Man Behaving Oddly

SHIFTING INTERESTS

Murray set out for the frontier as a graduate student, working on chromosome structure and stability with Jack Szostak, a Howard Hughes Medical Institute investigator at Harvard Medical School. "At that time, people were thinking hard about what a chromosome is," says Tim Hunt of Cancer Research UK, who shared the 2001 Nobel Prize. "The question was: Could you construct a whole chromosome? Were the only things you actually needed, the ends and the middle plus a selectable marker?" Murray tackled the problem and cobbled together the first artificial yeast chromosome. "It was really heroic stuff," says Hunt.

That done, Murray switched gears and went off to explore the workings of the cell cycle. Working with Kirschner, then at UCSF, Murray managed to produce extracts from frog eggs that could carry out the complete cell cycle, DNA replication, and mitosis. "It was an ambitious project," recalls Kirschner, now at Harvard Medical School. "It took him well over a year to find the right conditions to get the extracts to behave reproducibly."

Murray then used the extract to demonstrate that cyclin proteins essentially drive the whole cell cycle, and that cyclin must be degraded before the daughter cells could divide. In the key experiment, Murray destroyed all the RNA in the extract and showed that the only component needed to jump start the cycle is the mRNA encoding cyclin. "That was a gutsy experiment," says Kirschner. "If it had required two RNAs, it never would have worked."

As a young faculty member, Murray moved on to study how cells determine when it's safe to divide. He discovered mitotic arrest defective (MAD) proteins that check the spindle on which the chromosomes align. If the structure is damaged, the cell will not divide. The proteins constitute a mitotic checkpoint, and identifying them put the field on the map. Cancer cells may lose this quality control, a defect that Mitchison says many investigators are trying to exploit therapeutically.

Murray chalks these shifting interests up to intellectual restlessness. Hunt says that Murray is exploiting his talents. "Andrew was always a real pioneer. And you can't go on being a real pioneer, because fields mature. Andrew always wants to be out there in the blue sky, in the virgin snow," he says. "But he's an unbelievably talented biologist. And of all the people that have passed through my hands as a teacher, he's the most deep thinking and most original."

And Murray has always been attracted to original approaches, notes Kirschner. "He likes to find out what the deep question is and then he immediately reverts into this very creative experimental mode to figure things out." Mitchison adds, "He aims very high intellectually. He's wicked smart. And he's driven by lofty intellectual goals, trying to understand how life works."

THE 'EUROPEAN UNION' LAB

This yearning to understand the most fundamental principles of life brought Murray back to Harvard, where, in addition to continuing his work on cell-cycle control and the mitotic checkpoint, he has embraced a more systems type of approach to research by collaborating with colleagues who specialize in physics, math, and evolution. "The future of biology lies in trying to understand how the complicated things that cells do can be described in quantitatively satisfying terms, understanding how those processes interact with each other to make living cells, and how the properties of cells are shaped by evolution," says Murray. "I cannot even begin to conceive of how we can accomplish those things without relying on the interactions of smart, pointy-headed people from a variety of disciplines."

In his own lab, Murray has two postdocs who have degrees in theoretical physics, and a graduate student (whom he shares with Harvard physicist Daniel Fisher) who started life as a string theorist. "It seems the culture of the modern biology lab mimics the culture of this benighted country, which is to believe that the world outside its borders is either hostile, irrelevant, or both," laments Murray. "I think it's good to take a more European-Union view of the world."

Murray is also laboring to create an interdisciplinary approach to the life sciences at Harvard, using what he dubs a "mixture of recruitment, social engineering, and cheerleading." As director of Harvard's Bauer Center For Genomics Research, Murray has tried to assemble an intellectual melting pot by recruiting an exciting community of postdoctoral-level fellows from a variety of disciplines to work together in discovering interesting things about biological principles.

At the same time, Murray is attempting to replicate his Bauer Center success as chair of the Department of Molecular and Cellular Biology. He hopes to encourage his fellow faculty members to look outward and interface with investigators in sister departments, particularly those in the physical and mathematical sciences. Working with Kirschner and Mitchison, who steer the systems biology department at the medical school, Murray has helped establish a joint graduate program in systems biology and is busy recruiting bright, energetic new faculty who are interested in probing the general principles of biology. "The risk is whether he'll manage to hire enough good people who share his vision before he implodes," laughs Kirschner. "But so far he seems to be succeeding."

FEED THE YEAST

The approach comes to fruition in Murray's lab, where the former string-theory enthusiast, Michael Desai, is spearheading one of Murray's "big-picture" projects: clocking the speed of evolution in a population of budding yeast. In one set of experiments, the researchers force yeast to adapt to growth on reduced amounts of glucose. "We're asking them to revert from a junk-food American lifestyle to a slimmed-down ascetic diet," says Murray. They then determine how quickly the yeast accumulate mutations in response to the altered environment.

Nailing down real numbers would be a major accomplishment, because "there's no quantitative nature to evolutionary theory," says Kurt Thorn, a Bauer Center research fellow. And it would also help scientists get a handle on the question of sex. "One of the theories for the evolution of sex is that it helps you evolve more quickly," notes Desai. "But to answer that, you have to know: more quickly than what?"

Although Murray no longer engages in benchwork, the evolution projects smack of his style. "As far as I can tell, the experiments are really, really hard," says Thorn. "People in his lab grow 60 replicate cultures of yeast for three months. Physically it's a lot of work. And then they have to fish over the whole 12-megabase genome to find the mutations."

Murray revels in poring over the resulting data. "He always understands what you've shown, what you haven't, and what the possible issues and complications could be," says Desai. "And he always has a million experimental ideas, and they're usually good ones."

FOLLOW THE DNA

For Murray, probing the mechanism of genetic adaptation is a natural extension of his earlier explorations on how organisms shuttle their chromosomes from one generation to the next. "I have a running battle with some of my dear friends who insist that genetics is a technique, which it is." says Murray. "But it's also a science: the study of how genetic information is encoded, transmitted, and expressed." His interest in genetics, Murray says, naturally raises the larger question of how living systems have evolved: "How do cells, which are devices for shooting DNA into the future, actually work?"

Murray's approach to the problem is "clearly highly original," says Mitchison, which makes it difficult to assess. "At this point, I'm taking Andrew's word for it that it'll tell us how regular evolution works," he says.

"It's rather typical of Andrew that he would take something that's pretty far out and attempt to do it," adds Hunt. "But if anybody were going to succeed, you'd put your money on Andrew because he's so formidably clever and determined."

Murray's young charges admire his drive as well. Many successful scientists at this stage of the game would be tempted to sit on their laurels, says Thorn. "It's admirable that Andrew's trying to do new things that he thinks are interesting."

His inquisitive nature, coupled with the trail of As, Ts, Gs, and Cs that streamed from the Human Genome Project, also draws Murray down some fairly philosophical paths. "For reasons I can't explain, completing the sequence of the human genome really made me think hard about what we mean by free will and determinism," Murray says. His conclusion: "Free will is a mere charade of our fevered imaginations." The brain, he says, is like an old-fashioned pinball machine in which decisions are made the same way that the ball bounces off pins. With experience, we learn to change the placement of the pins to increase the likelihood of achieving the desired outcome, in the process creating "the illusion that you are this totally free agent acting to make decisions, rather than a product of this endless iteration of moving these pins around."

"That's about as frightening a concept as I can think of," says Murray. Even more frightening, it seems, than the idea of prancing around the front of a classroom in fishnet stockings and a form-fitting red rubber dress.