 Thank you very much. Good afternoon. We're going to have a good time together. No slides, dialogue with the audience. And I'm going to begin by asking you to reflect on a question or two. Should you get bored with me and your mind's wander a little? So the question is, what role should society have in trying to improve the human species? We'll leave that as a background question. Now, before I launch into the formal remarks I have, and I encourage questions and discussion at the end, I just wanted to tell you how pleased I am to be here. This institution has been part of my life for 25 years or more. There are some close friends in the audience. I'm honored to have Dr. Watson here. And I'm most honored that all of you have come here. I'm assuming most of you are not scientists or physicians, but you care deeply about your society and you realize the power of science and where it may take us. So much of what I have to say will reflect on how people have thought over the last century about human reproduction. I've divided the talk into sort of three parts. One is Bruce suggested an historical review of eugenics from about 1900 to just after World War II, with a little bit into the 40s and 50s. Then a topic you may not be thinking so much about, and that is the current role of involuntary coercion of reproductive behavior in the world at large. A topic that I published on recently so I'm drawing that. And finally, and perhaps most interesting for you, I see there's a lot of people in the room who probably have children or are starting families or about that age. What about the future uses of technology in human childbearing? And I think that is where I had the most surprises for you and the most cause of reflection. So having laid that out, let me begin. If one wants to just begin with the word eugenics, one traces it a word that means in the Greek more or less good birth. To the work of a polymath in England named Francis Galton, published the term and first used it in 1883, in a book called Hereditary Genius. Itself, a term laden with value, one can have a very spirited and appropriate debate about what extends genius is hereditary or to what extent it requires a deep nurturing environment as well. But this work was a rose at a time that both in the United States and in Western Europe, particularly England, there was what historians today call the progressive movement. And I'm mentioning this particularly because often the word eugenics is cast in a very pejorative light. And I think it is fair to say that was in the vast majority of cases. Not how I'm going to point out some of the negatives in the history. It was a well-intentioned idea. Just think about the United States. The Civil War is over. The nation is recovering both politically and economically. And there's a movement of foot as the economy gets better. How can we help our fellow man? That's really what the progressive movement was about. And over the course of 30 years, you saw a remarkable series of events in the United States that sort of reflected this. The first institutions to house and help the mentally retarded, the mentally ill. First schools for the blind. First schools for the deaf to try and educate people who had been marginalized in society. All that, I'm sure you would agree, whether futile or not is another question but was well-meaning. Now, there was another theme, and that was the theme, that we couldn't help most of those people very well because of the burdens they had. And wouldn't it be better if we used our resources in a caring way to reduce those numbers in society looking forward? And we'll come back to that at the end of my talk. Now, in England, the currents, the eddies of this thinking really did focus around what the historians have come to call positive eugenics. Using information to help people have larger and healthier families, to nurture children, things like that. That was true in the United States as well, but for reasons that are maybe a little difficult to follow. In the United States and in some countries, notably Germany in the middle of the war, the Second World War, the focus became one of negative eugenics. That is, if we can't fix it, let's take the people that are most at risk for bearing children with severe disorders. Let's limit their child bearing. A pretty, in our society today, a pretty challenging thought. But one that gained traction in the United States. Let me just give you a couple of facts that I know from my own research in this area that's kind of astounding. Around 1900, bills proposing to authorize state agencies to limit reproduction through sterilization were extremely common in the state legislatures. One year when I was doing research for one of my books, I counted that one year 600 bills were introduced in state legislatures that proposed in some way to limit reproduction by folks. Now why? And now I'm connecting back to, not directly to the work done at Cold Spring Harbor, but to the notion of a scientific world. At that time, 1900, 1910, in the frong of what we call mentalism, I'm assuming most of you aren't scientifically based or don't have that background. The notion that even the most complex human characteristics, particularly if they were disease-oriented, might be explicable by a single gene, and therefore the classic inheritance patterns of autosomal dominant like Huntington's disease, autosomal recessive