repetition of the act by providing incentives and so on. And in accepting the benefit when - re-annunciates and reaffirms the principle violated by the original deed in question. One question I have, and it may be a small question, but at the top of page 5 there were some restrictions on eligibility for federal funding of stem cell lines that I hadn't been aware of until I read this, which are only those pre-existing lines. It's not only that they must be pre-existing, but that they must be somehow certified not to have been derived from excess embryos created for reproductive purposes, and made available with the informed consent of the donors, and without financial inducement. So an initial question I have is, if the conditions for non-complicity are correct and adequate, then why worry about these other considerations? Presumably, these other considerations matter because even where you're using pre-existing stem cell lines, where the evil deed has already been committed, and where you're not complicit in that evil deed. You don't perform it, you don't abet it, you don't provide incentives for its being committed in the future. Even in those cases, there would still be complicity, or would they if you're using pre-existing lines that, let's say, where the donors have been given some payment? That would create complicity, but the underlying evil act itself wouldn't, and that's very strange. So the only way of making sense of those additional requirements of the pre-existing lines is that they somehow make it even worse, but could they make it even worse if the underlying moral evil were already tantamount to murder or homicide? It seems unlikely if I'm not complicit - and the same way to think about this we've discussed before using the fruits of the Nazi experiments, medical experiments in the concentration camps. Under what conditions can we use the medical data that came from these Nazi experiments without being complicit in them? And maybe the answer would have something to do with well, we didn't cooperate. We didn't abet the practice. We don't encourage it in the future. But then it would be odd to say, if that were the relevant analogy, it would be odd to say but we can only - we're only not complicit really if it turns out that the data was from these people who were tortured and abused, was made available, you know - oh, no they didn't give their consent. Oh well, in that case, no, no, then we would be complicit even though we're meeting these other requirements. Or if we're thinking of an example of using organs that had been extracted from prisoners, let's say, in a prison camp in some totalitarian society where it's reported that prisoners are killed for their organs in various countries. Now would we say well - what would be the policy? Would we say well, it's an evil to kill someone for his organs? We're not going to desist from using those organs, provided that those organs - that the killings were done before a given date, so we don't encourage it in the future. But we remove our complicity, provided we're not encouraging - we didn't cooperate in the killing and the extraction of the organs in this prison camp. We don't encourage it in the future, because from now on we're not going to do it. But we can use these organs to save lives. Let's suppose they're still available, been preserved. They're fresh enough so that they can - we'll use these ones. And furthermore, we'll even provide federal funding for the use of these organs, provided you don't do it again, provided you don't it in the future. Would we satisfy ourselves and say well, that's not really - we're not complicit. We're just using what's available. In fact, we're giving federal funding for those organs, but we're laying down these restrictions to make sure it doesn't happen again, and that we're not complicit. I think that would be a strange moral position to take if we really did believe that these organs did come from human beings in a prison camp who were killed to extract them, to get federal funding - but under these - I think we would still say we're complicit. So that's simply putting this together with the discussion we had of Peter Berkowitz' paper. What this suggests - the complicity discussion here suggests is that we would still consider it morally complicit to avail ourselves of the organs we found in that prison camp, even though we didn't kill the people, we didn't extract the organs, and we're not going to provide incentives to do it again, because from here on out, you can't do it. But in the meantime, they're there, we can save life. Let's get federal funding for these organs. CHAIRMAN KASS: Does someone want to respond directly to this? Mary Ann and then Jim, and Bill. PROF. GLENDON: I think maybe there's a simpler explanation for these conditions, which is that there are a number of policies being followed here. And one is that the government doesn't want to do anything to encourage the creation of embryos for other than reproductive purposes. Another is, you always want to support informed consent to procedures. And another is, you don't want to encourage commercial trafficking in human material. I just don't think that there needs to be or were thought of as involved at the complicity issue. I think the complicity issue... PROF. SANDEL: Let's just ask, Mary Ann, about that, what you've just said. But remember, this is in the context of only pre-existing one. PROF. GLENDON: Well, I'm coming to that. So the complicity issue has to do with pre-existing, to take your analogy to the use of materials that were obtained from victims of national socialism. One of the reasons why the complicity issue is not as acute in that case as it is here, is that behavior is not ongoing. It's finished. Here we're dealing with an ongoing situation, and the risk of encouraging future production of these lines is greater. PROF. SANDEL: So what would you do with the organ case of the prisoners in China, hypothetically, which could be ongoing? PROF. GLENDON: I'm sorry? PROF. SANDEL: Well, how would you respond to the organs derived from prisoners in a prison camp in the complicity issue? Do you think that comes closer to this example? PROF. GLENDON: If it's an ongoing situation. PROF. SANDEL: No, but if we say we're only going to use those organs that we came upon yesterday, and we'll get federal funding for those transplantations because the deed has already been done. But we're not going to allow any federal funding for any organs from prison camp victims after August 9th, after today. CHAIRMAN KASS: That one I think is easy, don't you think, Michael? Let me give you an American version, the eminent Dr. Kavorkian, mostly known for his interest in assisted suicide, actually had combined those proposals with a desire to get organs for transplantation. This was a double.barreled project of his. Imagine that you have the Good Samaritan euthanizers led by the good doctor, and that he doesn't get just ordinary healthy people. He waits for the terminally ill but not yet dead, and the cadre come in and extract the organs from the almost dying, and you've got a freezer full of these. And they're properly stored, and you catch them. And the question is, you've got a freezer full of good organs. You throw them out. And if you use them, or even if you use them, and use them in federally supported hospitals, are you, in effect, complicit in the dirty deed that was done? PROF. SANDEL: What do you say? CHAIRMAN KASS: I say no. And I say no under certain kinds of specified conditions; which is to say, you round them up. You punish them severely, and you make it perfectly clear in doing so that you're re-affirming the principle that they themselves have violated, but you can't somehow undo those deeds. And the use of those organs to save life does not make you guilty of the act, I don't think. That's, I think, debatable, but that would be a kind of analogy. PROF. SANDEL: But you would be complicit if this were not a case of euthanasia where people gave their consent, which meets one of these requirements. But if, instead, it were a prison camp where there was no consent - CHAIRMAN KASS: Do that to me again. PROF. SANDEL: You changed the case so that we have euthanasia with consent that generates these organs, the freezer full of organs. And I assume you did that to meet the requirement here. CHAIRMAN KASS: I didn't say with consent. PROF. SANDEL: So then it's not really euthanasia, or euthanasia against the will of the people. It's murder. CHAIRMAN KASS: They're comatose. What do they know? PROF. SANDEL: But to clarify the case of complicity, let's assume that these are people in a prison camp whose organs are taken out, and the organs populating your freezer are from victims of a prison camp or concentration camp. CHAIRMAN KASS: Yeah, I - PROF. SANDEL: Then there is no complicity. Even there in availing, in using them to save lives. CHAIRMAN KASS: That's, I think, my - I think that this kind of traditional moral - these are sort of - this is kind of a traditional moral approach to this question. It tries to deal with that, and I think would answer in the way in which I just did. PROF. SANDEL: But if even that's not complicit, then it would be strange to add these other requirements of the pre-existing organs in the freezer, that they be made available with informed consent, that there were no financial inducements and so on, wouldn't it? CHAIRMAN KASS: Gil, do you want to - PROF. MEILAENDER: I was just going to say, I mean, I think Mary Ann's answer is still the relevant one there. I mean, it would be possible to argue that that doesn't affect complicity, but there might be other things that one has concerns about, which we have traditionally had concerns about. I think that that - that these are, in a certain sense, separable from the complicity issue, because complicity itself does not depend on the gravity of the evil. It depends on the way in which one's will is aligned or not aligned with the act. PROF. SANDEL: So would you agree with Leon that there is no moral complicity in availing yourself of the organs from the freezer created in the prison camp? PROF. MEILAENDER: I agree that you wouldn't be complicit in the technical sense. You might still have reasons why you wish to distinguish that, the use of those organs from the first case. And there would be powerful reasons why one might prefer to die than to get those organs in transplant, but I wouldn't say that someone who took them or used them was complicit in the moral evil. PROF. SANDEL: And would you go so far as to say that federal funding should be devoted to the use of these organs? PROF. MEILAENDER: I can't even imagine how to think that through at the moment. I mean, it's too far a stretch for me to figure that out, because Mary Ann is right, once again, that there would be a whole range of things I'd need to think about. PROF. SANDEL: But it's not such a stretch because that's morally analogous to the federal funding of pre-existing stem cell lines. PROF. MEILAENDER: No, I think it's not. I think that what we have to give thought to is what these other factors were, how much emphasis we wanted to place upon them. DR. KRAUTHAMMER: If I could make a point here. If the President's policy had been not that we would only accept lines pre-existing on August the 9th, but we would accept in the future lines derived only from IVF, only from IVF for reproduction, only with informed consent, and with no commerce involved, then those three conditions would make sense. What's hard to understand is, if the policy was one of saying that will not happen in the future because that would be aiding and abetting otherwise, but the policy will be that only pre. existing lines can be used, it is hard to understand why these conditions are attached. Let's assume that there was a clinic, and there are clinics that create embryos for IVF purely for research, and one of those had developed a line, not for reproduction, before August the 9th. Why would we then want to say that that line ought to be prohibited? CHAIRMAN KASS: Bill, and then Jim Wilson. DR. HURLBUT: When I looked at this, when I read this, my thought was . and this goes to your question and to Charles' comment . my thought was that all the criteria on page 6 could again surface if a different President took over say five years from now, and said well, now I'm going to issue the same statement, because in the meantime, there was no federal funding. There are more cell lines created independent of federal funding, and so forth. All three could theoretically meet the same criterion as the original cell lines. Well, when I saw the President make his statement on August 9th, something struck me at the time, which I think maybe is the answer to this question. And that was, it seemed to me that he was adding something else into the equation, not just that these cell lines were created under the conditions that did not have the three objections, but that there was one other thing; and that was, that they were created in a climate of a certain moral ambiguity and innocence, if you will. And that it was before there was broad public debate, and that it was a very difficult subject, and difficult issue. And that up to now, these were made, but now it's time to say we need to take seriously this issue, not the three before, which were clear moral principles, but this new issue of what do we do with these IVF spares and so forth. That was the - it seems to me that that's why in five years from now another President can't turn around and say well, now I'm going to let another five years worth of - and keep the same position as the current President. Does that make sense? CHAIRMAN KASS: Jim Wilson. PROF. WILSON: I'm not sure whether Michael's concern is with the wording of the language here with the substance of the problem he poses. The substance of the problem, it seems to me, is easily managed. If we find in a recently occupied prison camp organs that have been extracted by clearly inappropriate, even torturous means, and we discover in the same prison camp a young girl whose life is in danger because her liver has been destroyed, we transplant one of those discovered livers into the girl, provided it is medically suitable. And we're not complicit in anything, especially since we're going to go about punishing as severely as we can the doctors and other barbarians who engaged in these illegal extractions. So the substance of the problem doesn't raise, for me, the word complicity at all. The interesting question is about the text. And it has nothing to do with whether we are going to use federal funding or not for prison guards to extract livers in American prisons from unwilling persons. It's whether the President, this President or some other President, is going to say the existing cell lines are running out. We need more. We don't have enough. We're not sure of the paternity of some of these, or maternity of some of these cells and, therefore, should people donate more cells. So I'm trying to clarify which of these two issues are you really talking about? Could I get Michael to just to give a brief answer? CHAIRMAN KASS: Yeah. It's a question to Michael. Please respond. PROF. SANDEL: All right. Well, just as a brief response, I think we're talking about whether the worry about complicity makes sense if you assume that — o go to the organ case from the prison — does the following position make sense? You find all these available organs in the prison that were extracted by evil means. You say we can use them without being morally complicit. We can even use federal funding to use them, provided we resolve that no federal funding will be used for organ extraction in the future. And furthermore, that it won't be legally prohibited for people to extract organs in this way in the future, but it will be - they can do it with private funding. But it will be - but there will be no federal funding for any ones that are done that way in the future, only private funding. That's the moral strangeness of the position if you believe that the analogy to the organ transplant is a good one. There's no incoherence — this goes back to the discussion in the first session — there's no incoherence if you reject the analogy to organ extraction. If people aren't being killed, but there's still a morally questionable activity, it's perfectly sensible to say we're not going to give it federal funding. We'll allow the pre-existing lines without complicity. It's morally dubious, but it's not killing people for their organs. So if you put this worry about complicity together with the permission of doing it, provided it's not federally funded, I think it shows that the organ transplant, that killing people for their organs makes no sense. PROF. WILSON: Well, of course, but the assumption is, I thought, was that if we find prison guards who evilly extracted these organs, they would be punished, ideally shot. The question, therefore, is are couples who go to an artificial reproduction center and donate and create fertilized eggs, and some are left over, should they be shot? Well, I don't think anybody has made an argument for them to be shot. So then the question is, what do we do with their leftover eggs? And the question that raises for the President's speech is, obviously, why did we suddenly say that eggs only up until August 9th, 2001 voluntarily donated can be used, but no eggs voluntarily donated after August 9th, 2001 can be used. That, to me, is a puzzle. PROF. SANDEL: Right. Well, I share that puzzle. DR. KRAUTHAMMER: Well, that's the point I tried to make, is that I think by building in those conditions for the pre-existing lines, the President's policy does create sort of a logical problem. Those would be the conditions you would expect if he had annunciated a policy that allowed ongoing use of discarded embryos. In fact, I remember when I listened to that speech, which I must say was the most unusual Presidential speech I've ever heard. I've never heard a Presidential speech in which a President seriously considered both sides of a serious issue. Normally, when you hear a Presidential speech, you know exactly where he's headed on line two. And I don't think anybody who listened knew which way he was going to end up on line two. I didn't even know on line seven. In the middle of that speech, I remember I turned to my son, and I said he's going to allow new lines as long as it's from discarded embryos, and he said no, he's going to make a line at August 9th. Of course, he was 16, and he was right, so I give him credit for that, you know, sort of respect he gave to both sides. But I, personally, would have come down on a position of allowing ongoing use of discarded embryos, and given the conditions he attached, you'd expect that would have been his position. At least logically I think it would have been expected. CHAIRMAN KASS: Bill May, then Elizabeth. DR. MAY: Two comments. One, I have a basic question about what the fundamental purpose of this council is. Is it retrospective, trying to figure out what the mind of the President was on that occasion, or offering a kind of apologia for the President in relationship to his right flank; that is, those who worried about the moral consistency of his accommodation to pre.existent destroyed embryos and stem lines? Or an attempt to offer an apologia in the other direction, hey, it could have been worse. He could have extended a ban to the private arena, you know. But that would all be retrospective debate, and it seems to me the council has an interest retrospective, but its basic interest should be prospective, what kind of advice does this council have to offer the President, which requires one to visit the issue of the merits of the case. Now if we offer this retrospective, then I think we . for the sake of completeness so it doesn't simply look as though we're blessing the President's action in the past . we do have to deal with the prospective issue. That's my first comment. And whether our discussions, both this paper, if it stands alone without discussion of the merits of the case, whether it makes sense for us to issue this paper without revisiting this other issue, which we dealt with at the beginning of the council's deliberations. My second point relates back to this retrospective glance, and the way in which we equip ourselves with moral language. Earlier, Leon talked about right/wrong. The tendency is we're talking there about absolutes not susceptible to compromise, as opposed to areas in which there are competing goods. And there, one is dealing with issues which are susceptible to compromise. As a matter of fact, the word "compromise" has different meanings in those two different areas. In the first area, if it's a clear distinction between right and wrong period, then to compromise is to defect from one's duty, pure and simple, and maybe from one's vocation, as well. In the latter area, we recognize compromise as a striking of some kind of balance and weighing. But as I read this paper, there's a tendency to look back to the Clinton Administration and say well, its reflections were technical, political, and so forth, but in the second case, we're dealing with moral principles. And then the contrast between consideration of moral principles and one's duty, one tends to see everything else as cost benefit analysis, harms, benefits, utilitarianism lurks out there in the wings. My problem is, I am a duty.oriented thinker. I think I am. But one of my duties is to consider harms and benefits, I mean, because I've got a duty to beneficence. I've got a duty to non. maleficence. It's not my only duty. That's where I differ from the utilitarians who weigh and balance all possible rules of the road in the light of what will produce the greatest net balance of good over evil. But I am pluralistic in my understanding of duties. And it isn't the case that I occupy high ground only when my duties are absolute. Because my duties are plural, that doesn't mean I'm a relativist. It does mean, however, I am caught in circumstances where I may need to strike off a policy line and so forth, that recognizes a duty, a principle, reaches a territorial limit when it comes up against another principle, which in the particular case is more overriding, and that solution isn't merely in terms of weighing harms and benefits. And furthermore, even when I reach a decision, which may have tragic dimensions to it, (a) I will have further duties of reparation; (b) the duty that yields to another duty, even under those circumstances, may maintain some pressures upon me, and how I pursue the particular line of duty that I face. So I've offered two comments here, one is what is the basic agenda purpose of this council. And second, whether we have too readily assumed on the one hand are those who are duty.oriented in their thinking, principle.oriented, and those duties do not admit of any exception as opposed to those who are merely awash in the sea of the relative, and all the precariousness of cost benefit analysis. CHAIRMAN KASS: Does someone want to join this comment directly? Dan, Elizabeth. PROF. BLACKBURN: We've had examples of extreme situations where we've talked about organs taken from prisoners and prisoners being killed, but we do have a very, you know, on the ground example which is very widespread in society, so we give a multitude of pediatric vaccines to the population in general. And we shouldn't forget the fact that a large fraction of those were based on fetal cells. That's where they came from, and so we have made that decision in this case where I think the issue that you raised of relative potential goods, you know, has been weighed, and the decision has been made very clearly. That's just a historical fact that we've done that. CHAIRMAN KASS: I have Paul. Robby, are you still on the list? No. Gil, and then myself. DR. FOSTER: I just wanted to follow.up on one thing that I think Bill was talking about. One - we've been talking about five a great deal. I'm sort of nervous about trying to interpret what is the soul of Presidents, and so forth. I remember early. on in this council, I used to say to Leon, before we became really good friends, I'd say well, what you think is this when we were arguing the whole cloning thing, and he would always respond, "You don't know what I really think." He never explained it to me what he really thought, but he said - Leon, won't remember that. And what I'm saying is, if we do such a paper as this, and also hear about the future, I think that under paragraph 3, it would be much more helpful to, instead of personalizing this to President Clinton or to President Bush, to simply say that this is what - in the Clinton Administration, this is what happened, without making a judgment about what his moral thoughts are on here. I mean, how do we know what his moral thoughts are, or President Bush's, for that matter. So I would certainly want to depersonalize this. It puts it like it's a conflict between a previous President and the sitting President, and that's not what we're here to talk about at all. And along the same lines, I do think that when we say that the majority of people want to do this, or a significant portion want to do that, I think there ought to be at least a footnote or something to give some sense of what the, you know, polls or percentages show. But I certainly would like to depersonalize this. It makes me very nervous to have somebody try to say what I'm thinking, and so forth. CHAIRMAN KASS: Paul. DR. McHUGH: I think this goes a little along the lines that both Bill and Michael, and Charles were saying, because I also don't want to say what's in the President's mind. But I can tell you what's in my mind, especially after listening to the President, and also contributing to this council. I thought that the President did an important thing at the time of his speech in August; namely, by enhancing a moral position, and bringing some moral distance to recognizing what had previously been a more casual approach to the embryonic life, human embryos, and wanted to call our attention to the fact that maybe we had been much too casual about our thinking about that. I also, though, felt as a doctor, and as a person interested in conditions that might respond to stem cells, that he did an important - made an important addition to the science by saying here are some stem cells, and now the ball is in your court, scientists, to show us that this is an important tool for the treatment of, the success of some aspect of the developing human science that we could use. We are not going to go farther along this road until something much more compelling comes from you scientists. Okay? Now although I have views about what might or might not ultimately lead to a further development like Jim was mentioning, I thought that this was a coherent and practical policy in relationship to where Americans were in this complicated matter. He showed us that there was moral significance in the embryo, and he said to the scientists that claimed there should be total license in what they were doing. Here you can do something and prove to us that you need more. And ultimately, that's why I ask at this council again and again when people come in and say they object to the limits that President Bush put onto the use of these cells, I ask them always well, have you exhausted the cell lines that are now available to the point where you have a