The RNA Tie Club: Its Search for the Genetic Code
- >> David Shalloway
Welcome to the first Ef Racker lecture in - [ Pause ] [ Laughter ] I just want to announce that before we go forward, tomorrow's lecture, which was originally scheduled in the Biotechnology Building at 4:00 PM, is going to be moved to this room for obvious reasons.
We appreciate everyone's attendance.
Ef died a little over a year ago, as he would have wished, after a full day's work in the laboratory.
His superb scientific accomplishments are well known and are briefly summarized in the program so I'm not going to repeat details that are given there.
To me, it was the breadth of Ef's interests and work that was really most impressive.
He was interested in everything.
His early experiments on brain metabolism drew his interest into the area of the fundamental role of glycolysis in cellular energy production, and his many contributions in this area are well known and include the discovery of the first catalyst, the membrane link ATP synthesis, experimental evidence indicating the important role of asymmetrical molecular architecture of biological membranes, and evidence in support of the chemiosmotic hypotheses in vitro reconstitution using purified components of many membrane linked energy coupling reactions, such as light driven ATP synthesis.
During the last years of his career, Ef focused on the role of protein phosphorylation [phonetic] in cellular energy metabolism and signal transduction, particularly on the role of phosphorylation in cancer and in Alzheimer's disease.
Many of these studies pursued by him are still being pursued and bearing fruit.
Beyond his work as a scientist, Ef played an important role as the leader at Cornell in biochemistry here.
Coming here in 1966 as the Albert Einstein professor of biochemistry, he was chairman of the section of biochemistry and molecular and cell biology and played an instrumental role in its development.
He was an energetic teacher who loved interacting with students.
Thus, it's particularly appropriate, I think, that as another memorial, the small conference room in the Biotechnology Building is being dedicated in his name, this being the seminar room where he led many of the graduate student seminars.
Many of you attended the symposium in Ef's honor this summer where we had the opportunity to commemorate his accomplishments and recall special personal experiences that made him dear to us.
Although it was already apparent to me from my own direct experience with Ef, that telling a story after story by students and colleagues from around the world served to further highlight his ability to be interested in everything and to bring out the best in each of us.
But the purpose of our meeting this evening is not to commemorate Ef by reminiscence, but in the way that he would appreciate best.
Actually probably the only way that he would appreciate at all.
By getting down to work and discussing science.
So this is the inauguration of, I'll get it right this time, Ef Racker lectureship in biology and medicine at Cornell.
It will be a continuing memorial to Ef and give the Cornell community the opportunity for additional interactions with superb scientists in basic biomedical research.
This lectureship has been endowed with funds donated by Ef's friends, either directly or through the purchase of his paintings.
Some of these are still on exhibit in the lobby of the Biotechnology Building, and if you haven't seen them, I encourage you to take a walk over there and see them.
On behalf of the section of biochemistry, molecular, and cell biology, and on behalf of Cornell as a whole, I want particularly to thank Ef's wife, Dr. Francis Racker, for her thoughtfulness and unflagging energy in and generosity in arranging for the exhibits and sales in some of Ef's artworks, and this lectureship would not exist without her efforts.
[ Applause ] This evening we're particularly delighted to have Dr. Jim Watson, the director of Cold Spring Harbor Laboratories, as our first lecturer in the series.
Not only because of his eminence as a scientist and as a leader in the world of science, but because Cold Spring Harbor played a particularly important role in Ef's life.
Dr. Watson will be introduced by Dr. Jeff Roberts, chair of the section of biochemistry and molecular and cell biology.
[ Pause ]
- >> Dr. Jeff Roberts
So Jim Watson really does need an introduction to those of you who only know him as a co-discoverer of DNA because he's done other things for which he's extremely well known in the community of biologists.
After DNA, there are three things that I think are, he's remembered for particularly.
One is that he established at Harvard University a laboratory of molecular biology when he was a professor there, which nurtured some of the best known and most prominent molecular biologists, people like Walter Gilbert, Klaus Faber as well as a lot of rather lesser likes who came out of the laboratory.
And many of the, good number of the laboratories nowadays are populated with the alumni of that place.
Second, he wrote a textbook called "Molecular Biology of the Gene", which was written at a time when he said one person could know everything important there was to know.
I probably misquoted him, but it's something I think to that effect.
And he was the person who knew it and wrote it down, and that textbook, since it was written in the 60's, became the standard introduction for everyone to the field.
Again, a whole generation of molecular biologists as well, in fact, anybody else who wanted, a reasonably intelligent person who was interested in the subject wanted to pick up a book and learn about it.
And the last thing that he did was to become director of Cold Spring Harbor Laboratory, which was probably somewhat of a backwater and an eccentric place, and he transformed it into one of the world's real centers for not only conducting but also promoting biological research through the meetings and publications that it supports.
And all of those things are done with the sort of intensity and intelligence and style that's really matched nowhere else in the world.
And, finally, I could mention that he wrote a personal book called "Molecular", I'm sorry, called "The Double Helix", which his own reminiscences of the discovery of DNA.
And what he's going to talk about tonight is his personal remembrance of the history of molecular biology in the period just after that.
So it's a pleasure to introduce Jim Watson.
[ Applause ]
- >> Dr. Jim Watson
Thank you, Jeff, and it's a great pleasure to be asked to give the first Ef Racker lecture here at Cornell.
Ef was just a, he was, well, Cold Spring Harbor is a, always had the reputation for only having good people at it.
And, you know, the reputation partly came because Ef used to go there in the summer.
And so when I first went there, I became acquainted with the Rackers, and I want to start my talk with some slides which show Ef as an artist.
And so just to, I should say to start with, my talk will be sort of three parts.
First, I want to talk about Ef and show some slides of some drawings and paintings he did which are now thanks to the wonderful gift that Francie Roberts are now the property of the Cold Spring Harbor Laboratory, and they have been placed in the, our old famous fireplace room where the first symposium were held, and that's now known as the Racker Reading Room.
So the Racker Reading Room has these wonderful drawings, which you'll see slides of.
Second, I want to say something about the finding the double helix.
It's been more than 25 years.
So the book, and then I'll go out and talk about what happened to Francis and I right afterwards.
