 I'm Robert Krollwich, and welcome to DNA, the next generation. I would presumably be you watching. If you're over 50, well, I mean, I'm over 50, so you can stay. Today, we're bringing students and scientists together to explore the past, the present, and the future of the molecule that carries our shared inheritance. It is, of course, the DNA molecule. When James Watson and Francis Crick unraveled the mystery of DNA's double helix structure, that famous shape that was 50 years ago, their description gave us startling insights into the fundamentals of life. No one could imagine the amazing advantages that their work would inspire, and no one could really foresee what we are now going to celebrate today. The Human Genome Project has successfully sequenced all three billion DNA letters in the Human Genetic Instruction Book, meaning that there are that many little letters that takes that many letters to build a person. It's impossible to exaggerate the impact of both events, the description of the double helix, that shape, and now the new thing, the completion of the human genome that those two events have had and will continue to have on our lives. So this program is going to consider how far our scientific knowledge has advanced over these 50 years, and we're going to explore just how far it may take us. I'm pleased to honor a man who has traveled the path from DNA's double helix to the three billion steps of the human genome. I'd like to welcome Jim Watson. And the other guy I want to talk to is Francis Crick. Francis Collins, I'm sorry, is director of the National Human Genome Research Institute. He's been running the show here for about 10 years. You get the yellow chair. Unfortunately, Dr. Francis Crick was not able to join us here today, but he was kind enough to share these recollections about how he and Dr. Watson changed the course of scientific history. On Saturday, February the 28th, 1953, in Cambridge, England, Jim discovered the way the four bases, the four letters of the genetic alphabet, are paired in DNA. The reason this was so exciting is because it immediately suggested that the way genes might replicate. And so convey an immense amount of information from one generation to the next. Jim recalls that we went to the local pub, the Eagle, where I announced to everybody that we had discovered the secret of life. For all people who are getting B-minuses in biology, did you get mostly A's or? I got a B in my first course. Oh, good, okay. Yeah. Come on, the second. Thanks. Oh. Were you the smartest kid in the class? No. You were on a quiz program in Chicago for whiz kids. Yeah, it was called the quiz kids. The quiz kids, which was for geniuses, right, who knew a lot of stuff. Well, in my case, we lived next door to the producer. So they had to have losers, you know, there were either bright ones, and then they had the older kids who would lose to the bright younger kids. So how old were you when you went on the show? It was 13, old. Oh, you were old. So how old did you do? I was on three times, and then I lost to a six-year-old girl. Now, you're 17 years old when you ask the question, how come a hippopotamus will always create a baby hippopotamus, or a giraffe, a baby giraffe? You never get a mama giraffe creating a hippo. This never happens. So you were 25 when you found out the answer. What is that like? Well, my belief is that when you're 18, you know, your brain is in pretty good shape. So you don't have to wait to 25 to try something difficult. In the moment when you actually figured it out, this is one of those things where you always wonder, was it an adrenaline rush? You thought, oh, yes, sort of like a high school basketball game kind of thing? Or was it relief? Well, 50 years ago, I can't remember. I'm sure I was just felt very happy. You know, I had the answer, and the answer seemed so good that it was gonna be right. And how important was it that you had a partner? Very important, because I didn't know any physics, and interpreting data from physical measurements was important. So I had to have someone who would say, well, this really means this. Initially, I thought I'd have to learn physics, but then I realized it was quicker just to ask Francis. Francis is a physicist and you're a biologist, yet the subject is really chemistry. It's, well, how do you figure out the structure of a chemical? Yeah, that was our problem. Neither of us knew any chemistry, and we were trying to do chemistry. So we floundered for the first couple of months we looked like fools. And just so we have a perspective, Francis Collins, at the time when this discovery was made, what did people know about inheritance? Not a lot. Certainly people knew that inheritance somehow traveled from generation to generation, and that that was somehow mediated by chromosomes that you could see under the microscope. And back in 1944, it was pretty convincingly showed, although not everybody believed it, that it was DNA that was the hereditary material that mattered, but nobody understood how that worked or how it could possibly carry all this information. And everybody knew that there was some kind of code or some magical formula in there that gave the mother hippo the way of telling the baby hippo, you're a little cell now, but you're supposed to grow up and be a hippopotamus just like me, which is a lot of information in a... They presumed that, but until Watson and Crick came along and laid out this beautiful structure, and it really is a structure which has a beauty to it that only a few things could claim in