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Distinguished Professor and NAS Scholar at Stony Brook University
Wimmer’s major early accomplishment, spearheaded by Naomi Kitamura and other members of his laboratory, was the elucidation in 1981 of the structure and genetic organization of the poliovirus genome, the first sequence of a eukaryotic RNA virus. The primary structure of the genome was unique at the time amongst RNA viruses as it was 3’ polyadenylated and 5’ covalently linked to a protein called VPg. VPg was later shown by Aniko Paul to be a primer in RNA replication. The resulting gene map provided irrefutable evidence for the existence of the polyprotein, the only polypeptide that poliovirus synthesizes. Polyproteins, first postulated by David Baltimore, are a hallmark of gene expression in many viruses and in all retroviruses. Wimmer’s lab not only provided proof of the polyprotein but also largely identified the pathway by which the polyprotein is processed into functional polypeptides, where Bert L. Semler showed that the cleavages occur predominantly at evolutionary preserved Q^G sites. These studies were the basis for the discovery of the “internal ribosome entry site” (IRES) in a picornavirus genome by Sung Key Jang (1988), independently described also by Nahum Sonenberg and his colleagues. IRES elements allow initiation of protein synthesis in a cap-independent manner, which violates a long-standing dogma in protein synthesis of eukaryotic cells. IRESes have now found widespread recognition in cell biology and application in biotechnology. An IRES chimeric oncolytic poliovirus [PV(RIPO)], originally constructed in Wimmer’s laboratory, has now been developed by Matthias Gromeier at Duke University for the treatment of human glioma.
Wimmer is co-discoverer of the poliovirus receptor CD155, a cell-adhesion molecule and tumor antigen, whose expression is regulated by the sonic hedgehog pathway. A decade-long collaboration with Michael Rossmann’s laboratory and Steffen Mueller in Wimmer's lab has yielded the crystal structure of the two outer domains of CD155, an achievement that has solved the architecture of the poliovirus/receptor complex.
In 1991, Molla, Paul and Wimmer published the first de novo, cell-free synthesis of any virus. This experiment has led to biochemical studies of the complete poliovirus life cycle in cytoplasmic extracts of naïve mammalian cells. Many investigators have since used this strategy involving a cell “juice” void of the barrier of a cellular membrane, of nuclei or of mitochondria, for the study of key steps in poliovirus translation and genome replication.
Using the nucleotide sequence of the genome deciphered in 1981, Wimmer followed up on the work published in 1991 by synthesizing chemically the genome in the form of double stranded DNA (“cDNA”), which was then transcribed enzymatically into genome RNA and “booted to life” in the cell free system. This work, published in 2002 by Cello, Paul and Wimmer, was the first test-tube synthesis of an organism in the absence of a natural template achieved outside living cells. The poliovirus synthesis caught global attention, high praise, ridicule and fierce condemnation. Several years later, Wimmer published an essay in EMBO Reports reflecting on hotly debated issues that this new kind of research generated (ethical matters, questions about the global eradication of poliovirus, concerns of “dual use research”). Apart from providing a ‘proof of principle,’ the experiment heralded the total synthesis of organisms with computers as parents, a strategy that allows investigating the structure and function of an organism’s biology to an extent hitherto impossible. Meanwhile, synthetic biology has led to a new kind of RNA virus genetics and has been used to develop rapid methods for computer-aided chemical synthesis of viral recoded genomes. This strategy allows for the generation of new vaccines in a very short time.
Recently, Wimmer’s lab has elucidated the key step in the morphogenesis of poliovirus that has been elusive for decades.