Building the Case
Interviewed by Richard M. Cohen; published 2002.
Dr. Weissman was interviewed for the Albert and Mary Lasker Foundation by Richard M. Cohen, former CBS News Senior Producer and Emmy Award winner.
The Science
Cohen: Dr. Weissman, you are standing in the middle of a rather intense debate. It's a little like you are standing in the middle of a busy intersection, the cloning and stem cell highway. Do you feel like you are going to get run over?
Weissman: No, I don't think that I am going to get run over. What I am trying to do is to let people know that cars are coming.
Cohen: Well, tell us which cars are coming and tell us what your role is in this debate?
Weissman: I was probably chosen to be head of the National Academy's panel on human reproductive cloning, and its effect on any legislation on nuclear transfer, because I am one of the founders of the field of adult stem cell biology. My background was as an immunologist, but I am really probably best known for isolating first the mouse blood-forming stem cell and then isolating human blood-forming stem cells that work in human transplants; and then finding the method to isolate, most recently, human brain-forming stem cells, again from more mature tissues rather than embryonic. So I knew this field of adult stem cell biology pretty well, and of course I have been an active participant in it.
Cohen: Did you anticipate the day when your work and this issue would be on people's lips and very much in the political dialogue?
Weissman: Not at all, because I thought that adult stem cell biology was separate from embryonic stem cells. Even before I headed this committee, I had the view that embryonic stem cell research was important, but I hadn't thought out clearly how the field of embryonic stem cell, and especially the field of what is called nuclear transplantation, would affect my thinking.
Cohen: Tell us about nuclear transplantation.
Weissman: Sure. The field of nuclear transplantation to create a new embryonic stem cell line began oddly enough with the efforts to clone whole individual animals. The way it is done is to take the nucleus of any body cell, and put that into an egg from an animal of the same species after you have removed the DNA or the chromosomal material from that egg, so that the only genetic instruction in that egg comes from the body cell. The next step is to give it a little jolt of electricity, which activates the egg to go into the program of cell division. This can result in a two-cell, then eight-cell, then sixteen-cell stage of development, and so on until it's about a 164- to 320-cell early pre-implantation embryo, called a blastocyst.
Now let me explain the term early pre-implantation embryo because I use it a lot. Normally when an egg is fertilized, all the events I said and all the cell divisions I said are occurring as the egg is falling through the fallopian tubes toward the uterus. So the egg came out of the ovary, was fertilized in the fallopian tubes and as it's going through its cell division, it's floating. It's only when it implants in the uterus that you begin the process to make a whole animal or a whole human being. The pre-implantation blastocyst embryo has got two kinds of cell types in it. It has an inner cell mass, each cell of which is uncommitted but will give rise to parts of the real embryo fetus adult as it develops. Then it's got an outer shell of cells, a sphere's surface of future placental cells, which implant. So they land on the uterus, they recognize the uterus that is prepared hormonally, as in a normal cycle, and then they send out little fingerlike projections of cells that go into the uterus that starts to form the placenta. That's implantation. So at that stage of development, you have two kinds of cells — those that make the embryo and those that make the placenta. If instead of allowing that stage to implant, you remove the inner cells and culture them in a test tube with factors, then those cells can start dividing and they still remain as undifferentiated as they were in what is called the pre-implantation blastocyst. These are called pluripotent embryonic stem cell lines.
Cohen: So this is very much reproductive as opposed to therapeutic cloning.
Weissman: Let's not use those terms yet because I want to go back and redefine the terms. Reproductive cloning means you would implant it, and you would allow it to go forward throughout pregnancy and an individual is born. I will tell you a lot more about that in a second because it is a critical and important issue. If you don't implant it and just extract it as I have just described to make embryonic stem cell lines, those stem cell lines could be used for a number of purposes, one of which is called therapeutic cloning.
