PROFILE Profile of Eckard Wimmer he finding caused an uproar. vitalism—the belief that chemicals in liv- Researchers at Stony Brook Uni- ing systems are somehow distinct from Tversity in New York had engi- the chemicals in inorganic systems, such neered poliovirus in a test tube as salt and rocks. That notion was shat- (1). The discovery, led by Eckard Wimmer, tered in 1828, when German chemist elected in 2012 to the National Academy Friedrich Wöhler synthesized the organic of Sciences, dispelled the belief that compound urea from inorganic pre- viruses require a live host to grow cursors (5). and spread. By the 1940s, theoretical physicists and The thought of synthetic viruses terrified biochemists had begun to wonder about an American public still reeling from 9/11 what constitutes life. Wimmer was en- and the subsequent anthrax attacks. What thralled. Biochemistry squared perfectly if the technology to engineer viruses with his worldview, the idea that something wound up in the hands of bioterrorists? as seemingly profound as life could be pared However, today, just a decade later, it is down to its simplest—chemical—form. widely accepted that the ability to engineer While completing his second post- viruses also allows researchers to develop doctoral fellowship at the University of viruses that work as synthetic vaccines, British Columbia in Vancouver in the to carry genetic material into a cell for use mid-1960s, Wimmer attended a talk on in gene therapies, or to preferentially viruses and had his eureka moment. “It attack cancer cells (2). was clear, even though it wasn’t men- Wimmer says his motivations for engi- tioned in that talk, that if viruses can be neering polio were strictly scientific. crystallized just like chemicals, it must be Wimmer had solved the code—or genome possible to describe their components, the sequence—for polio in 1981, but his goal, virions, with an empirical formula,” he “ he says, was to boot the synthesized ge- Eckard Wimmer. says (6). At that conference, Wimmer ” nome for it to become a virus. The discussed the idea with Elias Reichmann, boot worked. a plant virologist at the University of Il- Few realized that Wimmer had done munist regime that had taken root in East linois in Urbana–Champaign. Reichmann fl something extraordinary for science and Germany. The family ed again, ulti- asked Wimmer to join his laboratory. society. Viruses, Wimmer and others have mately becoming refugees in what was “Now I was stuck and had to work on long believed, hold a unique place in bi- then West Germany. Through so much viruses,” Wimmer jokes. ology: Outside the body, they behave like dislocation, Wimmer says, “the family lost chemicals, but, once inside, they propagate its roots.” Adopting Polio “ in true Darwinian fashion. Viruses are Wimmer suffered nightmares through- At Reichmann’s laboratory, Wimmer ” chemicals with a life cycle, Wimmer says. out his teen years and long thereafter. initially worked with plant viruses, his “ Once they get into living cells, they begin Forced to question the senselessness of mentor’s specialty (7–9). However, that to replicate, following the laws of heredity human strife early on, Wimmer emerged topic of study proved time-consuming, as ” and genetic variation. Put another way, from his childhood an avowed atheist. both plants and their viruses are generally “ viruses hover on the boundary between life Every child who has been exposed to slow-growing. A colleague suggested that and nonlife. warfare or lives in an area with warfare ’ ... ” Wimmer take a look at poliovirus, which Wimmer s Inaugural Article brings him carries a burden for his whole life, was fast-growing. “Poliovirus fulfilled all one step closer to pinning down the inner Wimmer says. my expectations,” Wimmer says. “You workings of poliovirus (3). In this case, The desire to understand life via sci- could grow it in six hours.” Song et al. looked for the parts of the ence, not some higher power, would ul- — ’ In 1968, Wimmer became an assistant polio genome that make it so deadly that timately become integral to Wimmer s professor in the microbiology department is, the parts of the code that allow the virus later career. Wimmer chose to study at Saint Louis University in Missouri. to replicate and kill host cells. The re- chemistry in large part because his father fi There, Wimmer found himself in an empty searchers found two hidden signals: nu- studied chemistry. After nishing his un- laboratory with almost no funding. And cleotide sequences dubbed α and β. dergraduate degree in chemistry at the yet, he recalls, “I was professionally in- University of Rostock in Germany in dependent for the first time in my life and War Child 1956, Wimmer went to the University of in control of my career. I felt like a