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 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 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 . 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 . 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- 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 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 , 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 , 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 Downloaded by guest on September 27, 2021 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. That picture began to grow cluding nuclei and mitochondria. He was scratch provides amazing power to treat clearer in the late 1980s. In 1988, Wimmer left, he says, with a very clear juice. Then, and even solve some of today’s most found that some viruses trigger protein Wimmer mixed the polio genome into the pressing medical concerns, Wimmer says. synthesis in a manner that deviated en- juice and tested whether it would produce For instance, after Wimmer engineered tirely from the established mechanism, more of itself in this new medium. Could polio, another research team resurrected “ ” “ known as cap-dependent translation. the polio, in other words, be booted to the long-lost flu virus of 1918 (H1N1), ” “ Using a virus related to poliovirus, life ? When the boot worked, it simpli- a deadly pandemic that killed between 50 fi ” Wimmer discovered that an unusually ed the study of how viruses replicate, and 130 million people. The resurrection “ ’ large segment of the viral genome (450 Wimmer says. It showed that we don t let the team decipher what made the flu ” nt) was attracting ribosomes, the protein really need nuclei and this and that (23). so lethal (28). Their work is now yielding synthesis factories of cells. The attraction It would take another 10 years for insights into its modern-day cousin, the enabled the ribosomes to initiate protein Wimmer to show that real poliovirus is not bird flu (H5N1). synthesis. Wimmer called this segment an required for replication to occur. By internal ribosomal entry site (IRES) (16, returning to the chemical structure of the Still on the Clock 17). Interestingly, Nahum Sonenberg, polio genome he deciphered in 1981, In the nearly four decades that Wimmer a biochemist at McGill University in Wimmer and his collaborators began has spent at Stony Brook, he has earned Montreal, made the same discovery at making the entirety of the virus from a number of awards, including the Bei- about the same time (18). scratch. That required stringing together fi ’ jerinck Prize from the Royal Today, that nding may hold the key to polio s 7,500 nt, a daunting task (1). Netherlands Academy of Arts and Sci- treating glioma, a deadly brain cancer. Nobody had ever built a virus before. ences in 2010 and the Robert Koch Gold IRES elements differ from virus to virus, The Defense Advanced Research Project Medal in 2012 for his lifelong research on yet they can be exchanged between viruses Agency initially provided approximately ’ viruses. At age 76, Wimmer could easily through genetic engineering. Wimmer s $200,000 for the project, a relatively small retire, spending more time with his wife, laboratory had been creating these chi- amount, later expanded by approximately Astrid, whom he met in Germany; and his meras to see how IRES elements work. the same sum. According to Wimmer, the two children and three young grand- Matthias Gromeier, who was then a post- group barely managed to limp over the ’ fi children. And he would be able to focus doctoral fellow in Wimmer s laboratory, nish line when they published in 2002. on his hobbies, which include singing, replaced the IRES from polio with the That work triggered another landmark gardening, and skiing. IRES from human rhinovirus. To his finding. In 2002, Wimmer’s team inserted “ ” However, Wimmer feels retirement surprise, he found that the resulting chi- 28 nt changes, or watermarks, into the would mean leaving behind too much and mera grew well in glioma cells but not in synthetic genome to demonstrate that the says he can’t bear to part with his polio healthy cells of the central nervous system virus growing from it was not a laboratory research—not when the promise of syn- (19). A modified form of the chimera is contaminant. Surprisingly, one of those thetic vaccines is so close at hand. The currently in clinical trials for the treat- changes weakened the virulence of the hope is that synthetic vaccines will one day ment of glioma (20). synthetic virus. That observation has now cost less and cause fewer side effects than Following his discovery of IRES ele- become the basis for constructing a virus conventional vaccines (29, 30). Wimmer ments, Wimmer began investigating just that preferentially targets cells in neuro- says he hopes to “see these [synthetic] how poliovirus enters the cell. Animal blastoma, a rare childhood cancer (24). vaccines developed in my lifetime.” viruses, like poliovirus, enter organisms by Although many scientists hailed binding to a specific receptor on the sur- Wimmer’s achievement in creating po- Sujata Gupta, Freelance Science Writer

