Electrical engineering isn’t usually the major of choice for M.D./Ph.D. students. David Clapham chose the field for both personal and practical reasons. He had an interest, and a co-op program at Georgia Tech gave him a part-time job, helping to cover college costs while gaining experience in the field.
But the job—at a power company—didn’t excite him. Clapham also was interested in biology and had thoughts of becoming a physician. “I was idealistic…. At the time, there was a big need for doctors, and I wanted to become a doctor and go to Africa.”
Then a course on ion channels brought his engineering and scientific interests together.
Ion channels regulate the traffic of calcium, potassium, and other important ions across cell membranes. They’re key in a range of activities, including muscle contraction, metabolism, and reproduction.
“Ion channels are the transistors of the cell,” Clapham says. “They’re fundamental to all cell signaling.”
Taught by Louis DeFelice (now at Vanderbilt University), the course fascinated Clapham, who began working in DeFelice’s lab. The work led to an M.D./Ph.D. program and a postdoctoral stint in Germany with Erwin Neher, the co-inventor of a technique called patch clamping. In this technique, a small glass tube is placed on a cell’s membrane, and the current is measured from a single ion channel or the patch is ruptured and currents are measured from the entire cell. In 1991, Neher and Bert Sakmann won the Nobel Prize for developing the technique.
After his postdoc, Clapham started a lab while finishing an internal medicine residency at Brigham and Women’s Hospital in Boston.
His lab achieved a major result almost immediately. Cells communicate with the outside world through receptors that couple to G proteins. G proteins are messengers and have two major components: α and βγ. The α components were thought to be the only type that could signal, while βγ was relegated to an anchoring role. Clapham’s lab, in collaboration with Eva Neer’s lab, found that βγ was a true signal molecule in its own right.
“We got into a huge battle with some established researchers,” Clapham remembers. “Eventually, we were proven right, but it took five years. That’s the good thing about science—there is only one answer in the end.”
Clapham and his family then moved to Minnesota, where he spent nine years at the Mayo Clinic. He admits he “probably would have stayed there forever,” but the death of his 9-year-old son Ben, from a degenerative neurological disease, made the family want a change.
Clapham was being recruited by Children’s Hospital in Boston at the time, and he accepted the offer. “I liked the idea of working at a children’s hospital because of Ben,” he says. “I thought maybe I could work on some things that might potentially help kids.”
Clapham spends much of his time on channels called TRP (“trip”) channels. There are 30 of them, and many appear related to senses—temperature, pain, smell, hearing. “But they do much more than that,” Clapham says.
TRPM7 is his favorite. This channel works both on the surface of the cell membrane and in membrane-bound organelles. It also acts as a kinase—a protein that regulates other molecules. When Clapham’s lab created mice that lack the gene for TRPM7, the resulting embryos died before 7 days in utero. “It’s doing something important, and not just as an ion channel, but we don’t know what yet.”
Clapham also works on TRPs in the brain that are linked to fear and anxiety and on TRPs associated with a degenerative disease in children called mucolipidosis. In this disease, dysfunctional ion channels don’t properly regulate the parts of the cell that degrade harmful proteins. The disease causes eye problems and degeneration of the nervous system.
Clapham’s group was the first to patch-clamp mitochondria, the “powerhouses” of human cells. Mitochondria have their own membranes, and in 2006 Clapham published work showing that these membranes could be patch-clamped. The group discovered an ion channel that imports calcium to boost energy production.
Clapham may be best known for research that doesn’t exactly dovetail with his position in a cardiology laboratory. His team discovered ion channels that are found only in human sperm. These channels, called CatSpers (for “cation sperm channels”), are necessary for sperm to penetrate the egg.
The discovery led to quite a bit of publicity, including an interview with the New York Times titled “Understanding the Way of the Warrior Sperm.”
“As soon as you put sex into anything, even ion channels, it becomes interesting,” he says.
The work was not just interesting—it was groundbreaking. Clapham’s team was the first to patch-clamp sperm, allowing them to get the first recordings of electrical activity in these cells. “For a patch clamper, that was amazing,” he says. “It was like being the first person inside an ancient pyramid.”
They discovered that CatSper channels bring in calcium, which revs up a sperm and changes the way it swims, giving it the power to penetrate the egg. Without CatSper, there would be no reproduction.
“This work is fascinating to me, and no one else is really working on it, and that’s one of the things I like about it,” says Clapham. “Among many of my colleagues, reproduction was never considered all that interesting—the brain is the ‘cool’ part of the body. But this is a whole world of biology that we’re trying to figure out.”