(It’s Nobel season! Please enjoy a few from our archive on this topic)

As of November 2005, 776 Nobel Prizes have been awarded (758 to individuals, 18 to organizations) in physics, chemistry, medicine, literature, peace, and economics. In that same month, according to the U.S. Bureau of Census, there were an estimated 6,469,818,677 people alive in the world. Consequently, the average person (or even the average scientist) has a very small chance of winning a Nobel Prize or even ever knowing anyone who has done so. However, there is a very small group of people whose odds of winning this estute award are exponentially increased. These people were the members of an elite brotherhood consisting of 20 members, known as the RNA Tie club. Eight of these members went on to win Nobel Prizes making the odds of winning a Nobel Prize in this specific ‘population’ 2 in 5. Indeed, this crude analysis is riddled with copious confounders. However, for the purposes of this discussion they have been wittingly ignored.

Founded in 1954 by Russian physicist George Gamow, the RNA tie club served the purpose of encouraging comradery and collaboration between some of the forward researchers of the time. This inter-disciplinary ‘team’ met bi-annually to try and solve the mystery of RNA structure and how it contributed to the formation of proteins. In the meantime, they wrote letters to one another proposing new ideas that were not yet developed enough to be submitted for publication in scientific journals. Gamow believed it was imperative to advancement and discovery that scientists from different fields share their ideas and results. However, this club was also an excuse to gather and drink whiskey and beer. If one were to speculate, it could be thought that this may be part of the reason why Marshall Nirenberg (not a club member) beat the entire RNA tie team to deciphering the first letter of the genetic code.

The members of the RNA tie club that achieved the most popular fame were Drs. James Watson and Francis Crick. Every club member received a moniker after one of the 20 amino acids. Dr. Watson was named after proline, and Dr. Crick after tyrosine. In the April 25th 1953 issue of Nature, one of the most eminent papers of all time was published by Watson and Crick: “Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid”. It is within this article that they announced that DNA was a right-handed double helix. Before this, there had been a frenzy of work and publications attempting to explain the structure of DNA. The key to Watson and Crick’s model was that the nucleotides were assumed to be laying perpendicular to the plane of the phosphate backbone with hydrogen bonds between a purine on one strand and a pyrimidine on the opposing strand. They also propose that the specific pairing that they suggested insinuates a copying mechanism for DNA. Watson and Crick received their Nobel prize in 1962 for this discovery, and thus did not benefit from the RNA tie club in this regard. Crick would later be able to attribute some success in proposing the adaptor hypothesis, and later the wobble hypothesis, to interactions with other tie club members. In fact, Crick refers to his proposal of the adaptor hypothesis in a letter to other members of the RNA tie club as the most influential unpublished paper he had ever written. In this letter he proposed that there existed twenty adaptors and twenty enzymes, one for each amino acid. The specific enzyme would join the amino acid to its corresponding adaptor, which would then travel to the RNA template and be held in place by hydrogen binding. This was essentially correct, although Crick did not discover the tRNA molecule.

Lesson number 1: perform the work for winning a Nobel prize before joining a prestigious club so that you can sit back, relax and get the most out of conversing with your fellow scientists.

George Gamow founded the RNA Tie club after his first attempt at deciphering the genetic code. Gamow postulated in a 1953 Nature paper that there existed a diamond shaped cavity formed between 4 nucleotides in which amino acids could fit in a stereotypic fashion. The amino acids would line up within this groove, and once complete, an enzyme would come along and link them all together. He proposed this as an overlapping triplet code; he was correct on the triplet aspect, but not on the overlapping sequence. Crick would later use the protein sequence data available at the time to show that the diamond code model was unfeasible; there were known patterns of amino acid repetitions that the diamond code was not able to reproduce. Gamow continued on and proposed the triangle code; an overlapping triplet code that again was disproved by another RNA tie club member. This time, it was Sydney Brenner (2002 Nobel Prize winner, also known as valine) who used the protein sequencing data to show that overlapping codons could not contribute to the amino acid sequence. By doing this, Brenner ended the era of the overlapping triplet code.

Although Gamow’s work masquerading as a molecular biologist was largely unsuccessful, he is still well known for work pre-RNA tie club where he established the theory of alpha decay. He also showed that as a star burns hydrogen it heats up, thus providing strong support for the Big Bang theory. Gamow’s personal life was almost as remarkable as his career. He was born in the Russian empire to which he returned after his post-doctoral training at the University of Copenhagen and at the Cavendish Laboratory with Ernest Rutherford. He made two attempts to flee the increasing oppression in his native country by trying to kayak across the Black Sea with his wife to Norway. After failing both times because of bad weather, he used his wits a bit more and obtained permission for both he and his wife to attend a conference for physicists in Brussels. They never returned to Russia and instead set up a new life in the United States. George Gamow never received a Nobel Prize.

