University Distinguished Prof. Ralph Budd, M.D.
If collaborating has been a theme for Budd as an administrator, its roots go back to his own early days as a researcher. After graduating from Cornell University Medical College, Budd began a residency in internal medicine at Dartmouth-Hitchcock Medical Center, with plans to go into private practice. But before that transpired, he met a rheumatologist who introduced him to the world of autoimmune diseases and the relatively new field of immunology.

“Clinically the diseases were fascinating because they’d present in all sorts of ways,” says Budd, listing skin rashes, heart disease, neurologic disease, and joint disease as some of those presentations. The challenge of diagnosing and treating them was exciting, and Budd settled on a rheumatology fellowship. But by the end of his fi rst of two years, he’d grown disheartened by the fact that the only “treatments” were essentially aspirin and steroids, and decided instead to spend time behind the scenes, in an immunology lab, to hopefully discover more treatments. Two years later, he began a postdoc fellowship from the Arthritis Foundation, that allowed him to go to the Ludwig Institute for Cancer Research in Lausanne, Switzerland. It was a conscientious decision Budd and his wife, Lenore, a wildlife biologist, made to experience life outside the United States (“New country, new language, new baby, new laboratory — piece of cake!” he laughs). It turned out to be transformative, the one period of his life Budd would live over, if given the opportunity. It’s also where the groundwork for his focus on collaboration was laid.

“It taught me a lot about how to make science work,” he says of the Ludwig. “It was a fairly small institution — probably about half the size of UVM. I had been at big places before and I went to big places afterward, but that place taught me that with the right people you can do top-rate science with a small group if they get along and they talk to each other.” And it was there that Budd began his research on a mouse model of lupus. Although it didn’t teach him much about autoimmunity at the time, because it had a single gene mutation in a death receptor, working with it transformed his thinking around the immune system, specifically the role of memory in the system. Though the idea that the immune system can “remember” is a concept as old as Jenner’s smallpox vaccine, Budd’s lab was able to locate the genetic marker that arose when lymphocytes were activated. They then found a minor subset that had the marker and demonstrated that those cells housed immune memory. When he came to Vermont after a couple of years at Stanford and Genentech, he brought the lupus mouse model with him. Like Lausanne, Budd says, UVM was a “smaller place with very talented people.” In addition, UVM would allow him to work across departments in a way that was harder at a larger university.

“What appealed to me was that by talking to people in different fields you can make a connection to versus talking to 20 immunologists all looking at T-cell development,” he says. “It’s thinking laterally as opposed to vertically. That’s what happened back in Lausanne. We had a small group of cancer biologists next to us, a small group of biochemists next to us, but we all talked all the time and found interactions.”

Ralph Budd, M.D., mentors students
In Vermont, Budd continued to look at the death receptor defect. In addition to lupus, the mouse had enlarged lymph nodes, but it took a couple of false starts in understanding where all the extra cells came from before Budd and his team had their lightbulb moment.

“The reason we’d missed it is because it’s very subtle and slow,” he says, likening the lymphocytes to an engine in a firehouse, perpetually running just in case the alarm goes off . Approximately 3 to 5 percent of the lymphocytes in a human body are turned over every day, which doesn’t sound like much until you take into consideration what that looks like after a month — or six — of the body not ridding itself of them. Through microarrays, they found upregulation of a lot of cytolytic molecules, which in turn could cause significant damage if they were so abundant that they invaded the wrong tissues. Then, using fl ow cytometry, they moved the mouse model to humans and found the same upregulation. That suggests “that this process of homeostatic proliferation is going on in all of us, but when it gets accelerated, as possibly in lupus, it may well contribute to the inflammation we see here,” says Budd. Those studies are ongoing.

They also looked at what makes lymphocytes sensitive to the death signal, and through a now famous “failed” experiment (“As I tell students: ‘never come in my office and say the experiment didn’t work — usually it did, and it’s trying to tell you something you didn’t expect.’”), they determined that by simultaneously stimulating growth and giving a death receptor signal, the cell not only did not die, it actually grew faster. The graduate student went on to show that one of the molecules in the death signaling pathway was also required for cell growth. That finding was not initially well received in the fi eld, but was subsequently confirmed by several other labs. More recently, Budd contributed to a study that appeared in Science Signaling in which he and his co-authors (who included Assistant Professors of Pathology and Laboratory Medicine Iwona Buskiewicz. Ph.D. and Andreas Koenig, Ph.D.) examined a pathway through which the immune system detects foreign viruses. They observed that in lupus patients this pathway is activated in the absence of viral infection, and this is likely driven by oxidative stress in cells. They further found that an antioxidant that specifically targets mitochondria may serve a therapeutic effect in people with lupus, potentially significant news, given that exactly one new drug to treat the disease has been developed in the last half-century.

Despite these findings, of late, Budd has had to maintain a near-exclusive focus on the VCIID and his students and postdocs and junior faculty, which steadily impinges on the amount of time he can spend on his own research. But he has no regrets.

“Are you going to go for your own career your whole life or are you going, at some point, to devote a little bit of your time to help the junior folks? And I just decided it’s the right thing to do, to get them going,” he says, adding that he is more than okay with fewer personal grants and a smaller lab. In life outside the lab Budd indulges in his love of chamber music. He is a former board member of the UVM Lane Series, and a pipe organist (he first studied it at college as a break from science, though until he convinces Lenore that there’s room in their house for an instrument, he’s making do with a piano).

The father of two and grandfather of one, Budd wouldn’t mind a little more down time. But not just yet. He’s keeping a window open for research and hoping that the antioxidantrelated fi ndings will lead to an adjuvant therapy for lupus.

“It would be fun, after all the years of research, to do one thing that really impacts human health,” says Budd. “So few people get to do that.”

Story by Sarah Zobel
Photos by Andy Duback