Profile of Nahum Sonenberg

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.

Nahum Sonenberg. Image courtesy of Howard Hughes Medical Institute.

“I remember my father said, ‘There is America, the country where everything is possible,’” says Nahum Sonenberg, the Gilman Cheney Professor of Biochemistry 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 unexplored 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 honors. Sonenberg is a fellow of the Royal Society of London and Canada, Foreign Member of the American Academy of Arts and Sciences and the American Association for the Advancement of Science, Associate Member of European Molecular Biology Organization, and an Officer of the Order of Canada. He has received numerous prizes in the biological sciences, including the Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Science, the Wolf Prize, and the Gairdner Foundation International Award.

Life in Transition

Sonenberg’s childhood unfolded in the aftermath of World War II. His parents were Jewish textile workers who had fled from Poland to Russia in 1939 to escape the Nazis. Soon after their arrival, Sonenberg’s father was arrested by the Russians and accused of spying for the Germans. He was sent to a forced-labor camp; meanwhile, his mother was assigned to work for the Russian army. The unwed couple returned briefly to Poland when the war ended but found no relatives left in their former village of Alexandrow, near Lodz. They married and made their way to American territory in Germany where, in 1946, Sonenberg was born in a displaced persons camp.

At age 2, Sonenberg and his parents immigrated to Jaffa, an ancient city known for its lush orange groves. By the time Sonenberg turned 10, he and his family had moved again to the suburbs of Tel Aviv. There was no television in Israel at that time, and his neighborhood offered scarce entertainment, so Sonenberg says he had two choices: reading books or listening to the radio. He fell in love with the weathered pages of a large world atlas and eventually learned all the capital cities. “I was the person to ask about geography,” he recalls.

His fascination with the natural world narrowed to a microscopic scale during his adolescent years. He attended high school in the 1960s, as researchers raced to understand the genetic code: how DNA encodes the composition of proteins, whose building blocks are amino acids. In 1963, Sonenberg marveled at a groundbreaking study by American biochemist Marshall Nirenberg, who was the first to decipher the DNA “letters” that code for a single amino acid, phenylalanine.

By the time Nirenberg shared the Nobel Prize in Physiology or Medicine with Robert Holley and Gobind Khorana in 1968, Sonenberg was an undergraduate microbiology student at Tel-Aviv University. Inspired by the pace of genetic discovery and a compelling biochemistry professor, Sonenberg resolved to enter this exciting field of research.

“What attracted me to the field was that the nature of proteins and everything that follows—our behavior, our wellbeing, everything—is dictated by genes,” he recalls.

Prelude to RNA’s Role as an Enzyme

Sonenberg received his Master’s degree in microbiology and immunology from Tel Aviv University in 1972 and enrolled in a doctoral program at the Weizmann Institute, considered Israel’s premier research center.

Researchers there were examining ribosomes, the cellular machines that string amino acids into proteins according to assembly instructions provided in the mRNA template of the DNA. Sonenberg sought the guidance of a young professor, Ada Zamir, who had recently completed a postdoctoral project with Holley.

In Zamir’s laboratory, Sonenberg explored the molecular superglue that links amino acids together into a peptide chain. He knew that the bond is among the strongest covalent forces in nature, so stout that it shatters only when a protein is boiled in acid. Using a technique called “affinity labeling,” developed by his comentor Meir Wilchek, he set out to identify the ribosomal enzyme that forms this bond.

He expected the enzyme to be a protein. However, in a 1975 PNAS article, Sonenberg and his mentors reported the surprising revelation that RNA—specifically, the 23S RNA that makes up a large portion of the ribosome—is positioned at the core of the enzyme peptidyl transferase, which catalyzes peptide bond formation (1).

“The only enzymes that were known to exist at that time were proteins,” he says. “We didn’t know back then that RNA was able to work as an enzyme, so we did not realize the true meaning of this finding, but it was very exciting.”

In 1975, a team of researchers at the Roche Institute of Molecular Biology in Nutley, NJ, uncovered another piece of the protein synthesis puzzle. They determined that eukaryotic mRNA has a cap-like structure at one end that plays a role in protein synthesis (2). The finding stirred Sonenberg’s curiosity, and he contacted the team, led by biochemists Aaron Shatkin and Yasuhiro Furuichi, to inquire about a postdoctoral position. “I thought it would be a very simple project to figure out why you need this cap and how it works,” Sonenberg says.

International Pursuits

In 1976, with a PhD degree from the Weizmann Institute in hand, Sonenberg moved overseas to join Shatkin’s laboratory. Within two years, Sonenberg and his colleagues made a major discovery: They identified a protein that recognizes and binds to the cap. This critical action kicks the cell’s translation machinery into gear so that the mRNA can start the process of protein synthesis (3). The protein was later named the “cap-binding protein,” eIF4E.