So if we could start with the first slide.
[ Pause ] Oh. Maybe I'm supposed to.
Oh, here it is.
Now, here's Ef, and this is a picture taken in the late 1940's at Cold Spring Harbor on the porch of Hooper House.
And you can see Ef is drawing.
Now, there's someone behind, and I can't figure out who it is except that it's a man, but he's being drawn.
And so if we can go, let's see.
[ Pause ] OK. I think I [inaudible].
OK. Now this is a painting of Max Delbrook.
Max was I think Ef's favorite model, and in part because Max looks very dramatic, and Ef was in Vienna.
And so he knew these sort of faces.
Max sort of fitted into sort of German expressionism.
This is of Al Hershey.
And as far as I can tell, these were all done in the, probably, I think many of these in 1950.
Hershey came to Cold Spring Harbor permanently in 1950.
Now this is painting of Jacques [inaudible].
And probably, possibly done in 1946, which is when Jacques and Andre LeBoeuf came to the symposium called "The Genetics and Microorganisms" in Cold Spring Harbor.
So Jacques then would have been about 35.
And so whether, you know, that looks like Jeff Goldblum, I don't know, but anyway.
So. So, this was done in 1950.
I was 22 years old, and I had just got my Ph.D., and I was in Cold Spring Harbor in August about ready to get a, the boat to go to Copenhagen and learn biochemistry with Herman [inaudible].
This is a face that should be familiar to many here.
This is Bruce Wallace, who was doing Drosophila genetics at Cold Spring Harbor.
This is Aaron Meier, who was the famed evolutionary biologist.
This is Ron [inaudible], who came many, many summers to Cold Spring Harbor.
Worked on [inaudible] transformation.
This is McFarland Burnett, who was in Cold Spring Harbor for about six weeks in the summer of 1950.
And this [inaudible].
This is Max again, Delbrook.
[ Pause ] That's me.
And it was, as far as I could see done in the same summer, and that's another view probably [inaudible].
This is Seymour Colon.
A really very talented biochemist who fought all the time with [inaudible].
And [inaudible] really wanted the truth to come from genetics, and Seymour kept saying, you know, you had to do biochemistry.
And Seymour just had no grace whatsoever, but he was right.
And, but he was sort of out of favor.
This was done a little later.
This is a later one of Dan Cufler, the editor of "Science".
This is Charles Weiss.
These are later.
These were done during that period.
This is Gordon Saddow, who did so much to get the role of growth factors and cell cultures.
And you can see this is the, looking into the room.
This was the room in Blackford Hall at Cold Spring Harbor where the symposiums were first held beginning in 1953.
So that room was, can take comfortably about 60 people, and that worked until probably 1941 when it was the famous symposium when genes and chromosomes.
It had about 100 people, and then it began to expand out.
And there's the picture of Ef, which is above the fireplace.
And you can see now how the drawings are arranged.
And we had enough drawings, in fact, so we could spill over into two other rooms, that's Aaron [inaudible], and we've named the main dining room after Aaron, who came every summer to Cold Spring Harbor for ten years from 1943 to '52.
And there's Roland Hutchkiss that we've named a sort of addition.
So this is, as you can see these drawings really bring back many memories, and I think they're just marvelous drawings.
They really look like the people.
I mean, I guess I should say myself excepted, but.
But I recognize the people.
So we're just very, very fortunate, this gift from Francy to Cold Spring Harbor to sort of have this room which I guess can do several things when people come to Cold Spring Harbor.
They can actually see that, you know, we respect biochemists.
That's distinct from, you know, molecular biologists.
Biochemistry is very important.
And so the, and likewise the room [inaudible] just the prime importance that, you know, no biologist should ever for a moment not think in terms of evolution.
So now I'll go onto the next part, and this is picture of Francis Quick and I as we looked, I suspect in the fall of 1953.
And Francis and I used to talk a walk every day after lunch.
So that it would be five days a week, and the walk used to last a half an hour, and it would inevitably go through Kings and depending on how much time we would get down to Trinity.
But this was where we would be every day.
And so we're looking I think slightly worried.
And because we were interested in DNA and really were getting nowhere.
And then just almost 40 years ago, in December of 1952.
We heard through Peter Pauling, who would come as a research student to Cambridge the fall, that his father had a structure for DNA.
And to say the least, we were worried.
Because Linus was ever perceived by everyone as the greatest biochemist.
He had outsmarted the Cambridge group and got the alpha helix when they had failed, and which is new.
He had to think about DNA.
And we kept telling the people at Kings, you know, that Pauling will be there.
And so the paper, we knew he had a paper, a structure, but we didn't know what was in it.
They only thing that gave us comfort was that we thought if he had something interesting we would have heard what the interesting thing was.
But so I went off to Switzerland for the Christmas vacation and was away about three weeks, and after I was back about two weeks, and Peter Pauling came in and said he had his father's manuscript, and so we eagerly read it and were puzzled.
Because it was a molecule with three chain, and I should say that at that time all my chemists thought of DNA as a polynucleotide, and it was a single-chain molecule.
But the x-ray crystallographers knew the diameter of the molecule.
They knew roughly how many nucleotides were there and realized that the crystallographic image contained more than one chain.
And the best guess was three chain.
So two wasn't ruled out.
And so Pauling had, in fact, built a three-chain structure, and it held them and put the phosphate, sugar phosphates in the center of the molecule and held them together by hydrogen bonds using uncharged phosphate groups.
So there was a hydrogen atom on the phosphate, and that was forming a nice set of hydrogen bonds and holding the thing together, and we couldn't understand that at all because DNA was an acid, and those hydrogen atoms should have been ionized off.
And, in fact, we had built models, and I had tried to hold them together by thinking that the secretive structure might be some form of calcium phosphate.
Some clever arrangement, and we had poured over Pauling's book "The Nature of the Chemical Bond", which was arisen out of the Baker lecture series by now and which first edition had come out in the mid 30's, and I was, we were using the second edition of the book.
But so Linus had proposed this strange structure, and all we could think of is that he had invented a new law of chemistry, which through those.
And so we went to the chemists and said, you know, could DNA not be an acid, and so the Cambridge chemists said this is nonsense.
So this was a paradox.
