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Home , Gary Ruvkun, Victor Ambros

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wash in the faint glow of a fluo- Brush with Molecular 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 . 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 , 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 , 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 , 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 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 —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 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 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 , 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 , 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 and Massachusetts A Star Turn for RNA microRNAs on the map for most biolo- General Hospital in 1985. Although the idea of regulatory 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 , 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. interference, which had been discovered found that worms with an inactive lin-4 But neither the genes nor the model sys- a few years earlier. Baulcombe’s discovery gene showed defects in development, with tems in which they were found lent helped cement the ubiquity of regulatory early traits lingering late into the worms’ themselves to the kind of sophisticated RNAs of a size typical of microRNAs. developmental timeline. This finding analysis of genetic interplay that could be Because both microRNAs and RNA suggested that the gene helped worms easily carried out with the worms. To the molecules involved in RNA interference along in their path to adulthood. In con- extent that microRNAs have now become share a small size, the reasoning went, trast, the loss of lin-14 led to precocious a growing focus of scientific study, the they were likely generated by the same development in the worms, which ac- molecules were then largely dismissed by cellular machinery. To identify the ma- quired traits sooner than they were due. many as curiosities peculiar to nematode chinery, Ruvkun struck up a partnership The yin and yang of lin-4 and lin-14 on worms. After all, there were no known with University of Massachusetts Medical the worms’ developmental fate suggested mammalian counterparts for lin-4 and lin- School biologist and Stan- that the two genes likely interacted. “But 14. “There was a general feeling among ford University biologist , we didn’t know how they conspired to developmental biologists that this was who shared the 2006 Nobel Prize for their produce the temporal patterning of de- a funny corner of biology concerning lin- discovery of RNA interference. The velopment,” Ruvkun says. eage control in worms, unlikely to be partnership illuminated the role of en- Ruvkun and Ambros joined forces to applicable to flies or mammals,” Ruvkun zymes dubbed Dicer and Argonaute in unpick the genetic interaction. Working says. “But the molecular biologists work- the generation of microRNAs. Other re- together, the researchers found that lin-4 ing on RNA loved the idea of a new way searchers had previously found that the controls the amount of protein expressed in which RNA could regulate gene ex- enzymes helped snip short, single- by the lin-14 gene. More importantly, the pression. They were on the lookout for stranded RNA from double-stranded duo discovered that the regulatory control universal principles, and they saw the po- RNA during RNA interference, which was of a nature that had not been observed tential in the discovery.” helps control gene expression in a range before. Writing in back-to-back 1993 pa- Close on the heels of Ruvkun’s dis- of animals. The role of Dicer and Argo- pers, the pair announced the discovery of covery of the first microRNA and its naute in the generation of microRNAs the first microRNA and described how it mechanism of action came his finding of drew the conceptual link between micro- regulated protein synthesis. The product a second microRNA—in the same de- RNAs and RNA interference. In his 2011 of the lin-4 gene, it turned out, was a 22- velopmental pathway. The second micro- PNAS inaugural report, Ruvkun de- nucleotide stretch of RNA that latched on RNA gene, dubbed let-7, controlled the scribed how endogenous small RNA through Watson-and-Crick-style base- amount of protein made by another gene molecules participate in RNA inter- pairing to a complementary stretch of called lin-41, harkening back to the yin ference and genome surveillance in C. nucleotides in a region of the lin-14 gene and yang mechanism of microRNA- elegans (7). immediately following the protein code. driven genetic control (5). Like the first Soon, many molecular biologists re- The latch limited the amount of lin-14 microRNA gene, the discovery of let-7 alized that microRNAs represented a dis- protein that the cell could produce, thus might have been of minor import to de- covery of serious scientific moment, and controlling its embryonic fate. The 22- velopmental biologists, but it proved to be reports of microRNAs in mammals nucleotide stretch of RNA came to be a turning point, one that later revealed trickled into a stream before swelling to dubbed microRNA, heralding a regula- a realm of microRNAs largely unknown a flood. Consider: a PubMed search for tory role for RNA that had been largely to most biologists in an array of animals. microRNAs today yields 6,000 articles reserved for proteins until then (4). “It was 1999, and the human genome reporting the roles of a range of tiny RNA

