The President's Council on Bioethics click here to skip navigation

 



Meeting Transcript
September 13, 2002

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



COUNCIL MEMBERS PRESENT

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

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

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

Francis Fukuyama, Ph.D.
Johns Hopkins University

Michael S. Gazzaniga, Ph.D.
Dartmouth College

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

Alfonso Gómez-Lobo, Dr. phil.
Georgetown University

William B. Hurlbut, M.D.
Stanford University

Charles Krauthammer, M.D.
Syndicated Columnist

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

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

Gilbert C. Meilaender, Ph.D.
Valparaiso University

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

Michael J. Sandel, D.Phil.
Harvard University

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


INDEX



SESSION 6: REGULATION 7: INTERNATIONAL MODELS (GERMANY)

CHAIRMAN KASS: Good morning. Welcome once again.

This morning's first session returns to our inquiry into the ways other countries have been looking at the regulation of biotechnology, their principles, their institutions, their practices, and we're extremely fortunate to have Professor Spiros Simitis with us this morning.

Professor Simitis' resume, a very modest version of it, is provided at Tab 15 in the briefing book. He is Professor of Labor and Civil Law, Computer Science and Law at the Goethe University in Frankfurt, and as of last summer, the Chair of the new German National Ethics Council.

We're delighted to have you with us.

Professor Simitis will begin with just some introductory remarks, but this is an opportunity for us to ask lots of hard questions about how these things work and what we might learn that might be relevant to our own situation.

Thank you very much, and welcome.

PROF. SIMITIS: Thank you very much for your invitation. It is a pleasure to be here.

I must say that at first I was slightly puzzled by the combination of the hotel and the room, Monaco and Athens.

(Laughter.)

PROF. SIMITIS: But on second thought, I decided that this was an allusion to our work, a mixture of gambling and critical thought.

(Laughter.)

PROF. SIMITIS: And that increased my pleasure even at being here.

Now, let me start with a few rather general remarks. The first, why I accepted immediately to come is that the German National Ethics Committee is of the firm belief that we deal with problems which at first may look like national problems, but every question we are faced by is only seemingly national.

None of these problems can be limited to a particular country. None of these problems is specific to a particular country.

The answer to that is that if we want to find solutions, we have, of course, to depart from our national structures, our national principles that we have to attempt to find international answers.

The German committee is already doing this. It is closely cooperating with the French National Commission, and we are expecting that by the beginning of next year we will have a first common proposal on one of the main topics we are discussing at the moment.

I will come back to that in a minute, too, because we are in a rather particular situation, the situation being that both Germany and France are members of the European Union, and because they are members of the European Union, they have a particular interest in common solutions on the Union level.

And we are also very well aware of the fact that speaking of international solutions means in the traditional way of thinking international conventions and international conventions may be a solution, but there may be a risk also because of the fact that most of them consist of lots of compromises, and we are in a field where compromises are sometimes very difficult, to put it that way.

Having said this, I want to say a few things about the actual situation in Europe. I will start with some remarks on the National Commissions.

Up to this day, you cannot say that every member of the European Union has a National Commission. On the contrary, we have some states not yet having a National Commission or having a National Commission which has not up to now started working.

We have some states like Great Britain, which has more than one commission, and you find something similar, for instance, in Sweden, too. But if you look at these various commissions and on the condition that you bear in mind that they do have their particularities, there is at first one striking common element.

To understand it, I would ask you to think back at the beginning of the '60s when for the first the problems or the questions of information technology came up. We were in a very similar situation.

We knew at the time that it would be a radical change in our society due to the use of computers. We knew that the computers would transform both the activities of the state and of the private firms, but knew nothing about the real consequences of the use of computers.

At that time, most of people spoke in visions, too. It was the perfect state that we all expected and the perfect rational firm that we also expected.

By now we have replaced the perfect state by the perfect person or the perfect man, and by now we are talking in visions, too, like we did it in the beginning of the '60s.

It took some time, years I would say, until in Europe the various states reacted, and they reacted in a very similar manner by installing not National Commissions, but what we called at the time Data Protection Commissioners.

And exactly as in the case of the Data Protection Commissioners, the states reacted, too, in the case of biotechnology by installing this time Ethics Commissions. Now, these Ethics Commissions, talking mainly of Europe, have two, I would say, or, no, three outstanding characteristics.

First, despite all of the difference, they are supposed to answer questions brought up by governments and parliaments. Just to give you one example so you can understand better what I have in mind, when a little more than a year ago the German National Ethics Commission was installed, in the very same moment, the Chancellor of the German Republic greeted the first members. He assigned them — I'm putting that undiplomatically — a task.

He assigned them a task by saying that we were all aware that we were in the middle of an important discussion, the question whether stem cells could be imported into the Federal Republic or not.

This is a question which at the time played an enormous role because there were first projects for importation of stem cells. All of those projects were projects by university institutes and professors, and the German scientific community was very favorable to the importation of stem cells.

At the same time we had a parliamentary commission dealing with these problems, and the parliamentary commission was at the time already obviously critical, and at the same time, we knew that by the end of the year or the beginning of the year 2002, the parliament would have to decide.

So what we were asked to do is to try and submit an opinion by the end of the year. In order to underscore our independence, we answered by saying we will think about it, but it was absolutely clear that we had no choice in the situation because we did not only have the scientists looking at us very critically. We did not only have the general public looking at us and saying, "At last there's someone who's going to say something." But we had the press and the mass media outside our doors continuously. We were for six months under siege I can only say.

So we concentrated on the importation of stem cells, and we were lucky enough to finish our work by the end of the year, as we had promised.

Why I'm saying this? This is a common characteristic of most of the commissions in Europe. It is a characteristic which has advantages and disadvantages, too. It has the enormous advantage that the commissions are so to say in the middle of the general discourse, and they are seen as an important actor of the general discourse.

It has the disadvantage on the same time that it narrows the march of your own decisions, what kind of questions you can take up and when you are going to discuss them.

So at the same time it was said that we will provide ourselves our own agenda, which we did at the same time, but I'm repeating that this is the expectation in Europe once you do have a committee like ours.

The second common characteristic is that we are not only expected to react to questions put by parliament and government, but to promote at the same time the public discourse. The public discourse in the sense that it is thought that a committee like Ethics Committee is there in order to address the general public, to understand what the questions are that the general public has, to take up those questions, to provide information, and to try to react also to the remarks coming from the general public.

We have very much thought about this point. I'm coming back to the example which is most familiar to me. I'll come to another commission in a moment. It is something very difficult to fulfill because that would mean that the commission would be permanently, so to say, on the road, in order to discuss in all parts of Germany with people who are interested in what the important questions are and what the answers could be.

What we have done, we will start in a month from now with a series of public presentations of subjects we know that they are widely discussed to which the general public is invited, and during which we will try to have a broad discussion, except the fact that members of the commission are by now increasingly going, which I think is very good, into schools and universities to discuss with school children, and with university students, value subjects. They have been been raised by the school children and by the university students.

In that forum, the first subject we're going to deal is a subject very familiar to all of you. It is the question whether a child can be damaged, and that is a torts question which has arisen in Germany after a very recent decision of the German federal court, and we will have the judge discuss the decisions with the general public together with members of the committee.

CHAIRMAN KASS: Excuse me, Professor Simitis. Could I just ask you to repeat the question?

PROF. SIMITIS: The child has the damage, you know, in the cases where a child is born. You know, the American cases, you are very familiar with it.

PROF. GLENDON: Wrongful birth.

PROF. SIMITIS: Yes, wrongful birth, and we use the word in a more crude way. We say not wrongful birth; child is damaged. I admit that this is less nice, but nevertheless it is the core of the problem.

In a second forum we will discuss the problem of patents because there's a very recent decision of the European Patent Officer. We'll come to that, too, back in a second.

And the third common point the commissions have, they are expected not only to answer questions that are put either by the public or by government or by parliament, but to anticipate the development of biotechnology, and by anticipating the development of biotechnology, to raise on time subjects to which parliament should react to, governments should react.

This is the most difficult part of it, but I think it is exactly the same that happened with information technology. This is what the protection commissioners do to a large extent, too, and this is what we expected to do also.

There are many ways of doing that, but we are thought the be the instance which timely could draw the attention to certain developments and ask for reactions by parliament.

And let me sort of say again one information which I find quite interesting. I have brought with me an English translation also of the German act on the importation of stem cells. Now, if you read that act and if you read also the general act on the research on embryos, there is one point I would like to draw your attention to.

These laws not only in Germany, but in all other European countries, too, finish by saying that this decision of parliament is a provisional decision. It has to be rediscussed and they indicate most of the time in a period of two years or three years.

That means that, like in information technology, in the field of biotechnology for the first time explicitly European legislators accept that there is no definitive answer to our problems, and that parliament is under the duty to react again after some time against the most recent developments of biotechnology to rethink and think over whatever has been said before, and to try and adopt other and new solutions wherever necessary.

So we do have a permanent discourse, a permanent public and permanent parliamentary discourse, and our commissions are part of that parliamentary discourse, too.

Now, let me come to the commissions as such. First, I have to deceive [sic] you or to confirm what you have already thought. There is no uniform model in Europe of the commissions.

You can, in fact, distinguish between two models. The first one is the more traditional, and it is by now the minority model, I would say. It is a traditional experts commission. The commissions are small. They have a limited number of members, and the members are, as a rule, scientists.

Now, there are differences there, again. You can see it best in Sweden still to this day, where you have a commission, for instance, consisting only, only of medical experts, biology experts, microbiology experts, experts in the very fields to say of biotechnology.

Experts are now understood even in this model in a different way. You do have philosophers. You do have lawyers, too. But still it is a committee consisting most of the time exclusively of professors and most of the time this is an expert committee in the very traditional sense, to put it like that, working like the similar committees we have had in the past in other fields, too.

Now, the prevalent model now is a different one. The prevalent model is a model which one could call a representative model, a representative model in the sense that you do not only find experts in the narrowest sense of the word, but you do find representatives of the general, so to say, population, too, and let me give you immediately two examples so that it becomes more clear.

The oldest commission, the most venerable, I should say, by now it has been installed about 20 years ago, is the French commission. The French commission has 40 members.

Now, at first, this is rather shocking. I admit it, but the 40 members are members and non-members, to put it like that, in the sense that they are subdivided in two groups, and this is a very interesting phenomenon because this is unique in Europe.

They are all equal — they have all the equal right to be addressed as members of the commission, but out of those 40, only about 20 do really participate in the debates and have the right to express their opinion and to vote when and if it comes to vote.

Why is that so? Let me give you an example, and it becomes, again, more clear. You do find among those 40 members four members who represent different religious communities, a Catholic and a Protestant bishop, a rabbi, and a specialist of the Koran. He's a professor of Islamic religion.

It is thought by the French parliament, will be French government because it's also the commission which is like yours and like ours; it's, again, a president's commission of the French Republic. It is thought that, of course, it is indispensable to have in a discussion like ours, representatives of the main religious communities in a country.

But it is also clear — I'm slightly now exaggerating in order to better illustrate what I mean — that the representatives of the religious communities most of the time have very clear ideas about what technology commissions are talking about, and that therefore, they are there to be consulted. They are there to be heard. They are there to be included in whatever the commission says, but they are not there to co-decide.

This corresponds to the Laicist model of the French Republic, but nevertheless, I think it is very interesting.

So among the 20 other members, you do find representatives of the religious communities. You do find not many, but to a certain extent representatives of handicapped persons. You do find besides the representatives of handicapped persons also representatives of the general political scene in political discussions, so to say, in France of very different organizations, non-government organizations dealing with these problems. Nevertheless that is the model.

The German model is similar to that. We have 24 members, and those members, well, I must say that in the course of its birth, the Commission grew more and more, but that has all the reasons which I can explain to you, but nevertheless, the fact is that we have 24 members, and among those 24 members, for instance, you do have a Nobel Laureate in molecular biology, but you do have also two bishops, a Catholic bishop and a Protestant bishop.

You do have three professors, biologists and well known biologists, but you do also have lawyers. They are apparently always indispensable. And you do have philosophers. You do have political scientists, but also you do have representatives of the trade unions, one representative of the trade unions, and one representative of the employers association.

Now, since I am detailing this, I'm sure that you would be inclined to ask me how does this work. It works, I would say after a year of experience, in a surprising manner. When the commission was first constituted, the media had only one problem: to discuss whether it was not very clear from the beginning how this commission would decide.

Since the members have been appointed by the chancellor and the federal government and as it was presumed at the time, the chancellor and the federal government was rather in favor for biotechnology for blunt economic reasons, the answer to that was that you only have to look at the commission to see what they are going to do.

But it was not so easy for them because they could conclude that they were right by looking, for instance, at some of the scientists, but they had on the other side the bishops who were sure they would not be very much in favor of what the government was expecting to do.

They had in between people like myself, where they were not sure, too, what I was going to do, and I will give you an example in a minute. And they were constantly, while we were working on the importation problems, making calculations, what at the end we would decide and who would vote for what.

My impression was after the first meetings that it is, indeed, true that you do have members with very clear ideas, and it cannot be. There is no alternative to that because a representative commission to a certain extent mirrors the reactions and the feelings in general society.

So you will find partisans of the most different views who at least at the beginning have very clear views. Those may change after some time, but in the beginning you think you know very well what they are going to say.

This is not correct. First, there is the dynamics of the group, because in a group even of 24, you are forced to say exactly what you think. And not only you are forced; you are constantly harassed by the questions of your colleagues, and your colleagues listen very carefully, according also to their own opinions. So at the end, you have a common discourse.

Now, I can give you an example for that. On the side of those who are extremely critical about technology, who in fact are not ready to accept most of things scientists expect to be done, you do have, of course, the two bishops. You do have one of the theology professors. The other one is more skeptical, contrary to what the mass media expected.

And you do have — and this is why I'm saying this, and this is typical for Germany, you do have a former Minister of Justice, a federal Minister of Justice, who was also the Chairman of the Social Democrat Party, the most respected person in the Federal Republic.

