Recorded: 20 Aug 2006
Now at the Caltech conference Francis Crick had told me that they have a very powerful rotating anode, a novel bit of technology at the MRC in Cambridge. And Francis was quite interested in the RNA problem. And said, Look if you get good fibers, good patterns and you want to come over and improve them let me know. So I wrote to him, and he invited me to come over to continue doing diffraction work.
MP: Okay, now I want to know what did you write to him? That you want to come…do
you remember this moment? Like..Why did you want to go there? Because x-ray machines were not such as strong as here? What was the reason?
AR: The main difference is the x-ray machine that I was using which is a sealed tube gave off a very weak x-ray beam which meant you had to have a large fiber, expose it for a very long period and it was very difficult to get good data. But the rotating anode was a very bright and powerful beam. You could take a very small fiber, put it in that beam and get a diffraction pattern very quickly. So you could actually, it would accelerate enormously the rate at which you could get data. So, I remember we were beginning to get patterns from polyriboadenylic acid, poly-A . And, ah…So we went over. Uh, I ah…so , I accepted his invitation. And then went to the, to Cambridge arriving there in June of … late June of ’55. And he very kindly offered to put me up at his house in Portugal Place. And Odile was very gracious as a... warmly welcomed me to the household. The uh, …that work continued on. And actually at the time Jim who had already moved to Harvard had an agreement that he could take off a year in a fellowship before starting. And indeed he came to Cambridge as well. And Leslie Orgel who had been at Caltech and was quite interested in RNA, likewise was in Cambridge. So we continued working together. Now the original intention was for a very short visit. But… I mean of maybe 3 or 4 weeks. But one Saturday, Odile was late in making breakfast. Francis was still in bed. On Saturday Nature arrives in the mail. So she had her young daughter Jacqueline take this up to Daddy. And she knew that as soon as he got it he would read it, and that would give her time to prepare the breakfast. So finally after some time Francis came down, the breakfast was ready. I sat down, as we were eating … as I was having tea and toast, I asked him “Anything interesting in nature? “ He said “No, not really. Oh yes there was one article by the Courtauld’s group, Bamford.” Now Courtauld’s group was an industrial laboratory dealing with polymers and they made polymers of amino acids. Bamford was a very, was the head of the lab and a very distinguished scientist, did a lot of infra red work. They made a polymer of glycine which was different from the normal polymer of glycine. The normal polymer of glycine is completely stretched out. It’s almost a linear chain with every other residue oriented like this, so in going from one residue to the next you move ahead and turn 180˚ and then you just continue. But this new pattern, the new form had a different infra red spectrum. He also… in the paper put in a powder x-ray diagram. Now the powder diagram has no orientation but it tells you some rings are stronger than others. Ah, so as we were eating breakfast, we said “You know it shouldn’t be too difficult, to solve, to figure out what the structure is. Let’s try and do it in the lab.” And what that meant is we would see if we could see if we take molecular models of glycine, make a chain of them and see if we could find a way to fold them up to predict the information that was in the x-ray pattern. We went to the lab, and we decided the extended form of polyglycine has every other residue, it’s really a helix with two residues per turn and 180˚ rotation from one residue to the next. So we said, well let’s try a helix with three residues per turn, that is 120˚ and then another 120˚ and so on, making a helix. When we did that we discovered, gee it’s possible to bring these chains together and they make a very tidy system of hydrogen bonding. So every, every chain made hydrogen bonds to 3 neighbors as it went around this helix. And in looking at that lattice we could predict what the reflections would be in the powder diagram and we could predict their intensities, cause certain planes had lots of atoms, and those would have intense, ah…ah intense reflection. By noontime we had the problem solved. And Francis was feeling very good about that.
MP: I’m sorry. Alex could you please I destroyed my machine. Can you say again, by noontime…
AR: This was in August 1955. And after having built the model, convincing ourselves that it was correct, Francis had a great idea: “Why don’t we write it up, have Bragg send it to Nature and see if we could bring it out the next Saturday?” Ha, ha! Then he thought about it and said, Well… if we do that the people at Courtauld’s, Bamford, they’ll feel very badly about it. So maybe it’s better to invite them and then do it. So I said, Okay. And they came and they looked at the structure, they agreed it was the answer, and so on. And then we sent it in on the structure of polyglycine II, by Francis and myself. And it was well, we felt pleased that we could do it in a short time.
