How I discovered DNA - James Watson

[Music] [Music] [Applause]

Well, I thought there'd be a podium, so I'm a bit scared. Chris asked me to tell again how we found the structure of DNA and since you know I follow his orders, I'll do it. But it slightly bores me and, uh, yeah, I wrote a book, so I'll say something. I'll say a little about, uh, you know how the discovery was made and why Francis and I found it. And then I hope maybe I have, uh, at least five minutes to say what, uh, uh, makes me tick now.

Back of me is a picture of me when I was, uh, 17. I was at the University of Chicago in my third year. And, uh, I was in my third year because the University of Chicago let you in after two years of high school. So, uh, it was fun to get away from high school and, uh, 'cause I'm very small, no good in sports or anything like that. But I should say that, uh, my background, my, uh, father was, you know, raised to be an Episcopalian and Republican. But, uh, after one year of college, he became an atheist and Democrat. And, uh, my mother was Irish Catholic, but she didn't take, uh, you know, religion too seriously.

By the age of 11, I was no longer going to Sunday Mass and going on bird watching, uh, walks with my father. So, uh, early on I heard of Charles Darwin. Uh, I guess you know, he was the big hero, and you know, you understand life as it now exists through evolution. And at the University of Chicago, I was a zoology major and thought I would end up, uh, you know, if I was bright enough, maybe getting a PhD from Cornell in ornithology.

Uh, then, uh, in the Chicago paper, there was a review of a book that, uh, called "What is Life" by the great physicist Schrödinger. That, of course, has been a question I wanted to know, you know, Darwin explained life after it got started, but what was the essence of life? And, uh, Schrödinger said the essence was information, uh, present on our chromosomes, and it had to be present, uh, uh, on a molecule.

I never really thought of molecules before, you know, chromosome, but this was a molecule and, uh, somehow the information was probably present in some digital form. And there was a big question: how did you copy the information? So, uh, that was the book. And, uh, from that moment on, I wanted to, uh, uh, be a geneticist, understand the gene, and through that understand life.

So, uh, I had, you know, a hero at a distance; it wasn't a baseball player, it was Linus Pauling. And, uh, so I applied to Caltech and, uh, they turned me down. Uh, so I went to Indiana, which was actually as good as Caltech in genetics. And, uh, besides, they had a really good basketball team. So, I had a really quite happy life at Indiana.

And it was in Indiana, uh, I got the impression that, you know, the gene was likely to be DNA. And so when I got my PhD, I should go in search of DNA. So, I first went to, uh, Copenhagen because, uh, I thought, well, maybe I could become a biochemist. But I discovered biochemistry was very boring.

Uh, it wasn't going anywhere toward, you know, saying what the gene was; it was just nucleotides. And, uh, oh, that's the little book; you can read it in about two hours. And, uh, but then I went to a meeting in Italy, and, uh, there was an unexpected speaker who wasn't on the program, and he talked about DNA. This was Morris Wilkins; he was trained as a physicist, and after the war, he wanted to do biophysics, and he picked DNA because DNA had been shown at the Rockefeller Institute to possibly be the genetic molecule on the chromosome. Most people believed it was proteins, but Wilkins, you know, thought DNA was the best bet.

And, uh, he showed this x-ray photograph, and it sort of crystallized, so DNA had a structure even though probably different molecules carried different sets of instructions. So, there was something universal about the DNA molecule. So, I wanted to work with him, but he didn't want a former bird watcher, and I ended up in Cambridge, England.

So, I went to Cambridge, uh, it was really the best place in the world then for x-ray crystallography. And x-ray crystallography is now a subject in, you know, chemistry departments, but in those days it was in the domain of the physicist. So, uh, the best place for x-ray crystallography was in the Cavendish Laboratory at Cambridge. And, uh, there I met Francis Crick. Uh, I went there without knowing him; he was 35, I was 23. And, uh, within a day, we, uh, decided that, uh, maybe one could take a shortcut to finding the structure of DNA, not solve it by, you know, uh, rigorous fashion, but build a model, a molecular model using some coordinates, some, you know, lengths, all that sort of stuff, uh, from x-ray photographs.

But just as to what the molecule, how should it fold up? And the reason for doing so is the center of the photograph. This line is Ping about 6 months before he proposed the alpha helical structure for proteins. And in doing so, he vanished the man on the right, Sir Lawrence Bragg, who was the Cavendish Professor.

This is a photograph several years later when Bragg had caused a smile. He certainly wasn't smiling when I got there because he was somewhat humiliated by Pauling getting the alpha Helix and the Cambridge people failing because they weren't chemists, and, uh, certainly neither Crick nor I were chemists. So, we tried to build a model.