Now, he is extremely critical, but he is extremely critical not for the same reasons as the bishops. He is a person of 70. He's at the age of 75 now. Because of his experiences during the Nazi period, because of the constant discussion we have had after the Nazi period, because of the fact that he, as many of us, thinks that these are not unique events, but under certain conditions very similar things can happen again; so he is very critical.

But he is open for other solutions, too. So what I want to say is even if in advance you can speculate, at the end it does not mean you're right.

What was the consequence for our commission? One I did not like and still don't like, and I'm going to tell you that, too. In the case of the importation of stem cells, what we did is we said we will start in fierce discussions to try to distinguish arguments, and we will confront the different arguments because we understand ourselves as a commission that has to provide parliament and government with arguments.

We are not there to substitute their decision. We are not there to take ourselves a decision. But we are there to make the decision more difficult, but more transparent and to be put in a better way.

So after we put the arguments together, which you see how, opinion, we came up with different models, with four different models. The one categorically rejecting the imports; the other one less categorically being in favor of the importation, and two in between.

The one favored by many members of the commission to do something similar to what you have done — that is why we look so instantly at your decision — to ask parliament for a moratorium, and the other one which said yes to the invitation, but under very, very strict conditions, which have been described in detail and for a provisory decision which would have to be rediscussed after a certain period of time.

We, all of us, all of us thought this is the best way of doing things and let the parliament decide. But a few days before we had finished, and everyone was talking about nothing else in the Federal Republic — what are these people doing from the morning to the evening? — what happened is the journalists started again with the speculations, and journalists who do their job very well, start by calling members of the commission who were not used to be called by journalists, and the result of that was that they started asking, "Will you vote?"

And the answer was, no, we will not vote.

But what are you going to do then? Since you don't vote, how does parliament know which is the solution you prefer?

"We don't want the parliament," some of them said, "to know what we prefer. We don't want parliament to think."

So they said, "Now, don't worry about it. You are 24. This means 24 calls, and by tomorrow we know how you will have voted if you vote."

So at the end we voted, and the result of the vote you can find it is for the solution that was the prevailing. You had the two — I don't want to say "extremes" — but the two more radical solutions going more towards the center, to the moratorium, and to the conditioned yes, and the conditioned yes had I would say a majority, a small majority, but nevertheless a majority.

But since then, it is our conviction that we should avoid votes by any means.

The other thing — I uncover for you all our secrets — and the other thing which became manifest during these discussions, too, and that we were successful. Of course there are members that want to submit minority votes, minority — dissenting opinions. Put it like that. That is unavoidable, but we thought that we should do our best to try and write our opinion in a way which would incorporate the arguments and avoid to have so to say a sequence of opinions favorable or disfavorable, and that we were successful, and that is the model we have decided to stick with.

To the extent that this is possible, avoid dissenting opinions, and include the arguments in the general presentation. Whether we will be able to do that I don't know.

We are, for instance, discussing at the moment pre-implantation diagnosis, and it is a very hard discussion, an extremely hard discussion, and I don't know what the result will be at the end.

But in that discussion on the pre-implantation diagnostics, there was one point which became obvious and which I want to mention, too, because I think that that might interest you.

We do get continuously calls by persons directly affected by genetic problems. I myself, for instance, get continuous research calls, and I think, and it is the conviction of the commission, too, that we cannot ignore these calls; that even if we disagree, even if we think that we should say no to certain things, we are under duty to explain, to speak to the people, to have them come if they want to discuss with us and to raise in public their arguments and try to explain them.

Why? Not only because this is part of the respect and they're entitled to as citizens of the country. It is also part of a problem we all have, the problem consisting that if, for instance, there is someone who has a particular case of anemia and that particular case of anemia could, could, could after some time be dealt by unassisted production of another child — we come back to that in a second — if we say no to that therapeutic cloning, as it is also called to a certain extent rightly or wrongly, that same person may cross the frontier and go to Belgium or go to another country or go to Chicago. We know what the prices are. We know what the places are.

And the question is: what does that mean? It does not only mean that the German insurance companies, to give you that example, tell them you have that case of Mediterranean anemia. You could, so to say — your child is going either to die after some time or it is going to be increasingly ill and it will cost us more and more money.

The best thing could be the assisted production. You could do it in another country, but we have to say to you that if you do it, that will reduce, of course, our costs. That will save the save the life maybe, the life of your child, but we're not going to pay for that because that is illegal under German law. So it's up to you to find the money to go abroad and do whatever you think you have to do.

Now, this is no way of discussing these problems, and therefore, we're under the duty to discuss them with the persons concerned for one more reason, and I would pass then to my next point.

The one more reason being is that our whole discussion is under the impression of predictions. No one knows whether they are correct or not. You do have from one day to the next new possibilities announced in the media, that by next year or within the next month I don't know what's going to happen.

We all know that this is not correct. We all know that there may be some chances if science, quote, unquote, progresses in a certain direction, but we don't know when that will be, and we don't know what that will cost from the political and the social societal and the ethical point of view.

So our duty is, and we have done that in our report, to say; be careful. Don't believe. No one knows at the moment. Let us admit that we talk about things we have no idea or we hope. We talk about hopes, but not about reality.

And this we have underscored, and this is something we insist very much upon.

Now, the other point I want to raise in connection with the commissions, there are two different ways of approaching the problems. I will illustrate it by taking the examples of the French and the German commission.

The French commission has a clear case-by-case approach. That means that the French commission as a rule, not always, but as a rule works on the basis of questions of problems that are put to the commission either by the general public or by scientists.

The German commission is the exactly opposite. It works in a more abstract way, looking so to say in an abstract way at the problems and trying to act also in a rather abstract way on the basis of general ethical principles, on the basis of the German constitution, on the basis of other additional arguments.

Now, the French approach has one advantage, and we have seen that very clearly in our discussions with our French colleagues. Their arguments are much more precise, and their arguments are not only much more precise. In fact, most of us do not like them. We do not like them because they confront you with the problems in a very direct and harsh way.

If you have the model of the so to say child with Mediterranean anemia and they have to discuss it, things are very difficult psychologically, too, for the members of the commission. You do not discuss in abstract about therapeutic cloning. You discuss about assisted reproduction, a horrible word, but nevertheless, assisted reproduction in a particular case, and that is very disagreeable I can tell you.

But, on the other hand, the disadvantage of the French approach is that you risk from a certain moment on not to see what the general implications of what you're going to say are. You only look at your case as you find you have found a very solid solution for your particular case. But whether that solid solution is a solid solution truly you can only answer by looking at other cases.

Now, let me give you an example which is the problem we would have or we are dealing, all of us. We will deal with it next year, the so-called therapeutic cloning.

The French commission, in an opinion which has been rendered rather recently — this has not yet been published — has under certain conditions said that that could be done. They had, for instance, one Huntington case, and they had some other cases, too, but their approach is an approach where for the first time at the address of parliament and government it said, "Think about it."

It is not an approach which says, "Strictly no." Why? I don't know how we will decide. That I must say, but there is one thing we know. It is easy and you can do it as a rule in three minutes to stand up and condemn reproductive cloning. You can do that in three minutes. There's no problem.

You can have an international convention of that in ten minutes, I would say. But (a) what exactly is reproductive cloning? (b) What exactly is therapeutic cloning? Are we precise enough? How do we react in those cases? Which are the cases we are talking about? And what do we think that should be done?

So we know that we are nearing now a very decisive point and that, therefore, we are going to have a very hard time. Nevertheless, I think that the mixture of the two, the case-by-case and the more abstract discussion, is the right thing, but I wanted to illustrate that.

Now, let me come say a few words about the general situation in Europe. The first thing you have to have in mind when you speak about Europe is that in Europe we do by now have a series of texts which are for us extremely important and which have to be taken into consideration any time you speak about the problems we, both of our commissions, are interested in.

We do first have one text which is generally unknown outside the European Union, mostly unknown, though not unknown to everyone, but nevertheless unknown to most people. The text, which is the text you have to start by, though lawyers have some second thought, but I'm going to come to that in a second, is the European Union's charter of fundamental rights.

In the European Union's charter of fundamental rights, which has been adopted in 2000 by the chiefs of state and the prime ministers, there is an Article III. The Article III is called right to integrity of the person. The second paragraph of that article reads:

"In the fields of medicine and biology, the following must be respected in particular:

"(a) The free and informed consent of the person concerned, according to the procedures laid down by law;

"(b) The prohibition of eugenic practices, in particular those aiming at the selection of persons;

"(c) The prohibition on making the human body and its parts as such a source of financial gain; and"

Fourth, "the prohibition of the productive cloning of human beings."

There's not an Article II in which the — together with this article, the respect of the genetical constitution of every citizen of the European Union is asked for.

Now, to deal very quickly with the usual remarks of lawyers, the usual remarks of lawyers is, "That sounds very good. What kind of paper is that? Is that binding?"

The correct, formal, formal and correct answer: it is not binding formally. It is not binding because it is thought to be part of also the discussion and of the constitution of Europe, which is discussed also at the moment.

But that answer is only half the answer. It is half the answer because, for instance, the European Community and the European Commission has already clearly stated that no decision of the European Commission will be taken incompatible with the charter.

The court in Luxembourg has already taken up the charter. There are all the many examples that show that this charter in practice is already applied, and that means that you have to revise your own policies and so to say make them compatible with what is said here.

Now, let me give you an example immediately for that. The problem with the European Union, which that is what makes it so difficult for non-so to say Europeans to understand what exactly is going on there, is that the European Union, to put it in a very exaggerated way, has gone the exactly opposite way than the United States.

The United States started as a political union and developed more and more into an economic union. The European Union started as an economic union and develops into a political union.

So we are now in the period where we say, so to say, we are a political union and we have to think and to act as a political union.

Why I'm saying this? Because the European Commission which is, so to say, the incorporation of the economic unit has up to now a very clear policy. the policy is to promote the common market, and to promote the common market in the eyes of the European Union was also to promote those industries that will make Europe more competitive.

And to promote industries which will make Europe more competitive would mean to promote biotechnology, and in this sense they first reacted. There is a European Commission on Ethics, too. I was a member of that commission, too. I left it because I was afraid that I would have conflicts of interest between the two commissions, but that European Commission was not taken seriously up to now because the European Commission had other, so to say, other scopes in mind.

And I will give you one example. We are discussing now to what extent and under what condition the European Union or the European Commission should subsidize research. That means biotechnology, too. The first answer of the commission was, of course, this is an important field. We have to put all of our energy in it.

In the discussions in the council, which consists of the representatives of the governments, four governments, the German government, the Greek government, the French government, and the Italian government, said, "Wait. That is too quick. Have you taken into consideration the ethical implications? Have you taken into consideration the whole discussion we do have?"

And that was a very difficult discussion because you had on the other side the British and the Swedish, the Swedish being enthusiastic since President Bush's famous address, and they offer their cell lines within Europe, and the British having a very, very differentiated opinion on these problems, but they are more favorable for research and more favorable for things we do not yet, so to say, accept in the same way.

What was the result, to cut it short? The result is well known to you. The result was that much to the surprise of the commission and much to the surprise of Britain and Sweden, the majority of the council decided moratorium.

You are not going to say yes, but you are going to say if there is going to be research, then you have to consider the ethical implications. You have to consider the discussions in the European countries, and in each country this discussion has to be promoted so that we can arrive to a common solution.

So you see on the one hand it is obvious we do need common rules. On the other hand it's also obviously that we have divergences. I think that we will reach common rules. It will be difficult. I'll give you again an example. The French have, for instance, in the case of the stem cells, offered or said, "Why should there not be a common stem cell bank for Europe? We are ready to install it."

Now, to install a stem cell bank is one thing. The other thing which is even more important, what for and under what conditions is it going to be used? And this is what we're talking about at the moment.

You do have problems, for instance, with privacy, very important problems concerning that. You do have the problem of genetic tests, and you do have additional problems in the case of the embryos. And you know all of those problems.

Just to sum it up, there is a charter. There is the decision of the council that we should try and have a common approach, but we have not yet reached that point.

There is a second document I have to mention. Let me say, by the way, if this all what I'm saying raises your appetite for more documents and more information, this is why I'm here, and I just want to offer you whatever you want. You send us an E-mail, for instance, for the French opinions, and we will try and procure you the materials. We cannot promise that they will be in English, but what we can promise is that we will send you the materials.

The other document is a part of what is called in Europe euphemistically by the lawyers the family of documents. The family of documents means that we take into consideration documents which are not genuine documents of the European Union, but they are documents of another organization with which the European Union cooperates intensively. That is the Council of Europe.

The Council of Europe has in 1950 adopted a Convention on Human Rights. That convention of 1950 was in 2002 complemented by an additional protocol on human rights and biomedicine concerning transplantation of organs and tissues of human origin.

Now, that convention, that additional protocol has yet not been ratified by five members of the Council of Europe, five members belonging to the European Union, for a different reason. Germany did not ratify it; it did not even sign it because it says it is too lenient.

Belgium said it's not lenient enough. So you have the same problems.

Now, that brings me to the other point you have raised in your letter. There is a chapter in the convention on organ and tissue removal from living persons. The general rule is removal of organs for tissue from a living person may be carried out solely for the therapeutic benefit of the recipient and where there is no suitable organ or tissue available from a deceased person and no other alternative therapeutic method of comparable effectiveness.

And then it says — and that is a crucial point — organ removal from a living donor may be carried out for the benefit of a recipient with whom the donor has a close personal relationship. That is the German law, too, as defined by law or, in the absence of such relationship, only under conditions defined by law and with the approval of an appropriate independent body.

The second part was considered by Germany to be too lenient. By Belgium it was thought it is not enough.

And there is another article I just wanted to quote because that is in the middle of the controversy. That is Article XIV, protection of persons — I can leave you my copy of the convention here — protection of persons not able to consent to organ or tissue removal.

"No organ," it says at the beginning, "or tissue removal may be carried out on a person who does not have the capacity to consent." Now comes Part 2 of the article. "Exception." I always give an opinion that we should start reading articles and laws from the end and go upwards. That would save enormously time. "Exception: and under the protective conditions prescribed by law, the removal of originality of tissue from a person who does not have the capacity to consent may be authorized providing the following conditions. There is no compatible. The recipient is a brother or sister. The donation has the potential to be life saving for the recipient, and the authorization of his or her representative or personal body provided below has been given specifically and in writing."

