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Cracking the Code of Life PBS Airdate: April 17, 2001 Transcript

1 Instructions for a Human Being 00:00:00 ROBERT KRULWICH: When I look at this—and these are the three billion chemical letters, instructions for a human being—my eyes glaze over. But when scientist Eric Lander looks at this he sees stories. ERIC LANDER (Whitehead Institute/MIT): The genome is a storybook that's been edited for a couple billion years. And you could take it to bed like A Thousand and One Arabian Nights, and read a different story in the genome every night. ROBERT KRULWICH: This is the story of one of the greatest scientific adventures ever, and at the heart of it is a small, very powerful molecule, DNA. For the past ten years, scientists all over the world have been painstakingly trying to read the tiny instructions buried inside our DNA. And now, finally, the "Human Genome" has been decoded. J. CRAIG VENTER (President, Celera Genomics): We're at the moment that scientists wait for. This is what we wanted to do, you know? We're now examining and interpreting the genetic code. FRANCIS COLLINS (National Human Genome Research Institute): This is the ultimate imaginable thing that one could do scientifically...is to go and look at our own instruction book and then try to figure out what it's telling us. ROBERT KRULWICH: And what it's telling us is so surprising and so strange and so unexpected. Fifty percent of the genes in a banana are in us? ERIC LANDER: How different are you from a banana? ROBERT KRULWICH: I feel...and I feel I can say this with some authority...very different from a banana. ERIC LANDER: You may feel different... ROBERT KRULWICH: I eat a banana. ERIC LANDER: All the machinery for replicating your DNA, all the machinery for controlling the cell cycle, the cell surface, for making nutrients, all that's the same." ROBERT KRULWICH: So what does any of this information have to do with you or me? Perhaps more than we could possibly imagine. Which one of us will get cancer or arthritis or Alzheimer's? Will there be cures? Will parents in the future be able to determine their children's genetic destinies?

ERIC LANDER: We've opened a box here that has got a huge amount of valuable information. It is the key to understanding disease and in the long run to curing disease. But having opened it, we're also going to be very uncomfortable with that information for some time to come. ROBERT KRULWICH: Yes, some of the information you are about to see will make you very uncomfortable. On the other hand, some of it I think you'll find amazing and hopeful. I'm Robert Krulwich. And tonight we will not only report the latest discoveries of the Human Genome project, you will meet the people who made those discoveries possible, and who competed furiously to be first to be done. And as you watch our program on the human genome, we will be raising a number of issues: genes and privacy, genes and corporate profits, genes and the odd similarity between you and the yeast. And we'd like to have your thoughts on all these subjects. So please, if you will, log on to NOVA's Website—it's located at pbs.org...it'll be there after the broadcast, so do it after the broadcast—where you can take a survey. The results will be immediately available and continually updated. We'll be right back. Major funding for NOVA is provided by the Park Foundation, dedicated to education and quality television. This program is funded in part by the Northwestern Mutual Foundation. Some people already know Northwestern Mutual can help plan for your children's education. Are you there yet? Northwestern Mutual Financial Network. Scientific achievement is fueled by the simple desire to make things clear. Sprint PCS is proud to support NOVA. Major funding for this program is provided by the National Science Foundation, America's investment in the future. And by the Corporation for Public Broadcasting, and by contributions to your PBS station from viewers like you. Thank You. ROBERT KRULWICH: To begin, let's go back four and some billion years ago to wherever it was that the first speck of life appeared on earth, maybe on the warm surface of a bubble. That speck did something that has gone on uninterrupted ever since. It wrote a message. It was a chemical message that it passed to its children, which then passed it on to its children, and to its children, and so on. The message has passed from the very first organism, all the way down through time, to you and me—like a continuous thread through all living things. It's more elaborate now, of course, but that message, very simply, is the secret of life. And here is that message contained in this stunning little constellation of chemicals we call DNA. You've seen it in this form, the classic double helix, but since we're going to be spending a lot of time talking about DNA, I wondered, "What does it look like when it's raw, you know, in real life?" So I asked an expert. ERIC LANDER: DNA has a reputation for being such a mystical high-falutin' sort of molecule—all this information, your future, your heredity. It's actually goop. So this here's DNA. ROBERT KRULWICH: Professor Eric Lander is a geneticist at MIT's Whitehead Institute. ERIC LANDER: It's very, very long strands of molecules, these double helices of DNA, which, when you get them all together, just look like little threads of cotton. ROBERT KRULWICH: And these strands were literally pulled from cells, blood cells or maybe skin cells of a human being? ERIC LANDER: Whoever contributed this DNA, you can tell from this whether or not they might be at early risk for Alzheimer's disease, you can tell whether or not they might be at early risk for breast cancer. And there's probably about 2000 other things you can tell that we don't know how to tell yet but will be able to tell. And it's really incredibly unlikely that you can tell all that from this. But that's DNA for you. That apparently is the secret of life just hanging off there on the tube.