15044 | www.pnas.org/cgi/doi/10.1073/pnas.1111960108 Nair Downloaded by guest on September 29, 2021 molecules in a raft of cellular processes. bernation, dauer is a time when worms assess the impact on the worms’ longev- Those roles, in turn, have implicated tamp down energy metabolism and amp ity. For example, inactivating the worms’ microRNAs in a host of diseases, in- up fat storage. Ruvkun and his coworkers ribosomes—cells’ protein synthesizing cluding cancer, heart disease, and found that one such worm gene was tell- factory—leads to longer-living worms. schizophrenia. Yet Ruvkun says, their ingly similar to the mammalian gene en- That puzzling finding might be partly importance to life remains a mystery, coding the insulin receptor, suggesting explained by the fact that toxins in the partly because the loss of many micro- that the worm possessed metabolic path- environment tend to target components RNAs does not lead to fatal consequences ways similar to those implicated in human of the ribosomes. Thus, Ruvkun reasons, for most animals, despite their evolu- insulin resistance, or type 2 diabetes (8). by monitoring the status of the ribo- tionary conservation. “The conservation Moving seamlessly between genetic ex- somes, the worms can help trigger de- of many microRNAs shows that they periments with the worms and database- fense against such toxins and enter mediate functions under strong selection driven sequence analysis, Ruvkun’s team a state of suspended animation devoid of pressure, but those functions may not be singled out a handful of players in the feeding and reproduction; in effect, the essential for the growth and development worm’s insulin-like signaling pathway. worms live longer. “I think that’safun- of animals under laboratory conditions. The genes, named daf-2/age-1/pdk-1/daf- damental insight into the mechanism of One tantalizing idea is that microRNAs 18/akt-1/akt-2/daf-16, regulate the worm’s aging that’s not yet appreciated by the may regulate a wide range of stress re- sugar metabolism, revealing insights into aging research community,” he adds. For sponses that are not usually assessed in the onset and progression of type 2 di- more than a decade, the community’s lab settings,” he says. For their discovery abetes in people. attention has been largely consumed by of microRNAs as a class of regulatory What’s more, the daf-2 insulin signal- caloric restriction, an approach founded molecules in animal cells, Ruvkun, Am- ing pathway, it turns out, helps control on the hope that reducing caloric intake bros, and Baulcombe shared the 2008 the worms’ life span (9). “So we surmised will increase human life span, as it has for Basic Medical that insulin might regulate aging in peo- done for mice. The jury on caloric re- Research. ple, too,” Ruvkun says. Other researchers striction is still out, but Ruvkun says the are now finding that similar human genes answers to the mystery of human aging Worm’s-Eye View of Disease and Age in the insulin-signaling pathway, in- might lie elsewhere. Ruvkun’s Lasker award was a nod to his cluding key gene switches, are mutated in Time will tell whether Ruvkun’s work codiscovery of microRNAs, yet he had centenarians, suggesting that a key to might lead to approaches to extend hu- long made his mark as a molecular bi- mimicking the Methuselah-like longevity man life. Meanwhile, he says, the coming ologist, thanks to his studies of metabo- of the worms might lie buried within the years will find him uncovering unique lism in the roundworm. Beginning in the insulin signaling pathway in people. Yet forms of cellular microRNAs and un- early 1990s, Ruvkun identified worm another key, Ruvkun says, emerged from raveling their roles in animals’ stress genes that act as gatekeepers for the an RNA interference screen that his response. worms’ entry into a state of slumber, team performed, scotching the pro- called “dauer diapause.” Similar to hi- duction of essential cellular proteins to Prashant Nair, Science Writer

1. Ruvkun GB, Ausubel FM (1980) Interspecies homology of mediates temporal pattern formation in C. elegans. Cell norhabditis elegans. Proc Natl Acad Sci USA 108: nitrogenase genes. Proc Natl Acad Sci USA 77:191–195. 75:855–862. 1201–1208. 2. Ruvkun G, et al. (1989) Molecular genetics of the Cae- 5. Reinhart BJ, et al. (2000) The 21-nucleotide let-7 RNA 8. Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G (1997) daf- norhabditis elegans heterochronic gene lin-14. Genetics regulates developmental timing in Caenorhabditis ele- 2, an insulin receptor-like gene that regulates longevity 121:501–516. gans. Nature 403:901–906. and diapause in . Science 277: 3. Ruvkun G, Giusto J (1989) The Caenorhabditis elegans het- 6. Pasquinelli A, et al. (2000) Conservation of the sequence 942–946. erochronic gene lin-14 encodes a nuclear protein that forms and temporal expression of let-7 heterochronic regu- 9. Morris JZ, Tissenbaum HA, Ruvkun G (1996) A phos- a temporal developmental switch. Nature 338:313–319. latory RNA. Nature 408:86–89. phatidylinositol-3-OH kinase family member regulating 4. Wightman B, Ha I, Ruvkun G (1993) Posttranscriptional 7. Zhang C, et al. (2011) mut-16 and other mutator class longevity and diapause in Caenorhabditis elegans. Na- regulation of the heterochronic gene lin-14 by lin-4 genes modulate 22G and 26G siRNA pathways in Cae- ture 382:536–539.

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