I remember, one of the nice things about research in Britain is teatime. In the afternoon, mid-afternoon, you stop doing your work, you go and have tea. And I remember that day Francis and I went to have tea outside the Cavendish. And as we were sitting there, a nice sunny day, I said, Francis I said, I’ve been looking at that lattice. And I noticed that the NH bond of glycine was in the same plane as the C-H bond, which if you have alanine or any other residue you’d have more atoms there. And in particular what that meant is you could make a ring containing these, a pyrrolidine ring, and that would be the amino acid proline. Furthermore, I knew from work that had gone on…Linus had been very interested in collagen, the fibrous, ah… the long, thin molecule of fibrous tissue. It had a very characteristic x-ray pattern but nobody had been able to solve it. But I knew that it had sequences proline followed by hydroxyproline, and about a third of it was glycine. And so it had sequences glycine, proline, hydroxyproline, and then repeated. And I realized, I said, you know if you take three chains out of the lattice you can make a polymer Gly-Pro-Hypro and then maybe you could twist this around to make it fit the collagen pattern. And so we went back… to the lab. Ah… the translational repeat in polyglycine II was 3.1 angstroms. But we found if we took these 3 chains and just twisted them, then we ended up with a coiled coil in which the translational along the axis of each residue was 2.86 angstroms and that’s exactly what collagen had. So we thought this looked like a very promising thing. So what we did, is… we made a very large model, about 6 feet tall and about 2 feet wide. The model had 3 chains, these were done with metal skeletal rods, so called ‘Kendrew models’, which are brass rods welded together, and then with attachments to hold them together you could build a molecular model. So we built this long model, we took it into the basement where there was a very long hall, mounted a piece, sheet of paper on the wall. And at the other end of the hall we had an arc lamp, very bright. And we put the model in front, and the shadow, the projection of that model on the paper is very clear. So we went carefully with a pencil and put a little circle wherever an atom was. And this was a view of collagen. But since collagen had 6-fold symmetry; it meant you were looking at 6 views simultaneously. So, what you then do is you take this very large sheet of paper and use what’s called a reducing pantograph. And what you do is you put the pantograph on an atom, and then there’s another little arm, a much shorter arm, which allows you to drill a hole in a metal plate. So the plate was about 8 inches by 3 inches, and it had lots of little of holes drilled in it wherever there is an atom. And with that, you now have the potential of looking at its diffraction pattern using light, sending light through it. Now, we knew that the people at Courtauld’s, Arthur Eliot in particular, had a very large and very elegant optical diffractometer. And so we asked them, Could we use it? And they were very gracious. It tells you it always pays to be polite and not hurt people’s feelings. So we went there. We put the sheet in the pantigra…in the optical diffractometer, and then developed the photograph of the diffraction pattern, and low and behold there was a characteristic collagen pattern. We knew we had the right molecule. And ah…There was a little…we ah, we had a little problem though. We had assumed that if you just took 3 chains out of the lattice that’s all there was. And we were rather far along when we discovered that in fact the lattice is not hexagonal, it’s trigonal, three-fold symmetry. Which meant that there’s another group of 3 chains you can take out. And so this meant that we had two models, collagen 1 and collagen 2. They looked very similar but they were different. And one of them had a pattern that looked more like collagen than the other. Anyhow, we wrote that paper up and sent it into Nature. It was, it came out in the late fall of ’55. And the net effect of the collagen work is my stay which was planned for 3 or 4 weeks ended up over 6 months. And not only that, my wife came over, and we ended up in the same Crick household. I must say they were, Odile was very nice about that. The ah, …but it was very pleasant there. Now all this six months, I should say, we were still concerned with the RNA structure.
MP: You know, I want to interrupt you. Don’t forget what you want to say. But do you remember the atmosphere of your daily life. How is that to be a scientist at that time? That’s what I want to know. What did you do? I just want you to describe for me two days prior to discovery day, after that, how did you live?
Alexander Rich (b. 1924), biologist and biophysicist, is the William Thompson Sedgwick Professor of Biophysics and Biochemistry, at the Massachusetts Institute of Technology, Department of Biology. Rich first joined the MIT faculty in 1958. Subsequent to serving in the U.S. Navy from 1943-1946, Rich earned his undergraduate degree (A.B., magna cum laude, 1947) and medical degree (M.D., cum laude, 1949) from Harvard University. While doing his postdoctoral work at Caltech under Linus Pauling, Rich met Jim Watson and they began their collaboration on the structure of RNA. From 1969-1980 he was an investigator in NASA's Viking Mission to Mars, the project which designed experiments to determine if there is life on Mars.
Alex Rich's most well-known scientific discoveries are left-handed DNA, or Z-DNA, and the three-dimensional structure of transfer RNA. He has been elected to the the National Academy of Sciences (1970), the American Academy of Arts and Sciences, the Institute of Medicine, the French Academy of Sciences, the Russian Academy of Sciences, and the Pontifical Academy of Sciences (the Vatican.) Among other awards and honorary degrees he has received are the Medal of Science granted by President Clinton in 1995, the Rosentiel Award in Basic Biomedical Research, and the Presidential Award of the New York Academy of Sciences.
Since the 1980s Alex Rich has been actively involved in number of companies in the pharmaceutical and biotechnology industries. He co-founded the pharmaceutical company Alkermes Inc. in 1987 and currently serves as a director. He is also Co-Chairman of the Board of Directors of Repligen Corporation, Inc., a biopharmaceutical company, a member of the Scientific Advisory Board of Roseta Genomics, and a member of the Board of Directors for Profectus Biosciences, Inc.