Alex Rich on Left-Handed DNA
  Alex Rich     Biography    
Recorded: 20 Aug 2006

And the real question is, “What does the double helix really look like?” In 1973, together with my students we found that we could crystallize a short fragment, in fact two short fragments of an RNA duplex. We used a ribonucleoside diphosphate. Sorry, a …a …two nucleosides held together by one phosphate. So we had ApU and CpG . We found we could crystallize them separately. They diffracted to 0.8 angstroms. And we solved the structure which in those days was a considerable undertaking. It was before we had all the advantages of using computers and so on. But we solved the structure and out came these two fragments of an RNA double helix. The CpG I put into the Proceedings, PNAS. And the other one I sent into Nature, ApU. Both, the ApU structure showed for the first time that you could make a Watson-Crick base pair in a double helix. And the Nature News and Views wrote an article saying that this was, this structure was the missing link of nucleic acid structure. Finally resolved the question of the hydrogen bonding. And it’s amusing. I had sent a preprint of these papers to Jim, who read them and called very excited the next day, saying he had his first good night’s sleep in twenty years. Because up to then it wasn’t clear whether in fact the pairing that he had suggested twenty years earlier was the correct one or not. And here finally in a single-crystal structure we could see it. But this, these structures solved at 0.8 angstroms showed everything: ions, water molecules, all the details. And it defined essentially the backbone parameters of the RNA double helix for the first time. The, ah, …If you took these structures and simply continued the symmetry operation inherent in going from one base pair to the next you generated a molecule that looks just like double stranded RNA that we’re familiar with. And it solved finally the mystery of why that structure is different from the DNA double helix. The…now this was done in 1973, well before it was possible to make nucleic acids by synthetic chemistry. That happened only half a dozen years later. And in fact one of the early chemists who could make DNA strands was Jacques Van Boom, and we agreed to try to solve the structure of DNA. And he asked me, What sequence? And I said, I don’t know, but GC base pairs are more stable than AT base pairs. Why not try CG CG CG which is also self complementary. So he made that molecule. Andy Wang in the lab, crystallized it and to our astonishment it diffracted to 0.9 angstroms. Atomic resolution. We said, Wow! Now we’ll finally find out what DNA is like. And in the spring of , ..now this is 1979. In the spring of 1979, Francis was lecturing in the Boston area. He was lecturing about supercoiling, which…He was doing that because a very serious model had been proposed by some Indian workers, the so called side-by-side model in which the DNA duplex would go right-handed for a while, and then left-handed, and then right-handed, and you could separate the strands. His lectures on supercoiling clearly showed that that was not valid. That you had real chains that were entangled together. So, I remember at one of these lectures, a student asked, “How will we really find out what DNA looks like?” He said, “Oh just wait till Alex Rich finishes solving his structure. And then we’ll know.” Now solving this structure took quite a while. Because we had these heavy atoms and it was quite laborious. But eventually, it came out. To my astonishment…it was left-handed. And then, I hurriedly did a lot of reading, and realized that Pohl and Jovin had shown that poly (dG-dC) which has a normal circular dichroism pattern in a physiological solution. But if you raised the salt concentration to 4 M (molar) the spectrum really, nearly inverts itself. And I realized that what we had captured in this crystal was another alternative confirmation. When the structure came out, I called Francis. I said, “Francis the structure is solved.”

MP: What was his reaction?

AR: And, I said it’s left-handed… There was silence on the telephone line. Francis rarely is speechless, but he just said nothing. At which point I began to feel very guilty [chuckles]. And so, I then said, “Well, actually there’s very good reason to believe that what we have crystallized is an alternative confirmation, and that the real DNA is right-handed. Then he began breathing again.

MP: And you published this in ’79?

AR: That was in ’79 we published it, yes. But that was a big surprise to anybody.

MP: Yes, this role of Z-DNA, how did the scientific community accepted it?

AR: Well everyone was puzzled. The problem was the following. Here is a solution, left-handed DNA. What’s the problem that it solves? Who needs it? Because everything in biology seemed to be solved by right-handed DNA. Why do you need left-handed DNA? And it took a long time before we began to sort that out. And it was only with the discovery of proteins that bond to left-handed DNA which were co-crystallized and then solved and we could see the way they were that we then realized there was a biology there.

MP: Wait, hold on a second. Repeat just the last sentence.

AR: It was only when we had discovered proteins that bond selectively and specifically to left-handed DNA, we co-crystallized them and solved the structure. And at that point we realized there was a biology behind it. And that’s what we have been working at lately.

MP: Okay, perfect.

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.