ROBERT KRULWICH: And already DNA has told us things that no one...no one had expected. It turns out that human beings have only twice as many genes as a fruit fly. Now how can that be? We are such complex and magnificent creatures and fruit flies...well they're fruit flies. DNA also tells us that we are more closely related to worms and to yeast than most of us would ever have imagined. But how do you read what's inside a molecule? Well, if it's DNA, if you turn it so you can look at it from just the right angle, you will see in the middle what look like steps in a ladder. Each step is made up of two chemicals, cytosine and guanine or thymine and adenine. They come always in pairs, called base pairs, either C and G, or T and A for short. This is, step by step, a code, three billion steps long—the formula for a human being. ROBERT KRULWICH: We're all familiar with this thing, this shape is very familiar. ERIC LANDER: ...double helix... ROBERT KRULWICH: ...double helix. First of all, I'm wondering...this is my version of a DNA molecule. Is this, by the way, what it looks like? ERIC LANDER: Well, give or take. I mean, a cartoon version, yeah. ROBERT KRULWICH: Cartoon version? ERIC LANDER: A little like that or so, yeah. ROBERT KRULWICH: So there are...in every...almost every cell in your body, if you look deep enough, you will find this chain here? ERIC LANDER: Oh yes, stuck in the nucleus of your cell. ROBERT KRULWICH: Now how small is this, if in a real DNA molecule the distance between the two walls is how wide? ERIC LANDER: Oh golly... ROBERT KRULWICH: Look at this. He's asking for help. ERIC LANDER: This distance is about from...this distance is about 10 angstroms. ROBERT KRULWICH: That's one billionth of a meter when it's clumped up in a very particular way. ERIC LANDER: Well no, it's curled up some like that but you see it's more than that. You can't curl it up too much because these little negatively charged things will repel each other so you fold it on its...I'm going to break your molecule. ROBERT KRULWICH: No, don't break my molecule...very valuable. ERIC LANDER: You got this. And then it's folded up like this. And then those are folded up on top of each other. And so, in fact, if you were to stretch out all of the DNA it would run, oh, I don't know, thousands and thousands of feet. ROBERT KRULWICH: But the main thing about this is the ladder, the steps of this ladder. If I knew it was A and T and C and C and G and G and A... ERIC LANDER: No, no. It's not G and G, it's G and C. ROBERT KRULWICH: I'm sorry, whatever the rules are of the grammar, yeah...if I could read each of the individual ladders, I might find the picture of what? ERIC LANDER: Well, of your children. This is what you pass to your children. You know people have

known for 2000 years that your kids look a lot like you. Well it's because you must pass them something, some instructions that give them the eyes they have and the hair color they have and the nose shape they do. And the only way you pass it to them is in these sentences. That's it.

