Post Manhattan Project FOMO – George Gamow, “maladia biologica”, and early computational biology

There’s no doubt that the 1953 publication of “A structure for deoxyribose nucleic acid” by James Watson and Francis Crick (with crucial contributions from Rosalind Franklin and Maurice Wilkins) was a truly landmark moment in the history of biology. The magnitude of the discovery drew in academics from a wide variety of disciplines, who quickly found ways to expand upon the initial discoveries highlighted in the publication and began work to solve some of the publication’s immediate pressing questions. One already prolific physicist who became somewhat obsessed with the cracking some of the newly unlocked questions surrounding the genetic code was George Gamow. Gamow was at the time (and is still to this day) far more renowned for his work in developing and popularizing the Big Bang theory, however the implications of the Watson and Crick paper intrigued him, particularly the issue of determining how to code for amino acids from the four letter nucleotide alphabet – which became known colloquially as the self-describing “coding problem”. 

Part of this influx of outside biological interest likely came from a large number of accomplished physicists finishing up work on the Manhattan Project, and looking for work of similar magnitude. However, Gamow is a unique case from the other post World War II “unemployed bomb-maker” physicists for a number of reasons. Most obvious is the fact that he was not actually involved in the Manhattan Project, despite his obvious caliber as a cutting edge physicist involved in nuclear research. His omission likely came from his history as a Soviet Union defector. Because of his situation, Gamow provides an interesting look into a prominent physicist’s dip into biological sciences. It is enlightening to delve into Gamow’s history, correspondences, research, and the environment surrounding him, and how it led him into becoming an influential figure in the nascent fields of genetics and computational biology. Despite the significant influx of physicists into the biological sciences during the same time period, Gamow found himself to be heavily involved for somewhat different reasons than those of his colleagues, and in turn, he briefly became a significant synthesizer for the sudden merge of research fields.

The Coding Problem

The coding problem was the theoretical question that emerged almost immediately following the landmark 1953 Watson and Crick publication. It appeared to be a highly theoretical and mathematical question that required little intensive biology or chemistry knowledge, and it is likely for this reason that it became the puzzle that Gamow and numerous other “outsider” physicists quickly caught wind of.

The coding problem can be simply explained in the following way. Start from the central dogma described in the original publication, “DNA makes RNA makes protein”, which leaves a few unanswered questions. The transcription from DNA to RNA is straightforward to understand, because it mainly involves a like for like switch from Thymine to Uracil (Adenine -> Adenine, Cytosine -> Cytosine, Guanine -> Guanine, Thymine -> Uracil). However, the translation from RNA to protein is less straightforward, because it involves an (at the time) undiscovered coding of unknown length sequences of base pairs which correspond to amino acids, and in turn proteins. With regards to sequence length, it was clear that using just pairs of letters could only form 16 distinct combinations (AA, AG, …), so any solution would require at least sequences of length 3 (giving a total of 81 potential sequences) and therefore an enormous computational problem at the time. Put simply, the coding problem involves mapping RNA sequences to 20 amino acids, and it was already clear that this mapping would be instrumental in the advancement of future genetic research. Gamow was the first to publish a serious solution to this problem, and although it was later proved wrong, his approach to the problem, the tools he used, and his response to its rather quick disproval are a glimpse into his involvement and influence on the field.

Gamow before his genetics foray

Gamow was a particularly interesting character in a time where the physics academic community was already chock full of interesting characters. His correspondences to his colleagues are full of jokes, exclamation points, vacation plans, and dubious tangents. His symposium is full of entertaining stories of his research and communication style, as well as his wild excursions into neighboring or sometimes even distant fields of research (genetics being one of the most significant). He wrote several books (some of which are still being sold) covering broad topics in science that were written to be approachable to the public, while still existing at the cutting edge of scientific research. Gamow was a fiercely optimistic individual who pursued anything that he felt was important to science (regardless of field) or simply was of interest to him.