So here's the process of therapeutic cloning — say we take one of your body cells, take the nucleus from it, put it in the egg, activate it, allow it to develop to the pre-implantation stage, extract the inner cells, grow them in a culture. Now we have your own genetically prescribed stem cell line. Now let's say that you had to have a liver transplant and in the best of all possible worlds, we had worked out the technology, so what you would do is to allow the embryonic stem cell line to be coaxed into developing liver stem cells. Then you would transplant those liver stem cells back into you. It would be a close genetic relationship to you because all of the nuclear genes, all of the chromosomal genes came from you. So it would be like an identical twin, except that there is another set of DNA in the mitochondria that are important for energy metabolism, and all of the mitochondrial DNA in a nuclear transfer come from the egg, not from the nucleus donor.
Cohen: Are you saying that there is not necessarily a clear line between reproductive and therapeutic cloning?
Weissman: I think there is a very clear line, and the clear line that we define in our National Academy's panel is that in reproductive cloning you have to put the blastocyst into a prepared uterus with the intent of creating a child. In nuclear transfer to produce embryonic stem cell lines, it is not the intent to do that; and all you do is extract the cells at a stage where you can make an embryonic stem cell line from it. Now, it all depends on intent. Right? Whether one intends to create an embryonic stem cell line or whether one intends to create by reproductive cloning a human. So our panel looked at the experience in animals of this reproductive cloning, and we found a dramatic thing that I actually was not aware of until I went on the panel; and that is that 99.2 percent of all pre-implantation blastocysts put into a prepared uterus die during pregnancy. Whether its sheep, cow, mouse, pig, etc., 99.2 percent of them die. And they don't just die as in a miscarriage in the first month or two of pregnancy; they die randomly throughout the whole pregnancy.
We found in the literature on the subject that quite often the embryo or the fetuses were abnormally large as part of the defects that they had; and if they were large and the pregnancy had gone on to the second or third trimester, the later stages of pregnancy, they often took the mother with her. So we could say clearly without any religious or moral value background, but strictly from medical and scientific reasons and from the Nuremberg code about human subjects (human participants in clinical research) that reproductive cloning was essentially unsafe at any speed. This was not medically allowable; this was not scientifically feasible and in terms of human subjects, the risk to the fetus and the risk to the mother clearly outweighed any potential benefits. So we asked for a legally enforceable ban on human reproductive cloning, which we defined as placing a nuclear transfer, pre-implantation blastocyst into the prepared uterus. And I'll use the term nuclear transplant research as a short-hand for putting the nucleus into an enucleated egg, getting it up to the blastocyst stage, taking out the inner cells and making an ES(embryonic stem)-cell line.
So now what were the reasons, what were the things that could be accomplished scientifically and medically by nuclear transplantation that could not be accomplished by any research on adult stem cells or any characteristics of the 64 or so human embryonic stem cell lines that were allowed by the President, and which were derived by excess pre-implantation blastocysts sitting in in vitro fertilization clinics? That was the question we had to answer. I'm going to go through as least four categories of things that could not be done with any known and independently verified technology today.
The first one is getting a diversity of embryonic stem cell lines that matches the diversity of humans in America. So if you think about it, the President allowed the use of those 64 or so ES-cell lines, embryonic stem cell lines, because it was important to be able to study human development from the ES-cell to a tissue-specific cell like the blood-forming one we have, or the brain-forming one, or the liver-forming one and so on. And then from there to allow them to develop into the real tissues, the liver, parts of the blood-forming system and so on. Now, one can do that kind of developmental study in a test tube or one can place the developing tissue-specific stem cells into mice that lack an immune system and they will complete their development in that mouse.
So one can, as a backup to the kinds of research one can do, one can study development of cells from embryonic stem cells both in the test tubes and in the context of the mouse's body where everything so far seems to be done appropriately. So now let's go back to the question, what's the genetic diversity of the population that those 64 stem cell lines represent? They represent, of course, people in in vitro fertilization clinics and in the U.S. — which means mainly well-to-do, mainly white, all infertile.
Now if you ask yourself, how does that represent the kinds of things we need to know about normal or abnormal development that might be peculiar to one or another population — sickle cell disease in blacks, type II diabetes in the southwestern U.S. native American population, a number of genetic diseases in Jews who come from certain areas of Europe, etc.? The answer is that the diversity of those cell lines is not sufficient to give us information of the diversity of the population of the U.S. You can't guarantee that you're going to get that diversity out of those clinics, but you can guarantee that you could get that diversity by transplanting nuclei from body cells from representatives of each of those populations into an egg and then making an embryonic stem cell line from it.