compelling case that there should be more? I think when the American people come to that decision in relationship to real data and real experience, we will face another moral problem, I agree, but a problem that will be a more matured problem and, in fact, a problem that we scientists can look at and speak about from data. CHAIRMAN KASS: I have Gil, myself, and then Michael. PROF. MEILAENDER: Two comments. One, in terms of what our task is, whether prospectively or retrospectively, I think our charge is to monitor the stem cell research that's going on, that has begun in light of the President's policy announced in 2001. And I would interpret that literally. In other words, we're supposed to monitor and report on what, in fact, is being done. We may have different views about whether that's enough that's being done, or too much being done, or just the right amount, or whatever, but it seems to me our task it to monitor that, and so we should keep that in mind. The second is, the thing that I think is good about this Staff Paper is that it does show a way in which, again rightly or wrongly . I'm not worried about that right now . there is a certain kind of moral foundation built into that policy announced in 2001. And the paper captures it nicely. The general question is, well, will these cell lines be enough? I mean, that's the way the question is always formulated. It was formulated immediately, in fact, after the announcement of the policy. And the one thing that's clear in all the complications of the complicity argument, is that a complicity argument will only work if the answer to that question is well, I guess they'll have to be enough. In other words, if it's a shifting line, then you can't, in fact, make the complicity argument work. The complicity argument depends on doing nothing to encourage future. And as say, whether that's a good policy or bad policy is a separate question, but I think the document nicely captures what, in fact, is the essence of the policy. It will not work as an argument about moral complicity, or avoiding such complicity unless the answer is well, it will have to be enough. CHAIRMAN KASS: Does someone want to piggyback quickly on what - because it looked like people were leaping to say something to Gil, and I'll yield. Michael, did you - DR. GAZZANIGA: To Paul's point, I think we have to step back a little bit and keep in mind how science works. And for every dollar invested, you get about a 1 percent return on a successful piece of science, so the compelling logic that you suggest there in come on scientists, it's your turn, is a little bit misleading in the sense that 1 percent of 12 lines finally hitting the ground here isn't much. And you're really asking the scientists with their hands tied behind their back, you're giving them a couple of test tubes, one centrifuge for the whole nation. You know, it's just not of the scale that any scientific community would go after a problem. And that's what everybody is complaining about, and that's the underlying issue here. It's not of the scale to find things out in an efficient and intelligent way. That's the issue. DR. McHUGH: By the way, Michael, I know that, but because this becomes an issue of much more intense moral concerns, I think the scientists are going to have to work with a little sand in their saddlebags and should stop complaining about it. CHAIRMAN KASS: Let me try to respond to some of the things that have been very nicely said by several people. Let me start with Bill May's, which is sort probably a meta.question about what we're doing here. This document is hardly a report, and would be simply the . after an introduction, an opening chapter. And there are criticisms properly made already about what's stated in here, both about personalization, any suggestion that only one side has moral principles will be eliminated, if there's any hint at that. That wasn't the issue. And indeed, for my money, the most important contribution that one could make here is to have - never mind how this policy differs from the previous administration. It's terribly important if you're trying to discuss - if you're trying to monitor activities that are taking place under the current policy, you should be fairly clear what the current policy is, and on what its foundations are. Because if you mean to try to propose some changes in the policy, you ought to be able to see what kind of arguments and what kind of evidence might be relevant to seeing that that policy is changed, so that's the first point. I mean, to be sure, this is - and it's not meant to be an apologia, but it's meant to be an explication. And I have read countless things, countless statements about what this policy is or what it rests on, which are simply wrong, simply wrong. And we have an obligation, I think, as part of laying out of what's going on in this field to try to do the best we can as a preamble to our monitoring, to say under what aegis is this activity now taking place, and how do we understand it. That would be the first point. And I think I've partly given an answer to your second point about moral versus merely prudential or calculative. We will adjust, I think, the way this is presented. Next, let's see. I think the next comment, I think, should go to - let me leapfrog the comments that are directed to Michael to come to Paul's remark. Paul's formulation of this, and also echoed in part by Jim Wilson, is to say look, we've got a wait and see policy here. Let the scientists go and do their work, come back to us in two years, five years, ten years, and we'll rethink this. Now that's a sensible way to think about this if, in fact, the policy rests upon a kind of cost benefit analysis of the weight of the research as over against something else. But it matters a great deal, I think, whether the policy is right or not is another matter, but it matters a great deal if it's really the case that the policy has been based upon a foundation such that empirical evidence on the ground of the state of the research could change it. That's your wish, and I think is probably Jim Wilson's wish, but I'm not sure that it's a correct understanding of the foundation of the policy, and that matters. I mean, that is probably implicit in what Gil said. Now let me try to say something with respect to articulated moral foundations of the policy, and whether or not the complicity argument works. Let me, for the moment, bracket those possibly embarrassing, but I think Mary Ann may well have taken care of additional given reasons for maybe, maybe. But Jim Wilson seems to be bothered by the fact that this arbitrary deadline of the 9th of August, if something is wrong after the 9th of August, then it was wrong before the 9th of August. But that, I think, can be really explained entirely on the complicity argument. It's not that you've been complicit in the previous act, but if you say we will continue to fund research on lines derived after this date, we are, in effect, rewarding the subsequent activity. We are participating in it. We are in a way declaring that we will take advantage of the results of previous destruction, without being complicit. We didn't cooperate in it in the first place. We will not reward this activity in the future. And, therefore, we are providing any encouragement. And by the way, we're saying we don't believe federal funds should be spent on this at all, period. We affirm the language of the Dickey Amendment. DR. KRAUTHAMMER: In what way are we encouraging if you continued to use discarded embryos after August 9th? CHAIRMAN KASS: With federal funds? DR. KRAUTHAMMER: Yes, there's no commerce involved. I mean, assuming - CHAIRMAN KASS: You're, in effect, saying that people can continue to do so with the expectation that once the deed is done, the lines are available for research. DR. KRAUTHAMMER: Right, but what's the encouragement? I mean, you go to IVF to have a child. You sometimes end up with discarded embryos. CHAIRMAN KASS: Fine. DR. KRAUTHAMMER: What's the connection to the research in terms of encouragement? CHAIRMAN KASS: You would be offering financial reward after the fact to those who would be deriving new cell lines. DR. KRAUTHAMMER: That's my question. I was assuming there would be no - we're assuming there's no commerce here. If there were, you could simply say that we ban the commerce, without banning the use. CHAIRMAN KASS: You are rewarding the researchers who will be doing the research on those lines and, therefore, you'll be, in a way, countenancing the future act. That, I think, is clear. DR. KRAUTHAMMER: But my question was about encouragement of the "original sin". You can dispute whether it is. I'm not - I mean, the argument that if you were to permit the use of discarded embryos created after August 9th, you'd be encouraging - creation of discarded embryos is a tenuous one, and I'm trying to pursue how that encouragement works, if there's no - if they're donated and there's no commerce. PROF. MEILAENDER: You're encouraging not their creation, but their destruction. DR. KRAUTHAMMER: But they're going to end up being destroyed anyway, whether - PROF. MEILAENDER: Maybe, maybe not. DR. KRAUTHAMMER: Maybe they end up in freezers eternally. PROF. MEILAENDER: There's no good solution, I understand that. DR. KRAUTHAMMER: No, but I still have a trouble with - DR. FOSTER: Gil, entropy - there's no doubt that ultimately nothing lives forever in freezers or anything. There's no doubt that those embryos are going to be gone, absolutely no doubt. Entropy does not disappear because one objects to the fact that . . CHAIRMAN KASS: The issue is not about - it's not just about the destruction. It's - the operative issue is may federal funds be used on research in which embryos are destroyed or damaged? That's the language of the Dickey Amendment. If you say in the future, federal funds may be used for the products of embryo, for research on the products of embryo destruction, are you not, in advance of that fact, saying you will reward the results of that act with research funds? PROF. WILSON: No. I mean, we're struggling once again to redefine the special, but not conclusive respect that is owed to an embryo. If we believe that an embryo at the fifth or tenth day of its existence deserves the same respect as a eight and a half month old fetus, or a newborn child, then the answer is that President Bush should not have allowed any research at any time, using any kind of money. If we think the nascent human life in a five or ten day old blastosphere is meaningless, then they should use federal money to encourage people to produce them at random, and pay women to do it. The position we have, I think many of us have tried to take, is that blastospheres - embryos created as a result of in vitro fertilization, left aside because they're not needed, headed ultimately to destruction, as Dan correctly says, are a continuing opportunity to possibly solve important human lives, provided these blastospheres are not kept alive for more than a certain number of days in their active stage. That's what we're trying to do by way of defining special respect as an intermediate position. And, therefore, I don't follow your argument. CHAIRMAN KASS: Rebecca, can you help? I'll try one more time if Rebecca doesn't solve this for me. PROF. DRESSER: Okay. I'm sure you'll get another chance. This is the same argument that was played out with fetal tissue transplant research. The whole concern was by making federal funds available for research, will this create a new incentive for abortion, so that there might be some women on the fence who might say well, since I have this option available that has some positive dimensions, maybe I'll go ahead and terminate the pregnancy. So the way it eventually got worked out was, they set up a procedure where enough people were comfortable that the decisions would be separated. That is, you couldn't raise the issue of donation for research until after the woman had made the decision to go ahead and have the abortion. So here, I guess the question would be, are there individuals who go through IVF and they are deciding they've had a child or two, and they're deciding okay, well, here we have all these extra embryos. Perhaps there would be people who might say if the donation for research option is available, well, okay, let's do that, because some good could come of this. Whereas, if that option is not available, at least the federal funds are not supporting that option, then they might be more likely to say well, maybe we'll try to have another child, or maybe we'll give them to another couple to try to allow them to have a child. So I guess that would be the way that there would be some sort of incentive created for destruction if federal funds, whereas, it wouldn't be there without them. DR. KRAUTHAMMER: I understand the train of logic. I just - I think the universe of people who would be affected by that logic is rather small. CHAIRMAN KASS: Are you disputing that the formulation of a decision that - are you disputing the formulation of the moral foundations of this policy as articulated? Never mind whether it's a good one or not, are you - DR. KRAUTHAMMER: Disputing the? CHAIRMAN KASS: The description of - that this was a question, given that these lines exist, given that the law prohibits federal funding for the creation of those lines, isn't the question that remains, especially when lots of one's supporters are saying this research shouldn't be funded, because if you fund it you're, in fact, complicit in the dirty deed. Isn't the question that remains whether one could support research on the lines that exist, though the destruction has taken place, and I believe in the President's speech he alluded to the fact that those - that the embryos from which these lines came are already gone. Isn't the question then, can one support research on these existing lines without, number one, being in some way complicit in the deed that created them? And (b), can one not by saying no funding for any new lines, is one not asserting the kind of principle and removing any kind of reward for researchers would derive them subsequently. I take it that's the way to make - whether you like it or not, I think it's a way to make morally consistent coherence out of exactly what was done. DR. KRAUTHAMMER: I think that was the intention of the final policy. I'm not sure that the logic, the Point B that you raised really holds up to scrutiny. CHAIRMAN KASS: Why not? DR. KRAUTHAMMER: Because I don't think it's very realistic to think that if you were to use discarded embryos from IVF clinics on an ongoing basis, you are encouraging the creation of those embryos. And, therefore, if - the prohibition on that seems to me to be illogical, given the original position. And I think the point that Michael made, that in the original policy where they built.in those conditions for discarded embryos from lines created before August 9th, those conditions don't make a lot of sense because, as he argued I think with the analogy of the prisoners, however you would have derived earlier lines from anything, since we were clearly not complicit, having those restrictions does not make a lot of sense. It seems to me those restrictions, no commerce, consent, and embryos created for the purpose of reproduction, those conditions logically apply to embryos, to stem cell lines derived from embryos produced after August 9th. CHAIRMAN KASS: It seems to me Bill Hurlbut gave - between Mary Ann and Bill Hurlbut, I think they've given a perfectly adequate answer; namely, those lines that existed prior to that date would have been - in fact, those kind of conditions would probably - the text of the guidelines produced by the Tilghman Committee would probably support this. Those particular criteria would have been operative for permission - conditions attached to the lines available for funding previously. DR. KRAUTHAMMER: Let's assume that we discovered that one of our 12 lines came from an embryo created in a clinic where the parents were not given informed consent, or were paid . would we destroy those lines tomorrow? CHAIRMAN KASS: Would we destroy them, or would you - DR. KRAUTHAMMER: Would we not use them? CHAIRMAN KASS: Would you render them ineligible for funding? DR. KRAUTHAMMER: Of course. And the answer would be no, so what I'm arguing is, those pre.conditions are not logical. CHAIRMAN KASS: Does someone want to join? PROF. MEILAENDER: Let me try to join, because I - my problem is I'm incoherent. And that is the whole purpose of a growing moral experience, to make yourself steadily more coherent over time. And what I appreciated about the President's position, I really notice the same concerns that Michael and Charles are raising. On the other hand, I felt that if the President had said we couldn't use any cells, and human stem cell research was - embryonic stem cell research was outlawed, that this message would be an inappropriate stopping of our moral development. And even though I'm against embryonic research, by the way, I am against that, I feel that over time if the scientists have an opportunity to do their work, that they can show these benefits to us in some ways, and then we might be able to get stem cells in a way that would not offend me and my views about future embryonic research. And that would be a moral progression along with a scientific progression, and that's why I support this idea. And why I don't go quite along with you, Leon, when you say that if I take this view, that ultimately I'm going to say well, eventually I'm going to want to do that research but start killing off those embryos. No. I want to be able to say here are some stem cells, here are available stem cells, here's what we can do with them. And then we have to find a way to get similar stem cells in less morally obnoxious fashion. CHAIRMAN KASS: We are close to the end. Michael Sandel, anyone else in the queue? Janet. Michael first, and then Janet. PROF. SANDEL: Bringing the two sessions, what we've been trying to do, as I understand it, is to identify or draw out the moral logic of the position that the President took. What would be the best way of making moral sense of a position that prohibits federal funding on new stem cell lines, but does not ban embryonic stem cell research done privately. And that even extends federal funding to pre-existing ones. What assumptions make moral sense of that position? And the argument has been that it's not possible to make moral sense of that position, if you assume that embryonic stem cell research is infanticide, is like yanking organs from infants. It's not possible to assume that because in that case, there would not be a good reason not to ban the practice, short of civil war. It also doesn't make sense of the restrictions, the much discussed restrictions on the pre-existing lines, because if complicity isn't a problem with the - if complicity with infanticide or prison extracted organs, if that's not a problem, then it certainly - then dealing with consent or financial inducement is not necessary. And so the best way of making sense of the position is on the assumption that the status of the embryo is in the category of the intermediate view, that we've much discussed here. CHAIRMAN KASS: Or in doubt, right? PROF. SANDEL: Either in doubt, or the intermediate view. And the other part of the discussion has been taking that assumption as the best way of making sense of the position. Either it's in doubt, or the intermediate view, some version of the intermediate view is correct. And then trying to apply that assumption in ways that Paul did, and that Charles and Jim did, to suggest the practical implications for future federal funding beyond what's already been embodied in the policy. And so it makes perfect sense of the position construed in this way, which I think is the most charitable way of making - to say as Paul did well, maybe the reason for the restriction now in the federal funding to the pre-existing is to say to the scientists the ball is in your court. Show us what you can do, and then come back to us. That makes sense on the intermediate view, or in the view of doubt, because it says look, the embryo is not to be toyed with for nothing. It's not to be used wantonly. But if you can show really significant and morally compelling, and scientifically promising things can be done well, then given the intermediate view, or the view of - the agnostic view, then we may revise the policy in the light of what you can show us. So Paul's extending the underlying principle in that direction, and Charles is suggesting an extension in another direction. If what underlies this policy is some version of the intermediate view, then that would give reason to consider the use now of leftover spares from IVF clinics, if the intermediate view is the one that's underlying this policy anyhow. Now, of course, you would reject Charles' position, if you reject the intermediate view, but the whole discussion today, going back to Peter's paper, shows that this policy itself only makes sense if you accept the intermediate view, and so it's open to the kind of question that Charles and Jim, and Paul have raised. CHAIRMAN KASS: I think there are . and they'll speak for themselves, I'm sure . not everybody shares your conclusion that the conversation has shown that last point. Various people have suggested that they're either settled practices, or they're questions of prudence as to what you can try to do when. And if you're suggesting that the authors of the Dickey Amendment are somehow being morally inconsistent, while at the same time insist on an absolute ban of all embryo research, that doesn't necessarily follow as a matter of consistency. You seem to suggest that people of principle have to be fanatics in order to prove that they're men of principle, and that if they don't sort of push for the whole hog, you sort of suspect the grounds of their judgment. It seems to me that we live in a complicated society where sometimes people of profound principle will, just as people who might favor this research, might be willing to cede publicly that their fellow citizens who oppose it on deep moral grounds have enough standing to say that the regime ought not to officially pronounce its blessings on it. So it seems to me that in these kinds of matters where there is settled practice, and the embryos are in the freezers, and people are donating and the research is going forward, that Members of Congress, either as a matter of respect or as a matter of the sense that they cannot now muster the will to stop this, muster the support to stop this, would settle for this matter. I don't think the conclusion that you draw from the existing arrangements implies what you say it implies, but - PROF. SANDEL: May I quickly, I'm not suggesting that there's any - I don't think that people are fanatic to insist on their principles. I think that people who both oppose federal funding of abortion and who also argue for banning abortion are not fanatic, they're principled. And it's a position that makes perfect sense against - given a certain view of when human life begins. There's nothing fanatic about that, any more than there's anything fanatic about abolitionism. PROF. MEILAENDER: But there's also nothing unprincipled about not pushing dogmatically forward to get everything that one might think best at any given moment. PROF. SANDEL: It depends what's at stake here. If murder is at stake, if infanticide is at stake, and that's what you believe, then you would push forward. PROF. MEILAENDER: That is not - PROF. SANDEL: If you believe it's short of infanticide, then there would be good reasons for not pushing forward, and I think that's what the President very reasonably has done. PROF. MEILAENDER: That's not necessarily true. I mean, I don't know who the "you" is in that sentence. It may be that that's what you would do but, you know, to construe the argument as having gone in a certain way is mistaken. Not everyone thinks that holding certain positions means that they - that you must, in a sort of a dogmatic spirit, push for the whole of them at any given time. You may have reasons, both moral and prudential, for stopping at certain places. CHAIRMAN KASS: Janet, you've been patient. I'll give you the last word. DR. ROWLEY: Well, I'm not sure that I'm going to have necessarily the last word, but I would like to make two points. One does follow on from the discussion that we've been having, and it does relate to the way the paper, or some of the tone of this particular draft. I think it is important as one looks at some of the statements, that when one talks about the embryo being inviolable, you know, this should be modified because, as has been pointed out by a number of the participants, that may be an inappropriate word to use in the context of this report. My major concern is that the report stops short of discussing the consequences of these decisions. And it's okay for Paul to say well, scientists have to put up or shut up. I think Michael's point was well.taken, that to put up requires money. Now the report indicates this is not a problem, you just do it privately, so you don't need federal funds, though there are some federal funds available. But I think that at the present time, the amount of federal funding of research, and we'll find out from Dr. Zerhouni fairly soon, is fairly minor as compared with what really needs to be done in this particular area. And I'm not sure whether, in fact, this Staff Working Paper will be followed on by a second paper that does deal with the consequences of this policy, or else the consequences of this policy need to be included within this to make it a - put it in, I think, a more appropriate or - that's the wrong word - a more complete perspective. CHAIRMAN KASS: Thank you. We are at 12:30. We will have
Dr. Zerhouni, and then Dr. McClellan in the session from 2 to 3:30.
Both of these men are taking time out from very busy schedules to
join us, so let's be sure to start promptly at 2:00. (Whereupon, the proceedings in the above-entitled matter went
