Scientist Lee M. Silver on cloning wars, bioethical battles, and new and improved genes
Molecular biologist Lee M. Silver is a happy--and increasingly prominent--warrior in the ongoing battles against bio-Luddites on both the left and the right. His thought-provoking 1997 book, Remaking Eden: Cloning and Beyond in a Brave New World (Avon Books), thrillingly explores how cloning, combined with other fast-developing biotechnologies, will soon revolutionize medicine and human reproduction.
Born in 1952, Silver started out as a physics major at the University of Pennsylvania. As a senior, he concluded that "even though I loved studying relativity and cosmology, I was never going to be able to go beyond what had been done by Einstein and others." After an all-night discussion with a friend who was a biology major, Silver changed course. "He told me about DNA and RNA and proteins and all about molecular biology," recalls Silver. "And I said, `This is great. This is what I want to do.'" He got his Ph.D. in biophysics from Harvard and went on to a post-doctoral fellowship at Manhattan's Sloan-Kettering Institute to learn about the biology and genetics of mice. Then came four years as an independent investigator at Long Island's Cold Spring Harbor Laboratory, which is run by Nobelist James Watson, one of the co-discoverers of the double helix structure of DNA.
Arriving at Princeton University in 1984 as a professor in the Departments of Molecular Biology and Ecology and Evolutionary Biology and the Program in Neuroscience, Silver has recently shifted his focus to behavioral genetics. "To my mind," he says, "we basically understand pretty much everything about the basic principles of biology except for how the mind works." Silver is now studying how genes affect behaviors such as alcoholism, aggression, sexuality, and curiosity in mice. He points out that "almost every single gene present in mice is also present in humans. So if you find a gene in mice that clearly affects what psychologists call novelty seeking, you can go see if it does the same thing in humans."
When Silver is asked if he thinks he may be afflicted with the novelty-seeking gene, he replies with a laugh: "I am definitely afflicted with novelty seeking. Absolutely. Absolutely. I can't stay still--I will jump from one thing to the next."
Silver's tendency to jump from one thing to the next is not a quality appreciated by some of his scientific colleagues. "There is a conflict going on between the faculty in my department and me," he admits. "My literary agent says I have been Saganized because I am popularizing science," he says, referring to the late planetary scientist and public television star Carl Sagan. "I think [my co-workers] are sort of angry at me for spending time with something that they think is not worth spending time on, which is going out in the world and talking, as opposed to sitting at the bench doing science." One result of his going out in the world: Later this year, Silver will become a half-time professor at Princeton's Woodrow Wilson School of Public and International Affairs.
REASON Science Correspondent Ronald Bailey interviewed Silver in his office in February.
Reason: What do you think is the most exciting development in biotechnology?
Lee M. Silver: The most exciting development is that we now have genetic descriptions of lots of organisms, including humans. We are going to have a whole catalog of all human genes very soon. It has already been done for some 15 different microorganisms, and it is going to be done for lots of different animals useful to biotechnology research. This is going to provide a phenomenal database that is going to allow pharmaceutical companies to be able to develop a new field, "pharmaco-genetics." Pharmaco-genetics will use genetics as a way to distinguish subsets of disease so that we can tailor cures based on the particular genes that individual patients carry. The problem that drug companies have right now is that they have therapies that work in some people and not in others. Researchers are all convinced that the difference in effectiveness is a genetic difference.
Biotech is also going to revolutionize agriculture and energy production--in 100 years, it will be possible to create oil. We are going to create microorganisms that will make long-chain hydrocarbons. We will have huge power over simple living systems, and even complex systems like animals. We will be able to create any substance we want using microorganisms or animals. Once you have genetically engineered an animal, you have essentially created a biodegradable factory. Even its wastes are biodegradable. It's a reproducing factory. Startup costs are huge, but upkeep costs are very, very cheap. That is the future of biotechnology.
