Nicholas R. Cozzarelli (1938–2006) Carlos Bustamante* Howard Hughes Medical Institute, and Departments of Molecular and Cell Biology, Physics, and Chemistry, University of California, Berkeley, Berkeley California 94720
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icholas R. Cozzarelli, Professor of Molecular and Cell Biology at the University of California at Berkeley, a star scientist of first magnitude, a colleague of uncompromising integrity, a great teacher, and warm friend, died on Sunday March 19, 2006, of complications associated with the treatment of lymphoma. Nick was born in New Jersey, the son of immigrants from southern Italy. His father was a shoemaker and his mother worked editing phone books. As a young man, Nick obtained a full scholarship to attend Princeton where he graduated with an A.B. Magna Cum Laude in 1960. He then entered Yale University with the intention of becoming a lawyer, but became instead interested in medical school, which he attended from 1960 to 1961. It was during this period that he realized that his true vocation was research and thus he applied and was admitted to graduate school at Harvard University where he obtained a Ph.D. in Biochemistry in 1966. Following graduate studies, Nick joined Arthur Kornberg’s laboratory at Stanford, where he became engaged and passionately interested in DNA replication. The discovery of topoisomerases in the early 1970s sparked a host of experiments to understand how these molecules controlled the topological state of DNA molecules. Soon it became evident that these important enzymes were involved in many other central cellular processes besides their function as regulators of the degree of DNA supercoiling. Topoisomerases facilitate the opening of the double helix during DNA replication and transcription, thus favoring the www.acschemicalbiolog y.o rg
translocation of these enzymes along the DNA. Moreover, these enzymes are also essential to allow the proper segregation of chromosomes prior to cell division. Many ingenious mechanisms had initially been proposed for topoisomerases, but they proved to be incorrect. Nick and co-workers demonstrated instead that DNA was passed through enzyme-bridged breaks. This allowed these enzymes not just to change supercoiling, the activity which first defined topoisomerases, but also to disentangle and decatenate DNA. The Cozzarelli lab also showed that decaten ation, not supercoiling or relaxation, was the vital function of topoisomerases III and IV. Cozzarelli and co-workers demonstrated that type II topoisomerases act, in a way, as Maxwellian demons, removing the topological links far past equilibrium, using the energy of ATP hydrolysis. They also uncovered the mechanism underlying this feat. Topoisomerase IV has yet additional specificity: the Cozzarelli lab showed that it removes (+), but not (–) supercoils, so that it can promote the movement of the replication fork without eliminating the (–) supercoils, which are essential for chromosome organization. Early, during his initial involvement with topoisomerases, Nick Cozzarelli realized that the number and type of possible products of the topoisomerase catalyzed reactions were restricted by powerful mathematical theorems that dictate the topological transformations of closed space curves possessing connectedness, such as circular DNA. What followed was his elegant unification of biochemical and mathematical methods to determine the conformation
Nicholas R. Cozzarelli
*To whom correspondence should be addressed: E-mail:
[email protected].
Published online April 21, 2006 10.1021/cb600153e CCC $33.50 © 2006 by American Chemical Society
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and topology of higher‑order DNA structures such as supercoils, catenanes, and knots. In this effort, Nick Cozzarelli realized that these mathematical restrictions (called topological invariants) made it possible also to infer the possible molecular mechanisms used by enzymes that catalyzed the modification of these DNA topological states. Using this approach, his group was able to suggest possible enzymatic mechanisms for these topology-acting catalysts. The most recent set of contributions by Nick and co-workers concerns the global structure of chromosomes. This subject had deep roots in Nick’s past studies. He and co-workers first found that free (–) super coiling in bacteria plays an unexpected and vital role in DNA compaction. They showed that many DNA gyrase mutants failed not at initiation or elongation of replication, as was initially expected, but because decatenation of DNA by topoisomerase IV was blocked. They then showed that super coiling increases the rate of decatenation by many orders of magnitude. They also studied the mechanism of DNA condensation by condensins and found again that loops of supercoiled DNA played a critical role in this process. In addition, Nick and co-workers showed that, in bacteria, topological domains are much smaller than that which was presumed to be the case over the past 30 years. These domains have been found to be, on average, only 10 kb in size. Moreover, the Cozzarelli laboratory discovered that the domain barriers are not DNA sequence-specific and are, in fact, quite transient. Nick and his students then went on to characterize, through genetic and biochemical screens, four proteins that are involved in maintaining the topologically closed domains of a bacterial chromosome. Because of their importance in DNA metabolism, topoisomerases have become the target of numerous antibiotics and cancer treatment drugs. Here, Nick Cozzarelli’s group played an important role in the deciphering of the mechanism of 124
