PROFILE

Profile of R. Scott Hawley

eiosis sets the stage for sexual younger Pauling told Hawley that if he reproduction through a tri- really wanted to do something about Mfold and tightly choreogra- birth defects, he should learn about phed dance: Chromosomes what caused them. So Hawley enrolled from the mother and father form pairs, in a genetics course. Suddenly every- exchange genetic material, and then sep- thing Ellison had written about in the arate from their partners. Geneticist R. Ticktockman story clicked. Growing up, Scott Hawley, who has studied these three Hawley says, all he knew was that “being steps for the better part of his career, has different was bad and there was a price dubbed the sequence a “meiotic ballet.” to be paid for it. Then I took genetics Although the dance steps have been and I realized that the whole point of known for more than a century, major genetics was to cherish the exceptions. By questions remain unanswered. How do looking at the things that are different, chromosomes find their partners or ho- you can figure out how things work.” mologs? What controls the exchange of By his sophomore year Hawley had genetic material? And what happens be- begun work in the laboratory of fly ge- hind the scenes when paired chromosomes neticist Dean Parker, where he began his first divide? earliest research into meiosis. Hawley Studying meiosis is both a biological and published a paper in his senior year on a philosophical pursuit, says Hawley, how radiation impairs the segregation of a researcher at the Stowers Institute for homologous chromosomes (2). Medical Research in Kansas City, MO, and a member of the National Academy of Lure of Meiosis Sciences since 2011. How, he asks, do By the time Hawley graduated from homologs know to pair with each other and University of California (Riverside, CA) not with another chromosome? Philo- R. Scott Hawley. in 1975, the field of genetics had gained sophically speaking, he asks: “How do you momentum: Genetic regulatory mecha- identify your partner? And how do you tell well to medication and his seizures were nisms were being mapped for the first time self from nonself?” brought under control. But the medical and genomics was on the horizon. Meiosis, Better genetic and biochemical tools, as condition set Hawley apart from his by contrast, seemed to have passed its well as increasing sophistication in imaging peers and brought him into contact with prime. Hawley wondered whether he techniques, now allow researchers like many special-needs students. Suddenly, it should switch gears, but his interest in Hawley to probe the intricacies of meiosis seemed, he was no longer “normal.” At meiosis was difficult to relinquish. In 1975, in greater detail than ever before. Re- around that time, Hawley latched onto he began studying for his PhD in the searchers can identify, even manipulate, science fiction writer Harlan Ellison, par- laboratory of geneticist Larry Sandler at specific chromosome regions and in- ticularly his short story “Repent Harlequin!” University of Washington (Seattle) where dividual proteins to map out their Said the Ticktockman. “It is an incredible he explored how homologous chromo- involvement in meiosis. In that vein, story about how people who are a little somes pair. Specifically, Hawley set out to Hawley’s Inaugural Article combines ge- bit different can make a difference in the test the hypothesis that chromosomes netics and imaging techniques with bio- world, even if it’s a little ripple,” Hawley have specific pairing sites “kind of like chemistry to identify the amino acid says. That message stayed with Hawley, buttons on a shirt or a blouse.” With no interactions that drive progression through who soon became aware of epileptics’ molecular or imaging techniques yet meiosis (1). Unraveling meiosis at that long history of persecution. “I remember available, Hawley compared crosses in- level of molecular detail, in turn, holds the when I was 14, I was reading the Alma- volving structurally abnormal chromo- promise of explaining major medical nac, which is as close to reading the somes to normal crosses—a purely mysteries, such as why meiotic abnormal- phone book as it gets,” Hawley says. “And genetic study that provided early evidence ities are more prevalent in human females I came across marriage laws that had for such a theory (3). as they age. been created during the American Eu- After graduation, Hawley joined genics Movement. I discovered that there Kenneth Tartof’s laboratory at the In- From Bookworm to Laboratory Rat were a bunch of states in the Union stitute for Cancer Research in Phila- With a father in the United States Navy, where people who had epilepsy could not delphia in 1979 as a postdoctoral fellow, Hawley spent his childhood years on the get married.” where he began studying a new problem. go, moving from Naples, Italy, where he When Hawley entered the University He wanted to see how cells maintained was born in 1953, to the outskirts of San of California at Riverside, CA, in 1971, thenumberofcopiesinasetoftandemly Francisco in Castro Valley, where he he initially considered studying law. As repeated genes and what triggered var- finished high school. The constant up- someone who came of age in the 1960s, iations in those numbers. Through that heaval turned Hawley into an avid reader. Hawley believed legal action was the work, Hawley and colleagues identified “Books,” he says, “were my best friends. surest way to initiate change. “You passed and manipulated key genes that con- I loved them.” Before he even reached laws. You passed constitutional amend- trol copy number variations (4, 5). To- middle school, a love of Arthurian leg- ments. You created social change the way day, researchers continue to study the ends led to him tackling Old English. “It Dr. Martin Luther King did,” Hawley was weird, but I was too young to know says. But Hawley’s first undergraduate that it was supposed to be hard,” he says. advisor turned out to be microbiologist This is a Profile of a recently elected member of the Na- Then, at age 13, Hawley was diagnosed Crellin Pauling, son of chemist and tional Academy of Sciences to accompany the member’s with epilepsy. Fortunately, he responded Nobel Laureate Linus Pauling. The Inaugural Article on page 6382 in issue 17 of volume 109.