like cystic fibrosis or Tay-Sachs disease. And with our limited knowledge, the extension of this thinking far exceeded the knowledge that we had to justify it. Now, as Bruce suggested, for a period of about 30 years, Cold Spring Harbor was an epicenter of efforts to understand the impact of heredity on human disease. Charles Devonport, its original founder, a notable and noted science who was not a particularly wild-eyed eugenicist, published a textbook I think in 1911 about heredity in human disease that became the leading textbook of its era. I actually have read that textbook and there's actually much in it that is correct. Even from that century ago, he had it right and he had some things that were wrong. Today, we don't much think about, for example, in the genetics of criminality. But as recently as the 1970s, there was a huge debate in our society among both people in criminal law and people in genetics about the so-called XYY chromosome having an extra Y chromosome and whether that predisposed to criminality. And I think the final rule on that is if you're born with that syndrome, you tend to sort of physically develop a phenotype that is much like Hollywood's image of the thug. So in fact, what some researchers found was that people with XYY syndrome weren't particularly awful criminals but they were much more likely to be caught. So this gets very complicated very quickly. So Cold Spring Harbor was the home of an institution called the Eugenics Record Office. There was a staff here, there were many hardworking scientists and technicians sort of like how you might think of a genetic counselor today, for those of you who know these terms. And they and others compiled these vast pedigrees of families, maybe hundreds or even thousands of members through several generations, trying to elucidate without the tools that the labs here have today, whether or not there was a genetic force at work and what it might be. And so there was a setting where there seemed to be a scientific support for the notion that there was a cause, that the phenotype be it epilepsy, criminality, whatever bipolar disorder, there might be an underlying gene and maybe we can do something about it by limiting birth. So the story now enters a legislative phase. In 1907, Indiana became the first state in the union to enact a compulsory sterilization law. It was aimed at prisoners, males, and it made the vasectomy a condition of parole. The notion is that their germ, maybe a good idea by the way, but it adopted the notion that germ plasm, the sperm of the criminal might transmit criminal tendencies. In the space of about 20 years, more than half of our states enacted similar laws, very few focused on prisoners, most focused on institutionally, what we would have called them mentally retarded individuals, or mentally ill. And by fits and starts during the period from 1910 to 1925, a various number of state agencies employed such programs pursuant to state law. And in most cases, when they were challenged these laws, they were upheld at the state level, but it never really went to the Supreme Court until 1927. Many of you have heard or read in the newspapers about Buck v. Bell, which was the decision growing out of a Virginia statute that by about a seven to two, the Supreme Court said that it was permissible after appropriate review for state authorities to, without her consent, sterilize a young retarded woman. That decision opened up the golden era, if you will, of negative eugenic legislation. And for a period of about 18 years, till about the end of World War II, some 60,000 Americans were sterilized without their consent. Now you can imagine what a report like this how that would appear on the front page of the New York Times today. But it wasn't as obvious as one might have thought because these were almost all institutionalized individuals who were sort of in the background of society. But 60,000 is a pretty large number. And it was actually growing during the 30s. But at the same time, and I'm trying to weave together scientific advance with social attitudes here, which is what you are all interested in. At the same time, during the 30s, the reason for sterilizing people changed. And this calls on the first of two themes that are actually very relevant to the current election process that's going on. Immigration and the treatment of women. Let me illustrate this. And I did deep archival work on this for a book I wrote earlier in my life. And what the archival work shows that until about 1927, 1910 to 1927, by a factor of about five or six to one, the sterilizations were done on men. Now there's a couple of very simple reasons for that. It's a lot easier to sterilize a man than a woman. And it was technologically challenging. Cutting of the fallopian tube as a form of sterilization was only actually well developed about 1938. Before that, it was a total hysterectomy. And there was a significant death rate associated with it. Much easier to cut the spermatic cord. But in the 30s, as the technology's improved, and this is very important and Cold Spring Harbor played a very positive role in this regard, as the understanding emerged that this notion of a single gene cause of complex traits could not be supported. There was a shift, an intellectual shift, away from sterilizing women, young women, because they were at risk for having children with severe problems