I bet that in 50 years, all the old factories for making drugs will be shut down and all drugs will be made in cow's milk. You will have a herd of cows making human insulin, human growth hormone, etc. Each herd of genetically engineered cows will make a particular drug in their milk. Consequently, the price per therapy will drop some 100-fold. After all, what does a gallon of milk cost--$2? A genetically engineered cow will produce an amount of drug in each gallon which costs thousands and thousands and thousands of dollars to produce today. So competition kicks in, and all drugs come down in price. I think that is going to begin to happen in 10 years.
Reason: Biologists at Johns Hopkins University and the University of Wisconsin supported by the biotech company Geron recently announced that they had isolated and were now growing human stem cells from embryos and fetal tissue. Stem cells are the precursor cells that are capable of being turned into any tissue. Where do you see this technology going?
Silver: Stem cells are very exciting, and, again, I think that we will also be seeing some of the benefits of stem cells in 10 years. Creating bone marrow is one of the easier things to do with stem cells, but I don't think we are going to be able to create whole organs from stem cells in 10 years. However, one of the things I think we will be able to do over a much longer period is to create animals that have been engineered so that their organs can be used for transplantation into humans without being rejected.
Reason: Last year we heard reports from Korean researchers that they had cloned a human embryo as part of stem-cell research. What do you think was going on there?
Silver: All previous instances of advances in cloning technology have come from biotech companies or from researchers in universities that are interested in using cloning as a biotechnology tool, not a reproductive tool. The biotech industry is just interested in making medical products. On the other hand, fertility clinics have no interest in making medical products. Their whole purpose is to help people have babies. Now the Korean group was a fertility clinic. Fertility clinics don't do research on stem cells. That is not part of their purpose. So if you are a fertility doctor, trying to create a cloned embryo with a woman's egg (and in this case using her own cells), there is no other reason to do this unless your intention is to produce a child. So what I think happened--and this is an honest speculation--is that the embryo didn't look very good and therefore the Korean researchers aborted the experiment. And then, they had this huge outcry, and so I think they devised the stem cell story as a cover.
Reason: Why haven't researchers been more successful in using somatic cell gene therapy--replacing defective genes in a patient's tissues with normal versions--to cure genetic diseases such as cystic fibrosis?
Silver: Somatic cell gene therapy is very difficult to do. A living person has millions of cells, and you are trying to get a new gene into a reasonable percentage of those cells to fix a disease like cystic fibrosis. Cystic fibrosis patients have a defective gene that keeps them from making a certain protein. So in theory, if you put the good gene into those cells, they could make the protein. This would prevent the buildup of fluid in the lungs of cystic fibrosis patients, the most deadly symptom of the disease. In practice, though, it is very, very difficult to get those genes into a large number of cells. This has always been the case.
However, I should say that whenever I have said that something was hard or impossible, I have been shot down by the advance of science. There are a lot of people working with somatic cell gene therapy who are very smart, and maybe they will figure out the magic bullet that will get the DNA into the right cells and make it work. And if it works, it will work overnight. In other words, if you can figure out how to get DNA into a large number of cells in a target tissue, that's it. If you can get over that barrier, then somatic cell therapy will be possible for lots of folks. I don't see it happening right away, but I could be surprised.
Bone marrow gene therapy is the first one that will work. Because you take out the bone marrow from somebody, you add the gene, you find the one cell in a thousand that has picked up the gene. Then you multiply that cell and then put the modified bone marrow cells back in.
Reason: What about germ line therapy? Germ line therapy means introducing a gene into an embryo or egg at an early stage of development so that the gene appears in every cell in an animal or person's body. Is germ line gene therapy more feasible than somatic cell therapy?
Silver: Absolutely. Germ line therapy is easy. We have already gotten it to work on lots of different animals. Mice were the first animals in which it was perfected. It has been working on mice now since the 1980s, when the genes for human hemoglobin were put into embryos. Since that time, it has become commonplace and easy to do. My graduate students learn how to do it in their first year. There are tens of thousands of people who can do germ line genetic engineering on animal embryos. And the important thing is that, under the microscope, you can't distinguish a mouse embryo from the human ones. So if you can do it with mice, you can, in principle, do it with humans.
