PROFILE Profile of David C. Page ere it not for geneticist David C. Page, the human Y chromosome might still be relegated to the genetic Wjunk pile. Page has doggedly devoted his career to revealing the Y chromosome’s genetic cargo, evolutionary history, and role in male infertility—in sum, bringing dignity and respect to this chromosomal runt. Page’s mapping and sequencing of the human Y chromosome has triggered a renaissance in sex chromosome re- search, stimulating new efforts to de- code the Y chromosome of chimpanzees and mice and the Z and W sex chromo- somes of the chicken. His studies of Y deletions have illuminated the molecular basis of male infertility, and his investi- gations into genes shared by the X and Y chromosomes may improve under- standing of Turner’s syndrome, a genetic disorder in which only one X chromo- some and no Y chromosome is present. Elected to the National Academy of David Page with his family in the Bugaboos, BC, Canada, in July 2005. From left to right: daughter Sciences in 2005, Page’s Inaugural Arti- Charlotte, Page, daughters Lucy and Julia, and wife, Elizabeth. cle in this issue of PNAS (1) explores germ cell sex determination—how pri- store,’’ as Page describes it, led him to laboratory exercises where students con- mordial germ cells decide to become dabble in international economics, pol- firm something that somebody figured eggs or sperm. Page and his colleagues itics, and religion, before finally set- out 30 years ago, says Page, ‘‘fumbling show that retinoic acid may regulate tling on chemistry. At Swarthmore, my way through a novel experiment that this decision, suggesting its role as a nobody had ever done before was a sex hormone. everybody was passionately absorbed in some type of intellectual pursuit, says completely exciting experience.’’ Page Child of Sputnik Page. ‘‘I found that exhilarating. I felt was the first in his family to attend college and graduated from Swarthmore Born in Harrisburg, PA, in 1956, Page like I had stepped into a parallel uni- in 1978 with highest honors in chemis- grew up in the countryside surrounded verse, a world of ideas. I guess I try, which he says is his proudest by close family; in addition to his never stepped back out,’’ he says. achievement. mother, father, and two older sisters was Catching the Research Bug a host of nearby relatives who were Liberia, Medicine, and Science farmers. He spent much of his early Page’s first taste of research was a Page entered the Harvard–Massachu- childhood playing baseball, hiking, and week-long stint his sophomore year setts Institute of Technology Division of backpacking. Page’s attraction to biology working with the late Swarthmore alum- Health Sciences and Technology (Cam- sprang from his earthy interest in the nus Robert T. Simpson, who was then at bridge, MA) in 1978, which basically natural world, such as collecting leaves, the National Institutes of Health (Be- offered an M.D. program with research rocks, and insects, but his earliest expo- thesda), studying chromatin structure. It opportunities. After the freedom of his sure to science was in high school. ‘‘I was a pivotal experience during which honors program, Page found his first think I was really a child of Sputnik,’’ Page says he ‘‘caught the research bug.’’ year of medical school dull. In the sum- says Page, who attributes the quality of In fact, Page was so taken with research, mer of 1979, he leapt at the chance to his high school science classes to the he returned to Simpson’s laboratory get back into research and asked fellow space race of the 1950s and 1960s. during his senior year. Swarthmore’s Swarthmore alumnus and Nobel laure- When the Soviet Union launched the honors program allowed him to attend satellite Sputnik I in 1957, the United class just one day a week and spend the ate David Baltimore for advice on which States countered, in part, by investing in rest of his time in Simpson’s laboratory, laboratory to join. ‘‘[Baltimore] said, science education. Thus, even in a rural where he worked with postdoctoral fel- ‘There’s this guy, David Botstein, who public school, Page secured a solid foun- low Arnold Stein on the physical bio- has new ideas about human genetics, so dation in science. chemistry of nucleosomes. Simpson and why don’t you go talk to him,’’’ says In 1974, Page attended nearby Swar- Stein were rigorous mentors but gave Page. thmore College (Swarthmore, PA), even Page the freedom to design his own Botstein introduced Page to Raymond though his high school guidance coun- experiments. ‘‘I started to realize that a White at the University of Massachu- selor described the student body as scientist could be the first person in the setts Medical School (Worcester), where ‘‘weird.’’ Page found the comment in- world to know something,’’ says Page, triguing, and when someone told his fa- ‘‘and that was very intoxicating.’’ This is a Profile of a recently elected member of the National ther, ‘‘I wouldn’t let my son go there . In Simpson’s laboratory, Page found Academy of Sciences to accompany the member’s Inaugural it’s too liberal,’’ Page was determined to that designing experiments came natu- Article on page 2474. attend. Swarthmore’s ‘‘intellectual candy rally to him. Compared with college © 2006 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0600615103 PNAS ͉ February 21, 2006 ͉ vol. 103 ͉ no. 8 ͉ 2471–2473 Downloaded by guest on October 1, 2021 Page began developing a genetic linkage the question of what to do with his life: blitz and the scrutiny from my scientific map of the human genome. The sign- medicine or research. colleagues that would result from the posts he needed for his map were re- attention. I became a public figure very striction fragment length polymorphisms XX Males and XY Females early, and I simply wasn’t ready . and (RFLPs). But these were the early days After receiving his M.D. in 1984, Page it took me a while to recover from it,’’ of human molecular genetics and only decided to pursue research full-time but he says. two RFLPs had been identified in the was not sure where or with whom. Once In 1989, however, a British research human genome. ‘‘If you found one, it again, he turned to Baltimore for ad- team led by Peter Goodfellow and was a really big deal,’’ Page says. He vice. He suggested that Page apply for a Robin Lovell-Badge began reporting detected RFLPs randomly by fishing fellowship at the then-new Whitehead that ZFY was not the coveted sex- probes from Thomas Maniatis’ human Institute for Biomedical Research (Cam- determining gene. Their mapping efforts genome library and screening Southern bridge, MA). His acceptance by the suggested that the gene actually lay dis- blots. ‘‘The first RFLP that I found in Whitehead Institute in 1984 provided a tal to ZFY. This finding led Page to this library happened to come from a perfect segue from medical school to reexamine his data. In the Russian rou- site of homology between the X and Y research. ‘‘I was the first Fellow of the lette of human genetics, one of Page’s chromosomes,’’ he says, ‘‘and that Whitehead Institute, and I’ve basically XY females was found to have two dele- kicked off the rest of my career.’’ had one job since then,’’ says Page. tions rather than the assumed one. In White moved to Utah, so in 1981, af- He was already fascinated with the X this rare case, it was the second noncon- ter his third year in medical school, and Y chromosomes, and as a Fellow tiguous deletion that marked the site Page returned to Botstein’s laboratory. began studying the gender-bending mys- of the sex-determining gene, which After a few months, Page decided to tery of XX males. Since the Finnish Goodfellow and Lovell-Badge dubbed take a year-long leave of absence. ‘‘I was SRY (5). enjoying research, but I was still very in- Although the Page and Goodfellow͞ terested in international economics͞ ‘‘A scientist could be Lovell-Badge groups published their re- politics, but I had never traveled, never sults in the same issue of Nature (5, 6), left North America,’’ he says, ‘‘so I de- the first person Page was recast as the loser of the race cided to spend 6 months in lab and 6 and again faced a media onslaught. months in a third-world country doing in the world ‘‘That whole extended episode was a medicine.’’ The logistics of organizing trying and gut-wrenching time, in part his trip took longer than expected, and to know something.’’ because of the media attention,’’ he 1 year away from medical school turned says. After the discovery of SRY, many into 2. ‘‘When I asked for a second researchers abandoned work on the Y year’s leave of absence, it was not medical geneticist Albert de la Chapelle chromosome, in keeping with prevailing warmly received. They start asking if had identified the first XX male in 1964, wisdom that it was barren except for a single sex-determining gene. Page, you are thinking about leaving medi- physicians had determined that 1 out of cine,’’ he says. Undaunted, Page secured however, continued to study the Y chro- 20,000 men had this genetic sex reversal, a 3-month stay at a hospital in Liberia, mosome but resisted pressure from col- possessing two X chromosomes rather Africa. By the time he arrived, he had leagues to focus on SRY.