PROFILE Profile of Nahum Sonenberg PROFILE Ann Griswold, Science Writer Five years after the final shots of World War II rang out, a child and his father stood on the coast of the Mediterranean Sea. From their vantage point in a cemetery in the town of Jaffa, Israel, the boy gazed across the sea and envisioned stepping onto the sands of a distant shore. He pointed to the horizon and asked his father what lay beyond. “I remember my father said, ‘There is America, the country where everything is possible,’” says Nahum Sonenberg, the Gilman Cheney Professor of Biochem- istry at McGill University in Montreal. Sonenberg, elected as a foreign associate to the National Academy of Sciences in 2015, has spent nearly five decades looking beyond the horizon to map un- explored territory in molecular biology. His research has uncovered the cellular control knobs of protein synthesis and revealed how this process drifts off-course in cancer, obesity, diabetes, and neurological diseases. His achievements have garnered numerous hon- ors. Sonenberg is a fellow of the Royal Society of London and Canada, Foreign Member of the Amer- ican Academy of Arts and Sciences and the American Association for the Advancement of Science, Asso- ciate Member of European Molecular Biology Orga- nization, and an Officer of the Order of Canada. He has received numerous prizes in the biological sciences, including the Lewis S. Rosenstiel Award for Distin- guished Work in Basic Medical Science, the Wolf Prize, and the Gairdner Foundation International Award. Nahum Sonenberg. Image courtesy of Howard Hughes Medical Institute. Life in Transition Sonenberg’s childhood unfolded in the aftermath of By the time Sonenberg turned 10, he and his family had World War II. His parents were Jewish textile workers moved again to the suburbs of Tel Aviv. There was no who had fled from Poland to Russia in 1939 to escape television in Israel at that time, and his neighborhood the Nazis. Soon after their arrival, Sonenberg’s father offered scarce entertainment, so Sonenberg says he had was arrested by the Russians and accused of spying for two choices: reading books or listening to the radio. He the Germans. He was sent to a forced-labor camp; fell in love with the weathered pages of a large world meanwhile, his mother was assigned to work for the atlas and eventually learned all the capital cities. “Iwas Russian army. The unwed couple returned briefly to thepersontoaskaboutgeography,” he recalls. Poland when the war ended but found no relatives left His fascination with the natural world narrowed to a in their former village of Alexandrow, near Lodz. They microscopic scale during his adolescent years. He atten- married and made their way to American territory in ded high school in the 1960s, as researchers raced to Germany where, in 1946, Sonenberg was born in a understand the genetic code: how DNA encodes the displaced persons camp. composition of proteins, whose building blocks are amino At age 2, Sonenberg and his parents immigrated to acids. In 1963, Sonenberg marveled at a groundbreaking Jaffa, an ancient city known for its lush orange groves. study by American biochemist Marshall Nirenberg, who This is a Profile of a recently elected member of the National Academy of Sciences to accompany the member’s Inaugural Article on page 12360 in issue 44 of volume 113. www.pnas.org/cgi/doi/10.1073/pnas.1711714114 PNAS | August 22, 2017 | vol. 114 | no. 34 | 8905–8907 Downloaded by guest on September 29, 2021 was the first to decipher the DNA “letters” that code for a gear so that the mRNA can start the process of protein single amino acid, phenylalanine. synthesis (3). The protein was later named the “cap- By the time Nirenberg shared the Nobel Prize binding protein,” eIF4E. in Physiology or Medicine with Robert Holley and Sonenberg’s discovery revealed a key element of Gobind Khorana in 1968, Sonenberg was an un- protein synthesis. He and other researchers kept picking dergraduate microbiology student at Tel-Aviv Uni- apart the process to understand the regulation of protein versity. Inspired by the pace of genetic discovery and production and the consequences of aberrant regulation. a compelling biochemistry professor, Sonenberg re- Upon completing his postdoctoral studies in 1979, solved to enter this exciting field of research. Sonenberg joined the Biochemistry Department of “What attracted me to the field was that the nature McGill University as an assistant professor. Emerging of proteins and everything that follows—our behavior, findings documented the importance of gene ex- our wellbeing, everything—is dictated by genes,” pression in behavior, disease, and physiology. When he recalls. gene-sequencing tools emerged in the late 1970s, Sonenberg and others set out to parse the connec- Prelude to RNA’s Role as an Enzyme tions between protein synthesis and various diseases, Sonenberg received his Master’sdegreeinmicrobiology such