Alex Rich on Single-Crystal Diffraction
  Alex Rich     Biography    
Recorded: 20 Aug 2006

AR: When,… in 1957 we discovered a three-stranded structure could be formed. One in which the third strand, poly rU, inserted into the major groove of DNA. And I realized that it could form two hydrogen bonds, one to N7 of adenine and one to N6. So these were different, not the same as the Watson-Crick hydrogen bond which would use N1 and N6. Two years later, Karst Hoogsteen made a single-crystal of 1-methyl thymine and 9-methyl adenine. And the same hydrogen bonding is found in the single-crystal. It’s now called Hoogsteen hydrogen bonding. It’s the hydrogen bonding which we’d seen two earlier in the poly A, which I should say which we inferred two years earlier in the Poly fA plus 2 Poly rUu structure. Over the next several years people realized that the way to determine what the real structure is, is to use single-crystal diffraction. In single-crystal diffraction you have thousands, many thousands of experimental points that you measure. In contrast to a dozen or two in a fiber. And for a macro-molecule, you have to define the position of each atom which alone takes three coordinates, three measurements, X, Y, and Z. And multiplied by the number of atoms, you need thousands of measurements to make that. So, single-crystal diffraction would prove structures, which you could not prove with fibers. For example, at that point, I … a year later, I think 1961, I had a post doc who crystallized …three…, a cytosine residue and a guanine residue. And for the first time, we could see three hydrogen bonds holding a G-C base pair together. Now Watson and Crick as you perhaps realize postulated only two hydrogen bonds. Pauling pointed out that the geometry was such that it would be three. Now it’s interesting. Francis of course knew that it could form three. But he had some, as he described it, some mystical idea that maybe it had to use two just as the A and T used two for symmetry purposes. But any how, with this single-crystal we could demonstrate for the first time experimentally that there are three hydrogen bonds. However, over the next several years, many co-crystals with adenine and uracile or thymine derivatives were solved, every one of them was a Hoogsteen pairing, none of them had a Watson-Crick pairing. And people, even there was even a paper on a Hoogsteen model of the DNA double helix. And the diffraction data that predicted it looked not bad. So, there was considerable uncertainty.

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.