terms of the scientific world to live up to this standard, and suddenly it all made sense. This is how you carry information. This is how you replicate information. And last question, if it's a beautiful problem, did you know you had it when the solution looked beautiful to you? Just seemed unlikely there'd be another solution that could be as good. So you just looked at the thing, the way you'd fit it together and you went, yeah. We had a scheme for how you could copy a specific molecule and everyone thought, that's very tricky to have it very accurate and we had an accurate scheme and most people saw it and they said, it's right. Dr. Collins, if you think back to your days as a student, can you recall your reaction on learning that someone had come up with the structure of DNA or does that go back a bit too far? Well, it doesn't go back as far as it should because I regret to say when I was a high school student taking biology, I don't think they taught me this stuff. So I didn't learn about the structure of DNA until I was already a graduate student in physical chemistry. That was my original field of scientific interest and I took this additional sort of mind-expanding course and what do you know, it really expanded my mind. Can you go with me over to this table here? I have something I wanna do with you which may bring back to the old days. The problem to be solved is we were going to have four chemicals, this one and this one. Now, Jim, what was the problem you were trying to solve? These four chemicals, which may very well be the ones that tell the next generation how to grow, have to be organized in some way. What was the problem? The problem was I thought they had different sizes and shapes and how could we put them together in pairs so they occupied exactly the same space and such that any base could be on either of the two shapes. So you wanted the chemicals to sit comfortably one on top of another like in an apartment building or something? Well, they were to pair. They were to come together in pairs. And the size of the pair, all pairs should have the same size. Yet we had four different bases. Let's just reverse so we can see what we're dealing with here. All right, I've got an A and a C and you've got a T and a G. So when my shapes, they just... Doesn't work. I think you really want to do it this way. Let's see, yes. Okay, so that's one configuration you got. Can you duplicate that one? All we're looking here for is same-same. If we can get same-same, we're in... Here, but give it to the Nobel Laureate, take this. We were doing something like that. Now, let me just get the sense here. Once you realize that they are the same and that they sit opposite each other and they flip, and you can break them in half and they'll break them in part, at that moment, that's the moment of discovery. Yes, that they have these wonderful shapes so that any base could go on any train. You make this discovery entirely by yourself. There's no one else in the room. But Francis comes in now, about 20 minutes later, right? He comes in about 20 minutes later and he sees this symmetry as good for the flip-flop. It actually works perfect. So after 20 minutes, you realize what you'd figured out? Yeah, our success came from doing it. Once you started doing it, it was trivial. So we're over here looking at this model of DNA and there seems to be something missing. That would be... What's missing here? The sugars and the phosphate backbone. Yeah, so you can see the bases here sort of nicely stacked up, but there's nothing holding them together except for this funny sort of strand in this big post in the middle. I don't think DNA has a post in the middle either. So we have to figure out how to make this whole thing hold together. We'll see if we can fix it up. Okay, so just pretend I have the sugar here and the sugar here. And since they're running anti-parallel, one of them would have a phosphate group on the fifth carbon and it would stick out. And on the other end, on the same side, the same side, this same strand with the same length of bases attached to the same backbone, then at the other end, there would be the last phosphate group would be on a three prime, a third carbon. And on the other one, it would just be the offset. I'm really sorry, this is very convoluted. We'll have a quiz in about 30 seconds. Everybody got your pencils, we're ready to go. No, you got it, great, that's fantastic. You can go back, you see, thank you very, very much. And with the description of the double helix in 1953, scientists, much like her, learned the structure of DNA and even slower than she's taking it. So it took another 13 years actually to crack the genetic code and that accomplishment determined the three-letter words that specify the all-important building blocks of proteins. It eventually became clear that if scientists could determine the order of all these three billion letters in human DNA, we would have a complete instruction book for building, running and maintaining human life. The dataset that we're creating here is going to provide an extraordinarily rich and deep foundation for biomedical research in the next century and beyond. And I think it will change how we do that sort of work. Now here today, we have maybe 15 people sequence 100,000 molecules of DNA a day. And the way we actually do that is by taking a pretty big piece, a large piece of DNA into our lab and breaking it up into smaller pieces, taking those smaller pieces, each as individuals and sequencing them one by one, determining the order of