When Gamow decided to actively try to defect from the Soviet Union in the early 1930’s, he was already in correspondence with numerous United States professors, including several physicists at the University of California at Berkeley. Gamow expressed a serious interest in coming to California, both to Ernest O. Lawrence and Raymond Birge at UC Berkeley, and Robert Oppenheimer at Caltech. Lawrence pressured both the Rockefeller foundation and the UC administration significantly in an attempt to both help Gamow’s defection, as well as bring in another distinguished member to Berkeley’s already illustrious physics faculty. Gamow’s letters to Lawrence in 1933 become increasingly stressed and explicit, and eventually Gamow plainly states “It will be of great help if you could send hence a paper for Rockefeller foundation saying that the University of California would appreciate my presence here this year and that (if you think it possible to write it now) there probably will be a certain possibility for me to stay there in the future”, to which Lawrence quickly responds “I shall do all I can to find a suitable place here [Berkeley] for you.” Eventually Lawrence tells him that the UC administration is unwilling to cover the portion of his compensation that the Rockefeller foundation would cover, but Gamow happily responds with news of his appointment as a physics professor at George Washington University. Lawrence and Gamow’s correspondences continue until the early 1940’s, where it would seem that Lawrence, as well as several of the other physicists that Gamow kept a correspondence with become involved in the Manhattan Project and other wartime efforts. As a result, their communication stops. 

Gamow thanking Lawrence for supporting his efforts to secure a faculty position in the US. Bohr and Fermi anecdotes make appearances as well!

Research-wise, Gamow was significantly involved in the development and popularization of the Big Bang theory through his foundational theoretical work, and this (along with his popular and digestible science books) is what he is most well know for. He was also a significant contributor to the early theoretical work behind radioactive decay, particularly the theory of alpha decay of a nucleus via tunneling. This intense theoretical physics work certainly provides a relevant contrast to the genetic code work that Gamow became nearly obsessed over for short period.

Gamow’s genetics involvement

Gamow’s initial foray into genetics began immediately following the seminal Watson and Crick publication. He was soon after charged headlong into developing a solution to the coding problem. In a fashion typical of his optimistic and boisterous nature, Gamow began looking for a solution using the methods that had already served him in the field of physics – searching for mathematical and theoretical perfection within a stripped down and modeled version of the problem. Gamow’s initial theory required enormous amounts of computation to develop, and his work with Nicholas Metropolis (another significant member of the Manhattan Project) and his MANIAC machine at Los Altos National Laboratory allowed him to come to his initial (later proved wrong) conclusions about how to decode the genetic code. This use of a computer to solve a biological problem forms the roots of computational biology, and gave those involved an idea of how computationally intensive genetics was going to be and how reliant the research community was going to be on this developing technology. Decades from this first foray, computers would be a critical part of biology, with a particular highlight on the sequencing of the human genome.

It’s interesting to think about why Gamow became involved in the biological sciences, and how his interests developed and changed as he became both a more involved academic synthesizer and contributing member to the field. His and his colleagues’ correspondences during this period provide an excellent look into his work, as does his research itself and work as a founding and active member of the influential RNA tie club (more on this later).

Gamow’s interest in biology parallels numerous other physicists developing interests into biology. In fact, one of the letters to Wendell Stanley (head of UC Berkeley’s virus lab) from George Gamow addresses this entirely, saying “There seems to be an epidemic among the physicists, ‘maladia biologica’ you may call it”. Gamow even asks for Stanley to talk to one of his physics graduate student who has developed an interest in biology, which is telling of the growing irresistibility of the genetic field in the wake of the groundbreaking Watson and Crick paper, especially among up and coming academics.

“Maladia biologica”

Gamow was already a highly prominent physicist in the field of nuclear physics, with pleasant ongoing technical correspondences with at least Ernest Lawrence and Robert Oppenheimer (both of future Manhattan Project fame). His exclusion from the massive project and the end of longtime correspondences with academic colleagues who had at one point vouched for his “defection” and his installation into the American academic community may have been difficult for Gamow to deal with. His letter to Vannevar Bush following the use of the atomic bomb in Nagasaki outlines this line of thought “As you know I was in no way connected with the project of ‘atomic bomb’ development, while on the other hand, working all my life on nuclear physics, I naturally could not help not thinking about it and have rather clear ideas about the possibilities involved etc.” There is a notable tone of exclusion in this letter from Gamow, and he uses this rest of the letter to ask for advice on how he to best approach the topic of nuclear explosive reactions with his colleagues and students now that knowledge of the bomb and Manhattan Project is more or less public. In this context that it is easy to see why Gamow would not want to miss the next big science opportunity, and when the scientific world shook with Watson and Crick’s “A structure for deoxyribose nucleic acid”, physicists who hadn’t been involved and didn’t want to miss something again (like Gamow), as well as physicists who had enjoyed their taste of large scale, government backed big science both jumped at the opportunity to be a part of something they knew was going to be important.