Reason: Looking over the horizon, what is the next big thing in biotech?
Silver: The DNA chip. The reason the DNA chip is so powerful is that up until now, if you wanted to figure out whether you have the breast cancer gene, or the cystic fibrosis gene, or the gene for sickle cell anemia, we would have to do an assay for each gene. Somebody would take your blood--take your DNA--and look at the relevant gene to see if you had the normal version or the version which predisposed you to a disease. That is what people do now in clinics, assaying one gene at a time. You get a result back 24 hours later. But once all 70,000 human genes are catalogued, a DNA chip will be able to look at all 70,000 of your genes at the same time. And you will get your results back in three hours. You need almost no DNA to do it, just a scraping from your mouth. A DNA chip genetic assay could also be done on an early embryo, giving you a complete profile.
This is going to revolutionize medicine. It is also going to revolutionize our understanding of the connection between genes and who people are. For example, say you are born with a predisposition to a hot temper. This temperament is not the result of a single gene. There is no such thing as a hot-tempered gene. There are probably a multitude of combinations of 30 or 40 different genes that together in certain combinations predispose people to have a hot temper. Using the DNA chip, you can assay 10,000 people to find out the constellation of genes that predisposes you to a hot temper, or predisposes you to being depressed, or predisposes you to any kind of trait. That is phenomenal. Most people right now don't understand the power of this yet. The incredible thing is that this technology already exists. What we need now are the 70,000 genes to put on the chip. We are waiting for the Human Genome Project [which is being coordinated through the National Institutes of Health and the U.S. Department of Energy] to finish; then we can take those 70,000 genes and put them on a DNA chip.
The original version of that project was simply going to catalog all the genes present in human beings--the genome. There are, according to the latest estimates, somewhere between 60,000 and 90,000 genes comprising the human genome. The catalog by itself doesn't do very much--which is where the DNA chips come in. The 70,000 human genes come in different forms. For example, say gene A comes in forms 1, 2, and 3. Using the DNA chip, we can look at people that have form 1; look at people that have form 2; and look at people that have form 3. By looking at the various forms of gene A, we will be able to determine what effects the different forms have on people--how they affect their health and their behavior, etc. That will be the next step of the Human Genome Project.
Reason: What do you think about artificial chromosomes? Are we going to have those soon?
Silver: Yes. An artificial chromosome will again give you unprecedented power to alter cells. Because right now when we put genes into cells, we are putting in one gene at a time. The artificial chromosome means that you can create what I call "gene packs." You can hook 40 genes on this chromosome. The function of some of the genes will be to shut down natural genes, while others [will] replace natural functions. In the next two or three decades, we are going to be able to build modules of 30, 40, 50, or 100 genes on an artificial chromosome and insert it in the genomes of human embryos and other creatures.
Reason: In Remaking Eden, you basically come out in favor of human cloning. Would you consider cloning yourself?
Silver: I am not interested. I already have my children. Obviously, I have been asked this question many times. I felt the need, probably instinctive, to have children with my wife. And I didn't want to have children that were just for me. I wanted to have children that consummated my relationship with my wife to the greatest extent, and that is why I have my children.
Reason: Why do you think there was such a negative reaction when Ian Wilmut of the Roslin Institute in Scotland announced that he had cloned a sheep? Why do most people oppose human cloning?