Now, this, according to many members, can be interpreted — I don't want to go into the details — in a way which is too lenient in the case of persons not able to consent for themselves and facilities, so to say, the access to the organs.

Nevertheless, this convention is also part of the discussion, but it is a contested convention. I have to say that, and I must again repeat that what ultimately decides are the genuine texts of the commission, and that is the charter. As such that doesn't change anything.

Transplantation is at the moment one of the crucial points. We have not yet raised it in the commission, but the situation in Germany is the following. The German law is clear. I said you can only donate. You cannot commercialize, so to say, the body. And you can only donate under very strict conditions prescribed by the German law.

Now, the ongoing discussion at the moment is should it not be radically changed in order to accept a certain commercialization of the body. Why that? The argument promoted especially by medical professors is that we do not have enough organs, that the donations are scarce, and that we need far more organs, and the fact that we do have, for instance, a European kidney bank or very similar things is not enough.

The professors who argue in favor of these solutions have increasingly happening meetings as the main allies American professors, especially professors of economics, for instance, like Barry Becker, and you know them better than I do.

An I will come to my final point now. That is something that worries us particularly, that in all these fields the discussion is dominated by the Internet, by the Internet, because whatever you need, quote, unquote, you get the offer on the Internet. And the question is: how do you proceed afterwards?

And we have had those cases in Germany. You can literally get everything, the offers, continuously. I don't know if you know them. I don't want to list them here.

But, for instance, we had very recently in Germany one case which made us very much think about what is going on, the import of kidneys from Turkey. That was done in Britain already. That was done in Britain already, but increasingly there was a real, very well organized — we spoke of the kidney mafia — offering the kidneys. And the same applies to African countries.

And that brings me to my last point, which I spoke for. How long? You encouraged me to speak long. So I spoke longer than I thought.

The kidney problem and the similar transplantation problems we have had has induced us — I mean the German Commission now and the French Commission and the European Union — to table a subject which up to now has scarcely been discussed. What exactly the implications of our discussions are with regard to Third World countries? Can we limit ourselves to elaborate principles we agree about, but at the same time tolerate that the industry does exactly the opposite of what we are expecting to be done in a Third World country? In view of the particular social and political problems in this country, can we ignore that?

Now, to be clear, we are not so much arguing for an international convention. It would be good, but it would take very long. We are arguing for rules within the European Union, and we are at the same arguing for broad public discussion to draw the attention in all countries to this particular point because it cannot be that the Third World countries are the field of experimentation for our industries.

It may be very well worth to promote our industries, but not at the cost of the people in these countries. And this exactly the problem we are confronted by at the moment.

And one last word because that was raised in your E-mail, too, and we can talk about that, too: patenting. Now, this is on the agenda for the German Commission.

There is a very recent decision of the European Patent Office. I would have brought it with me, but the reasoning has not yet been published. It is expected for the weeks to come. We will have someone in Berlin to speak with us about it, but as soon as a decision is there, I will mail it to you.

Patenting, well, I will call it human beings, is according to the charter, if you read it correctly, and to the other documents, illegal, inappropriate and illegal.

Now, in the particular case, the European Patent Office — I don't want to go into the details — had granted a patent, and the patent was afterwards revoked in an opposition procedure because the European patent law or the directive for the European Patent Office provides that member countries of the European Union can oppose, but also organizations interested in a particular field.

So Greenpeace and the German government, among others, had opposed that patent. The interesting thing is that good lawyers that they are at the European Patent Office, they said that the patent had been misrepresented by those who had submitted the application, and it was not clear that it includes human beings, too.

The other interesting is that it was a patent application by a Scottish university.

Now, we have a few thousands of applications all over the world which are in this direction. Most of the applications of the European Patent Office come from the United States. The second in the line is Britain and Scotland, in particular. And this is amazing to a certain extent because one could ask, well, we all know about Dolly, but why are they so interested.

Now, in my view, and that's my personal view — I want to just put the problem to you — it has something to do with the situation of the universities. For the Scottish universities and British universities who have been denied subsidies and grants by the state under the Thatcher government and since then, this is an important source of income, but that is an un-American question, and I know it, but it is a very European.

The question is: to what extent if in a field of common interest and of decisive importance for the future of our society the research is commercialized and leads to a monopoly through the patent which instigates the research at the same time, reserves the monopoly, and commercializes its research, to what extent is this state — and this is the question we have put — is the state — but we have not answered it yet. We are going to discuss it — under the obligation to provide funds to university to insure a minimum of common knowledge for researchers all over the European Union, for instance, and not have the universities, so to say, retire into the patent in order to get the defense all the more; that what we expect is a maximum of transparency. We will see it in the stem cell importation, a maximum of transparency because we say that we know that to think that you can prescribe science, what it will do, is an illusion, but what you can expect is transparent research and public discussed research.

And if you have, to put it in an American way, a robust public discussion, then you may prevent certain things like in the case of the European patent law, it was not the European Patent Office. It was the general public that reacted, and then you have to think about other policies.

That was my very last remark. I thank you for your patience, and excuse myself that I was long. That underlines my pleasure.

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

I'm sure lots of people would like to get in. Let me just ask for clarification. Now it's simply about the German Ethics Council.

You have simply advisory function; is that correct? You have —

PROF. SIMITIS: Yes.

CHAIRMAN KASS: And the relation to the government that you've chosen so far at least is to lay out the arguments, the issues being complicated; that you want to make sure that the arguments are out there, but to leave the burden of decision to those who are charged with the burden of decision; is that correct?

PROF. SIMITIS: Exactly.

CHAIRMAN KASS: And is there some body, some national body, that has something like the regulatory authority, let us say, of the British Human Fertilization and Embryology Authority?

In other words, if one were looking for places not simply to discuss the ethical issues and lay out the arguments, but actually to govern the practice?

PROF. SIMITIS: The answer is yes to a certain extent. In the German law — I will leave you the English copy here on the importation of stem cells — and in our opinion, we have pleaded for the installment of a body of independent experts with a regulatory function. We think that when you enter very specific problems like the importation, for instance, or there may be other cases, too. We haven't talked about it. Then you may need that.

But we think that so far as we are concerned, we have to give advice, but then it is the responsibility of the government and of the parliament to take decision.

We may disagree with those, and we will say it, but it is not our task to interfere with the regulatory process as such. You may have like the importation. You may have a particular independent body, but not us.

CHAIRMAN KASS: But this recommendation then would be for a regulatory body that would deal on an ad hoc basis with each case that comes along or is there some thought that there might be the need or the Canadians who we had representative from here earlier have designed an institution that would set policy and even have enforcement powers in the whole area of research involving embryology, genetics, reproductive technologies and the like?

Just institutionally speaking, is it too early to think about these things or is it thought to be not a good idea?

PROF. SIMITIS: Remember at the beginning I pointed at the experiences with privacy and information technology.

CHAIRMAN KASS: Right.

PROF. SIMITIS: When we drafted those very first laws, the State of Hessian Germany was the very first state drafting a law, and in that draft, we act exactly like you did now, and we said also in addition to that since we have to admit that we do know a few things, but not enough, we need a body that makes proposals, but that can interfere to a certain extent, and those were the Death Protection Extension. There were registers in Sweden, which were at that time, at that time, introduced and other means.

So my feeling is — but I'm very careful as far as that is concerned — that at a certain point — I don't know when, but at a certain point — when the discussion has become a little more broad and more precise than it is at the moment in Germany where it is a very general discussion, indeed, the moment may have come to have such an institution, but for the moment the only thing we have is in the importation case.

CHAIRMAN KASS: Okay, and if people would indulge me, let me just continue on just a few sort of factual things.

Well, these are sort of related questions. The special interests, the people who have a high stake in this, whether they be the lab technologists or the medical researchers, on the one hand, or the various religious bodies or the Greens, how do they affect the work, let us simply say, of your own council? And to what extent does the assessment of the ethical issues take into account those various kinds of pressures both in terms, for example — you've in a way alluded to this — in terms of the composition of the body? You've apparently seen to it to provide room at the table for people who somehow represent these interests, but —

PROF. SIMITIS: I know this is a very complicated question. My first reaction would say that these possible conflicts of interest should have been considered before putting the commissions together, but that was not the case.

And we were very sensitive to whether scientists, members of the commission do have their own private firms, which is increasingly the case. It was in the case of one member, but that member sold the firm, and not to my surprise, I would say I thought this was a very distinct case.

The big, the renowned enterprise that bought that small firm dissolved the firm within minutes because it thought it would be at the moment competition it would not particularly like to have.

But nevertheless, we are aware of that, and it is thought that especially the Chairman of the Commission has to look thoroughly at the members where such things may happen and react on time if there is a suspicion that the interests may influence the decision.

And up to now I must say we have had no such case, neither in the case of the employers, of the person, former minister who is now, again, a candidate for parliament, nor in the case of the unions, nor in the case of the scientists.

On the contrary, I must say we are aware of that. We look thoroughly at every one of us every time, but I think that personally if you ask me, that's my very personal view. I think that if there is such a collusion possible, collusion, then someone should not be a member or at least it should be very well known in advance what kind of interest he or she possibly represents.

But just to say it again, the more you are inclined to have a representative model, the more you run those risks, and whether there is someone who is absolutely fully under the old conditions independent is something very difficult to say, too, I must say, by experience.

CHAIRMAN KASS: Okay. One last thing. It is commonly said in the debates in this country that the kinds of restrictions that are certainly prominent in Germany with respect to certain embryo research, for example, that this is somehow incompatible with or throttling to a thriving biotechnology. Yet the reports are that Germany at least of the nations of Europe has perhaps the highest rate of growth in biotechnology.

And the question is: to what extent is the scientific community in Germany, not just the industry, but the scientific community, comfortable with the belief that science can proceed notwithstanding the existence of these ethical limitations politically enforced, or is the scientific community quite unhappy with the restrictions and eager to have them lifted? Is there a difference between you and us on this kind of question generically speaking?

PROF. SIMITIS: Well, I must say that I don't know exactly what the position of every one of you is, but what I can say is that there is no such thing as a uniform reaction of the scientific community in Germany.

Let me give you an example. In the case of stem cells, like everywhere, one of the main issues was to what extent can you work with adult stem cells, and by that, so to say, avoid the problem of embryonic stem cells.

In the scientific community in Germany, there are two groups. There's one group clearly saying there can be no fruitful research if you do not do it with embryonic stem cells. There is another group, the smaller group, very prominent scientists in that group, too, saying that you could restrain yourselves to adult stem cells.

And there is a third group, and that is the one that played a role in our discussions, too, saying that you may need research with embryonic stem cells for a certain period of time in order to be able to put the right questions afterwards when you work with adult stem cells. This is the position of the French Commission, too.

So it is certainly true that from the economic point of view there is pressure to advance biotechnology, and this is why we have written into our report that we are not taking economic and similar considerations into account. We refuse to do that. We said that explicitly.

But of course, in a country where there is a high degree of unemployment and where the economy has to be restructured to a certain extent, biotechnology is a particular hope.

And you do have within Europe the constant hint if we do not do it, then the others will do it. But I have learned by now that there's everything that if we do not do it, the others will do. So at a certain point we have to say we're done to it, and we do other things. This is not the only thing we can do.

But nevertheless, there is pressure. But since our opinion, and you can see it in the decision of the parliament, the discussion has quieted. It is not only more reflective, more critical than it was before, but it is not the kind of discussion we had until we published our opinion where everyone was saying it has to be done today. If it's not done today, it will be never done.

CHAIRMAN KASS: Thank you very much.

And thanks to the group.

I have Michael and Mary Ann and Alfonso.

PROF. SANDEL: Well, first of all, thank you very much for a really terrific and masterful presentation. It gave us a full sense of the process and the approach in Germany and in Europe.

And I, if I could, would like to ask you a question about the legal and ethical heart of the question that your council has been confronting on importation of stem cells, and that for you arises as the big question, the big ethical question and of public policy precisely because, as Chairman Kass was saying, you have a more restrictive background law on embryonic stem cell research.

Because the production of embryonic stem cells is prohibited in Germany, the question for you arises: well, can we import them? And so that's what you've been grappling with, and that's what this opinion deals with.

So those pressures are all shifted, and the ethical arguments then are shifted to the question: well, if we can't produce them here, can we import them from somewhere else?

And I'd like to ask you about that and about the opinion and the law if I could. It's not a question that you haven't considered before, I'm sure, and it's about the puzzling feature of the solution legally and ethically.

The legal position, as I understand it, or the legal solution is you can't produce them here even from excess embryos, not in Germany. But under certain special conditions, they can be imported from elsewhere. And in the vote, this complicated vote, but I've gotten used to reading complicated votes over my experience here; as I understand it on the importation question 15 said permit importation; ten said let's have a moratorium, but within those categories, within the ten who wanted a moratorium, there was four who wanted a permanent ban and six who wanted a moratorium, and apparently the four who wanted a permanent ban joined with those who favored a moratorium to produce the ten, which is an ingenious position ?-

PROF. SIMITIS: True.

PROF. SANDEL: — to take.

But then there's a comparable thing on the other side, which is of the 15 who wanted to permit it, nine took the position that ethically it should be permitted to use embryonic stem cells from excess embryos in Germany or abroad. Therefore, of course, we favor importing them, but the nine said we would also favor permitting that here. Whereas six of the 15 didn't say we should permit it here, but they said still we should import them.

Do I have that right?

PROF. SIMITIS: Absolutely. I was one of the six, yes.

PROF. SANDEL: You were one of the six?

PROF. SIMITIS: Yes.

PROF. SANDEL: Oh, then my question is all the more relevant to you.

Now, the six who say we shouldn't permit it here, but we should import them from abroad, now, that's actually the legal position as well. This moral argument corresponds to the actual legal position in Germany.