The Politics (and a little more science and medicine)
Cohen: This is emerging as a hot button issue, and yet I get the sense that it's terribly complicated and little understood, at least by the public.
Weissman: It's not understood in the public, it's not understood in the Senate. It's not really understood in the biological community except by those who have taken the time to learn, or have taken the time to practice this subject.
Cohen: But now we're facing the Brownback bill, the legislation to ban all cloning.
Weissman: That's right. That's why the presidents of the three National Academies had asked us to look at that issue to clarify it, especially to say what if human reproductive cloning was banned but along with it — the Brownback-Weldon bill in the House and the Brownback bill in the Senate — that the research on nuclear transplantation was banned also. So we looked at it and in contrast to the reproductive cloning, which was medically unsafe and dangerous, there was little danger and no medical reason not to proceed with nuclear transplant research.
Cohen: Do you think it's a fair statement that the future of this kind of research may be hostage to the politics that surround it?
Weissman: There is no doubt that almost everybody that you know or I know, including us, you and I, have certain inherited genes that give us a risk for one or another disease. This is true for all cardiovascular disease that has a genetic predisposition. It's true for auto-immune diseases, and they include juvenile diabetes, neurodegenerative diseases, like multiple sclerosis, rheumatoid arthritis, all allergies...I could go on and on, just to say that probably the majority of diseases that affect us, that cut short our lives, are from genetically predetermined predispositions for the disease.
Now, you and I might have one or more of those genes for arthritis or diabetes or something, but we didn't get the disease. But there are plenty of people who we know, including some in our families, who got one of those diseases. Now what you do is take the nucleus from a body cell from somebody that has a genetically determined disease, and they will have not only one of the genes that is the principle suspect, but all of the genes necessary to get that disease. That nucleus put into an enucleated egg, giving rise to a predefined embryonic stem cell line, would have the instructions for how to make that disease. And now we can just go through every one of those diseases and say, if we had an embryonic stem cell line available to the best and brightest in academia, as well as in commercial entities, every day you could go in and have a hypothesis of how that disease is caused, which gene might be involved in it, and how you might change it, because you can study it. This would represent the first time that we could follow the development of genetically inherited human diseases directly without studying the patient.
If you think that I am talking science fiction, I can tell you that the experiments have already been done in mice (mainly by Rudi Jaenisch at the Whitehead Institute at MIT) where you take the body cell of a mouse with a genetically determined disease, make an embryonic stem cell line of it, and that stem cell line faithfully recapitulates the whole development of that disease. So by banning research on nuclear transfer, you're saying we're going to take away this tool for human genetically determined diseases. This is kind of ironic because we just spent a lot of money and a lot of time sequencing the human genome, so we could find the gene that might be involved in these diseases and therefore correct the genes one at a time in a test tube. Now you cannot do that with the current human ES cell lines. They certainly don't have the genetic instructions for the several hundred human inherited diseases. You cannot do it with adult stem cells and you can't do it even with prison volunteers — the ones I believe Senator Brownback suggested are potential volunteers for such research.
Okay, now let me take one more step. Let's look at cancer development. In cancer cells you might have a genetic predisposition for the disease, but in fact the cancer cell in your body came from a normal cell that had several mutations during its life history and only after the last mutation does the cancer cell emerge. That means the only cell in the body that has the full life history and instructions for making that cancer cell — let's say a breast cancer — is the breast cancer cell itself. Now if you take the nucleus from that cancer cell and put that into an enucleated egg and make an embryonic stem cell line from it, you have the possibility to study an actual cell line that will recapitulate the development of the cancer with high probability in a test tube, or in an immunodeficient mouse.
And again just like the previous one, every day you could come in and have a hypothesis about what genetic variants or mutations were important in giving rise to that cancer, for example breast or colon cancer, or lymphoma or leukemia to name a few. And then test that hypothesis directly. We need to do the research that will make this line of investigation possible.
