Winding Your Way Through DNA Symposium

San Francisco, California
Friday Evening, September 25, 1992

James D. Watson, PhD

Harold has given me a relatively simple task of essentially repeating my little book, The Double Helix, and so I prepared some slides from the book, the pictures in it, and I will race through the story and then make a few comments at the end, seeing the discovery after 40 years.

The origin of the work goes back to my days as a student at the University of Chicago where I believe it was the fall of 1945, I read a little book called What Is Life? by the German physicist Erwin Schrodinger, who had received the Nobel Prize for his work in wave mechanics. Schrodinger said the essence of life was essentially heredity, and the key problem was, "What is the gene?" And in particular, "How can you copy a gene?" The gene must carry very specific instructions, and there must be some marvelous trick by which you can exactly copy the structure of a gene. So that inspired me, the following term at the University of Chicago, to go to the lectures by a very famous geneticist named Sewall Wright, who gave a course entitled Physiological Genetics. From that I came away with the feeling there were three problems.

1. "What is the gene?" Wright in his course had recounted the experiments of Avery which suggested that the genetic substance was DNA.

2. The second problem was one which Schrodinger posed, "How is the gene copied?"

3. The third problem was, "How does the gene function?" It controls the cell, the essence of cells are proteins. There were already some experiments which could be summarized under the idea that every gene somehow provides the information to make protein. As a result of Wright's course, I decided to go to graduate school and learn genetics. I went to Indiana University and there had the good luck to work under Salvador Dali--not Dali, but Luria. (laughter) [Aside by Watson: There is a reason for this mistake, which is that Dali once invited me to lunch with Mia Farrow, and I've just seen (her) latest movie. (The lunch was) A long time ago; I didn't even know who she was.]

I worked on bacterial viruses and did a thesis which Max Delbruck, who was teaching at Cal Tech, told me that I had the good fortune that it was a very dull thesis. So I wouldn't make the mistake of continuing it but could try something better when I went on as a post doc. But I did go to Copenhagen. I was supposed to learn biochemistry but I was bored by it. I went to Naples for two months, and there was a scientific meeting at which I met an English scientist Maurice Wilkins, who I hadn't heard of before, who had taken x-ray pictures of DNA.

The marvelous thing I heard was that these pictures were very good. So there was a well-defined structure. I had known before that DNA yielded x-ray diffraction patterns but it was sort of murky. But this time there was a marvelous structure that someone could find. And by this stage I had since realized that the essence of a gene was a molecule and genetic experiments were never going to say something deep about the molecule, and I had to study the molecule.

Suddenly from seeing the x-ray picture of Wilkins it was clear that someone was going to be capable of studying it and I thought, "Why not me?"

After I'd left Naples I went to Geneva and my friend Jean Weigle, who was also at Cal Tech, told me that Linus Pauling had solved the structure of proteins. Linus had done it by just guessing it. I got back to Copenhagen and wrote to Luria and said, "I want to do x-ray crystallography. Can you help me get in a lab?" By luck Luria had met John Kendrew, then a young English scientist who was working to solve the crystal structure of the protein myoglobin. Kendrew was looking for someone to work with him and he told Luria that I could come there. I went to Cambridge and discovered I really didn't want to work on proteins. I really wanted to work on DNA and that was helped by meeting Francis Crick.

Francis was doing experiments and said, "Well, why can't we imitate Pauling and just guess the structure?" That's what Pauling had done. The rules of chemistry would lead you to the structure and we said "Why not?" If one considered the essence of it, the essence of DNA was it was a linear molecule. The exact chemical bonds had been worked out actually in Cambridge just that year by the laboratory of Alex Todd and it was essentially a nice linear molecule where it was a polymer. The monomer was called a nucleotide and there were four types of nucleotides depending on the four bases: adenine, thymine, guanine and cytosine. So that was the thing. How would this molecule fold up? That was the question we wanted to answer.