the letters, the G, the A, the T, the C. As it moves down the hallway, it gets chopped up into small bits that work their way through all of these robotic lines to get purified sequence and eventually hit a sequencer which will give you the fluorescent readout of every base pair in that fragment of DNA. And at the end of that process, assembling all that information, all those letters, and actually reconstructing the original molecule we started with, we can't suddenly optimize how we're doing this. We don't consider that we've ever found the right way to do it, but we should just keep trying to make it better every single day. Ultimately, we'd like to be able to sequence everybody's DNA so that we can assist them in preventative medicine and in other cures for genetic diseases. In order to understand a little bit more about genes, it's a challenging subject and many of our ideas about ourselves and others come from this search. So here's what we're gonna be talking about. We are going to perform an audition for your taste buds. This is called the PTC test. And here to help us is Dennis Draina. He's a PhD. He's from the National Institute on Deafness and Other Communication Disorders. And he's a leader of a team that has just identified the gene responsible for an important difference in our ability to taste bitter substances. And so he's gonna go ahead and take us through the exercise. Thank you, well, welcome to your genome in action, so to speak. I see all of you by now have your little strip of white paper and on that white paper, don't test it yet, is a substance that some people in the world can taste and some people in the world cannot. Because of the progress of the Human Genome Project, we have just recently been able to make a discovery as to the actual underlying genetic difference that actually causes this in all of us here today. So we're first gonna do a demonstration and I'm gonna ask you all to put the piece of paper in your mouth now, all right, and wet it with saliva. Go ahead. Do we have it? We've all got it. Can we take it out? Okay, can you all take it out, please? Very good. Now, I heard a few things that would suggest to me some of you tasted something, all right? Is that true? Do we have some people who could taste something? Could I see the hands of people who didn't taste anything? Wow, a large difference. Excellent. So it turns out about worldwide, about a third of the people in the world are unable to taste this normally. And about two thirds of the world can taste this. It turns out this simple difference between us is inherited as a simple trait, was discovered more than 70 years ago, but it wasn't until a few months ago with the help of the genome project that we were actually able to identify the gene which causes this, all right? Turns out it is due to a gene which resides on chromosome seven and it's a gene which specifies a bitter taste receptor. This is a gene, the gene product of which exists, it's expressed in the taste buds on our tongue, all right? And it turns out there are two major forms of this gene in the world today. There is the taster form and there's the non-taster form and they are very ancient origin, all right? Now, here to help me explain our two loyal assistants who are going to help lead through this. Now, the first thing I'd like to point out here on the first screen is that the genome is a very, very large amount of information, so much so that you can't put it on paper. It turns out there are two forms of this gene. There is a taster form and there's a non-taster form and they differ at actually three positions, all right? There is a so-called proline at this position, there is an alanine at this position and there's a valine in the third position in the taster form of the gene. Whereas those of you who are not tasters can see that in this case where the tasters have a proline, you probably have an alanine and likewise there's a valine in the middle position and a nice elucidine in the last position. So that is the basic underlying difference between the DNA in our chromosomes. So who would have known about this? I know that you have more to share with us, Dr. Draina, but first I'm gonna ask you in the audience now. How many or rather how much of your DNA, just take a look at your neighbor just for a second and ask yourself how many of the letters in the neighbor are the same as your letters in your DNA? The answer is 99.9% the same. There's only one tenth of 1% difference between any two people on earth and I'm talking about a sumo wrestler and a pygmy warrior. So this one tenth of a percent, Francis Collins, gotta be a pretty interesting one tenth of a percent. Absolutely, and remember the genome is three billion letters so even one tenth of a percent is a lot of differences between two people, something like that. And that accounts for all the differences we see? It accounts for all of the hereditary variations that we see, of course there are differences between people that aren't hereditary. Look at identical twins, they're not quite identical if you look close enough. Right, okay, all right. Well, for a closer look now at how scientists analyze these variations in genes, let's return to our example of the PTC gene and to Dr. Draina. Well, the additional interesting point about this gene is that in fact there are two major forms of this gene in the world in general with one important exception. In the part of Africa that is below the Sahara, so in what's called sub-Saharan Africa, it turns out there are many more forms of this