Silver: Let me answer you this way. In the spring of 1998, I gave a lecture to a group of well-educated residents from Princeton, New Jersey, who were not scientists. I began by telling them about the bewildering number of high-tech treatments now available to infertile people. I told them that there were a number of reproductive protocols under consideration, including cloning. But before I discussed cloning in detail, I wanted to get their opinion on another fertility protocol. The protocol under consideration is for cases of severe male infertility, when only the precursors of sperm were present. The proposed treatment entailed the injection of one of the man's testicular nuclei containing all of its DNA into an egg cell from his wife that had previously had its nucleus removed. Anyway, I go through this whole long thing and I say, you come out with a baby and the baby kind of looks like the father. The baby might even kind of behave like him, but unless you told anybody, nobody would know that it wasn't just a son produced in the normal way between him and his wife. Is his son a clone? And two-thirds of the people said, no, the son is not a clone.
Reason: OK. (Laughter.)
Silver: Which is amazing. Of course, he's a clone. I didn't do an exact count, but I looked at the hands raised and it was about two-thirds. My point is that people--even educated people--still don't know what cloning is. They have the notion that cloning is more than it really is. People think of the word in a context beyond genetics, that somehow there is a soul that has been replicated in some way that goes beyond the genes. And when I explain that the genes are the same but that the human being that develops is not the same as the human being that existed before, the response I get from lots of people is, "Is that all it is?" So I think the word is actually used incorrectly. You are not copying a person. You are having a child born who has all his genetic material from one parent. When biologists talk about cloning, they are talking about just copying genes. Nothing else. But in this culture, the word has a different meaning--copying, replicating, duplicating.
Now all of a sudden, Ian Wilmut says he cloned a sheep. If he had used a different word, I don't think it would have caused the same response. I also think that there are people who are against cloning for religious reasons and who know perfectly well what is going on, but who are willing to take advantage of the confusion to reach a certain political goal.
Reason: Who and why?
Silver: Oh. I think that it is from a right-to-life perspective. Some people believe that God controls reproduction, and we shouldn't be messing with reproduction, period. And if God doesn't want you to have babies, you shouldn't have babies. And if God decides that you are going to have a baby with a birth defect, well, then that is the way it has to be. This is a religious point of view, and cloning is seen as one more way in which we are interfering with God's will.
Reason: Are embryos people?
Silver: The confusion people have is with the meaning of the words life and alive. We use the words in two very different ways, one meaning vegetative life, the other conscious life. To biologists, life in a vegetative sense simply means the life of cells. In fact, in this beaker [gestures toward beaker containing a pinkish fluid], there are living human cells. Millions of human cells. They are perfectly alive and they are perfectly human, but they are not conscious. But when you talk about human beings and persons, we are talking about consciousness. The best example of the difference that I know of is what happens when a person is shot with a bullet in the heart--he dies almost instantly. And yet, most of his body is still alive. So the person is dead, even though his body, for the most part, is alive. That is the distinction between vegetative life and conscious life. Human embryos are cells, and they are alive in a vegetative sense, not a conscious sense.
Reason: So would you be comfortable with saying something like, "Brains are people and genes are not people?"
Silver: Well, it is the mind that comes out of the brain--and that is sort of a subtle distinction. But I think it is an important distinction. The brain gives rise to the mind, and people, I think, are defined by those minds. Now, genes play a role in building the brain. Genes provide the framework for the human mind. The human mind, of course, is a dynamic entity, while its genes are static.
Reason: That reminds me of an interesting sentence in Remaking Eden: "The human mind is much more than the genes that brought it into existence." What do you mean by that?
Silver: From the moment of conception or of cloning--however you might begin--the genes don't change. And so the genes in each individual are completely static and unchanging. The genes provide instructions for building a brain, but the mind which comes out of that brain can respond to the environment. The mind can change continuously. And the mind--the human mind especially--can be aware of itself. Human beings are different than all other animals because human minds can understand that their genes have given them instincts that they can then turn around and not follow. That's pretty amazing. I mean, Richard Dawkins' The Selfish Gene makes sense in every animal except human beings.
Reason: Because those minds are now able to control their genes?