And, uh, Francis knew Wilkins and said he thought it was the Helix; the x-ray diagram he thought was compatible with the Helix. So, we built a three-stranded model. The people from London came up, Wilkins and this, uh, collaborator or possible collaborator, Rosalind Franklin, came up and sort of laughed at our model. They said it was lousy. And, uh, it was (laughs). So, uh, we were told to build no more models; we were incompetent. And, uh, so we didn't build any models, and Francis sort of continued to work on proteins, and basically, I did nothing, uh, and, uh, except read. You know, basically reading is a good thing; you get facts.

And, uh, we kept telling the people in London that Linus Pauling is going to move on to DNA. If DNA is that important, Linus will know it; he'll build a model, and everyone will be scooped. And in fact, he'd written to the people in London, could he see their x-ray photograph, and they had the wisdom to say no. So he didn't have it, but there was one in the literature actually; Linus didn't look at them that carefully.

But, uh, about 15 months after I got to Cambridge, rumors began to appear from Linus Pauling's son, who was in Cambridge. His father was now working on DNA, and, uh, so one day Peter came in, it says Peter Pauling, and gave me a copy of his father's manuscript, and boy, I was scared 'cause I thought, you know, we may be scooped. I have nothing to do, no qualifications for anything, uh, and, uh, so there was the paper and he proposed a three-stranded structure.

And I read it, and it was just, it was crap. So, this was, you know, unexpected, uh, from the world. And, uh, so it was held together by hydrogen bonds between phosphate groups. Well, at the pH that cells have around seven, those hydrogen bonds couldn't exist. We rushed over to the chemistry department and said could Pauling be right? And Alex said no. So, uh, we were happy and, uh, you know, we were still in the game, but we were frightened that someone at Caltech would tell us that he was wrong.

And, uh, so Bragg had built models, and, uh, a month after we got the Pauling manuscript, uh, I should say I took the manuscript to London to show the people, you know, that Linus was wrong. And they were still in the game and should immediately start building models. But, uh, Wilkins said no. Uh, Rosalind Franklin was leaving in about two months, and after she left, uh, he would start building models.

And, uh, so I came back with that news to Cambridge and Bragg said build models, or of course I wanted to build models. And, uh, there was a picture of Rosalind; uh, she really, you know, in one sense she was a chemist, but really she had been trained to, she didn't know any organic chemistry or quantum chemistry; she was a crystallographer. And, uh, I think part of the reason she didn't want to build models is she wasn't a chemist, whereas Pauling was a chemist.

And, uh, so Crick and I, uh, you know, started building models, and I learned a little chemistry, but not enough. Well, we got the answer on the 28th of February, '53, and it was because of a rule which to me is a very good rule: never be the brightest person in the room. And, uh, we weren't. I mean, we weren't the best chemists in the room. I went in and showed them pairing I'd done, and Jerry Donahue, he was a chemist, he said it's wrong; you got the hydrogen atoms in the wrong place. I just put them down like they were in the books. He said they were wrong.

So the next day, you know, after I thought, well, he might be right, so I changed locations and then we found the base pairing, and Francis and me, they said the chains run in opposite directions, and, uh, we knew we were right. So, uh, it was pretty, you know, it all happened about 2 hours, you know, from nothing to being. We knew it was big because, uh, you know, if you just put an A next to T and G next to C, you have a copying mechanism.

So we saw how genetic information is carried; it's the order of the four basically. So, in a sense, it is a sort of digital type of information, and you copy it by going from, uh, strand separating. So, it's, you know, if it didn't work this way, you know, you might as well believe it because you didn't have any other scheme.

But that's not the way most scientists think. Most scientists are really, uh, rather D—they say we won't think about it until we know it's right. But, you know, we thought it was at least 95% right or 99% right. So, think about it.

Uh, the next 5 years, there were essentially something like five references to our work in nature, none. And, uh, so we were left by ourselves and, uh, trying to do the last part of the trio: how do you, uh, how, what does the genetic information do? And it was pretty obvious that it provided the information to an RNA model molecule, and then how do you go from RNA to protein?

Uh, for about 3 years, we just—I tried to solve the structure of RNA. It didn't, uh, yield; it didn't give good x-ray photographs. I was largely unhappy; a girl didn't marry me. It was really, you know, sort of a shitty time.

Uh, oh, there's a picture of Francis and I before I met the girl, so I'm still looking happy. But, uh, there is what we did when we didn't know where to go forward—we formed a club, uh, and called it the RNA TAE Club. George Gamow, the great physicist, uh, he designed the tie; he was one of the members, and the question was how do you go from a four-letter code to the 20-letter code of proteins. Fan was a member and Teller and F.

Uh, that's the only photo; no, we were only photographed twice, and in both occasions, you know, one of us was missing the tie. There's Francis up on the upper right, and, uh, Alex Rich, the MD turned crystallographer, is next to me. This was taken in Cambridge in, uh, September of 1955, and, uh, I'm smiling, sort of forced, I think, 'cause the girl, boy, she is gone. And, uh, and, uh, so I didn't really get happy until 1960, uh, because then we found out basically, you know, that there are three forms of RNA, and we knew basically DNA provides the informational RNA, RNA provides the information protein.

