Profile of Andrew W. Murray

While speaking about his work as a biologist, Harvard University’s Andrew W. Murray likes to quote the words found on theoretical physicist Richard Feynman’s blackboard on his death: “What I cannot create, I do not understand.” Murray, who feels he has much in common with physicists as well as biologists, uses Feynman’s quote to explain aspects of his own research, including his work as a graduate student creating an artificial chromosome and the research reported in his Inaugural Article (1), which uses synthetic biology to examine how cell differentiation evolved in multicellular organisms. “The point of building synthetic things is to determine whether you really understand the science behind their natural counterparts,” he explains. Murray, who was elected to the National Academy of Sciences in 2014, is the Herchel Smith Professor of Molecular Genetics, a Howard Hughes Medical Institute Professor, and the Director of the FAS Center for Systems Biology at Harvard University.

Andrew W. Murray. Image courtesy of Renate Hellmiss (Harvard University, Cambridge, MA).

Lucky Breaks

Murray grew up outside Cambridge, England, in the small town of Linton, a child of expatriates from the United States. His parents met at the Trevi Fountain in Rome while traveling after graduating from college. They married three months later in Naples and moved to Cambridge, where Murray’s father held a fellowship to study Italian history. As his father completed his PhD over the next seven years, Murray and his four siblings were born, leaving the family “solidly settled in England.”

“When I was six,” recalls Murray, “I used to orbit the back yard, pretending to be [cosmonaut] Yuri Gagarin, and when I was 12, I wanted to be a race car driver. No coordination and slow reflexes persuaded me that studying might be a useful backup plan, and by the end of high school, I’d decided that I might want to be a scientist.”

Murray began studying biochemistry in college in October of 1975. Before entering college, however, he decided to spend time with an aunt and uncle in Boston, where he hoped to volunteer in a laboratory. Just after Murray arrived, his uncle met someone at a mixture party who had a friend at Massachusetts Institute of Technology (MIT) who owed him a favor. It was MIT cancer researcher Nancy Hopkins, and she hired Murray to work as a technician in her laboratory. After his first few weeks, Hopkins asked a postdoctoral fellow to teach Murray how to conduct experiments.

“The experience changed my life,” he explains. Murray returned to the United Kingdom to study biochemistry at Clare College at Cambridge University, convinced he would become a scientist but unsure of his focus, even after graduating. He decided to apply to graduate schools in the United States, because he would not have to declare his research interests right away, and he chose Harvard over Stanford University, because the program allowed him to rotate through different laboratories for the first two years. “It turned out to be fantastic,” he says. “It was not very disciplined, but it was really good for me.”

From Chromosomes to Cell Cycle

At Harvard, Murray worked with molecular biologist Jack Szostak, who would later win a Nobel Prize in Physiology or Medicine in 2009. “When he was but a humble yeast geneticist, I worked in his lab building artificial chromosomes,” Murray says in jest.

The project was a perfect example of Feynman’s tenet, says Murray. By this time, researchers had identified what they thought were the basic building blocks of chromosomes: telomeres, a replication origin, a centromere, and genes. However, Murray’s first attempt at building chromosomes failed. He later showed that the length of the synthetic chromosomes relative to natural chromosomes was key to the construction of synthetic chromosomes (2).

Murray moved from building chromosomes at Harvard to studying what drives cells into and out of mitosis at the University of California, San Francisco (UCSF), where he worked with cell biologist Marc Kirschner. Murray’s longstanding friendship with his mentor, Tim Hunt, a British researcher who discovered the protein cyclin, inspired his postdoctoral work at UCSF. His goal was to test some of Hunt’s hypotheses about how cyclin regulates cell division. He used a technique developed by Canadian scientists Yoshio Masui and Manfred Lohka to make extracts of frog eggs in which researchers could visualize and experiment on the cell cycle. Using this technique, Murray was able to show that the synthesis of cyclin drove the cell cycle into mitosis (3) and that the destruction of cyclin was required for cells to exit mitosis (4).

After Murray completed his postdoctoral training in 1989, UCSF hired him as an assistant professor, and he established his own laboratory to continue studying the cell cycle, a booming area of research that would lead to a Nobel Prize for Hunt in 2001. Murray’s laboratory used the frog egg extracts to examine chromosome segregation in vitro (5). Along with others, his team showed that another protein had to be degraded before sister chromatids could separate (6).