How could the world's greatest chemists propose a structure which was chemical nonsense?
And, well, so we took pleasure, you know.
But on the other hand, maybe, you know, he was really the world's greatest, and there was a new law and some fancy way by which he twisted the [inaudible].
So we didn't know, but in possession of the structure, I decided to take the manuscript into the people at Kings to [inaudible] friend for several years of Francis.
And take it into Kings and say the, you know, get off your butt.
They actually had to worry about DNA.
That is, those of you who have read my book will realize that the experimental work was, had started in London after the War by Morris Wilkins, who on a trip to the States came back and discovered that his professor had hired Roslyn Franklin to work with him.
They didn't get along, and soon the problem was Roslyn.
So Morris was very frustrated.
And so Roslyn was hired because she was, knew some x-ray crystallography, and Morris was just a physicist that said, well, we really, that's like the [inaudible].
So the experimental work was being done by Roslyn, and she had, was quite vehement that the molecule was not a helix.
She was working on the crystalline form.
Wilkins, of course, had taken pictures like this, and she had much better ones, and her rather [inaudible], Francis called a red herring.
She had said this wasn't a helix.
So, but I went in and first saw Wilkins, and then he said Roslyn was next door.
So I went into her and said good news, Linus' structure is wrong.
And she said I knew it's wrong because it's not a helix, and I said, but it's a helix.
And then she was very angry at me because I essentially knew nothing.
So, you know, what right did I have to say anything.
And so then I went back and talked to Wilkins, who said, well, you know, Roslyn has another thought.
And here's a, so there's Wilkins, and for those of you who have seen the BBC movie, Alan Howard, who played him, really looks like Wilkins.
And there's Roslyn.
And who was played in the movie by Julia Stevenson.
Actually a superb actress on the London stage.
And I think in the movie, the conversations between Wilkins and Franklin are done very well.
Well, here's the photograph which Morris showed me, and Francis and I had no idea existed, but if there was ever a helix in this world, it was this.
So I remember getting very excited telling Morris he's got to work on it, and then went back to Cambridge, and the next morning.
It was a Friday night, and we went to, saw Francis and told him of the x-ray photograph, which had a 34 Angstrom repeat and a very strong 3.4 Angstrom, which said there were ten faces on every chain.
And the question was did you have a two-chain or a three-chain molecule.
And I thought, well, we were getting nowhere with three, and why not try two because it was easier to build a model, too.
And so, and then there was the question of the, you see, we were trying to do structures like this, and Francis said, well, we, you know, we got nowhere with this.
Why don't we put the bases inside?
And we had never put the bases on the inside because we said that the sequence must be irregular.
So how could you form a regular structure out of an irregular sequence?
Now it turned out that it was a lousy argument.
So when Francis said build it in the, you know, put the bases in the center.
And so I did.
I mean, it was more or less, you know, we knew we weren't, we had no ideas at all about keeping the bases outside.
In fact, there was, then you had to figure out you knew the bases could form hydrogen bonds because there had been structures published [inaudible] where they formed hydrogen bonds.
I'll come back and show that in a second.
And then there was the fact that I had learned as soon as I got to Cambridge, which was essentially ignored, which said that when you exposed DNA to acid or alkaline the hydrogen atoms which can ionize on the bases don't ionize at their normal ph but are protected.
And you can see that there's a, it takes a much lower ph as you first would now call denature, and then there afterward they are exposed.
And this was the work of John [inaudible].
Again, you can see ph. There was a nice viscous molecule, and then suddenly it seemed to lose its structure.
It's either high or low ph. At a time when we would either acquire a hydrogen atom or lose it, and the simplest interpretation of this data, which we had ignored, said all the bases were a hydrogen [inaudible].
So the natural.
And so I started out as you see that adenine, that adenine, there was already a crystal structure like this.
So then I said, well, you could form something almost like that.
This, so you could form a two-chain structure which everything paired, but it wouldn't be regular because purine and pyrimidine aren't the same size.
But I still liked it because it said, well, if you actually form this structure, and you have to have the rule, which I couldn't see why it should, but adenine goes to adenine for other reason, then you could replicate DNA, which was the real thing we were trying to always.
There was the big puzzle.
How do you copy a DNA molecule?
So I actually was excited that you might, you know, even though I knew it wasn't a pretty structure, that at least it was a [inaudible].
So I went back there the next morning into the lab and explained it to an American chemist, Jerry Donohue, who had come from Pauling's lab where he was, had done x-ray structural analysis.
And he said that my structure was wrong because he said guanine is not in the, you know, form where [inaudible].
And he said even though all the textbooks show thymine with hydroxyl up their top.
In fact, it should be a [inaudible].
So I made models with the form that Donohue said, and on a Saturday morning, which I think was March 1, '53, suddenly, one saw the base pairs.
Now, this was done completely independent of [inaudible] data, but it gave me a [inaudible] result.
And you can say, well, why didn't we start with [inaudible] results, and the, there were two answers.
One answer was the data didn't show complete [inaudible].
In fact, really good analytical data didn't appear until after we found the structure.
So it was adenine is almost equal to thymine.
Guanine is almost equal cytosine.
So I didn't know that it was a hard fact.
The second was it was a solid hard fact with [inaudible] was the most unpleasant person I had ever met.
So I didn't want to use his data.
Now, Francis was, you know, the better scientist than I.
He had actually heard of [inaudible] data from [inaudible].
We met him the previous June, just, well.
Yeah, late June or first week in July when [inaudible] was on his way to the biochemical congress.
We met him in Cambridge, and he didn't like us, and we didn't like him, but afterward Francis thought that conceivably if there was some attraction of adenine to thymine, it could give you a self-replicating molecule.
And the trouble was that, so he talked about it to a chemist friend of his, John Griffiths.
A very, very bright young Cambridge chemist, who, interestingly, was the nephew of the original Griffiths who discovered the transformation [inaudible].
And he said, oh, I can explain it.
We'll put adenine on top of thymine.
So no hydrogen bonds at all.
Griffiths was a chemist [inaudible] doing a charge transfer.
So they essentially got diverted away from hydrogen bonds.
Now you could say in retrospect lousy chemistry.
But Griffiths was a bright person.
