PROFILE

Profile of Andrew W. Murray PROFILE

Beth Azar, Science Writer

While speaking about his work as a biologist, Harvard After his first few weeks, Hop- University’s Andrew W. Murray likes to quote the words kins asked a postdoctoral fel- found on theoretical physicist Richard Feynman’s black- low to teach Murray how to board on his death: “What I cannot create, I do not conduct experiments. understand.” Murray, who feels he has much in common “The experience changed with physicists as well as biologists, uses Feynman’squote my life,” he explains. Murray to explain aspects of his own research, including his work returned to the United King- as a graduate student creating an artificial chromosome dom to study biochemistry at and the research reported in his Inaugural Article (1), Clare College at Cambridge which uses synthetic biology to examine how cell University, convinced he would differentiation evolved in multicellular organisms. become a scientist but unsure “The point of building synthetic things is to determine of his focus, even after grad- whether you really understand the science behind their uating. He decided to apply to natural counterparts,” he explains. Murray, who was graduate schools in the United elected to the National Academy of Sciences in 2014, is States, because he would the Herchel Smith Professor of Molecular Genetics, not have to declare his re- a Howard Hughes Medical Institute Professor, and search interests right away, the Director of the FAS Center for Systems Biology and he chose Harvard over Andrew W. Murray. Image courtesy of at Harvard University. Stanford University, because Renate Hellmiss (Harvard University, Cambridge, MA). the program allowed him to Lucky Breaks rotate through different labo- Murray grew up outside Cambridge, England, in the ratories for the first two years. “It turned out to be small town of Linton, a child of expatriates from the fantastic,” he says. “It was not very disciplined, but it United States. His parents met at the Trevi Fountain in was really good for me.” Rome while traveling after graduating from college. They married three months later in Naples and moved to From Chromosomes to Cell Cycle Cambridge, where Murray’s father held a fellowship to At Harvard, Murray worked with molecular biologist study Italian history. As his father completed his PhD over Jack Szostak, who would later win a Nobel Prize in the next seven years, Murray and his four siblings were Physiology or Medicine in 2009. “When he was but a born, leaving the family “solidly settled in England.” humble yeast geneticist, I worked in his lab building “When I was six,” recalls Murray, “Iusedtoorbit artificial chromosomes,” Murray says in jest. the back yard, pretending to be [cosmonaut] Yuri The project was a perfect example of Feynman’s Gagarin, and when I was 12, I wanted to be a race tenet, says Murray. By this time, researchers had iden- car driver. No coordination and slow reflexes per- tified what they thought were the basic building blocks suaded me that studying might be a useful backup of chromosomes: telomeres, a replication origin, a cen- plan, and by the end of high school, I’d decided that tromere, and genes. However, Murray’sfirstattemptat I might want to be a scientist.” building chromosomes failed. He later showed that the Murray began studying biochemistry in college in length of the synthetic chromosomes relative to natural October of 1975. Before entering college, however, chromosomes was key to the construction of synthetic he decided to spend time with an aunt and uncle in chromosomes (2). Boston, where he hoped to volunteer in a laboratory. Murray moved from building chromosomes at Just after Murray arrived, his uncle met someone at a Harvard to studying what drives cells into and out of mixture party who had a friend at Massachusetts In- mitosis at the University of California, San Francisco stitute of Technology (MIT) who owed him a favor. It (UCSF), where he worked with cell biologist Marc was MIT cancer researcher Nancy Hopkins, and she Kirschner. Murray’s longstanding friendship with his hired Murray to work as a technician in her laboratory. mentor, Tim Hunt, a British researcher who discovered

This is a Profile of a recently elected member of the National Academy of Sciences to accompany the member’s Inaugural Article on page 8362 in issue 30 of volume 113.