off the record at 12:32 p.m.) SESSION 3: STEM CELLS: MOVING RESEARCH FROM THE BENCH TOWARD THE BEDSIDE: THE ROLE OF NIH AND FDA CHAIRMAN KASS: I think we should get started, notwithstanding the fact that a few of our members are delinquent. We'll just keep them after school. This session is entitled "Stem Cells - Moving Research from the Bench Toward the Bedside: The Role of the NIH," and then in the second of this session, the FDA. This afternoon we move from the principles of the stem cell policy to its implementation with a review of the contributions of NIH and the FDA to efforts aimed at bringing research from the bench toward the bedside. Administering government funding of stem cell research is largely the task of the National Institutes of Health where, as we heard from Dr. Baldwin over a year ago, vigorous efforts have been made from the very beginning to make cell lines available to characterize their properties to support research, training, and infrastructure. Today we are very pleased, and greatly honored, to have with us the Director of the NIH, Dr. Elias Zerhouni, who has kindly agreed to give us a progress report on the developing field of stem cell research as it looks from the strategic center of federal support and direction. Dr. Zerhouni will make a presentation after which we will have discussion. He has to leave sharply at 3:00. Dr. Zerhouni, we are in your debt for taking the time to give us the benefit of your observations and insights. Thank you very much. DR. ZERHOUNI: Thank you, Dr. Kass, and members of the Council. It's a pleasure for me to be here and to share with you what NIH is doing in promoting the field of embryonic stem cell research in particular, and stem cell research in general. What I'd like to do is really give you an overview of what has happened since the implementation of President Bush's policy on August 9, 2001, at NIH, how NIH is tackling the field of stem cell research, what we are seeing as the major priorities and challenges that we need to overcome as we speak. I will not spend too much time on the promise of stem cell research. I think this Council knows all of the implications of cultured pluripotent stem cells and the challenges that are needed - that need to be met to transform these cells in differentiated elements that can serve in overcoming loss of function and help regenerating lost function. You know also the hierarchy of stem cells that go from totipotent to pluripotent to multipotent stem cells. To this point, we've never demonstrated a return from a pluripotent to a totipotent stem cell, but there is one paper that indicates that that may be happening in mouse stem cells. And we will talk about that a little bit; we'll touch upon it. But clearly, there are two known ways currently to make pluripotent stem cells. One is obviously using the inner cell mass, and one is using germ cells. This method was promoted by Dr. Gearhart at Johns Hopkins and Dr. Jamie Thomson at Wisconsin. So when you then ask yourself, what is so unique about human embryonic stem cells, clearly two properties come to mind - the fact that they have an unlimited capacity for self-renewal and culture, and that potentially they can differentiate into any adult cell type under the right conditions. From the standpoint of NIH, as in any field of research that begins to be funded at the federal level, there is an approach that needs to be followed in the sense that research is done by people with resources, with strategies. And in the area of stem cell research, as soon as I became director, I convened groups of scientists at NIH, and we tried to define what the milestones should be and what the pathways should be for this area of research to grow as rapidly as possible to fulfill its promise. And when we look at that, there are several phases that need to be understood, and this is the underlying strategy that supports our activities at this point. One, clearly, is you need to build scientific capacity. Remember that prior to the President's decision there was no federal funding for this kind of research, and, therefore, the scientific capacity in the country was likely to be underdeveloped. So the number one priority was to create career development pathways, training courses, and, more importantly, establish the infrastructure needed to do the research. Then, when you look at the field itself, there is a need to prove the long-term stability of the cells, characterize them very fully at the molecular level, and understand both theirgenetic stability and their stability in the host, understanding the differentiation, the growth factors, the gene regulation - all of the events that control that specialization. End cell cycle control - obviously, these cells are pluripotent, and one of the safety fears that everyone has is that they would divide uncontrollably in the host. So we need to understand that mechanism. And, obviously, since we're talking about regaining lost function in a host, we need to understand cell host interactions. To do so, one of the first actions that I took as NIH Director was to create a stem cell task force at NIH. Prior to my arrival, I think NIH had put together the beginnings of an implementation policy. But I thought that given the challenge and given the wide-ranging spectrum of activities that the agency needed to get into, I thought it was very important to elevate this activity at the level of the director and to have a specific task force, including both intramural and extramural researchers, to look at what were the most important roadblocks to overcome, the most important avenues of research to stimulate quickly, and where was the - where were the pressure points, if you will, where we needed to intervene to accelerate the field. Well, obviously, the task force divided itself into working groups, as you can see. And, no surprise, career pathways, resources, the peer review, since obviously NIH is based on peer review and we needed to have a cadre of competent reviewers. And in a new field it's always a challenge. Tools and technologies, and obviously the ability for us to reach out to the research community throughout the country. This stem cell task force has members who are both active in the field or have knowledge in the field of developmental biology and cell cultures and other fields and are advising the director through the task force, which is chaired by Dr. Jim Battey. As we looked at the challenges, it was quite obvious that the immediate challenge for NIH and the human ES cell research community was first to generate and characterize the distribution quality human ES cell lines from the NIH. It's very important to understand what "distribution quality" means. It is not - a cell line being available is not enough. A cell line having been derived is not enough. It needs to be characterized, it needs to be quality controlled, it needs to be expended, and it needs to be immediately available to the research laboratories that need it. The second was the need to stimulate more research on basic biology, and the third was the training of investigators. In the basic tools of the field, first and foremost, before the use of stem cells and the approach of hypothesis-driven research, we needed to have a cadre of confident and competent investigators in the field. So those were the action lines that started pretty much last year, a little bit over a year ago. Now, when you look at the issue of lines, I know that the public always tries to understand why is it that the President's policy talks of 78 lines, and we talk about 12 lines that are available. And there is always a little bit of confusion, so let me, if you don't mind, give you the steps that are needed to go from a derivation to a fully available line. And I think that semantics sometimes get in the way. But fundamentally, as you know, derivations occur when you are collecting the inner cell line - cell mass, and you're developing your primary colonies. And then, through subcultures, about 1,000 cells per well, you then expend these cell lines with about a 10 percent survival rate. So as we know today, these cell cultures are not as efficient or effective as we would like them to be. Then, you have to basically then multiply these lines through multiple passages. Well, obviously, because these cells have the potential differentiation, you need - at each passage you need to characterize through molecular marker studies and assure yourself that these have remained stem cell lines. So one flask grows up to 100,000 cells, and one bank that would be capable of fulfilling distribution needs requires at least two billion cells. That takes about nine months to a year. So, and when you distribute these cells, depending on the distributor, there are about two million cells needed per vial, and that means ready for distribution. So when people look at this, they forget that on August 9, 2001, there were 64, 78 lines, whatever the number of qualified lines was at the exact time. We end up qualifying 78 sources, but to make those sources expended and characterized to the point where you need - you have lines available — takes about 12 months. So when you look at the schedule, what we have accomplished is about — last year there was one line that was widely available, and today there are 12. And that's the reason between the 78 versus 12 numbers that you hear around. There are other lines that are being expended as we speak. There are agreements that are being signed. One has to remember that these lines do not belong to the Federal Government; they belong to their own derivers, and, therefore, are subject to intellectual property agreements, which sometimes are easy to negotiate and sometimes are not so easy to negotiate. But I think our role was to increase as quickly as possible the number of widely available lines that the researchers could have access to to do the research. So the way we did this was by rapidly awarding to organizations with entries on the NIH-eligible cell line registry, funds to develop those lines into distribution quality cell lines, and that's the difference between eligible and distribution quality. We gave them a two-year period of support. We granted eight awards for a total of over $6 million, and we have about 12 lines now ready for shipment, meaning in my criterion for that, which I insisted be the criterion which is listed on the website, is you can pick up the phone and get the line delivered to you within a measurable matter of days. So the program announcement will be reissued, because we have now other sources of lines that are interested as they have learned more about the expendability of the lines, interested in making their lines commercially available. In addition to that, I think there are many sources of lines that have reserved derivations for further expansion as we learn more in the research. So those are the infrastructure awards that accomplish that. Then, NIH has two means, really, of supporting research. One is obviously training; the second is to fund investigator-initiated research, which can be either spontaneously generated or can be stimulated by NIH. And the way NIH stimulates research is by issuing program announcements or requests for applications around areas of research that are either aligned with the mission of the Institute that issues these RFAs and PAs, or are general announcements that the entire NIH wants to support. So one of the program announcements we made was to have grantees develop short-term courses in human embryonic stem cell culture techniques. We use the T15 mechanism, and it's supported by 11 NIH institutes. And basically, we have been able to award four of these. These are courses that can take up to two or three weeks at certain centers, and investigators can send their own core investigators or personnel to these centers. And these have been extremely well received by the research community. We have also career development awards, career enhancement awards for stem cell research specifically issued by several institutions, which allow an investigator to spend up to 24 months with $50,000 of direct cost exploring the field of embryonic stem cell research as well as have training in the uses of stem cells. And then, requests for applications are directed towards areas of scientific priorities that the NIH feels need to be stimulated. So we have stimulated multi-investigator teams. We have infrastructure, growth and maintenance, research into biochemical/molecular markers, and so on. And we are trying now to establish exploratory center grants that will lead to, then, formal centers that will have for a primary mission the development of the applications and the basic science of human embryonic stem cells. Then, obviously, as you can imagine, there is a tremendous amount of interest in rapid application in particular disease areas. So institutes now have also issued very specific RFAs in avenues of research that are deemed to be potentially fruitful in the short term. So innovative concepts and approaches to developing functional tissues and organs from NHLBI, plasticity of human stem cells in the nervous system, and you can obviously imagine what these applications area - recovery of cardiac function, the recovery of neural function, recovery of endocrine function in the case of diabetes, and obviously basic and applied stem cell for arthritis and musculoskeletal disease. The Institute feels that this is a high priority area, given the fact that musculoskeletal disease and arthritis is emerging as the number one cause of disability in an aging population. And then, development and repair of orofacial structures. I will just go quickly now in terms of some of the more fundamental research - for example, NIDDK is promoting comprehensive programs in beta cell biology, again a diabetic target. And then, obviously looking at the genome anatomy of the hematopoietic stem cells, given the genomic techniques that are available to us, and so on. So I don't want to take too much of your time on details, but this is the strategy that we have implemented. In addition, we have also stimulated intramural research. When this field started, you could basically identify one or two labs at NIH intramural that had an interest and lead in embryonic stem cell research. Dr. Ron McKay, through mouse embryonic stem cells, was probably the most prominent. Today we have nine laboratories in NIH working aggressively and publishing in these areas. We have a much expanded interest as cell line availability becomes more straightforward. So we knew that that was a roadblock that needed to be overcome before anything else could happen, and that's what we worked on. In addition, through the identification of roadblocks by the stem cell task force, one of the things that became very obvious for us, for all of us in the field, was that unless we had a formal way of characterizing and identifying the characteristics of each cell line, it would be very difficult to compare experiments from lab A to lab B to lab C. And when we surveyed the field and we surveyed the level of knowledge needed for characterization cell markers, molecular characteristics, and so on, we realized that there wasn't a worldwide agreement, nor was there a U.S. consensus about how to really make sure that you're dealing with a stem cell, and how do you know that over a period of time, and how do you compare line A versus line B. So we decided to establish an intramural research program dedicated to the characterization of stem cell lines. We think that this is an important investment, because it will give us for the first time the ability to call a stem cell a stem cell in the real scientific sense of the way - of the word. So, in summary, what I think you can see between 2002 and 2003 is that we have built the infrastructure, we have accepted investigator-initiated awards, we had 21 applications in '02. Now remember, in NIH parlance FY2002 goes from October 1, 2001, which was a month after the announcement of the policy to September 30, 2002, and 27 applications in '03. We have awarded 25. We have also awarded 66 administrative supplements. These are scientists who have already accumulated the knowledge base to work with stem cells, either in adult stem cells or mouse embryonic stem cells, and we issued a rapid series of supplemental grants to allow them to work with human embryonic stem cells. So we have 66 additional grantees, or groups anyway, that are able to use human stem cells. We also had a research symposium in June that showcased both the research conducted and supported by NIH, but integrated this with the GM cell symposium that occurred here in Washington on June 10th and 11th, to look at the entire field and try to understand where the field was at the time. On the research horizon, I think what came out of those meetings is that the priorities today are the following. One is to define, standardize, human ES cell culture conditions that obviate the need for either mouse or human feeder cells. This is a priority. We already have grants from investigators that have been funded. We have several reports from groups that have been funded by NIH looking at the characteristics of, what is it that gives a mouse feeder cell the ability to grow human embryonic stem cells? What's so special about that versus human feeder cells versus feeder-free cells? And there have been recent papers that indicate that you could - once you understand the molecular drivers of that growth, you can probably foresee the ability for us to develop, soon I hope, culture conditions that will obviate the need for any feeder cells. Then, the second is you can hear many - you can hear through the scientific community those enabling tools and technologies to further characterize stem cells as they become specialized cells are needed. And that goes from specialized antibodies to identify very specific markers of multiple different lineages. But it's also a - there is also a requirement from the scientific community to understand what the genetic events - what the gene expression patterns are between a multipotent stem cell and the one that becomes, let's say, a muscle cell or a blood cell. And that is an area of very, very important research that is ongoing, and there have been several papers published trying to identify which genes are really turned on or off as you go from the stem state to a non-stem state. And that essentially defines the point number three, which is understanding the molecular pathways that specify differentiation into these different specialized cells. And then, obviously, we're not talking about cells just in culture. They have to survive and function within the host, so that many, many researchers are now focusing their attention on the critical factors and conditions that drive the long-term survival of these cells in the host. And then, obviously, the one question that requires resolution before any human clinical trials are even envisioned is the assurance that we need - and I lwill let my colleague Dr. Mark McClellan talk about it - to make sure that we can control cell division and prevent the development of a malignancy or untoward complication. Now, as we speak about this, you will hear that human feeder layers are a very important step, and the research already alluded to this. And the point here is that until recently all human embryonic stem cells were grown on mouse feeder layers. And new conditions are being established using human feeder layers. We know from the Johns Hopkins group there was a recent paper from the Technion Institute in Israel about developing matrix-like substances that grow - that can grow without human feeder cells, these human embryonic stem cells. There was a publication - not a publication, but at least an announcement from the Singapore company that you could do that. There are at least unpublished reports of multiple groups having worked and working on developing these lines. Now, this is presented often as a sine qua non of further research. I'm sure that Dr. McClellan will address the issue of how you go about qualifying any cell lines that are grown or not grown on animal or human feeder cells. Now, but that is still in our mind an issue that requires work, requires development. It will be much more desirable for us to have understood the culture conditions without having the variability associated with either mouse or human feeder cells, even though that - from the conclusions from FDA and many others — indicate that it is not a complete obstacle to clinical trials. But in my mind, it's much more desirable not to have that factor come into play at all if we can avoid it. But it seems to be doable, and the research is ongoing. Now, just quickly some important research results. The group at the University of Wisconsin has been able to report on homologous recombination in stem cells. For those of you who are not familiar with that, it's the ability to essentially introduce genetic material that will modify the genetic makeup of the cell, and so that you can control - experimentally anyway - some of the characteristics of these cells. That is an important step, we think, in the field. In terms of application, you have heard about the work from Dr. Ron McKay primarily, showing a method that can drive the differentiation towards dopamine-secreting neurons using these in an animal model and demonstrating, in fact, recovery of function in a model of Parkinson's disease - very, very promising avenues of research here. Then, one of the key areas of research, as I indicated before, was to identify the key genes, the master genes that control the state of stemness that we need to understand in terms of being able to maintain cell cultures in the state that we wish them to be in over the long- term. And this is a very important advance in the sense that we are identifying now new genes. One is nanog - after the mythological Celtic land of eternal youth - which basically maintains the self-renewing properties of mouse embryonic stem cells, and he has expressed these as inner cell mass. You couple that with other research ongoing in human embryonic stem cells - Dr. Rowe at the NIH, Dr. Goldman, I think, is doing similar research - where gene array studies of these cells are coding down on a subset of genes which seem to be essential to the stemness state. So we are very hopeful that within a short period of time we will be able to at least identify some of the key master genes that are really at play in this type of cells. Then, you see advances in terms of not just looking at the stem cell state, but looking at a differentiated state and understanding the pathway going from stem to a specific type of cell, with multiple papers indicating recipes at this point. They are not well understood. But clearly, researchers are able to show that through multiple approaches they can lead a cell to become, for example, a myocyte that beats, just like a cardiac cell would, an endothelial cell or a neuron with very specific functional measurements. This is the most exciting part, if you will, of the research, because it indicates that there is really proof of concept occurring in multiple subsystems from the same kind of cells that are being worked on. Duke University found that you can, in fact, grow a progenitor - from progenitor cells myocytes. The group in Israel also has shown that they can differentiate human embryonic stem cells into beating myocytes. Clearly, both in adult stem cells and human embryonic stem cells you see early results that seem to indicate that cardiac function recovery can happen with stem cell therapeutic approaches. That's very interesting. Obviously, NIH supports research on many types of stem cells. I'm focusing my comments on human embryonic stem cells, obviously. But as you know, adult stem cells have been funded for many, many years, particularly in the field of cancer and hematology malignancies. Just to give you a sense of the relationship, in FY2002, our investment in human adult stem cell was over $170 million. In FY2002, which is the very first year of stem cell research on embryonic human stem cells, our total investment was about $10 million. This year's investment is probably going to be $17-, $18-, $20 million in the human embryonic stem cell research, and will be about the same number, maybe $180 million, in adult stem cell research. This is not counting animal stem cell research on mouse embryonic stem cells or other types of stem cells. So as you can see, the investment is growing. But, again, we hope for advances in all fields of stem cell research. We think that given the very early nature of our knowledge, our understanding, and the limited nature of our understanding, it is important to promote both areas of research, we think, at this point as aggressively as we can. You know about the multipotent adult progenitor cells that Dr. Verfaillie has developed. It shows capabilities for self-renewal and differentiation to many specialized cells. I don't want to take too much time, but we can see glial stem cells that can produce neurons in culture - very interesting paper from Nunez. And satellite cells in muscle that have been identified as adult stem cells that can divide in response to injury. And, clearly, some early results that indicate that we can turn on these cells, particularly in patients with muscle-wasting diseases. At NIH recently there were stem cells identified in baby teeth that have also quite a bit of potential. So, clearly, a lot of things are happening. You can see also bone marrow stem cells that are redifferentiated towards neural stem cells. There are a lot of questions on the mechanisms by which these occur. Some people feel that fusion might be the reason, rather than just the stem redirection. So we'll see about that as we go forward. And we're providing also a large amount of information to the research community on our websites. I have material here that I could give you also - I don't know if I'm okay on time - comments about the stem cell sources and what is really happening in terms of stem cell sources in the world right now, to just give the Council an idea of how these things really develop and what happens in terms of research groups using them. So this is the paper that I wanted to mention. By the way, before I go into that area, there's a paper from Hubner in Science using mouse embryonic stem cells. They were able to generate what appeared to be oocyte-like cells in vitro. This is the very first paper on an animal system that seemed to indicate that you can revert from the pluripotent state to the totipotent state. It is not confirmed at this point. We don't really know that the - what they look at and define as structures resembling blastocysts in the petri dish are really blastocysts, whether they have the potential or not. If these experiments can be repeated in human embryonic stem cells, there will be important implications for the creation of new cell lines, generation of tissue, and so on. So this is a paper that I think the Council should pay attention to, because it is quite surprising actually to see these events in these oocyte-like - in these culture conditions. So in terms of cell sources, the first one that was available was the H1 line from Wisconsin. It has about 300 vials in inventory. It has shipped already about 105 orders. About 78 of these were in U.S. institutions, and the rest was overseas. And then, the cell characteristics are quite well defined, and these cells seem to - these are the most healthy it looks like, from the point of view of passages. These cells are in passage 22 and are available immediately. So this is a very healthy colony that seems to grow to the right number with a limited number of passages. H7 is another line. They have just made this one available. Obviously, it's now commercially available, has slightly different characteristics. And H9 has - there are about 10 orders that have been fulfilled with H9. These have all been made available in the past four or five months, so it's not ? and, again, 10 orders have been filled in. The major other source is BresaGen from Athens, Georgia. It has two lines available. These lines also have interesting characteristics. You can see they have shipped eight total lines - five in the U.S., one to the U.K., Israel, and Australia. In the world of research in stem cells, the countries that were just mentioned seem to be the most active, because there is a heterogeneity in the policies of the different countries as you well know. From ES Cell International, there are five lines available, and there were about 33 international shipments and 16 U.S. shipments from this Australian source. We have a source in Korea. It has one line. There were 20 shipments