And so Francis thought about it for a brief while and then stopped talking about it.
So we really ignored Francis until suddenly, I mean, we ignored [inaudible] until the base pair.
And then very soon afterwards, and we realized immediately because Francis saw immediately that you could put, there was a dyad symmetry of the base pair.
So any base could be at either of the two chains, and so that morning we realized we had a self-replicating molecule if you would separate the two chain.
So up to then, I was doing all the work.
From then on, Francis knew it was, had to be put in real hands.
So he started building a model.
And that's, this is not the, the first was just two base pair, but that's a picture taken after we had written the manuscript.
And after we left Cambridge, the model was taken apart, and various people had pieces of it.
And so we ourselves have no artifacts at all from it.
And a few of them showed up and were auctioned off for the benefit of the science museum in London.
And for the movie, the BBC movie, they built a complete replica of that, and that's what's in the science museum in Kensington.
So we knew it was a very great discovery, but, you know, to say that someone should preserve the model would be very un-British, at least at that time.
Because we knew that until the moment we found the structure, most of us really thought we were unpleasant.
And so quickly the model in Cambridge became known as the WC model.
[ Laughter ] OK. Now, where do you go from there, and where, obviously, is that when we found the double helix, we had done several things.
The first was that until the double helix was found, virtually no one believed that DNA was the gene.
There was a [inaudible] experiment, but people, you know, most biochemists were protein chemists, and he didn't want to believe that what they were working on wasn't important enough to be the gene.
So there was all this talk about was there some minor contamination and was DNA the total answer.
And it wasn't really settled until people saw the double helix, and then all questioning of DNA as the gene.
So really DNA didn't effectively become the gene until the double helix [inaudible].
The second thing, of course, would be when we saw the double helix was that it was clear the genetic information in DNA had to be carried by the sequence of bases.
All DNA molecules have the same structure.
So you had, and then the third question, which wasn't the answer, was, you know, how does DNA control the structure of proteins, which was the essentially conventional wisdom by that time.
[Inaudible] one gene in, one enzyme hypothesis, which we would get one gene, one polypeptide.
So you really had, then had the problem of how this is sequence of bases in DNA determine the sequence of amino acids in a protein.
So that was pretty obvious, but there was a complication when you thought about it, which was that it was very clear that DNA directly itself did not determine this sequence of amino acids and proteins but had to go through an intermediate, which was RNA.
Now this was our hypothesis at the time, but the major reason is DNA was in the nucleus, protein synthesis was in the cytoplasm, and we didn't know what to do with RNA.
So RNA could carry the information.
So that I think was Francis and I talked about that as early as '52.
That one went through an RNA intermediary.
But until you knew the structure of DNA, you didn't really start focusing on RNA.
And so I decided that the obvious thing to do was that you had to solve the structure of RNA.
So I tried to take an RNA picture in Cambridge that spring, but it wasn't good, but once we anticipated that when I got to Cal Tech, which I was moving to in the fall of '63, that I could then try and sort of take, start taking x-ray pictures of RNA with the thought that maybe we could guess the structure of RNA, and then if we had the structure of RNA, then we would see some, something about a structure which would provide the clue into which would order the amino acids in proteins.
So that was the problem we knew was the big problem.
I didn't think it was worth thinking about until we got RNA.
But one person.
And that's it, you know.
How do you determine the sequence.
OK. But one person actually was worrying about the coding problem, and that was the physicist George Gamoff, and Gamoff was, read our second paper in "Nature", called "Genetic Code: Implications of the DNA Structure", which came out in late May of 1953.
Read it. He was told about the paper by the physicist Alvarez.
Alvarez said there was an interesting paper, and Gamoff didn't get to read it until he got to the University of Michigan, where he was giving lectures in the middle of the summer, and then found the paper.
And this was a letter he wrote to us on July 8, 1953.
"Dear Dr. Watson and Craig.
I am a physicist, not a biologist, and my interest in biology can be justified, if anything, only by my recently published book, "Mr. Tomkins Learns the Facts of Life", Cambridge University Press.
But I am very much excited by your article in May 30 "Nature" and think that this brings biology over into the group of exact sciences." I mean, until then, you know, biology was, you know, not for real scientists.
I mean, there were, you know.
You know, biology was only if you were a frustrated artist.
I mean, you know.
So you could draw what you saw under the microscope.
Anyways. So, but Gamoff hit it correct, the exact science.
"I plan to be in England through most of September and hope to have a chance to talk to you about all of that, but I would like to ask a few questions now.
If your point of view is correct, and I am sure it is at least in essentials, each organism will be characterized by a long number written in quadrical [phonetic] question mark." He can't spell, and I can't either.
You see his question mark system, which figures one, two, three, four standing for four different bases or by several section numbers, one for each chromosome.
"It seemed more than logical to assume that different properties, single genes of any particular organism are not located in definite spots of chromosomes, but rather determine by different mathematical characteristics of the entire number." I mean, this was getting crazy.
Something like the coefficients in a Fourier series.
[ Laughter ] "For example, an animal will be a cat if adenine is always followed by cytosine in the DNA chain, and the characteristics of a herring is that guanine always appears in pairs along the chain.
This would open a very exciting possibility of theoretical research based on common [inaudible] and the theory of numbers.
I am not clear, though, how such a point of view would fit with genetic experiments such as crossovers, which lead to gene locations along the entire length of chromosome.
But I have a feeling that this can be done.
What do you think?
Please write to my home address, George Gamoff, [inaudible] Drive, Bethesda, and I will be here through July 18th.
If there are only four basic groups attached to DNA chain, why are viruses so choosy in selecting their hosts?
P.S. If one puts DNA extracted from one animal into the solution containing four bases, would it reproduce, and if not, why?" So, you see, Gamoff was anticipating Arthur [inaudible], and was really an interesting person.
Now, who was George Gamoff?
Well, both Quick and I had heard of Gamoff.
He was famous for his tunnel hypothesis of how apple particles escaped from nucleus.
He was a Russian-born physicist, who had been in Copenhagen in the, around 1930, and was a good friend then of Max Delbrook.
So Delbrook used to talk about Gamoff, and Gamoff was famous for his practical jokes and for his sort of lighthearted approach to science.
