 The 20th century opened with the rediscovery of Mendel and ended with the sequencing of the human genome. By the middle of that century, the structure of DNA was deduced by James Watson and Francis Crick using the X-ray crystallography images of Rosalind Franklin. I just turned over a page in my life and said this is the new book. None of these things could be understood until we knew the structure of DNA. The characteristic of this discovery is it was so desperately needed. It was desperately needed. Anybody who wanted to apply science to understanding life was just marking time, waiting for that to happen. There once were immediately how all many of the questions that had arisen in genetics could be answered and that the model actually explained how one could get a chemical basis, if you like, for inheritance. So that from somebody like Jim and Francis' standpoint, they could say the critical question in biology was, how does DNA work? And we'll learn about that by looking at its structure. The questions had a linear flow to them and with Francis there to tell us what they really, you know, to help formulate them. It was like a logic game. I was meeting together with Jim and Francis and Sidney Brenner who was visiting and Jim points out the window and says, see that fellow down there? That's Frank Stahl and he thinks he's pretty hot stuff. Let's give him the Hershey Chase Blender experiment to do all by himself in a single afternoon and see if he can do that. So I thought, oh, there's a poor guy down there. I better go talk to him. So I went downstairs and I introduced myself and here's this fellow who is actually selling gin and tonics. He had a big bottle of gin and tonic and ice and limes and people would come by and he'd sell them a gin and tonic and make a few for himself that way. And he was trying to solve a problem that involved radiation genetics of bacteriophage. And we got to be friends and started talking and turned out he was going to Caltech. At that time this would be in the 50s, the early 60s. Caltech was a major center for the pneumo-molecular biology. Both of them were being done there and the fact that everybody who was active in the field would come through Caltech at one time, another in talk. The famous Mezzles and Stahl experiment was being done at Caltech where they demonstrated that the two strands actually do come apart on replication. I had an idea which wasn't the right idea but with Frank Stahl we got to the right idea eventually for how to test this semi-conservative replication. And so the idea of the experiment was to start by growing bacteria in heavy medium. We used heavy nitrogen which you could buy in those days. They still buy. And then that would give only one band in the place where heavy DNA should go. And then quickly separate those bacterial cells from their medium by centrifuging them and resuspend them in light medium. So now any new DNA would be made out of light nitrogen and that would form a band higher up in the tube near the top. Now if DNA replicates semi-conservatively that heavy DNA both chains are heavy. If it comes apart each chain separately and makes a new chain then you'd have DNA that has one heavy chain and one light one and that would be half heavy. It would form a band in between the fully heavy and the fully light. And when everything is replicated once and only once the band would be exactly in between and it would be the only thing you'd see. And that's what happened. Before Messelsen-Stahl's experiment there were several competing theories about how DNA replicated itself. Messelsen-Stahl demonstrated decisively that only one of these was right and this was the one that had been advanced by Watson and Crick in their original paper in 1953. The news of Messelsen-Stahl travelled very rapidly through the world of molecular biology on both sides of the Atlantic. It had been known for some time that proteins were not made in the nucleus but they were made in the cytoplasm and RNA was involved in this. And so people thought that RNA would be involved in the manufacture of proteins once this had come about. And so the puzzle was that once we had got to the idea that proteins were made in ribosomes, sorry, then the question is where was the information? How did you get the information out of DNA and get it into ribosomes? And out of this came the messenger RNA hypothesis with Renje Cobb and Brenner and Messelsen were involved in putting that forward. And then it was called the messenger because it took the message from the DNA, you see, the message from the DNA into the cytoplasm where it was transformed. In England, Sidney Brenner and in France, François Jacob were devising a theory about how the information in DNA was carried out to the cell. This involved a molecule called RNA and in 1960 they went to Caltech to use the Messelsen-Stahl methods to see if they were right. We arrived there to do this experiment. We had about three weeks to do it here and it didn't work for quite a long time. We were centrifuging ribosomes in very strong salt and didn't occur to us. We had to up the magnesium because the salt was competing with it and everything came apart. It was a very delicate experiment, very difficult to do. And so once that realization came to me on a beach, we ran back to the lab and because I got up and started to jump up and down and say, it's the magnesium, it's the magnesium, let's go. So we did the experiment again. It was the last time and we actually found that it worked. The key element in the central dogma was the adapter, the tRNA, another idea of Cricks. Gamoff had created the coding problem, formulated the coding problem as one in which he looked at the DNA and saw various cavities. And so he very naively assumed some properties about these cavities, which were wrong. Francis Crick solved that when he suggested the adapter molecules, RNA, and the messenger concept which came from Jacob and Brenner and others. The adapter was nucleic acid and that you had an enzyme that coupled the amino acid to the adapter. And then the adapter would go and find its place on the nucleic acid. And of course, at the time he put this forward, biochemists stood up and said, this is impossible. On the grounds that had there been 20 enzymes, they would have already discovered them, so they aren't 20. And that was the last piece of the puzzle, because now you had the transfer from DNA, the messenger RNA, the adapters that made it into protein, and then proteins could go out and do their thing. But that still left open the question of the code. That is, how is it that the sequence of base pairs in the DNA actually instructs the ribosomes in the cell what kind of proteins to produce? Watson and Crick wrote two papers. The first paper was the structure itself and the second paper was about the implications, that last sentence of the first paper was. And in that, it's already clear that we're talking about a code, that we're talking about ways of decoding. Meanwhile, the coding problem sort of bounced along. Brenner and Crick did their very ingenious experiment, suggesting that it was probably a triplet code. We needed then to see that we could explain everything by mapping one sequence written in a four-letter language onto another sequence written in a 20-letter language. And that formulated the problem of the genetic code. I was aware of the ideas about the code, but they didn't have much meaning to me. I mean, Crick and Brenner, I remember in 1957, I think, came to the NIH and gave a talk. I don't know, even though if they mentioned anything about the code, I mean, I thought that messenger RNA probably existed and directed amino acid incorporation into protein. Nirenberg did the dramatic experiment with the in vitro protein synthesizing system, showing that polyuredilic acid coded for polyphenylalanine. We went ahead and we fractionated ribosomal RNA, and we found, as we expected, that only a small portion of the ribosomal RNA was active as a template for protein synthesis. So then I rounded up as many different kinds of RNAs as I could find, and I got some viral RNA, tobacco mosaic virus RNA, some yeast ribosomal RNA, and polyu. One of the polymers we made was a polymer with just urodilic acid residues. And one day Marshall Nirenberg appeared, he worked down the hall in another lab, and he appeared at the door and wanted some polyu. And that was the first opportunity to define one of the codons in DNA. Polyu stimulates the incorporation of phenylalanine into protein. That was staggering, because it was clear that a sequence of use in polyu corresponded to the RNA codon for phenylalanine. And of course the famous polyu, polyuridilic acid worked. It made a uniform product of polyphenylalanine, which you could test by incorporation. And so it became very clear that you could get quite far. We call that ultimately the genetic code, and it took about ten years after the DNA structure for the genetic code itself to be worked out. Tom Kasky and Dick Marshall then asked the question, is the code universal? And they compared the code of E. coli with transfer RNA from the code of Xenopus and the hamster mammal, and they found that it was the same code. And then when it happened you had this enormous rapid development, getting the code, understanding mutation, understanding protein synthesis. It all had to happen like just a trunk opening up and spilling out.