made, 17 to Korea, and three to the U.S., all of which were sent to the NIH for the purpose of that - of characterization of the lines. UCSF has now one line commercially available and has 60 vials in inventory, has shipped 19 - 15 to the U.S. and four to foreign sources. And I guess those are the reports I wanted to give you. And I'd be happy to take questions, Dr. Kass. CHAIRMAN KASS: Thank you very, very much, for a thorough, illuminating presentation. Let me remind the Council that Dr. Zerhouni has a 3:00 departure. Let's try to keep the questions brief, and no speeches. The floor is open. Janet Rowley. DR. ROWLEY: Well, I certainly speak, I'm sure, for the rest of the Council. We very much appreciate your taking the time to come and update us on the current status, and certainly the plans - the present implementation and the plans for the future I think are ones that many of us would applaud. I have a series of questions. One of the first is for the cell lines not established on feeder layers, this implies that there will be new ES cell lines developed. And so the question is, these would then not fall within President Bush's August 9th cutoff date. And I guess, is that really so? DR. ZERHOUNI: No. Actually, we did an inventory just prior to a hearing to just make sure that we had all our facts together. There were several sources - in other words, institutions or companies - that had derived cell lines already by August 9th. They have not exposed all of their lines to human - to mouse feeder cell lines. And, in particular, we have specific information on the lines in Sweden - Gutenberg and the Karolinska - whereby the - as you saw in the process, there is a process of - where between derivation and exposure to mouse feeder cell lines you can freeze the lines and keep them. So there are at least those, which is about 16 lines, I believe, that have not been exposed to either mouse or human cell - human feeder cell lines. And the reason given to us by the investigator is very simple. They thought that the field was not mature enough, and the understanding of the culture conditions was not there. So I think what they're doing is they are basically doing experiments on non-approved U.S. cell lines, non-approved by - for federal funding, and they have reported, for example, experiments where they are trying to use methods that will require neither human or mouse feeder cell lines. And they stated very clearly that once they master those techniques, they will then apply them to the federally fundable cell lines. DR. ROWLEY: Okay. The next question is: what kind of restrictions on intellectual property are attached to the lines? For example, those from the University of Wisconsin, because I understood that there were certain very important restrictions. And I know also that NIH was trying to get some of those modified, and I wondered what the current status was. DR. ZERHOUNI: Right. Basically, the restrictions are, one, the recipients cannot implant the provider cells in the uterus, mix the cells with an intact embryo, or attempt to make a whole embryo. The recipients and recipient institutions are free to publish their research results as they wish. The providers retain ownership of the original material. So WiCell retains ownership of the original materials and any unmodified derivatives. However, the recipient institutions own any new materials and inventions its researchers create. DR. ROWLEY: Okay. DR. ZERHOUNI: Those are the agreements that NIH negotiated with WiCell, and made those agreements transferrable to NIH-funded investigators. The provider of the cells can request a sample of any new materials for internal research users. So WiCell could request samples from the university to develop something new for their own research, and is free to use that for its own internal programs - any newly patented invention. So WiCell essentially is saying that if somebody discovers something, they can use that for their own needs internally. Other restrictions - basically, the main restriction is that WiCell, for example, granted any PHS-funded nonprofit investigators the right to use its patented technology, and granted a royalty-free non-commercial research license to PHS-funded researchers as long - and this is the real important statement - as long as the agreements with such third parties were no more onerous than those in the WiCell agreement. And WiCell specifically excludes sponsored research where the research sponsor gives commercial rights to a third party. In other words, let's say, you know, Dr. Foster receives cells at UT Southwestern, and then using those cells and whatever discovery he or she makes, goes to a third party and conveys commercial rights without WiCell being - having its right respected. So those are the interesting issues I think that govern that. DR. ROWLEY: Can I ask you just one more question, which there is - in Britain, the MRC is trying to develop a cell bank, and I just - presumably, it would be parallel with the cell bank that's being developed at NIH. And is there any collaboration or coordination of efforts? DR. ZERHOUNI: Okay. Let's be careful. NIH is not developing a cell bank. It's developing a cell characterization unit. In other words, we will develop the reagents, we will have the lines that we will compare, and we will do a full catalog of all of the characteristics that researchers tell us are very important. Make the reagents available, make the antibodies available. We're not going to be distributors of cell lines as we speak. The British model is a little different. They have a commission, obviously, that approves or disapproves requests, and all lines developed under that policy have to be deposited in the cell bank. To my knowledge, to this - I think last week there was an announcement that the first line had been successfully derived. And, therefore, those derivers have the obligation to deposit that in the British bank for wider distribution. So they're assuming, if you will, the infrastructure role that we granted to the sources here, they're assuming it within the cell bank. Any collaborations we communicate constantly. The most important areas of collaboration, from my standpoint, are we need to understand the characteristics of cell lines. We need to exchange information. We need to have a more formal way of understanding what the field is doing worldwide. And those are the things that we're doing with the MRC and others. DR. ROWLEY: Thank you. CHAIRMAN KASS: Michael Gazzaniga. DR. GAZZANIGA: I just think it's important to get the scale down here. So in terms of current embryonic stem cell research, the investment at NIH is .1 percent of your budget. It's extremely small. Would you - what would be your guess that - should more cell lines be made available through a change in the current policy? How fast do you think that would scale up to be more in line with adult stem cell vessels? DR. ZERHOUNI: I don't think the limiting factor is the cell lines. I really don't. I really think the limiting factor is human capital and trained human capital that can quickly evaluate a wide range of research avenues in stem cells. So I am not of the opinion that the number of stem cells - you can see the shipments, how many have been requested, and there are many more available. So I think it's more important to stimulate the field at the human capital level in my mind, and it will take - as you know, it takes time. You have to have fellowships. You have to have centers. You have to have young post-docs that really get involved in the field and have new publications and ideas and grants of their own for that to grow. It's not something you can, you know, drive top-down, I don't think. DR. ROWLEY: And just in that vein, your slides showed that there were three post-doctoral fellowships awarded in FY02, and out of four applicants. So this highlights, I think, the problem of human capital. DR. ZERHOUNI: I think you're right. But we see a lot of is in the applications that are granted, R01 types or program, what you see is that post-docs tend to be funded through those grants directly, without going through a fellowship route. But I think you're making a good point, and we want to stimulate that. CHAIRMAN KASS: Bill Hurlbut. DR. HURLBUT: I want to clarify something. The 16 cell lines - I think that's what you said that were not grown on mouse feeder cells - are those part of the original 70 designations? DR. ZERHOUNI: That's correct. I don't know if it's 16 or 12. I mean, I can give you the exact information, but it's about that number. DR. HURLBUT: These were essentially disaggregated and then frozen. DR. ZERHOUNI: Right. DR. HURLBUT: Doesn't it stand to reason that given the months preceding this policy there might be thousands of such disaggregated embryos out there? DR. ZERHOUNI: Do you mean between August - prior to August 1 - August 2001? DR. HURLBUT: Everybody saw it coming, right? DR. ZERHOUNI: I'm sorry? DR. HURLBUT: Everybody saw it coming, that there might be such a policy that would say, "No further derivations." Isn't it possible that there are quite a few cell lines out there? DR. ZERHOUNI: I wasn't at NIH at the time. But I can tell you that the NIH staff that worked on that truly canvassed the world and made sure that whatever lines there was documentation, there was informed consent, there are some - so it may be that there are lines out there that have been derived before August 9th, but they may not fit all of the other characteristics - informed consent, no inducement, and so on. I don't know the answer to your question, but I don't think there are thousands out there that were waiting for the policy to come out. DR. HURLBUT: I shouldn't have said thousands. It was a hyperbole. But let me ask you two other specific questions. As you characterize these cells and understand the molecular signals, and so forth, obviously the hope is that you can derive them without creating embryos somehow back - pull them down or something. Is there any special program that NIH is looking at in an effort to bypass the moral problem? And would it be reasonable to fund such a specialized effort? DR. ZERHOUNI: I thought you were the program to do that here. (Laughter.) I think Dr. Kass is in charge of that program. (Laughter.) No. I don't think there is a particular program that scientifically could look at the moral or ethical issues. There is no question that we have in every one of our human subjects and animal subjects a - you know, a very strong moral and ethical review based on institutional review boards or the - you know, the typical ethical considerations that you attach to research. But I think this one is not something that NIH is looking into, feeling, and I said that in jest, but I think it's serious. I think all of the institutions that have looked at this issue would be the National Academy of Sciences, the Institute of Medicine. The administration feels that this is a debate that really needs to happen in forums like this one. I don't know if I'm answering your question. DR. HURLBUT: Well, I didn't really mean debate it. I mean, I think everybody agrees if you could de-differentiate an adult cell down to an ES cell, a pluripotent cell, without making it totipotent, that you would have a moral solution to the derivation of ES cells. And I just wondered if there's - if the science might be ripe for a special program to seek those avenues and what you might call morally derived ES cells. DR. ZERHOUNI: Well, that's the adult stem cell program in some ways. That's what Dr. Verfaillie is trying to do by using adult stem cells. And then, going back in history and trying to de-differentiate them, that's really the - now that I understand your question, I mean, that is the hope of those investigators. Cord blood was another source that is used that does not have the same moral connotation as human embryonic stem cells derived from embryos. So yes, actually, if that's - I'm sorry. I didn't quite understand your question. But absolutely, there are - as you can see, there is a tremendous amount of activity in adult stem cells and understanding the differentiation pathways. CHAIRMAN KASS: I have a couple of questions as well. In part, you give the impression that we're still at a very early stage in the road from the bench to the bedside. And you've indicated at least some of the obstacles that - some of the steps that would have to be taken and some of the obstacles in the way. One of the things that you didn't speak about was research addressed to the immunoprotection problem. And I wonder whether there are special efforts in that area with respect to stem cell research. And, second, notwithstanding the fact that we seem to be at a very, very early stage in this research, you do indicate that there is some work going on to look for fairly immediate clinical payoffs, say in the area of cardiac disease. I wasn't absolutely clear that that was with human ES cell - with cells derived from human sources or not. But how do you square the sense that on the one hand we are at a very, very early stage, and on the other hand the field might be ripe already for certain kinds of clinical trials. What message should we take away on that particular point? DR. ZERHOUNI: I think I may not have - I may not have been clear, but what I refer to as "host cell interactions" imply immunological responses. We need to understand those. We need to clearly make sure that either the transplant is not destroyed, nor is the transplant left to grow in an uncontrolled fashion. So I didn't mean to ignore those issues. They are there, and they need to be addressed. Now, science, as you can imagine, advances by leaps and bounds, and investigators have passion and sometimes believe there is a shortcut or not a shortcut. So that the two areas of research that I think are driven to applications are those that, through what I call, you know, recipes or lucky strikes or understanding of pathways, whatever it is, try to find an application, a path to application, in a proof of concept fashion, usually in animal systems. And that's really what researchers tend to do. In other words, you try to build from the solid ground you're at, and then you go out and build an island, and then you fill in the blanks. The fill in the blanks are still in the basic region that I described. Even if you showed today that there was a recovery of cardiac function through some pathway, you still will have to do the demonstration that you understand the host cell interaction, you understand immune response, you understand all of the safety considerations, and so on. So I don't mean - in my view, they are not incompatible with each other. At least the characterizations I gave are very compatible. What happens typically in biomedical research, you have multiple avenues, and that's the strength I think is to let people demonstrate that. Your question about, is it in humans - adult stem cells have been reported to have been used in humans in Italy, in Brazil, from bone marrow sources. So adult sources that have then been implanted in the heart, it is not clear, really, that it is the implantation of those adult stem cells that has accomplished the result. We've had embryonic stem cells injected in rat hearts that have been infarcted that showed recovery. But those are proof of concept experiments. CHAIRMAN KASS: Thank you. Bill May. DR. MAY: At one point you talked about arcing back from pluripotent to totipotent. Is a reversal from pluripotent to totipotent in effect the creation of a new cell line? DR. ZERHOUNI: That's a very, very difficult question for me to answer, because there's one experiment that showed that, at least on the surface in a mouse model, that you had structures that seemed to form not only a totipotent cell but an oocyte-like structure. So that - a blastocyst-like structure. So the question is: are you creating a new cell line, or are you creating a new organism - is not clear in that. But this is a very early area of research at this point. DR. MAY: It does bear on the August 11th cutoff date I guess, doesn't it? DR. ZERHOUNI: It could. CHAIRMAN KASS: Michael, and then Janet. DR. GAZZANIGA: Just a followup, because I think your point on the human capital is important. Sort of in the labs in various biomedical institutions, there's an unwillingness on the part of many young investigators to go into this field because of the uncertainty of its political scientific status. And so there's an interaction here where if it was clear that this program is going to move forward, it was clear that there are going to be more lines developed, because certainly more lines are going to be needed for a variety of biomedical issues, that the human capital aspect of it might be solved very quickly. Certainly, that is what happens in all other fields which are not constrained by the sort of - these sort of political moral issues. But if there's a new technique, gene expression work - as you know, overnight it remade the field, the DNA chips, and so forth. So if it was clear what the policy would be in the future, wouldn't your guess be that the human capital part would be solved rather quickly? DR. ZERHOUNI: Again, that's a question that goes from a premise that there is an issue. Clearly, when you look at the increase in publications and names on publications, you see a lot of new entrants. I wasn't at the first meeting at NIH two years ago about these issues, but the symposium that we had in June, 600 people all supported in some fashion or another. How you compare that to another field, I don't know. The other anecdotal piece of information is I visited a few sites, and they don't report a dearth of post-doc candidates for their programs. Once they're established, you see - if you go to Jamie Thomson, he has a tremendous amount of required - or demand for trainees to come into his program as post-docs. And so once you have an established program, it seems like you are able to attract people. If you go to an institution where there's no leader, no established program - I knew from my experience at Hopkins, John Gearhart, he had his pick. I mean, he could choose whoever wanted to come. So I think it's the program that drives the young investigators to enter the field - program with funding, with available resources. Is the fact that cell lines are under the policy a driver of going and not going into the field? I don't have the answer to that. But obviously, since this is an issue of federal funding, private funding is also available, an avenue that is not prohibited, as you know. And the biotech industry - there was a recent report that shows that there is still quite a bit of activity in the biotech - and growing activity in the biotech industry for stem cell research. So I'm not sure that from the standpoint of human capital that there is a monofactor here that you can identify, saying, "Well, this will prevent for sure the growth of human capital." I can't answer that question in the affirmative. CHAIRMAN KASS: Last question before we let Dr. Zerhouni go. Jim Wilson. PROF. WILSON: Do you have any estimate - it would have to be crude, I assume - as to how much money private sources are putting into stem cell research? DR. ZERHOUNI: Actually, there's a paper that was published just recently, and I can give you a copy of it. And this is not an NIH study, but I understand that there is spending of $200 million per year in stem cell research, embryonic stem cell research, and 1,000 FTEs, full-time equivalents doing research worldwide. About 60 percent of those are in the United States, about 15 in Europe, and 27 percent in the rest of the world, primarily Australia, Singapore, Korea, Japan. I have that reference if you want it. PROF. WILSON: Thank you. CHAIRMAN KASS: Actually, if you can take one more, Janet had been on the list - if you'll make it brief. DR. ROWLEY: I just want to make a question and a comment. The comment is actually related to Kay Hubner's paper in Science, and I think that it is important to recognize that this is work that was done in the mouse. And we've had a great deal of difficulty in terms of translating success in the mouse and other animals into humans, so this is going to take some time. The question is you mentioned that there is a program at NIH now for characterizing these cells, and I wondered what institute it was housed in. DR. ZERHOUNI: The Institute - NINDS, neurological diseases, under - actually, it's associated with Ron McKay's laboratory, because we feel he has the best expertise in that area. DR. ROWLEY: Thank you. CHAIRMAN KASS: Dr. Zerhouni, thank you very, very much for a wonderful presentation and very frank discussion. We really appreciate your presence. Thank you. (Applause.) CHAIRMAN KASS: As we learned from Dr. Zerhouni, we are at a relatively early stage in our journey from basic stem cell research to therapeutic benefits. And as one looks ahead down this road, we see in advance the important role that the FDA is going to play in verifying the efficacy and the safety of any eventual stem-based - stem cell based therapies. In recent months, the FDA issued its guidance regarding xenotransplantation, the introduction into human beings of materials of animal origin or derived from materials having contact with animal tissues. Almost immediately, there were press reports, many of them grossly off the mark, about what this guidance might mean for the possibility of future clinical trials using material derived from the Presidential cell lines. To help us separate fact from fiction, and, more importantly, to help us understand how the oversight and regulatory activities of the FDA might eventually figure in the area of stem cell based therapies, we're very fortunate to have with us Dr. Mark McClellan, who is the Commissioner of the Food and Drug Administration. Dr. McClellan, many thanks to you for taking the time to help us understand this important aspect of the road that we are on that will take us from the bench to the bedside. Welcome. DR. McCLELLAN: Thank you, Dr. Kass. And all of you on this distinguished Council, thank you for inviting me here today to discuss the role of the FDA in helping to make new safe and effective xenotransplantation treatments available, including potentially valuable stem cell treatments. FDA's job is to protect and advance the public health, and one of our primary responsibilities involves helping safe and effective products reach patients and consumers quickly. Our Center for Biologics Evaluation and Research, which I'm sure many of you are familiar with - goes by the acronym CBER - has the lead in FDA for regulating xenotransplantation, including emerging cellular therapies. FDA regulates cellular therapies under broad authority from the Public Health Service Act and the Federal Food, Drug, and Cosmetic Act. Under this authority, FDA has taken many steps to foster the development of safe and effective stem cell therapies, while assuring appropriate protections for human subjects involved in the research. As you know, xenotransplantation is a set of procedures that includes the transplantation or implantation into a person of live cells from non-human animal sources, including human cells that have had ex vivo contact with live non-human animal cells or tissues. And as you just heard from Dr. Zerhouni, recent evidence suggests that transplantation of cells and tissues may one day provide many important therapeutic benefits for diseases such as neurodegenerative disorders, diabetes, many other conditions involving organ dysfunctions and cellular dysfunctions. Because the potential health benefits may be considerable, it's appropriate that there are many clinical research and development studies going on now to better characterize the risk and benefits of these potentially important treatments. Xenotransplantation products, under the Food, Drug, and Cosmetic Act are treated in accordance with our statutory provisions governing premarket development. And so they are subject to FDA review and approval. Investigators of such products should obtain FDA review of proposed xenotransplantation clinical trials before proceeding. In addition to providing necessary assurances of protection for human research subjects, FDA takes many steps in its regulatory oversight to help researchers and product developers avoid mistakes and translate good research ideas into safe and effective treatments as efficiently as possible. And in an area as complex and with as many practical uncertainties as stem cell research, this regulatory guidance can be extremely helpful for obtaining the most public health benefit from basic science insights. For example, applied research conducted at CBER has been instrumental in improving our understanding of safety issues associated with xenotransplantation. CBER is engaged in a range of scientific investigation of safety issues, including on known and emerging infectious agents, immunological issues, transfer and differentiation issues, and others that will need to be overcome for the safe and effective use of xenotransplantation products. The results of these studies have helped CBER in its safety assessment, including assessment of risk and the development of better diagnostic methods and standards to assess risks. CBER researchers are continuing to develop assays appropriate for safety monitoring and are working with sponsors and collaborating with other government scientists in the development of these assays. In addition, to improve our regulatory policies related to xenotransplantation, CBER working groups are analyzing data and events and developing and proposing strategies for appropriate studies, for risk assessment, for prevention, for communication, and agency response or regulatory action, such as requests for more data from sponsors or for particular product assays and the course of clinical investigation, or, when necessary, the placement of clinical holds on clinical investigations. We discuss all of these proposals and strategies with our advisory committees when needed or at public meetings as appropriate to make sure we've got full opportunities for public comment on the most effective way to regulate these important but complex new areas of medical technology. CBER has also developed a mechanism for the systematic and regular evaluation of the scientific and clinical literature relevant to xenotransplantation as well as careful scientific evaluation of the submissions that we get in our xenotransplantation product files. If you put all of that together, that not only the research studies but what we see in terms of the studies, the details of the studies that are ongoing now, not just the published studies but the ongoing work, this amounts to the most extensive data available on the practical application of stem cell technologies. We have a xenotransplantation product review or working group, which consists of the review staff responsible for the review of xenotransplantation submissions, the clinical product and pharmacology and toxicology reviewers, as well as our veterinary staff. They all meet regularly to discuss application of the principles that are in our relevant regulations and guidances to review and discuss current scientific and medical data and literature relevant to xenotransplantation, to review and discuss the current status of xenotransplantation applications that are before the agency, to discuss, the unique issues that these