The 2025 Nobel Prize in Physiology or Medicine was awarded today to Princeton graduate alumna Mary Brunkow “for groundbreaking discoveries concerning peripheral immune tolerance that prevents the immune system from harming the body.” 

Brunkow is senior program manager at the Institute for Systems Biology in Seattle. She received her Ph.D. from Princeton in 1991 in molecular biology. She shares the award with Fred Ramsdell and Shimon Sakaguchi.

Together, the laureates created a new branch of immunology, the field of peripheral tolerance, which has already led to new treatments for cancers and autoimmune diseases, and has implications for organ transplants. 

Their discoveries about how the immune system is kept in check "have been decisive for our understanding of how the immune system functions and why we do not all develop serious autoimmune diseases,” said Olle Kämpe, chair of the Nobel Committee. 

"Princeton congratulates its alumna Mary Brunkow, whose trailblazing achievements illustrate the power of high-quality scientific research to improve human health and change our world for the better," said University President Christopher L. Eisgruber.

Brunkow was one of the first graduate students to join Princeton's Department of Molecular Biology. As a student, she was bold and “incredibly bright,” said her Ph.D. adviser Shirley M. Tilghman, president of the University, emeritus, and a decorated molecular biologist. “Her Nobel work is path-breaking.” 

“We are so excited and proud of Mary Brunkow,” said Rodney Priestley, dean of the Princeton Graduate School. “We encourage our students to be bold in their research. We tell them they can push the forefront of human knowledge to benefit humanity. Mary is an inspiring example for Princeton graduate students of how their education and training can lead them to breakthroughs that transform the world.” The University is celebrating graduate alumni and the 125th anniversary of the Graduate School later this week at the Many Minds, Many Stripes conference.

The science behind Brunkow’s prize

“Peripheral immune tolerance” refers to a subtle but vital component of the human immune system — a piece that balances the body’s need to fight off external threats without attacking internal systems. 

For years, researchers believed that this balance was achieved through “central immune tolerance,” in which new T cells that could attack the host are weeded out in the thymus before they are unleashed upon the body. 

Brunkow, Ramsdell and Sakaguchi added a layer of complexity to that story.

The initial discovery, from Sakaguchi, revealed an unknown class of immune cells that protect against autoimmune diseases: regulatory T cells. Brunkow and Ramsdell moved that work forward by identifying a mutated gene linked to an autoimmune disease. 

While scanning for genes is now quick and easy, thanks to enormous advances in genomics and technology, it took years of meticulous work over long days in the lab for Brunkow and Ramsdell to find the one gene, which they named Foxp3, that makes some mice susceptible to a skin disorder — and which has a human equivalent responsible for IPEX, an autoimmune disease. 

Two years later, Sakaguchi showed that the Foxp3 gene controls the development of regulatory T cells, which prevent other T cells from mistakenly attacking their own host. Regulatory T cells also signal to the immune system when it can stand down after it fights off invading viruses or bacteria.

Brunkow at Princeton

In Tilghman's lab at Princeton, Brunkow "was one of the first students brave enough to tackle the mysterious H19 gene,” which had been dismissed as junk by other scientists, said Elizabeth Gavis, chair of molecular biology and Princeton’s Damon B. Pfeiffer Professor in the Life Sciences. Brunkow’s graduate research, largely unrelated to the work for which she has been honored with the Nobel Prize, contributed to the current understanding of genomic imprinting — the concept that a gene can be shut down depending on whether it was inherited from the mother or the father.

“She was incredibly bright, bold and took on a project in my lab that had a very unexpected twist,” said Tilghman, professor of molecular biology and public affairs, emeritus. “That twist led us to propose that a very mysterious gene we were studying at the time — the first long non-coding RNA to be described — must have an important function and wasn’t either ‘junk’ or a mutated gene that was no longer functional.”

“Mary’s Ph.D. research on a seemingly obscure gene bears little resemblance to her later work on regulatory T cells,” Gavis said, “but I hope that Mary’s story will inspire our students to be brave, ask hard questions and embrace the process of learning to be a scientist. Mary’s story also illustrates the importance of basic research and scientific inquiry to our ability to understand and control disease.”

Brunkow joins other Princeton faculty and alumni who have been awarded Nobel Prizes, including Nobel Prize laureates in physiology or medicine James Rothman (2013) and Eric Wieschaus (1995) and 17 prior graduate alumnus laureates.

The award was announced by the Nobel Assembly at Karolinska Institutet in Stockholm, Sweden. The prize amount is 11 million Swedish kroner, or about $1.2 million, divided evenly among the recipients.

This story will be updated through the day.