So here's the question. How ethically speaking is it possible to take the position that it's wrong to do embryonic stem cell research on German embryos, but it's okay to import foreign ones?

PROF. SIMITIS: Thank you for the question, and I will try to explain it.

You could have been more blunt, and you could have said, as many people have said: is that not a hypocritical way of dealing with problems, saying we are not doing anything with our embryos? Let us import foreign embryos and do what we don't want to be done with the embryos in this country.

Now, to understand that, you have follow the tormented path of the minds of lawyers. I fully agree with you, with what you have said. The first question was — I'm trying to reconstruct to explain — is the importation permitted or not.

From what you said, it sounds like one could have said the importation is not. It may be permitted or it is not permitted, and we have to permit it.

Now, what the lawyers in Germany said is this, and I have to say that to explain it. The law you have mentioned, research with embryonic stem cells, they say is a penal law, and it is a penal law that means that it applies only under certain conditions which are described in the law, and it doesn't say anything about import or the importation because it's a penal law.

And because it doesn't say anything about the importation, we have to limit ourselves to the question can they be imported or not.

I fully agree with you and lawyers who have said this is not the way to act. You have to say to start do you agree with research or not, and then you have to proceed.

In order to illustrate this, and what we said, I constantly pointed at the situation in France where research, embryonic research, under certain conditions may take place, but importation is prohibited. This is the opposite, you see.

And the question arose in France: why do they react in that way? And their answer to that is if we agree with research, we have to have research in accordance with our own principles. So don't want stem cells to be imported as long as we don't know how those stem cells were, quote, unquote, produced at all.

So in order to solve our dilemma because we said it is a penal law, and if it is a penal law we can or we have to say something of the importation, but the German law continues to exist, the one you mentioned unless you revise that German law, and because the majority of parliament, the absolute majority of parliament, and the majority in the public discussion was to don't revise yet the law, we said, the six said, "Let us accept the importation for a specific period of time. Use the importation as a means to promote the discussion, too, and then in two years decide whether the German law should be reviewed as such or not."

I'm well aware that this is a complicated decision, but it is due to the fact that the majority of lawyers in Germany said you could import, and they reduced whole questions to the import. They did not want to discuss the other law.

But I think that we probably will do that because we have, like the French who are ready now to admit importation to a certain extent; we do have always the question you cannot ignore where they come from, and you cannot stop asking how did they get those and under what conditions.

And we have written all of that into the law and tried to find a way out of the problem. This is how it came about.

Otherwise let me say our discussion — I know nothing about yours — but our discussion is always a mixture. Our points of reference are, first, constitutional, five points of reference. The German federal constitution which states that you have to respect the dignity of every person, and all these discussions are linked to the dignity principle.

Now, we don't need to argue long about that this is a question of interpretation, too, and that we do understand dignity in very different forms from one decade to the other, but nevertheless, you have this mixture of constitutional law oriented discussion with ethical principles because the ethical principles are used as means of interpretation of the principles of the constitution.

And, therefore, I mentioned the charter before. But, again, I understand very well what you have said, and this was a dilemma we were well aware and we are living with that.

CHAIRMAN KASS: Mary Ann Glendon.

PROF. GLENDON: Well, I, too, want to thank you very much for this presentation, which illuminated so many problems that we've been discussing over the past several months. In fact, I wish that we had had you visit us earlier, and I do ?-

PROF. SIMITIS: You can come and visit us on your terms.

PROF. GLENDON: Well, I also wanted to say that it's so impressive to hear about the degree of collaboration your group has already had with groups in other countries, and I do hope that this, as they say at the end of Casablanca, will be the beginning of a beautiful friendship, that we can continue to exchange experience.

It's just so interesting to hear about the experience, which coincides with ours in many ways, but also it's different. And my question really relates to some of the points of difference, in fact, to one of your points of reference.

I'd very much like to have you say a little bit more about one of the items that is mentioned in the European charter. You mentioned that the parts of the charter that pertain to our issues are not binding in a technical sense, but that they are in another sense.

As I understand it, one of the reasons that some of those principles are already binding is that they weren't something new in the charter. They were aufgehoben as it were, taken up from principles that were already pervasive in most of the civil law systems, but not, interestingly, in the United Kingdom, Scotland, and Sweden.

So you referred to Article III of the charter and the general heading of the integrity of the person. That, of course, is a familiar concept in other human rights documents, and under that heading, the third item you mentioned was that the body, the human body, should not be a source of financial gain.

And that's the point I'd like to hear you say a little bit more about if you could because it's my understanding that this is a fundamental principle in many civil law systems, and it's a somewhat unfamiliar principle at least legally speaking. In the United States, it's unfamiliar to us.

So could you say a little bit about where this idea that the body is outside commerce came from? How pervasive is it? And then why do you see — you mentioned that there's a little bit of questioning of that principle now, encouraged by some American economists who think it's just fine to be buying and selling.

PROF. SIMITIS: Some English speaking German.

PROF. GLENDON: Yes. Thank you.

PROF. SIMITIS: Thank you.

Now, let me explain again the birth of the charter, so to say. The birth of the charter was very much contested. It is the result of the change of the European Union into a political union that was directly addressed in the Amsterdam treaty.

And in order, so to say, to specify what exactly a political union means, the first question which arose was should there not be a constitution of the European Union and we do not have in that constitution also a part on human rights, so to say.

Now, as you quite rightly said, the ones opposed to that were especially the British because the British — and I have to be impartial — the British and the Danish, the British especially because they said, "We do not need such a thing as a constitution," and they said by referring to the fact that Britain had some years ago ratified at last the European convention on human rights, and that had led to spectacular changes in British law because of the decision of the Court of Human Rights in Strasbourg.

So they said, "Once is enough. We don't want so quickly another document which may lead to equal far reaching changes."

And then as a compromise it was said, "Now, let us not speak any more of the constitution. This will have to be done later on, but let us concentrate on the charter," the charter being, so to say, the genuine document concerning human rights for the political union, which later on could, could be integrated into the constitution.

And in order to find a compromise to discuss the charter — it could have been you — as they explained it, they said, "We don't want something absolutely innovative, something which, so to say, starts from the ground, but we wanted to codify our common constitutional traditions."

How do we codify our common constitutional traditions? By taking into account (a) the existing constitutions; (b) the European Convention of Human Rights of 1950; and (c) the decisions of the constitutional courts and the decisions of the court in Luxembourg, the European court.

In discussing now that, the parliament or representatives of the parliament in the convention, those were the most active members, I must say. The representatives of the European parliament in the convention came up — after the statement that everyone has the right to respect what's adopted — came up by pointing up the biotechnology protocol I mentioned before of the Council of Europe.

And they said in a modern charter, we cannot stop at that very abstract statement. We need to do two things. One thing is Article III, and this is partially or literally taken out from the convention, and the other thing, to give you another example is that we have to introduce into the charter the protection of personal data, privacy. And that was Article VIII.

And so you have to read in the case, for instance, of genetic data III and VIII. Both provide, so to say, the protection actually. So it was a mixture of what existed, but with some articles which were not incorporated into the constitution.

So to give you one more example which is not particularly relevant for what we are discussing here, but I always found that an astonishing thing, they could not agree whether or to what extent they should include what we call the social rights, the right to unionize, the right to strike, and so on; could not agree about that and until someone find an ingenious solution, they introduced a new chapter called "Solidarity."

And in that chapter, "Solidarity," you do find the rights of employers to organize. You find the rights of the citizens, but it is now under the head "Solidarity." It sounds very good and gives the impression that this is not by all means the whole thing. It is something — it is the whole thing, in other words.

But this is old and partially new.

CHAIRMAN KASS: I have, let's see, Alfonso, Rebecca and Janet.

DR. GÓMEZ-LOBO: Unfortunately Michael Sandel stole my question. So I'm going to have to resort to something along those lines but rather different.

The first is a clarification question. Does Article III, Section 4, prohibit every form of cloning? Does it distinguish cloning according to further application, whether for biomedical research or for productive reasons?

That would be my sort of factual question.

My other question is broader, and it's really trying to elicit an opinion from you because from what I've heard today, I'm tempted to think that a German constitution and in general German law by insisting on the dignity of every person I would say surely is reacting to the Holocaust, to the horrors of the Holocaust. It seems to me that putting that in the forefront is very significant.

And then this charter in its Article III again puts in the forefront the right of integrity of the person, and among others, the prohibition of commerce in bodily parts.

Now, from the work of your commission, it seems to me that thinking heads in Europe are sort of deviating from that. Is there an erosion of this firm principle of protection of the person?

And, for instance, I'm thinking if we're talking about importation of stem cells, surely there's going to be payment involved. I mean, no one is going to ship them for free.

And this, of course, ties in with your legitimate concerns about Third World countries. It seems to me that the free market has many virtues, but it also has the vice that if you come in a weakened position to the market, you're bound to sell whatever you had, be it your labor force or be it your organs if you're desperate for money.

So, I mean, I totally agree with you that that should be a very major concern in those countries that have developed biotechnology. What sort of exploitation of Third World — and I think above all about women — could come about precisely because of the needs arising from that.

And of course, the reaction would be to say, well, this leads to the moral imperative to be very, very strict in maintaining the wording, so to speak, of Article III of the charter.

Thank you.

PROF. SIMITIS: Thank you.

Now, the first question is the easier one to answer because the charter says the prohibition of the reproductive cloning, nothing more. We all can start arguing what exactly is that, but nevertheless, this is what it says.

Now, the second question is far more difficult and complicated to answer. Let me first say that, of course, the Holocaust has played a very important role, but especially the six members mentioned before, or the two, especially for the former German Minister, are people who, on the one hand, say we have to support science, but on the other hand say we have to be critical of science, not because so much of of the Nazis and the Holocaust, but we have other examples.

One example I mentioned, for instance during the discussion is a familiar example to many of you because it is an American example, too, is lobotomy. If you take the example of lobotomy, for years, for years European courts and Swedish courts, in particular, pointing at the experience in the United States, said in the case of schizophrenia what's the answer: lobotomy.

What was the result of that? A growing number of cripples, people you destroyed. You destroyed by applying a method which obviously was not respecting the integrity, was not fulfilling why it had to do and had those consequences.

And we had in the case of Sweden where until the '70s merely you had eugenic practices applied. So we said we cannot say we accept whatever science, and we can define science, if you define science other than what the scientists say, but we have to sit down and discuss and have them explain, and we have to think in common about the implications.

In the case now of the importation, the dilemma is obvious. It is the one you mentioned. It's the same dilemma the French had. You can say yes to the importation, but you cannot stop at that yes. You cannot stop at saying, "I am for the importation, but I'm not interested in where do they come from and how have they been, quote, unquote produced."

Therefore, the law says — I will leave you the text here — that a competent agency — that is the one we were talking about — has to satisfy itself (a) — that is already the answer to one of the questions you put me yesterday — the embryonic stem cells were derived before January 1st, 2002.

The reason, that was against the position of most of the scientists. The reason why we said that is we do not want to provoke the impression that they may have been produced for that particular purpose.

In the country of origin — that's complicated, and the importance comes afterwards — in accordance with relevant national legislation — that's not satisfying yet — their end are kept in culture or are subsequently stored using cryopreservation methods of an embryonic stem cell line.

(b) The embryos from which they were derived, the stem cells, have been provided by medically assisted in vitro fertilization in order to induce pregnancy and were definitely no longer used for this purpose.

So whether it is enough or not is another question, but the purpose is obvious. There can be no importation of embryos specifically produced for research purposes, but you have to prove as a professor, for instance, if you want to import at your university to work; you to prove how were they produced, when were they produced; and what were they produced for.

And then the law continues and says, in answer to your question, no compensation or other benefit in money's worth has been granted or promised for the donation of embryos for the purpose of stem cell derivation.

So whether this is enough I don't know, but nevertheless, this shows you what the intention is, and that complies with what the charter says and what the biotechnology convention says.

But I brought the example of transplantation because I don't want to evoke the impression we have solved the problem. We have solved nothing. We have, so to say, said what we want, but we are now confronted — and those are German doctors as we all try to read whatever is published. They know very well what's happening in the United States ?- and they say — I'll give you one more example — "Let us talk about how we can increase the number of transplants. How can we do that?"

In order to do it, we have to induce people. What can we do to induce them? We can pay them, all of the people we can map. We can give them tax advantages.

If you say — so to say, you can deduct a certain amount from your taxes on condition, of course, that you offer a kidney or whatever, I don't want to say anything about that. I'll let you think yourselves, but I can imagine what you're thinking.

But anyhow, they have many other such proposals, but they all say without an economic instigation there will be no increase of organs, and therefore, let us do it.

And you see, the professor who is the champion of these ideas, a very impressive and cleverly arguing person, is at the same time professor in Germany and in Israel, and the imported embryonic cells or the ones that will be imported, they all come from Israel.

CHAIRMAN KASS: We are coming up on the break. Let's ask briefly Rebecca and then Janet for brief questions and then we'll break because I don't want to steal time from the next session.

PROF. DRESSER: Well, you said so many interesting things it's difficult to choose.

I was interested in some more information about your procedures, how you are chosen, not just the public representatives, but everyone. Do you have staggered terms? Is this an ongoing group so that it's in perpetuity or how is that set up?

Another question I had I'm very interested in this public representation issue/problem. Could you comment a little on the participation of the public members, the independence, the ability to deliberate with experts, sort of maybe the education that's needed for people to be effective in that role?

And also, you said you were starting to interact yourselves more as a commission with the public. Have you — if you've done some of that, how has that gone? Do you have some comments on that aspect?

PROF. SIMITIS: Yes, very briefly, first, the commission has been installed by the federal government for eight years, first term, but two terms. We, the members, have been installed as members of the commission for four years.

We were chosen — well, formally we were named by the federal Chancellor. We were chosen by the federal government, a group of ministers directly interested, so to say, in these questions, maybe justice, maybe research, and those were their criteria.

Don't ask me which. I don't know, and I constantly say in public I don't want to know. I don't know it. I look at my colleagues and that's all I can do.