Silver: Oh. Absolutely. That is exactly right. In fact, yes, the evolution of the future is going to be totally different from the evolution of the past. Evolution by natural selection was based on chance combinations of genes and new mutations that provided a benefit to the individuals that carried them. The offspring of those individuals would out-compete other offspring. That is the way evolution has worked in the past. It was totally by chance. The individuals involved had no control over the evolution. Today, we can control our own evolution. We can decide what genes we give to our children. So we are actually taking control--or will take control in the future--over the evolutionary process by picking the genes we want our children to have. And then those children will have children who can pick the genes they want their children to have. Already, that is being done to a limited extent with embryo selection in fertility clinics. Even with selective abortions, you are choosing not to put certain genes in your child. In choosing to have another pregnancy, you are choosing to have a child without particular genes. So you are controlling evolution there.
Reason: What do you think of bioethics and bioethicists in general?
Silver: I have been called the anti-bioethicist. And that is unfortunate. In fact, I think I am very ethical. I debate and challenge many of the views [held] by some very prominent bioethicists--Leon Kass, Glenn McGee, Art Caplan, and Thomas Murray, for example. I think I am being completely ethical in my point of view, and I think that the opinions of some prominent bioethicists are silly or misinformed. Now there are some bioethicists, like Ruth Macklin, of whom I happen to have a very high opinion. She is a bioethicist at the Albert Einstein College of Medicine. She is a scholarly bio-ethicist, not a media bioethicist. My opinion is that very often many bioethicists talk about things they don't understand and they make fools of themselves by doing that.
Reason: I've been reading a lot about bioethics lately and it struck me that many prominent bioethicists apparently hate biotechnology. Do you get that feeling too?
Silver: Of course, of course. Because if they didn't, they would have nothing to argue against. I mean, if you agree with everything, nobody is going to ask you for interviews. They have to be against biotechnology to get attention. I think many also see themselves as playing a role in society as the brake. For some reason they assume that we need brakes. They think their role is making everybody stop and look [at] what is going on before we go anywhere.
Reason: Leon Kass of the University of Chicago fears what humanity might do with increased control over our own evolution. He would prefer to put up with the random events of nature than be subject to human whims. How do you respond to Kass' arguments?
Silver: I respond by saying that he should have the right not to use this technology when he has his own children, but that he doesn't have the right to tell other parents how they should have their own children. I think that children don't belong to "society," or to the world. Children come out of parents and parents can do what they want with their children--as long as what they are doing is not going to hurt their children, of course. Leon Kass pretends to be a secular bioethicist, but he is not. I believe that his point of view is grounded in religion. Kass has written, "We are repelled by the prospect of human cloning because we intuit and feel immediately and without argument the violation of things that we rightfully hold dear." This is not an ethical argument but a religious one. It is the same one used by the church to persecute Galileo in the 17th century and by current religious leaders who still rally against the teaching of evolution. There is no logic to it. Kass and others are saying, "It is unnatural; we are repelled by it; therefore we shouldn't do it." That is not a valid ethical argument. Kass has written an essay called the "The Wisdom of Repugnance" which is so easy to dismantle. I'm surprised that somebody of his stature can make such a weak argument.
Reason: Do you think that religious points of view have no place in the public debates over genetic technologies?
Silver: I think that people should be allowed to hold their religious points of view and to practice their own religions. I think people should be able to do what they want with themselves and with their children. I am not against that. I am completely for that. That leads me to say that Leon Kass can believe what he wants about biotechnology. That's fine. He doesn't have to use the technology. But morally, he can't stop other people from using the technology.
Reason: What do you think of the argument by Boston University bioethicist George Annas and others that cloning and germ line enhancements are really experimentation on the unborn without their consent?
Silver: I think that is total nonsense. A one-cell human embryo is no different than another human cell. Now if you want to turn that one-cell embryo into a human being, it is unethical if the technique has not been proven. I would agree that if you don't know what is going to happen, you don't do it. But that is no different than any other medical experimentation protocol. Obviously, you want to test it before you do it in a way that brings forth a child.
Reason: So you aren't very concerned about the possibility that cloning and other biotechnologies will be abused?
