Michael Yaffe, physician and biochemist, knows what it’s like to see a patient who’s doing well suddenly take a drastic turn for the worse. He’s also knows you often have no idea why.
He cites the example of two patients with the same problem — say, localized pancreatic cancer. Both are basically healthy. Both come through surgery in pretty good shape. But a few days later, one gets an infection and soon is desperately ill.
So even with patients whose situations are nearly identical, he notes, “one can be out of the hospital in a few days and the other has to spend four months in the intensive care unit.”
Most of us would chalk up such differences to luck — the homebound patient, for example, having avoided some bacteria that turned up in his unfortunate counterpart’s food. But Yaffe, an MIT biology professor, says something else may be at work: problems with the dizzyingly complex dance of natural substances in our bodies that regulate everything from our moods to our immune systems.
Among key participants in this dance are proteins: hormones like insulin, enzymes like those that go to work in our stomachs when we eat, antibodies that help us stave off disease.
Many proteins play a critical role is signaling. Take an event most of us are oblivious to — damage to our DNA. It happens all the time in cells throughout our bodies. But in virtually every instance, specialized proteins “find” the problem and trigger activities that cause other proteins to clump together. The resulting clump — a kind of enzyme — then acts like an electric company dispatcher, setting in motion a process that quickly repairs the DNA.
Without this unseen interplay, we’d be in tough straits. “There’s a rare disease in which individuals have a mutation in a key enzyme, so their bodies can’t sense DNA damage properly,” notes Yaffe. “They starting getting tumors as children and they die in their teens.”
But the DNA-repair system is just one of many in which protein-protein linkups are crucial, and Yaffe has dedicated his career to mapping the signaling networks that reflect such connections. “Understanding these networks,” he says, “will be the key to 21st century medicine.”
Probing such issues wasn’t in Yaffe’s original career plan. The Baltimore native majored in materials science and engineering at Cornell. But then, he experienced the allure of a combined M.D.-Ph.D. program. (Part of the reason medicine may have felt like a good fit is that at age 8, Yaffe spent a cumulative total of six months in the hospital being treated for broken legs and related conditions. “I was a fanatic bicycle rider,” he explains.)
Late-Night Lab Work
Yaffe received doctoral and medical degrees from Case Western Reserve University, and his subsequent experiences with patients convinced him to focus on signaling networks. Still, he didn’t want to abandon medicine. “When I was doing my residency,” he notes, “on the nights when I didn’t have to be in the hospital I would spend most of my time in the lab. It was crazy.” But the work also left Yaffe well prepared to shed light on an almost unbelievably complex system.
The problem for those probing signaling networks is that there are so many signals, signalers, and other players to deal with. Yaffe notes, for example, that science understands a lot about how a specific protein — say, a hormone — may interact with another, like the cell-surface connector for that hormone. But given that there are 10,000 or more proteins with signaling responsibilities, he says, trying to do something medically useful with such limited information “is like trying to make a plan for the Greater Boston area by concentrating on what’s happening in MIT’s Room 10-250.”
So you need to map major chunks of such networks. Thus, Yaffe’s group has developed a computer program that lets them find small stretches on many different proteins that are critical to letting these natural agents, as he puts it, “shake hands with each other.”
It’s not yet a medically useful innovation. The group has been able to pinpoint and analyze some 120 of these snippets from different proteins — but the total universe of such snippets may be well over 1,000.
Minimal Time Off
“We’re a long way from the point where these results affect how we treat patients,” says Yaffe. But he also notes that advances like the decoding of the human genome, along with the growing ties between computer science and biology, provide ample grounds for optimism about future progress.
So, he spends most of his time on his basic science studies at MIT. But one weekend a month, he oversees the Surgical Intensive Care Unit at Boston’s Beth Israel-Deaconess Medical Center. He typically works Friday evenings, and Saturday and Sunday days — but “there are weekends when I never go home.”
Why carve that time out from a thriving research career? Partly, says Yaffe, it’s the simple desire to assist others as best he can. Another factor: he can put his engineering background to work.
“ICU patients have to adjust to the fact that their lives are being regulated to a large extent by machines,” he notes. “It’s very scary for them, and I try to add a human touch.” But there’s also the contrast with the lab.
“When you’re a biologist at MIT,” he notes, “you’re surrounded by great people, and that means you’re likely to be successful. But when you take care of a group of very sick patients, you realize how hard it is to apply what you’re learning in the lab to help make them well. And that helps keep you humble.”