products may present and to highlight areas of concern where further expert advice and solicitation of public opinion, and outside expertise may be needed. This working group structure gives us an approach - gives us a consistent and up-to-date review approach for xenotransplantation applications, and it helps us recognize patterns or trends or common problems that may be associated with xenotransplantation products, and, again, a highly - a new and high emerging research area. And it should be communicated to xenotransplantation product developers and other interested parties in a timely way. Our data evaluation and management process is linked to this regulatory process, and it's applied during regulatory decisionmaking and product and policy design at the agency. We have augmented our own experience with cell therapies by sponsoring and participating in a large number of open public meeting and workshops, both domestic and international, that focus in whole or in part on cellular therapies. These activities are essential for both sharing information and receiving public input on relevant issues. To make sure that our insights and our assistance reach those involved in planning stem cell trials effectively, FDA has also been proactive in educational partnerships, workshops, and guidance development. And this work collectively includes discussing preclinical pharmacology and toxicology studies, and good clinical practices, and product characterization studies - all difficult issues that need to be addressed effectively in these emerging sciences. All of this work is intended to support our goal of helping clinical research and development of stem cell therapies proceed as efficiently as possible. And our extensive experience with cell therapy clinical trials, and the processes for obtaining effective outside expertise, has helped a wide variety of clinical studies involving xenotransplantation of stem cells proceed with public confidence about safety and without avoidable costs or complications for the subjects involved. With respect to the details of our oversight of clinical xenotransplantation studies, as in other areas, FDA allows INDs - investigational new drug applications - for these trials to proceed as long as they don't pose unreasonable risks to the human subjects. Reflecting both the flexibility of our risk-based regulatory framework and the energy of this important new research area, well over 1,000 separate INDs for all forms of cell therapies have been implemented over the past decade. Hundreds of subjects, hundreds of human subjects, have received experimental products comprised of animal cells or human cells that have had contact with animal cells since the early 1990s under FDA oversight. Hundreds of additional human subjects have been treated with a human skin cell product called Epicell that was grown on mouse feeder cell layers. FDA discussed this Epicell product at a public advisory meeting in January 2000, and we agreed with the advisory committee's conclusion that the safety data concerning the use of the well characterized mouse feeder cells in this case was sufficient to allow clinical trials to proceed generally. And that is, the lesson here is that when murine cells can be characterized as in this Epicell product, then as a general regulatory matter there is no overarching need for monitoring and surveillance with respect to this particular safety concern. FDA is continuing to support the development of safe and effective cellular therapies, and we work directly with sponsors to help ensure that all promising therapies can be clinically evaluated in an ethically sound, scientifically rigorous, and efficient manner. The agency evaluates each individual product on its own merits. FDA's regulations, our guidances, and our policies, provide useful information on safety and product development issues to help sponsors interested in development of cellular products. CBER's regulatory guidance and regulations are continuing to evolve, and this is appropriate to ensure that the continued advancement of a very dynamic and growing field is matched by continuing advancement in our regulatory guidances to support it. The hundreds of patients that have been treated in clinical trials in which non-human animal cells have been implanted or infused directly, or in which human cells that have had ex vivo contact with animal cells have been administered, have been treated using protocols that meet FDA safety standards. For Phase I or early clinical trials, the most important aspect of safety is the demonstration of the products not contaminated with adventitious infectious agents, including viruses, bacteria, fungi, and so forth. This safety criterion needs to be met, and it has been met by most FDA-regulated products, including biological products, before they can be used in the clinic. For all cellular products, including human cells, non-human cells, animal cells, or human cells that have been exposed to such cells, which often can't be tested for sterility prior to administration because they can't always be stored, FDA has pursued a flexible approach that does not compromise patient safety. In particular, FDA has allowed sponsors to administer the cells based on the results of interim, in-process, bacterial and fungal sterility testing in which the absence of infectious agents is demonstrated. The sponsors then perform sterility tests on the final product, though results are frequently not available until after the products have been administered. A positive sterility test on the final product is quite rare if the interim tests have been negative. But if the result is positive on the final test, the results of these sterility tests are used to inform subsequent patient treatment. To address potential viral contaminants, FDA requests that prescreening of components that could introduce viral infections occur. For example, before using porcine tests in humans, sponsors have been asked to demonstrate that the pig tissue that they use doesn't produce infectious porcine endogenous retrovirus. In the case of Epicell that I mentioned a few minutes ago, the manufacturer was able to use standard techniques to show that the transmission of murine viruses to the co-cultured human cells shouldn't be a problem. As a safety net, the recipients of animal cells or human cells exposed to non-human animal cells are monitored for unexpected infectious diseases. When human cells are transferred from one human to other humans, whether or not animal cells enter the equation, FDA asks that the human cells, and, if possible, the donors of those cells be thoroughly tested for known viruses. So we've overseen treatment of thousands of patients with human cells or with animal cells, or with human cells that have been exposed to animal cells, in which the transmission of infection has been tightly controlled. Human embryonic stem cells are just one type of living human cells among the many somatic cellular therapies that FDA regulates. Most of the issues that will be involved in the production of human embryonic stem cells for clinical use are shared with these other cell therapies. Of course, there has been a high level of interest, as I've heard in my time here today, in the research involving particular human embryonic stem cell lines that are listed in the NIH registry. Just about all of these cell lines - all of these cell lines have been in ex vivo contact with live, non-human animal cells or tissues. And the exposure of such human cells to animal cells, though, represents only one of a large number of issues to be considered in evaluating the development and use of human embryonic stem cells. Among the many further technical challenges to be addressed are the manufacture and testing of the human embryonic stem cell products, preclinical testing of human embryonic stem cells in animals to show potential clinical benefit as well as potential toxicities, appropriate clinical trial design issues, and appropriate followup of human subjects treated with human embryonic stem cells. And our regulations and our guidance has to address that whole panoply of issues. Recognizing the potential importance of new cellular therapies that may be derived from these cells, FDA extended an invitation to each of the derivers of the NIH registry cell lines to meet and discuss critical issues pertaining to the derivation of these lines to help us assure safety in the clinical studies. We discussed FDA expectations of safety, and we gained insights from the derivers on how they can best meet those expectations. We also gathered information from the derivers of the HES cell lines regarding specific methods of preparation and propagation of the cells to add to our understanding of the manufacturing of these novel cell lines. FDA is in the process of publishing a series of guidance documents through a notice and comment process to assist sponsors and investigators interested in conducting clinical trials in the field of xenotransplantation. These documents are providing reasonably detailed and timely pragmatic guidance to sponsors regarding xenotransplantation product safety and clinical trial development, including specific recommendations for how FDA believes that studies can be conducted efficiently and with adequate safety assurances. The guidances that we published so far include a guidance for industry for human somatic cell therapy and gene therapy published in 1998, a guidance for reviewers on instructions and templates for chemistry, manufacturing, and control of human somatic stem cell investigational therapies, published in the past year. And, in addition, earlier this year we published a new xenotransplantation guidance for industry entitled "Source Animal Product Preclinical and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans." All of these guidances are available online at FDA. We also recently just this past month published a draft guidance for our reviewers to go along with this xenotransplantation guidance for industry. These guidances provide information to sponsors interested in developing products that include animal cells or exposure to animal cells. All of the human stem cell lines, as I mentioned earlier, are subject to this guidance. And the goal here is to provide a comprehensive approach for the regulation of xenotransplantation that efficiently addresses the potential public health and safety issues associated with xenotransplantation, and at the same time to provide guidance to sponsors, manufacturers, and investigators regarding xenotransplantation product safety and how to conduct clinical trial design and monitoring. One of the many issues that's addressed in the guidance is the development of human embryonic stem cells that have had ex vivo contact with mouse cells in clinical trials. In our guidance, we note that this guidance is relevant to all of the stem cell lines, all of the human embryonic stem cell lines that have used mouse feeder cell layers, and so fit into - this fits into the definition of xenotransplantation used in our guidance and in our broader public health service guidances. FDA has had a number of meetings, as I said, with the derivers of these stem cell lines, and what the guidance focuses on is that certain precautions are required to maintain the safe use of any xenotransplantation product. In the case of the existing embryonic stem cell lines, the precautions include appropriate testing of cells in mice if the mouse feeder cell layers continue to be used for adventitious agents. This testing is manageable and is readily available and achievable using current technologies. So our xenotransplantation guidance provides some specific, useful steps that sponsors can and should take to address safety concerns. A sponsor who wishes to investigate a stem cell product derived from existing human embryonic stem cell lines in a clinical trial may need to demonstrate to FDA that the stem cell line is free from infectious agents, including the murine infectious agents. Given the current technologies available as described in the guidance, this should be feasible without undue burden. The same recommendations apply to other xenotransplantation products that contain human cells with a history of co-culture with non-human animal cells. So overall we are very committed at FDA to evaluating each specific product that comes into us on a case-by-case basis. We try to augment this with guidance to make it as straightforward as possible. And this is important, because in a world where most clinical trials and most products that enter clinical development fail to show benefit, each new individual proposed clinical study might still provide a crucial step forward. There are multitudes of patients who have yet to benefit from the biotechnology revolution, and as a public health agency we are committed to making sure that every experimental product to be tested in humans is as safe as possible, with the ultimate goal of getting safe and effective products as quickly as possible. I want to thank you all for listening to me today, giving an overview of FDA's regulatory and guidance activities in this important area of emerging science, and I'd be pleased to answer any questions that you all might have. CHAIRMAN KASS: Thank you very much. Dan Foster, are you on the way to - no, I'm sorry. Let me start and, first of all, thank you, really, for a very comprehensive and helpful account. And I emphasize that because I'm going to ask a sort of flat-footed and dumb couple of questions. If I wanted to say, Dr. McClellan, the take-home lesson, if I wanted to sort of put it in a nutshell, would be xenotransplantation involving stem cells in contact with murine cells, we have experience with that, and we are careful. We know what to do, and it's - while it's something to be paid attention to, it's not an insurmountable obstacle or one that deserves extra special attention. DR. McCLELLAN: We've certainly had experience, successful experience, in thousands of patients in documenting the safety of cells that have been exposed to animal feeder cells, mouse feeder cells, and the like. The other take-home lesson that I think is important is that while this is a very important emerging area of technology, this is a quite complex cellular therapy that presents many new safety issues as well as effectiveness issues that have to be evaluated. And we've got multiple parallel efforts to try to assess and help manage and address the different risks that are involved in stem cell therapy treatments, so that we can hopefully as a result get more rapid development of stem cell therapies that really work, and that can be used widely. But as is the case with all of the biologicals, especially complex new technologies like this, ultimately it's nature that determines whether the products are really going to benefit the needy if we can - and we need to unlock, through a whole - evaluation of a whole host of complex safety and effectiveness issues, whether they can - whether those benefits can be demonstrably given to patients. And we're still very early on in that process. And the mouse feeder cell issues are one area where we have a regulatory process in place to address it, but there are many other safety and effectiveness concerns that remain to be addressed, and that we're working hard to help product developers address effectively. CHAIRMAN KASS: Thank you. And let me just very quickly - am I right in thinking that cells grown on human feeder cell layers would be subjected to - have to be subjected to the same kinds of - DR. McCLELLAN: Yes, they do. They are incorporated in our same xenotransplantation guidance, and they are subject to the same kind of evaluation of potential exposure to adventitious infectious agents. They need to go through the same kind of testing procedures and the like. CHAIRMAN KASS: Thank you. Questions or comments? Dr. GÓomez-Lobo. DR. GÓMEZ-LOBO: This is a question out of total ignorance. I have great confidence in FDA. In fact, I think it's a great institution and - DR. McCLELLAN: I do, too. DR. GÓMEZ-LOBO: Well, I'm glad you do. But here's my question. I'm also convinced that human knowledge is very limited, and you speak with great confidence about identifying bacteria and viruses, etcetera. Could it be the case that at a nano level there might be problems, say, with some of these products that we cannot yet detect? In other words, what I'm thinking about is, what's the next step when we go into, say, gene therapy and that kind of thing? Is FDA going to be able to detect any problems with that? Should we be cautious, or should we just trust FDA and just rush forward? In other words, it's a very general, sort of prudential question that I'm raising. DR. McCLELLAN: Yes, that is a good general question. FDA is not usually accused of making people rush forward, but glad to hear that's - (Laughter.) - the perception in at least some corridors. These are very challenging new technologies, and there's a great scientific concept out there and a great potential. And that's something that generates a lot of media interest, and the like, and holds out a lot of hope. I think, you know, with some reason that we are going to be able to bring new benefits, important new benefits, to many millions of patients that don't have effective treatments available today. But as with so many other areas of emerging technologies, moving from ideas that seem to work well even at the proof of concept stage, to treatments that demonstrably can be shown reliably to be safe and effective in patients is very difficult. And we are early in that process now for these complex biological treatments. I have talked a lot about some of the issues related to transmission of infectious diseases related to feeder cells, because that's gotten a lot of the attention. But you're absolutely right that there are a host of other important safety issues and effectiveness issues that also need to be much better understood before these treatments can be used reliably and confidently by the public to improve the health of the public. And that's what this investigational process is really all about. That's why we have a comprehensive guidance for the INDs involving stem cell therapies and many other types of therapies as well, so that we can conduct those studies in a way that's - that relies on the best-available knowledge as to whether we're presenting patients with unreasonable risk. We can do it in a controlled setting, so that we can learn from the latest studies and add to the state of knowledge that exists from what goes before. And then we can modify our research protocols and guidances and research activities accordingly. But this is a difficult process. You know, a lot of people talk about the fact that it takes over a decade for going from - for something as simple as a small molecule drug, just a simple chemical, from the time that it's first identified and people first suspect that it's going to have a benefit in patients. It can take well over a decade to go from that proof of concept to a product being commercially available to the public. It's a long, complicated process. And these complex biological treatments and cellular therapies are far more complex and have far more potential interactions and consequences that are not well understood than a simple small molecule drug. So this is an ongoing process, a careful one, and I don't think we're rushing headlong into this. But at the same time, I want to make sure that our regulatory staff is apprised of all of the latest science, is working closely with researchers and others involved in product development, to make sure that we're making the most of the available knowledge, both for the sake of the patients that are involved in these clinical studies and for the sake of creating the knowledge base we need to get safe and effective treatments to patients as quickly as possible. CHAIRMAN KASS: Rebecca Dresser. PROF. DRESSER: Thank you very much for your overview. I guess a comment and a question. I do think it's interesting there has been so much in the press about this particular issue as a potential safety issue as I think you've observed, compared to other safety issues that this technology might present such as tumor risk and, you know, the ability to channel the cells into the - DR. McCLELLAN: Pluripotency. PROF. DRESSER: - appropriate tissue, and all of those things. So it seems that in some ways you and your colleagues are being forced to address this issue, at least publicly, with more attention than these other issues. And I'm glad to hear that you're thinking about these other issues. But I guess just to play devil's advocate, isn't there a risk with xenotransplants that there is an undetected animal virus, an undetectable virus we don't even know about, that could be present and transmitted if the cells are grown on animal feeder layer, that wouldn't be a risk if you had, you know, the absence of a feeder layer or a human feeder layer? And so wouldn't it be nice if you could avoid that risk? DR. McCLELLAN: It's certainly possible that there are completely unknown, you know, animal viruses that could potentially be transmitted to humans. We just haven't ever seen them observed, and that's why an important part of our guidances here is followup on the patients who are involved in these studies, so that as we learn more over time we'll be able to identify any problems that might subsequently emerge in the patients that have been brave enough to participate in these early studies, and to make sure that we can let the patients know if there is new technology that becomes available that ought to influence their subsequent treatment. But there are - you know, those kinds of hypotheticals exist in each and every one of these many complicated aspects of stem cell therapy. There are the potential for human cells to harbor completely unknown illnesses that might also be transmitted. It might even be easier to transmit to humans than in animals, and even for cells that are harvested and used in treatment without the use of any kind of feeder layers. There are still a host of other issues, as you identified, that could present important safety concerns. We do have to make our regulatory decisions and allow studies to go forward under uncertainty. You know, these issues are never going to be fully resolved, and I think that the best job we can do is try to make sure we're apprised of all of the latest science, all of the, you know, concerns that might impact on potential risks and benefits for patients involved in the studies, and then do as careful of a job as possible in making sure that the best and latest knowledge is applied as we move forward in this important area of emerging science. CHAIRMAN KASS: Thank you. Permit me one very quick question. You've indicated how your experience with xenotransplantation in other areas gives you some confidence that you might not have received with this aspect of it. Is there any precedent and experience for dealing with the specific kind of risk of teratoma or tumors that are associated with - well, possibly it could be associated with, say, residual, undifferentiated stem cells that might accompany a population that have been differentiated? DR. McCLELLAN: That's certainly something that we're monitoring for here. And some of the - and in many of the earlier human stem cell - I mean, human cellular studies that - or cellular studies more generally, they were differentiated cells involved. And so it raised different kinds of issues than a pluripotent or an undifferentiated stem cell might. It's definitely something that's on people's minds, and we're watching carefully. We don't know of any specific evidence of important problems there yet that we haven't accounted for, but we are monitoring it carefully. I think that's one reason we pay so much attention in these protocols to understanding and tracking the exact conditions under which the cells were derived, because that can potentially have an impact on how they might differentiate and act in - after implantation subsequently. It's just an area where we have to watch closely, because it's not very well understood. CHAIRMAN KASS: Well, Dr. McClellan, thank you very much for being with us, for your presentation, and for your very good work. DR. McCLELLAN: Thank you. CHAIRMAN KASS: We're adjourned for 15 minutes. (Applause.) (Whereupon, the proceedings in the foregoing matter went off the record at 3:35 p.m. and went back on the record at 3:55 p.m.)