Whether this will go on after the four years I don't know because there was a parliamentary commission. Whether there will be a new parliamentary committee or what is going to happen after the elections I don't know. Until 2004, I'm sure that we are there and you are welcome as many times as you want in Berlin.

Now, the other thing is as far as the public discussion is concerned, I'll give you an example. In October we will have a public discussion on what we and the French call biobanks, which are organs and stem cells, for instance.

By the way, the French, who are always very keen to choose another language said that the word "bank" induces that money plays a role, and then they said it's better to speak of biolibraries.

(Laughter.)

PROF. SIMITIS: Whether you like that better and want to say "bibliotheque," it sounds much better, but nevertheless, this is what they have.

Now, we have a public meeting on biobanks. How is that organized? The way it will go is we have certain topics, genes and so on. These topics will be presented in the morning by experts, external experts. We are listening, too, so to say, because we are in the process of thinking.

We have invited handicapped organizations, for instance, organizations interested in biotechnology like Greenpeace, for instance, and other organizations, and we have invited the general public, and the ideas that the whole day until six o'clock after the presentations, the public will debate with the experts, and we have at the end, at six o'clock in the afternoon, from six to eight, a round table with members of the commission who work on that subject and that particular instant. That's our model.

As to schools and universities, we haven't done enough, but the times it was done, that went very well. There were young children, for instance, and they were extremely interested, and they have very pertinent and I must say I liked those meetings. Some of those were the best meetings I have ever been, and they look at you and they know very well whether you want to use your authority in order to not say anything or whether you are really taking them seriously.

And we have got letters from the schools asking us to come, and I think it's a very good idea, but we haven't yet done it. Importation prevented us from doing it more, but we will do it more and more.

CHAIRMAN KASS: Thank you.

Finally Janet. Thank you.

DR. ROWLEY: I want to make a comment, and then I had several questions, but I'll ask only one. The comment related to the document that you just read again about prohibition of money to donor in terms of the embryos brings up again a favorite issue, I think, of Rebecca's. So the woman and the families get nothing, but the companies can charge $5,000 per cell line, which is, you know, in theory immortal.

So I think that that raises at least for me some serious issues.

The question I want to ask is something that you touched on amongst the topics that the commission is studying and relates to patenting, and you indicated that the European Patent Office had recently issued an opinion that patenting is illegal. And I wondered just what the dimension of that was because there's been, of course, a great deal of patenting of DNA or of parts of genes for various purposes, and I assume that that's not what the patent was covering, or was it?

Because this is an issue that we've also talked on.

PROF. SIMITIS: So let me answer.

DR. ROWLEY: Yes.

PROF. SIMITIS: Let me answer. First, you're right, of course, in what you are saying, that this is an issue one has to think about. The term used for that issue and we use or use half of the terms we use is in English by now; the term we use and you probably also use is benefit sharing.

The idea is that there should be a benefit sharing by those who are in favor that something should be paid for exactly the reasons you mentioned, is that this would be morally speaking and politically speaking and economically speaking a benefit sharing.

This benefit sharing idea has come up in the Iceland Project where the genetic data of the entire population are collected, and the Prime Minister and parliament said that this is the only thing Iceland can offer. It has no coal. It has no steel. It has nothing else, but it has genes, and those genes could be, so to say, an important source for research in the pharmaceutic industry; that the individual person should also be profit.

The offer from all I know was at the time that they were given to Hoffman LaRoche for research purposes; that Hoffman LaRoche would, so to say, give the Icelanders medication, Hoffman LaRoche medication, of course.

Now, whether this is benefit sharing, I don't know.

(Laughter.)

PROF. SIMITIS: I'll leave it to you.

The problem is, indeed, as you know, from the American cases, too, if you go into that direction, then inevitably you commercialize. You may think that it is unjust, but that is the door for commercializing at the same time.

And our idea and parliament's idea was since we have something like three embryos every time in the case of in vitro fertilization, sometimes a little more than three, then in parliament the idea was proposed to adopt the embryos, but that's a very complicated question.

And then the other issue that we discussed was in that case, it may be acceptable if the parents donated for research purposes abroad. Whether we would do that in Germany afterwards, I don't know, but I'm just trying to explain it, why we did that.

Sorry. You had the second question was?

DR. ROWLEY: About the potential patenting in the European Patent Office.

PROF. SIMITIS: I have brought with me, and I will leave it here so I can be very short, the opinion submitted by the European Ethics Council. In that opinion there are materials, too, explaining how the discussion went on in Europe, especially in Europe.

But I have to repeat, the lawyers are careful people, and the lawyers of the European Patent Office never said it cannot be done. They said it was misrepresented, and we never that the intention could have been to use it for human material, to put it like that.

And because it was misrepresented, we revoke it, you see. So they didn't say more than that. That's all, but the argument of the German government and of Greenpeace was because of the biotechnology convention, it is illegal to use material for purposes of research by a private company because you commercialize them at the same time, and then there would be all of the legal and ethical arguments, but I will leave you the French opinion here or the committee's.

CHAIRMAN KASS: Professor Simitis, thank you for an extraordinarily fine morning.

We've run a little over. We started a little late. I don't want to keep Dr. Sweeney waiting, and I don't want people to have to leave. So let's do a ten minute break rather than 15. We'll start at ten minutes of the hour.

(Whereupon, the foregoing matter went off the record at 10:40 a.m. and went back on the record at 10:53 a.m.)



SESSION 7: ENHANCEMENT 5: GENETIC ENHANCEMENT OF MUSCLE

CHAIRMAN KASS: All right. I know there are some counsel members with planes to catch, and I don't want us to waste any more of Dr. Sweeney's time. We're delighted to welcome Dr. Lee Sweeney, who is Professor and Chairman of the Department of Physiology at the University of Pennsylvania, who has done just a significant amount of outstanding work on muscle physiology and who is going to speak to us today about the genetic enhancement of skeletal muscle and its performance.

Thank you very much, Dr. Sweeney, for being with us.

Push your button there. There we go.

DR. SWEENEY: Thank you.

Yeah, I'm going to just try to give you in half an hour or so background about some of the work we're doing, and then I'm hoping just to allow you to drive a lot of the discussion because I'll set up some of the issues that I see, but as a scientist, I'm afraid I don't think some of the ethical ramifications through quite to the extent of the discussions I've already heard this morning.

My interest is in disease states of both skeletal and cardiac muscle. I'm going to restrict it to skeletal muscle because I think it gives you a good example of really how gray the boundary is between therapeutics and enhancement when one is starting to think about what can be done with genetic manipulation in adults.

Skeletal muscle is a big target in a person because it makes up the majority of the mass of their body, and it's an interesting tissue in that it has built into it cells called satellite cells which are not differentiated muscle cells, but which are actually cells that are called upon to divide and differentiate and regenerate the skeletal muscle.

So they're not really a resident stem cell population because they're not pleuripotential like a true stem cell, but they're an uncommitted set of cells that can with the proper stimuli be induced to become skeletal muscle. They can become other types of tissue as well, but a fairly limited repertoire.

Now, my interest in this began with years ago the beginning of the whole promise of gene therapy, and of course, the idea at the beginning of gene therapy was really to tackle the simplest of genetic diseases, those that involved single genes and usually the genes being missing or at least defective, which was the cause of a large number of diseases, most of them fairly rare diseases.

The issue, and still the issue, the recent gene therapy really hasn't as quickly progressed as we all would have hoped it would have ten years ago, is because the problems are really finding the right vector for a given tissue, that is, a delivery device to actually get the genetic material into the adult tissue, and then also figuring out how to get it there, the delivery.

So these are still the key stumbling blocks in gene therapy today, although great inroads have been made.

Now, in terms of muscle what is sort of emerging as the best sort of ways to deliver genes to muscle are sort of listed here, and this is as of today. Muscle is actually quite good at taking up so-called naked DNA or just plasmid DNA. This is DNA that is not encapsulated in anything.

When I say quite good, I mean it does it with some efficiency. It's perhaps one or two percent of the cells if you inject DNA into a given muscle would take something up.

So this is not an inefficiency that's useful in correcting a primary genetic disease of the muscle itself. However, this would be useful in terms of getting the muscle to produce a substance that would then be secreted into the blood.

And, in fact, this technique has been shown to be successful in an agricultural setting where a colleague of mine has taken DNA that codes for the growth hormone releasing hormone. This is actually a protein which stimulates the release of growth hormone, and in doing so, he can demonstrate that the pigs will now secrete much larger much larger levels of growth hormone.

Obviously one of the other problems with it is it's transient, but in that sort of setting perhaps it's useful to be transient just to sort of give them a growth boost through some period, and then it will go away, but obviously not something one could think of for permanent sort of genetic correction, and especially not a genetic correction of the muscle itself.

Now, viruses are still the preferred gene delivery vehicles in terms of efficiency. Getting genes into a given tissue are what viruses are engineered to do, and so they can be reengineered to deliver therapeutic genes instead of viral genes.

And probably the best vector for muscle is a virus that's known as AAV, which stands for adeno-associated virus. It's a virus that's unrelated to adenovirus, which has been used, as you're probably aware, in gene therapy trials with complications, and the most severe which took place at my own institution.

But this is a different virus that actually does not cause any known disease in humans. Often it can be found in 20 percent or so of the human population that have been infected by AAV with no consequences that can be demonstrated.

And in the last maybe two years a number of different sort of variants or serotypes of the virus have been isolated, and at least two of them are extremely efficient at targeting skeletal muscle. And so there are now gene therapy trials that have begun and many more that are about to be proposed and started that use this virus to try to get genes into skeletal muscle or in the liver. It turns out that this virus is also very good at targeting the liver, which would be very useful in diseases where one wants something secreted into the blood, like in the case of hemophilia.

There's an ongoing trial now with AAV targeting the liver to get the liver to secrete in this case Factor 9 for patients with Factor 9 deficiency.

Adult stem cells obviously are useful in sort of the idea of helping regenerate the tissue, although I must say that although there are a number of types of adult stem cells that can become muscle, again, efficiency becomes the problem, whether they're muscle or bone marrow derived stem cells. It's very difficult to get a large percentage of the muscle rebuilt using this approach in animal models where it's been attempted.

Nonetheless, we and others see the ability to use adult stem cells now as not in the stem cell sense of rebuilding the tissue, but perhaps in the sense of viewing them as a vector where one would take the adult stem cells in the laboratory, put new genes into the stem cells. That would then allow the tissue that they've incorporated in to secrete a substance that would then affect the surrounding tissue or if it's designed to go into the blood.

So you could sort of put adult stem cells then not only in the tissue regenerating sense, but in the sense of being a vector to carry genes into a tissue, to incorporate into the tissue, then to produce something else in that tissue.

And the advantage that they may have over viruses is one of the easiest systemic delivery. In many disease situations it may be that one could simply put the adult stem cells into the blood and they would home in on the tissue. They would home to the tissue that was actually being damaged by whatever the disease process is, and so it would be a very efficient way of targeting the tissue, which with viruses is more difficult at least at this point in time.

So I'm going to give you an example then of using the adeno-associated viral mediated gene transfer, but the example is actually one that we're now trying to do with adult stem cells, which is why I brought this up, because we think we can accomplish the same thing and deliver it much more simply using stem cells that are bone marrow derived from in this case we're working with both adult human cells, as well as adult rodent derived cells.

Adeno-associated virus, as I said, has the huge advantage for skeletal muscle in that it readily infects it. In fact, this may be the preferred tissue target of this virus at least for various forms of this virus.

It's limiting in that the size of its entire genome is only on the order of about 4.7 kilobases. So this is very small and really smaller than most genes in the human, and so one can only make synthetic genes that code for relatively small proteins. And so one has to be judicious in the choice of what one can attempt to do with this virus.

Delayed onset of expression, perhaps more so than some of the other viruses, but nevertheless, with the more robust infection that one gets with serotype one and five, expression commences within a week of injection of the virus into the tissue or systemic delivery of the virus into the tissue.

There's no viral gene expression. This is one of the big advantages of using this type of vector. You can make the synthetic vector without any viral genes, and because of that, there's no immune response against the virus itself.

Obviously there could still be immune response against whatever the product that you're causing it to make, but an example I'll give you, which is one of the advantages of it, what we're making is not something that's missing from the body, but something that we're just trying to get the body to make more of. And so there's nothing for the immune surveillance to pick up on, and so no possibility of immune response.

It integrates at a low frequency, which is both useful, but also a point of some concern in sort of the regulatory and side effect case. The integration, with any integrating virus there are two things to worry about. One is the possibility of oncogenesis being initiated by an integration event.

We have not seen this in our animal models, and other people have not seen this. So the possibility with this virus seems relatively low because there's some evidence that the integration events of AAV are somewhat site specific, and so not very likely to induce oncogenesis.

The other problem, of course, is whether or not one could get germ line transmission, and compared to something like lentivirus, the ability to do germ line transmission is not zero, but it's fairly low probability of germ line transmission, but again, this depends on the route of administration.

It would be more likely that you might get germ line transmission if you're doing a vascular delivery than of direct injection into the tissue, and the duration of expression, because of the integration, essentially is the life of the nucleus that you infected. And so as long as that cell in that nucleus exists, one will get expression. And so for the animal models that we look at, it's the life of the animal essentially.

Just to show you what efficient means, here's a cross-section through a muscle. So these are now — if you think of the muscle fibers and muscle cells as very long cylinders, this is now slicing through them so that you basically just see their circumference and not their length.

And as you can see in this example, this is now using AAV-1. Essentially every muscle, well, every muscle in the field is now producing a protein that gives a color and an enzymatic reaction that's developed in the laboratory, a bacterial protein that can be used to give this colormetric readout, and you can see that every muscle fiber in the field is blue, and in fact, one can do vascular injection with this virus, and every fiber and every muscle virtually in the leg of the animal will be blue after vascular administration of a large enough dose.

So the efficiency is extremely high if one puts in enough of the virus.

So potential applications, which is what got me interested in using this in the first place, obviously the initial goal of all gene therapies of this sort was primarily genetic diseases, and for muscle that would mean Duchenne and Becker muscular dystrophy is the most common, but also others, such as the limb-girdle muscular dystrophies, myotonic muscular dystrophy, and whatnot, where one can point to a genetic defect in a single gene as the cause of the disease.

