Alexander Rich, 1924-2015

Alexander Rich. Photo by Donna Coveney.

Alexander Rich. Photo by Donna Coveney.

Today we remember Dr. Alexander Rich, a student and colleague of Linus Pauling who passed away in April at the age of 90. Rich and Pauling were among the group of scientists who embarked on one of the most exciting scientific quests of the 20th century – the so-called “race for DNA.” Rich’s friends and colleagues also remember him for his endless desire to know more about the processes propelling life, a trait that is evident in his career as a biochemist. According to Pauling, this holistic interest in and understanding of science allowed Rich to make invaluable contributions to multiple disciplines.

Nucleic acids – the carriers of genetic information within a cell’s nucleus – were first identified in 1868 when Friedrich Miescher isolated the DNA compound for the first time. For some eighty-five years, however, the structure of DNA remained undescribed. In the 1940s and 1950s, scientists around the world began to focus more on the problem, working to build an accurate model of the DNA molecule in hopes of fully understanding its role in the process of gene expression.

In 1953, using Rosalind Franklin’s experimental data, James Watson and Francis Crick published their proposal of a double helical structure for the DNA molecule, and quickly became scientific celebrities once their model was deemed correct. Like Rosalind Franklin and, indeed, Linus Pauling, Alexander Rich was among the many researchers whose work and contributions to the understanding of proteins and nucleic acids abetted Watson and Crick’s discovery of the DNA molecule’s structure.


rich-young

Born in Hartford, Connecticut in 1924, Alexander Rich served in the U.S. Navy during World War II, then went on to Harvard University, where he received a bachelor’s degree in biochemical sciences in 1947 and graduated from Harvard Medical School in 1949. Soon after receiving his medical degree, he moved to Pasadena, where he worked as a research fellow in Linus Pauling’s lab at the California Institute of Technology, and where he lived with future Nobel laureate Martin Karplus, a fellow student of Pauling’s.

Blessed with a nimble mind, Rich was able to jump back and forth between chemistry and biology as his research interests progressed, all the while paying close attention to the broader implications of his research for the field of medicine. Rich became particularly well-known for his work on the structure and chemistry of fiber compounds, research which quickly became useful to the study of nucleic acids. By isolating strands of nucleic acids within fibrous compounds, Rich was able to produce images of their structure.

Though his pictures were not as clear or impactful as those captured by Rosalind Franklin, many have since posited that his work could have been of equal significance to Franklin’s had Caltech housed more fine-focus x-ray equipment.  Regardless, Rich was held in high esteem by Watson and Crick who, before publishing their DNA structure, asked that Rich review their work and corroborate their ideas.

Collagen model built by Alexander Rich and Francis Crick. September 1955.

In the wake of Watson and Crick’s triumph, the structure of nucleic acids continued to intrigue Rich. This time around however, it was RNA that caught his attention. Like DNA, RNA carries genetic material and is vital to the formation of proteins. It is thus necessary to understand the structure and function of RNA to fully comprehend DNA’s role in protein formation.

Rich began research in this area during James Watson’s brief stay at Caltech, and some now speculate that Rich’s interest in RNA images led Watson to focus entirely on RNA. While in Pasadena, Rich and Watson collected different images of RNA in an attempt to understand its physical structure, but the x-ray crystallographic photographs available at the time were not sufficient enough to discern a conclusive model.

Rich’s stint at Caltech came to an end in 1954 and he subsequently moved into his own laboratory at the National Institute of Mental Health (NIMH). While there he continued to delve into questions regarding the structure and composition of RNA. At the NIMH Rich was, at long last, successful in creating an image of RNA that provided hints about its structure. Rich concluded that RNA consists of a single-stranded nucleic acid that binds with complementary strands of RNA to form a temporary double helix – a process he described as molecular hybridization. Many were skeptical that a single-stranded nucleic acid could temporarily form a double helix, but Rich was able to show that this is made possible by the shedding of water molecules that comes about when the two strands bind.