Now here's a picture.
You will see Gamoff.
You can see who he's with.
Kline, Bore, Heinzenberg, [inaudible], Gamoff, Landoff, [inaudible].
So he was in the front for a reason.
He was a very great physicist.
And so suddenly his interest was turning to biology, and on the other hand, we had this wacky letter, and we did, I guess as, you know, we should be expected to do.
We didn't reply.
But when Francis got to New York, soon he came into contact with Gamoff, and I came into contact with Gamoff in Christmas in 1954 when I went down to Washington and saw him for lunch at the Watergate Inn.
Charming place on the site of the now famous Watergate Hotel.
And Gamoff gave me a copy, and he was very pleased of his book "Mr. Tomkins Learns the Facts of Life", translated into Japanese.
And you can.
Now there was a reason for this because I opened up the book, and it said wrong side.
Because the Japanese books go the other way around.
So this was Gamoff, and when I learned that Gamoff was, in fact, coming to the West Coast and wanted to visit Cal Tech and see his friend Delbrook, but he equally important he had an idea of the first potential code.
And he was basing that there would be an equal number of amino acids as there were base pairs in the DNA.
And the reason for it was that if you stretch out a polypeptide chain, the distance between amino acids is 3.6 Angstrom.
And this was roughly the distance of base pairs.
So you might think you go along the double helix, and then insert an amino acid every base pair.
The problem with that, however, the consequence of that is that since there are 20 different amino acids and only four base pairs, the, if you have this sort of code, which is an overlapping code, which means that any given amino acid, the two given amino acids share base pairs in common.
Is that you have some amino acid sequences.
>> If you have this sort of code, the nice thing about this idea is you can look for sequences which don't exist, and maybe you can prove it.
So Gamauf had proposed it, and had a paper.
Oh there's a picture of Gamauf with his friend Landau in Copenhagen.
And well, Francis and I when we got the Gamauf's letter actually asked ourselves how many amino acids.
And Francis wrote out a list and said there were 20, that there's ignore hydroxi proli [phonetic], 'cause it's only found in collagen.
And sort of -- if you look in most proteins, what amino acids are present, and that was the list.
Okay, so here was my second letter from Gamauf.
He was heading west.
Dear Watson, or is it a simpler Jim, as you see, I'm going straight to Frisco and by train, but I'm getting in Frisco a brand new white Mercury convertible with [Laughter] which will be named Lita [phonetic], and which we'll drive over some time before Max leaves for Germany to see both of you.
Francis was in Washington a few days, but was too besieged by Department of the Terrestrial [inaudible] people to talk to him much.
Sitting in my room and looking at Yosemite, there's some thinking about the riddle of life.
I arrived at a possible relationship between DNA and RNA, which I cannot check however, for lack of sufficient knowledge in my head, and biology library in the train.
[ Laughter ] Do I remember correctly that DNA is completely absent in plant viruses, which have only RNA?
I guess I do question, is DNA also absent in plants, in general?
[Laughter] I mean non-parasitic plants, not like bacteria and orchids.
[ Laughter ] I do not know, but if this is true, the following argument could be made.
And you can see steak and meat proteins are broken down into amino acids and sent to cells.
Idaho potatoes, vegetables, and [inaudible] are broken down into sugars and sent.
As you can see, he was having fun, amino acids plus DNA leave the certain proteins, sugars, plus RNA lead to other proteins.
He was most probably wrong with me, but I'm having a good time anyway, finishing my fourth -- [ Laughter ] Okay, well when George got down to Pasadena, he gave a copy of his manuscript, which you can see is Gamauf and Mister Tompkins, the imaginary character in all his books.
And this paper had been submitted to the proceedings of the National Academy, and George had to go over to Merle Tube's [phonetic] office, he was asked to go over there.
Merle said that this paper will be regarded as a slap in the face by the biology community.
He didn't say that you shouldn't have this imaginary person as a co-author.
[Laughter] And I didn't really care, because I knew that DNA didn't make, you know, it was Gamauf's folly, because you weren't going to go from DNA to proteins.
And so to think in terms of this type of structure.
So -- but this is a picture -- Gamauf gave a seminar and Dulbrook [phonetic] was there, and Vicekoff [phonetic] was there, and I think actually Fineman [phonetic] came over.
And then two days later George had a free day and didn't know what to do, and I didn't know what to do, so we thought we'd go to a southern California beach, and we picked out on the map Long Beach.
So we went down there, there were no girls, but lots of oil derricks.
[Laughter] And so there were no girls to photograph, so I photographed me.
And so it was a bust.
And this was February, '54.
And his blazer had been -- I had purchased when I -- just before I left England, [inaudible] said I had to look decently, and so I tried to look English.
And you can see Gamauf as the -- at that stage, you know, one felt obliged and totally irresponsible, and I was very pleased 'cause he said I reminded him of Landau.
And then he went back to California and [Laughter] -- I mean he went up to Berkeley, and he wanted to build his own DNA molecule.
And with the help of Melvin Kalvin [phonetic], got some models.
I received the plastic rings for the bases and got two boxes of Fisher [phonetic] models and -- down the line And you can see that he's trying to do it, and playing -- he's playing with the new -- a triangle thing where you could have a code based off one chain, because he was beginning to take RNA seriously.
He just couldn't fly on the face of the facts.
And there was the model he built.
And when we went up to Berkeley and saw it about a month later, there was hardly a chemical bond in the right place.
I mean [Laughter] -- but it didn't matter to him.
Like it didn't matter if you couldn't spell or anything like that, if you were [Laughter] - he was having -- he had great fun playing as a biologist.
And just as a hint about Gamauf that he had a student called Alpha, and they were publishing a paper really which was on the background cosmic radiation or prediction about the big bang.
And he thought that if you have alpha and there's Gamauf, there had to be beta.
So they got [inaudible] beta's consent to put Bega's [phonetic] name, and it was an alpha beta gamma effect.
[ Laughter ] And -- [ Silence ] [ Laughter ] Now this letter is in response to a visit which I paid to Berkeley in conjunction with the [inaudible] theoretical -- he was then a theoretical chemist, Lesley Orville, and we went up and saw Gamauf at Gunther Spence [phonetic] house.
