PROFILE PROFILE Profile of Jay C. Dunlap Paul Gabrielsen Science Writer On moonless nights, the wakes of oceangoing back to oceanography,” Dunlap says, “but I boats sparkle with the blue bioluminescence just thought clocks were the greatest things of unicellular dinoflagellates. As a graduate I’deverheardabout.” He chose to attend student at Harvard University, Jay C. Dunlap Harvard. pondered the carefully orchestrated biological Dunlap found Hastings’ approach to his rhythms that direct dinoflagellates to produce students’ research to be supportive but hands light only at night. Dunlap, a student of off. “He provided all these resources,” Dunlap oceanography at the time, realized that the says, “but he never told people what to do. He field of biological rhythms was still a wide- would give you great feedback on what you open frontier, with many fundamental ques- were doing, but you needed to find your own tions yet to be answered. “This was a place,” way. And if you were lucky enough to do that, he says, “where I could make a mark.” then you really learned how to do science.” Dunlap, Nathan Smith Professor and Chair In 1977, Dunlap attended a 10-week of Genetics at Dartmouth’s Geisel School of summer course on biological rhythms at Medicine and a member of the National Hopkins Marine Station in Pacific Grove, Academy of Sciences since 2009, has devoted California organized by Colin Pittendrigh, his career to answering those fundamental who, along with Hastings, had made pio- questions. His work has uncovered how cir- neering advances in the field of rhythms. The cadian rhythms work at a genetic level, how course attracted scientists studying rhythms environmental cues, such as light, can set bi- along with their graduate students, who, ological clocks, and how the clock can regu- Dunlap says, composed an entire generation Jay C. Dunlap in the 1990s with strains of late key cellular mechanisms. of rhythms biologists. Pittendrigh himself Neurospora and race tubes for visualizing circadian rhythm in development. Photo cour- Oceanography and Biochemistry taught extensively and brought in other sci- “ tesy of Joseph Mehling (Dartmouth College, Dunlap grew up in York, Pennsylvania as the entists to share what they had learned. It was an incredible smorgasbord of everything Hanover, NH). third of four children. He became an Eagle ” Scoutandwaschosenasoneofadozen that was going on in the field of rhythms, Dunlap says, “and an introduction to every- for Scouting’sNationalExplorationAward, insensitive to ambient temperature or nutri- body who was doing it.” which required applicants to write essays tion. “By sticking to a restricted definition,” Pittendrigh, Hastings, and other chrono- about their career goals. Dunlap had explored says Dunlap, “much of the biological noise biologists had made great strides in rhythms biochemistry at a summer program for high that came from loosely considering non- research beginning in the 1950s but had also school students at Ohio University and imag- circadian developmental or metabolic cycles “ run up against roadblocks. First, although ined a goal of studying biochemical ocean- fell away. With a defined phenotype you can ” therewereempiricalgeneralizationsabout ography. Earning the award, he says, do genetics” (2). circadian rhythms as biological cycles with solidified his interest in oceanography and Second, the research was hampered by a aperiodofaboutaday(1),thefieldlacked led him to attend the University of Wash- lack of molecular biological tools. As Dunlap a rigorous means to exclude extraneous ington beginning in 1970. began his postdoctoral fellowship with Jerry ’ rhythmic but noncircadian processes. “With After earning bachelors degrees in ocean- Feldman at the University of California, that loose definition, you end up pulling in ography and chemistry in 1974, Dunlap was Santa Cruz in 1979, he began laying the all sorts of biology that has no common admitted to two prominent oceanography groundwork for pushing through this molecular basis,” Dunlap says. graduate schools: Scripps Institution for roadblock. Oceanography and Woods Hole Oceano- “The most important thing to my mind,” graphic Institution. On the suggestion of a Dunlap says, “was restricting the phenotype Building and Winding a Clock friend, Dunlap also interviewed at Harvard to what we now consider in the strict sense a Dunlap aimed at elucidating the genetic and met J. Woodland “Woody” Hastings, circadian rhythm. This effort by Hastings, and molecular mechanism of the clock and whose research on bioluminescence in sin- Pittendrigh, and others made my work pos- the circadian system. A handful of circadian ” gle-celled dinoflagellates had led to an inves- sible. A circadian rhythm, as it has come to clock-related mutant gene loci had been tigation of the circadian clock elements of be defined, has a period around 24 hours previously identified in Chlamydomonas the dinoflagellates’ light show. Dunlap was under constant conditions. The timing of fascinated. “My rationalization was that I peaks and troughs in the cycle can be