gene that naturally occur. And the explanation for why there are only two major forms of this gene in the rest of this world probably has a great deal to do with the fact that most of us in the world today are actually the descendants of a small group of people who made it out of Africa perhaps 100,000 years ago and subsequently rapidly expanded to colonize the remainder of the world. Thank you very much. Who knows where genomics will take us next? It has been even for scientists, it's kind of hard to keep up with today's rapid pace of discovery and things are likely to move even faster in tomorrow's world. So before we rush headlong into the future, let's listen carefully to these words from Dr. Crick. In biology, a new world is expanding in front of our eyes. May we learn to use it wisely. As we enter the world or this new era of the genome, wisdom is an important word. Advances are certain to affect many areas of our lives in medicine, in law, in agriculture, in ecology. The list does seem endless. And because this era touches so many areas of our lives and raises so many issues, questions that often cannot be resolved quickly or very simply, but demand everybody's attention, we thought we'd pay attention to some of these issues. Dr. Watson began to tackle these questions when when he was the first leader of the Human Genome Project, he set up something, actually devoted three to 5% of the budget for research into the ethical, legal and social implications called LC issues, which is ethical, legal, social implications. It's an acronym. This idea was unprecedented in biomedical research. Why did you decide to do that? Well, I think everyone is concerned with the privacy of their own genetic information. Most of us wouldn't want to know that someone else was reading this information because this information is way, it's sort of saying what our future is gonna be like. Hints as to whether we might die at 50 or die at 70 or maybe at 20. But by the very nature of things, since I'm no expert in how to do this, if someone takes my blood and takes my DNA, somebody or some machine owned by somebody is gonna see this stuff. Someone writes, I couldn't keep it private and still learn it. Well, I think it could be, there could be a law which says it's illegal for someone who takes my blood, say to measure cholesterol concentration to look at my genes. So right away you knew that you had to take some of the money that you've been given and put it into these questions which flow right out of the medicine and right out of the science. Because if other people have the knowledge they might discriminate against me or my children or something. And Francis Collins, you've been running the program for about a decade now. Have the issues that come up, have they been well handled or is it, what are you trying to do, solve them or just notice them? I think this is an experiment. We've never tried this before where we're exploring the ethical, legal and social implications of a genetic revolution while the revolution is happening, not waiting for some future moment where there's a crisis and everybody goes, oh my gosh, why didn't we think about that? And so over the course of these 10 years, thanks to Jim's wisdom in starting this program, we have funded a cohort of some of the best and brightest ethicists and social scientists and lawyers and theologians to look at these issues and try to prioritize where we need to take action and then fed that information to legislators and policymakers and ask them to do something. But weren't you worried that some issue would come up and the answer to the question you asked would be, stop, don't do that, don't take the blood, don't find out, don't know, don't learn. You know, the answer to that is that would be the most unethical thing you could do. If this research is gonna give you answers to schizophrenia and heart disease and cancer, you're gonna really say, I'm sorry, we can't figure out these ethical issues so we'll have to stop now. Won't fly. Okay, and you didn't worry about it. What did you do? So therefore, you just wanted scrutiny. I wanted people to be aware of the issues. I knew they would not be easy to solve but we should be aware of them. Now, let's look for, well, let's ask some questions about this because these are tough issues not only for you and watching but for the students here joining us in our discussion. So we're gonna ask Vince Bonham of the National Human Genome Research Institute to join us. Vince, you can come on in and sit, you get the red chair which I guess you color coordinated with the ties. That's good. Vince Bonham is not only a professor of law but he's also written extensively on race and genomics. Welcome. Thank you. Our students have some questions for you Vince. Anybody wanna start? Just a hand up, just someone volunteer, yeah. Go ahead. I want to know, does and if so, how does genetic information affect minorities? Let's talk about that question, affect minorities. And so the question is, what do you mean by minorities? And when you think about this country, the United States and the issue of minorities, clearly as you've discussed today there's not genetic differences based on specific minorities. There are differences in populations. But our history of our country where minorities have been treated differently that some people have been treated differently based on their ethnicity and their race. And so there is a historical issue here that is of concern with regards to genetic information making sure that people have access to services