My Memories of Alexander Spirin

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V. Ramakrishnan^a

MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK

Received April 30, 2021; Revised April 30, 2021; Accepted May 1, 2021

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KEY WORDS: ribosomes, translation, mRNA, ribosome crystallography.

DOI: 10.1134/S0006297921090017

I first encountered Alex Spirin at the ribosome meeting in Berlin in 1992. It was the first time many of us had been to the former East Berlin after the wall had come down in 1989. Of course, Spirin was very well known in the ribosome field, and at the time, I was still a relatively unknown early to mid-career scientist. Spirin gave a talk on which of two models for tRNA binding to the ribosome was correct. What impressed me almost immediately was that unlike many of the talks, which were so dry that you could fall asleep within a few minutes, Spirin’s talk was brilliant and full of passion. It was entertaining. It was clear and logical, and held our attention until the very end. In hindsight, it also happened to be wrong.

In that talk, Spirin revealed many of the qualities that made him a great scientist. He showed that truly great scientists are bold and are not afraid to be wrong occasionally, as in his skepticism about whether the ribosome has an E site. He kept his attention on the most important problems of translation throughout his career. I mention just a few of those that stand out.

In early work in the 1950s, he and his mentor Andrey Belozersky showed that the large variability in the DNA base composition was not present in the RNA. They suggested that much of the RNA was conserved for other reasons and only a small portion of it must represent coding RNA. At that time, many thought that ribosomal RNA actually carried genetic information to be translated, and Spirin and Belozersky’s work presaged the discovery of messenger RNA by others and our current realization that ribosomal RNA is a separate class of non-coding RNA.

A second major advance made by Spirin was in our thinking about how ribosomes move along mRNA during translocation. This movement is normally catalyzed by elongation factor EF-G, which uses the energy of GTP hydrolysis during the process. Spirin suggested that during this process the ribosomal subunits must move relative to each other in locked and unlocked states and work something like a Brownian ratchet in order to proceed unidirectionally along the mRNA. Although the hybrid states model proposed around the same time by Mark Bretscher proved to be closer to the movement that actually occurs, the general idea of movement between subunits and the idea of a Brownian ratchet influenced the scientific community in thinking about translocation. An even more striking piece of work was that his lab was able to drive translocation even in the absence of elongation factors and GTP. This remarkable result showed that translation was an intrinsic property of ribosomes and therefore could have occurred before the evolution of factors, thus shedding light on the origins of protein synthesis.

Spirin’s lab also applied their fundamental knowledge of the biochemistry of translation to develop an in vitro system in which the consumed reagents were continuously refreshed to produce very high yields of protein. It paved the way for the many large-scale in vitro protein synthesis systems that are prevalent today.

My own work directly benefited by the pioneering work in Spirin’s lab. After the first crystallization of the large subunit by Ada Yonath and Heinz Günter Wittmann, Spirin was keen to tackle the goal of obtaining an atomic structure of the ribosome. Marina Garber had just introduced the Thermus thermophilus system into Spirin’s institute in Pushchino and produced small crystals of the ribosome. Two of Spirin’s students, Marat and Gulnara Yusupov, joined the effort, and with some key help from Sergey Trakhanov and others, produced crystals of both the 30S subunit and the entire 70S ribosome. These crystals were the basis of my own 30S structure. In addition, because of the early work in Pushchino, and subsequent work done by the Yusupovs working with Jamie Cate in Harry Noller’s lab, my lab ended up using Thermus thermophilus to obtain a high-resolution structure of the entire ribosome bound to mRNA and tRNAs. So, the work in Pushchino on the use of Thermus thermophilus to obtain crystals of the ribosome and its small subunit laid the groundwork for my own structural work on the ribosome.

After I began working on the structure of the ribosome, I encountered Spirin several more times. Once, at a small meeting in Germany, he recounted the difficulties he had in continuing the ribosome crystallography work in Pushchino, which was the result of external pressure. In what must have been a real disappointment to him, the Yusupovs felt they had no alternative but to leave and pursue the project in Harry Noller’s laboratory.

After the first structures were solved, I made my first and only visit to Russia on the occasion of a symposium in Pushchino to celebrate Spirin’s 70th birthday. I was very curious to see his institute, but I was also excited to see Russia, because I had studied Russian for many years when I was young and had long been fascinated by the country and its culture. To conclude the symposium, Spirin gave a lecture that lasted more than three hours, or roughly as long as David Lean’s film of Boris Pasternak’s Doctor Zhivago, and at least as entertaining. Like the film, the lecture too had an intermission, and just as in the previous much shorter talk of his I had heard in Berlin, it was gripping throughout. Unlike a dry recounting of accomplishments, Spirin told us his story, narrating the context, logic, and motivation behind his tackling various problems and how one thing led to another. It was a masterful performance.

Spirin was much more than a great scientist. He was also a leader and helped to build an internationally respected institute in Pushchino whose alumni have gone on to have a major impact on ribosome and other research. He was also a man of great integrity. Despite the obvious pressures of his time, he never joined the communist party, and as a member of the Soviet Academy of Sciences, he refused to sign a petition to expel Sakharov from it. It was an honor and a pleasure to have known him.

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