PROFILE PROFILE Profile of Bruce Levin Beth Azar “Dr. Foster was what a teacher should be,” Science Writer recalls Levin. “He was totally supportive of me, a hardly stellar undergrad. He introduced For population biologist Bruce Levin, open- “Hopped Up” on Research me to two graduate students working on mice, Mike Petras and David Rasmussen, ing the incubator to see how yesterday’sex- LevingrewupintheBronx,NewYork,and and gave me a desk in a room I shared with periment worked is his ideal way to start the his parents hoped he would pursue a career some 1,000 deer mice. With Mike and David, day. That anticipation has kept the Emory in medicine. Not cut out for medicine, Levin I did my first research, a computer simulation University professor of biology excited about decided to major in engineering when he of the population genetics of a lethal gene his research on the population and evolu- was accepted at the University of Michigan, complex in house mice.” tionary biology of bacteria for more than 40 Ann Arbor. “Once I saw how much fun research was, I “ years, and motivated a shift in interest from Engineering was legitimate for my parents, was totally hopped up and saw no choice but ” multicellular organisms to bacteria. Any- though not as legitimate as real doctoring, to go to graduate school,” he says. thing that takes longer than a day to see says Levin. However, engineering was not Levin stayed at Ann Arbor for graduate results, says Levin, takes too long. what he had expected. “My vision was that school. Thanks to his programming skills, he Levin uses mathematical and computer of a 19th century inventor. It was a very met William J. (Jack) Schull who agreed to be modeling and experiments with bacteria to romantic idea and not at all like what I was his PhD advisor, despite their differing inter- investigate basic ecological and evolutionary learning in school.” ests. Levin wanted to become an ecological questions. He employs the same techniques After his second year, Levin switched to geneticist focusing on Drosophila, and Schull to study health-related problems, including zoology. The subject matter was interesting, was a mathematical-statistical geneticist work- the epidemiology and evolution of patho- but he was no more motivated as a student. ing on human populations. “Although I genic bacteria and the population and evolu- He soon discovered the joy of research dur- had my own lab and worked independently tionary dynamics of antibiotic treatment inganintroductorygeneticsclasstaughtby of him, Jack was always there when I needed ” and resistance. Morris Foster. Levin wanted to avoid writing advice. He still is, even now at 92, says “ Elected to the National Academy of Sci- the required term paper and decided to le- Levin. He was extremely supportive of me ences in 2012, Levin uses mathematical and verage the computer programming skills he and taught me to be the same with my ” computer simulation models to determine had gained as an engineering student. He students and postdocs. the optimal way to use antibiotics to treat asked Foster whether, instead of writing the Switching to Bacteria acute infection, as described in his Inaugural paper, he might work on computer simu- As a graduate student, Levin decided he Article (1). lations of genetic phenomena. would integrate population genetics and pop- ulation ecology. At the time, in the mid-1960s, ecology was concerned with the distribution and abundance of species and population ge- netics was focused on the genetic basis of evolution, and the two spheres rarely over- lapped. He achieved his goal, but only after he switched focus from Drosophila to bacteria, moving from Ann Arbor to Brown University as an assistant professor after completing his PhD in 1967. Working with Drosophila was unsatisfying, says Levin. He could not control the envi- ronment, and evolutionary experiments were long and difficult to repeat. With bacteria, in particular Escherichia coli, he could perform ecological and evolutionary experiments in real time and test hypotheses within days under well-controlled and reproducible conditions. Brown colleagues Seymour Lederberg and Frank Rothman made his transition from This is a Profile of a recently elected member of the National Academy of Sciences to accompany the member’s Inaugural Bruce Levin. Image courtesy of Emory University Photo/Video. Article, 10.1073/pnas.1400352111. www.pnas.org/cgi/doi/10.1073/pnas.1408161111 PNAS Early Edition | 1of3 Downloaded by guest on September 24, 2021 Drosophila to E. coli seamless, and within studies with bacteria were becoming legiti- The “CRISPR-Cas Biz” about eight weeks he had enough data to mate,” says Levin. Although antibiotic treatment and resistance publish a paper in Science (2). In the paper, Levin also began studying the population studies continue to dominate Levin’sre- he presented evidence that two strains of dynamics and evolution of infectious disease. search, recently he has been studying an E. coli could stably coexist