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