Francis was a friend of Wilkins. Wilkins came out to lunch and we learned two things. One is that Wilkins said, "I actually thought the molecule contained more than one chain." They were sort of guessing there were three chains. That was a really important new fact. The second thing he said was that there was trouble, and when he had been in America his problem had been given to a woman named Rosalind Franklin, and they didn't get along. But he said he didn't know what Rosalind was doing but she was going to give a seminar in several weeks and I could come and hear it.

I went and heard it. And I won't say, but I heard it wrong. I came home... and we said, "Well, we will make a helix." I had heard her talk wrong and thought there was very little water in it and therefore it should be a rather compact structure. We tried to make a structure. We said, "Well, there are four types of bases. There is no way we can stick in a regular sequence of bases in the center in a regular fashion." So we tried to build molecules where the main chain was on the inside.

I should say that what Francis and I generally did was we talked most of the time, or we walked. I think we walked for an hour after lunch.

We ended up with a structure in which we thought that conceivably the phosphatidyl groups were held together by magnesium ion, and we built a structure with three chains and it wasn't perfect but we were very happy. We called up the people at King's College [at the University of London], particularly to get in touch with Miss Franklin and she said she would come out [to Cambridge] and look at it. She looked at it and said it was all wrong. The molecule was filled with water and we sort of retreated and we were told in fact the problem belonged to the people at King's.

I really had nothing to do with it except grow my hair for about six months without cutting it. This was a response to Crick's wife's comment: she said I was bald because I had a crewcut. She said I looked like an American serviceman so I decided to grow my hair.

We got slightly worried when we knew Linus Pauling was going to come, because we thought he might see Miss Franklin's data. But then he couldn't get a passport because the State Department thought he was too friendly with the Communists. So he never came. The only visitor we did see was an Austrian chemist by the name of Erwin Chargaff who showed up in the middle of the summer and talked to Francis and me, and talked about doing an analysis of the bases in DNA. He said that the amount of adenine was approximately equal to thymine, and guanine to cytosine. In different DNAs of ratio of adenine to guanine would vary, but what was always constant was that adenine approached that of thymine, and guanine and cytosine.

Francis got quite excited about it. I didn't like it at all because Chargaff was probably the most unpleasant person I'd ever met. I just wanted to ignore anything the wretched man said.

Now, Francis actually then knew a chemist named John Griffith. They got talking and Francis saw that maybe A and T could attract each other and that might explain [Chargaff's ratios]. Unfortunately, instead of doing it the way the base pairs are now, they put the adenine on top of the thymine. Griffith did some calculations and with time Francis lost interest. Interesting, Griffith was a good chemist. He was the nephew of the Griffith who discovered transformation. But nothing really happened.

I was doing bacterial genetics to pass the time, but then we heard about Linus Pauling and we were really frightened that Linus would get on to the problem and just guess it. We heard that he had a structure. We said, "Well, he doesn't know the data at King's." So we kept telling ourselves he doesn't have it. Then his son Peter had become a research student at Cambridge and a manuscript [from his father] was sent to Peter late in January. We read it and the structure was just lousy. We couldn't believe it. It had to be wrong.

So I rushed into London and told Wilkins that Pauling proposed this. He proposed something crazy. Maurice told me a couple of things. One, the good news was that Miss Franklin was going to leave and he could get back working on it. Then he showed me a picture which he had taken. This was a perfect picture of a helix. So I saw this picture and then actually saw Rosalind Franklin briefly and told her that Pauling had published a structure which was wrong. She said--well, you know, she was annoyed with me. We didn't get on.

Anyway, I went to supper with Wilkins and said, "This picture is such a perfect helix." We kept saying it was a helix. This picture means that we should get back and build models. Maurice was more or less saying, "I'll do it when Rosalind leaves the lab." But I went back to Cambridge and told Francis and told Professor Bragg that there was this extraordinary picture, and there was no doubt about it being a helix and we should go back to trying to build models.