1974 | www.pnas.org/cgi/doi/10.1073/pnas.1221558110 Gupta Downloaded by guest on September 27, 2021 1. Cello J, Paul AV, Wimmer E (2002) Chemical synthesis 11. Lee YF, Nomoto A, Detjen BM, Wimmer E (1977) A glioblastoma multiforme. Cytokine Growth Factor Rev of poliovirus cDNA: Generation of infectious virus in protein covalently linked to poliovirus genome RNA. 21(2-3):197–203. the absence of natural template. Science 297(5583): Proc Natl Acad Sci USA 74(1):59–63. 21. Mendelsohn CL, Wimmer E, Racaniello VR (1989) Cellu- 1016–1018. 12. Kitamura N, et al. (1981) Primary structure, gene or- lar receptor for poliovirus: Molecular cloning, nucleotide 2. Wimmer E, Paul AV (2011) Synthetic poliovirus and ganization and polypeptide expression of poliovirus sequence, and expression of a new member of the im- other designer viruses: What have we learned from RNA. Nature 291(5816):547–553. munoglobulin superfamily. Cell 56(5):855–865. them? Annu Rev Microbiol 65:583–609. 13. Rothberg PG, Adler CJ, Kitamura N, Wimmer E (1980) 22. Gromeier M, Wimmer E (2003) US Patent 6,518,033. 3. Song Y, et al. (2012) Identification of two functionally VPg: The genome-linked protein of . Bio- 23. Molla A, Paul AV, Wimmer E (1991) Cell-free, de novo redundant RNA elements in the coding sequence of synthesis, Modification, and Processing of Cellular and synthesis of poliovirus. Science 254(5038):1647–1651. poliovirus using computer-generated design. Proc Natl Viral Polyproteins, ed Koch G (Academic, New York), pp 24. Toyoda H, Yin J, Mueller S, Wimmer E, Cello J (2007) Acad Sci USA 109(36):14301–14307. 309–319. Oncolytic treatment and cure of neuroblastoma by 4. Brockmann H, Wimmer E (1965) Die konstitution 14. Wimmer E, Paul AV (2010) The making of a a novel attenuated poliovirus in a novel poliovirus- des e-, η-, ξ-, und ζ-rhodomycinons. Chem Ber 98: genome. The Picornaviruses, eds Ehrenfeld E, Domingo E, susceptible animal model. Cancer Res 67(6):2857– 2797. Roos RP (ASM Press, Washington, DC), pp 33–55. 2864. 5. Wöhler F (1828) Ueber künstliche bildung des harnst- 15. Kräusslich HG, Wimmer E (1988) Viral proteinases. 25. Wimmer E (2006) The test-tube synthesis of a chemical offs. Annalen der Physik 88(issue 2):253–256. Annu Rev Biochem 57:701–754. called poliovirus. The simple synthesis of a virus has 6. Stanley WM, Loring HS (1936) The isolation of crys- 16. Jang SK, et al. (1988) Evidence in vitro for internal far-reaching societal implications. EMBO Rep 7(spec talline tobacco mosaic virus protein from diseased to- entry by the translational machinery in the 50 non- no):S3–S9. mato plants. Science 83(2143):85. translated region of encephalomyocarditis virus RNA. J 26. Chumakov K, Ehrenfeld E, Wimmer E, Agol VI (2007) 7. Wimmer E, Reichmann ME (1968) Pyrophosphate in Virol 62:2636–2643. Vaccination against polio should not be stopped. Nat the 50-terminal position of a viral ribonucleic acid. 17. Jang SK, Davies MV, Kaufman RJ, Wimmer E (1989) Rev Microbiol 5(12):952–958. Science 160(3835):1452–1454. Initiation of protein synthesis by internal entry of ribo- 27. National Research Council (2004) Biotechnology Re- 8. Wimmer E, Chang AY, Clark JM, Jr., Reichmann ME somes into the 50 nontranslated region of encephalo- search in the Age of Terrorism (National Academy (1968) Sequence studies of satellite tobacco necrosis myocarditis virus RNA in vivo. JVirol63(4):1651–1660. Press, Washington, DC). virus RNA. Isolation and characterization of a 50- 18. Pelletier J, Sonenberg N (1988) Internal initiation of 28. Tumpey TM, et al. (2005) Characterization of the re- terminal trinucleotide. J Mol Biol 38(1):59–73. translation of eukaryotic mRNA directed by a sequence constructed 1918 Spanish influenza pandemic virus. 9. Wimmer E, Reichmann ME (1969) Two 30-terminal se- derived from poliovirus RNA. Nature 334(6180):320–325. Science 310(5745):77–80. quences in satellite tobacco necrosis virus RNA. Nature 19. Gromeier M, Lachmann S, Rosenfeld MR, Gutin PH, 29. Coleman JR, et al. (2008) Virus attenuation by ge- 221(5186):1122–1126. Wimmer E (2000) Intergeneric poliovirus recombinants nome-scale changes in codon pair bias. Science 320 10. Yogo Y, Wimmer E (1972) Sequence studies of po- for the treatment of malignant glioma. Proc Natl Acad (5884):1784–1787. liovirus RNA. II. Polyadenylic acid at the 30-terminus Sci USA 97(12):6803–6808. 30. Mueller S, et al. (2010) Live attenuated influenza virus of poliovirus RNA. Proc Natl Acad Sci USA 69(7): 20. Goetz C, Gromeier M (2010) Preparing an oncolytic vaccines by computer-aided rational design. Nat Bio- 1877–1882. poliovirus recombinant for clinical application against technol 28(7):723–726.

Gupta PNAS | February 5, 2013 | vol. 110 | no. 6 | 1975 Downloaded by guest on September 27, 2021