2 Getting the Letters Out 00:10:07 ROBERT KRULWICH: And to show you the true power of this molecule, we're going to start with one atom deep inside, and we pull back and you see it form its As and Ts and Cs and Gs and the classic double spiral. And then it starts the mysterious process that creates a healthy new baby. And the interesting thing is that every human baby, every baby born, is 99.9 percent identical in its genetic code to every other baby. So the tiniest differences in our genes can be hugely important, can contribute to differences in height, physique, maybe even talents, aptitudes and can also explain what can break, what can make us sick. Cracking the code of those minuscule differences in DNA that influence health and illness is what the Human Genome Project is all about. Since 1990, scientists all over the world in university and government labs, have been involved in a massive effort to read all three billion As, Ts, Gs, and Cs of human DNA. They predicted it would take at least 15 years. That was partly because in the early days of the project, a scientist could spend years...an entire career trying to read just a handful of letters in the human genome. It took 10 years to find the one genetic mistake that causes cystic fibrosis. Another 10 years to find the gene for Huntington's disease. Fifteen years to find one of the genes that increase the risk for breast cancer. One letter at a time, painfully slowly... ROBERT WATERSTON: One, two, three, four, five... ROBERT KRULWICH: ...frustratingly prone to mistakes... ROBERT WATERSTON (DNA mapping pioneer): ...Cs in a row. NARRATOR: ...and false leads. We asked Dr. Robert Waterston, a pioneer in mapping DNA, to show us the way it used to be done. ROBERT WATERSTON: The original ladders for DNA sequence, we actually read by putting a little letter next to the band that we were calling and then writing those down on a piece of paper or into the computer after that. It's horrendous. ROBERT KRULWICH: And we haven't mentioned the hardest part. This here, magnified 50,000 times is an actual clump of DNA, chromosome 17. Now if you look inside you will find, of course, hundreds of millions of As, and Cs, and Ts and Gs, but it turns out that only about one percent of them are active and important. These are the genes that scientists are searching for. So somewhere in this dense chemical forest are genes involved in deafness, Alzheimer's, cancer, cataracts. But where? This is such a maze scientists need a map. But at the old pace that would take close to forever. ROBERT WATERSTON: C and then an A. ROBERT KRULWICH: And then came the revolution. In the last ten years the entire process has been computerized. That cost hundreds of millions of dollars. But now, instead of decoding a few hundred letters by hand in a day, together these machines can do a thousand every second and that has made all the difference. ROBERT COOK-DEEGAN (National Research Council): This is something that's going to go in the textbooks. Everybody knows that. Everybody, when the Genome project was being born, was consciously aware of their role in history.

ROBERT KRULWICH: Getting the letters out is...has been described as finding the blueprint of a human being, finding a manual for a human being, finding the code of the human being. What's your metaphor? ERIC LANDER: Oh, golly gee. I mean, you can have very high falutin' metaphors for this kind of stuff. This is basically a parts list. Blueprints and all these fancy... It's just a parts list. It's a parts list with a lot of parts. If you take an airplane, a Boeing 777, I think it has like 100,000 parts. If I gave you a parts list for the Boeing 777 in one sense you'd know a lot. You'd know 100,000 components that have got to be there, screws and wires and rudders and things like that. On the other hand, I bet you wouldn't know how to put it together. And I bet you wouldn't know why it flies. Well we're in the same boat. We now have a parts list. That's what the human genome project is about is getting the parts list. If you want to understand the plane you have to have the parts list but that's not enough to understand why it flies. Of course you'd be crazy not to start with the parts list.

3 One Wrong Letter 00:15:43 ROBERT KRULWICH: And one reason it's so important to understand all those parts, to decode every letter of the genome, is because sometimes, out of three billion base pairs in our DNA, just one single letter can make a difference. Allison and Tim Lord are parents of two-year-old Hayden. TIM LORD (Father of son with Tay Sachs): The two things that I think of the most about Hayden, which a lot of people got from him right from the beginning is that he was always, I thought, very funny. I mean he loved to smile and laugh and he just used to guffaw. And this was later when he was about a year old, he just found the funniest things hilarious. And so he and I would just crack each other up. ROBERT KRULWICH: Hayden seemed to be developing normally for the first few months but Allison began to notice that some things were not quite right. ALLISON LORD (Mother of son with Tay Sachs): I was very anxious all the time with Hayden. I sensed that something was not the same. I would see my friends changing the diaper of their child who was around the same age, their newborn, and see the physical movement, and the legs moving, and things like that, and Hayden didn't do that. ROBERT KRULWICH: Doctors told them that Hayden was just developing a bit slowly. But by the time he turned a year old, it was clear something serious was wrong. He never crawled, he never talked, he never ate with his fingers and he seemed to be going backwards, not progressing. TIM LORD: I remember the last time he laughed. And I took a trip with him out to pick up a suit because we were going to a wedding that night, and we came back and it was really windy, and he just loves to feel the wind, and so we had a great time. We came back and I propped him up right here on the couch and I was sitting next to him and he just kind of threw his head back and laughed, like, you know, what a fun trip, you know? And that the last time he was able to laugh. That's really hard. ROBERT KRULWICH: It turned out that Hayden had Tay Sachs disease, a genetic condition that slowly destroys a baby's brain. DR. EDWIN KOLODNY (NYU, Department of Neurology): What happens is the child appears normal at birth, and over the course of the first year begins to miss developmental milestones. So at six months a child should be turning over—a child is unable to turn over, to sit up, to stand, to walk, to talk. ROBERT KRULWICH: Tay Sachs begins at one infinitesimal spot on the DNA ladder, when just one letter goes wrong. Say this cluster of atoms is a picture of that letter, a mistake here can come down to just four atoms. That's it. But since genes create proteins, that error creates a problem in this protein which is supposed to dissolve the fat in the brain. But now the protein doesn't work. So fat builds up, swells the brain, and eventually strangles and crushes critical brain cells. And all of this is the result of