www.pnas.org/cgi/doi/10.1073/pnas.1211580109 PNAS | August 28, 2012 | vol. 109 | no. 35 | 13883–13885 Downloaded by guest on September 29, 2021 link between copy number variations a major breakthrough, Hawley and his homology allowed chromosomes that did and cancer. laboratory cloned the nod gene. That led not recombine, namely chromosome 4, to Hawley continued that line of research to the identification of Nod as a kinesin- pair nonetheless (10). in the early 1980s as an assistant professor like protein or a protein critical to chro- at Albert Einstein College in New York mosomal movement within the cell (8). Live Imaging, Mutants, and a Model City. However, his foray from meiosis Cloning nod also demonstrated the fea- of Meiosis proved short-lived. On Christmas Eve of sibility of analyzing the segregation step Hawley’s research on Nod and hetero- his second year in New York, Hawley down to the molecular level. chromatic homology illustrated how found himself substituting for his graduate Without a way to view the inner work- newly available imaging techniques student in the laboratory. There, in a vial, ings of the cell, the team’s conclusions could help identify the key players in he saw the progeny of a fly that he realized were based entirely on genetic data that meiosis. However, the requisite research had to be carrying a new meiotic mutant. could be described only by blackboard materials—meiotic mutants—were in When X chromosomes segregate prop- drawings. Then, at a Drosophila meeting short supply. So in the mid-1990s, Hawley erly, the progeny look different from the in Asilomar, CA, Hawley attended a talk screened for more mutants and generated parents, he says. In this vial, however, most by William Theurkauf, then a postdoc- some 15–20 varieties (11). Other labora- females looked like their mothers and toral fellow at University of California tories around the country used a similar most males like their fathers. “Maybe if (San Francisco). “Bill had one of the first approach. With these additional mutants, you didn’t ‘grow up’ in a meiosis lab, you confocal microscopes and he was showing the study of meiosis in Drosophila took might have just said, ‘Oh that’s weird’,’” these truly astounding pictures of female off. “All of a sudden we could see stuff,” Hawley says. “But I was trained to rec- meiosis in flies,” Hawley says. “Bill was Hawley says. “We could build this ognize when homologous chromosomes showing things that had never been Christmas tree of meiotic events and start fail to segregate.” Such mutants were seen before.” hanging these mutants on it.” a rare find and Hawley was intrigued. After the meeting, Hawley sent The- When these tools became standard, “Pretty soon the entire lab had migrated urkauf a batch of normal and nod mutant Hawley expanded his work to study the over to meiosis,” Hawley says. flies to examine. The pictures he received entire process of meiosis. “How does in return, Hawley recalls, revealed one pairing work? How does recombination Unveiling the Mutants’ Secrets of nod’s secrets in a single instant: After work? How do you control progression Researchers first puzzled over the mys- chromosomes pair and recombine, they through the cell cycle?” he asked. For the terious inner workings of meiosis in the line up along a structure known as the past decade, these questions have framed early 1930s, when Barbara McClintock meiotic spindle. Fibers attach to specific Hawley’s research at the Stowers Insti- began exploring the field of maize ge- points—the centromeres—on each ho- tute. The technological resources avail- netics. McClintock, a renowned cytoge- mologous pair and stretch from the able at the institute allowed Hawley’s neticist and Nobel Laureate in Physiology chromosomes to the ends of the spindle. group to replace still images with movies and Medicine, was the first person to In normal flies, the Nod protein sits along of meiosis in real time, trace recombi- describe how chromosomes crossed over the arms of the chromosomes and pushes nation on a genome-wide level, and study during meiosis. Her work thus laid out them