moved This is a Profile of a recently elected member of the National could study a marine organism and learn by exposure to real-world time cues, like light Academy of Sciences to accompany the member’s Inaugural biochemistry and physiology, and then go and temperature, but the period is relatively Article on page 16995 in issue 48 of volume 111. www.pnas.org/cgi/doi/10.1073/pnas.1514590112 PNAS Early Edition | 1of3 Downloaded by guest on September 29, 2021 chromosome walk through the Neurospora the genes involved would be organism- genome, examining short DNA sequences specific, they put forth that the organizing and reintroducing them into Neurospora to principles of clock–gene output regulation identify the sequence that altered the fungus’ would be similar in all eukaryotes. circadian behavior. Meanwhile, Loros, work- ing at Dartmouth as a postdoctoral fellow, Clock-Controlled Genes began the first screens for clock-controlled For the Inaugural Article by Dunlap and genes or ccgs, which have products that are coworkers (12), he and his colleagues col- involved in circadian output rather than laborated with the US Department of Energy the core circadian mechanism. The frq gene to perform high-throughput RNA sequenc- was cloned in 1986, and the first ccgs were ing on Neurospora cells over the course of found in 1987, with both results published two days under constant conditions. The in 1989 (4, 5). The cloning of frq was results, he says, indicate multiple overlapping featured on the cover of Nature,thefirst levels of regulation for fine-tuning clock- of seven journal covers featuring the regulated gene expression. “There are genes work by Dunlap and Loros. These genes whose expression is active at one time of day provided the molecular entrée into the but whose RNA products peak much later,” circadian system. he says. “There are genes whose expression is Dunlap notes that the logic underlying cyclical, but whose gene product is steadily circadian clocks in fungi and animals is quite present, and genes that are expressed con- ” Jay C. Dunlap and Jennifer Loros in 2009 similar. Both are driven by a feedback loop, stantly, but whose products are rhythmic. Up to 40% of Neurospora’s genes may be with the genetic and physical map of Neu- in which two proteins constitute a hetero- dimericgeneswitchthatdrivesexpressionof controlled by the circadian clock, he found. rospora. Photo courtesy of Jon Gilbert Fox one or more genes, and those gene products, Daytime-transcribed genes were typically re- (photographer). in turn, act as negative elements to depress lated to metabolism, whereas nighttime genes the activity of the transcription factor (6). were involved in cell growth. The result, he says, is cyclical expression of green algae, fruit flies, and Neurospora crassa, Championing Neurospora the filamentous fungus used by the renowned frq, detectable by levels of the prototypic Dunlap and Loros have remained at Dart- geneticists Beadle and Tatum (3) to develop protein FRQ. After the elements of the mouth’s Geisel School of Medicine while their 1941 “one gene-one enzyme” hypothesis feedback loop began to fall into place, Dunlap andLoroscouldaskhowreal-worldtime raising their two children and mentoring of genetic function (3). At the time, only one more than 40 students and postdoctorate of the three organisms, Neurospora, could be cues, like light, can reset the clock. They found that exposure to light promoted the students, nearly two-thirds of whom have genetically transformed. Therefore, Dunlap “ ’ expression of frq.Furthermore,exposureto entered academia. It snowonderwefound began his study of the fungus that continues ” “ light at different points of the feedback loop out so much, he says, given such terrific today. “It’sawonderfulorganism,” he says, ” could shift the phase of the circadian cycle. people to work with. Dunlap also serves with well-defined genetic tools that make the ’ For example, early light exposure while frq as the first chair of the school s Genetics genome of Neurospora relatively simple to levels were increasing could bring frq mRNA Department, which was organized in the manipulate. However, Dunlap says, “It’sbi- levels to their peak immediately instead of late-1990s. ologically complex enough to be interesting.” at a later time, thereby advancing clock In the mid-1990s, Dunlap and Loros began During his postdoctoral fellowship, Dun- phase. Similarly, late exposure to light could work on a textbook with the goal of codifying lap learned basic molecular techniques and restimulate frq mRNA production and effect the field of rhythms biology, and the final worked closely with biology graduate stu- a phase delay. The result had broad signifi- effort drew significant help from chronobi- dents, including Jennifer Loros. Loros and cance, because clocks in both Neurospora and ology pioneer Patricia DeCoursey. Published Dunlap later forged a permanent partnership, mammals are reset through light induction in 2004 as Chronobiology: Biological Time- marrying in 1984. Loros has since established of negative elements.