SESSION 4: STEM CELLS: MOVING RESEARCH FROM THE BENCH TOWARD THE BEDSIDE: THE ROLE OF NONGOVERNMENTAL ACTIVITY CHAIRMAN KASS: Could we get started, please? Our fourth session of the day is on stem cells, moving research from the bench to the bedside, the role of non-governmental activity. Progress in stem cell research proceeds not only with government support, important though such support surely is. Biotech companies are vigorously active in the field both with embryonic and non-embryonic cells, and disease related and other philanthropic foundations are actively supporting such research. Our monitoring of stem cell research would not be complete without some review of what is going on under these auspices. This afternoon we are fortunate to have with us representatives from two leading biotech companies very active in stem cell research and from two leading private philanthropic research foundations who will tell us something about the strategies they are pursuing to develop stem cell based experimental therapies, how close they are to developing such therapies, and what obstacles currently stand in the way. As they have all been asked to avoid commercial pitches, criticisms of competitors, or advocacy for or against legislation currently pending before Congress, I would ask Council members to refrain from prodding them to do otherwise or to ask them for investment tips or other privileged information. (Laughter.) CHAIRMAN KASS: Our guests in order of presentation are Dr. Thomas Okarma, who is the President and CEO of Geron Corporation, a company that emphasizes embryonic stem cell research and formerly supported the work, among others, of John Gearhart and James Thomson, and that has solid patent positions in this field. Second, Dr. Theo Palmer, who is an assistant professor in the Department of Neurosurgery at Stanford, a stem cell researcher working on nervous system applications, and today representing the Michael J. Fox Foundation for Parkinson Research on whose scientific advisory board he serves. Third, William Pursley, President and CEO of Osiris Therapeutics, Inc., a company in the forefront especially of mesenchymal stem cell research, with many strong patents in this area and exploring clinical applications for cardiac therapy, immunomodulation, among others. Finally Dr. Robert Goldstein, who is the Chief Scientific Officer of the Juvenile Diabetes Research Foundation International, an organization with extensive activities, including a recently announced program of training grants to draw top young researchers into the stem cell field. Gentlemen, thank you very much for taking time from your busy lives to travel here and to give us the benefit of your knowledge. We'll start with Dr. Okarma. DR. OKARMA: Thank you, Dr. Kass, for the opportunity to spend some time with you today. It's a visit that's probably overdue. You asked me to address three topics: our progress in the development of products based on embryonic stem cells; our thoughts about immune tolerance and immune rejection of the transplanted cells; and, lastly, impacts of various policies on our progress in the private sector in 15 minutes. So I will be terse and not do justice to either question, but try to give you an overall picture. By way of background and the take-home point, clearly human embryonic stem cells are a special case, and this Council has certainly debated the issue of the moral status element of that specialness. But I would argue that there are two other elements to its specialness. First, the biology which is unique amongst all the cells in the universe and its promise for medical therapeutics. And thirdly and not well understood, this paradigm is in the industrial sector, not in the academic sector, and that has some very important implications to the development of this technology, and I'll try to make those points as I go through. Geron, as you may know, has been at the forefront of human embryonic stem cell research since 1995 when we first entered the field. We funded the work done in Jamie Thomson's lab, John Gearhart's lab, and Dr. Pedersen's lab at UC-San Francisco, and as such, we're the movers technically, technologically and proprietarily in this entire field. We have spent over $70 million on this technology, most of it since 1999 after the cells were derived. That's a number against which the NIH disbursements pale by both absolute and relative terms, and there are some reasons for that that I will touch on. So let me move first then into our development plans and our developmental progress. First, let me talk a bit about some of the infrastructure basic science components that we've established. You've heard a lot of discussion about how these cells are grown on mouse feeder cells. We've established a scalable way to grow these cells not only off of feeder cells, but now with a fully qualified set of reagents. These can be scaled virtually limitlessly. We've established ways to scalably produce seven different differentiated cell types from each of the lines that we have. So one line now makes seven different kinds of cells that we'll describe in a moment. We have verified the stability of the embryonic stem cell line in culture. Some of the lines have been grown continuously for over three years, more than 600 population doublings, and there's a manuscript in press now describing four lines studied over that period of time that demonstrates that the karyotype, surface marker, differentiation potential, and gene expression level, the stability of these undifferentiated cell lines grown under our culture conditions. We have had a preliminary meeting with FDA, and we have now qualified two of our cell lines for human use. They have passed every assay the FDA has asked us to submit them to, even though they are appropriately classified as xenogeneic. I will return to that later. In collaboration with Celera, we've established an annotated genomic database of undifferentiated embryonic stem cells. One hundred fifty thousand EST sequences have been sequenced, and the physical clones are deposited in Menlo Park. This is fully annotated. We can query this database. We understand what the gene expression pattern of stemness really is and what genes are up and down-regulated as these cells differentiate. That has been a crucial foundation for our ability to learn how to produce differentiated cell types. And lastly, we, too, have developed methods to genetically modify these cells. Now, the cells that we have learned how to make are characterized by their normalcy. Virtually every cell that we have made, without exception, expresses completely normal cell biology. So the islet cells we have derived express insulin, and they express insulin in a dose-dependent fashion as a function of glucose concentration in the media. The oligodendrocytes we have made myelinate spinal cord cells in animals. The dopaminergic neurons we have made secrete dopamine. The cardiomyocytes that we have made express all of the molecular markers consistent with their being human cardiomyocytes. They respond in appropriate dose response fashion to cardioactive drugs. The bone cells that we have made in Roslin have absolutely normal biology. The techniques to look at the bone formation these cells make in vitro by X-ray diffraction are absolutely spot-on normal. We are close, but have not yet derived chondrocytes. That is also a project funded at the Roslin Institute. And lastly, bone marrow cells, hematopoietic progenitors, which again are absolutely normal in their cell biology, producing all three cell lines normally. Now, some of these cells have progressed into animal studies, and I'll detail those in a moment. The first take-home point to make is that we have never ever seen in any single animal the formation of a tumor. That is because we only put in differentiated cells. The issue about growing the cells in the undifferentiated state is to keep them from differentiating. So when we remove them from the undifferentiated culture conditions, these cells want to differentiate, and we have molecular markers to prove that they are differentiated. We also have cytotoxic technology capable of detecting one out of ten million cells that are undifferentiated should we need to apply that later on in scale-up. So which cells are in animal models? Well, first the hematopoietic cells are in Canada, and we've demonstrated now engraftment of these human embryonic stem cell derived hematopoietic cells in the appropriate nude mouse model, which repopulates the animal's peripheral blood. That has important implications not only for an alternative source of cells for bone marrow transplantation, but for the second question regarding immune rejection. We've made dopaminergic cells which are engrafting robustly in animal models of Parkinson's disease. This is a huge tissue engineering challenge where these cells must penetrate to the cortex of the animal to completely correct the Parkinsonian defect. We have not yet demonstrated significant behavioral improvement in the animals. We are still working on that, but the cells engraft robustly and, again, without tumors. The cell type that is most advanced is the oligodendrocyte, and there will be a very exciting manuscript later this year from our collaborator at UC-Irvine, Hans Keirsted, in which we have transplanted the human oligodendrocytes into a model of spinal cord injury and not only show statistically significant functional improvement of the animal, but we have shown at the histologic level that the animal cells are remyelinated by the cells that we have injected. Lastly, we are now in animal studies in three different labs with cardiomyocytes injected into animal models of heart failure and myocardial infarction. Again, no tumors; again, the cells engraft, and we have histologic evidence that these cells begin now to communicate with the animal cell in situ in the heart. So the work is early. There is much more to do, but we are quite pleased with the progress that we've made thus far and would predict that the oligodendrocyte will be the first cell to enter the clinical environment, and that an IND, if all goes well, could be submitted in late '04 or early '05, which is quite a bit ahead of most people's expectations. At this point our second cell type into the clinic would probably be cardiomyocytes, based on the data set we have today. As part of that first question, you asked about obstacles. There are clearly many, many technical and scale-up obstacles that we yet have to traverse, but those we think are fungible. Our major problem is funding. We have done two reductions in force in the company since a year ago. We are one third of our former size. The political uncertainty of this field not only turns off investors, but also turns off the other source of funding for biotech, which are pharmaceutical partners, who at this point in time are completely uninterested in this field. Turning to the issue of immune rejection, first, there are a number of very exciting, new immunosuppressive drugs in clinical development. So I think the field of immune suppression through pharmacology will dramatically advance, and we hope to take advantage of that. Secondly, it's now known that pure effector cell transplants, in other words, not organs that are contaminated by the donor's immune system, are much less immunogenic in animal models and in a few cases in human than is an entire organ transplant, again, auguring well for the size of the problem of immune tolerance. Thirdly, there is some very exciting work that we are doing not yet published, so I can only hint at it, that establishes the human embryonic stem cell as being unusually unique in its immunologic properties. It has inherited some of the immunosuppressive properties that are existent in the blastocyst. Why is it that the mothers never immunologically reject what is an allograft, the blastocyst? Well, there are specific reasons for that, and those reasons are, in fact, inherent in the undifferentiated embryonic stem cell. But in terms of our strategy, notwithstanding the prior points of how to control immune rejection, we have one that makes a lot of sense, and that is hematopoietic chimerism. We know from the bone marrow transplantation work that if a patient who gets a bone marrow donation from me will be completely tolerant to receiving a kidney allograft or a heart allograft from me. The prior bone marrow transplant has tolerized the patient to the antigens in my tissues. We also know now from work done at Stanford that patients who are status post whole organ transplant patients can be completely weaned off of immunosuppressive drugs by giving them a mini bone marrow transplant taken from a donor with the same tissue type as the prior kidney donor. This is the strategy we plan to use out of the box in our clinical program, having now established that we can derive hematopoietic progenitors from one of the lines. A dose of those cells should tolerize the patient to any effector cell transplanted into that individual derived from the same stem cell line. So that is my answer to Question 2. Lastly, you asked me to address issues of policy that affect our ability to develop the programs. Certainly the fact that this is primarily an industrial paradigm helps with regard to FDA. I've worked with Kathryn Zoon and Phil Noguchi since the mid-'80s in my prior company in cell therapies. Many of the points to consider that are now published came from our mutual collaboration in the early work in the '80s and '90s in cell transplantation. The pathway to regulatory testing and commercialization with this technology is clear. There are some idiosyncracies, it is true, but we understand the pathway, and we have thus far been very pleased with our early interactions with the agency. The NIH has a different issue: to recognize the primary role in this field that has been played by industry. That is not their fault. They were prohibited by law from funding this arena. That is how we got into it. That is how we got ahead of everyone. But that has some special implications. For us, as I manage Geron, we have two platforms: the stem cells that we're talking about today and a cancer program based on telomerase. And the management and depth of technology in both of those platforms is hugely different with, I think, important consequences both for patients and for policy makers. On the cancer side, we have sent the telomerase gene to hundreds of laboratories all around the world. We have many, many collaborators. Many people have worked independently of us on telomerase. So as we move into the clinic with our anti-cancer platform, our scientific understanding of how to use telomerase as a vaccine, how to develop drugs that inhibit telomerase, how to use the promoter of telomerase to drive oncolytic viruses is very, very deep. That reduces risks to patients and increases the likelihood that our first entré into the clinics will be successful, as we are, in fact, seeing with our telomerase vaccine program in the clinic at Duke. That is to be contrasted with our program in embryonic stem cells, where we have a small number of collaborators, the bulk of which are frankly either in California funded by us and the State of California, or in other countries, the U.K. and in Canada. So there's no question that when we think we are ready to move into the clinic expeditiously and cautiously, having checked all of the appropriate boxes the FDA wants us to check, we will still be skating on relative thin ice in terms of the science behind the product that we are testing in people. So the narrower science base in embryonic stem cell research increases risk of technical failure and exposes patients to greater risk from the experiment. The second point under policy I would make sort of illustrates a problem that's about to happen. We've heard a lot about the issue of are the old existing lines okay. What about new lines? Will they be different? Will they be better? Well, the existing lines, as you've heard today, can be used in human clinical trials, but they will not last forever, we don't think. There's no reason to assume that. And these current lines, all of them, were derived on mouse embryonic layers and, as such, are appropriately classified as xenogeneic transplants with increased risk to patients and a much increased burden on the sponsor to follow these patients for life after they receive these cells. That's appropriate. So the FDA is urging us appropriately to derive new lines that not only have not seen mouse feeders, but whose entire pedigree is from reagents that are qualified for human use and that the entire process of derivation be under GMP, good manufacturing practices. We will be successful in doing this. We will generate such a line very quickly, very soon, and then the implication of the current policy, however, is that arguably this would be the best line to use and to qualify and to share, but because it was derived after 2001 in August, the NIH will be prohibited from studying it. And what are the implications for when we take that cell line into the clinic? Will we be unable to share that cell line either from a funding or a technology perspective with the NIH? So those are my brief comments on the three questions. We are unquestionably the leader in the field because of circumstances that enabled us the freedom to operate, and in some ways, particularly with regard to FDA and scale-up and GMP, that's good for the field. But in terms of getting this technology embedded rapidly in the most sophisticated biomedical community in the world, we are amiss. Thank you. CHAIRMAN KASS: Thank you very much. I think we should hear from all four people together and then have questions. Dr. Palmer, please. DR. PALMER: Thank you, Chairman Kass, members of the Council. I'm here on behalf of the Michael J. Fox Foundation, and I was asked by the foundation and by the Council to give a little bit of an overview of the foundation's efforts in targeting Parkinson's disease. So I'll talk to you a little bit about Parkinson's disease, or PD, and then also the role of stem cells in our portfolio; finally, a little bit about what we've learned in three years of trying to use stem cells in this very targeted application. The foundation is relatively new. As you know, it started in late winter of 2000. The goal of the foundation is to match funding to scientists who are pursuing every avenue of research to find a cure for Parkinson's disease. Our secondary goal and my primary goal as an advisory board member is to make sure that this funding reaches the investigator with speed, and one of the things that we've found that has really speeded the research is to short circuit some of the delay in an investigator coming up with a good idea and then getting the funding to that research. So we're targeting Parkinson's disease, and our efforts in stem cells are quite narrow compared to many of the applications that you'll hear today. But Parkinson's disease is the accelerated loss of a dopamine neuron in the adult brain. These neurons control movement, and the loss of the neuron does not allow the brain to initiate movement. So one of the strategies, of course, is to replace those neurons with a stem cell derived dopamine neuron population. This is part of our research effort. The other part, and in fact, a larger part, is to understand the disease itself and then prevent or augment the remaining system, prevent degeneration. So the brain doesn't replace these neurons, and the stem cell biology really comes into play when you've got a patient who's missing a substantial portion and is now dysfunctional in terms of their ability to move. It's a slow disease. It progresses over years, often decades. There's a declining quality of life, and the disease is lethal. It affects more than a million people in the U.S. alone, and there's no cure. In the context of PD, stem cell technology has promised two significant advances that are not available in any other context or form. A single culture can create enough dopamine neurons to cure the entire population of PD patients if we can get the technology to work. This may not necessarily be true in practice, and we heard one reason why this might not be true, if there are limits to the ability to expand the culture. But a second reason and perhaps one that's not very well explored by the Council is the ability to use ES cell lines as a tool for research and particularly as a way of making authentic human dopamine neuron for drug screening or high throughput assays of some sort or another. Now, this is a very important point I'll come back to later. I'd like to go over the portfolio of the Fox Foundation and just give you a picture of the research that's being funded in PD by a private sponsor of research. To date the foundation has funded 28 million in Parkinson's related research overall. This is since our inception in late 2000. Twenty percent of that fund has gone to stem cell research of one sort or another, and it's a carefully chosen array of stem cell strategies in mouse, non-human primate, and human embryonic stem cell systems. At the time the grants were funded, so beginning in 2000, very few investigators had either the ability or access to human lines, and by default rather than by design, at this point except for one study, all of the studies that we fund use approved lines. Now, this will change in the near future, and we anticipate in the next rounds that we may see a significant increase in the request for funding on non-approved lines. And in part, we feel this is driven by the FDA and the requirement for lack of adventitious agents and just the ease at getting a cell line product through the approval process if it has been isolated without the use of the animal cell lines or animal products that were not characterized. So we have seen in the past several years a significant increase in requests for stem cell funding in the review of our funding portfolio and our upcoming funding efforts so that we're attracting new scientists, people who have not really used stem cell technology in their research into the area of Parkinson's disease. So as a tool, it's an attractive tool for a scientist who knows Parkinson's as a model, but now wants to expand their repertoire to use a tool that seems to have much higher promise than the current strategies they're using. So we're seeing an increase in new researchers in the field. In our annual fast track funding, this is an independent, investigator-initiated pilot study where investigators send in unsolicited proposals. In 2001, we had roughly 200 applications in Parkinson's in general. Ten of these were stem cell applications. The total request at that point was just a little over a million dollars. In 2002, we had a similar number of total applications, and our requests went up. We had 12 requests. Two and a half million dollars would have funded all of those stem cell requests. And in our pending round in 2003, we have over 200 total applications that we're anticipating, and more than 20 of these are stem cell related. And over time, we're seeing a significant increase in both the application of stem cells to cell replacement in Parkinson's, but more interestingly, a recognition of their utility as an in vitro source of authentic human neurons, where people can study drug effects or the genetics of Parkinson's disease itself. And these are studies that are not necessarily targeted at replacement, but more at understanding the disease and then coming up with a non-stem cell basis for treatment. So the foundation's experience has given us some insights into what a moratorium would mean in terms of research on stem cells and also what the current policy on federal funding is. We have a diverse portfolio. We have studies on embryonic stem cells as well as fetal stem cells and adult stem cells. Many of these projects were funded early in our round because the advisory board felt that stem cell strategies had very high merit, and one of our first efforts was in creating cell lines that could be used for transplantation. So we have now and unusual point of view where we can actually compare the preliminary results from a variety of efforts. After two years of focused research, we can see that if this was a foot race and we were comparing adult stem cells to fetal stem cells, there's no competition. There really is no race involved at all. We have data generated from our funded research that shows that the adult tissues are not presently a robust source of cells, particularly when it comes to creating dopamine neurons in our focused effort to treat Parkinson's disease. Optimists would say that there's still potential, and there is still potential in leveraging the adult stem cell to our goals as a Parkinson's research foundation. But to contrast the progress made in the same time frame with embryonic stem cells, it's a fragile hope at best to say that in the immediate future the adult cells hold the promise that we had hoped two or three years ago that we would see in the research. So it is now clearly demonstrated in vitro, and when we started this was still an unknown, but now quite well established in several of our funded laboratories that the human embryonic stem cells can make authentic dopamine neurons. What's left now is the practical application of making this work in a transplant, and these are ongoing studies. So I mentioned a moment ago the proliferative potential provides a means to treat many individuals from a single isolate. Unfortunately our research experience is now encompassing a number of cell transplant strategies. The farthest along of these is fetal tissue transplantation where you harvest from the fetal tissue an authentic dopamine neuron and transplant that into a Parkinson's patient. One of the key observations now that we have had blinded clinical trials tell us that there may be additional problems that were unforeseen, a key point is the presence of a fairly robust immune response in many of these patients, and this is something that cannot really be ignored. I have to take my hat off right now and put on my own personal hat so that I'm no longer a foundation representative here. I work in adult stem cell biology, and it's my hope that we can make endogenous neural progenitors do the job of an embryonic stem cell, but in studying the behavior of newborn neurons from endogenous precursors, we have just run into a very serious impediment that involves the immune system. The immune system, if activated in the context of a developing neuron, essentially shuts off this early progenitor's ability to make a functioning neuron, and if we're looking at cell transplantation as a way to cure Parkinson's disease and the cell transplants are not well matched to the host or if there isn't a strategy for making the host tolerant, then having just a few lines is going to be a very serious impediment to applying the existing lines to clinical research. So getting back to the foundation portfolio, there is another benefit to looking at additional lines of ES cells. Putting cell replacement aside and now looking at the technology that stem cells in the culture dish provides, there's a body of research that has been going on for nearly 20 years or more, and that's the technology of transgenic animals and, more recently, the use of embryonic stem cells in creating mice that carry very discrete genetic mutations. Now, one of the strategies that we as a foundation trying to cure Parkinson's disease contemplate is the value of having embryonic stem cells that actually carry the genetic profile of a Parkinson's patient, and although we're not talking today necessarily about nuclear transfer technologies, this clearly pops into mind as a strategy for making an in vitro authentic dopamine neuron population that is identical to a class of patients that are presenting a certain disease phenotype. So the disease is diverse. It presents early and progresses rapidly or it can present very late in life when a tottering gait is really commonplace in that age bracket and, therefore, it's not as big of an effect. But this variability is really as variable as human life itself, and so having 11 or 12 lines from normal individuals does not allow us to access to that technology, and the creation of drugs that would more readily target a type of dopamine neuron depletion or a disease context. So the targeted manipulation of genes in an embryonic stem cell is another aspect of this that is now just entering science, and the ability to introduce genes into human ES cells or to target mutations to an individual cell population obviously gives you a potential way around this, but this is a technology that's novel. Nuclear transfer technology would circumvent that. It gives us the baseline from which to understand how to create ES cells through a non-embryonic process, but there has to be a way to get from Point A to Point B, and this is where the additional lines and the exploration of new technologies comes into play. I'd like to finalize or just summarize here with an overview of current research concerns. In the near term, human ES cells are already undergoing efficacy trials in preclinical models. So human ES cells, as we heard earlier, are in animals, and there's great hope that we'll see that they're at least as effective, if not more so, if the immune complications can be overcome than the fetal tissue transplants that are so commonplace now. To move forward with these lines, there are several limitations with current policy that seem to inhibit our progress as a foundation that's trying to promote cure or intervention in stem cells. The first is what I've targeted mostly in my presentation, and that's the heterogeneity of these current cell lines and limited numbers. So if you start with a few lines and the cell lines are heterogeneous, some will make, in our experience, a lot of dopamine neurons, and others really seem to be impeded in their ability to respond to the same cues provided in the same dish. So in this preliminary data that we see presented in summarizing our funded work, we're observing that one line will work beautifully well in a paradigm. Another line is basically eliminated from the study because it has an inability to make enough dopamine neurons to be useful. So heterogeneity in the