By banning nuclear transplantation research, Congress could end up banning a field of research that is as important as recombinant DNA was in the late 70s. As you know, the same kinds of groups have lined up before against recombinant DNA research — well-known individuals and para-environmental lobbies and so on. A lot of them still don't think you should have done recombinant DNA research, but in fact there's no doubt that the products of recombinant DNA research, purely unanticipated in the 70s, save over 100,000 American lives a year. I am talking about drugs such as erythropoietin, interferons, antibodies to breast cancer or B-cell lymphomas, insulin, human growth hormone, GCSF (granulocyte colony-stimulating factor) and so on and so on.
It would be unwise, to say the least, to block this line of research unless the case was so compelling that you knew — and everybody knew and everybody believed — that you were killing human beings to do it.
The Politics
Cohen: What is your assessment of the ratio between heat and light in this debate?
Weissman: It's mainly heat and very little light because people are keying off on their own gut reactions and the words that are used. You can't use the word cloning in a scientific sense in the general public without recalling the Boys from Brazil or mad scientists and so on. You can't say the word embryo without people thinking of a fetus that has arms, legs, a head and so on. (Embryos at the preimplantation blastocyst stage have no recognizable body parts or organs, only about 60 cells in inner cell mass, and these have no resemblance to any cell in an adult tissue or organ.) So the wording has contributed to the amount of heat and the anti people, the anti groups for doing this kind of research, have used that. On the other side, there is far too much heat when people who want this to work say that tomorrow we'll have cures by therapeutic cloning for all these diseases.
Cohen: President Bush has framed this issue in terms of spare body parts and designer children.
Weissman: I know, but that is completely false because the stage at which one extracts the inner cell mass has no body parts, and all of us, including the National Academies, agree that we're not moving beyond the stage where you have undifferentiated inner cell mass. There's no kidneys, there's no hearts, I mean there's no nothing. He is mistaken. It's unfortunate that his advisors have not informed him what the real data are, what the real science is. I'm sure that if he really had had a fundamental understanding of the issues that he would have at least framed....
Cohen: Yes, but that gets to the politics of the issue because I suspect that it's less a question of what he really understands as opposed to the constituencies that he's playing to.
Weissman: Well, yes and no. I think that certainly amongst his advisors are not only those that are playing to those constituencies, but on the other hand, I cannot believe that once he knows what the information is, and has a real understanding of this stage of development, and how research in this arena is so pivotal for biomedical science and therapies that he would be so unequivocally against it. He's too smart for that.
Cohen: The White House says that anything less than a total ban is impossible to enforce. Do you agree with that? Tell me about that.
Weissman: That's not true at all. Let's go through what would have to happen to have human reproductive cloning go on under the laws, let's say under Hatch and Feinstein's bill. So that bill says you can do nuclear transplantation for research but you can't do human reproductive cloning — it's the same million-dollar fine and ten years in jail. So now, who does the research? Who does the nuclear transplant research?
Let's say I'm able to do it and I do it in my lab. Now I make the pre-implantation blastocyst, but what would it take for me to disobey the law? It would take me having about a hundred of those ready to go and a hundred women prepared. I told you that 99.2 percent of the time it fails. And I would need to have a gynecologist, an anesthetist, a whole clinic setting, which of course is a health care institution regulated by law. I would have to have an intensive care unit nearby, because anybody who would implant this into the uterus would have to do what in vitro fertilization clinics do when they implant a blastocyst. You would have to have a pretty big conspiracy, all of whom know that it's a million-dollar fine and ten years in jail. You can't just make a blastocyst and throw it in a uterus. The woman has to be prepared; the woman has to have hormone treatment to build up the wall of the uterus to receive the blastocyst to implant. Otherwise implantation can't occur.
Cohen: Do you support the Hatch-Feinstein Bill?
Weissman: Personally, I do but let me just say you can't say, and nobody should say, that I'm doing that in my role as the head of that National Academy panel.
Cohen: No, I just mean personally.
Weissman: Of course I do. I mean I think that this is just essential research to be able to do, and for the wrong reasons, I believe, is likely to be banned, say in the Brownback bill. People are not looking at the real issues.
