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 Early Edition | 1of3 Downloaded by guest on September 24, 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.