Not only did this finding contribute enormously to the understanding of RNA’s structure and function, but Rich’s contributions to the understanding of molecular hybridization in nucleic acids has opened up many more possibilities. For example, polymerase chain reaction, a process used to identify genes, is based on the principle of hybridization. Today, methods of this sort are fundamental to all sorts of work in biotechnology and to the analysis of DNA.

Alexander Rich with Linus Pauling, among others, at a scientific meeting in the Soviet Union.  Image Source: Alexander Rich Collection.

Alexander Rich with Linus Pauling, among others, at a scientific meeting in the Soviet Union. Image Source: Alexander Rich Collection.

Following his tenure at the NIMH, Rich became a professor of Biophysics at the Massachusetts Institute of Technology, beginning in 1958 and lasting until his death. His investigations there included the discovery of Z-DNA, which is a type of DNA molecule that takes a zigzag form and follows a left-handed wind rather than the more common right-handed wind. His work at MIT also showed that protein synthesis occurs in a polysome – the name given to a cluster of Ribosomes that work together.

Alexander Rich received high honors for his contributions, including election to the National Academy of Sciences and receipt of the 1995 National Medal of Science – the highest scientific honor bestowed by the U.S. government.  It is no wonder then that Linus Pauling recalled his former pupil with great pride. “Of the several men with MD degrees who have worked with me,” he once noted, “I think that Dr. Rich may well be the one with the broadest grasp of science as a whole.”

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Congratulations to Martin Karplus

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We were delighted to learn last week that Martin Karplus will be one of three individuals to share the 2013 Nobel Prize for Chemistry. Karplus is among Linus Pauling’s many scientific descendants, having worked as a graduate student under Pauling in the early 1950s. A bit later, Karplus worked with Pauling and E. Bright Wilson, Jr. on an ill-fated project to publish a revised version of Pauling and Wilson’s 1935 text, Introduction to Quantum Mechanics.  We documented this story in May 2010.

In another life, the blog dabbles in oral history and it was our great good fortune to interview Dr. Karplus during a trip that he made to Corvallis just this past summer.  A few excerpts about his Pasadena experience are included below; the entire interview has been archived in our History of Science Oral History Collection (OH 17).


On choosing Caltech after finishing his undergraduate studies at Harvard...

My brother was at the Advanced Institute working with Oppenheimer and I’d decided I wanted to go west and I would either go to Caltech or Berkeley. I was admitted to both of them. And, as I said, I visited my brother and he introduced me to Oppenheimer, who had been professor both at Berkeley and Caltech and I asked him what he would do. And we talked a little bit about things and I’m not sure that he was aware that really I was going to go into biology rather than into chemistry. But he – I still remember the statement of his that Caltech was a ‘shining light in a sea of darkness,’ and he strongly recommended going to Caltech as being a smaller place where somebody like me would be able to really do what I wanted to do. So I think that was it. I mean, in those days you didn’t visit the schools or anything. So I think he was basically – well I talked with my brother about it, also, but that was sort of how I made my decision to go to Caltech and I think it was a good decision.

On taking classes from Pauling…

He was a great lecturer. But the most impressive thing was that he gave the students problems as homework problems and everyone worked very hard on them. Then it turned out that he actually didn’t know the answer to this problem and so there was a lot of discussion of this. At the time I was sort of annoyed, but afterwards realized that this was really very important, to learn the difference between doing your homework when you know that there is an answer, you can always find it, and doing research, where obviously there may be an answer somewhere but it’s not so easy to find. But that was part of his methodology.

On Pauling as a doctoral adviser…

…people built their careers on Pauling’s ideas. I still remember when I started, every morning when I would come in there would be this little yellow sheet in my mailbox, saying ‘wouldn’t it be interesting to do so-and-so?’ And at first I felt ‘okay, well Pauling wants me to look at that, I’ve got to work on it. I don’t have time to do what I’m really doing on my thesis.’ So this went on for a little while until Alex Rich and some of the other people that I talked with said ‘look, Pauling does this to everybody, he doesn’t expect you to do it. You can either throw them away or you can store them and maybe they’re ideas that you could really work out.’