Cohen: The White House says that cloning violates basic principles of medical ethics, but I wonder if part of the problem is that there really are no clear principles of medical ethics in this area.
Weissman: There are no clear principles of medical ethics in the question of research on human eggs to human pre-implantation blastocysts. Now it is, of course, a personal and religious, if you like, ethical question as to when human life begins. If we knew for certain that all human life began and was wholly contained within an egg, then you could have a real debate about the importance of that human life. It is a personal opinion only and no degree of arguments or philosophy or religion, at the end of the day, will tell us for sure when personhood begins. When is there a "soul?" When is there a real human? We can't do that because we don't know it because that's the province of opinion and not the province of findable facts.
Cohen: Aren't the barn doors open and the horse gone on this issue? There's going to be cloning all over the world. What are they accomplishing with this bill even if it passed?
Weissman: I agree with you that appropriate research on nuclear transplantation to create embryonic stem cell lines will go on in other many other countries. It's already going on legally and is funded in some other countries. Now, I don't think that the barn door is open on reproductive cloning. It is so dangerous that commonly applied law against reproductive cloning probably will prevent anybody but the most foolish practitioners from trying it. I happen to think that if somebody tries to do reproductive cloning today...if they tried to do that experiment on humans that that would be completely in contradiction to the Nuremberg code that we all accepted. I think they are truly criminals if they do it.
Cohen: There are those who would suggest that you give the White House too much credit in terms of knowing the truth and that, in fact, they are playing to very well established constituencies in the Republican Party whose views on such issues are very well known, and a lot of people are convinced that this issue is not going to be decided on its merit.
Weissman: If the White House remains ignorant about what I just said, and what many scientists are saying, it would be true they we might end up with an uninformed decision.
Cohen: I don't want you to think I'm cynical, but I don't know why you presume ignorance.
Weissman: Because...I will give you an example. First, most of my colleagues in biomedical science are surprised when I let them know of the several points I outlined previously in this interview. Next, just two weeks ago, I talked to Senator Bill Frist, a trained scientist physician, who was in the field of transplantation, and as I went through three of the four arguments, the ones that I told you, like my biomedical colleagues, he had not heard previously or understood the kinds of concrete and important medical research opportunities that would be lost. Does that mean he's going to change his mind politically? I don't know. I think it might be a matter of conscience with him, which of course is his right. But if Senator Frist hadn't been party to hearing it from the other stem cell biologists — we are certainly in a field that he is not in — then certainly those who are advising (the President) haven't heard it, haven't presented it. I think that we should not yet believe that the President is going to make a purely politically decision. I think we ought to leave the President enough room to say, "I have learned something new and I now understand that I'm standing in the way of some huge potential benefit on the same magnitude or on the same order as recombinant DNA and the products and the treatment that came from it." I think it's wrong for us to back him in a corner until he's had a chance to learn it. If he learns it and then still does it, then I'm willing to be part of the attack team.
Cohen: It just sounds like the Hatch-Feinstein bill is safe middle ground and responsible.
Weissman: I think it is responsible, that's for sure. I spent a fair amount of time talking to Senator Hatch and watching him evolve his opinion. I think he actually said it just about as well as anybody in his press conference on the Senate floor. I'd look back at his speech; I'd have somebody read that online because I think that's just about as impressive of an encapsulation of the argument that I've seen.
One more thing I would like to add, and I think that it's really critical that everyone understands this: when we decide to make policy based on what we know in science. We should make policy on science that is not only published in peer review journals but replicated independently in many different ways. We wouldn't try to have the FDA approve a drug based upon an unpublished manuscript, or even one that was published by only one person but not really tested thoroughly. The FDA requires for human health, and for the protection of human health, that it is absolutely locked in, everything known about it.
Right now, the debate that's going on — and especially from Senator Brownback and Representative Weldon — is that there are discoveries locked up in laboratories which are not yet published, or only recently published, on which we should base the policy to ban research. I've reviewed the papers that they're thinking about and talking about many times for the journals, and I would just say that there lots of different interpretations and lots of different possibilities from these papers.