king.” Wimmer’s interest in science coincided Göttingen in Germany for graduate His first grant application to sequence the with growing doubts about his Protestant school. There he began his earliest work polio genome was roundly rejected, as no upbringing. Born in Berlin in 1936, in structural analysis and synthesis of one thought it could be done. Then, in Wimmer survived tragedy and war early natural compounds. His task was finding 1969, Wimmer was invited to spend six in life. His father died when Wimmer was the structure of rhodomycinons (4), months working with David Baltimore, just three years old. By then, Hitler a class of compounds whose derivatives a biologist then at the Massachusetts In- had begun his march across Europe. have antitumor activities. Wimmer’s mother whisked him and his During his postdoctoral work in the stitute of Technology in Cambridge, MA. two older brothers to her parents’ place in early 1960s, also at Göttingen, Wimmer Baltimore taught Wimmer the ins and outs Saxony, where the family largely escaped enrolled in a course in microbiology. the violence. In Saxony, however, Wim- There he heard about biochemistry, then fi ’ fl fi This is a Pro le of a recently elected member of the mer s grandfather was labeled a capitalist, a edgling eld in Germany. Bio- National Academy of Sciences to accompany the member’s a term that was anathema to the com- chemistry arose out of the ashes of Inaugural Article on page 14301 in issue 36 of volume 109. www.pnas.org/cgi/doi/10.1073/pnas.1221558110 PNAS | February 5, 2013 | vol. 110 | no. 6 | 1973–1975 of polio research (10). Eventually, Wimmer face of a cell. Once inside the cell, the virus liovirus in a test tube, he also faced in- was able to achieve the goals postulated releases its large genome, programmed to tense criticism, even ridicule. However, in his original grant application. make more of itself. Wimmer wanted to the technology to invent viruses already In the mid-1970s, Wimmer moved to find the cellular receptor that polio sub- existed, Wimmer says. All he did was put New York to help start the microbiology verts, so he inserted human genes into it to the test. Several years later, Wim- department at the then-new state school mouse cells to make them susceptible to mer published an essay in the journal at Stony Brook. He has remained there polio (mice lack a polio receptor and are EMBO Reports reflecting on his 2002 ever since. Soon, Wimmer and his col- thus not susceptible to the disease). Then, publication and the subsequent uproar leagues deciphered poliovirus’ chemical using an antibody, he combed through (25). In it, he acknowledges that creating structure, a finding that provided the millions of mouse cells to find the receptor viruses from scratch does, in theory, ne- foundation for Wimmer’s subsequent it bound to. By cloning those rare mouse gate our ability to eradicate those vi- efforts to map the biological information cells, Wimmer identified the receptor, ruses. He also notes that any eradication hidden in the viral genome, a feat he which now goes by the name CD155 (21). plan must take into account this reality. accomplished in the early 1980s. The re- Subsequent studies revealed that tumor That burden is the consequence of sulting gene map proved for the first time cells overproduce this receptor, revealing progress, he says, of which the synthesis that the poliovirus genome encodes a sin- it to be a good biomarker for cancer (22). of poliovirus is a part. Case in point: gle giant protein, the polyprotein (11–13). Polio has proven so resistant to eradi- Although the presence of such a poly- Launching Life cation that the World Health Organiza- protein had been predicted, Wimmer’s It had been known for decades that tion and other private research work proved its existence (14). He was inserting a purified, or naked, form of the foundations are now funding efforts to also able to identify the parts of the ge- RNA genome of poliovirus into cells could develop new polio vaccines (26). Syn- nome that created the enzymes needed to prompt it to complete its life cycle and thesizing poliovirus, Wimmer continues, cleave the polyprotein (15). produce more virus. However, it took until fits under the National Institutes of the 1990s for Wimmer to realize that he Health “dual use research of concern” Deconstructing Viruses just might be able to create poliovirus designation—that is, situations in which The genome sequence gave Wimmer without cells—or without a live host. In the same technology can be used for a sweeping view of poliovirus. However, 1991, his team mashed human cells and malfeasance or human betterment (27). he didn’t yet know the intricacies of its stripped them of essential elements, in- The ability to create viruses from workings.