A more difficult problem, but actually in some ways, I mean, biologically a more difficult problem, but in fact, the problem that we focused on initially, which is a very real problem in this society where the society is living to be older and older, is the fact that as we get older our muscle function, our skeletal muscle function diminishes both in size of the muscle as well as the relative strength of the muscle and this is a big problem not only from an ambulatory standpoint, but also from a whole body metabolic standpoint.

If the mass of skeletal muscle drops below a critical threshold, then the whole body metabolism is no longer supported properly because the muscle actually functions not only to move the body, but as an important metabolic organ within the body.

Then the last sort of issue, which is actually a trial, trials have been ongoing in this area, is the use of gene transfer into muscle to get therapeutic proteins in the blood, such as Factor 9 deficiency.

So the initial hemophilia trials with Factor 9 were trying to actually get muscle to secrete Factor 9, but now they've shifted to liver because the liver is just a better organ for secretion into the blood than muscle is, although the muscle is capable of it.

So I want to first tell you about where we started some five years ago, which was looking at this problem that the NIH has coined sarcopenia. I think they coined a term to sort of make it sound more like a disease, probably for congressional purposes, but basically what they're really talking about is this progressive loss of muscle mass in force that essentially begins in the fourth decade life in humans and then progresses throughout.

It's slowed, but it's not prevented by exercise, and obviously as I've already mentioned has negative impacts on health and quality of life. It occurs in all mammals, which is useful because that means all of the laboratory animals one works with undergo the same process, and since they live for a much shorter period of time than humans, their life spans are much contracted.

The whole sort of progression occurs on a time scale that one can approach in the laboratory, and our hypothesis back in '96 or seven when we began this was that in large part we thought that what it was really due to was not inactivity. There had been a lot of discussion that as people got older they were just inactive and that's really the main thing that drove it, but we really thought there was a more fundamental cause, especially since there were studies showing that exercise could slow it down but not stop it.

And that was the fact that the repair mechanisms of skeletal muscle decline as you get older, and this causes the muscle to lose function because it's essentially not being repaired properly, and this goes back to what I said at the beginning, that it has within it a resident population of cells, these so-called satellite cells, that when the muscle is damaged — and muscle is always damaged as you're using it — are called upon to repair the muscle and rebuild it.

So this sort of rebuilding process involves some sort of damage signal coming out of the muscle which then activates the satellite cells to begin to proliferate, and they proliferate, then they make the commitment to be muscle, and then they either fuse with the existing muscle to repair it, or if the muscle has been severely damaged, they form new muscle.

So what is involved in this are a number of growth factors, some that drive the process, some that inhibit the process in sort of a yin and yang, but the one that we felt was really the most critical and the one that might be the candidate for what's going wrong in aging is a growth factor called IGF-1, which stands for insulin-like growth factor-1, which in normal muscle is involved in growth. It drives protein synthesis, and it decreases protein degradation, and importantly form the repair standpoint, it stimulates this population of satellite cells to both proliferate and differentiate.

And this is an important fact that it can do both because many of the growth factors will drive proliferation but block differentiation, and so increasing their levels could actually interfere with repair, which has been shown in some cases, but here you have one that has a little built in clock. It will drive proliferation for a while through one pathway, and then it will drive through this pathway, and then it will drive differentiation through another pathway, which it turns on with the delay.

So just the sort of thing you might want to try to drive more successful growth and repair. And the reason we thought it might be a problem in aging is because it's really part of the whole growth hormone IGF-1 axis, which as you know, the signals from the hypothalamus, the growth hormone releasing hormone, that are then taken to the anterior pituitary to stimulate it to produce growth hormone go down with aging.

The levels of growth hormone in the blood go down. The levels of IGF-1 produced by the liver; the liver produces all of the IGF-1 that circulates in the body. All of these levels go down with aging.

And what that means is that the IGF-1 levels in the various tissues of the body will also be diminished with aging.

Now, tissues like muscle and other tissues of the body have two sources of IGF-1. They make it themselves under conditions of either injury or rapid growth, but also they have an IGF-1 input that comes from the liver that's ongoing throughout their life.

And so it's this component in particular that's being lost in the aging animal. And so we sought to essentially replace it by supplementing the amount of IGF-1 that the muscle itself could make.

So the strategy was quite simple that we took. We would use gene delivery into the muscle to give it a synthetic gene to have it produce more IGF-1 so it would not be particularly dependent on the liver for a source of IGF-1.

And then the question was: would that then in muscle promote growth and regenerative pathways and would that, in turn, allow the muscle to function throughout the life of the animal without the aging related loss?

So it's a very simple synthetic gene that we put together using a muscle specific promoter driving the rodent IGF-1, and then it's flanked by the viral ITRs and packaged into the AAV viral capsid, and then just to inject into the animals either a vascular delivery into the leg or a direct injection into specific muscles.

And we could how — this is just using PCR to detect the existence now of our synthetic gene that four months, nine months, even two years after injection the synthetic gene is present and producing IGF-1 messenger RNA.

So then we asked the question with it: is this going to increase the rate of muscle regeneration and maintain mass and old age? And this is the paper that I included in your packet.

What we showed was that if we injected mice, essentially middle aged mice or late middle age in mice — mice live to be about 27 to 30 months in age at least in our colonies, and so we injected them about halfway through their life where they were all just beginning to start losing muscle mass, and then we asked, you know, what would their muscle mass in force and force for cross-section look like when they became old.

And so looking at them at 27 months, which was nearing the end of their life, they normally would have experienced in terms of mass about a 15 to 18 percent drop over that age period compared to a six month old mouse when they're sort of at their peak.

Whereas if we had injected them in middle age, they maintained the same mass or even a little greater than they had when they were younger. The same with the amount of force they were able to produce. Their muscles were able to produce normal force instead of showing the decline in force that they would normally see, and the force for cross-sectional area was maintained, as well.

But the speed of the muscle was maintained and the power output was maintained to an even greater extent because one of the other things that happens as the animals get old, as mammals get old, is they selectively lose their fast and most powerful fiber type.

So skeletal muscle is a heterogeneous tissue in terms of it has some of the fibers in it that are small. Some are big; some are slow; some are fast. We lose the very fastest ones as we get older and preferentially replace them with slower fibers. That's one reason why some of the first athletic things that go are your ability to compete in power events or speed events, because that's the first loss that you experience before you really lose muscle endurance or any of those sorts of properties.

And we were able to prevent that totally. The mice did not lose any of their fast fibers, and they had the same speed and power output when they were 27 month old muscles as they did as animals that were only six months of age.

So from that we were able to conclude that IGF-1 over-expression could prevent all of the hallmarks of age related atrophy and loss of skeletal muscle function in mammalian aging, at least based on the rodent model, and now we're hoping to pursue this in larger animal models.

The skeletal muscle regeneration rate is diminished in old animals, and we showed that in another paper other than the one I showed you, and that seems to be the primary problem, that even if you injure the old muscle, it cannot mount a normal regenerative response, but if you maintain IGF-1 expression, it can maintain a normal repair response, and this also, of course, is this hypothesis that we were looking at.

And also it suggests that one could go about this whole pathway as a therapeutic means of maintaining muscle mass either through the strategy that we used so far in these animals, which is to give them an IGF-1 gene supplement or, as I'll mention at the end, one can think about doing it in other ways that might actually be a little simpler to achieve that we're still evaluating.

This also suggested that maybe in dystrophic muscle where the rate of muscle degeneration or the rate of muscle damage is so high that it exceeds the rate of the muscle to repair it, we wanted to ask the question: if you actually increase the rate of muscle repair by up regulating IGF-1 production, could you slow down the damage, the cumulative damage in these dystrophic animals and maintain their muscle mass?

So that's what we looked at, and here is just now comparing a dystrophic muscle where now we've taken a transgenic approach, but we've also done this with virus, showing that — this isn't projecting very well, at least not from where I am, but this, the IGF-1 producing tissue shows a lot less of degenerative signs than the dystrophic muscle where there's lots of fragmentation of fibers, lots of clumping, lots of regeneration.

There's infiltration from macrophages because there's an ongoing destruction and inflammatory response in the muscles. Even in the diaphragm, which is virtually destroyed by the time these animals reach about 20 months of age, there's been massive sort of hypertrophy and hyperplasia in the diaphragm. So the diaphragm has become much larger and stronger, and interestingly, the amount of connective tissue.

So here one of the big problems is that as the muscle is destroyed, it basically becomes like a rubberband. It's replaced with fibrotic tissue and fat infiltration.

The driving IGF-1 over-expression not only drives more successful regeneration, but it prevented a lot of the fibrosis. So you can see the normal amount of fibrosis is measured by collagen content here in the dystrophic mouse, and we've normalized that and sort of brought that down to sort of normal levels with the IGF-1 over-expression in the MDX mouse versus just IGF-1 over-expression alone or wildtype.

And furthermore, this is now injecting a dye into the blood stream of the animal and let the animal run around, exercise a little bit, and then see if the dye is taken up in the muscles because normally the dye would be excluded because the muscle membrane would be intact.

This is showing that in the dystrophic muscle they're so fragile and being damaged at such a high rate that the dye penetrates quite easily either in the diaphragm or in the muscle that's being used to run at a very high rate, whereas in the same sort of animals, same dystrophic animal that's now over-expressing IGF-1, the fibers are being maintained in such a better state of repair that there's very little dye penetration in either the diaphragm or the leg muscle, suggesting that these muscles are going to be able to be preserved.

And so this is something that we would now like to really look at in large animal models because there are dog models of muscular dystrophy, with the idea of trying to evaluate whether this would be a potential basis for thinking of therapies in humans, and again, either delivery of an IGF-1 gene or some other way of driving this regenerative capacity is a way to think about attacking this general sort of category of human diseases, the muscular dystrophies, and it may not — you might not even have to understand totally the primary problem if you could just drive the regeneration for some of the muscular dystrophies where it's really still not very clear what the primary problem is.

So this all leads to the idea that this IGF-1 signaling can increase satellite cell proliferation under growth and repair mechanisms that will drive muscle hypertrophy in extreme conditions, even muscle hyperplasia. Hyperplasia means the muscle is actually making more muscle fibers, not just repairing its existing ones or making them larger.

So I addressed these first two issues that we were interested in, but then it also suggests that IGF-1 over-expression should increase the rate and amount of skeletal muscle growth in young animals, and indeed, we showed that early on that that's true.

If you inject one leg of a mouse and not the other leg while it's in its young adult ages, you can actually show that the muscles of the leg get larger. This is, again, looking at the diameter. It's on the order of about 18 to 20 percent larger, and this is a sedentary animal.

And so this is one leg versus the other leg. Just the only difference here is the injection of the synthetic gene to make IGF-1, and if you do it systemically and look at all of the muscles of the animal, you can see here is a forelimb of an animal where there's no over-expression of IGF-1. Here is IGF-1 over-expression in all of the forelimb muscles, and here at the hind limb.

And so you can see there's pretty massive hypertrophy, again, on the order of 20 to 25 percent overall in the adult animal, and the games are even larger during the rapid growth phases. So in a young animal that's growing, it may outstrip its age-matched control by as much as 40 percent at a given point in its life in terms of its muscular mass.

So there are a lot of benefits then from IGF-1 over-expression, but from the standpoint of now I've been talking in terms of trying to use it therapeutically, but obviously from what I just showed you, one could think about it in terms of a gene enhancement, in terms of either an animal or a human.

And in terms of a human, those were some of the relevant papers, but in terms of humans, the question that we were asked so often and that has been really since the day we published our first paper on this on people's minds: could this sort of gene transfer into skeletal muscle actually be used for a genetic enhancement of athletic performance or even just cosmetic purposes?

Just say you'd like your pectoralis muscles to be a little larger because you want to look a little better at the beach. Just take a few injections of the virus, and a month later while you're watching television, your muscles have gotten bigger.

So, you know, a lot of implications in terms of genetic enhancement, and so I'll show you a little bit of our attempts to now evaluate this in a rat model. The rats are easy to sort of train. We didn't have much luck trying to make the mice exercise for us, but rats are fairly cooperative.

So we had the rats climb ladders with weights velcroed to their tails, and so fairly large weights that we would increase over the time of the training, and so this is sort of a progressive weight training protocol for eight weeks.

What we did was we took control rats who were not asked to exercise, and we injected the IGF-1 virus into one leg, but not the other, and then we had weight training animals where, again, we injected IGF-1 virus into one leg but not the other, and then we had another group where we went through the weight training and then let the de-train for three months. And three months would normally be enough time to lose all of the benefits from the weight training. This is one of the depressing things about exercise.

You know, you can work as hard as you want for two months straight and then sit back for three months and do nothing, and it's like you never did anything. So we had the rats go through that, too, because we wanted to address whether the IGF-1 would help maintain the mass once you stopped, which would also be of interest in terms of an athletic population or an elderly population.

So what we saw was in terms of the muscle mass — this is after the eight weeks — so this is the average mass of the animals that did nothing. In the leg where the IGF-1 was injected, on average the muscles are about 15 percent larger.

In the weight trained animals, they worked very hard. It was really quite a severe weight training exercise, and we were able to induce about a 23 percent increase in mass, and in the animals in their legs that had the IGF-1, they experienced an ever larger increase in mass, up to about 32 percent.

But in terms of the force output of their muscles, it was even a more striking difference in that the IGF-1 injected muscles with no exercise got almost 16, 17 percent stronger on average, whereas the ones that were weight trained were actually no stronger than the animals that had IGF-1 and sat in their cages for the two months. They were about the same strength, but the muscles that had the combination of weight training and IGF-1 were almost 30 percent stronger.

So the effect in mass is not as large as the effect on the overall strength of the muscle, and the reason for that was, in fact, the severe weight training had lowered the sort of force per unit mass of the muscle in the weight trained animals, whereas we had an enhancement in the IGF-1 treated animals, and sort of an intermediate with the weight training and IGF-1 together, and the reason for that is shown. Again, some cross-sections of muscle.

