PROFILE

Profile of Jeffrey C. Hall hen geneticist Jeffrey C. Hall looks back on his ca- reer path, he offers praise for each of the personali- tiesW he has encountered, from his deaf undergraduate advisor to his fellow Civil War scholars—not to mention the small, elegant, and urbane fruit fly. ‘‘They’re very complex organisms, quite sophisti- cated and interesting,’’ he says of Dro- sophila, the neurobiology and behavior of which have occupied his research since college. To Hall, Drosophila are valuable for more than just their easily manipulated genomes. As he grew to ‘‘love the fly,’’ he also began to delve into the insect’s genetics, neurobiology, and behavior at a deep level. Convinced of the worth of analyzing Drosophila mutants for study- ing behavior, Hall has dedicated his career to probing the neurobiological underpinnings of the fly’s courtship and behavioral rhythms. His research with Jeffrey C. Hall Drosophila genetics has elucidated the mechanisms of biological clocks and opened a window into the basis for fruit flies. Ives, who had been a student sophila laboratory of Lawrence Sandler, sexual differentiation in the nervous of geneticist Albert Sturtevant, lost his also a research descendent of Stur- system. hearing in graduate school and was rele- tevant’s. Hall worked with Sandler on Hall, a Professor of Biology at Bran- gated to a non-tenure-track research several research projects, starting with deis University (Waltham, MA), was a career that included shepherding under- the analysis of age-dependent enzyme recipient of the Genetics Society of graduate students like Hall through changes in Drosophila (2) but with a America Medal in 2003, the same year small projects. Yet Ives excelled as a main focus on the genetic control of he was elected to the National Academy researcher and was dedicated to his chromosome behavior in meiosis (3). of Sciences. His Inaugural Article in this mentoring role. He exhorted his stu- After a few years of research, Hall dents to ‘‘love the organism,’’ Hall says. issue of PNAS (1) investigates the fruit- was summoned into the office of Her- ‘‘This sort of resonated, because I really less gene, which controls behavior such shel Roman, the department’s founder, did like the little fruit flies. They’re ex- as the recognition by a male of whom chair, and longstanding father figure. tremely appealing, one reason being that he might ‘‘choose’’ to court and court- Roman took a sharp interest in the fate they’re small and cute, as silly as this ship singing behavior, by analyzing the of his department’s students, and he rec- may seem.’’ As a model for research, behavioral meaning of this gene’s ommended that Hall do postdoctoral Drosophila strike a good balance of work with Seymour Benzer at the Cali- expression within various regions of qualities, Hall points out, in that they the nervous system. fornia Institute of Technology (Pasa- are small enough to handle in large dena, CA). Hall knew Benzer to be a Small and Simple Research numbers, large enough to facilitate ob- highly regarded geneticist who had servations, and simple enough to yield moved from research on bacterial vi- Born in Brooklyn, NY, Hall grew up in large amounts of data but ‘‘not so pa- the suburbs of Washington, D.C., where ruses during the 1960s to study behav- thetically simple as to be dreary and ioral genetics and neurogenetics. Benzer’s his father worked as an Associated Press boring.’’ reporter, covering the U.S. Senate. His signature approach was to induce ran- With Ives, Hall spent a year studying dom mutations in fruit flies, screen father’s attitude permeated his con- recombination and translocation induc- sciousness in many ways, Hall says, caus- them for noteworthy behavioral charac- tion in Drosophila. This research project, teristics, and then use the genes defined ing him to, for example, ‘‘read more which Hall describes as ‘‘intrinsically than just the sports section each morn- by these mutations to dig as deeply as rather silly,’’ turned out well, and de- possible into the neurobiology of such ing.’’ A good but not stellar student in partment faculty took notice, recom- high school, Hall planned to attend behaviors. mending that he pursue graduate studies Roman phoned Benzer as Hall sat in medical school when he entered Am- at the University of Washington (Seat- herst College (Amherst, MA) in 1963. his office, and two days later Hall was tle), which had the unusual distinction on a plane down to southern California Halfway through earning his bachelor’s of having an entire department devoted to interview with Benzer. At the end of degree, however, he found his curiosity to genetics. ‘‘I applied there, just follow- the brief visit, Benzer offered him a for medicine replaced by one for basic ing orders,’’ Hall says, ‘‘but I’m glad I science. did, because they were absolutely right.’’ For his senior honors project, Hall This is a Profile of a recently elected member of the National hoped to gain experience in formal re- A Push Down the Coast Academy of Sciences to accompany the member’s Inaugural search and began working with Philip When Hall arrived in Seattle in 1967, he Article on page 16550. Ives, a genetics researcher who studied already knew he wanted to join the Dro- © 2005 by The National Academy of Sciences of the USA

