PROFILE Profile of David M. Hillis hilippe Padieu was called a mod- down through the maternal line. However, ern-day Casanova. Women said both types of analyses had their short- Pthey were drawn to him for his comings: chloroplast DNA analysis was sweet personality and charm. restricted to plants, and mtDNA evolves However, Padieu harbored a secret. In so quickly that it was best suited for 2009, he was found guilty of aggravated reconstructing relatively recent di- assault for purposefully infecting six vergence events. So Hillis looked to nu- women with HIV and sentenced to 45 clear ribosomal DNA, as well as nuclear- years in prison. Credit for Padieu’s guilty encoded proteins, to reconstruct the verdict goes partly to David Hillis, an evolutionary history of amphibians. The evolutionary biologist at the University results revealed enormous hidden di- of Texas at Austin. versity among morphologically similar Hillis, elected to the National Academy amphibians (2, 3). Rather than throwing of Sciences in 2008, has devoted his re- out centuries of morphological work, search career to phylogeny, the study of however, Hillis worked to integrate mo- evolutionary relationships. His work tack- lecular and morphological studies of les some of the greatest questions of evo- phylogeny (4). lutionary biology: How do species arise? Soon Hillis turned his attention to how How do genes diversify and acquire new individual genes evolve and diversify. For functions? How do pathogens evolve, and instance, when Hillis and his colleagues how can that information be used to un- studied the evolution of the ZFY gene, derstand diseases? And ultimately, can we then thought to trigger male development reconstruct the complete Tree of Life and in mammals, they found that the gene was use that information to help make pre- unrelated to sex determination in reptiles dictions about biology? (5). “It was one of the first indications Before the Padieu case, Hillis and col- that the ZFY gene was not actually the sex leagues had used phylogeny to determine determination gene, as it was initially the degree of relatedness among HIV David M. Hillis. thought to be,” Hillis says. Soon after, the carriers. However, in the Padieu case, actual sex-determining gene of mammals, prosecutors needed to show that the HIV SRY, was discovered. traveled from Padieu to his victims, rather no distractions like television or anything Hillis’ work in frogs and reptiles made than the other way around. HIV was like that. The primary way I had to en- clear that phylogenies could reveal how known to infect each host with billions of tertain myself was to run around the life on Earth evolved. Rather than look at virions. However, when the virus travels jungles of Africa and catch lizards and single species, Hillis now devotes much of from a source to recipient, a genetic bot- snakes and butterflies,” Hillis says. his time to modeling evolution on com- tleneck occurs and typically only one of That scientific curiosity stayed with puters and coming up with ways to detect those virions makes the jump into the new Hillis as the family fled the Congolese civil evolutionary patterns in enormous data- host. Because the virus evolves rapidly, war. The family later lived in Calcutta, sets. Although his early interest in science Hillis’ team was able to show that six of India, and then Baltimore, MD, where may have come from his father, Hillis the samples were derived from the sev- both Hillis’ parents took up faculty posi- gives credit for his more recent work to enth. In court, that seventh sample was tions at The Johns Hopkins University. his mother, a biostatistician. revealed as belonging to Padieu (1). By high school, Hillis had grown intrigued by reptiles and amphibians. “I became Watching Evolution Amphibian Evolution fascinated with reptiles in Africa, where Hillis’ shift toward statistical and com- Much of Hillis’ early exposure to science I’d caught and kept lizards and learned putational approaches to evolution began came through his father, an Air Force that many adults were scared of snakes,” when he accepted a faculty position at the physician and epidemiologist. Hillis was he recalls. “A little kid with a snake feels University of Texas at Austin, where he born in Copenhagen, Denmark, but his powerful, I think, as many adults have now works. There, he met his colleague family later relocated to San Antonio, learned an unnatural fear of them.” As an Jim Bull, initially a skeptic of phyloge- TX. There, in the early 1960s, Hillis’ fa- undergraduate, Hillis realized that am- netic analysis. “He didn’t think there were ther treated a veterinarian who had con- phibians were also ideal organisms for any convincing studies of the accuracy of tracted hepatitis from one of the chim- studying how species diverge and evolve. phylogenetic methods,” Hillis says. Bull panzees used in the US space program. He graduated in 1980 with a degree in had reason to doubt. By that point in the That case and