And I had the idea, being strongly influenced by England, but being a member of no club that we should found our own club, and so proposed to Gamauf that we found an RNA tie club.
And the RNA tie club, you would have a tie with a model of RNA on the tie, and that there would be 20 members of the club, one for each amino acid.
[Laughter] And Gamauf loved this idea, because it gave him an opportunity to design a tie [Laughter], as well as choose the members of the club.
So it's generally assumed that Gamauf formed the club, I was -- my idea, because I mean I was living in utter hell.
I mean in Pasadena there was smog, and only one woman student in the whole Cal-Tech.
And so it was, you know, you needed some amusement.
Anyways -- and so what Gamauf is saying is that he's going to go to Woods Hole for the summer, or for a few weeks, and stay with the Hungarian biochemist Albertson [inaudible], and I was planning to go to Woods Hole for the summer to teach him the physiology course.
So we planned to get together, and you can see that.
And so Francis Crick [phonetic] was going to come up from Brooklyn, and so the summer turned out to be really quite intellectually very exciting, with lots of discussions on codes.
Now before Gamauf arrived, we had the idea of essentially playing a practical joke on Gamauf, which was to send out a letter under George's name inviting many people to a party to honor his arrival.
And so if I could read this, to celebrate my arrival in Woods Hole, you are invited to meet Mister Tompkins and the facts of life at a whiskey twisty RNA party in the [inaudible] on Muscle Beech -- note beach is spelled like the tree -- Thursday [Laughter] August 12th, about 8:30 p.m. Yours, George Gamauf, RSVP Professor [inaudible].
This invitation caused enormous happiness, because most people in Woods Hole, of whom hundreds got the invitation, had never been invited to the Zenjorgie [phonetic] house.
So they all thought that their invitation was because the Zenjorgies had told Gamauf that they should be invited.
So it caused a lot of happiness until Gamauf arrived and said he hadn't sent out the invitation.
And -- but Gamauf and I got together, and I purchased beer, and he purchased a large amount of whiskey, and the party was held.
And it was quite a party.
[Laughter] Francis Quick invited the red-haired cashier from the local theater.
[ Laughter ] So it was -- but the more serious thing, as you can see here, there's George building a model of me, and [Laughter] with my hat and my sneakers, and this double helix.
And there I am looking at the [Laughter].
So -- and for about three weeks, Francis and Gamauf and Sydney Brenner talked seriously about codes, and avidly looked at any existing poly peptide sequence to see if we could say anything about whether these would be compatible with codes.
And I just really didn't do anything.
And we got into trouble with Mrs. Zenjorgie because of my shoes, because one day I got a letter from her which was a bag full of sand, which she said return to its rightful owner, I had dragged it into her house [Laughter].
Now when the summer was over, you can see that George's -- had several concerns.
One is he was still trying to think about codes, but he was also thinking about getting a tie.
And I had gone to a haberdasher on Colorado Avenue in Pasadena, using a design from George, and had the first RNA ties made.
And so -- and there you can see the tie.
[ Laughter ] And it's correct -- I mean in the sense RNA was chosen to be single-stranded, and the reason we made it single-stranded is the x-ray pictures were so lousy.
I mean I -- with Alex Rich we have worked for about 6 months hoping that we would get something that you could ever interpret, but we got nothing.
So I concluded that even though there were traces of a double helix in the x-ray photograph, you should make it seem stranded.
And here is more correspondence.
You can see that Gamauf is looking at sequences, and ACTH was out, and so it's contradictory to his diamond code.
And this is a typical Gamauf thing.
And you could see, it's -- he's thinking.
And okay, and so the main experimental thing was the newly rising -- like there's an [inaudible] sequence.
Glucodon [phonetic] had come out, and there was ACTH.
But then we got this letter soon after from George, in which -- this was a letter that you would pass around, send on to the next member.
He had chosen the members of the tie club, and then we had to choose our amino acids.
And George wanted to be alanine, and the reason was that he could have a tie pin with three letters saying Al [phonetic].
And that was fun until he tried to cash a check.
And ALL did not agree with the name on the check.
And you can see that the members of the club included Teller [phonetic], Leslie [phonetic], Orgel [phonetic], Delbert [phonetic], Fineman [phonetic], Gamauf, Martinez, Iches [phonetic], Kelvin [phonetic], and entomologist in Gordon, myself, Alex Rich, Francis, Charga [phonetic] who absolutely bizarre reasons consented to be a member, even though he hated us.
[Laughter] It hadn't been finished, but you can see there's his tie -- the tie pin project.
[ Laughter ] And my -- as the fall was wearing on, more and more sequences were accumulating, and Sydney Brenner who had returned to South Africa, had essentially put together an argument.
In fact these overlapping codes were just wrong.
They're much more likely to be a group of let's say three bases that determine one amino acid, another three bases another amino acid, and so on.
But -- so he's concerned with the tie pins again.
And I had a very bad idea, and so he was reacting to -- and I was wondering why, you know, adenine and thiamine were -- seemed to go together some of the RNA, but not enough to really say anything.
And then finally, the members were chosen, and so Gamauf printed our stationery, and the motto was RNA tie club, do or die, or don't try.
And he is listed as not the president, but as the synthesizer of the -- I am listed as the optimist, because I believe that eventually if we got a structure we would see cavities into which the side chains in which the amino acids would fit.
Francis, however, said this will never work, because how will you ever distinguish between lucine and iso lucine or glycine and alanine, which differ only by a metho group, or only give you a kilocalorie of energy, and has a factor of 10, and you're not going to be able to make proteins this way.
So in fact, Francis had written a paper and sent it to all members of the tie club, it was called a note to the RNA tie club, of which he proposed his adapter hypothesis that amino acids are first attached to trinucleotides, and then the trinucleotides bind to a group of three nucleotides long, an RNA chain, and you go on this way.
Francis' idea never explained how you could get the amino acids stuck to the trinucleotide, but we later revised that the whole business of transfer RNA was basically like this, you attach the amino acids to something which could act with the hydrogen bond to RNA.
So you can see there was the model we were worrying about electing four honorary members, but no one wanted to pay money for their ties.
I mean the honorary adanine, thymine, guanine, and cytosine.