as cancer. and immunology from Tel Aviv University in 1972 and “Much was unknown,” he says. “And, you know, enrolled in a doctoral program at the Weizmann Institute, the unknown is far more interesting than the known.” considered Israel’s premier research center. Sonenberg’s first major task as a freshly minted Researchers there were examining ribosomes, the principal investigator was to determine how protein cellular machines that string amino acids into proteins synthesis shapes polio pathogenesis. Researchers had according to assembly instructions provided in the isolated the polio virus in 1908, and Jonas Salk and mRNA template of the DNA. Sonenberg sought the Albert Sabin unveiled their first polio vaccine in 1955 guidance of a young professor, Ada Zamir, who had and 1961, respectively. However, even in the 1980s recently completed a postdoctoral project with Holley. researchers still remained unsure how the virus In Zamir’s laboratory, Sonenberg explored the causes disease. molecular superglue that links amino acids together Sonenberg dove into this mystery during a year-long into a peptide chain. He knew that the bond is among visiting professorship with David Baltimore at the the strongest covalent forces in nature, so stout that it Whitehead Institute for Biomedical Research in shatters only when a protein is boiled in acid. Using a Cambridge, MA. The groups of Baltimore and Eckard technique called “affinity labeling,” developed by his Wimmer at Stony Brook University, Long Island, New comentor Meir Wilchek, he set out to identify the ri- York, discovered that the RNA of poliovirus lacks caps. In bosomal enzyme that forms this bond. a 1988 article in Nature, Sonenberg showed that, with- He expected the enzyme to be a protein. However, out the cap, poliovirus translation occurs in a unique in a 1975 PNAS article, Sonenberg and his mentors re- way, beginning when ribosomes bind to a sequence ported the surprising revelation that RNA—specifically, inside the 5′ noncoding region (4). This insight helped the 23S RNA that makes up a large portion of the ribo- reveal how poliovirus commandeers the cellular ma- some—is positioned at the core of the enzyme peptidyl chinery that produces proteins, killing human cells. transferase, which catalyzes peptide bond formation (1). “The only enzymes that were known to exist at that Parsing Proteins time were proteins,” he says. “We didn’t know back Sonenberg returned to McGill as a tenured professor of then that RNA was able to work as an enzyme, so we biochemistry, and his curiosity turned to cancer. In a did not realize the true meaning of this finding, but it 1990 Nature article, Sonenberg’s team reported that an was very exciting.” overabundance of the cap-binding protein eIF4E can In 1975, a team of researchers at the Roche Institute cause eukaryotic cells to proliferate out of control and of Molecular Biology in Nutley, NJ, uncovered another form tumors (5). Twenty years later, in a PNAS article, piece of the protein synthesis puzzle. They determined his team showed that the addition of a phosphate tag that eukaryotic mRNA has a cap-like structure at one end to eIF4E sparks the synthesis of proteins involved in that plays a role in protein synthesis (2). The finding stir- tumor formation and that high rates of phosphorylation red Sonenberg’s curiosity, and he contacted the team, often track with aggressive disease progression in pa- led by biochemists Aaron Shatkin and Yasuhiro Furuichi, tients with prostate cancer (6). The findings hinted that to inquire about a postdoctoral position. “I thought it drugs preventing eIF4E phosphorylation might prove would be a very simple project to figure out why you to be potent anticancer agents. need this cap and how it works,” Sonenberg says. In 1994, he published an article in Nature revealing another protein synthesis regulatory process: a family of International Pursuits proteins that bind to eIF4E to turn off protein synthesis In 1976, with a PhD degree from the Weizmann In- and stall cell growth. The team found that insulin can stitute in hand, Sonenberg moved overseas to join interrupt the binding of these proteins, called “eIF4E Shatkin’s laboratory. Within two years, Sonenberg and binding proteins” (4E-BPs), thus impairing protein syn- his colleagues made a major discovery: They identified thesis (7). Over the next decade, Sonenberg and a protein that recognizes and binds to the cap. This others revealed that 4E-BPs indirectly contribute to critical action kicks the cell’s translation machinery into diseases such as cancer, diabetes, and even autism by 8906 | www.pnas.org/cgi/doi/10.1073/pnas.1711714114 Griswold Downloaded by guest on September 29, 2021 responding to mTOR complex 1 (mTORC1), a protein quintessential regulators of gene expression. Re- cluster that senses the cellular milieu and directs protein searchers had known for a long time, indeed since synthesis accordingly (8).