one bad letter in that baby' s DNA. DR. EDWIN KOLODNY: In most cases it's a single base change. As we say, a letter difference. ROBERT KRULWICH: One defective letter out of three billion, and no way to fix it. TIM LORD: That's my boy. ROBERT KRULWICH: Tay Sachs is a relentlessly progressive disease. In the year since his diagnosis, Hayden has gone blind. He can't eat solid food. It's harder and harder for him to swallow. He can't move on his own at all. And he has seizures as often as 10 times a day. DR. EDWIN KOLODNY: For children with classical Tay Sachs Disease, there's only one outcome. And children die by the age of five to seven, sometimes even before age five. ROBERT KRULWICH: As it happens, Tim Lord has an identical twin brother. When Hayden was diagnosed, that brother, Charlie, went to New York to be with Tim. And of course, Charlie called his wife Blyth to tell her the news. Blyth had been Allison's roommate in college and her best friend. BLYTH LORD (Mother of daughter with Tay Sachs): Charlie told me that Hayden had Tay Sachs. He called me on the phone and he told me immediately what it was. I went up into the computer and looked it up and then just couldn't believe what I read. ROBERT KRULWICH: Blyth and Charlie had a three-year- old daughter, Taylor, and a baby girl named Cameron. Cameron was healthy and happy except for one small thing. BLYTH LORD: On the NTSAD Website it talks about typically between six and eight months is when the signs start coming, but one of the early signs is that they startle easily. And Hayden had always had a really heavy startle response. But we had noticed that Cameron had a comparable startle response. Not quite as severe but absolutely not like Taylor had had. ROBERT KRULWICH: As soon as she saw that early warning sign on the Tay Sachs Website, Blyth went to get herself and Cameron tested. CHARLIE LORD (Mother of daughter with Tay Sachs): It was another week. It was exactly a week until we got the final results on Cameron's blood work. And then the Tuesday before Thanksgiving we went into our pediatrician's office and he had the results, and we found out that night that Blyth was a carrier and that Cameron had Tay Sachs. BLYTH LORD: He said...all he said was, "I'm sorry." ROBERT KRULWICH: Tay Sachs is a very rare condition and it usually occurs in specific groups, like Ashkenazi Jews. And even then, the baby must inherit the bad gene from both parents. So even though there is a Tay Sachs test, the Lords had no reason to think they would be at risk. And yet incredibly, all four of them, Tim and Charlie and both their wives—all four were carriers. That was an unbelievably bad roll of the genetic dice. TIM LORD: Charlie and I are incredibly close and have been all our lives. And when I think about him and Blyth having to go through this, it just seems really cruel. It just seems too much. CHARLIE LORD: I had already geared myself up for being my brother's rock and I couldn't imagine having to help him and go through it myself. ROBERT KRULWICH: For families like the Lords, and for everybody, the Human Genome project offers the chance to find out early if we're at risk for all kinds of diseases. TIM LORD: I would like to see a really aggressive push to develop a test for hundreds of genetic diseases so that parents could be informed before they started to have children as to the dangers that

face them. And I think it's within our grasp. Now that they've mapped the human genome, I mean, the information is there for people to begin to sort through. They're horrible, horrible, horrible diseases and if there's any way that you can be tested for a whole host of them and not have them affect a child, I think it's something that we have to focus on. ROBERT KRULWICH: Hayden Lord died a few months before his third birthday.

4 The Sequencing Race Begins 00:24:56 ROBERT KRULWICH: What makes this story especially hard to bear is we now know that a loss that huge—and it was a catastrophe, by any measure—started with a single error, a few atoms across, buried inside a cell. Now, that s...