have are not discriminated against because of their certain group. But clearly from a genetic perspective there's not a general difference with minorities and majorities in the United States. How much genetic DNA profiling should be used in our everyday life for identification and is a 10th percent enough to make it work on a large scale? How much genetic, like what kind of situation are you thinking about? DNA profiling, like for getting your credit card numbers or something in a shopping market. And is a 10th percent enough for that to work on a large scale? No, I think there is plenty of information in that 0.1% to uniquely identify you or any one of us, unless you have an identical twin, you are unique on the planet. And so that certainly could be a viable way to do that sort of identification. But it does involve looking at your own instruction book and revealing stuff about you that you may just assume not have out there in somebody's database. So I don't think that's a practical way that we ought to be going. To what extent would the human genome be altered if genetic engineering was allowed? For instance, would it be only to prevent certain genetic diseases from happening or would it also be able to be used for altering a person's physical preferences? Out of curiosity, if I were to offer you the sight of an eagle, assuming that it could somehow be, would you want it? I don't know. Good answer, okay. I think that's a great question and the answer is largely gonna be up to all of you. Where do we want to set limits, if any? Clearly everybody's excited about the possibility of using genetics to cure terrible diseases, but there is no sharp dividing line between diseases and traits. If we could come up with a genetic way to cure obesity, would that be a good thing? Well, obesity can be a terrible disease. But if you imagine that being used just so that people who are already thin can get even thinner, then you're starting to wonder what we're doing here exactly. And exactly how that plays out is partly a function of the science because a lot of the things people talk about enhancing are not traits that are gonna be at all clean in terms of the genetics and a lot of its environment and we have to keep that in mind. And it's partly gonna be a consequence of societal norms and where we decide as a group, we think the boundaries ought to be if there are any. But there's some diversity that we also... I think it's important to our society with regards to differences in background and conditions of individuals. So some modifications may be going too far and I think that's one of the challenges that we all have ahead of us, particularly our students. But I'd argue that the choice should be left to the individual, the prospective parent. How would minority communities be encouraged to get involved in the genetic research? Well, I'll start with that question and then Francis, I know you can add to it. I think it's very important that we have a real diverse group of scientists involved in studying genomics because it's important scientists bring their background and their baggage to their work. And so it's important as we frame the questions and look at the findings that we have a variety of individuals involved. So it's important that you have the appropriate background and I'm gonna ask Dr. Collins to share some of the type of backgrounds that potentially we can meet. Well, surely if we want this field to blossom the way it now can building on this foundation of the genome project, we want the best and the brightest to work on it. And they don't all come from one particular group so we're hoping. And particularly to reach out to minority populations where perhaps science has not been a traditional pathway in the same way that I would love it to be, to make it clear that this is an opportunity where the doors are open and where the involvement of people with different backgrounds is gonna be crucial, both for pushing forward the basic science and also for thinking carefully about the societal implication. While we're talking about jobs, is there anything else you wanna say about jobs? Well, how many of you are interested in possibly taking on a career in science, particularly genetics and genomics? Is that something that's on your mind? Well, that's pretty impressive. Okay, see me afterwards, it'll sign you up. Well, let's frame the question differently. How many people may be interested in health policy or looking at the ethical issues and the legal issues? You know, my background is law, but I'm working with physicians and geneticists and individuals that are doing genomics research. So there's different ways to be involved and be engaged in the research. It is now time for us to end this program. We have been especially fortunate to have Dr. Watson and Dr. Collins with us today. I also wanna thank our students. Couldn't have done it without them. We also hope that you're convinced that the future of DNA truly belongs to you. Thanks to our ever-expanding knowledge of the human genome, DNA will play a greater role in your lives and your health than it has for any generation that's ever gone before. The era of the genome will also influence your career choices, your judicial system, even your self-identity, and none of this should be taken lightly. But let's also remember that the tremendous potential and power of this research to improve our world is there for you to use as you wish, led by you and your generation. We can only look forward to what the genomic revolution will bring. Thank you.