Over the centuries, few scientists have thought and strived more concertedly regarding the nature of science and its direct impact on the progression of humanity than the legendary Max Perutz (1914-2002). Born in Vienna Austria, the infamous scientist who was not only of Jewish descent but also a relapsed Catholic believer, Max came to be known as an individual who sought the truth in science, what was right, as well as what was worthwhile in life. The first half of Perutz’s life was mainly dedicated to the seemingly insurmountable structural biology problem of trying to solve or map the protein’s structure at an atomic resolution. However, it was in the second phase that his career blossomed further, as he went on to conduct some of the best work as a scientist that even won him a Nobel Prize.
This momentum began back in 1947. Max had experienced a tumultuous period seven years prior, where he had been interned and deported from the US as a Canadian alien, only to be back for the sake of working on a top-secret and bizarre war project. It was after this that he founded a small research team along with James Watson and Francis Carrick intending to discover the DNA structure. Under his leadership, the research group went on to become the most famous and most consulted Molecular Biology laboratory across the globe. At the time, the discovery of X-ray diffraction through wet protein crystals had provided mass inspiration for a new generation of scientists that wanted to identify the method of translating that theory on protein structures. However, interpreting X-ray diffraction not only required understanding the directions and intensities of the diffracted rays through direct measurement but also required comprehending the phases of diffraction; thus making the concept a formidable stumbling block. It remained a problem, until Max Perutz introduced the isomorphous replacement procedure in 1954, after nearly a decade of research and laboratory testing. Five more years of intense work were then required to determine the structures of the haemoglobin protein (Max) and the myoglobin structures by his colleague John Kendrew. It was this accomplishment that won him the 1962 Nobel Prize, shared with Kendrew.
This breakthrough subsequently launched an unprecedented era in medicine, heralding the contemporary advances seen in terms of the genetic basis of diseases. Afterwards, David Phillips, along with his colleagues, drew inspiration from the replacement method and solved the lysozyme structure. This was followed by mapping of the a-chymotrypsin, ribonuclease A, and carboxypeptidase, which then opened the floodgates to the exploration of three-dimensional structures of proteins. Max, in turn, went on to become an ambassador for science, an accomplished writer, and a champion for human life who inspired both scientists and non-scientists alike. He also decided to continue the exploration of molecular structures, considering them as a springboard towards understanding the secrets of life, thus switching to an enzymologist.
It was this switch that inspired the author of “Gene Mutation: The Race to Decipher the Secrets of the Ribosome,” Venki Ramakrishnan, to jump onto the Biological transformation that was occurring in the 1970s. Venki, who had traveled from Bombay (India) to the US with the objective of pursuing a PhD in Theoretical Physics, abruptly decided to switch to the revolution of DNA structure and molecular biology; following in the footsteps of Max Perutz, among other illustrious scientists like Francis Crick and Max Delbruck. He then read an article on the concept of the ribosome in the ‘Scientific American’ magazine and spent approximately two years at the University of California (San Diego) as a graduate student in molecular biology. In the article, Ramakrishnan believes that without Max Perutz offering a glimpse of the structure of proteins, he would not understand how molecules communicate in the cells; and that the progress of his groundbreaking mapping of the ribosome would be unthinkable without Max’s pioneering work.
Peter Moore
Peter Bartlett Moore, who is currently a Sterling Professor of Chemistry as well as department head of Biochemistry and Biophysics at Yale University, was born on 15th October 1939 in Boston, Massachusetts. He gained an early appreciation and interests towards biological concepts thanks to his father who was had not only made pioneering contributions on transplantation surgery as a Harvard professor but was also the top surgical doctor at Peter Bent Bingham Hospital. This background ensured that he went to an elite private high school where he met two teachers – one of them teaching mathematics and the other guided chemistry and astronomy- who actively steered him towards a more physical scientific direction. After attending Yale and completing his undergraduate degree, Moore abruptly decided to follow his father’s lead by joining Harvard University for a graduate training in biophysics. It was this somewhat fortuitous move that led to a meeting with his supervisor James Watson, who was already famed for his work on the DNA double helix. In their work together, Watson introduced the concept of Ribosome to Moore, which eventually came to be his career’s primary focus.
For his postdoc work, Peter went to work with Alfred Tissieres at the University of Geneva, who was both Watson’s friend and collaborator in the field of the ribosome. It was here that Moore made significant progress in the primary purification of the fifty different proteins that typically made up the ribosome. However, he realized that caveat to understanding the ribosome lay in fully comprehending its structural intricacies by applying skills of structural analysis. As such, he left Geneva and headed for the Medical Research Council (MRC) Laboratory of Molecular Biology located in Cambridge, England. This move to MRC-LMB that saw him introduced to the H.E Huxley laboratory, a descendant lab where both Watson and Crick had previously worked on the DNA, where he started working on the concepts of ‘structural biology.’ At the end of this LMB stint, Moore returned to the US as a bona fide faculty member in Biophysics and was appointed in the Yale department in 1969; which he has been a part of from then to the present day.
From an outsiders perspective, Moore seemed to be at the right places during the right times throughout his early career. Even the infamous scientist and celebrated writer believe that the biochemical path forward for his generation of scientists trained in elite schools and well-established laboratories was remarkably smooth. However, his long-term colleague at Yale (Donald Engelman) debunks such a contention attributing everything to luck, as he vehemently asserts that Moore always fully committed himself to the opportunities given to him. It was during this time (around 1971) that Moore and Don heard a proposal by Benno Schoenborn from Brookhaven National Lab of how neutrons could be utilized in the study of biological molecules. This talk allowed the two scientists to understand how to make a ribosome, where two proteins with the heavy deuterium isotope rather than the hydrogen atoms themselves, thus allowing the neutrons to scatter differently. Applying neutron scattering allowed them to accurately map as well as triangulate the locations of the fifty proteins and three RNA strands within the ribosome. This eventually resulted in a 15 year or more journey of amazing and groundbreaking scientific discoveries as well as approximately 20 widely acclaimed papers co-authored between them; leading to the modern mapping of the small ribosomal subunits.
It was in their quest for biochemist or physicist that could use a nuclear reactor to produce enough neutrons in the neutron scattering experiment that intertwined Moore’s path with Venki Ramakrishnan. After having been introduced to each other by Engelman and having corresponded several times over letters between Yale and California, the two eventually met at a conference in San Diego at a scientific conference; where he offered the Venki his first work in the Job Market after graduating. When Venki arrived at Moore’s Chemistry lab at Sterling University, the first few proteins had been located through deuteration of proteins to mix them into a solution, then (under right conditions) the purified RNA and proteins were reassembled into functional subunits. The author of “Gene Mutation: The Race to Decipher the Secrets of the Ribosome,” spent the next three years mapping and locating over half of the proteins within the ribosome as well as writing several papers revealing their location. Although Venki did oversee the entire project due to the end of his postdoc period (finished by Malcom Capel), it is apparent that Moore played a significant role in establishing his foundation in the world of the biological structures. It is this foundation that served as a massive springboard towards his biochemical work that eventually won him the 2009 Nobel Prize along with Thomas Steitz and Ada Yonath.