performance of an individual line may limit what can be done with the existing lines, and of course, the absence of genetic diversity within the existing lines, the absence of a representation of disease genotype is limiting in what can be done at the research bench in understanding the disease process, and of course, heterogeneity in HLA matching may be a very serious concern, and it will require additional complexity and treatment if we don't have a matched donor and host or fairly stringent strategies for tolerizing the host to the incoming cells. Finally, I think there is this question that's been touched upon quite broadly today, and that's the presence of adventitious agents in the existing lines and whether or not the foundation's research can transition quickly to clinic really depends on how well an existing line can meet FDA requirements. And I've heard that this is possible, but it also places an extreme burden of follow-up on a funded project that makes it difficult for a private foundation to fund. So in the absence of federal funding, is private support really up to the task? And I think really to summarize this, the private foundation's focus is to pilot research, to find very good strategies or promising strategies, and that's where our funding really runs out. The NIH has typically stepped in at that point, after the pilot study stage, and proceeded with the larger experiments, the validation, the expansion. If the foundation funds unapproved lines, that has nowhere to go at this point. So there is a serious concern that though we may be able to use private funding to our benefit, that there will be a stall or serious delay in getting this to clinic. So these burdens loom particularly large to us as a foundation as the Baby Boomers age, and the number of Parkinson's patients increases. The social and economic costs go well beyond just the Parkinson's community, and I think the economic costs in terms of the cost of clinical care is just one part of it. The economic cost in delayed development of drugs because we cannot use in the public sector privately funded ES lines for drug screening or nuclear transfer lines for screening, lines that carry a disease phenotype. I think this is an economic burden that our society has to face and one that should be very carefully weighed in the Council's discussion. I think the foundation very much appreciates the ability and the invitation here to give our experiences, and we understand that you have a very difficult task ahead of you as counsel to the President, and we thank you for this opportunity. CHAIRMAN KASS: Thank you very much, Dr. Palmer. Mr. Pursley, please. MR. PURSLEY: Yes. Thank you. Thank you for having Osiris here. We've been involved in mesenchymal stem cell, adult stem cell research for about 11 years now. Our technology came out of Arnie Kaplan's lab and was acquired from Case Western at that time, and we've been solely focused in that area since on several applications. Our development strategy is very straightforward. It's tissue engraftment and regeneration without immune suppression. Let me back up a moment, too, to set the record straight. In some of the earlier media documents, it has me as a Ph.D. I'm not a scientist or a physician. I'm a businessman, and if my technical explanations aren't satisfactory, most of what I'm going to report on is published or we believe will be published in acceptable peer review journals, and in fact, correct me if I'm wrong. This panel should have been provided privately an embargoed manuscript that will be submitted. Okay. Our technology is the universal application, and I'll explain that term in a moment, of adult MSCs, or mesenchymal stem cells, with no in vitro manipulation. In other words, if you will, these very smart cells do what they do in vivo. We simply put them in there and let them go, so to speak. And I'll define that in some of our programs. What I mean by universal application, we started out as an autologous cell company and later found out that we can provide from any donor, unrelated, HLA unmatched, any donor these cells to any recipient without immune rejection. And in fact, what you'll see in our first program, we found them to be immune selective, T cell-suppressive in some instances. So we are now working on what would be literally an off-the-shelf product for whatever the indication may be. The process we use under anappropriate IRB protocol, again, we take an unrelated, unmatched, volunteer adult donor. We take a bone marrow aspirate, a whole marrow aspirate from the iliac crest, bring that back to our manufacturing, and then we will culture and expand that currently to about 1,000 doses from one donor. We are going through an expansion now that's not a change in process. It's an expansion of process. We will ultimately get that to about 10,000 doses per single donor. A very nice advantage of this is that we don't have to expand cells indefinitely. We can go back to new donors. Currently one donor can provide bone marrow six times in their lifetime. These are usually younger people because the younger you are, the more MSCs you have. We will then cryopreserve the finished product in liquid nitrogen, and at that point it is ready to go to clinic for use. We also now have done stability and potency testing to have that stored at a lesser temperature over X period of time in certain containers so that it's easier for the hospitals to use. The safety of these cells in the universal application has been proven now. Allogenic MSCs have been given to 56 human beings. Thousands of various animals models have been used, rats, mice, goats, dogs, pigs, and baboons. This has been done in conjunction with the NIH, Hopkins, Cedar-Sinai, Texas Heart, et cetera. And at this point, over several years now, there has been no possibly or probably related serious adverse events associated with MSCs. This includes no infusion or direct administrative toxicity. There's no ectopic tissue formation. In other words, they aren't differentiating in cartilage in the heart, on the knee, et cetera, and there is no tumor formation at this time. And, in fact, we have two lead programs in Phase 2, which by definition from the agency standards, the FDA, means we have met their safety standards for biologic in order to move into Phase 2. So we are very happy to report we see and now the agency sees these cells as safe, allowing us to move into Phase 2. Now, the precise mechanism of action regarding this universal application is not known. All we do know is apparently there are certain cell surface characteristics of the MSC that do not elicit an immune response, and in fact, as I said, as you'll see in our first indication, are actually immune suppressive. As far as how close are we to developing therapies, our first two programs are in Phase 2. The first is peripheral blood stem cell transplant support for patients with hematologic malignancies, and again, forgive me if you're very familiar with this pathology, but basically if you have a leukemia, a myeloma, a lymphoma, et cetera, a blood cancer, you receive total body irradiation and/or chemotherapy, with the goal of obliterating the bone marrow because that's the source of the cancered blood. These patients then need to receive a transplant. They receive a peripheral blood transplant of hematopoietic stem cells so they can produce enough platelets to clot and white cells to fight infection and red blood cells for volume, and gain a natural state of hematopoiesis. And those cells usually come from a sibling or a parent. The problem is for these patients who have no choice but to go through this, ten percent and up to 20 percent can actually die from this procedure, with the vast majority of graft versus host disease, and that means the hematopoietic stem cells are rejecting the recipient. And so what we did in a Phase 1, in a multi-center Phase 1, is provide MSCs, mesenchymal stem cells approximately four hours prior to the transplantation with, first of all, in a Phase 1, the primary goal for a biologic is always safety, and you look for secondary efficacy trends, which are great if you reach them, and we did in a very big way. What we did is reduce significantly graft versus host disease. So we believe there was a T cell suppressive effect in working with the patient or with the hematopoietic stem cells not to reject the patient, if you will. Now, the reason we say selective T cells suppressive, these Phase 1 patients are now out three years. They have also had a significant reduction in return of the cancer, which means we did not suppress the T cells fighting GVL, graft versus leukemia. This was a very big concern. If these are immune suppressive, are we going to hurt the patient's own ability to fight the cancer coming back? And what we've seen at three years out is this is not only not the case. They have a less incidence of return of the cancer. So with those data we are in Phase 2. This is an IV preparation. The status is we should have Phase 2 data reportable in time Q3 of '04. If that goes well, we will go into a Phase 3, and this should be available to the hematologic malignancy population if things go as planned, and Murphy has a way of raising his head in this business and always will, but even with some of those considerations, we would hope to be commercially available to humans by 2007 with this. Just after that program, a very similar situation but a different mechanism of action, which is the amazing thing about these cells. That was a T cell suppression effect to reduced GVHD. In a similar sense there are infants to adolescents primarily who don't have matched donors who will receive cord blood transplants, and their problem is not GVHD because there are so few hematopoietic stem cells in the cord blood transplants. Their problem is establishing a natural hematopoiesis. So some of these kids will lay in the hospital an average of about 90 days. It's fairly replete in the literature, and they aren't released from the hospital until they produce enough platelets to get out, and so they can sit for 90 days in a subacute state with bleeds and infections, et cetera. This is a tiny population. It's an orphan indication, but there's nothing that can be done for these, and in a Phase 1 study with an admittedly retrospective comparison to that database. All of these kids are in a single database in the U.S. Our primary goal was to decrease the time to platelet engraftment, to get these kids out of the hospital and establish a natural hematopoiesis, and the kids that received MSCs got out in an average of about 38 days compared to retrospective control, historical control of 90. And so that program is in Phase 2, and we hope it would be available also to humans in the '07 time frame. The very large and much more talked about program, our cardiac program for acute MI, will be in humans this December in conjunction with Boston Scientific. Most of this preclinical work was done in swine models at Cedar-Sinai and Hopkins, and the primary goal here is for these cells to reshape the baseline morphology, the heart, and regain the baseline function of the heart pre-MI. It is fantastic preclinical data, and I say that with humility after looking at preclinical data for 24 years in this business. After you see so many pig hearts grow back and get back to normal function, you start to believe it. And the IND has been filed, and the FDA will allow us to go into clinic at the NIH and Duke this December. The idea here, too, in this indication, something we just found out in '99 in rats, this will be an IV administration. It is not a direct injection or catheter application to the heart. Apparently these very smart cells - and I can call them that because I'm not a scientist - find their way to an inflammatory site. And an acute MI is a very strong inflammatory event, and an inflammatory cascade that probably lasts in a strong manner for seven or eight days. And basically these are given IV. They swim to the heart. They regenerate the infarcted area of the heart, which the heart doesn't then respond with a compensatory thickening like normal, and that happens in about four to six weeks, and in about six months the heart gets very close back to pre-MI function. And if that gets in the clinic in December as planned, and it should, these are going to be much larger trials because of acute MI. We would like to think that this product could be available to the public commercially in 2009 or 2010. The next product which we have an IND filed for and will be in humans before the end of '04 is meniscal repair in the knee. This is the most common knee injury at least in this country. There's about 850,000 meniscal tears, from the Weekend Warriors. This will be a high regulatory bar. It should be. These are healthy young people normally, and so the safety is going to be critical. Preclinical work has been done in 72 goats, and basically what we do is do a partial to full meniscectomy as is done with the patients. There's nothing you can do for this today but take out part or all of the meniscectomy to ease the pain. After whole or partial meniscectomy, it is replete in the literature that one goes on to develop osteoarthritis. And what we do is give about 150 million cells directly into the knee, and it grows back the meniscus in about six weeks time, and hopefully then it will obviate any progression to osteoarthritis, and we hope to be in the clinic with that as well in, again, '04 and, again, should be commercially available to humans in a similar time as the acute MI product in '09 or '10. The last advanced program, also in concert with Boston Scientific, is maybe the largest unmet definitive therapy in terms of societal cost, and that's congestive heart failure or, maybe more appropriately, chronic ischemia leading to congestive heart failure. At Texas Heart, in the canine model, we put an amaroid occluder in place in these dogs to mimic chronic ischemia. Basically you do that for about 30 days until you create an ischemic model. About 30 days later you give the MSCs. The ejection fraction in the amaroid occluded non-treated dogs, once it drops below 17 percent, they die. The ejection fraction in the treated dogs with the occluded, LAD still in place, the occlusion remaining in place, goes back to normal function in about six months. So basically we've restored the heart morphology and the baseline heart function pre-ischemic model with the amaroid occluder in place, and there is possibly some form of angiogenesis going on here. So those are the advanced programs, and in all of these programs and all of the animal models to this date, there have been no serious adverse events associated with MSCs, again, neither infusional toxicity, ectopic foci, or tumor formation. Finally, we have many, many orthopedic models in a preclinical area where we will or will not use a scaffolding or a matrix for these cells in some of those applications. And finally, we are involved in grants from DARPA and NIST looking at wound healing and CNS repair, respectively. As far as what obstacles stand in the way, the usual. One is enough money, especially in today's very tight private equity market, and it's probably going to stay that way until the IPO lid comes off. Cell biology talent. We will be forever understanding what goes on with these, which leads to another point I'll get to in a moment. And then one, to put into an equal bag where we can all take an equal share of guilt, and that's politics, corporate greed, and academic ego, which is a bane always in the development of any of these, and I don't say this lightly. Again, as a personal comment after being involved in this 24 years and being fortunate enough to be at Genentech when they grew up and then at Genzyme when they grew up and at TKT with maybe the most elegant protein technology I've ever seen. Have never seen anything like this. The hardest thing about managing this company is keeping it focused. There is no application that can't be brought up that we can deny the possibility of the use of these cells or cells like this. Bill Krivits up at Minnesota has given these to kids with lysosomal storage diseases and they are not transduced. They just start secreting the enzyme they're missing. The immune modulation possibility now that we found out almost serendipitously with our first program, that's a whole new area of arthritis, et cetera. It literally is limited by our imagination, and it's bigger than any of those entities I mentioned by far. It is the closest thing - and I'm sorry for the drama - of a human health care miracle that I've seen in a quarter century. And I just hope somehow those entities can synergize to bring this as quickly as possible and as safely as possible to the millions and millions of people. As far as approaches to overcome immune reaction, we don't have any. We have found that there is no immune reaction against these cells, and not only that. We have found them to be immune suppressive selectively in appropriate situations. As far as the federal policy impact, depending on what your patent portfolio is, that drives your answer on this. Right now we think from the Patent Office's perspective it's a very good thing. We have had senior scientists that have stuck with this from the beginning because they believe with this their inventions have been protected, and it is allowed to go on in a protected manner to develop those. As far as the NIH, again, anything that can be done by that institution to further synergize itself with commercial endeavors without feeling it is bastardizing its academic purity, and exactly what that means and how that is getting done we don't have an answer, and I don't know who does, but it certainly could help all efforts. And the FDA, first of all, I want to say, again, in a long experience over several technologies, they have been a very good partner with us in this, and we appreciate that. We're a tiny company. We need a lot of guidance, and it hasn't been an adversarial situation. It has been a partnership situation, and anything to continue to increase that. We are in the good fortune of being by far the most advanced company in the world in adult stem cell research, and so it has got to be in partnership with the FDA that we understand how these are to be regulated because I think that will set the bar for how it is done from this point on. I think one of the things that will be looked at, and we have to understand where we draw the line to accept, is especially in the technology where everything is happening in vivo, basically from a cell that's the same ex vivo. Without all of the black box answers for mechanism of action, why, how, where, how long known is how that will be weighed against the actual clinical outcomes of safety and efficacy and how that regulatory guide pole is looked at is critical. Thank you very much. CHAIRMAN KASS: Thank you very much. Dr. Goldstein, please. DR. GOLDSTEIN: Chairman Kass and members of the President's Council on Bioethics, thank you very much for inviting me to testify today. I'm the Chief Scientific Officer for the Juvenile Diabetes Research Foundation. JDRF was founded in 1970 by parents of children with juvenile diabetes to find a cure for diabetes and its complications through the support of research, and this year we expect to fund approximately $90 million worth of research. Since its inception JDRF has funded diabetes research all over the world, and it turns out it's the world's leading nonprofit, non-governmental funder of diabetes research. At your July 25th meeting, you heard from Charles Queenan, a JDRF volunteer, who spoke about the advances in islet cell transplantation that are showing dramatic results in people with Type I diabetes. I'd like to briefly summarize. As of April 2003, more than 250 patients worldwide had received islets infusions using the so-called Edmondton protocol. About half of these patients received islets alone. The other half received islets in conjunction with or after a kidney transplant. Most patients have enjoyed insulin independence, reduced hypoglycemic episodes, and improved quality of life. Despite this success, there are too few insulin producing cells available from organ donors that at its max could help perhaps five, six, 700 people a year. JDRF, therefore, believes that embryonic stem cell research could lead to the discovery of new ways to develop additional and unlimited supplies of insulin producing beta cells with the hope that everyone with the disease can be treated and cured. With this background, I want to cover some of the activities that JDRF is engaged in over the past several years in the United States and abroad to help advance the embryonic stem cell research agenda. In the spring of 2000, we announced our intention to support embryonic stem cell research. We began to build a research portfolio that promoted human and animal stem cell research. To insure the ethical conduct of this research we formed a stem cell oversight committee consisting of leading researchers, policy makers, ethicists, and lay volunteers who were charged with providing a second level of review in addition to the usual scientific peer review for all human stem cell research applications that we received and considered. We recognize that stem cell research may require innovative and novel public/private partnerships, and we included in our request or solicitation the notation that we would support the derivation of human embryonic stem cell lines. The scientific principles that form the basis for stem cell research funding program is as follows. We recognize the need to support research using human stem cells from all sources and that very basic research is the necessary precursor for the development of cell based therapies; that adult stem cell research is a complementary approach. We have long supported efforts in both adult stem cell research, as well as more recently human embryonic stem cell research. JDRF believes in providing a collaborative environment that will encourage or maximize the opportunity and promise of this research, and we work to insure easy and public dissemination of embryonic stem cell lines without major restrictions as to the usage, and we're committed to sharing information and data as they become available. We also participate in forums for public dialogue and dissemination information. JDRF embryonic stem cell research activities today include everything that I mentioned, cells from all sources. This year we have applied approximately $6 million in support of stem cell research with out-year commitments of about $16 million over the next four years. Of the $6 million this year, about three million is for research to direct the differentiation into glucose-responsive, insulin- producing cells using human embryonic stem cells as starting material. About two million is for research using human stem cells from other sources, and one million for animal work. About one third of JDRF's funding for human embryonic stem cell research supports work done in the United States. The rest supports research outside the United States where in many cases investigators work in more favorable environments, often with special government programs that provide extra resources for human embryonic stem cell research efforts, for example, Sweden, the United Kingdom, Australia, and Singapore. We initially received very few applications from U.S. based investigators, perhaps related to concerns over policies and restrictions. We have received consistent feedback from U.S. investigators that they are wary of entering this field even with private funding due to the limitations imposed by the federal policy. They, in addition, mentioned a limited number of federally approved lines, the lack of genetic diversity among the lines, insufficient characterization, variability in the developmental capacities of the lines, difficulties in distribution, as well as the ubiquitous presence of the mass feeder layers which we've been discussing which make the development of clinically useful cell therapies not impossible, but more difficult as has been mentioned. These barriers we feel need to be removed to increase the value of using the approved stem cell lines for research and then for the development of therapies. We acknowledge and recognize the efforts of the NIH, particularly the NIH stem cell task force, and we are working closely with NIH on this. But I think that it's our international partnerships that are pertinent to the conversation this afternoon. JDRF's international efforts have continued and been expanded in the area of stem cell research both through independent funding of investigators, as well as through partnerships directly with other governments. We have established a series of co-funding partnerships with government research agencies in the United Kingdom, Sweden, Canada, Australia, France and Singapore, and we have ongoing discussions with others. In some of these partnerships, local foundations within those countries also provide support. In addition, in many of those countries, we have provided funding for very basic embryonic stem cell research that was not necessarily connected to diabetes in any particular way since the research was at the earliest stage. Because of our extensive international work and leadership, JDRF was invited in January 2003 to be a founding member of the International Stem Cell Forum established by the Medical Research Council of the United Kingdom under the leadership of Professor Sir George Radda. This group currently includes representatives from government agencies in the United Kingdom, Australia, Canada, Finland, France, Germany, Israel, Japan, Singapore, Sweden, and the Netherlands, as well as the NIH. The objectives of the forum are to encourage collaborative research across nations, boundaries, and disciplines; to encourage sharing of resources and data; to fully capitalize on the existing available human stem cell lines; to identify key research gaps and address these by capitalizing on national strength; and to identify funding schemes that actually facilitate transnational collaborations. In specific terms, this group has agreed to develop a set of criteria that could be adopted globally for optimizing the derivation characterization and maintenance of human stem cell lines from all sources; identify a small number of international laboratories that would commit to using the agreed criteria to characterize existing human embryonic stem cell lines; and to identify opportunities for sharing resources, cell lines, data protocols, and guidance documents on an international basis; to coordinate or make an attempt to coordinate national stem cell banking activities. This group has already convened a working group to characterize stem cell lines with a series of recommendations. The United Kingdom has one of the more progressive environments for stem cell research as a consequence of the British government providing strong political, regulatory, and funding support in this area. The recent establishment of the U.K. Stem Cell Bank is one example. This will provide access to existing and new quality controlled adult, fetal, and embryonic stem cell lines. It will have a good manufacturing practice arm for research leading to clinical applications. Academic researchers and companies from the U.K. and elsewhere will be eligible to deposit and to access lines according to a code