too. Sterilizing women because of their underlying mental retardation or mental illness, they would be unfit to be parents. They couldn't take care of their child. Not directly about genetics here. And or the burden of having children would actually be too much for them. So the shift in intellectual thinking, which is really very apparent if you go into the archives and state institutions, was a shift saying, we're sterilizing these women for their own good. A dramatic shift and one that was politically at the time seemed very acceptable. Again, I've acknowledged that the numbers were small, since 60,000 is a very small number compared to the population at all. But I think that the dramatic shift from five, six to one men to women to five, six to one women to men was a very dramatic piece of information suggesting a change in attitudes. Now, one of the interesting sides in this challenge is both institutions like holds being Harbor and this audience is if by the 1930s we knew that a Mendelian conception of complex traits like criminality, seizure disorders, whatever it might be, in some cases, poverty. If we knew that couldn't be true, why did the programs continue for another 10 years? And the most difficult problem I've had in researching the history of this has been why didn't scientists in a more organized way speak out to refute these ongoing practices? There certainly must have been a large cohort that understood it, but they were scientifically flawed ideas. And there were a few well-known scientists who did speak out, but when you think about the role that our leading scientists have today in setting policy, things like these Syllamar Conference back in the 70s to worry about the escape of recombinant organisms, other commonly held conferences to try and set policy, you see no evidence of that back in the 30s. Maybe the institution of science just had to mature a little further. Now, a couple of other things I'd like to say to put this in context for you has to do with placing the eugenics movement in an international context. I've already told you what eugenics is, but let me say a word about movement. How dare and on what basis would I claim that this is a movement? Well, I alluded to one thing already and that is the vast number of bills proposed in state legislatures. That doesn't happen. You don't have hundreds of bills proposed if there isn't much at work in the land of thinking about this. For some of the research I did, I forget whether it was 1905 or 1906, but thereabouts, I did a research on the index to public periodicals, all the topics and the Atlantic Monthly, McMillan's, and eugenics came up as one of the top three, three years in a row. There were literally hundreds of popular press articles published about it, so it was very much, it was in textbooks, I have old biology textbooks from high school chapters on eugenics, so the thinking was broad. And it wasn't just the United States and it wasn't just Germany. At least 25 other countries, besides those two, adopted this kind of legislation to a greater or lesser extent. Now, with the horrors of the Holocaust in Nazi Germany, very rapidly, the number of institutionally-based sterilizations in the United States dropped. By about 1939, there were about 4,000 to 5,000 state-based sterilizations a year, mostly on women in the United States. By 1950, there were probably 500, and then the number petered off to almost nothing very rapidly. One, there were no surgeons around to sterilize, they were all in the war. Two, we learned about Nazi Germany and its successes. And by the way, its successes were profound. We all think horribly about the death camps and things like that, but after the enactment of the law in Germany that created the so-called hereditary health courts, a home court system developed in Germany to deal with who should be sterilized. 400,000 or more court orders were issued in less than 10 years to sterilize people in Germany. So way, way, and for far more reasons, for example, deafness was a reason to sterilize. So that was the ugly excess of it and just one of many ugly excesses of that era. So that is a little bit in the limited time I have to share with you. That's a little bit about the background. Overoptimistic science being developed 100 years ago in a progressive era with the intention to do good, not to do harm. And the movement of that idea into, I suppose, I assume, well-meaning state legislatures who said this will be good for the people who were sterilizing. One, among other things, if one were sterilized in some of these institutions for the mentally retarded, one could leave the institution. And I've read the letter saying, well, Molly can't get pregnant now. She's wonderful. She'd make a very nice household maid. And you could say, this was freeing these individuals. I once was in charge of the care of 1,000 patients in one of these hospitals for many years. And to take them from the limitations of an institution, allow them in a kind home where they would do work. It may sound not quite right to you now, but it was a big improvement in their lives. And I think we all know we have to be careful about judging history, judging the past with today's values. But the world began to change and went in another direction. And so this is part two of the talk. And what I want you to think about now is, to me, an even more troubling story that is not connected