The RNA tie club

An intriguing side story to Gamow’s foray into the field of genetics is his founding and significant involvement in what became known as the RNA tie club. Many of the colleagues Gamow already kept a correspondence with became members of this club – in fact James Watson and Francis Crick themselves were members (with Watson as a co-founder). The RNA tie club was named based off of a classic Gamow style joke, where each of the 20 members were assigned an amino acid, and a corresponding wool knit tie with the RNA helix stitched onto it. The initial purpose of the RNA tie club was to solve the coding problem, and the group produced a number of successes, including the concept of the codon, the number of nucleotides in a codon, and the adaptor hypothesis. On top of this, numerous members of the group were later awarded Nobel Prizes for their work in their respective fields. It was a closed off “boy’s club” of high achieving physicists and academics in the biological field that enjoyed alcohol and cigars while pushing the boundaries of sciences.

The RNA tie club was both a powerful group in the development of genetic science, as well as a way for Gamow to remain involved in a field he was deeply interested in. It also allowed him to hedge his lack of knowledge in biology and chemistry by surrounding himself with leading minds in those fields, in a casual environment where he did his best work. It was as much a scientific endeavor as it was a social experience and (at least) bi-annual semi-informal conference for all those involved.

A few RNA tie club members. Each was assigned an embroidered tie mapped to an amino acid. (Gamow’s was ALA – Alanine)

Gamow’s Diamonds

Gamow’s initial solution to the coding problem is known as Gamow’s Diamonds, and is even today held up as a mathematically beautiful, yet thoroughly wrong example of academic research. Gamow took the coding problem and simplified it to an understandable model, a technique commonly used to great success in physics, and a technique that had clearly served him well in the past. However, this biological problem was not as mathematically clean as problems Gamow was familiar with in physics, and his simplification of the problem led him to a beautifully wrong solution. A rough explanation of his work can be described as an overlapping code within RNA for protein coding. Gamow recognized that the encoding length for amino acids must be at least three bases long in order to cover all twenty amino acids, but he theorized that these triplets would overlap (ex. AGAG contains two triplets and describes two amino acids, AGA and GAG, despite only being length four). Both the mechanism for translation’s perfect fit (mathematically) into the very architecture of DNA, and the rigorous computational work that was done leveraging Nicholas Metropolis’ MANIAC computer to come to this conclusion seemed evidence enough of the correctness of the work. However it was quickly shown (by future RNA tie club member Sydney Bremner) that this overlapping diamond code, despite its mathematical superiority and architectural perfection, was wrong quite simply through contradictions in Gamow’s mapping to examples of observed sequence to protein mappings. 

Gamow’s early thoughts on the elegantly incorrect Diamond solution.

Gamow as the Synthesizer 

Gamow’s interaction with Nicholas Metropolis is an excellent example of the remnants of the Manhattan Project searching rather desperately (based on the surprisingly broad number of topics they explored) for applications for some of their results. Metropolis’ MANIAC at Los Altos National Laboratory was used for an array of different experiments, and Gamow’s use of it highlighted the rising computational scale of genetics research, and set a precedent for computational biology. However it highlights a key difference between Gamow and other physicists moving into the biological field. Gamow, as an outsider to the Manhattan Project, recognized the utility of the tools developed and was able to use them in novel ways. His MANIAC use also highlights his role as a synthesizer within a field in which he is actually an outsider to. While working with Metropolis’ MANIAC, Gamow began working with numerous subject matter experts outside of physics, such as Jon von Neumann, one of the fathers of early computing and Gunter Stent, a bacteriophage biologist. It is this broadening of connections and interactions that set the groundwork for Gamow’s developing role as a synthesizer in a young modern genetics field.

Gamow would work with Nicholas Metropolis (above) and the first digital computer MANIAC to explore the coding problem. This was a seminal moment in the history of bioinformatics.