Sonenberg’s discovery revealed a key element of protein synthesis. He and other researchers kept picking apart the process to understand the regulation of protein production and the consequences of aberrant regulation.

Upon completing his postdoctoral studies in 1979, Sonenberg joined the Biochemistry Department of McGill University as an assistant professor. Emerging findings documented the importance of gene expression in behavior, disease, and physiology. When gene-sequencing tools emerged in the late 1970s, Sonenberg and others set out to parse the connections between protein synthesis and various diseases, such as cancer.

“Much was unknown,” he says. “And, you know, the unknown is far more interesting than the known.”

Sonenberg’s first major task as a freshly minted principal investigator was to determine how protein synthesis shapes polio pathogenesis. Researchers had isolated the polio virus in 1908, and Jonas Salk and Albert Sabin unveiled their first polio vaccine in 1955 and 1961, respectively. However, even in the 1980s researchers still remained unsure how the virus causes disease.

Sonenberg dove into this mystery during a year-long visiting professorship with David Baltimore at the Whitehead Institute for Biomedical Research in Cambridge, MA. The groups of Baltimore and Eckard Wimmer at Stony Brook University, Long Island, New York, discovered that the RNA of poliovirus lacks caps. In a 1988 article in Nature, Sonenberg showed that, without the cap, poliovirus translation occurs in a unique way, beginning when ribosomes bind to a sequence inside the 5′ noncoding region (4). This insight helped reveal how poliovirus commandeers the cellular machinery that produces proteins, killing human cells.

Parsing Proteins

Sonenberg returned to McGill as a tenured professor of biochemistry, and his curiosity turned to cancer. In a 1990 Nature article, Sonenberg’s team reported that an overabundance of the cap-binding protein eIF4E can cause eukaryotic cells to proliferate out of control and form tumors (5). Twenty years later, in a PNAS article, his team showed that the addition of a phosphate tag to eIF4E sparks the synthesis of proteins involved in tumor formation and that high rates of phosphorylation often track with aggressive disease progression in patients with prostate cancer (6). The findings hinted that drugs preventing eIF4E phosphorylation might prove to be potent anticancer agents.

In 1994, he published an article in Nature revealing another protein synthesis regulatory process: a family of proteins that bind to eIF4E to turn off protein synthesis and stall cell growth. The team found that insulin can interrupt the binding of these proteins, called “eIF4E binding proteins” (4E-BPs), thus impairing protein synthesis (7). Over the next decade, Sonenberg and others revealed that 4E-BPs indirectly contribute to diseases such as cancer, diabetes, and even autism by responding to mTOR complex 1 (mTORC1), a protein cluster that senses the cellular milieu and directs protein synthesis accordingly (8).

Sonenberg’s work sparked a string of accolades, including a 1996 Distinguished Scientist Award from the Canadian Medical Research Council. The next year, he received the International Research Scholar Award from the Howard Hughes Medical Institute. In 2002, he received the Robert L. Noble Prize from the National Cancer Institute of Canada and the prestigious James McGill Professor Award from McGill University.

Memory Makers

In the early 2000s, Sonenberg’s research took still another turn, focusing on the role of protein synthesis in learning and memory. A 2005 article in Nature reported that an enzyme called GCN2, which inhibits protein synthesis by adding a phosphate tag on eIF2α, a molecule known for its role in activating protein synthesis, also shapes the strength and number of connections between neurons (9) and thereby influences learning and memory. He then showed that long-term memories depend on the phosphate modification of the eIF2α protein (10).

Another research topic that excites Sonenberg is the mechanism of action of microRNAs, which are quintessential regulators of gene expression. Researchers had known for a long time, indeed since their discovery, that microRNAs impair the translation of mRNA, but exactly how they did so remained unclear. Sonenberg’s team found that microRNAs interfere with the earliest step of protein synthesis: recognition of the cap (11). This information is highly important for the now-widespread use of microRNAs in genetic manipulation.

Now, at age 71, Sonenberg thrives on scientific diversity and curiosity, and he enjoys exploring how eIF4E/4E-BPs influence a variety of diseases. In 2013, his team showed that eIF4E/4E-BPs contribute to autism-like features in mice (12). That same year, Sonenberg’s laboratory found that 4E-BP1 is influenced by the circadian rhythm and that mice lacking 4E-BP1 adjust more quickly to shifting light/dark cycles and are not as stressed by constant light exposure as mice carrying normal amounts of 4E-BP1 (13). Adding to this string of findings, earlier this year, he found that the antidiabetic drug metformin can reverse the core behavioral deficits in a mouse model of fragile X syndrome (14).

“These projects will surely keep me busy for a long time to come,” he says.