with Cold Spring Harbor in any way. And that is the use of sterilization to restrict family size in the world at large. And a subpart of that is to look at, and I'll only do it for a few minutes, look at the role of sterilization as a coercive weapon against indigenous peoples. So for example, you know that in 1973 China adopted a one-child policy. I think that the Chinese one-child policy, which is just loosening now after 40 years, may be the largest single social experiment in the history of humankind in that literally untold millions of babies that one would expect were not born. There emerged a very disturbing and fairly well-documented trend to terminate female fetuses because the culture was going to have one child and they wanted a male fetus, to the point where now the largest single gender discrepancy between women and men is in China. And it is so large that one wonders where one is going to find a wife and whether this will contribute to social unrest. Its numbers, depending on who you read, 20 or 30 million missing girls. In India, it's the same story, but it is not as dramatic because although there was a short time when Indira Gandhi embraced a one-child family in sterilization, it still happens a lot. I can't give you the details because of time, but in the literature in groups like Amnesty International investigate this, in the literature one can find clear evidence of what I would call involuntary, but you might only call coercive efforts to sterilize large numbers of Indian women that are going on today. They have what are called sterilization camps. These are women who are living in poverty, who often have a number of children. And for roughly the equivalent of $10, which of course is a lot more valuable there than it is today, different regions will pay women by the thousands to undergo sterilizations. It doesn't reach a number that will really have a dramatic effect on anything. And what's curious about it is that it's not really supported by any facts. One can go to regions of India that are quite wealthy and find a fertility rate of between two and 2 and 1 half, just about like the United States because the families have money. They can take care of their kids, et cetera, et cetera. Or you can go to the state of Bihar in the South, where the fertility rate is about five or six children. And the women, you could say gladly, but they are being paid. And I might add, the number of vasectomies is about 2% of the number of tubal ligations, which raises some, again, the theme about the treatment of women, probably the single most important issue in bringing the world to a better place, in my opinion. Uh, there is also, in isolated areas, Brazil, Peru, good evidence of selective pregnancy termination or sterilization of Native Americans as part of an overall drive to move people off of land. And it's not, I wouldn't say it's large numbers, but that it exists today is, I think, troubling to all of us. Now, before I turn to the future, because I want to have lots of time to talk with you, I want to say a word about the other theme I mentioned that was relevant to the presidential race. And that's immigration. I think it's fair to say that at least for one half of the parties running for president, immigration is a major issue. There was a time, and we, of course, are a nation of immigrants, as you all know. But there was a time coincidental with the eugenics era in the United States, actually 1907, the very year that Indiana passed that sterilization law that I mentioned was the apogee of immigrants into the United States. And in terms of the percentage of immigrants coming into the country compared to the population as a whole, the amount of immigration coming into the country today is trivial. Yet it elicited a huge response. And here, Colespring Harbor's eugenics record office did have a big influence, not through the institution itself, but through a man named Harry Hamilton Laughlin, who actually was the director of the eugenics record office. He, in this curious era of the 10s and 20s of the 19th century, he merged as the most vocal support and most actually active lobbyist Congress to change immigration laws. This led in 1922, I believe it was, it might have been 21, to a major amendment of immigration policy in the United States that basically reset the quotas for who could enter the country. And this will be no surprise to you, sharply protecting immigration from Northwestern Europe, England, Scotland, Spain, and sharply restricting it from Russia, Poland, Southern Italy, and Greece. This was on top of the very first immigration laws. Anybody here grew up in San Francisco? The first immigration laws in the United States were in 1877. They were the Chinese Exclusion Acts. Here we were using the Chinese to build our railroads and wash our laundry. But the first act refused the Chinese men the right to bring wives across, which was obvious and really was designed to send circle men, circle them back to China. And from there, we went forward. But the law, astoundingly, when you think about it, the law that was enacted, federal legislation in 1922, stayed on the books for 46 years until 1968. That was when Congress finally revised the immigration law to have a more parody, if you will, on who could enter the country. I guess the reason I'm sharing that with you is one to reflect on the debate today. Even if you accept the