back toward the center of the mei- protein interactions that take place dur- the three key steps of the meiotic ballet: otic spindle. That process holds true even ing meiosis (12, 13). His long-term goal chromosome pairing, the exchange of for tiny chromosome 4, which never re- is to map the process of meiosis at the genetic material known as recombination combines (8). In nod mutant oocytes, molecular level. Toward this goal, Haw- or crossing over, and segregation (6). however, the two fourth chromosomes ley recently collaborated with a group Eventually, it became known that these encountered serious trouble: They flew at Dartmouth College in Hanover, NH, three steps did not always go as McClin- off the developing spindle. “We had who crystallized the Nod protein and tock described. In flies, for instance, never imagined that you actually had to determined its 3D structure (14). That chromosome 4 never recombines. The do something specific to keep them on ability to identify the proteins involved progeny are nonetheless completely the spindle. That was not even a process in meiosis has also helped Hawley and healthy, each receiving one copy of we were worried about,” Hawley says. others screen for a new generation chromosome 4 from each parent. In 1936, Imaging techniques also answered an- of mutants. George Beadle and Alfred Sturtevant other key question in meiosis: How do Hawley’s laboratory has also taken a proposed that something must allow for homologous chromosomes that do not closer look at the synaptonemal complex meiosis to continue on to the segregation recombine hang on to their partners long (SC), a protein structure that forms be- step even in the absence of recombination enough to segregate? Hawley and col- tween homologous chromosomes during (7). That something, however, would re- leagues eventually identified the “glue” as meiosis. When the team looked at the main a mystery until Hawley and others heterochromatin. Once thought of as earliest stages of meiosis to determine returned to that line of inquiry more than “junk DNA,” heterochromatin is com- when the SC first appears, they found that half a century later. It became critically posed of long regions of highly repetitive the SC forms very early on in the vicinity clear that segregation could occur even DNA that usually flank chromosomes’ of the centromeres, further suggesting when chromosomes failed to recombine. centromeres, where chromosomes are that centromeres initiate the pairing Finding the basis of such a backup system, held together. Hawley illustrated that process or synapsis (15, 16). “In flies, it’s Hawley realized, might help elucidate the homologous chromosomes recognized the first insight into how synapsis begins,” normal meiotic process. each other via matching heterochromatin Hawley says. By the early 1990s, Hawley had moved sequences or heterochromatic homology The hope is that these insights will allow to University of California (Davis, CA) to (9). In 1996, Hawley collaborated with for a detailed tracing of human meiosis. study two mutants with backup system University of California (San Francisco) That tracing would help meiotic biologists impairments. Specifically, these mutants graduate student Abby Dernburg, who address the century-old question of had chromosome pairs that had both used imaging techniques to directly ob- why older mothers are more likely than failed to recombine and failed to segre- serve heterochromatin’s role in meiosis. their younger peers to miscarry or bear gate. In one of those mutants, the eggs Her work showed that such pairings ac- children with genetically abnormal chro- could not produce a protein called Nod. In tually occurred and that heterochromatic mosome numbers, a question that has