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inhibition of key antibiotics and anticancer agents, including quinolones such as ciprofloxacin and coumerins such as novobiocin, both inhibitors of DNA gyrase, an essential type II topoisomerase in Gram-positive and Gram-negative microorganisms. Today, about two-thirds of all cancer chemotherapy regimens contain a topoisomerase inhibitor. Thus, unlike the work of many scientists, Nick’s academic endeavors were shown to have a direct impact in the treatment of diseases. Although trained originally as a biologist and a biochemist, Nick Cozzarelli saw before many that scientific research is a playground where many disciplines converge and where understanding often requires bridging apparently disconnected realms of knowledge. He saw clearly the need to break the language and cultural barriers that still separated biologists from physicists and mathematicians in the last quarter of the twentieth century. Thus, because of his own frustrating experiences attempting to communicate with mathematicians, Nick formed in 1985 the Program in Mathematics and Molecular Biology (PMMB). This program got biologists, mathematicians, and physicists together for a number of years and has been the model for subsequent programs of science in which people try to reach across the scientific interface. Nick Cozzarelli’s leadership in science is widely recognized in the scientific community. Elected in 1989 to the National Academy of Sciences, Nick became Editorin-Chief of the Proceedings of the National Academy of Sciences in 1995. In this position he transformed a respected publication with an arcane submission process into the premier journal for the publication of first rate scientific articles in biology and other disciplines. Nick Cozzarelli is broadly regarded as the best Editor of the Proceedings. Nick’s interest in fostering the development of science also led him to play Bustamante
a number of important roles in various Academy committees. Thus, he was the chair of the National Academy of Sciences Section on Biochemistry, a member of the Academy’s Committee on the Funding of Young Investigators, a member of the Committee on strengthening the linkages between science and the mathematical sciences, and the committee on research standards and practices to prevent the destructive application of biotechnology, among others. Finally, it is important to mention his leadership in the promotion of a freer access to the scientific literature. The journal that he edited, the Proceedings of the National Academy of Sciences, has taken a leadership role in this regard. He was also an important contributor to the establishment of PubMed Central and the Public Library of Science. When I moved to Berkeley in 1998, Nick and I talked about a number of problems that were just then becoming accessible to analysis by the methods of single mole cule manipulation that my students and I had been developing at the University of Oregon. What ensued were some of the most exciting years of my scientific career. Endowed with a keen sense of what is important, Nick was a mind constantly on the move, thinking of new ways of using these powerful new methods to study important problems in biochemistry. Working with Nick was one of the privileges that I cherished upon joining the faculty at Berkeley. Our meetings, coded by our students either as a “Cozzamante” or a “Bustarelli” meeting, to indicate whether they were to be held in Nick’s or in my laboratory, respectively, led to some of the most exciting science and publications of my career. It was in this small gatherings that I learned to admire Nick Cozzarelli’s scientific insight, his unmatched ability to ask the crucial questions about any problem, and his intellectual honesty which only accepts one adjective: uncompromising. There, in these often-heated w w w. a c s c h e m i ca l biology.org
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scientific discussions, we became good colleagues first and then good friends. He was a tough, critical evaluator of his own science and that of his colleagues. Our common Italian background was a cultural reference that we enjoyed sharing with one another. He enjoyed life, the good cuisines of the world, the good wine, art, music, and the theater. Having acquired a classical education, he never used it to show off but to make instead incisive, appropriate comments that benefited from the wisdom of the old culture. His premature departure robs us from one of the true creative talents in quantitative experimental biology. Throughout his almost two-year battle against the disease, Nick Cozzarelli taught his friends and students one final lesson. Hemingway has written that the “true measure of courage is to display grace under pressure”. Those of us that worked close to him witnessed, often in disbelief, his dedication to work until the very end, never uttering a com-
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plaint even when it was plainly obvious that he was in pain, uncomfortable, or suffering. He refused to stop a meeting or to interrupt an argument because of his condition. In one of the opportunities in which I drove him to Stanford for his chemotherapy session, our scientific discussion got so animated that we passed the exit for the Dumbarton Bridge by 20 miles, before we realized it! In fact, those of us that worked closely with him until the very end often had the impression that he was treating his own condition as an inconvenience, a nuisance of secondary importance that should not distract us from our tasks at hand. It was his last lesson, his lesson on courage. It was his way to remind us how much was still left to do in the lab, his way to tell us, true to his Latin background, “ars longa, vita brevis”. Today, I can only reflect in these so many lessons about science and life that I learned from Nick Cozzarelli. I will miss greatly my friend.
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