….And, if we’re talking about experiences, one was my qualifying oral, where Pauling asked me to discuss his theory of metals, which I knew something about. So I said innocently, ‘well, let’s start with copper,’ and I said ‘let me see, what’s the atomic number of copper?’ And so Pauling looked at me and said ‘well, you start with hydrogen and you work your way up and then you’ll get to copper.’ So, with a certain amount of fumbling, I finally did get there, but everybody was terribly amused and Pauling afterwards sort of said to me ‘now look, you’re a very bright fellow. But one thing, if you’re a chemist, you should know, is the periodic table. So that very much impressed me.

Martin Karplus and Linus Pauling, 1960s.

Martin Karplus and Linus Pauling, 1960s.

On a memorable party with the roommates…

We had a big party at the – we lived in this house in Altadena where a number of us, Sidney Bernhard, Alex Rich; Matt Meselson was involved in it too. We all lived together. I and Sidney were the cooks and the others washed the dishes and cleaned up, and we had this big party. We had often had parties and Dick Feynman would come and play the drums. And Pauling and Ava Helen came to this party.

We had a lot of snails in the garden and Pauling went out and collected them. And I thought, ‘okay, he likes snails, he’s going to go home and Ava Helen is going to cook them.’ What I discovered later when I was working – I did a lot of cooking and working in restaurants – is that it’s really a very complicated process to prepare the snails and you would have to let them sit for about a week or so until they eat up all their own slime. I never asked what they actually did with them, with this collection, but he had this big collection of snails which he took home.

On Richard Feynman…

I remember he gave a public lecture on water which was just unbelievable. He really had insights, and of course there’s this now famous quote in the Feynman lecture series, which is something like ‘everything that happens in life has to do with the wiggling and jiggling of atoms,’ and now almost everybody who works in molecular dynamics uses this quote as a sort of introduction on their importance. I talked with him a number of times about looking at larger systems and he was very encouraging. Though I must say that when I took his quantum mechanics course, it was difficult in the sense that he taught quantum mechanics from his point of view, with path integrals and such, and for people who didn’t know quantum mechanics already, it would have been very difficult. On the other hand, it was a difficult period, but it actually taught me a lot of things, which I’ve used since then.

Anyways, when he came to our parties he played the drums; he was really part of the Caltech spirit. I think most other schools you wouldn’t expect a professor like that, to come to the party with some students, say ‘look, why don’t you come up there, we’re having a big party tonight…’

DNA: The Aftermath

Pastel depiction of the DNA base pairs by Roger Hayward.

Pastel depiction of the DNA base pairs by Roger Hayward.

The solving of the double helix structure of DNA is now considered to be one of the most important discoveries in modern scientific history. The structure itself suggested a possible mechanism for its own replication, and it also opened up a huge window of opportunity for advances in multiple fields ranging from biology to genetics to biochemistry to medicine. Almost immediately after James Watson and Francis Crick announced their structure, new research began based on the structure’s specifications.

An Early Idea from George Gamow

The Pauling Papers contain an interesting example of research done on the structure of DNA mere months after its discovery. On October 22, 1953, the Russian-born physicist (and founder of the “RNA Tie Club“) George Gamow sent a letter to Linus Pauling that mentioned some work he had been doing with DNA. Gamow explained that he had found a manner by which the twenty amino acids that make up proteins could be related to different combinations of the four nucleotides found in DNA.

At this time, it wasn’t known that the DNA strands unwind during replication, and Gamow assumed that protein synthesis occurred directly on the double helix. He suggested that a “lock and key relationship” might exist between each amino acid and that the “holes” formed between each complementary base pair in the DNA chain. Science is now aware that this is not the case, but Gamow’s letter is nicely demonstrative of the innovative research ushered in by Watson and Crick’s solving of DNA.

