Profile of Gary Ruvkun

PROFILE Profile of Gary Ruvkun wash in the faint glow of a fluo- Brush with Molecular Biology rescent lamp, a pair of serpentine The story of Ruvkun’s metamorphosis Anematode worms lie on a Petri from a keen undergraduate into a leading plate, their see-through bodies light in his field of study begins at Har- magnified 100-fold by one of several vard University, where he enrolled in microscopes arrayed in a darkened bay in a Ph.D. program in 1976 upon returning National Academy of Sciences member to the United States. Like many other Gary Ruvkun’s laboratory at Massachu- scientific institutions across the world in setts General Hospital. While one of the the mid-1970s, Harvard was astir with the worms wiggles its way around the plate, promise of recombinant DNA technol- the other shows no signs of life, ogy, and Ruvkun wasted no time em- its midsection ruptured and its innards bracing its tools. “My undergraduate strewn asunder. A filter slides into place, education had not prepared me at all for and the worms are bathed in a dull recombinant DNA, but I immersed my- green haze. The wiggling worm has a bea- self into its culture at Harvard, much of con of nerve cells in its head, the ganglia which was James Watson’s creation from lit up by a genetic trick that has rescued a decade earlier,” Ruvkun says. Propelled the worm from death; its neighbor wears Gary Ruvkun. by a desire to be a part of the culture of no such beacon. The worms were deprived basic molecular biology, all while per- of a tiny RNA molecule, called a micro- forming science with the potential to im- RNA, which helps shepherd them through not 5-year-old children. And yet that’s prove human lives, Ruvkun gravitated their development. Through genetic engi- what it did,” he says. So much so that toward molecular plant science research, neering, Ruvkun’s graduate student has checkout lanes in grocery stores, which thanks partly to his previous experiences rescued the wiggling worm by return- now showcase glossy magazines, then working with plants and traveling in the ing its microRNA along with a touted encyclopedias of science, written by developing world. In Harvard plant mo- gene for the green fluorescent beacon. the likes of Nobel laureates Linus Pauling, lecular biologist Fred Ausubel, whose Through such experiments aimed at un- George Beadle, and Edward Lewis. work was aimed at engineering nitrogen- raveling the genetics of development, “There was a genuine celebration of mid- fixing ability into plants to improve agri- molecular biologist Ruvkun helped un- dle-class America embracing science and cultural productivity, Ruvkun found earth a world of microRNAs—snippets of technology,” he recalls. a mentor. In the six years following, RNA that play a range of regulatory roles As time wore on, Ruvkun’s amateur Ruvkun and Ausubel unraveled the ge- —in living cells. Today, microRNAs, radio hobby led to an interest in elec- netics of nitrogen fixation, notably dem- which represent the smallest genes known tronics, but as he set out to pursue an onstrating that the genes encoding the to biologists, have become an intense fo- undergraduate degree in electrical engi- enzyme that catalyzes the reaction were cus of basic research, their study bearing neering at the University of California, remarkably conserved across several spe- implications for diseases such as diabetes, Berkeley, he found physics more appeal- cies of nitrogen-fixing bacteria (1). The schizophrenia, and cancer. ing. “Physics at Berkeley was taught in finding also suggested that some genes for Emblematic of the Sputnik era that a much more inspirational way than elec- the nitrogenase enzyme had been either spurred the scientific bent of many trical engineering; the courses featured conserved since their origin or exchanged researchers, Ruvkun’s childhood interest one scientific revolution after another,” among species in their recent evolution- in science began during the 1960 launch Ruvkun says. Coming of age during a ary past. “It was a prototype paper for of the first US communications satellite period of economic, social, and political me because I’ve since used similar strat- Echo, which could be seen as it inched turmoil in a city that is often considered egies to discover homologies between across the night skies over the San Fran- a home to the hippie movement, Ruvkun proteins and evolutionary conservation of cisco Bay area, where he grew up. His graduated in 1973 with a bachelor’s de- genes,” Ruvkun says, recalling a theme father, a civil engineer, nurtured his na- gree in biophysics, uncertain of the future. that recurs with metronomic regularity scent interest in astronomy into abiding “Many of my peers at the time wanted to throughout his research career. curiosity about the natural world. His study society’s ills, and finishing in science The theme played out during his