What happened in the exercised animals, and I'm not sure why my slides aren't projecting that well, but what happened there was the weight training was severe enough that we actually had a fair amount of injury and fibrosis in the muscle, and so that's what happens to athletes that can overtrain.

You know, you damage the muscles and you get fibrosis. Then it sort of works against you. It lowers the sort of strength per unit mass of the muscle, whereas the IGF-1 was so effective at the repair that even though the muscle was being massively overloaded, it rebuilt itself and looks just like healthy tissue and had normal sort of force for cross-sectional area.

So a number of benefits, and then the last benefit was when the animal stopped. You can see during the de-training, the weight trained animals went back down, and then after two months, as I said, they're back down almost to where they started before they lifted a single weight, whereas in the muscles that had IGF-1, the decline percentage-wise was a lot smaller, and they ended up with some gain over weight training alone and certainly a gain over just IGF-1 alone.

And so they were able to maintain some of the weight training benefit at least three months after the cessation of the exercise.

So this is sort of a summary of all that I was saying, but the bottom line, just to speed this along a little bit, is that this approach certainly would lead to genetic enhancement of athletic performance because it would increase the rate in amount of skeletal muscle growth with resistance exercise. It would increase the rate and extensiveness of repair following an injury. So you'd be better able to maintain muscle mass, strength, and speed after the training stops and certainly during aging, as we had shown before.

So tremendous benefits from the athletic standpoint I think not the least of which is how rapidly one could come back from an injury and how well one would sustain an injury and get complete repair of the muscle, not to mention that for speed and strength events, one might not see the precipitous fall in performance that normally comes after age 30 even in a training athlete.

So this little bit was what I presented to the World Anti-Doping Association because they're quite concerned about how close we are of genetic engineering or enhancement of athletes actually cropping up in terms of international sporting events.

And you know, as I said to them, I think the real danger of that — and this is just to acknowledge some of my colleagues — the real danger of that is not that it's going to happen any time soon in this country because we're still going at a fairly slow rate of trying to just really assess the safety of some of these gene transfer techniques even for treating, you know, primary genetic diseases, rare diseases for which there are no treatments.

And so the availability of this sort of technology to an athlete in this country is not going to happen any time soon, but on the world stage, in a world where countries in the past have shown that they want their athletes to win no matter what and they will give them any experimental drug that might be performance enhancing no matter what the long-term consequences, one can imagine that with enough money you could put together a program to genetically engineer your athletes and do it in such a way, which is what one is really concerned about that it would be totally undetectable unless you were to remove tissue from that athlete. There would be nothing in the blood, no signature in the blood or the urine to indicate that the tissues had been genetically manipulated.

So this is their concern, certainly not a concern, I think, in this country in the short term, but maybe a concern on the world stage maybe even in the next decade.

Just to let you know where we're going a little bit, I alluded to the fact that, you know, we started trying to intervene in this growth and regeneration pathway for aging by driving IGF-1, but what I didn't mention is in the last few years it has become really clear that there are major inhibitors of this whole pathway that the muscle actively is producing to sort of keep it in check.

And one unresolved question and one we're looking at and probably other people are looking at is whether some of these components also could help drive the repair and aging if you could block them. And so you could imagine there the approach would be either to create a substance in the blood that would interfere with the action of this protein, which has been called myostatin, or you could even imagine a small molecule screen might pick up a selective inhibitor of this protein which is in the — it's a TGF beta family member.

So this is a target I think you're going to see increasing interest from drug companies, and it may have application in aging. It may not, but it certainly probably does have application in such things as juvenile diabetes and maybe in some of the muscular dystrophies where interfering with the signaling of this protein might allow the muscle to rebuild itself better and stronger.

And that's going to be much easier to implement, and that certainly would be a performance enhancer for an athlete, and those drugs are being developed now, and the accessibility of an athlete to those sorts of drugs might end up in the same sorts of results as what I was showing you for the IGF-1 over-expression.

And certainly in the general population I think this could be used as an instant muscle builder, and the nice thing about a drug is you sort of take until you've got what you want, and then you stop taking it, and it doesn't drive the process indefinitely.

We're going into clinical trial in the next year or so with AAV targeted at a primary muscle disease, a deficiency in what is called the sarcoglycan complex, which causes a form of muscular dystrophy known as limb-girdle muscular dystrophy. These components are all small enough to fit easily into AAV, and so I think the first real clinical test of this virus for sort of directed at a primary muscle problem are going to be in the context of trying to repair this whole structure, which is deficient in limb-girdle muscular dystrophy.

And we'll learn a lot about how easy it's going to be to actually use this gene transfer vector in humans in the process of that, and it's actually a collaboration between myself and groups at Harvard and the NIH and the Généthon in France, which is funded by the French government and the French Muscular Dystrophy Association.

So we're planning to do multiple — sort of coordinate trials in this country and in France on this disease with the idea of then moving on to other primary muscle diseases and perhaps even looking at the IGF-1 myostatin axis as a possible therapeutic that we could then bring to humans in a muscle disease setting.

So that's my background on what we're doing, and I'd be happy to answer questions about where it's going.

CHAIRMAN KASS: Thank you very much.

Bill May and Dan Foster.

DR. MAY: I betray my ignorance, but I was wondering whether indirectly it might make a contribution to the treatment of women with osteoporosis, both increasing muscle strength, allowing them to increase their engagement in weight exercise that decreases bone loss and protects also against falls because you've got greater stability and strength in the muscles.

DR. SWEENEY: Yeah, I think that's a real possibility. I mean, the IGF-1 has a number of other advantages that I didn't show you data on, and one is that as the animals get older they're not only stronger, but they're leaner. Their body fat is much lower than a normal animal.

And also, the bone loss that the mice undergo seems to be prevented at least in the limb muscles that we've looked at, and we assume it's because they are loading the bones more because of the larger muscle strength, and that does prevent a significant amount, if not all, of the bone loss, at least in the leg muscles of the mice.

CHAIRMAN KASS: Dan Foster.

DR. FOSTER: That was a lovely presentation. I think you've already answered this because you said that if you used enhancement in humans that there was no marker. I was going to ask the question: is there any leakage of IGF-1 from the muscle into the blood? And if so, was this due to a movement from the leg into the liver?

The reason, if you have a persistent elevation of IGF-1, you know, you get a disease from that that's acromegaly, and I gather that there's no leakage and no blood contribution here.

DR. SWEENEY: Yeah, That was part of the design. There are a number of different splice forms of IGF-1, some which lead to ready secretion into the blood and others which are the forms the tissues normally make for themselves, which cause sort of a co-up regulation of the binding proteins that trap the IGF-1 in the tissue.

So we can detect absolutely no elevation in the blood, which was part of the inherent design of what we were trying to do. So the issue would be, you know, we want to look at this in larger animal models obviously before we would try it in a human, and then try massive overdoses of the virus to make sure, you know, at what point we actually do run a danger of exceeding the muscle's ability to trap it and spill it into the blood because that would have a lot of negative consequences.

DR. FOSTER: I just want to ask one real quick technical question. IGF-1 has, you know, effects on — anti-apoptotic effects. I mean, it's been used to limit infarcts and things of that sort. But it looks like — I mean, this is just a programmed cell death, you know, a signal death apoptosis, just a signal to die, and probably some of the stuff that he's doing in his muscle for the extra exercise and everything is just apoptotic effects.

And so one of the question would be: do you think that's contributing at all? I mean, I think all of the hypertrophy and everything you thought is not going to make that a major effect.

DR. SWEENEY: Yeah. Well, we've looked at this in the context of disuse atrophy, where you immobilize the animal's leg either in a cast or in sort of a simulated sort of weightlessness, hind limb suspension. Anyway, you don't allow the animal to use the muscle.

And just like if you casted one of our muscles, the animal will lose half of the muscle mass in the order of a month.

The IGF-1 doesn't stop that at all, which is why we were interested in looking at it. So even though it's anti-apoptotic especially in the heart, there's actually in the case of muscle disuse, there's a dominant pathway that blocks IGF-1, that shuts it down so that it doesn't allow it to have its normal anti-apoptotic effect.

We're combining IGF-1 delivery with other mediators of that pathway in skeletal muscle to show that you can then stop all of the loss not just with aging, but if you impose disuse on top of aging, then nothing happens. But the IGF-1 itself is probably anti-apoptotic in certain injury situations, but not in a non-load bearing situation where apoptosis seems to be sort of the dominant pathway that causes that rapid loss of muscle, and IGF-1 is shut down.

CHAIRMAN KASS: Bill Hurlbut.

DR. HURLBUT: Well, I want to ask you since what we're really interested in here is not the technical questions of even a therapeutic approach but the ethical implications. I want to ask you a broad question about what you see as some of the medical or scientific down sides of this and whether this actually holds potential for being a technique that could be casually used.

What I'm thinking of here are you very quickly alluded to the concern that's been raised in other fronts in gene therapy. There may actually be germ line incorporation when it's not suspected.

Daniel's question about systemic effects, obviously you add something into the body and it's going to affect more than just itself, if not directly through diffusible or circulating agents, then maybe just in the allometry, if you will, of proportions. You increase the muscle mass and you've got to have the supporting ligaments and bones to deal with it and so forth.

And then, of course, there are questions of whether it interferes with apoptosis you might induce cancer and these kinds of things, and so what I'm asking you is basically the scientific medical side of this. Is it a realistic concern that this might end up being used by anybody who wasn't just out and out reckless?

DR. SWEENEY: Well, as I said, I think that the technical barriers to doing that are sufficient enough that that just couldn't be casually done in a country such as this where the regulations would prevent it, but I think the real danger of it happening would be precisely what we're seeing, a government sanctioned program in another country where the whole goal of it would be athletic enhancement for the international sports stage.

But what may be something that's more relevant and more of a risk is if, in fact, the pharmaceuticals end up developing drugs with the idea of using them for diabetes or even some of the milder muscular dystrophies that target, say myostatin, and those are accessible, then those drugs are probably going to have a lot of the same effects that I've talked about in terms of muscle.

But depending on how specific they are, they're going to have side effects as you're alluding to. I mean, there the side effects are a little different from IGF-1 side effects. Myostatin is a TGF beta family member, and all of the drugs that exist now probably are going to have some cross-reactivity with the other family members, which will interfere with immune function and a number of other critical functions.

And so, you know, those are going to have to be very tightly regulated substances because, again, someone wanting the muscle enhancing actions could abuse it to the point where just like with anabolic steroids or growth hormone or anything else, you induce side effects.

Now, with the sort of genetic delivery of IGF-1, as I said, we tried to engineer safeguards against some of the issues you've raised in terms of trying to keep it out of the blood. In terms of if a cell that we had transduced became cancerous, the IGF-1 would be shut down immediately because the promoter that's controlling it is only differentiated muscle promoter.

So if the cell transformed, they would shut down. Now, that's different. What is possible is if there were a tumor in the tissue where there were high levels of IGF-1 in the tissue, then it might help the growth of the tumor to some extent, but the levels I'm talking about in the tissue are not 100-fold higher than normal. They are just several-fold, and so this is still, I think — I think the tumorigenesis aspects are at low risk.

I think the highest risk in this setting would be if we started spilling high levels of IGF-1 into the blood.

DR. HURLBUT: You haven't seen any insertional mutagenesis or anything like that?

And, by the way, I want to ask you also: have you seen an increase in longevity of these mice?

DR. SWEENEY: We've seen a slight increase in longevity, and it's small enough that we haven't got enough animals yet to make it statistically significant, but it might be ten percent or so at the end of the day.

I mean, it appears to us they are living a bit longer, but as I say, because it's a small effect, we haven't had a large enough number.

DR. HURLBUT: So is basically your answer that, to sum it up, you see this as a therapeutic agent in the face of a difficulty, but it would otherwise be very reckless at least in the near term and maybe even in the long term to do this kind of thing?

DR. SWEENEY: Yeah. Well, how reckless it is is going to have to be determined by a lot of safety testing that has yet to be done, and so it's difficult for me to see how reckless it would be in the long term.

I mean, my personal bias is that the general approach, if it can be technically made more — if it can be done more easily, I think would achieve our goal of in the aging population or in a dystrophic population of in one case improving quality of life and in the other case extending life.

And I think the potential side effects are minimal. The possibility of germ line transmission with the virus is there, although it's a very low probability, and if you're trying to make it happen, you can show some germ line transmission, but in the way I would view it delivered in a therapeutic setting, I think the possibility of germ line transmission is near zero.

But that could change as the viruses are made more efficient to get into muscle. They also might be more efficient in getting into the germ line, and so, you know, the FDA is quite concerned about this, and so we're trying to evaluate with all of these new serotypes whether or not at the same time we've got something that's better for muscle we've also got a higher risk of that type of transmission, and the data is just not there yet to tell you.

CHAIRMAN KASS: Let me follow and then Janet.

If you think just about the question of aging and the muscle degeneration, and leaving aside for the moment the question of the safety about which we don't know near enough, but why wouldn't one think of this not so much as species of enhancement as the species of prevention, and in principle, I mean, just to think it through, why isn't this something that one would be thinking that this fit for everybody long term?

DR. SWEENEY: Well, —

CHAIRMAN KASS: In other words, as a preventive measure to be given to people who are 30 years old?

DR. SWEENEY: I mean, and that was sort of our original thinking until it became clear that also, you know, it's also an enhancer. It not only prevents, but it allows you to be stronger and the muscles healthier than they would have been otherwise.

But, you know, if you take it away from the athletic context, which sort of muddies the whole thing, then I think of it — I do think of it as a preventative measure. I think if the level of safety was absolutely demonstrable that there was zero risk, then I think every person would want to be treated in this way when they're young enough so that, you know, you would never lose muscle function as you got old, I mean, assuming that you could show that there was no down side to it.

At least from my limited viewpoint, I would see it that way, and this is what I had said and actually the popular press article that I gave you. I think if we come to a point where there's no safety issue at all and no specter of germ line transmission or anything else and all you get out of it is you stay strong as you get old so that you can get around and have a better quality of life, it would be hard for me to believe that that wouldn't then gain acceptance.

