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Faculty Focus

Constance Brinckerhoff, Ph.D.: Incurably curious

By Laura Stephenson Carter

Once upon a time, Connie Brinckerhoff had no interest at all in tadpoles. But today she's a leader in the study of matrix metalloproteinases (MMPs)—a field launched by the discovery of how tadpoles lose their tails.

It was in 1962 that two Massachusetts General Hospital scientists—Jerome Gross, M.D., a developmental biologist, and Charles Lapierre, M.D., a dermatologist—found an enzyme that made tadpole tails decompose duringmetamorphosis. Tadpole tails are made of collagen, so they called the enzyme collagenase; it was the first identified MMP. Soon, other scientists determined that collagenase is a zinc-containing enzyme that, in people suffering from rheumatoid arthritis, can destroy collagen and other kinds of connective tissue such as cartilage, the tissue that surrounds joints. By the early 1970s, researchers had identified a whole family of MMPs. Today MMPs are considered therapeutic targets in several diseases, including rheumatoid arthritis, periodontitis, and cancer.

Little did Brinckerhoff know back in 1962 that MMPs would define her career. That in the early 1990s, she'd cochair the first Gordon Research Conference devoted to MMPs. That in the late 1990s, she'd receive a prestigious National Institutes of Health MERIT (Method to Extend Research in Time) Award, which recognizes superior scientists and funds their work for up to 10 years.

Brinckerhoff began her career studying autoimmune diseases as a graduate student at the State University of New York at Buffalo. After completing her Ph.D. inmicrobiology and immunology, shemoved with her husband (who'd just finished his Ph.D. in philosophy) to southern Vermont and spent the next few years teaching at Windham College, working part-time in a clinical lab at Brattleboro Memorial Hospital, and raising their three children. In 1972, she decided to do a postdoctoral fellowship at DMS

Brinckerhoff studies a family of enzymes involved in rheumatoid arthritis and cancer.

with Martin Lubin, M.D., Ph.D. For the next four years, she focused on tumor cell biology.

Finally, in 1976, she began working with MMPs when a leading rheumatologist—Edward Harris, M.D., a 1960 graduate of DMS who was then a member of the Dartmouth faculty—recruited her to work in his lab to do research on connective tissue disease. "It was really exciting and inspiring to observe how enthusiastic she was," says Harris, now an emeritus professor at Stanford.

"For the next six years," Harris continues, "we worked together and she became one of the thought and action leaders in the lab." With Brinckerhoff's help, Harris's team made important discoveries about how metalloproteinases are synthesized and how they degrade joints as rheumatoid arthritis progresses.

Brinckerhoff loved the work, often returning to the lab late at night to check on experiments. "We lived only four miles from the lab," she says. "I would set up experiments, go home, put on my nightgown, and . . . come back, park my

car, walk into the lab, and float around in my nightgown." She laughs. "I did that many a night."

"She has an optimism and a buoyant personality," says Harris. But that's "not to say that she [was] totally immune to self doubt," he adds. In 1978, for instance, Brinckerhoff was preparing to give her first big presentation—about lab-generated multinucleated giant cells that spontaneously make collagenase—at a plenary session of the American College of Rheumatology. "She was extraordinarily nervous,"Harris recalls. "We all had to sort of prop her up and assure her that she'd do a wonderful job, which of course she did."

"I remember this very well," says Brinckerhoff. "I was terribly nervous and . . . very relieved when it was all over." That presentation may have been over, but there were many more to come as Brinckerhoff's career began to soar. By the time Harris left DMS in 1983 to become chair of medicine at Rutgers, Brinckerhoff had her own funding. "She's moved well beyond my place in the field into new methodologies that [are] very modern and up-to-date," says Harris.

As Brinckerhoff continued to investigate collagenases, she began looking into their genetic underpinnings. She collaborated with Dartmouth biology professor Robert Gross, Ph.D., to learn new molecular biology techniques that have helped her lab isolate genes for collagenase and related enzymes. She studied MMP-1 and found DNA alterations that instructed the cell to produce too much of the enzyme; although collagenase can be useful, such as in helping to heal wounds, too much of it can be destructive, which is the case in rheumatoid arthritis.

The lab wasn't to be her sole province, however, for leadership roles began coming her way. She was acting chair of the Department of Biochemistry from 1989 to 1991, and in 1991 she was named associate dean of science, a position she still holds.

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Laura Carter is Dartmouth Medicine magazine's associate editor.

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