on a single limiting Many of these studies examined how infectious adaptive immune system that abounds in resource, glucose, contrary to the prevailing diseases evolve both within a host and over bacteria and archaea, called CRISPR-Cas. view that the number of coexisting species time among many hosts, asking questions CRISPR are short sequences of repeated had to be less than the number of resources. about how virulence evolves and is maintained. DNA separated by DNA commonly ac- “It was an important result at the time,” he A paper with his colleague and friend Jim quired from bacteriophage and plasmids. says. “But as I went on with my research I Bull, an evolutionary biologist at the Uni- The CRISPR-Cas system helps bacteria realized that the resource-species hypothesis versity of Texas at Austin, postulates that for abort infections by phage or plasmids that was untestable. Even though glucose was the some pathogens, such as poliovirus, virulence contain DNA identical to the acquired limiting resource, once you put bacteria in is the product of short-sighted evolution sequences, providing protection against there are an abundance of metabolic byproduct within hosts (8). The morbidity and mortality lethal phage. However, the system can also resources to share.” of infections are also often due to host fail- prevent bacteria from acquiring poten- While at Brown, Levin met the person he ings, says Levin. A paper he wrote with his tially beneficial genes borne on plasmids describes as “the most awesome mathemati- MD/PhD student Elisa Margolis (9) argues and temperate phage. cian and human being with a real interest in that virulence commonly results from the Levin’s first contribution to the “CRISPR- biology”:FrankM.Stewart,withwhomhe host’s runaway immune response. Cas biz,” as he calls it, was a theoretical study collaborated from the early 1970s through the “Things like sepsis are examples of the of the conditions under which this bacterial 1990s.Theirfirstpapertogether(3),published downside of our immune system,” says Levin. immune system would evolve and be main- after Levin left Brown for the University of tained (10). Along with North Carolina State Massachusetts at Amherst in 1971, was mo- “I believe that the future University molecular biologist Rodolphe tivated by the results of the Science paper but of treating infections is Barrangou and Université Laval microbiolo- was purely theoretical. Then, in 1977, along gist Sylvain Moineau, he examined the yogurt with Stewart and his first graduate student, not going to be with bacteria Streptococcus thermophilus and its Lin Chao, Levin conducted a study that would antimicrobial drugs but phage (11). “This study is a superb example serve as the model for much of Levin’scareer: rather by controlling the of why one has to do the experiments and combining mathematical and computer sim- ” how one learns most from models when ulation modeling with in vitro experiments immune over-response. they don’t fit,” says Levin. The molecular with bacteria to estimate the parameters of biology findings were accurate, but their Linking basic research and theory in the models and test hypotheses generated model of the population dynamics of phage ecology and evolution to applications in from the analysis of their properties (4). was not. The bacteria had unanticipated medicine have become a common theme tricks that enabled them to survive phage ’ ’ Bacteria for Bacteria s Sake in Levin s work. Since leaving Massachu- infection without CRISPR and produced When Levin initially switched to bacteria, he setts for Emory University in 1992, much compounds that prevented CRISPR-pro- was concerned about extrapolating his find- of his work has focused on antibiotic treat- tected cells from becoming established. ings to higher organisms. Soon, however, he ment and resistance. Along with Rockefeller University molec- “ realized there was a lot to learn from studying The motivation behind these studies is ular geneticist Luciano Marriffini, Levin has bacteria for bacteria’ssake. adesiretomakearealcontributiontohu- been examining the inadvertent drawback of ” “ In the early 1980s, along with Robert man health and well-being, says Levin. I the CRISPR-Cas system: preventing the ac- Selander, an evolutionary biologist now at have been particularly fortunate in this en- quisition of beneficial DNA. Their first study Penn State University, Levin studied the terprise to work with a phenomenal postdoc found that when they offered Staphylococcus population genetics of E. coli from natural Marc Lipsitch, who is now a professor at the epidermidis an antibiotic resistance plasmid sources. These studies were among the first of Harvard School of Public Health, and my needed for their survival—which CRISPR- what is now known as molecular epidemiol- now ‘brother’ Fernando Baquero, a brilliant Caspreventsthemfromreceiving—the ogy, including an 11-month study of the ge- microbiologist and physician from Madrid.” bacteria lose CRISPR-Cas (12).