And when that gains acceptance in the population in general, then, you know, the athletic government agencies are just going to have to deal with it because whatever enhancement it provides to those athletes the public is not going to care about.

CHAIRMAN KASS: Michael.

PROF. SANDEL: Just on that, so if you give it as prevention when someone is 30, does that have the effect of preventing the deterioration of muscle function as they age, or does it bump up where they were before they got their shot at 30 and then keep them at a certain level?

DR. SWEENEY: Yeah. Well, what we've seen in the animals, because we've looked at this, is if you inject them at a point where they're no longer growing at all, they've just leveled off like we would be at 30 or 40 or whatever, if they do nothing, then they don't gain any muscle, but if they exercise at all, they gain a lot more. They start to gain a lot of muscle.

So if you absolutely restrict them so that they really can't do much of anything except sit in their cage, then they get no gain, but they get proportionally more gain the more they're allowed to exercise.

So you know, just a Weekend Warrior could get tremendous gains probably, you know, beyond just not losing muscle. But if they are sedentary and you really restrict them, the answer is that they keep the muscle mass they had the day you injected them and don't go down from there.

But, in fact, if you inject them when they're really old, when they've lost a lot of muscle mass and also don't allow them any exercise, they won't go back up. They'll just stay where they were the day you inject them. They won't go down anymore.

But combining it with exercise, you can really then bump up and get an enhancement.

CHAIRMAN KASS: Janet.

DR. ROWLEY: I'd just like to go back to some more technical questions, and particularly because in your article you did all of this by injecting into the muscles, whereas you also describe research where you did it systemically.

And I'm curious, again, sort of following on with some of Dan's questions as well as Bill's. When you do inject it systemically, particularly in terms of the virus, you're saying that it homes preferentially to skeletal muscle.

So how long does it take to clear the blood? And does some of the virus really go to the liver?

DR. SWEENEY: Yeah, I know that —

DR. ROWLEY: And have systemic effects?

DR. SWEENEY: Yeah, well, now, the liver is the other organ that has a high tropism for this virus. So quite a bit of the virus will go to the liver. None of it will express IGF-1 because the liver can't turn it on.

DR. ROWLEY: Okay. So it's a muscle specific promoter.

DR. SWEENEY: Yeah. So that you can show that the genetic material is in the liver, but it's dormant. There's no way for the liver to activate it.

DR. ROWLEY: Okay. And just looking ahead, you were saying that some of the — you were thinking of using stem cells from bone marrow as vectors and having them home to the muscle.

DR. SWEENEY: Yeah, they will home preferentially to injured tissue. So if it's a primary muscle disease that's ongoing, they will home to the muscle under those conditions.

DR. ROWLEY: But then that wouldn't be an aging strategy, though you can say aging people have injured muscles. So that —

DR. SWEENEY: No, no. We were thinking of that as more of a way to get delivery, widespread delivery in a dystrophy background, although you can also get the cells to home to the muscle if you exercise the muscles hard enough to induce injury.

So if you run the animals hard on a treadmill for a while, then inject them, the muscles that they've been using and in doing low level damage to is where the stem cells will then home.

DR. ROWLEY: Thank you.

CHAIRMAN KASS: Gil.

PROF. MEILAENDER: I have to really show my ignorance here, but do rodents as they age show signs of dementia? That's something that we would —

DR. SWEENEY: Actually I don't know.

Do they?

PROF. MEILAENDER: I mean, I was just wondering in terms of what you had said before, which at one level makes sense to me. The issue was, you know, if you solve the safety questions, then it would be hard to know why any of us wouldn't want this just so that we'd be healthier, stronger, and less prone to debilitating injury as we aged.

And that made sense to me, but then I started to think about being so vigorous forever as I was demented.

(Laughter.)

PROF. MEILAENDER: And it's a complex question in a way to see what the benefit of these muscles would be under those circumstances or whether even if we can't sort of coordinate these several aspects of aging, whether it is desirable. I don't know if you've thought about that at all or not.

DR. SWEENEY: Well, I mean, that's interesting. My hope is that other people are working on some of these problems so that we might one day have a number of pieces of the puzzle together.

CHAIRMAN KASS: It's the assembly line, Gil.

PROF. SANDEL: So we will be able to get you in sync, Gil.

CHAIRMAN KASS: There was a hand down there. Paul.

DR. MCHUGH: I was fascinated by what you were saying, and this is, again, a clinical and technical question in relationship to muscular dystrophy. When you're doing this kind of injections into animals that have dystrophic muscles, do they regrow the muscles that they have lost so that even advanced patients with limb-girdle dystrophy and all might see a good bit of recovery, or does what's happened happened and you can only sustain them at this time?

DR. SWEENEY: It's totally a matter of how fibrotic the muscles are.

DR. MCHUGH: I see.

DR. SWEENEY: I mean, the best effects are going to be the earlier you go in, although we can recover some function not by virtue of rebuilding muscle in the fibrotic areas, but by expanding the muscle in the healthy areas.

DR. MCHUGH: I see.

DR. SWEENEY: So I think the approach would recover some function, but obviously the earlier the better in terms of trying to stabilize the function.

CHAIRMAN KASS: Rebecca.

PROF. DRESSER: I just wondered how elaborate a process it is to produce this. I mean, say, for the sake of argument, everybody does want this. I know you can't predict the price, but is it time intensive to prepare or what?

DR. SWEENEY: Yeah, I mean, the technology to produce it today is certainly not the technology that we would be using by the time we've dealt with all of these issues. I mean, it's gotten to do — I mean, to do these studies that I've talked about or even to do the dog studies, to treat the legs of a dog would cost a few thousand dollars at this point, but this is with technology that's far from optimized. This is laboratory technology, not scaled up technology.

CHAIRMAN KASS: Now, I'd like to raise a question that won't get any sympathy, but this is in a way the opposite of your question, Gil, where you're talking about the failure of the coordination of the aging of different systems, about which I know a vast collection of jokes, but I will spare you those.

But what's in a way at stake in this is something like the view of the life cycle and, forgive me, but a place of decline in the overall shape of a life, and while nobody from a medical point of view or even from an experiential point of view would choose debility, given the opportunity to avoid it, one at least has to wonder what the world would be like if you've got 75 year old men quite happily playing ice hockey and what the view of the life cycle would be if in a way what you really are aiming for — never mind the immortality research — but you're going to get everybody up to the brick wall sort of looking and acting as if they were 30.

And on that subject I promised Michael Sandel this, but there's a wonderful passage from Montaigne which I'd like to put in the record. Let me read this.

The question really was for those people who don't want to add years to life but life to years, of which this would be a great benefit.

All of us, I think, would want this, but the question is whether or not death would become even more of an affront and whether in some ways the fear and loathing of death would be on the increase in the absence of these signs of decline. And here is Montaigne's passage.

"I notice that in proportion as I sink into sickness I naturally enter into a certain disdain for life. I find that I have much more trouble digesting this resolution when I am in health than when I have a fever. Inasmuch as I no longer cling so hard to the good things of life when I begin to lose the use and pleasure of them, I come to view death with much less frightened eyes. This makes me hope that the farther I get from life and the nearer to death the more easily I shall accept the exchange.

"If we fell into such an exchange, namely, decrepitude, suddenly, I don't think we could endure it. But when we are led by nature's hand down a gentle and virtually imperceptible slope bit by bit, one step at a time, she rolls us into this wretched state and makes us familiar with it so that we find no shock when youth dies within us, which in essence and in truth is a harder death than the complete death of a languishing life or the death of old age inasmuch as the leap is not so cruel from a painful life as from a sweet and flourishing life to a grievous and painful one."

Now, that is in a way an existential question about how one looks at one's finitude, if one has no intimations of the mortality in decline, and then there's the sort of further sort of social question of what the world is going to look like if, in addition to our cultivation of youth in which all kinds of people are not acting their age, they would now have no reason to act their age because they would, in fact, be in many decisive respects indistinguishable from what we all are when we're 30.

I'm not —

DR. SWEENEY: Well, these mice still look old. They just don't look weak.

(Laughter.)

CHAIRMAN KASS: I believe we've got botox.

DR. SWEENEY: So much for Montaigne.

DR. FOSTER: Leon, I'm not sure that I agree with that. I think most people in medicine say that what they would like to do is to die suddenly with an intact mind, you know, healthy and with an intact mind. So that the lingering death that makes it maybe more wishful, I'm not sure that you'd be more afraid of this because most of us think that a sudden, you know, a Johnny Unitas death dying on the exercise thing is maybe the most blessed way one could go.

I don't know whether I buy into this —

CHAIRMAN KASS: I shouldn't be telling you that the Book of Common Prayer, if I'm not mistaken, asks that one should be delivered from sudden death for reasons which the gentleman at the end of the table —

DR. MAY: Sudden and unprovided for death.

CHAIRMAN KASS: Okay, but I wasn't introducing this as an objection to this, seriously.

DR. SWEENEY: No, I think you'd probably be outvoted by the population in general.

CHAIRMAN KASS: But it seems to me that this is one of those things which at first blush looks from a public health standpoint absolutely attractive, and yet it can't help but have all kinds of consequences for the perception of the life cycle and also for the relation amongst the generations even if us guys are a little more wrinkled than we were when we were 30.

That's not a moral objection that is going to stand, but I think one shouldn't underestimate the degree to which a change like this, if it became safe and if it became used would probably have profound consequences senility or no senility. The self-perception of oneself in an aging body is somehow part of our experience.

And if the body's aging which is mostly experienced by the fact that this damned equipment doesn't do what the will wants it to do and it used to do perfectly happy, I can't slide into second base anymore, though I still would like to do that; then it seems to me the feeling of a life would be different.

I'm not saying worse. It might be much better, but this is not a trivial matter about which you're speaking. It's not simply a public health matter. That was the point.

DR. SWEENEY: Yeah, perhaps I've sat out on this for a couple of reasons, personal, members of my family which were not so happily resigned to their loss of ambulation and basically lost their will to live because of it.

And also, I'm not going quite so happily myself in terms of reduced function. So —

CHAIRMAN KASS: Neither am I.

Bill, and then I think we'll stop.

DR. FOSTER: In my family, my boys pump iron, you know, and when I walk into the room the greeting is, "Hey, atrophied arms," and so I think I'm going to call Dr. Sweeney up and see if I can't get a little help for these insulting sons of mine.

(Laughter.)

CHAIRMAN KASS: For how many years do you want to fight them?

Bill, and then we'll stop.

DR. HURLBUT: Well, that's a hard comment to follow because what I was going to say was not just with a feeling of life changed from within a person, but the feeling of the relationships toward that life would change.

I mean, I remember watching my own father go through significant muscle atrophy and taking on a whole new relationship with him as I helped him move, and that was a meaningful part of the end of my relationship with my father.

And so I think in a way the larger question comes overarching here. Is the world in some way good either by the benevolent purposes of a creator or by the harmonious balance of a subtle evolutionary force or both, or is it just that one function was preserved because it helped the organism leave its genes in the next generation?

And it seems to me that's a crucial question because when I think about what you're talking about, the first thing that comes to my mind is IGF-1 does many, many things in the body, and you can't just go around tinkering with one thing and not damage a lot of things.

And that's the standard objection to these exaggerated projections mostly in popular magazines of the future of genetic engineering. People don't appreciate how complexly intertwined all of the genetic functions actually are.

We had pleiotropy and polygenic inheritance on the first level and then much more complex regulations and so forth. So if you change one thing, you're going to change many things.

But what you're suggesting raises a bit of an exception to that. You're suggesting that by targeting you can actually do a spatial and temporal modularization of a life reality, one that a more complex, overarching genetic system couldn't itself do.

So you're really suggesting there might be a way to bypass the multiple effects and possibly contain this. I mean, I know that you didn't overstate it.

DR. SWEENEY: Yeah.

DR. HURLBUT: You said the risks simply — but this is the point. The question then becomes —

DR. SWEENEY: Yeah. That's the conceptual advantage of it.

DR. HURLBUT: The question then becomes: is the world right the way it was made or can we basically go in and alter the blueprint of the thing with a later revision of it?

That seems to me what the question comes down to. Is there some human benefit beyond an obvious therapeutic benefit to interfering in the way natural life unfolds?

DR. SWEENEY: Yeah, I guess it comes to a more philosophical issue. Was the aging process by design or simply neglect?

DR. HURLBUT: That's it.

DR. SWEENEY: I mean, is it a designed process or is it just the lack of forethought at a time in life when you're no longer contributing to the propagation of life?

And so we've sort of — intellectually, from a scientific standpoint, I got at it that, well, this just wasn't thought through properly, and we can fix some of the things that could be tweaked a little bit to improve the long-term survival and performance of the tissue. Just addressing it strictly scientifically, not philosophically or morally, that's sort of the approach we're looking at, which is why the ability of gene transfer to give you modularization of the effect is so important to the type of thinking, because then you can think about affecting one type of tissue and not affecting the body as a whole.

DR. HURLBUT: Have you heard the saying Mother Nature always bats in the bottom of the ninth?

CHAIRMAN KASS: You should have the last word, I mean, if you'd like.

DR. SWEENEY: Well, again, I think it's whether or not Mother Nature designed the aging process or really just it's a fallout of not caring about the process.

CHAIRMAN KASS: Yes. I want to thank Dr. Sweeney for a very, very interesting and stimulating presentation.

I also want to thank you for your willingness to, not only on this occasion but on other occasions, alert people to the kinds of ethical and philosophical questions that your work raises and to lead us up to the edge of that and to entertain them and to do so in as thoughtful a way as you have.

So thank you very much. You've been a real service to the Council.

Thank you all. I will try to be in touch with you. I assume from some of the reports filtering back that some of you want to tell me things about yesterday. E-mails are, of course, welcome, phone calls too, and I'll be trying to get in touch with you in the meantime to talk about what's coming next.

Thanks for your participation. Safe trip home, and see you soon.

(Whereupon, at 12:11 p.m., the meeting was concluded.)


  - The President's Council on Bioethics -  
 
Home Site Map Disclaimers Privacy Notice Accessibility NBAC HHS