Steve Desiderio sees the fork in the road, and he plans to go both ways.
With the mapping of the human genome, there's no denying that Big Biology is, well, big. California is pumping $3 billion into stem cell research. Even the National Institutes of Health has a new gear: Historically a bastion of grants for individual scientists, the NIH now has a “roadmap” for speeding discovery to the bedside with funds earmarked for research proposals that cut across scientific disciplines. Can academic medical centers—long accustomed to incremental breakthroughs stemming from the labs of principal investigators—navigate this new age?
To Desiderio, an M.D./Ph.D. who focuses on the molecular biology and genetics of the immune system, it's not either-or. As head of the Institute for Basic Biomedical Sciences, an umbrella that opened here nearly five years ago to link several hundred researchers in the School of Medicine's eight basic science departments, he sees his job as fostering flexibility so faculty can cluster their talents around a big, common theme and stick with the questions that are driving their own individual labs.
The basic sciences institute was conceived as a way to share pricey core resources—a multimillion-dollar microscopy center, for example, and sophisticated DNA sequencing and microarray technology—that no single lab could afford. And, equipment in hand, it also was meant to jump-start unusual collaborations, a vision that has already helped a team here land a $17 million NIH Roadmap grant to develop new tools for looking at how proteins interact.
“Big Science,” Desiderio says, “works when a complex question requires multiple approaches—maybe the mass spectrometry expert doesn't know the biology and the molecular biologist doesn't know the technology. But the concern many folks have about an exclusive focus on Big Biology is that almost every major advance in biomedical research has come from small labs doing their own thing. If you rope all the little labs into consortia, it actually decreases the options available to the field in general. The groundwork for Big Science is laid in basic science.”
Michael Caterina: "I've always been curious about all the complicated things organisms do to stay alive."
Like many people, Michael Caterina is already thinking about work as he heads into his morning shower. And what puts his wheels in motion every day is the very act of fine-tuning his water temperature. How, he wonders, does he do a Goldilocks and know when he's got it just right?
To a nonscientist, the answer's obvious. You dart your hand under the spray until it's neither too hot nor too cold. But for this associate professor of biological chemistry and neuroscience, that explanation merely restates the question that's teased him for as long as he can remember. How, exactly, do humans, or starfish or single cells, for that matter, sense what's going on in their environment? And as so often happens in science, what Caterina started out looking for isn't what he's ended up finding.
An M.D./Ph.D. student here in the early 1990s, Caterina became intrigued by G protein-coupled receptors, a huge family of cell-membrane-spanning proteins that many different species use in many different tissues to detect their chemical or physical environments. Studying with Peter Devreotes (now chairman of cell biology), Caterina learned that single-celled slime molds rely on one of these proteins to sense when they're starving, then band together to form multicelled organisms to deal with the deprivation. Even more intriguing, he says, this molecular mechanism has parallels in the human ability to smell.
Caterina was hooked, and during his fellowship in cellular and molecular pharmacology at the University of California San Francisco , he became engrossed in developing an assay to identify another of these “sense” proteins. An outside group trumped him (“that was a dark day”), but his test turned out to be ideally suited for another challenge in the lab: cloning the receptor for capsaicin. When he succeeded, Caterina says, “I jumped in with both feet.”
Capsaicin is what gives chili peppers their “fire.” The substance was isolated in 1846, and scientists have known for years that it not only produces burning pain in humans by acting on small-diameter nerves in the mouth, skin and eyes, but that it also paradoxically numbs the sensation of pain with prolonged use. Today, this unlikely substance is an ingredient in self-defense pepper spray as well as ointments for treating the distress caused by arthritis and the burning pain of both diabetic and HIV neuropathy.
But actually finding the protein that capsaicin acts on to cause its unusual pain properties almost immediately produced a major wow: Capsaicin, it turned out, isn't the only stimulus that prompts its receptor to launch a pain message to the brain by letting calcium and sodium flood into cells. The temperature at which humans begin to perceive something as painfully hot to the touch—about 107 degrees Fahrenheit—also makes the capsaicin receptor open up. In other words, there's no difference between “spicy hot” and “temperature hot” at the molecular level. To the capsaicin receptor, picante and caliente are identical.
The receptor discovery ignited Big-Science interest on the part of pharmaceutical companies searching for new ways to counter pain. Now, with the capsaicin receptor in hand, they no longer have to go through the cumbersome process of trying to find pain-sensing nerve cells in rats or mice. Instead, they can generate the protein in quantity and screen thousands of compounds, aiming for one that blocks the capsaicin receptor and thereby relieves pain without first causing it, as current ointments do.
Caterina is delighted that the results of his research are being used to speed up such a tangible medical outcome as overcoming pain. But for him, finding the capsaicin receptor raised a very different question: If one protein acts as a cellular gate at 107 degrees Fahrenheit, could there be others that respond to higher or lower temperatures? Caterina and his UCSF collegues did indeed find a similar channel that's activated at 125 F—the point just below scalding—and now a subfamily of six related proteins has been identified. Since returning to Hopkins in 1999, Caterina has made his small lab (three graduate students, three postdocs, a full-time and a part-time tech) one of only a half-dozen in the world focused on how the body uses these multiple molecular thermometers to get a picture of its internal and external environments. And the surprises keep coming.
Following a spinal cord injury, for example, people may become either incontinent or unable to urinate because of involuntary muscle contractions in the bladder. And since some bladder nerves are sensitive to capsaicin, it's been used effectively to treat these problems. One explanation for how capsaicin provides this relief, Caterina says, lies in the fact that the receptor turns out to be expressed not only in bladder nerve cells but also in the epithelial cells that line the bladder, and he and his co-workers showed that mice lacking the receptor have trouble sensing when the bladder is full. More attention-grabbing still, when they began looking closely at a capsaicin-receptor relative they discovered that responds to temperatures in the warm range—80 to about 100 F—they found an abundance of these protein channels in epithelial cells in skin.
“Our reaction,” says Caterina, “was, What's up with this? Traditionally, only nerves have been viewed as having sensory cells, and here we have these two very different lines of research showing that some skin cells themselves are neuron wannabes. In terms of relieving pain, it means there's a whole new set of targets to explore. But at a more fundamental level, it totally changes our view of how animals use these different cells to respond to a tremendous variety of physical and chemical stimuli. Nature is very parsimonious—when it finds a way of doing things, there's a theme.”
Now, Caterina is joining forces with investigators in five other labs here who've been probing similar neurobiology in vision, taste, smell and hearing. Their goal is to tackle on a much grander scale the question of which sensory molecules are used by which cells under what conditions. With each bringing a few puzzle pieces to the table, they expect their combined results to be bigger than the parts.
Still, Caterina's convinced his own lab couldn't have reached this point if they'd started out with a Big-Science approach to the problem of pain. “You have to have faith that asking fundamental questions about how things work ends up explaining disease processes in ways you'd never expect and could not predict,” he says. “Science is about discovering what you don't know, not confirming what you already think you know.”
And that's precisely why Steve Desiderio envisions the Institute for Basic Biomedical Sciences as a bottom-up enterprise where people can collaborate—or not—as their findings take shape.
"The idea,” Desiderio says, “is that each laboratory will continue to function as a stand-alone entity. But since part of our culture is that you never turn down colleagues who ask for help, we're already ahead of the curve when it comes to putting together a proposal that requires the cooperation of a large number of labs. It's very easy to find a group of people here who are willing to work together on problems of common interest because many of them work together informally anyway.”