Murray’s laboratory also identified (7), in parallel with work by Andrew Hoyt (8), the “spindle checkpoint,” which is a mechanism for cells to determine whether their chromosomes are properly attached to the mitotic spindle. “If they’re not, the cells send a signal that says, ‘don’t separate the sister chromatids yet because something is wrong,’” explains Murray. “It’s a check and balance of sorts.” For the next 10 years, Murray and his team worked on the spindle checkpoint, identifying the genes involved and figuring out how different proteins interfere with the process that drives the cell cycle forward.

Physicist in a Biologist’s Body

To pursue a growing interest in evolution that Murray believed would be more fruitful if carried out in collaboration with physicists, Murray moved from UCSF—a medical school without departments of physics or evolutionary biology—back to Harvard. “Even though I didn’t do math formally past age 16, it turns out I think in a way that is quite similar to a lot of my physicist friends,” he explains. Like theoretical physicists, he says he wishes to understand the “rules of the game.” “When I was a graduate student, it was bad form to ask why things worked the way they did. You were supposed to focus on mechanisms,” says Murray. “But, actually, the ‘how’ is often shaped in important ways by the ‘why.’”

Today, much of Murray’s work focuses on yeast and how it responds to changes in the environment. “Almost certainly, their responses are related to their past history and the evolutionary equivalent of learning,” says Murray. The physicists in Murray’s laboratory work in collaboration with Harvard physicist David Nelson to tackle issues that include how populations of organisms, such as yeast, expand in space and time, the forces that control those expansions, and the factors that lead to or prevent the diversification of populations on expanding frontiers.

“I think that a large part of the future of biological research lies in the hands of scientists who can master both experiment and theory,” says Murray. “So it’s the students and postdocs who come from physics, with a strong training in theory, and are now learning how to do experiments, [who] I’m hoping will be the brave new creatures of tomorrow.”

Currently, Murray’s main research interests are in determining whether he and his colleagues can force yeast in the laboratory to evolve novel properties. One study tackled the question of how and why single-celled organisms joined together to form multicellular clumps (9). Murray and coworkers (9) started with the idea that the physics of diffusion allows cells to benefit from neighboring cells. Indeed, a single cell floating by itself using enzymes to convert proteins in its environment into nutrients can only capture a small fraction of those nutrients. If, however, a cell is stuck to a few of its neighbors, it absorbs not only a fraction of the nutrients that it creates but also, nutrients created by each of its neighbors. In fact, Murray and coworkers (9) showed that, when nutrients are scarce, clumping gives yeast an advantage over single cells, suggesting that sharing resources was a driving factor behind the evolution of multicellular life.

Although physics provides the foundation for many of Murray’s studies, synthetic biology, based on Feynman’s theory, gives him the requisite tools. In Murray’s Inaugural Article, he used synthetic biology to tackle the idea of how and why multicellular organisms developed differentiated cells. Murray and graduate student Mary Wahl wanted to compare two routes to this destination: in the first, cells would first evolve to form clumps and differentiate later, whereas in the second, they would differentiate first, supporting each other by exchanging nutrients, and only associate with each other later. Wahl and Murray (1) engineered strains of clumping yeast that allowed them to directly compare these two evolutionary possibilities. They showed that differentiation after multicellularity is a more stable strategy, because it is more resistant to invasion by mutants (1). Murray is careful to say that such findings do not prove that evolution happened this way. Rather, “evolution could have happened this way.”

Murray continues to create organisms that allow him to study the mechanisms by which new traits evolve. For example, he and postdoctoral fellow Gregg Wildenberg successfully created yeast that evolved a 24-hour oscillator, fluctuating from low fluorescence to high fluorescence over 24 hours, similar to an internal clock (10). Murray hopes to use what he learns about evolution in the laboratory to better understand natural selection. He also hopes to determine whether traits stem more often from mutations that disrupt genes than from a slow, incremental process that improves genes over time. “We’re really interested in looking at evolution in the natural world to try to find examples where traits evolved recently enough to ask whether it was by mutations that destroyed the function of genes or improved the genes,” says Murray.