Silver: No. I think that what people are going to want to do is make their children more likely to be happy, more likely to succeed, more likely to be healthy. That is the way I think it will be used. Parents are going to be able to give their children genes that other children get naturally, such as genes that increase athletic ability, genes that increase musical talents--talents are innate--and, ultimately, genes that affect cognitive abilities. Why shouldn't parents be able to give their child something that other children already get? The parents are going to say, "Why can't I do this for my children? I am not hurting my children."
Does that mean that there is no possibility that somebody might misuse the technology? No. We can't say that it will never happen. But I don't think that is an argument to say that nobody should be able to use this technology.
Reason: When your children marry and they come to you, their father who is a molecular biologist, and say, "Dad, we are thinking maybe we want to get some of the genetic advantages that you have been talking about for our children," what would you advise your children to do about your grandchildren?
Silver: I would ask a technical question first: Has the technology been validated? Is it safe? Assuming that it is going to work, I'd say, "Go ahead. I have no problem with it."
Reason: Do you think that will be the common view one day?
Silver: I think what is going to happen is what happened with in vitro fertilization. When the first test tube baby was born, people were asked, "Would you use this technology?" Nearly everybody said, "No, I would never do this even if I was infertile; there is no way I would go this far." And then, what happened? A small number of people started using it and they had babies and suddenly, you saw other people have babies and basically, people said, "It can help them; what is wrong with it?" The first response is negative, but I think it will become acceptable in our society. The question is, just how long that will it take? And the answer is that these changes can happen very quickly and society just zooms ahead.
Reason: In Remaking Eden, you suggest that in the future there will be genetic haves and genetic have-nots. Do you still think that way?
Silver: In the paperback edition, I basically backtrack. Evolution--the old-fashioned way, through natural selection--will stop because people will choose which genes to add to their children. Now those new genes will enter the gene pool of the whole human species, which is inextricably connected. If nothing else, the spread of AIDS around the globe has conclusively demonstrated that no human populations are sexually isolated from any other populations. And so, over many, many generations and in the distant future, these genes will spread throughout the gene pool. There is still going to be a question of access. Will genetic technologies be available to only 10 percent of the population? I don't believe it will be that restricted. The top 50 percent? The top 80 percent? Who knows? There are certainly poor countries whose citizens will have less access, but the fact is that the enhanced genes will spread. They will travel around the whole gene pool.
Reason: You are hopeful that these technologies will not only be widespread but fully accepted one day?
Silver: In the long term, I don't have any doubt that these technologies are going to be accepted. There is a lot of confusion and misunderstanding in the public realm right now, exacerbated by some bioethicists. But there is a basic common sense that seeps into the general population. If you see a better technology that is beneficial, doesn't hurt anybody, helps either you or your children be happier or more successful or healthier --and that is what biotech does--common sense tells you that people are going to accept it and desire it.
Reason: George Annas wants to create a federal human experimentation agency that would require biotech proponents to prove that there is an important social purpose for a line of research before they would be allowed to pursue it.
Silver: I think he is completely misguided. We already have procedures that we go through in this country to test new medical protocols. It is true that privately funded researchers don't have to do this, but almost all of them do it anyway. They have institutional review boards that look at experiments to make sure they are ethical and to make sure informed consent is obtained. I think informed consent is critical. I think that before any prospective parents use genetic therapies on their children, they have to be informed of everything. But I think George Annas is wrong.
Reason: You don't see, at this point, any particular reason for more federal laws regulating biotech?
Silver: No. That is not to say that I don't think there are certain ethical rules that I hope are followed. But the question is, what is the best way of making sure they are followed? I do not believe in a free-for-all. But my feeling is that very often when we are talking about the federal government, we are talking about some members of Congress who have their own particular goals in mind. Often you end up with something that you didn't start with. So even if somebody initially suggests a very rational rule, by the time it actually gets passed into law, it could be something totally different than what was intended.