other ones like it over- biology from Baylor University in Waco, late 1980s, phylogenetic analysis was turned the belief that chimps were im- TX, and entered a graduate biology pro- growing in popularity, but its accuracy mune to the disease, suggesting instead gram at the University of Kansas in remained in question. Because much that chimps could be carriers. Un- Lawrence to study amphibian evolution. evolution occurs over lengthy time scales, derstanding hepatitis’ mode of trans- At that time, phylogenies were largely it usually cannot be observed directly. mission consumed the elder Hillis’ constructed based on the morphology of Morphological change can be examined subsequent work, and the family re- organisms, by using such characteristics as in the fossil record, but molecular located to the Congo so he could study shape and size. However, Hillis realized chimpanzees in the wild. En route to that much more information on evolu- Africa, though, the Hillis’ belongings tionary relationships was encoded in ge- This is a Profile of a recently elected member of the Na- were stolen, a strangely serendipitous nomes. Researchers were just beginning to tional Academy of Sciences to accompany the member’s experience. “We had no toys. There were analyze chloroplast and DNA, passed Inaugural Article on page 21242 in issue 50 of volume107. www.pnas.org/cgi/doi/10.1073/pnas.1107823108 PNAS Early Edition | 1of3 Downloaded by guest on September 28, 2021 changes—increasingly the basis for phy- phylogenies as well as the bacteriophages tranceway of the biology building at logenetic studies—are not preserved they had studied in the laboratory (9, 10). University of Texas’ Austin campus. Next in fossils. In the mid-1990s, biologists began to the location of humans, the tree has Hillis was convinced he could get Bull tackling phylogenies with hundreds of a “you are here” sign. “At the beginning to come around. So they made a deal. species. Many people were skeptical that of the semester, there are always a lot of “The stakes were high,” Hillis jokes. “We such large phylogenies—which Hillis says mystified students looking at it saying bet a quarter.” For a convincing case, contain more potential solutions than ‘I don’t understand... is this a map of Hillis and Bull needed to find a species the number of fundamental atomic par- campus?’” Hillis says. that evolved fast enough to be observable ticles in the universe—could be recon- in real time—one that could grow, re- structed accurately. One of the larger Evolution Matters produce, and accumulate mutations in trees at the time was produced by Pam The theoretical groundwork laid, Hillis minutes rather than millennia. The two and Doug Soltis, evolutionary biologists became interested in applying phyloge- researchers settled on T7 bacteriophage, who now work at the University of Flor- netic methods to answer questions about a virus that doubles its population in less ida in Gainesville. The duo had recon- the molecular processes underlying evo- than 15 minutes. They started with a sin- structed the evolutionary relationships lution. Hillis first ventured into the study gle ancestral stock and let it reproduce among 228 species of flowering plants by of HIV transmission following a high- for hundreds of generations, separating comparing their ribosomal RNA genes profile case in the early 1990s in which an out colonies at predetermined intervals. (11). However, some researchers were HIV-positive dentist in Florida was ac- To encourage rapid evolution, the prog- unconvinced by the Soltises’ findings, ar- cused of transmitting the virus to several eny were exposed to a chemical that guing that efforts to recreate the evolu- patients. After evaluating blood samples promotes mutations during viral tionary histories of just a handful of from infected individuals, the Centers for replication (6). species required the analysis of many Disease Control determined that the HIV Hillis, who was blinded to the experi- more genes—and that the same principle strains in the doctor and his patients were mental setup to avoid biasing the results, should hold true for larger data sets, like related. Hillis was asked to review the mapped the genomes of the evolved ex- the flowering plants. results of this new methodology. The perimental viruses and used five phylo- To resolve the dispute, Hillis simulated methods the Centers for Disease Control genetic methods to reconstruct the the evolution of the ribosomal RNA genes used were sound, Hillis says, but the phage’s evolutionary history. When the on a computer. Expecting to find that case never went to trial because the dentist blinded labels were decoded, Bull agreed the Soltises needed more data, Hillis was died in the interim. that the estimated trees provided an ac- surprised to discover that denser sampling It took another high-profile case for the curate picture of the actual evolutionary of species generated more realistic phy- phylogenetic analysis of HIV to make history.