And you can see liponines and [inaudible] were obvious, but that never got -- happened.
[ Silence ] Now he was the -- by this is the summer of '55, this was the summer after we were together in Woods Hole.
And George is still concerned with ties.
And I had gone back to England, and I'd left Cal-Tech.
Francis was there in England, and the -- George managed to consume some 100 bottles of pure whiskey during the course of the summer.
Then in the middle of November, when I was away in Germany, a letter arrived addressed to me, which was opened up because it had come from Gamauf, which said a number of members of the tie club are bombarding me [inaudibles].
Will you please let me know by return mail the address of your haberdashery in Los Angeles where the ties are made.
What do you -- and then he goes what do you think about this Rundell paper?
Shouldn't we elect him as an honorary member of the tie club, or should we disband the club altogether?
I think I will go back to cosmology.
I think the most interesting thing about this RNA model is it explains that all proteins have three N amino acids, that is almost exactly Barbara Lowe's [phonetic] hypothesis of triple reading and [inaudible].
Oh gosh. I wasn't around, but this made Francis and Alex Rich very nervous, that someone in -- the claim was this had been published in the Journal of the American Chemical Society, which would take a month to reach England.
So Alex called Washington, and no one would read the paper.
So eventually this was Gamauf's last practical joke as a member of the tie club.
And now this is a little later.
Essentially Francis persuaded Sydney Brenner to leave South Africa and come to Cambridge, where they began working on the genetics of T4, with the hope of solving the code by doing mutagenesis.
And at the same time I went to Harvard and started working on ribosomes, and the mechanism of proving synthesis with Alfred Tisier [phonetic].
This is a photograph of us in Moscow in 1961.
This was the very historic biochemical conference, because it was at this meeting that an obscure American biochemist named Marshall Nuremburg reported his results in self [inaudible] synthesis, where adding poly U to the self-resistant produced polypeptides containing only penoalm [phonetic].
So this was really the code.
This was the first code letter solved if you went on assumption 3.
So you can see we're very happy toasting Nuremberg, but I think we were just drunk [Laughter] because we -- this was in our Russian mathemetician's house, and we were drunk on vodka.
So I was wearing an RNA tie at the time.
And we did see Joe a little later, 'cause I persuaded him to come to Harvard to give a lecture on cosmology, and so you can see he's -- this was announced with the department of biology and natural science, probably announced an evening discourse on origin of the universe by Professor George Gamauf.
You'll see this was [Laughter] -- so it contained the obligatory misspelling.
And now you may ask what a Nobel Prize like this is, Francis in 1962.
He's in deep conversation with the Swedish Princess Desiree.
I was -- [ Laughter ] My dinner partner was her mother.
[ Laughter ] This is the only photograph of five members of the tie club, it was in 1963 at the [Inaudible] Harbor Symposium, when the genetic code was about half established.
And you can see Francis, Alex Rich, Joe with a glass of whiskey, myself, and Melvin Kelvin.
By this stage, you know, we knew of messenger RNA, and in 1966 the code was solved.
And I'd say the whole -- it took only 13 years.
And the answer really came from a biochemist that was working out how proteins were made, not through and of Gamauf's type of approaches, but it was certainly fun.
And it was at a time when the experiments went very slow.
I don't think those of you who now live in the year of recombinant DNA knew what science was like when you could still take summer vacations, and -- without worrying that something would happen.
[Laughter] Now this is -- Francis for a year turned his interest to immunology, came to the [inaudible] Harbor Symposium of 1967, where [inaudible] came, and Burnet [phonetic] was there.
And the major problem was how with a limited amount of DNA could you make so many antibodies, so posed a theoretical question.
This was at the banquet.
This girl, you just see her back, but from the front she's even more attractive.
[Laughter] And now she told Francis, and he got very excited when she told him, this was over drinks, that she had a -- twin kittens called Lotsup and Quick [phonetic].
So Francis naturally asked her what are their sexes, and she said neuter.
[ Laughter ] [ Applause ] So this is the end of the story.
[ Applause ] >> Doctor Watson will be happy to take some questions.
[ Silence ] >> Doctor Watson, your [inaudible] wonderful story [inaudible] the relation of science and [inaudible].
Shortly before he won the Nobel Prize, [inaudible] and argued that beauty was truth, and a very good guide to truth.
In your book on the double helix, these are a number of passages that mean something like the way to fold it up was so brilliant, it had to be proved.
I wonder if you'd share with us your views on the relation of science and [inaudible].
[Laughter] >> I think, you know, why we said it was so pretty was that we really -- when we were -- before we had the answer, we really thought we'd have a DNA structure we wouldn't know how to interpret, and so we'd get no message.
'Cause [inaudible] when you looked at [inaudible] alpha helix, it was nice, but it didn't tell you anything about, you know, how a treptides [phonetic] function in proteins.
So it was just a marvelous simplicity when we saw this.
You know, maybe it was even -- instead of saying it was so pretty, it was so simple, 'cause we really knew DNA was so simple, you could really teach it at the, you know, grammar school level someday, and it's actually reached there now, you know?
And so, you know, if you say is there anything pretty about the [inaudible] cycle, no.
[ Laughter ] [ Silence ] >> Yes.
[ Inaudible Question ] >> No, no, no, they had essentially vanished with that letter, you know, saying the structure had been solved.
We, you know, we weren't going to get anywhere when we finally saw what RNA looked like.
Of course when we saw TRNA it did tell you something, but of course the truth didn't come that way.
It really came from the variety first from Nuremberg's experiments, and then a variety of ways, particularly the synthesis of the repeating trinucleotide sequences by Korana [phonetic].
And we fed them in, and out came the answer.
You know, it's -- you know, we reformed the company, we didn't know what to do.
So it just sounded like fun.
You know, it was way, you know, if you want to really, you know, I thought a lot about, you know, why did we get the answer.
And well, partly it was we were in Cambridge.
And being in Cambridge was such a, you know, it's a beautiful place, the science quality was very high, x-ray crystallography had started in England.
The Cambridge lab was -- the [inaudible] was the best place in the world for crystallography at that time, so people wanted to go to it.
So Jerry Donahue [phonetic] went there.