Lesson number 2: never be the founder of a prestigious club full of future Nobel laureates.

Lesson number 3: never attempt a daring escape of any kind with 2 physicists until they have had at least 2 practice runs.

Melvin Calvin, or histadine, won the 1961 Nobel Prize in chemistry for his work on the biochemistry of carbon fixation. Calvin exposed algea to the carbon-14 isotope and mapped the complete route that carbon travels through a plant from CO2 absorption to conversion into organic compounds, such as carbohydrates. Having worked out the major steps involved in the metabolic process of photosynthesis, this pathway would later take his namesake and be referred to as the ‘Calvin Cycle’. Calvin did not make any major public discoveries regarding the mysteries of RNA or the genetic code.

Lesson number 4: do not focus your research on anything even resembling what the other future Nobel prize winners in your group are doing.

Comradere was not always found between the members of the RNA tie club. Erwin Chargaff, or lysine, apparently did not get along very well with Watson and Crick from their very first meeting. However, his work was crucial for Watson and Crick to discover the structure of DNA. Chargaff has proposed two rules, fittingly known as the Chargaff rules. The first rule was essentially that in DNA, the number of adenine molecules equals the number of thymine molecules, and that the number of cytosine molecules equals the number of guanine molecules. He also noted that cytosine and guanine are of lesser abundance than the other two nucleotides. The second rule states that DNA composition varies between species, particular with respect to the relative amounts of matching nucleotides. This pointed strongly to DNA being the source of genetic material. Chargaff did not win a Nobel Prize, although many believe he should have shared the prize with Watson and Crick. He no longer has the opportunity to win the Nobel Prize as he passed away in 2002; the Nobel prize is not awarded posthumously.

Lesson number 5: not liking someone else who will win a Nobel prize is okay.

There are many more members of the RNA tie club not addressed here. They all have fascinating stories, with each one full of lessons to be learned. However, important lessons also stem from the men who actually cracked the genetic code, and were not RNA tie club members. Marshall Nirenberg and his colleague Johann Matthaei were able to uncover the first letter of the genetic code using an elegantly simple experiment. They took a test tube and added to it all of the components believed to be required for protein synthesis. This included ribosomes, free nucleotides, amino acids, energy and an RNA template. The genius part of this experiment was that the RNA template that they used consisted of a string of uracils. Protein synthesis ensued and resulted in a chain of phenylalanines. This showed that UUU coded for phenylalanines. They continued on and found that a succession of cytosines codes for proline. Har Gobind Khorana, a scientist from the University of Wisconsin, followed suite by synthesizing chains of dinucleotide repeats to decipher the rest of the coding sequence. Nirenberg and Khorana shard the Nobel prize in 1968 with Robert Holley, the discover of transfer RNA. Matthaei did not win the Nobel prize. He was a post-doctoral fellow at the National Institute of Health at the time and thus Nirenberg was able to take all of the credit for the work they did together. Some believe that he was much more deserving of this award than Khorana.

Lesson number 6: never work as a post-doctoral fellow for someone who will go on to win a Nobel prize.

Lesson number 7: joining a prestigious club may distract your from your Nobel prize winning work.

Although only a sampling of the RNA tie club members and some of the other major players in cracking the genetic code have been discussed, their stories hold some important lessons for today’s biologists. Unfortunately, it is unlikely that a club containing the leading researchers in the scientific community would exist as successfully today. There is a lot to learn from this club aside from lessons relating to the Nobel Prize (which have been introduced satirically). One of its main goals was to promote sharing of intellectual ideas; this is rare in today’s world of intellectual property and patents. It was also to create a focus on interdisciplinary learning, another side of science that has been ignored as the required knowledge base in each discipline expands. However, lately a myriad of ‘interdisciplinary’ programs are popping up in universities, usually related to biology and computer science. Many of the ideas proposed by the club members were formed by thinking about available data at length, forming a hypothesis and then testing this hypothesis through either experimental methods or mathematics. This methodology is often overlooked by scientists today who perform ‘high-throughput’ experiments and then later form hypotheses based on their results. This premeditation step before ploughing through experiments is key to designing the elegantly simple experiments seen a few decades ago. Until scientists begin to think like this again, we will be bogged down with papers regarding minute gene changes occurring in a cell without anyone seeking the answers to the big picture questions. The RNA tie club and its members not only laid the groundwork for all molecular biology today, they also taught us valuable lessons in how to win (or not win) a Nobel Prize and how we should conduct our research today.