of practice developed by interested parties. This bank will serve as an outstanding example of how to foster and enhance the research needed to develop therapies from stem cells of all kinds. Other countries are working toward the development of similar resources, and it is envisioned that the International Stem Cell Forum may serve to coordinate such activities in order to enhance the exchange of information and to provide complementary efforts in this burgeoning field of research. Examples of activities under consideration include the establishment of a registry posted on an international Web site that would provide appropriate scientific information about lines not listed in the current NIH registry; characterization of non-NIH registry lines, and comparison with NIH lines; in addition, joint training programs to assist new investigators. Organizing and coordinating these international research activities in order to better serve research efforts everywhere provides a model that is highly likely to bring results to the clinic much sooner. Well, this summarizes research activities to date. I do not want to provide the impression that these international activities, for example, can replace the resources which the federal government and United States could provide for this research. The limitations imposed by the current policy raise questions and provoke uncertainties about the future of human embryonic stem cell research in the United States. We think that one result is fewer scientists working, fewer graduate students, postdocs, et cetera, and universities who have less than an active willingness to invest in facilities, a comment that was made earlier in the afternoon. These resources could make a significant difference to research progress in the development of insulin producing beta cells for the cure of diabetes, and in this area, they need to establish and nurture collaborations between the world's experts in beta cell biology and the world's experts in stem cell biology so they can collectively conduct the necessary research. It remains a critical event. Expanded federal embryonic stem cell policy would make an important difference in helping promote this research. Much of the current knowledge of beta cell development comes from studies using mass embryonic stem cells that is not always easily translatable into human work. Several protocols, however, have been reported that direct mass embryonic stem cells to becoming functioning islet cells. Early studies in human embryonic stem cells suggest that they could be coached, though at the moment inefficiently to insulin secreting cells, and this work has gone a little more slowly than we would like. We do continue to support research on the differentiation of adult precursor cells into beta cells, but that's a severely limited field in terms of how successful it has been. Progress to date does underscore the need for continued investment in research in this area, including the creation of an environment in the United States that encourages and supports scientific discovery. The potential for this research to have a positive impact on the maybe 100 million Americans who suffer from a wide variety of diseases and injuries who might benefit is just too great to be ignored. Thank you for your invitation, your time, and your consideration. CHAIRMAN KASS: Thank you, Dr. Goldstein. Thank all of your for your fine presentations. Let me just throw the floor open. Let me, so that everybody knows where we are, we started late. We were originally scheduled to go to 5:15. Let's go to at least 5:25 and get people's questions out so that we take advantage of our guests who traveled so far to be with us. So, please, Jim Wilson. PROF. WILSON: Several of you referred to the political uncertainty of stem cell research in the United States, and in the course of making these remarks, you listed many possibilities. I would like to know from you as briefly as possible what you think is the chief political uncertainty. Is it money? Is it stem cell lines? Is it the number of researchers or what? What is the political uncertainty that you're concerned about? DR. OKARMA: Well, the quick answer is all of the above that you just mentioned. If I were to prioritize them, it is the pure political process of taking scientific inquiry out of the hands and hearts of the scientists and into the halls of Congress. Can the environment worsen with a different administration or with the same administration? These are exactly the things that our investors tell us that they are concerned about. But the fact that there is a very thin infrastructure to complement what we are doing at Geron, what other folks that you've heard are doing here makes the risk higher to achieve a commercialable and safe and effective product. They are intimately intertwined. PROF. WILSON: That is true, but Congress has always, since 1938, placed under legislation by its action important therapeutic regimes that might affect the safety or health of other people. Is this supposed to be exempt from that? DR. OKARMA: I'd like to hear an example of that that compares to the - PROF. WILSON: Well, the FDA constantly regulates. DR. OKARMA: That's not political; that's not congressional. This is different. PROF. WILSON: Oh, there's a difference between the FDA and Congress? You'll have to explain that to me. DR. OKARMA: I think there certainly is. PROF. WILSON: Anyone else have a response? DR. GOLDSTEIN: The universities during the past two years-plus, since the administration's policy, have had a variety of information coming. As Dr. Zerhouni told you, it has only been since his arrival that the stem cell task force was created. So some time was lost. The most simplest example that I can give you is the confusion over the application of federal policy to indirect cost of university researchers, and it has only been in the past four to six months where people have accepted the notion that they can do federally funded research next door to privately funded research without getting in trouble. The clarification of that was painfully slow, and people just didn't hop on the bandwagon immediately. The second part, I think, has to do with what investigators tell us, is it takes me six to eight months to work through my research office to get a material transfer agreement to get one cell line at $5,000. I'm hardly likely to be interested in studying two, three, or more at that pace and would prefer some more economical and more free distribution of more well characterized material. So that inherent slowness is not exactly a terrific ingredient for promoting and expediting research in a new area. It's one reason why the international community, for example, has taken a very strong position to complement the NIH activity and make materials, information available on a more free exchange environment. And you know, it's in a time when budgets for funding research worldwide seem to be down. I would point out that the U.K., Japan have put special extra money at this topic because they view it as an opportunity. That coincident with decreases in their regular research budgets. So people see this as a major opportunity. PROF. WILSON: Thank you. CHAIRMAN KASS: Alfonso. DR. FOSTER: Jim, were you through? PROF. WILSON: Yes. DR. FOSTER: Dr. Okarma, I wanted to ask one question that I wasn't sure about. You emphasized the oligodendrocyte as one of your chief cells that was moving on. You said you were working on this in spinal cord injury, but I presume this would be some myelinating agent in something like MS or multiple sclerosis or something as well. I don't know that, but the question would be if you put in a differentiated cell and let's say you have a balance between, you know, some autoimmune disease that's demyelinating and an oligodendrocyte that's myelinating, the question I was going to ask is that apparently a lot of times there's a block in the oligodendrocyte capacity to myelinate because there's a block in the movement from the pre-oligodendrocyte to the oligodendrocyte by, you know, a jagged notch interaction or something like that. So I guess the question I'm asking: is this differentiated cell going to be - we've talked about the problem of immune rejection and things like that - but is there another problem in certain diseases of differentiated cells that they might not work because of the primary disease that's present? DR. OKARMA: That's precisely correct, and we have yet done no work on systemic autoimmune based demyelinating diseases, although to your point, they could potentially be subject to - we have only worked on oligodendrocyte precursors in acute spinal cord injury. DR. FOSTER: Thank you very much. CHAIRMAN KASS: Alfonso Gómez-Lobo. DR. GÓMEZ-LOBO: I don't know who this question is going to go to. Probably Dr. Okarma. I understand my charge here in this Council primarily as a duty to worry about bioethics. I mean this is a Council on Bioethics, and that's the way I see my social role in this context. And one of the things that worries me is that in these presentations, in these wonderful presentations you have made, I don't see that dimension. For instance, it's one thing for there to be political problems and perhaps concentrated on Congress, but I think that there's the larger context of the whole nation and there's the larger context of our lives and of the respect we owe to each other, et cetera. And then the question arises: shouldn't we see a problem in the fact that a blastocyst that we know could be implanted and continue its journey towards being like one of us, if that's destroyed to extract the embryonic stem cells, whether we should not worry at all about that? Is that a reason why some people may have serious doubts not about the benefits, but about the means to obtain these benefits? DR. OKARMA: Well, first, sir, I was specifically asked not to address those concerns, but let me assure you that they are very prominent in the culture of our company. Approximately six months after I arrived at Geron in December of '97, I formed an ethics advisory board to discuss precisely those issues both for my own uncertainties, to more vigorously and rigorously dissect the issues as viewed by different Western religious traditions, as well as secular perspectives, and to expose the workers in the company to this body and have them ask their own questions of it, which has helped us enormously and has informed us about the issues of moral status and has comforted us in our position that this is not an ends justifies the means argument, but that the special circumstances, the scalability, the biological diversity, the normalness of the cells that we're able to manufacture from a single stem cell line made from a single embryo destined for destruction tilts the moral seesaw in our direction. And we are intellectually and emotionally convinced of that point. DR. GÓMEZ-LOBO: May I? CHAIRMAN KASS: Do you want to respond? DR. GÓMEZ-LOBO: Fair enough. Now, that's a straightforward utilitarian argument, and someone may say that, you know, even one adult could be sacrificed for many. So there are serious problems with that argument. Let me leave it at that. CHAIRMAN KASS: Does someone else want to respond to the question as put before I call on someone else? Dr. Goldstein. DR. GOLDSTEIN: I would like to make a general comment that we took the issue so seriously that we added an additional layer of oversight, and the charge to the committee was to provide and consider and revisit issues as they come up. We assumed this was going to be a dynamic field, and this committee developed guidelines. It watches over and it considers many aspects that we don't consider with typical research grants, with typical research grants that the IRB approves and you have all of the signatures on. So I think it has been taken in extremely serious ways. I don't have a specific response about, yes, this is the correct or incorrect or that kind of thing, but we made this effort because we saw this as an issue, and we decided we needed a serious way to deal with it. And this committee reports directly to our board. CHAIRMAN KASS: Janet, Janet Rowley. DR. ROWLEY: I'd like further discussion in two areas, and I suspect that maybe it's both Dr. Okarma and Dr. Palmer who might respond to this. First, I was surprised at your discussion of your funding problems at Geron and the fact that you're only a third of the size of a year ago because implicit in much of what has been written and discussed earlier this morning, the assumption was that the federal funding wasn't going to be important because private funding was so robust and we could sit back and let the private sector take care of it. And you've raised some question about that more rosy view. I have another question though about the role of nonapproved cell lines. So in a sense, both of you are counting on these nonapproved cell lines because they will obviate the need for feeder cell layers and things of that sort. But how do you view these being used in the future or being of benefit or are they only going to be of use outside of the United States and not be available for use for American citizens? DR. OKARMA: Well, first, let me clarify the premise of your question. There's no uncertainty that the current lines in Menlo Park that we have qualified for human use can go forward into early stage human trials. They are robust. They are clean. They differentiate repeatedly in the directions that we want them to go. But they are xenogeneic, and they will eventually die off, we think. We have no evidence for that yet, but we think it's the conservative and appropriate assumption to make, that these cells, despite their telomerase expression will not be immortal, as is a tumor cell. So for those two reasons, their natural life span and the desire to improve by taking advantage of what we've learned from the existing derivation protocols and improving them, putting those derivation procedures under GMP with completely qualified and pedigreed reagents so that even the antibody used to purify the growth factor has never seen a murine antibody; that's what we're talking about about GMP cell lines. And that is a normal progression within the entire field of cell therapy, and we think we are ahead of everyone in the restricted arena of embryonic stem cells. So stay tuned for that announcement. The issue, as you correctly point out, is that those cells by definition of the current government policy will not be available for study by U.S. government funded entities, and there's no question, as you correctly imply, that the international community will be very anxious to get their hands on those cell lines. DR. PALMER: I'd like to add then to that the idea of heterogeneity. If you're a publicly funded entity and would like to explore the utility of these cells and you find that only a few will perform the way that you are interested in and then only a few of those will work in a portion of the patients that you are interested in treating, then the new lines become absolutely critical; that you could not cure Parkinson's. You could treat a few people. If the cell lines run out, then you're done. So it is a critical aspect of expanding the research to a level where it's self-sustaining. CHAIRMAN KASS: Bill Hurlbut. I'm sorry. Excuse me. Michael and then Bill. PROF. SANDEL: This is a question for Dr. Palmer, and it goes back to something that Paul McHugh said in this morning's discussion. He was giving an interpretation, a sympathetic interpretation, of the President's current policy allowing the use of private funds but not public funds for new embryonic stem cell lines and limiting public funding to the preexisting. And the way that Paul interpreted that was as a challenge to scientists to say, "All right. Within this limited area, show us what you can do. Show us that there's not just speculative promise, but that there's genuine progress. Show us. Let the burden be on you scientists to show us not only that, but also that redeeming that progress depends on going beyond the 12 approved stem lines that are currently available for distribution, and show us also that redeeming that genuine progress requires federal funding for more than the existing approved cell lines." Now, much as I heard your comment, you were speaking in that spirit, addressing that kind of challenge with respect very concretely to Parkinson's, but I wonder if you could just, taking that challenge directly of Paul, address to him in a summary way the answer. As I understood your testimony just now, you in effect think you already now have the answer for Paul, and then I'd be interested to hear Paul's response. DR. PALMER: Let me speak about data that I have seen, but it's still proprietary and confidential in a general sense. In funding stem cell research, about half of our stem cell effort is in embryonic stem cells, and the remainder divided between adult stem cells and fetal stem cells. Within the embryonic stem cell projects, several of these proposals, their specific aim was to contrast and compare cell lines that were available to them, and what we have seen in the data that they present is that there is beyond a shadow of a doubt huge potential to create authentic dopamine neurons from human ES cells. That's good. The problem is that within the limited number of cell lines that they have tested that potential is hugely variable. These are cell lines that are theoretically pluripotent, and they should be equivalent embryonic lines. If you look at a picture of them in the dish, they look strikingly different from line to line, which has the stamp of their history, which cell lines they have been exposed to, which sera they had applied to them, which growth factors were used in their preparation in isolation. And this history of experience from these ES cells then imprints them to behave a certain way when their context is suddenly if they're asked to produce a dopamine neuron. So the heterogeneity tells me as a scientist that we have a problem, that some of these lines may work some of the time for some of the applications, but they will not all work for all applications. And this is a very strong argument for expanding the variety and the heterogeneity of the lines that we currently have access to. Eleven or 12 is not enough. DR. McHUGH: Yes, thank you very much, Michael, for asking that question because it was rather what I wanted to ask. But I have two responses to that. First of all, the heterogeneity that you mentioned may or may not be so compelling as to not allow you to find, after all, these are immortal cells, and if you get one or two or three lines from the 12 and the expansion of things that are going, you may well be able to tell us that you're already achieving with what we have in front of us adequate things for the future. That's the first thing. But more importantly to me, anyway, was what you said about the issues of the autoimmune problem and how you thought that the autoimmune problem was going to be the telling one as you have seen the cells die in the process when they're exposed in this way in a foreign turf and you looked forward to the opportunity perhaps of using somatic cell nuclear transplantation to develop dopamine cells that were, in fact, from the person themselves. And I wanted to say that I, of course, have spoken in this conference that I think that that is going to be the way in which embryonic cells ultimately will - as one of the ways that will get to this source of cells in ways that we will have to look more closely at its ethical basis and I see as distinct from the ethical source that comes from the zygote and the embryonic stem cells that the President was talking about in his August 9 speech. So, Michael, now to return to you, I just think that we've seen today from these wonderful four presenters just the kinds of things that I would like to see to enhance our conversation to get us to a place where we will talk about the direction science will go and the promise that it will take. And let's just finish off by a very small question that I wanted to ask you, Dr. Palmer, since I've got the floor, and that was aspects of the biology of Parkinsonism itself and the concern that I have that perhaps the disorder - are you sure that the disorder will not in itself being directed against dopamine cells, might not kill off the stem cells that are being produced and kill them more quickly than even the endogenous cells? So where is the understanding of the pathogenesis of Parkinsonism in relationship to this transplantation treatment? DR. PALMER: Let me turn this around maybe and expand your horizon in thinking about ES cells, embryonic stem cells, and again stepping one more step into the nuclear transfer arena or into the area where you can engineer, genetically modify a traditional embryonic stem cell. So there is no guarantee that making a pure population of dopamine neurons will cure Parkinson's disease. There is very good evidence that under some circumstances dopamine neurons from fetal tissue do help in Parkinson's disease, and what we would be striving for is a population that is renewable that would not require the use of fetuses for curing individuals. So in that sense, there is a gold standard that is working relatively well, but has problems to overcome to which ES cell strategies can aspire to, and that does work. And so I am optimistic that the stem cell strategy will also work, if not better, if we can eliminate the aspects of the fetal tissue transplant that may be giving us trouble in that particular clinical paradigm. Now, flip-flopping this a little bit, you brought up the idea that Parkinson's disease is a disease, and putting healthy cells into the diseased brain may be a bad idea and may not make it work. How would you understand the complexities of that disease? The way one might approach this is to use ES cells that harbor all of that genetic complexity of that disease and model it in a tissue culture dish. Try your drug screening strategies. See if you can't find mechanisms that are not possible to even understand in a whole organism by recreating the system in the dish. This is the real power of ES cell technology. CHAIRMAN KASS: Bill - sorry. Paul, did you want to just every quickly? DR. McHUGH: No. Thank you very much for that. CHAIRMAN KASS: Bill Hurlbut, the last question and then we'll stop. DR. HURLBUT: Well, thank you for your presentations and the very exciting prospects of going forward with the existing cell lines and the others that you suggest. The future looks like it has real possibilities. What I want to explore for a second is beyond the therapeutic potential. You've mentioned amazing possibilities for scientific research and drug testing and so forth. So even if this technology doesn't end up making its way into the clinics, it obviously is going to be very, very important for the whole future of biomedical science. So what I want to ask you is this. Given this amazing foundational, early stage of this new medicine, kind of a whole new wing on the mansion of medicine, and yet given the conflict that is going on within our culture where, depending on who you believe, which survey you believe, maybe half the population has problems about the moral grounding of this future of medicine, here's my question. I was speaking with a pediatrician recently, and she told me that it's not uncommon to have parents whose children are going to be vaccinated ask her was this vaccine grown on fetal tissues. So the problem is that even if the individual patient doesn't choose to employ the therapy that they have an ethical problem with, the whole foundation of medicine is going to be built on this technology, and so it's not just a vaccine that somebody can say, "Well, I don't want it." It's just sort of like everything will be built on this, right? And beyond the question of whether or not the President could change his policies, there is the Dickey amendment, and I think we heard this morning that to a very large extent his decision was an interpretation of the Dickey amendment itself. So given half the population roughly has ethical problems, given that this is going to be the future foundation of medicine, are there ways in the kind of research you're doing; do you see any hopeful ways that we can do this in a way that bypasses the moral problems? And as a part of that question, I'd like to ask you: how important do you think cloning for biomedical research is, so-called therapeutic cloning? And recently the work of Gurdon at Cambridge suggested that maybe you can find the cytoplasmic factors that can down-regulate or reprogram the nucleus of a somatic cell. Do you see any hopeful ways out of this? And are there ways we could fund this current research such that the moral impasse would be temporary if we could just get it launched with a good deal of support? DR. PALMER: I do agree with the sentiment entirely. So the real issue is how. Let's take two hypotheticals. One is that the U.S. is restricted in its ability to pursue these technologies on ethical grounds, on moral grounds, yet other countries are not. The moral question becomes can you then use the information and technology that was developed offshore morally. And that's something that would have to be discussed. We would be far behind in our technologies, in our drug development, in our ability to provide health care to our constituents. If we had the ability to temporarily recognize the value of the lines of research with the full intent that we need to understand what these cytoplasmic factors are, nuclear transfer technology is the prototype. It is the first working example of taking a genome, which is totipotent. So a cell's genome has all of the information that you need to make an individual. My cheek cell, if it has all of its genes, is totipotent, given the right cytoplasmic factors to program it. How will you circumvent this moral problem unless there is a decision or an understanding that the morality is a combination of concepts and beliefs? This is a very difficult question, and I don't envy your task as Council. If you were to take a fertilized egg and reprogram a nucleus, create an embryo out of that to make stem cells, that's not so technically different than just simply programming the nucleus to go through all of those steps to create stem cells, and it's one of an intellectual process coming to grips with a moral stance, a belief. It's going to be difficult to separate those two, I think. So technically I think there's great hope to program the genome in a way that would lead to an embryonic stem cell that's pluripotent. The prototype of that is nuclear transfer technology, and that is the technology that's going to give you those steps to get from Point A to Point B without creating the embryo. DR. HURLBUT: Within the constraints of existing policy, do you think we could if we funded it properly find a way to do that? DR. PALMER: It could happen tomorrow or it could be years. It will happen offshore regardless. CHAIRMAN KASS: Thanks to our four panelists for your presentations, your forthcomingness. Thanks to the Council members for enduring a long, but very interesting day. We meet again tomorrow morning at 8:30, and we meet again at 6:30 for convivial repast. The meeting is adjourned. (Whereupon, at 5:40 p.m., the meeting in the above-entitled matter was adjourned, to reconvene at 8:30 a.m., Friday, September 5, 2003.) |