concerns of what one of the candidates has suggested, it's a trivial issue in terms of numbers compared to what it was in 1907. And we got through that, so hopefully we'll get through this, right? So then to summarize, the thinking is no longer about whether or not a woman should have a child because there is something wrong with her genetic heritage. The thinking now is we just don't want to have too many people. And that's a much bigger thought. And once again, it's women internationally who are bearing the burden of that. I hope that China's policy with its changes is sinkling a big message to the rest of the world. But India remains very engaged in this. Arguing that it is not cause of its, you know, people are being recompensed for undergoing this. So in the last part of the talk, and this is the one where I really particularly would like to engage you, I want you to turn back to the question that I posed at the start, which was a question about what role society or an individual should have in judging or influence the reproductive freedom or activities of other human beings. And I want to, and it's probably the most important thing I can tell you about today because the past is the past. And what I'm about to raise are issues that are very relevant to the future of your children and grandchildren. We have a new technology emerging. I think it is a certainty that it will come to play. I can't tell you exactly when, but bear with me because this is the one technical part of my talk, so I have to explain it to you. Prenatal diagnosis has been available in the United States since about 1973. And as you know, it began with a search in older women of whether or not a woman was carrying a child with Down syndrome. So that was some 43 years ago. Interestingly, we have not budged an inch the number of children born each year with Down syndrome. And it's because of demographic shifts in the age which people are having children. As more older women have children, they're producing a larger cohort of Down syndrome fetuses that offset some of the technology. That may change very soon, but the background has been a growing use of prenatal diagnosis slowly and steadily, but it's about, I think, to change. And even if I'm wrong on the timing, it makes for great discussion with your friends and family. A holy grail in prenatal diagnosis has been the ability to capture a fetal cell in the woman's bloodstream. That means noninvasively, so we don't have to put a needle into the womb, so it's much safer for the fetus. It turns out that on the order of one in a million cells circulating in a woman's blood when she's pregnant is a fetal cell. It's not free fetal DNA I'm talking about. I'm talking about an actual fetal cell that contains the entire genome of the fetus. So the technology, there are two technologies, there are really three that I'm mentioning right now. One is the ability to identify and capture that cell and take it out of the mother's circulation. That's not perfected yet, but I know any number of labs and companies are looking at this and we can do it with a certain success rate. For a variety of technical reasons, we would like to have about five fetal cells to be analyzed so we don't make one cell alone. Could be mistakes, right, so we want to have about five. I say we're about a year away from confidently doing that. Then you take the fetal cell, which contains the entire genome, your 22,000 genes, and you amplify it. And there are ways to do that that folks at Cold Spring Harbor probably have been involved with and know much better than I do the story of that. But if you amplify it, then you can interrogate it. And you can instead of saying, does my baby, my fetus have Down syndrome, what among a thousand different disorders might my fetus have? And you can do it in an actionable manner in the sense that this is doable in about 10 weeks of pregnancy. So it's not a late, that's the way it looks right now. Now, we could have spent the whole hour on this, but let me, as you're thinking about what this means, let me make a few points. There are some unknown thousand of monogenic disorders, let's call it, people say 7,000, let's just say 5,000. The vast majority of those are so rare that they will never attract a commercial effort. If only four to 10 children a year are being born with a disorder or 20 or 30, no drug company's gonna, I know I'm in this business, they're not gonna develop a drug, it just won't compute fiscally. So that leaves open about some thousand plus disorders for which really the only technology is the technology of avoidance. With whole genome amplification, you can ask about any rare monogenic disorder you want and get an answer. But it's not that simple because we don't have, for a lot of these disorders, enough clinical data to be able to predict the real outcome of the fetus or the child. I remember living through this in the 80s and 90s when I was counseling women who learned that their fetus had spina bifida term, I think most of you know. And I can still remember both my own personal anguish and the anguish or agony of the women because let's just say I took 10 women and I said to each one of them, your fetus, whatever age, before week 20 certainly, your fetus has spina bifida, low lesion in the spine. And then the woman says back to me, well what's gonna happen to my fetus? And my honest answer would have to be I don't