[MUSIC] Today we're going to talk about DNA and the double helix. Before the double helix people knew about genes, but genes were abstract notions. They were abstract objects. And people also knew about proteins. And that proteins were enzymes, most proteins were enzymes. Most people had some ideas in the late forties that somehow the sequence of amino acids would determine the three-dimensional structure of the protein and hence its function. That was pretty clear. Now, this did not just explain how genes work through proteins, but did not explain how genes are replicated. The replication was the problem. What can replicate? So the common notion at that time was that genes were proteins because only proteins were sufficiently sophisticated to be sufficiently complicated to be genes. And so, the question was how do you replicate a protein? Now it's pretty clear that if a protein has a structure in space, that means that there are inside pieces and outside pieces, for inside resides or amino acids, and outside amino acids. So the current notion was the notion taking from sculpture, the notion of a mold. So you make a mold around the structure and then you somehow put inside amino acids so they would fit the mold. That's fine for the surface. But how on earth can you copy the inside was the greatest question. And since he had some deep understanding on protein structure, he knew that would be a really difficult task. So, there was circumstantial evidence that DNA could be the genetic material, but in the 50s, the evidence grew and became much stronger. And that's when he and Jim Watson decided to work on the structure of DNA. Now to do that, they were basically working in a structural, what we call, would call today as structural lab, biology laboratory. They were working with, in the lab of the Cavendish lab at Cambridge. Now the Cavendish lab is. It was and is a very famous lab because it has produced an enormous amount of information in physics and chemistry. The first professor was Maxwell of the Maxwell equations thermodynamics. Thompson discovered the electron at the Cavendish. Rutherford smashed the atom, that's how they call it, smash the atom. And Chadwick discovered the neutron, it's a pretty famous lab. At the time when Craig joined, the lab was head by an a gentleman named Sir William Bragg. Sir William Bragg was a crystallographer. He is, I believe still, the youngest man ever to get a Nobel prize. He got his Nobel prize at the early age of 25. Before most people get their PhD. And he got with his father proposing the rules of crystallography analysis of crystals, any crystals including purine crystals. So he was a pretty famous man and he had really one interest in life, which was his garden. So later on, Bragg would be elected chairman of the royal society and he would have to go and live in London for a year. So he would have to go and abandon his garden, which was a pretty dreadful thing for him. So, Bragg wrote a paper and looked for the small ads for people looking for a gardener. And he found a garden, a lady who was looking for a gardener not too far away from the building. And so he went there, introduced him as Willy, which was the way his friends would call him and got the job. So every afternoon, Sir William Bragg, the rights of society, would become a gardener and work in the garden of that lady whose name is unrecorded, I believe. And that lasted for a long time and Bragg was extremely happy. But one day, the lady had a party, and at the party came a bunch of other ladies to have tea and cookies and whatnot. And one of the ladies was the wife of a fellow of the Royal Society. And so she asks her hostess, my dear, what the hell is, she probably didn't say what the hell, what the hell is Sir William Bragg doing in your garden? And that was the end of Bragg's ten year as a gardener. Nobody would give him a job afterwards as a gardener. So he was a very stiff and somewhat difficult man. And there were a lot of people around him who were in way or another in working crystal. But one of the main, I don't even know what to call it the discovery, but one of the main events was actually made by Bernal who invented the use of x-ray analysis on wet crystals. Not the crystals like the salt that you have that you put in your salad, but crystal that still have more less liquid composition and where the atoms are not ordered as nicely as in a dry crystal. But you can still get a little bit image with a wet crystal. And so he was working with that and then came a third person who is usually not associated with the DNA structure. But with other structures, and that's Linus Pauling. Linus Pauling was a chemist, theoretical chemist. He worked at Caltech, he was a friend and colleague of Max Delbruck, Beadle, and he basically discover a major element of protein structure called the alpha helix. And that was a big pain and sorrow for the Cavendish people because they were beaten by Pauling. And they were essentially beaten by Pauling