Excerpt from Gamows letter to Pauling, October 22, 1953.

Excerpt from Gamow's letter to Pauling, October 22, 1953.

Click here to view Gamow’s entire letter, and here to read Pauling’s response.

RNA

As the buzz around DNA started to die down, scientists began to move toward the next logical step: RNA. By then, Watson and Crick’s structure was widely accepted, and it had been clear for some time that DNA was the site of the gene. So, then, how did DNA transfer its information to RNA, and finally on to proteins?

Gamow’s above suggestion was a possibility, but it didn’t even involve RNA. Watson spent some time playing with the matter, but was not able to equal his luck with DNA. Unfortunately, it would be quite some time before this mechanism was elucidated. Even now, some of the finer details of how this is accomplished are not completely understood.

Four members of the RNA Tie Club, 1955. Clockwise from upper left: Francis Crick, Lesley Orgel, James Watson and Alexander Rich.  Founded by George Gamow, the RNA Tie Club met twice a year in pursuit of greater understanding of RNA.

Four members of the RNA Tie Club, 1955. Clockwise from upper left: Francis Crick, Leslie Orgel, James Watson and Alexander Rich. Founded by George Gamow, the RNA Tie Club met twice a year in pursuit of greater understanding of RNA.

Eventual Honors

Unsurprisingly, as time went on, Watson and Crick began to accumulate awards for their work with DNA. On December 15, 1959, Linus Pauling responded to a previous letter sent to him by Sir William Lawrence Bragg soliciting Pauling’s support of the nomination of Watson and Crick for the Nobel Prize. In this letter, Pauling stated that he would indeed be willing to write the requested letter of support. However, contrary to Bragg’s suggestion that they be nominated for the prize in chemistry, Pauling stated his belief that a prize in physiology or medicine would be much more fitting.

Several months later, on March 15, 1960, Pauling finally sent his letter to the Nobel Committee.  By the time of its authorship, Pauling’s feelings about the importance of Watson and Crick’s work had become even more tepid.

While acknowledging that “the hydrogen-bonded double-helix for DNA proposed by Watson and Crick has had a very great influence on the thinking of geneticists and other biologists,” Pauling notes that their work was, at least to some degree, “stimulated” by his and Robert Corey’s incorrect triple-helix structure, and abetted by Maurice Wilkins‘ x-ray photographs.  Pauling also points out that Wilkins, Corey, Karst Hoogsteen and himself had already tweaked the Watson-Crick model a bit, “which suggests the possibility that a further change in the structure of nucleic acid may be found necessary.”

In the end, Pauling couldn’t bring himself to go through with the promised nomination.

It is my opinion that the present knowledge of the structure of polypeptide chains in proteins is such as to justify the award of a Nobel Prize in this field in the near future, to Robert B. Corey for his fundamental investigations of the detailed molecular structure of amino acids and the polypeptide chains of proteins or possibly divided between him and Kendrew and Perutz. On the other hand, I think that it might well be premature to make an award of a Prize to Watson and Crick, because of existing uncertainty about the detailed structure of nucleic acid. I myself feel that it is likely that the general nature of the Watson-Crick structure is correct, but that there is doubt about details.

Pauling’s hesitations served only to delay their inevitable receipt of a Nobel Prize for a short time. In 1962, Francis Crick, James Watson, and Maurice Wilkins shared the award in Physiology or Medicine “for their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material.”

The discovery of the structure of DNA was clearly one of the most important discoveries in the modern scientific era. Not only was it a huge breakthrough in itself, but it also opened the door for major advances in numerous other science-related fields. For more information on DNA, check out the rest of the posts in our DNA series or the website on which they are based, “Linus Pauling and the Race for DNA: A Documentary History.” For more information related to Linus Pauling, please visit the Linus Pauling Online portal.