And that led Marshall Nirenberg, you know, take RNA, synthetic RNA, put it in the system, making protein. You made, uh, probably, uh, uh, phenylalanine, probably you made. So, uh, that's the first, uh, first string of the genetic code, and it was all over by 1966. So that's what Chris wanted me to do.

It was, uh, so what happened since then? Well, at that time, uh, I should go back when we found the structure of DNA, uh, in my first talk at Cold Spring Harbor, the physicist Leo Szilard, uh, he looked at it and said are you going to patent this? But he knew patent law and knew we couldn't patent it 'cause you had no use for it.

And, uh, so DNA didn't become a useful molecule, and the lawyers didn't enter into the equation until 1973, 20 years later, when Boer and Cohen in San Francisco and Stanford came up with their method of recombinant DNA. And Stanford patented and made a lot of money. That is, they patented something which, you know, could do useful things, and, uh, then they learned how to read the letters of the code, and boom, we've, uh, now had a biotech industry.

And, uh, but we were still a long way from, you know, asking, answering a question which sort of dominated my childhood, which is, uh, how do you, uh, nature, nurture? And, uh, so I'll go on; I'm already out of time, but this is Michael Wigler, a very, very clever mathematician turned physicist. And he developed a technique which, uh, eventually will let us look at sample DNA at, eventually, a million spots along it.

There's a chip there, a conventional one, and then there's one made by a photolithography by a company in Madison called NimbleGen, which is, uh, uh, way ahead of Applera metrics. And, uh, we use their technique, and what you can do is sort of compare DNA of normal cells versus cancer.

And, uh, you can see on the top that cancers which are bad show insertions or deletions, so the DNA is really badly mucked up. Whereas if you have a chance of surviving, the DNA isn't so mucked up. So we think that this will eventually lead to what we call DNA biopsies. Before you get treated for cancer, you should really look at this technique and get a feeling of the face of the enemy. It's not a—it’s only a partial look, but it's, I think it's going to be very, very useful.

So we started with breast cancer because there's lots of money for it, no government money. And, uh, now I have a sort of vested interest; I want to do it for prostate cancer. So, you know, you aren't treated if you know it's not dangerous. And, uh, so, but Wigler, besides, you know, looking at cancer cells, looked at normal cells and made a really sort of surprising observation which is all of us have about 10 places in our genome where we've lost the gene or gained another one. So we're sort of all imperfect.

And the question is, well, if we're around here, you know, these losses or gains might not be too bad. But if these deletions or amplifications occurred in the wrong gene, maybe you really are sick. So the first disease he looked at was autism. And, uh, the reason we looked at autism is we had the money to do it.

Look at an individual; it’s about $3,000, and the parent of a child with Asperger's disease, the high intelligence ism, had sent his thing to a conventional company. They didn't do it and couldn't do it by conventional genetics, but just scanning it, uh, we began to find genes for autism. And you can see here, uh, there are a lot of them. So, a lot of autistic kids are autistic because they just lost a big piece of DNA.

I mean, a big piece at the molecular level. We saw one autistic kid, 5 million bases, just missing from one of his chromosomes. We haven't yet looked at the parents, but the parents probably don't have that loss, or they wouldn't be parents now.

So, our autism study is just beginning. We got $3 million; I think it'll cost at least 10 to 20 before you'll be in a position to help parents who've had an autistic child or think they may have an autistic child. And can we, uh, spot the difference?

So this same technique should probably look at all—it's a wonderful way to find genes. And so I'll conclude by saying we've looked at 20 people with schizophrenia, and we thought we probably had to look at several hundred before we got a picture. But as you can see, there, 7 out of 20 had a change which was very high, and in the controls, there were three.

So what's the meaning of the controls? Were they crazy also and we didn't know it, or, you know, were they normal? Uh, I, I would guess they're normal. And, uh, what we think in schizophrenia is there are genes that predispose. And, uh, whether this is one that predisposes, and then there's only a subset of the population that's capable of being schizophrenic.

Now, we don't have really any evidence of it, but I say to give a hypothesis, the best guess is that if you're left-handed, you're prone to schizophrenia. Uh, 30% of schizophrenic people are left-handed, and schizophrenia has a very funny genetics, which means 60% of the people are genetically left-handed, but only half of it show. I don't have the time to say it now; some people who think they're right-handed are genetically left-handed, okay?

I'm just saying that if you think, oh, I don't carry a left-handed gene, so therefore my, you know, children won't be at risk of schizophrenia, you might.

Okay, so it’s, to me, an extraordinarily exciting time. We ought to be able to find the gene for bipolar; there's a relationship. And if I had enough money, we'd find them all this year.

I thank you.