Vilcek Prize in Biomedical Science
Alexander Rudensky’s four-decade scientific career is a strident rebuttal of the airless dictum “Geography is destiny.” From humble beginnings in the former Soviet Union, his aleatory quest to widen his horizons has propelled him to the pinnacle of modern science. Today, Rudensky, a Howard Hughes Medical Institute Investigator and professor of immunology at Sloan-Kettering Institute in New York City, counts among the world’s foremost immunologists for his discoveries on the molecular architecture of a type of immune cell implicated in autoimmune disorders, inflammatory disease, and cancer.
Rudensky was born in Moscow in the late 1950s to Jewish parents. His mother was a schoolteacher who specialized in Russian literature, and his father trained as an engineer. So it is perhaps unsurprising that Rudensky was drawn to science at a young age. “The thing about growing up in the Soviet Union was that the choices were relatively limited; natural sciences were highly respected and less influenced by propaganda and politics than other fields. And there was excitement in society about science—physics in particular,” he recalls. During his middle and high school years, Rudensky felt his way through mathematics, botany, and chemistry before hitting his stride with biochemistry, which he pursued as a college student in Moscow’s Second Medical School.
There, he whetted his appetite for experimental biology and joined a research laboratory at Moscow’s Institute for Genetics of Microorganisms. Under the guidance of immunologist Vitalij Yurin, he immersed himself in the study of the interplay between the immune system’s main actors: T cells and B cells. Rudensky’s doctoral work examining how antigens are processed and presented to the immune system for the development of immunity was published in the European Journal of Immunology, signaling the start of a lifelong interest in the field.
With the fall of the Berlin Wall and parting of the Iron Curtain in the late 1980s, Rudensky seized newfound opportunities to partner with Western scientists, and plucked up the courage to reach out to renowned Yale University immunologist Charles Janeway. “I called Charlie from the kitchen of our apartment in Moscow, and the first thing he asked me was when did I want to come,” he recalls. He arrived at Yale in the winter of 1990, together with his wife and children, continuing his pursuit of immunology.
After a successful postdoctoral stint at Yale, where he unraveled molecular aspects of the process by which the immune system distinguishes self from nonself, Rudensky accepted an assistant professorship at the University of Washington in Seattle in 1992. There, his focus turned from the mechanisms that enable T cells to distinguish self and foreign proteins to the molecular underpinnings of T cell development.
Rudensky became particularly interested in a type of T cell called regulatory T cells, or Tregs, which were first described by Japanese researcher Shimon Sakaguchi and thought to play a role in suppressing unwanted immune responses. For nearly two decades, the molecular identity of Tregs and their precise role in autoimmunity presented a puzzle that Rudensky and his team helped solve. They found that a gene switch called FOXP3 controls the formation of Tregs in the immune system, keeping autoimmune diseases at bay. (The other major pieces of the puzzle fell into place, thanks to the efforts of immunologist Fred Ramsdell; for this work Rudensky, Ramsdell, and Sakaguchi shared the prestigious Crafoord Prize in 2017.)
Much of Rudensky’s career unfolded at Sloan-Kettering Institute of the Memorial Sloan-Kettering Cancer Center in New York City, where he arrived in 2008 and is currently chair of the immunology program and director of the Ludwig Center for Cancer Immunotherapy. There, Rudensky’s group made a wealth of discoveries on the diverse roles played by Tregs in immunity. Chief among them was the finding that in all placental mammals FOXP3 acts through a snippet of DNA called the CNS1 enhancer to trigger the formation of a cohort of Tregs designated “peripheral” (whereas most Tregs are produced in the thymus gland, which sits between the lungs, a subset of the cells act as sentinels suppressing runaway immune responses in the body’s peripheral tissues). Rudensky’s team found that during pregnancy CNS1-mediated formation of peripheral Tregs is crucial to preventing the maternal immune system from attacking the growing fetus, which is strewn with paternal proteins. Thus, deficiencies in peripheral Tregs can result in spontaneous miscarriage.
On another front, Rudensky showed that Tregs play a pivotal role in keeping gut inflammation under control. His team reported that fatty acids—butyrate and propionate—produced by microbes living in the human gut boost the formation of peripheral Tregs, which help ward off inflammatory gut disorders.
Further expanding the array of functions attributed to Tregs, Rudensky found that when faced with tissue damage and inflammation, they secrete a signaling molecule called amphiregulin, which mediates tissue repair and maintenance; the discovery established a central role for Tregs in inflammation and allergies.
More recently, Rudensky and his colleagues have explored how Tregs influence cancer progression. Because Tregs act to keep the immune system in check, they can inadvertently blunt the ability of immune cells to restrain or eliminate tumors. Rudensky’s team compared Tregs in normal human breast tissues with those found in untreated breast tumors, and found that Tregs in tumors were capable of more potent and aggressive immunosuppressive action. More importantly, Tregs isolated from patients’ tumors were studded with higher-than-normal levels of the immune molecule CCR8, which serves as a trigger for Tregs. Mirroring that finding, patients with CCR8-enriched Tregs showed poorer responses to cancer immunotherapy drugs, which work by unleashing the immune system against tumors, than those with lower levels of CCR8 on Tregs. Taken together, these findings suggested that targeting CCR8 could help enhance the efficacy of cancer immunotherapy—a goal that Rudensky and his team are now pursuing.
Rudensky hopes his work on Tregs will someday lead to improved treatments for a wide array of diseases. Despite the studious modesty of that hope, a handful of clinical trials involving Tregs in transplantation and autoimmune diseases are already underway, and the coming years are poised to see a crop of promising clinical leads for cancer treatment.
Numerous accolades have been bestowed on Rudensky over the course of his career, but he considers the Vilcek Prize a singular distinction. “It is special to me because it is a testament to the freedom of movement in time and space and across cultures. It also stands for acceptance and inspiration, particularly in times of intolerance and discontent,” he says.
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