13884 | www.pnas.org/cgi/doi/10.1073/pnas.1211580109 Gupta Downloaded by guest on September 29, 2021 fascinated Hawley since he first learned of America Award for Excellence in Ed- posthumously; he is not ready to share ei- about it in high school. ucation in 2008. He is also a Past Presi- ther effort with the general public just yet. dent of the Genetics Society of America Hawley’s eclectic approach to science— Branching Out and an American Cancer Society Re- and life in general—reflects how he grew Throughout his career, Hawley has nur- search Professor. He has also been elec- so engrossed in the study of meiosis, a tured his love affair with books, although ted to the American Academy of Arts topic that so often seemed dated in the these days he writes as much as he reads. and Sciences. cutting-edge field of genetics. “I some- Having authored books for lay and spe- However, like the bookish kid who times used to joke that I work on prob- cialized audiences, with a seventh book read everything from science fiction to lems that were the center of scientific underway, Hawley says writing is a way for Almanacs, Hawley has also remained very interest in 1935,” Hawley says. “But, in him to make sense of everything he has much a generalist. In his spare time, Hawley truth, we are just now getting close to learned. “There’s something very seduc- volunteers with REbeL and Thalia House, understanding how the process of meiosis tive about synthesizing a body of knowl- organizations that focus on preventing and works. Now is the best time to be studying edge into chapters and stories,” he says. treating eating disorders. Hawley also meiosis.” Sharing his expertise also comes naturally dabbles in poetry and he has been hard at to Hawley, who won the Genetics Society work on a novel that he plans to publish Sujata Gupta, Freelance Science Writer

1. Takeo S, et al. (2012) Shaggy/glycogen synthase kinase 7. Sturtevant AH, Beadle GW (1936) The relations of in- 12. Sekelsky JJ, et al. (1999) Identification of novel Dro- 3β and phosphorylation of Sarah/regulator of cal- versions in the X chromosome of Drosophila Mela- sophila meiotic genes recovered in a P-element screen. cineurin are essential for completion of Drosophila nogaster to crossing over and disjunction. Genetics 21: Genetics 152:529–542. female meiosis. Proc Natl Acad Sci USA 109:6382– 554–604. 13. Hughes SE, et al. (2009) Heterochromatic threads con- 6389. 8. Zhang P, Knowles BA, Goldstein LSB, Hawley RS nect oscillating chromosomes during prometaphase I in 2. Hawley RS (1975) Radiation-induced numerical aber- (1990) A kinesin-like protein required for distributive Drosophila oocytes. PLoS Genet 5:e1000348. rations in wild type Drosophila females. Mutat Res 33: chromosome segregation in Drosophila. Cell 62:1053– 14. Xiang Y, et al. (2007) The inhibition of polo kinase by 391–394. 1062. matrimony maintains G2 arrest in the meiotic cell cy- 3. Hawley RS (1980) Chromosomal sites necessary for 9. Theurkauf WE, Hawley RS (1992) Meiotic spindle cle. PLoS Biol 5:e323. normal levels of meiotic recombination. 1. Existence assembly in Drosophila females: Behavior of non- 15. Cochran JC, et al. (2009) The ATPase cycle of the and mapping of the sites. Genetics 94:625–646. exchange chromosomes and the effects of mutations nonmotile kinesin NOD allows microtubule plus-end 4. Hawley RS, Tartof KD (1983) The effect of mei-41 on in the nod kinesin-like protein. JCellBiol116:1167– tracking and drives chromosome movement.. Cell 136: rDNA redundancy in Drosophila melanogaster. Ge- 1180. 110–122. netics 104:63–80. 10. Hawley RS, et al. (1992) There are two mechanisms of 16. Takeo SA, Lake CM, Morais-de-Sa’ E, Sunkel SE, 5. Hawley RS, Marcus CH (1989) Recombinational con- achiasmate segregation in Drosophila females, one of Hawley RS (2011) A synaptonemal complex-dependent trols of rDNA redundancy in Drosophila. Annu Rev which requires heterochromatic homology. Dev Genet process of centromeric clustering is coupled to the Genet 23:87–120. 13:440–467. initiation of synapsis in Drosophila oocytes. Curr Biol 8: 6. McClintock B (1932) A correlation of ring-shaped 11. Dernburg AF, Sedat JW, Hawley RS (1996) Direct evi- 1845–1851. chromosomes with variegation in Zea mays. Proc Natl dence of a role for heterochromatin in meiotic chro- Acad Sci USA 18:677–681. mosome segregation. Cell 86:135–146.

Gupta PNAS | August 28, 2012 | vol. 109 | no. 35 | 13885 Downloaded by guest on September 29, 2021