So Crick and I did, and Francis said, "Why not put the bases inside?" When he said that there were actually facts which really said the bases had to be inside. There were two sorts of experiments. One is that DNA can be denatured. If you vary the pH to break the hydrogen bonds, the molecule collapsed. You could see that this is viscous and then as you raise the pH it falls apart. Then there was another experiment in which you essentially tried to titrate the bases. This had been done by Gullen and published before I got to Cambridge. If you look at it carefully it says all the bases are hydrogen-bonded. They can't just be sitting out interacting with water. So the bases must be in the center and hydrogen bonded so all the groups can't titrate as if they weren't hydrogen bonded. We said, "Why not two chains?" When you looked at the data it didn't have to be three chains, but it certainly wasn't one. Maybe we could form pairs between adenine and adenine, and guanine and guanine, and you could form a structure by which each of the bases attracted itself.

I was extremely excited because I thought maybe this was right. But then there was a real chemist in the lab, Jerry Donohue, who had been with Linus Pauling. Now this was the structure that I was manic about for a week. But Donohue dismissed it as being totally wrong because he said that all the textbooks have written the thymine and guanine in the wrong tautomeric form. They're ketos, not enols.

Now deep down he was slightly bluffing, because he just knew one structure which was keto, but he at least more or less raised doubt that maybe the textbooks were all wrong. So we wrote it the wrong way and I had made paper models of the bases and changed around where the hydrogen atoms were. Then one Saturday morning which I think was March 1, I found you could make two base pairs where adenine and thymine, and guanine and cytosine had exactly the same shape. Francis found you could flip-flop them over in a nice way of symmetry so that you could have all four bases on a different chain.

And there it was that you could build a structure. This was sort of the way we wanted to build it after the base pairs were found. Francis stopped working on proteins and actually built the model. This was the reason we were really excited, because you could imagine if you separated the two chains that you could form a complementary one. So if this were the structure of DNA, the way DNA was copied was probably known.

So we were, to say the least, happy.

Then the next thing I did was to write Cal Tech and Delbruck and tell them the news that we had found the molecule. The last sentence was, "Don't tell Pauling." I said this because we hadn't written the manuscript and I wanted to write the manuscript and then tell Linus. But in fact the first thing Delbruck did when he got the manuscript was to tell Pauling. But Pauling was very gracious and said, "It's a lot better than my structure." So really when everybody saw it everyone liked it. There was no reason why it wasn't right and if you really looked at it the x-ray data confirmed it. And the answer was yes.

Now there is actually after the manuscript had come out we were locally famous and the local Cambridge paper sent a photographer and we were photographed, and I'm changed there slightly [alluding to the picture being shown to the crowd]. Crick's wife said I had to actually look all right, so she went to the store with me and I got a blazer, tried to look okay, and Francis is sort of tweedy. There was a photograph of us drinking coffee in the room where we had talked for 18 months.

So this is really the encapsulated story. Now one thinks back about it. We could have solved the structure in about a month, if we had taken the chemical data which really said the bases were hydrogen bonded. It wasn't published obscurely, it was right there. So why didn't we do it? I think the answer is that neither Francis nor I knew any chemistry. And so we tried to avoid chemistry. And you could say, "Well, why did you succeed?" And I think the answer is there were two of us. And we were interested.

Then you go on, "Well, why didn't Rosalind solve it?" Interestingly, the answer probably comes down to the same thing. She wasn't a chemist. She wasn't an x-ray crystallographer. She was also an amateur. Because her data in the crystalline form showed a dyad, and she didn't understand what it meant. It really said one chain is going up and one is going down. So she (had) worked on Co-A and (had) never solved a structure before in her life, and she really wasn't really familiar with space groups. I think the other thing is she had no one to talk to. She had a research student who didn't know crystallography, a friend name Luzati who was slightly bizarre, and bright, very bright, but he didn't know crystallography.

But Francis, when he saw that dyad--Francis actually had learned crystallography and he went to Cambridge and we didn't need it but Francis knew that dyad had proved the structure. So, he knew the space group. Rosalind never knew what it meant. So she could have got it, if she had been trained in the subject.

The thing you can't answer is, "Why didn't Pauling get it?" And I'm still as much at a loss now 40 years afterwards as I was then. But it was good luck for me.

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