The Road to the Nobel Prize in Chemistry
Without DNA repair mechanisms, the longevity of many living organisms would be reduced. A healthy human body is able to repair much of the damage caused by attacks from the exterior (sun, environment, etc.) or mistakes caused by the body itself. Yet the study of repair mechanisms has long remained in the shadows. In 2015, the Nobel Prize in Chemistry sought to shed new light on the field by rewarding three specialists: Thomas Lindahl, Paul Modrich, and Aziz Sancar.
While proof of DNA repair dates to the 1950s-1960s, it was only in 1980-2000 that scientists were able to make the field a specialty in its own right, with its own journal DNA Repair and conferences. Moreover, the field finally had its own mythology: an official history of its early researchers and their trials and errors until their discoveries about the biological mechanisms of living cells that detect and repair damaged DNA.
Despite these developments, the lack of official recognition by the ‘international scientific community’ always seemed to concern researchers in this field, with some lamenting that the field had not received any recognized awards.
How to explain this lack of recognition? Would this be better explained by a geographical approach to the field? That is the hypothesis that we adopted. We studied the geography of scientific activities and groups globally by examining the growth of the contemporary scientific production system (all disciplines), seen through the dynamics of one specialty: DNA repair. First, we analyzed publications with the keyword “DNA Repair” in the 1960s, and then compared the global geography that resulted with that in 2006-2008. By precisely identifying the sites where this field of research emerged, this research identified the factors that enabled the field to spread geographically and to gradually emancipate itself from its origins in radiation research.
Out of the Shadows, into the Light
Errol C. Friedberg, an American pioneer in the field, offered one explanation for the lack of recognition: it was not easy to admit that DNA repair mechanisms existed because no one dared to think that genes could be damaged. For genetic transmission purposes, DNA was supposed to be stable, unassailable. Thus, it was physics researchers, concerned about the effects of radiation on living beings after the Second World War, who arrived at the conclusion that DNA strands could not only be damaged but also repair themselves.
Radiation biologists and photobiologists worked in laboratories in Oak Ridge in the United States (involved in the Manhattan project making the nuclear bomb), Harwell in Great Britain, Rijswick in the Netherlands, Pushchino in Russia, and Chalk River in Canada. For reasons of military and domestic security, and also simply because of the space needed for the large equipment (cyclotrons), these research sites were located well away from major urban centers. It was primarily in these remote labs, now focused on applied research, that the earliest evidence was found of DNA repair. As research priorities in these government laboratories changed, and links were found between DNA repair and the risk of cancer and aging, research then gradually moved to universities, hospitals, and cancer research centers.
The Geographical Expansion of the Field
While research conducted at Oak Ridge in 1960-1970 accounted for over 4% of the total number of articles on this subject, they only amounted to 0.1% of scientific studies in 2006-2008. A similar phenomenon was observed with Russian laboratories in Moscow, Pushchino, and St. Petersburg, whose activity level was significant until the 1980s. Conversely, there are places that were hardly or moderately involved in the early years, that are today very involved in our understanding of DNA repair: such as Texas cities and Dutch cities, with many teams of researchers working on this topic. Friedberg thus speaks of a “Texas Mafia” woven throughout this US state, while James Cleaver mentions a “Dutch Army” to account for the Netherlands’ experts.
While early on, some researchers in these two regions were very interested DNA repair, such as Walter Harm and Stan Rupert (Texas) and Dirk Bootsma and Paul Lohman (the Netherlands), their mere presence is not enough to explain the unusual process of local and global dissemination. However, monitoring the careers of pioneers (and their geographical mobility) and the co-authors of articles enables us to better understand the privileged bonds, that were gradually established between different laboratories, even internationally. Some of these connections have lasted over time, suggesting the establishment of serious partnerships between teams, for example with the regular exchange of junior researchers.
Despite the wealth of information obtained, the inevitable limitations of bibliographic sources should be noted. They do not provide information about the institutional context (such as material resources, opportunities for recruitment, or academic exchange programs), nor to the researchers’ modes of sociability when they meet and work together during events such as workshops or conferences. We did note, however, that the joint training program between the universities of Leiden and Rotterdam, which was gradually extended to the rest of the country, fostered the increase in exchanges among the Dutch teams in the 1990s.
The Career Paths of the Three 2015 Nobel Prize Winners in Chemistry
Having drawn up the map of scientific production on DNA repair at different periods, we then had a relevant grid of analysis for interpreting and better situating the trajectories of scientists in this field. Moreover, drawing on documents and accounts of the history of the field, we shed new light on the career paths of the three Nobel Prize winners in Chemistry in 2015.
First there is Thomas Lindahl, a Swedish doctor converted to biochemistry. His early research on DNA degradation and its consequences date from the early 1970s. In 1972, after his post-doc in the United States, he worked at the Chemistry Department of the Karolinska Institutet. There, he published the first decisive article for the specialty, foreshadowing the major discovery in 1974 of a previously unknown DNA mechanism: base excision repair.
With his career launched, he was appointed Professor at the University of Gothenburg and then in the early 1980s, head of the research team in one of the laboratories at the Imperial Cancer Research Fund (ICRF) of Greater London. He remained there a few years before being named director of Clare Hall Laboratories cancer research from its opening until 2006. At ICRF, which became Cancer Research UK, he took over from John Cairns and ensured the continuation of the innovative work begun by Cairns’ team on DNA repair, though not a fashionable subject at the time.
Paul Modrich and Aziz Sancar were on the other side of the Atlantic, and their career paths remained intertwined. While the former distinguished himself in the study of mismatch repair mechanisms, the second worked on the repair mechanisms triggered by UV radiation. They both received a professorship, the former at private Duke University in North Carolina and the latter in the public University at Chapel Hill, which strengthened the role of this geographical area, Research Triangle Park, in DNA repair. Second, their PhD supervisors, responsible for their early interest in this subject, were both from Johns Hopkins University (Baltimore): biochemist Robert Lehman supervised Paul Modrich’s thesis at Stanford, and biophysicist or photobiologist Stan Rupert supervised that of Aziz Sancar at the Southwest Center for Advanced Studies (Dallas), now the University of Texas at Dallas. Finally, Modrich and Sancar recently co-published an article in the Journal of Biological Chemistry involving the members of their laboratories to explore the links between the repair mechanisms by excision, by mismatch, and by cell cycle surveillance.
Unlike Lindahl, whose education led him to work on DNA repair in Britain, the careers of Modrich and Sancar are characteristic of the progressive expansion of the specialty to a small number of zones in the United States: the east coast, San Francisco Bay, and Texas. Given the large number of DNA repair mechanisms discovered since 1950 and the future perspectives for research on their relationships, their possible failures, their dynamics and variations, we expect that the progress made in this field, and the recognition it will receive, will continue to grow.
Crédits image à la Une : CC Pixabay MasterTux