Now…I’m discussing this for a reason. Because we spent 6 months from June to December, aside from the collagen work, mostly discussing RNA structure. Francis, Jim, and we discussed these polymers, because Jim then continued taking diffraction patterns of fibers, while I was working with Francis on collagen. And we talked about this for …what we might learn from them. And I’ll come back to that shortly, because I then returned to NIH. Continued working with these polymers. And …by then we could also make co-polymers. Now we’ve made a copolymer in which we put in both u …uridine and adenine residues. So it was polyribo A U, a random mixture. When I pulled that fiber and looked at it, by god it was the same diffraction pattern of all those other RNAs. So it made, it sort of confounded the mystery a little bit. But at the same time we knew that this polymer was linear, it was not branched. At some point in the spring of ’56, late spring, I decided to mix together polyadenylic acid and polyuridylic acid, not in the same chain but two different polymers. And to my astonishment as soon as you mixed them, the solution became very viscous. And you could draw up a fiber, and you got from this fiber a very well oriented helical diffraction pattern, and it was not the same as DNA. It was a different molecule. And this molecule had made a double helix. Now I don’t know what inspired me to do that. But I did go back and ask, …I then reflected on the following: How come for six months we were talking about these polymers and RNA structure… nobody, neither Francis, nor Jim, nor Leslie, nor myself. None of us said, Why don’t you mix poly A and poly U and see what’ll happen? Because it seemed like a most improbable thing to do. Furthermore, when I recently wrote an article about, recently, a few years ago, an article about this. And I called Francis, and I said, Why do you suppose we never in that six month period, we never thought about mixing these together? And he didn’t know, but he said maybe it’s because everyone felt it needed an enzyme to make a double helix. Because we knew that Kornberg would take deoxynucleoside triphosphates and it would make a DNA double helix. And in fact walking along the corridor of NIH I bumped into Herman Kalckar, a very distinguished biochemist, and I said to him, “Herman, we’ve just, we just discovered if you mix poly A and poly U together we get a double helix!” And he almost choked on his pipe. “What?!,” he said. “Without an enzyme?” You know. This was the mind set. And actually about the same time a note was published in Federation Proceedings by Bob Warner who worked in Ochoa’s department. And in this note he pointed out that if you mix poly A and poly U together you get a lowering of optical density. This is the hypochromic effect. And ah, …so the idea of mixing was there. But it was astonishing that there was this six month delay before these experiments were carried out. And the reason, the reason it seemed so surprising is there had never been a reaction, a chemical reaction of that type, previously. This was a reaction in which very long molecules, polymers associated with each other, side by side, in a specific fashion. There were no precedents for this at all. And that these two molecules would seek each other out, form this double helix, was astonishing. This was, … we didn’t have the word hybridization. This was the first, the discovery of nucleic acid hybridization. And ah, a reaction which has developed into one of the most powerful tools in biotechnology. In fact it’s the, what might be called the “foundation technology discovery.” Without it, it’s not clear we could have developed the discipline.

By that time, I should say previously, David Davies who had been at Caltech. I wrote to him and said, “Why don’t you come,”…and he had returned to England. Said “Why don’t you come to NIH and we’ll do work on the nucleic acids.” And he came, and so he was involved in this. And we sent, we wrote an article which we sent to the JACS. It’s interesting cause that, that’s where you published these things at the time. It’s chemistry. And there were no other places to publish it. It seemed inappropriate for the Journal of Biological Chemistry because it was a chemical reaction. We submitted this in….anyhow it was July, I think, and it was published in ..ah…no submitted in June. Anyhow and published I think in August. In it we describe this reaction, describe the diffraction pattern. Pointed out that the differences were considerable from the DNA pattern. It wasn’t clear what they could have been, they might have been. We point out as a possibility that the two strands were parallel to each other. We just didn’t know. The, but we knew that it wasn’t a DNA pattern. And, …the …parenthetically I should say a year later, Gary Felsenfeld joined the lab, we discovered that indeed you could even add a third strand. Another polyuridylic acid. And it would make a three-stranded molecule. Two Us and one A. Now two of those strands were in fact parallel to each other and one was anti-parallel. So the idea of making a parallel duplex was not a wild idea. But it turned out, that this, what had happened is this had formed a double helix, but the helix was much fatter than the DNA double helix molecule accounted for the fact that they were anti-parallel. The same hydrogen bonding for DNA but because of the different geometry the diffraction pattern was different. The… now many people were very skeptical of this result. And…

MP: Why, why I just want when you talk about this .. this why, I just wanted to ask you. Why they were skeptical and why did you such a strong belief in this? Start again.

AR: The reasons, Look, there are several reasons: A. …

MP: No, no, no. Start again. That, Many people were skeptical that…

AR: Many people were skeptical. And the reasons were quite clear. First of all it had never been seen before. People are in general, including scientists, are very conservative. If something is new, they tend not to believe it. Secondly, they pointed out, quite reasonably, that you start in this reaction you have these single chains, thousands of units long, and they’re all tangled up. And you end up with something that’s untangled. They would never untangle, you’d have these knots, it would never work that way. Furthermore, and this is a serious argument, you start with chains which are quite random, and you end with chains which are quite organized in a double helix. This is entropy going backwards, and that is not common in chemical reactions. So there were good theoretical reasons for questioning it. But, what these people didn’t know and we only had some intuitive feeling for, was that in fact the molecules had organized themselves around a hydrophobic core with the charges on the outside. And the stability of that core, stacking of the bases, was such that it overcame the entropy changes and other things. It’s interesting in that short paper that we sent into the JACS I made two points. One was that …this double helix of RNA, this reaction of putting two nucleic acid molecules together and having them associate using specificity of hydrogen bonding, could be used for many additional investigations. And in fact, yes, it says, “This method for forming a two stranded helical molecule by simply mixing two substances can be used for a variety of studies directed towards an understanding of the formation of helical molecules utilizing specific interactions. Now I had no idea at all of just how many studies it could be used for. And, ah…But this showed for the first time that RNA could form a double helix. It was a different helix than the DNA double helix. It did, I pointed out in the article, that it does provide a basis for understanding how viruses replicate using the same mechanism that was used for DNA replication. But this discovery then was made three years after the Watson and Crick model for the DNA duplex. And ah, it left still unknown the question “What is the exact geometry of this?” And this points to the fact that when you take a fiber x-ray pattern, you do not get enough information to really prove what the structure was. And indeed DNA was challenged for many years because people hadn’t learned to crystallize then. In 1973 we discovered we could make short…

MP: Oh, Alex, I want just to…before we go to the other discoveries, and then another one, I want that you comment about Huxley, and what he said about molecular sex.

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.