www.pnas.org/cgi/doi/10.1073/pnas.1612272113 PNAS | September 6, 2016 | vol. 113 | no. 36 | 9953–9955 Downloaded by guest on September 25, 2021 the protein cyclin, inspired his postdoctoral work at “I think that a large part of the future of biological UCSF. His goal was to test some of Hunt’s hypotheses research lies in the hands of scientists who can master about how cyclin regulates cell division. He used a both experiment and theory,” says Murray. “So it’s the technique developed by Canadian scientists Yoshio students and postdocs who come from physics, with a Masui and Manfred Lohka to make extracts of frog strong training in theory, and are now learning how to eggs in which researchers could visualize and experi- do experiments, [who] I’m hoping will be the brave ment on the cell cycle. Using this technique, Murray new creatures of tomorrow.” was able to show that the synthesis of cyclin drove the Currently, Murray’s main research interests are in cell cycle into mitosis (3) and that the destruction of determining whether he and his colleagues can force cyclin was required for cells to exit mitosis (4). yeast in the laboratory to evolve novel properties. One After Murray completed his postdoctoral training study tackled the question of how and why single- in 1989, UCSF hired him as an assistant professor, and celled organisms joined together to form multicellular he established his own laboratory to continue study- clumps (9). Murray and coworkers (9) started with the ing the cell cycle, a booming area of research idea that the physics of diffusion allows cells to benefit that would lead to a Nobel Prize for Hunt in 2001. from neighboring cells. Indeed, a single cell floating Murray’s laboratory used the frog egg extracts to by itself using enzymes to convert proteins in its en- examine chromosome segregation in vitro (5). Along vironment into nutrients can only capture a small with others, his team showed that another protein fraction of those nutrients. If, however, a cell is stuck to had to be degraded before sister chromatids could a few of its neighbors, it absorbs not only a fraction of separate (6). the nutrients that it creates but also, nutrients created Murray’s laboratory also identified (7), in parallel by each of its neighbors. In fact, Murray and coworkers with work by Andrew Hoyt (8), the “spindle check- (9) showed that, when nutrients are scarce, clumping point,” which is a mechanism for cells to determine gives yeast an advantage over single cells, suggesting that sharing resources was a driving factor behind the whether their chromosomes are properly attached to evolution of multicellular life. the mitotic spindle. “If they’re not, the cells send a Although physics provides the foundation for many signal that says, ‘don’t separate the sister chromatids of Murray’s studies, synthetic biology, based on yet because something is wrong,’” explains Murray. Feynman’s theory, gives him the requisite tools. In “It’s a check and balance of sorts.” For the next 10 Murray’s Inaugural Article, he used synthetic biology years, Murray and his team worked on the spindle to tackle the idea of how and why multicellular or- checkpoint, identifying the genes involved and figur- ganisms developed differentiated cells. Murray and ing out how different proteins interfere with the pro- graduate student Mary Wahl wanted to compare two cess that drives the cell cycle forward. routes to this destination: in the first, cells would first evolve to form clumps and differentiate later, Physicist in a Biologist’s Body whereas in the second, they would differentiate first, To pursue a growing interest in evolution that Murray supporting each other by exchanging nutrients, and believed would be more fruitful if carried out in col- only associate with each other later. Wahl and laboration with physicists, Murray moved from UCSF— Murray (1) engineered strains of clumping yeast that a medical school without departments of physics or allowed them to directly compare these two evo- — “ evolutionary biology back to Harvard. Even though I lutionary possibilities. They showed that differenti- ’ didn t do math formally past age 16, it turns out I think ation after multicellularity is a more stable strategy, in a way that is quite similar to a lot of my physicist becauseitismoreresistanttoinvasionbymutants ” friends, he explains. Like theoretical physicists, he says (1). Murray is careful to say that such findings do not “ ” he wishes to understand the rules of the game. prove that evolution happened this way. Rather, “ When I was a graduate student, it was bad form to “evolution could have happened this way.” ask why things worked the way they did. You were Murray continues to create organisms that allow ” supposed to focus on mechanisms, says Murray. him to study the mechanisms by which new traits evolve. “ ‘ ’ But, actually, the how is often shaped in important For example, he and postdoctoral fellow Gregg Wild- ‘ ’” ways by the why. enberg successfully created yeast that evolved a 24-hour ’ Today, much of Murray s work focuses on yeast oscillator, fluctuating from low fluorescence to high and how it responds to changes in the environment. fluorescence over 24 hours, similar to an internal clock “Almost certainly, their responses are related to (10). Murray hopes to use what he learns about evolution their past history and the evolutionary equivalent of in the laboratory to better understand natural selection. learning,” says Murray. The physicists in Murray’s He also hopes to determine whether traits stem more laboratory work in collaboration with Harvard often from mutations that disrupt genes than from a physicist David Nelson to tackle issues that include slow, incremental process that improves genes over how populations of organisms, such as yeast, ex- time. “We’re really interested in looking at evolution in pand in space and time, the forces that control those the natural world to try to find examples where traits expansions, and the factors that lead to or prevent evolved recently enough to ask whether it was by mu- the diversification of populations on expanding tations that destroyed the function of genes or improved frontiers. the genes,” says Murray.

9954 | www.pnas.org/cgi/doi/10.1073/pnas.1612272113 Azar Downloaded by guest on September 25, 2021 1 Wahl ME, Murray AW (2016) Multicellularity makes somatic differentiation evolutionarily stable. Proc Natl Acad Sci USA 113(30): 8362–8367. 2 Murray AW, Szostak JW (1983) Construction of artificial chromosomes in yeast. Nature 305(5931):189–193. 3 Murray AW, Kirschner MW (1989) Cyclin synthesis drives the early embryonic cell cycle. Nature 339(6222):275–280. 4 Murray AW, Solomon MJ, Kirschner MW (1989) The role of cyclin synthesis and degradation in the control of maturation promoting factor activity. Nature 339(6222):280–286. 5 Shamu CE, Murray AW (1992) Sister chromatid separation in frog egg extracts requires DNA topoisomerase II activity during anaphase. J Cell Biol 117(5):921–934. 6 Holloway SL, Glotzer M, King RW, Murray AW (1993) Anaphase is initiated by proteolysis rather than by the inactivation of maturation- promoting factor. Cell 73(7):1393–1402. 7 Li R, Murray AW (1991) Feedback control of mitosis in budding yeast. Cell 66(3):519–531. 8 Hoyt MA, Totis L, Roberts BT (1991) S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function. Cell 66(3):507–517. 9 Koschwanez JH, Foster KR, Murray AW (2013) Improved use of a public good selects for the evolution of undifferentiated multicellularity. eLife 2:e00367. 10 Wildenberg GA, Murray AW (2014) Evolving a 24-hr oscillator in budding yeast. eLife 3:e04875.

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