post- mother set a fine example for persever- was fairly rare. There was a prevailing doctoral work at Massachusetts Institute ance by graduating from college at the sense that you had to adhere to the norms of Technology and at Harvard, under the unlikely age of 50. In Ruvkun’s remem- of radical society, so polarization was rife,” tutelage of Walter Gilbert and Robert brances of his childhood, hints of a scien- Ruvkun says. Eager to find employment at Horvitz, both molecular biologists. Only tific temperament feature prominently: the height of a crushing recession and to this time his workhorse was a tiny, soil- television broadcasts of the Mercury and explore the world outside academia, dwelling roundworm called Caeno- Gemini rocket launches, the gift of a Ruvkun moved northward, working in rhabditis elegans, whose transparent adult telescope, hours spent poring over as- a tree-planting cooperative in Eugene, body with an uncannily precise 959 cells tronomy books at the Oakland Public Oregon for a year. When the grueling offers researchers a picture window Library, and a hobbyist’s passion for ham work took its toll, Ruvkun embarked on into the workings of genes in cells. “De- radio. “I was fascinated with under- a yearlong trip to Tierra del Fuego in velopmental biology was just coming into standing how the circuits generated and South America. The trip, Ruvkun says, its own, and the nematode worm seemed decoded radio signals,” Ruvkun says. But helped him cultivate people skills, explore those hints, he adds, also reflect a wide- other cultures, and broaden his perspec- spread cultural shift. “President Kennedy’s tive before narrowing his focus, ultimately This is a Profile of a recently elected member of the Na- plan to land men on the moon was really transforming him for the pursuit of tional Academy of Sciences to accompany the member’s meant to inspire engineers and scientists, his calling. Inaugural Article on page 1201 in issue 4 of volume 108. www.pnas.org/cgi/doi/10.1073/pnas.1111960108 PNAS | September 13, 2011 | vol. 108 | no. 37 | 15043–15045 Downloaded by guest on September 29, 2021 small enough to be described in a some- project had just started. I did a database what digital way,” recalls Ruvkun. search of the let-7 genetic sequence with Through molecular cloning experiments, my phone-in modem at home, looking for Ruvkun, his then postdoctoral collabora- let-7 counterparts in other animals—and tor Victor Ambros, and Horvitz pin- there it was: a human homolog for the pointed genes involved in determining the gene,” Ruvkun recalls. Soon thereafter, fate of the roundworm’s developing cells, Ruvkun and his postdoctoral fellow Amy as the worm progresses through its life Pasquinelli requested from researchers stages (2). Notable among their findings, around the world RNA samples from Ruvkun uncovered how a gene dubbed a menagerie of animals, from sea urchins lin-14, which acts like a master time- through earthworms through fruit flies keeper for the minutely orchestrated through mice. “A new FedEx bearing chronology of the worm’s embryonic de- RNA from a different organism would velopment, is itself controlled, shedding Expression of a microRNA rescued the glowing come in every day, and we would keep light on regulatory RNA sequences that nematode (Left) from death (Right). Image cour- running Northern blots and keep finding clock the gene’s activity (3). These and tesy of Zhen Shi (Massachusetts General Hospital, let-7,” he says. “The Nature paper that other findings helped signal Ruvkun’s Boston, MA). resulted from that work has nearly 20 arrival on the molecular biology stage and authors,” he adds, referring to the 2000 secure him an assistant professorship at report that helped emphatically ring Harvard University and Massachusetts A Star Turn for RNA microRNAs on the map for most biolo- General Hospital in 1985. Although the idea of regulatory RNAs had gists (6). Yet the account of Ruvkun’s discoveries slowly begun to gain ground in the mo- Around the time Ruvkun announced on the worm’s embryonic development is lecular biology lexicon, most such RNA the discovery of let-7, plant molecular no more than a frame story: nested within molecules were hundreds of nucleotides in biologist David Baulcombe, then at the it is the narrative of the discovery of the length, not tiny snippets of a size similar to Sainsbury Laboratory in Norwich, United developmental role of the gene lin-4 by that of lin-4. Simultaneously discovered Kingdom, reported similar 25-nucleotide- Ambros, Ruvkun’s longtime collaborator in chicken lymphomas, these regulatory long RNA molecules that regulated plant and University of Massachusetts Medical noncoding RNAs had been observed to physiology in a process known as RNA School molecular geneticist. Ambros had interact with genes implicated in cancer.

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