because Pauling, who was a very good theoretical chemist, had no preconceived idea about structure. And in particular, he didn't think that it was necessary that a helix has an even number of amino acid. And the alpha helix, as it stands today, has 3.5 amino acid per turn, not an integral unit. Whereas the people at the Cavendish were convinced that and there were other reason which we don't go into, but basically the missed alpha-helix. And so Pauling had this extreme aura and he decided also to work on DNA. And actually he proposed a structure for DNA, and that structure is shown on the first slide. And this is Pauling and Cory's Triple Helix Model. Now if you look at this model, first of all, it's beautiful. The Helix is beautiful, even though it's not the true DNA helix. But it is beautiful, which is an important aspect in getting the model accepted. What is unimpossible to understand, unbelievable today, is how did Pauling made a such a stupid elementary mistake as drawing the helix with the acid form of DNA. Of course you say deoxyribonucleic acid, so we call it an acid. But in real life it's never an acid. In biology, it's never an acid. It's always ionized. And so you have phosphate that carry negative charges. If you have phosphate that carry negative charges, you cannot put these three negative charges in the center of the helix because the negative charges will repulse each other. So it's completely crazy. Now, why on earth did Pauling not think about it? There's no explanation. And so, basically, this is going to be destroyed by Watson and Crick. This model. But Pauling was an important person, and he pushed a lot of people into thinking about structures. And so, basically, he's a godfather of double helix. Even though, he himself had tried this triple helix which is a monster. Okay, so At the time Watson joined the Cavendish, and Watson was the first PhD student of Lorie at Indiana, and Watson was 23. He was a young abrasive considered extremely bright, but too bright to be effective. So Watson did his PhD on phage work with Loria, and then decided to do a post doc on DNA replication. And to do that, he decided to draw on the lab of a very famous micro biologist, in Denmark. And so, he got a fellowship and went there. But, Mallow at the time, had left his wife, had met a young student who was absolutely adorable, so people say, and he'd left also the lab. So poor Watson was sort of abandoned in this lab which was not extremely functional at that time. So Watson got pissed and moved to Cambridge. And there he and Crick, and it's not yet clear who started, but he and Crick started to think about DNA, as an interesting structure, and possibly as the genetic material. So, they worked together for about two years, from 51 to 53. Before they published their papers. But most of the time they were actually working on something else because none of them was officially working on DNA. Crick was working on collagen structure and Watson, I don't remember, was working on some other structure, but not DNA. They were doing that on their spare time sort of. At the time there were very few people interested in DNA. Of course neurologists and biochemist provide that very good DNA be given to Avery. There was a guy who was working on on physical chemical properties. Hamersin in Sweden. And there was a lab in London. The lab in London was led by a very formal head professor kind of professor. Randall. Randall has a big lab, and he had slaves in his big lab, and he sort of would tell them what to do. That's a little bit of an exaggeration, of course but it's sort of the way it was. So Randall had a younger colleague named Wilkins who was a good friend of Crick, and Wilkins was convinced that DNA was a genetic material. And he was convinced that he would solve the structure by X-ray. And he'd make progress, but the progress was not extremely fast, and so Randi got a new post doc to come and work in the lab. And the new post doc was a lady named Rosalyn Franklin. And you probably have heard about Rosalyn Franklin. She was a very talented crystallographer. And extremely pushing and aggressive scientist. And of course she basically refuse to work under Wilkins who was a couple of years older and slightly senior. An she wanted to work on her own. And so she was in competition with Wilkins on the same project in the same lab. This happens unfortunately too often but it was a very unhealthy situation. And basically we don't know that Randall was aware of the situation or not. He probably was. And we don't know whether he enjoyed seeing the people compete against each other in his lab, that we don't know he didn't write about it. So they were struggling and fighting, and they wanted to do crystal, and solve crystal. What Palling had inspired in Greg and Watson was the use of models. If you use models you may learn more than if you try to solve crystals. And particularly if you use models, you can play much more quickly and may be gather the solution.