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0508533102 PNAS ͉ November 15, 2005 ͉ vol. 102 ͉ no. 46 ͉ 16547–16549 Downloaded by guest on October 3, 2021 spot in his laboratory, and Hall finished low from England to work specifically his doctoral work and moved to Ben- on the neurogenetics of singing behav- zer’s laboratory in 1971. ior. Kyriacou’s analyses revealed that the Drosophila courtship song is pro- Universal Slices of Courtship duced rhythmically with a normal peri- Hall soon realized that Benzer ran ‘‘a odicity of about one minute. When Hall lab where you make your own way,’’ in saw these findings, he recalled the pe- which students and postdoctoral fellows riod mutants generated by Ronald J. were encouraged to pursue research in- Konopka in the late 1960s in Benzer’s dependently. Benzer’s main suggestion laboratory. Konopka’s mutants displayed to Hall was to work with Doug Kankel, daily sleep–wake rhythms deviating from another postdoctoral fellow in the labo- the 24-hour cycle, and so Hall suggested ratory. Hall found Kankel to be replete to Kyriacou that they check whether with detailed knowledge of Drosophila these mutants had altered courtship biology that extended to neuroanatomy song cycles as well. In basketball terms, and neurochemistry, all of which Hall Male Drosophila following and courting a female this suggestion was ‘‘throwing up a gratefully absorbed. The pair began by singing to her. prayer,’’ Hall says. ‘‘It was crazy. There collaborating on two projects, both of was no reason to think that the control which progressed surprisingly well, Hall of this one-minute rhythm would have says (4, 5). courtship, anybody who is listening in- anything to do with the regulation of Hall left Benzer’s laboratory before stantly knows what you’re talking daily rhythms.’’ publishing any results, however. During about.’’ Yet Hall was mindful of the To their surprise, Hall and Kyriacou Hall’s third postdoctoral year, Roman conservative academic nature of many found that the period mutations affected called from Seattle to say that he had biologists at the time, and he kept these the courtship song just as they changed been lobbying on Hall’s behalf for open inchoate hopes for greater human signif- the circadian rhythms, by stretching, faculty positions at the University of icance largely to himself. shrinking, or obliterating both cycles Missouri (Columbia, MO) and Brandeis similarly (7). Using the then-emerging University. Such promotion was a gener- Transatlantic Songs tools of molecular genetics, Hall, Kyria- ous act of faith on Roman’s part, Hall Hall’s study of Drosophila courtship be- cou, and Michael Rosbash, a colleague says, because Roman was unfamiliar havior eventually encompassed the at Brandeis University, set out to isolate with Hall’s research in California. Bran- male’s courtship song, a pattern of the period gene. deis University offered Hall a faculty sounds emitted from a male’s vibrating position, and he joined the university as wings as he follows a female. In the Cracking the Case of Circadian Rhythms an Assistant Professor of Biology in mid-1970s, Hall began collaborating Hall and his colleagues used fruit fly 1974. with Florian von Schilcher at the Uni- molecular genetics to study biological At Brandeis, Hall carried forward the versity of Munich to correlate song clocks, but traditional circadian rhythm momentum of his work with Kankel, qualities with genetic sex. Hall gener- researchers had long preferred a nonge- who by that time was working at Yale ated Drosophila mosaics and shipped netic approach using a variety of organ- University (New Haven, CT). A particu- isms. ‘‘Many of them loudly and publicly larly intriguing research thread sprang denounced the genetic approach to from an offhand suggestion from Kankel ‘‘Singing behavior is study rhythms,’’ Hall says. He now con- during Hall’s last months in California. siders this a mixed blessing, in that the They had been generating fruit fly sex one of the exquisitely distaste of some researchers for molecu- mosaics—organisms part male and part lar genetics kept the number of compet- female—and staining them to determine quantifiable features itors to a minimum. The only other which nerve cells were male and which group also hunting for the period gene were female. Kankel mentioned that of courtship.’’ was Michael Young’s laboratory at The they should be examining each mosaic Rockefeller University (New York), before dissection to see whether male or which had been prompted by Young’s female courtship patterns were present. them to von Schilcher, each housed with previous analyses of Drosophila’s chro- From such observations, they would a bit of food in its own glass vial. von mosomal region in the vicinity of the have been able to correlate courtship Schilcher recorded and analyzed the white gene, near which period is located. behaviors with genetic sex in various flies’ songs before sending them back to In 1984, Hall and his colleagues found regions of the nervous system, which Hall. Hall then dissected and stained and isolated the period gene (8), roughly Hall eventually accomplished during his the flies that survived the double cross- at the same time as did Young’s group early years at Brandeis. Atlantic journey. It was an arduous ex- (9). Soon after the period gene was That casual comment triggered Hall’s periment, Hall says, but it allowed them cloned, its protein product was found interest in this area, and his subsequent to map nervous system regions that not to be a homolog of any known pro- career path of investigation into the helped contribute to the regulation of tein. ‘‘It was just this total mystery se- neurogenetics of Drosophila courtship courtship song (6). quence of amino acids,’’ Hall says. ‘‘We was born. Before long, Hall saw that Hall decided to bolster the song com- had to keep plugging away experimen- findings from this research could carry ponent of his laboratory’s research. ‘‘I tally, not just descriptively, to try to fig- greater significance beyond insight into realized from this study that courtship ure out what it was about.’’ Eventually, insect rituals. ‘‘The male gets interested singing behavior is one of the exquisitely Hall’s group, working closely with that in the female, gropes her with his fore- quantifiable features of courtship, well of Rosbash, started to understand the legs, follows her around and sings to worth delving into further,’’ he says. In role of the pacemaker cells in the fly’s her, and licks her posterior region,’’ he the late 1970s, Bambos Kyriacou joined brain and the oscillation of period’s pro- says. ‘‘When you describe Drosophila Hall’s laboratory as a postdoctoral fel- tein in them. They elucidated the self-

16548 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0508533102 Nuzzo Downloaded by guest on October 3, 2021 sustained autoregulatory feedback loop master regulator gene for courtship At Brandeis University, some stu- that provided the core of the circadian (17). ‘‘Taking into account effects of the dents encounter Hall only through the clock mechanism (10, 11). A few years several fru mutations, almost every fea- history department, where he has been later, the gene was found to have ho- ture of male courtship is controlled by teaching a course devoted to the Battle mologs in many other animals, including this gene,’’ Hall says. ‘‘Moreover, a por- of Gettysburg. Hooked on the subject humans. tion of nearly every region of the ner- after a family trip to the battlefield in Cloning period provided the spark vous system is making the fruitless gene 1983, Hall plunged into 19th-century that ignited current circadian rhythm product. For example, fruitless expressed history books and became acquainted research. ‘‘Molecular, neurobiological, in the brain almost certainly influences with several Civil War historians. In and behavioral studies of period ended up whether a Drosophila male can discern 1994, he achieved minor celebrity cracking the case of circadian rhythms,’’ that a companion fly is an appropriate among the Civil War set when he en- Hall says. ‘‘The outcome of these studies courtship object.’’ ticed a group of 250 visiting Princeton made circadian rhythms no longer one Hall’s PNAS Inaugural Article takes a University molecular biologists to take of these strange biological mysteries on step toward probing the behavioral sig- a full-day tour of the battlefield with the Third Rock.’’ nificance of fruitless’s expression within him, complete with a packet of accom- various portions of the central nervous panying maps. The incongruous scene Behind fruitless Courtship system (1). Adriana Villella, a senior seemed to aptly characterize Hall, and Hall’s studies of sex-specific behavior research scientist in Hall’s laboratory, it was recounted in Jonathan Weiner’s have prominently involved the fruitless led the study, which manipulated the popular science book Time, Love, gene. The fruitless mutant was identified function of fruitless neurons within de- Memory, which chronicled the career in the 1960s but had been neglected un- fined subsets of the nervous system. of Seymour Benzer and his research til Hall began studying it during his last ‘‘It’s trying to take the case of fruitless descendents (18). After this tour, few months at the California Institute of and analyze the behavioral meaning of Hall’s Civil War interests continued Technology. This mutant was behavior- the gene product’s presence in various apace with guest lectures, the Brandeis ally sterile: a fruitless male would court neural regions a little bit deeper than University course, and even a textbook both females and males indiscriminately just descriptive inferences,’’ Hall says. on Gettysburg, published in 2003 (19). but not try to mate with either. ‘‘They’re Hall’s passionate approach to the not homosexual, as some think. They’re Historical Back Roads Civil War is not unlike his genetic inves- bisexual,’’ Hall says. Hall is spending the summer and fall of tigations. By way of explaining the ap- From the late 1970s through the early this year on sabbatical at the University peal of Gettysburg, Hall quotes a letter 1990s, Hall’s group studied the fruitless of Maine (Orono, ME), living in a from his acquaintance and prominent gene solely from behavioral genetic house ‘‘in the middle of nowhere.’’ Civil War historian James McPherson, and anatomical perspectives (12–14). Whenever possible, he makes the jour- ‘‘You [Hall] . . . like me, apprehend vis- Then, in the early 1990s, Bruce Baker ney to campus on his Harley-Davidson cerally as well as intellectually the mean- at Stanford University (Stanford, CA) motorcycle, one of a series of different ing of the Civil War. And nowhere can proposed to Hall that they collaborate models he has owned over the last de- this . . . be grasped more meaningfully with Barbara Taylor at Oregon State cade. Not only does it make this 100- than at Gettysburg.’’ Hall might claim University (Corvallis, OR) and clone mile round-trip commute ‘‘infinitely less the same sentiment about Drosophila fruitless. They isolated the gene in the doleful than trundling along’’ in a car, and his scientific research: nowhere can the deeply conserved behaviors of mid-1990s (15), at about the same time Hall says, the hazards of motorcycle courtship and circadian rhythms be as did Daisuke Yamamoto’s laboratory riding force him to concentrate on the better understood than in the humble in Japan (16). road ‘‘moment by moment,’’ leaving no fruit fly. Cloning fruitless paved the way, show- time to worry about the usual grinding ing it acted as what might be termed a agonies that might await in the laboratory. Regina Nuzzo, Science Writer

1. Villella, A., Ferri, S. L., Krystal, J. D. & Hall, J. C. Konopka, R. J., Kyriacou, C. P., Rosbash, M. & 15. Ryner, L. C., Goodwin, S. F., Castrillon, D. H., (2005) Proc. Natl. Acad. Sci. USA 102, 16550–16557. Hall, J. C. (1984) Cell 39, 369–376. Anand, A., Villella, A., Baker, B. S., Hall, J. C., 2. Hall, J. C. (1969) Exp. Gerontol. 4, 207–222. 9. Bargiello, T. A., Jackson, F. R. & Young, M. W. Taylor, B. J. & Wasserman, S. A. (1996) Cell 87, 3. Hall, J. C. (1972) Genetics 71, 367–400. (1984) Nature 312, 752–754. 1079–1089. 4. Kankel, D. R. & Hall, J. C. (1976) Dev. Biol. 48, 10. Hardin, P. E., Hall, J. C. & Rosbash, M. (1990) 16. Ito, H., Fujitani, K., Usui, K., Shimizu-Nishikawa, 1–24. Nature 343, 536–540. K., Tanaka, S. & Yamamoto, D. (1996) Proc. Natl. 5. Hall, J. C. & Kankel, D. R. (1976) Genetics 83, 11. Zerr, D. M., Hall, J. C., Rosbash, M. & Siwicki, Acad. Sci. USA 93, 9687–9692. 517–535. K. K. (1990) J. Neurosci. 10, 2749–2762. 17. Kyriacou, C. P. (2005) Nature 436, 334–335. 6. Schilcher, F. V. & Hall, J. C. (1979) J. Comp. 12. Hall, J. C. (1978) Behav. Genet. 8, 125–141. 18. Weiner, J. (1999) Time, Love, Memory: A Great Physiol. A 129, 85–95. 13. Gailey, D. A. & Hall, J. C. (1989) Genetics 121, Biologist and His Quest for the Origins of Behavior 7. Kyriacou, C. P. & Hall, J. C. (1980) Proc. Natl. 773–785. (Knopf, New York). Acad. Sci. USA 77, 6729–6733. 14. Gailey, D. A., Taylor, B. J. & Hall, J. C. (1991) 19. Hall, J. C. (2003) The Stand of the U.S. Army at 8. Zehring, W. A., Wheeler, D. A., Reddy, P., Development 113, 879–890. Gettysburg (Indiana Univ. Press, Bloomington).

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