Gamow described his previous attempt in a 1954 draft to his colleagues “On Information Transfer from Nucleic Acids to Proteins”, which was both an introduction to the coding problem to interested parties, as well as a summarization of current and previous attempts. Gamow clearly states “Some time ago the author attempted to establish such a translation mechanism on the basis of Crick and Watson’s model of Deoxyribonucleic acid (DNA) molecule. It turned out however, that the translation suggested by DNA structure (diamond code) leads to a contradiction … This negative result is presumably due to oversimplification of the original problem.” Gamow recognized the shortcomings of a purely mathematical approach quickly in the field of biology because of his initial mistake, and his correspondences with his colleagues following his initial mistaken publication led to the formation of the RNA tie club.

In this context, the club seems to have been a way for the (self appointed) leading minds working on the coding problem to cover for each other using their experimental results in a field where mathematical perfection and theoretical proof were not enough. In another correspondence to Wendell Stanley, Gamow describes his prior work by describing it as the work of “misguided sleepless nights” and a lack of respect for existing biological/chemistry knowledge Gamow sees himself as the synthesizer in the quest for a solution to the coding problem. Within the RNA tie club, several members are given unofficial officer titles, keeping in traditions with Gamow’s entertaining and jocular approach to research science and academic correspondence, but also describing Gamow’s vision of himself within the research group. As an example of how true this was even among members of the group, the letter head for the RNA tie club describes Geo Gamow as the “Synthesizer”, Jim Watson as the “Optimist” and Francis Crick as the “Pessimist”. Gamow’s personality and tendency for tangents made him the right candidate for synthesizing the knowledge within the RNA tie club, and it is very likely that his initial mistakes in quickly publishing a theoretically pure but experimentally lacking solution were instrumental in Gamow forcing himself to develop into a synthesizer of the various fields interested in biological science, specifically the coding problem that existed as the main focus of the RNA tie club.

Gamow’s penchant for wild, intensely focused tangents is well documented by his colleagues during his symposium. He did not even stick to a single field within physics, bouncing from nuclear research, to trying to understand the beginning of the universe, to a developing a better understanding of radiation, and of course fields outside the physics discipline as clearly seen from his brief but intense interest in genetic coding. These fairly rapid but intense periods of research brought Gamow and his unique personality into contact with all kinds of academics and experts, and his interactions with them were highly influential in Gamow developing into a member of the academic community who could quickly understand concepts, organize research efforts, and coordinate various fields. These skills were put on display during Gamow’s brief and fruitful stint in the biological sciences.

Eventually, Gamow’s involvement in genetic research and the RNA tie club waned. As the field become more competitive and reliant on experimental results, Gamow was less able to contribute from a theoretical perspective. He quickly moved into writing about popular science for the general public on a wide variety of cutting edge and long known topics of academic research. This mass appeal work, along with his notable achievements as a proponent and developer of the Big Bang theory is what Gamow is most remembered for. However as a synthesizer between fields, a buoyant personality, and a serial research topic changer, Gamow was able to be successful synthesizing complex topics for a mass audience in a digestible way.

Several of Gamow’s “popular science” books. These books were written for the “layman” to be able to understand the cutting edge of scientific academic research.

From afar, Gamow’s individual contributions to the field of genetics are minor. Much of his major work was at some point disproved or expanded on significantly by a researcher more knowledgable in the field. However Gamow’s contributions are far more important than the published research on record. His work with Nicholas Metropolis’ MANIAC at Los Altos National Laboratory forms the foundation of computational biology, and truly exists as one of the first significant examples of computers being used to solve a problem in biology. His application of the tool was novel and serves as an initial example of Gamow’s work as a synthesizer between several clashing fields interested in advancing modern genetic research. His formation of the RNA tie club highlights both his clear charisma and entertaining approach to academia, but is also a transparently clear example of Gamow working to bring together leading minds across several fields to solve an important question, but also generate discussions about how to grow and apply the growing field. Through his synthesizing efforts both in and out of the RNA tie club, tremendous progress was made in the field of genetic research. Nobel prizes were won, and names were made. It is clear that George Gamow, although one of many infected with his self described “maladia biologica” in the wake of Watson and Crick’s publication, made himself influential by effectively synthesizing the various “infected” fields.

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