know. Your fetus could have minor problems, walk with braces and go to Harvard. Your fetus could have significant physical problems and low normal intelligence. Or you could have a devastating event with an infection and wind up having the child die of meningitis. So the reason I'm telling you that story is because I had the information, I even had the diagnosis, I even had the pictures. But I couldn't predict what was going to happen because these things unfold amidst thousands of other genes in the genome, amidst the background of the pregnancy, what environment you grew up in. So the challenge for these amazing new technologies would be to weight and measure the knowledge we're sharing with the woman and her husband. That's a problem in what we call computational biology. You just have to amass very large data sets and then be able to give yourself some predictive power. Of course it's still in the woman's decision. A recent example of this that I was involved with just to go on a tangent for a second was that in the 90s I was involved in developing and preparing the so-called BRCA1 test for breast cancer risk. And the problem we had, I chaired the clinical advisory board for the company in that time. The problem we had is we'd get samples from women with a clear family history of breast cancer or ovarian cancer. They were certainly based on history. They were real candidates whether or not they had a risk. And then we would study the gene, some 16,000 base pairs, and we would find mutations. But we didn't have a database to say how serious that mutation was. So 15% of the cases that were sent to us, we found a mutation of unknown significance. We couldn't call it a disease mutation or not. And it took about three or four years of just looking at this database over and over again and amassing it just to be able to say oh, that does predispose to ovarian cancer or whatever it might be. So there's always gonna be this period where you have a lot of information but you don't have a lot of knowledge. And that's really when I share with you. On the other hand, you haven't forgotten what I've said. The vast majority of severe monogenic disorders in my opinion will not in this century be dealt with by curative therapy. They will be dealt with by avoidance. I mean, with all the talk about the human genome project is doing great good and all these other things, the FDA is approving about three to four new drugs for monogenic disorders a year. I've just said there are thousands of them. It's not gonna change that much. We may get up to 10 but, and they're so rare, we're gonna figure another way about it. So you can ask what you would advise your daughters to say they're in their first pregnancy and they say, mom, dad, my obstetrician told me about this new test. It's just a blood test. And they'll give me this information and they'll sit down and work with me to help understand this. What do you think I should do? What do you tell them? Maybe somebody has an idea here who can share with us what you would tell them. I mean, unfortunately, we know that there will be a lot of uncertainty for sure but is that information, first of all, should we even be allowed to offer the test? There's a question. Or should there be some august body that decides when it's ready and it has to meet certain, if you will, certain criteria for informativeness? That's one way to think about it. Should we leave it in the free market? Is that a good or a bad idea? I don't know. What is the overall impact on society of embracing a test? And I know not everyone will take it but embracing a test that presupposes that you are looking to avoid the births of certain individuals. That ties it back to eugenics, doesn't it? See, so I'm in the closing minutes here, I'm arguing to you that the era of supposedly evil governments, and certainly a case of Germany, a definitely evil government, using technology against people is almost certainly over. But the notion that the society and enlightened society, young couples will want to engage information to plan their own pregnancy scene. Look, I'm only gonna have two children, I want them to be healthy, I don't want to. And I know, this is what I do for a living, I know so many families, I hear from a family every week for sure, some new event in their life that is life changing. So where does this kind of technology belong in our society? So that's the question I'm worried about right now. Just in closing here, just a few words about Cold Spring Harbor and the Eugenics Record Office. The Eugenics Record Office, which existed here until 1939, and the archives of which are now at the University of Minnesota, I've been there many times to look at them, was a period in which the activities and the search for explanations for disease was doing it the best it could in very limited context. We're in a similar era now where the information is much more sophisticated, but we have the same set of problems. What do we do with this information? And I'm so pleased to have had the honor of talking with you because it's not a decision to be made by us, the scientists or the physician, it's really a decision to be made by enlightened individuals who are thinking about the project. After all, that's the definition of a good society. So thank you for listening and I hope I've titillated you a bit and I hope we have time for some questions, Bruce. Thank you.