You know, if Donahue hadn't gone there, you know, we might still be believing in -- you know, thiamine was in the [inaudible] form.
So it was in that sense, you know, Quick went to Cambridge, because, you know, Cambridge had bright people.
I went there because, you know, I didn't know how beautiful it was.
You know, I went there again because it was supposedly a great center of learning.
So the sort of moral was, you know, Cambridge is a greater center of learning than London.
And because there really wasn't, you know, a stream of people in Wilkins or Franklin's lab.
So it was very important, you know, when you want to solve a problem go to a place where there are bright people.
'Cause you don't know what a, you know, if you know how to solve something, you'll do it.
So you need to, you know, seize upon the unexpected.
The -- we could have, you know, the real key thing was putting the right [inaudible] forms, and then accepting Goem's [phonetic] results that -- really the bases were hydrogen bond.
I mean the really mysterious thing was why calling didn't, you know, put the bases inside.
I mean the last chapter in the nature of chemical bond was on hydrogen bonds.
And, you know, he never thought of -- tried to hydrogen bond the bases.
And the [inaudible] was in the literature, and he had no reason to hate chart graphs.
So I mean he was, you know, he could have done it.
And I mean the [inaudible] was, you know, a very lonely man.
He could only speak to his wife.
And he was so good, that no other chemist could speak to him.
So it was like the Pope.
[Laughter] And he was -- see he had that sort of -- and so Linus, you know, there was no one at Cal-Tech who would say probably you know, they were afraid to tell, you know, ask Linus, you know, how could DNA not be an acid.
So it's a very bizarre story, which I've never had the courage to ask Linus, you know, why he did it.
And, you know, I'm still not, you know, we had him say forever, and, you know, it was a sort of insult, why did you, you know, do it.
So that's -- the -- Rosalyn Franklin probably didn't get the answer because everyone sort of thought she was a crystallographer, she really wasn't.
She had only worked on carbon, but she doesn't have a very interesting structure.
So she had never solved a molecule, and had been hired really by Randal [phonetic], who should have hired a real crystallographer, because a very key thing was the space group, which had a diad [phonetic], which if you thought about it meant something went up and something went down.
So if you really asked yourself, and said well is the structure two chains or three chains, there would have been a real clue, you know, you have something going this way.
So when Francis realized what the space group was from a report, this was really after we had the structure.
He knew, you know, this was a complete confirmation that what we had done was right.
So the -- so Rosalyn was really quite an amateur.
We knew we were, and she should have got more help with the English, or rather strange they don't like to go and talk to each other.
And, you know, Francis was thought very strange, 'cause he liked to talk so much.
I mean [inaudible] was to talk when you're not talking about anything important.
But -- so, you know, gossip and all that, so that's perfectly respectable.
But sort of being too interested in someone else's work, or asking advices sort of shows you, you know, don't -- haven't been trained well.
[Laughter] So, yeah.
[ Inaudible Question ] >> Oh well, yeah I'll just copy Francis, the [inaudible], you know, consciousness and all that business.
Yeah, that's a big unsolved problem.
And, you know -- and you -- yeah, I would think, you know, if I were young I'd think that's the only problem, in the way that we thought DNA was the only problem at the time, and sort of the -- and Francis, I mean that was really the real key, was the only problem.
So I had really nothing else to think about.
And so one kept going back to it, and I'd say we didn't deserve to solve it, 'cause we really didn't know any chemistry, didn't want to learn any chemistry.
[Laughter] And, you know, 'cause I had been, you know, Laureate had this thing about chemists.
They were awful people, they made money, and, you know.
[Laughter] So, you know, there were really a lot of phony and terrible arguments coming from intelligent people.
And so, you know, I went along with it.
But finally, you know, I, you know, I actually, you know, didn't know much chemistry, but I didn't dislike it that much I guess.
So I got an A in freshman chemistry, so, you know.
[Laughter] [ Applause ] [ Silence ]
About the speaker
Cold Spring Harbor Laboratory
Born in Chicago in 1928, James Watson's introduction to biology was through watching birds with his father. At the age of fifteen, he received a scholarship to the University of Chicago, where he majored in zoology and received his B.S. in 1947.
Dr. Watson then enrolled at Indiana University, because his interests had turned to genetics and Indiana at that time had three of the leaders in the field: Hermann Muller, Tracy Sonneborn, and Salvador Luria. His dissertation was on the effects of x-rays on replication of bacteriophage, a project that echoed the watershed research taking place at Cold Spring Harbor. He did his dissertation under Salvador Luria, and received his Ph.D. in 1950.
During a postdoctoral fellowship to continue his phage research in Copenhagen, Watson began to be interested in the structure of DNA. In 1951 he went to the Cavendish Laboratory at Cambridge University to learn the techniques of studying the three-dimensional structure of proteins. There he met British physicist Francis Crick, whose interests had gravitated toward genetics. With x-ray crystallography data from colleagues Rosalind Franklin and Maurice Wilkins, Watson and Crick put together a model of the now-familiar DNA molecule, with its spiral staircase double helix shape and it’s A,C,G,T base pairs. This work was published in 1953, and the three men were awarded the Nobel Prize in Physiology or Medicine in 1962 (Franklin died in 1958).
Dr. Watson then went to the California Institute of Technology, where he worked as a research fellow and then, following another year at the Cavendish, he moved to Harvard University as an assistant professor in 1956; he was appointed associate professor in 1958 and full professor in 1961. He became director of Cold Spring Harbor Laboratory in 1968, though he retained his appointment at Harvard until 1976. From 1988 to 1992 he directed the National Center for Human Genome Research at the National Institutes of Health in addition to Cold Spring Harbor Laboratory.
In addition to the Nobel, Dr. Watson has been honored with the Lasker Award of the American Public Health Association (1960), the John J. Carty Gold Medal of the National Academy of Sciences (1971), and the Presidential Medal of Freedom (1977). He is a member of the Russian National Academy of Sciences, the American Philosophical Society, the Danish Academy of Arts and Sciences, and was a senior fellow in the Society of Fellows of Harvard University. He holds several honorary doctorates, including degrees from Harvard, Notre Dame, Rockefeller University, The Albert Einstein College of Medicine, Indiana University, and The University of Chicago.