As a student, Catherine Drennan loved acting. So, in addition to courses for her chemistry major, she took drama courses and appeared in numerous plays.
Then there was her Vassar College classmate, Lisa. Lisa, a biology major, wasn’t that interested in theater. “I’m sure I did more acting than she did,” says Drennan. So what happened? Drennan became a scientist. Lisa, whose last name is Kudrow, picked dramatics, and has since become familiar to millions of TV viewers as Phoebe in “Friends.”
Drennan’s currently an MIT associate professor of chemistry, and her focus is a group of natural agents, including certain enzymes, with two key features. First, most of them do things — help our genes operate, allow living organisms to convert atmospheric gases into fuel — that enable us and other life forms to function. Second, they’re vastly complicated.
How complicated? When Drennan, early in her career, would inform colleagues of her plans to study such agents, in effect they’d tell her she was crazy. “’How about picking something that people haven’t tried, and failed, to solve for decades?’” was a typical comment, she says.
But Drennan persisted, and in the process has not only moved the field along but also potentially enhanced prospects for everything from attacking pollution to preventing heart attacks.
BIOLOGY IS BETTER
Growing up in northern New Jersey and eastern New York State, Drennan didn’t act the part of a future chemist. “I liked biology,” she says, “and I hated chemistry.”
Chemistry teachers at Vassar turned that sentiment around, and also helped instill what has become a philosophy of life. “You need to work on what you’re passionate about,” says Drennan. “The more I did science, the more I wanted to know what was going on at the most basic level, which meant the molecular level.”
Following college, Drennan taught at a Quaker school in Iowa. Students there were from all over the U.S. and Mexico. Some entered with outstanding academic backgrounds, but others came straight from enrollment in drug rehabilitation programs.
Teaching at that school, says Drennan, was an occasionally grueling but also enthralling experience. With one student she was especially close to, for example, Drennan’s best efforts fell short and the girl dropped out. The girl, though, later earned a high-school equivalency diploma, says Drennan. “She’s now an emergency medical technician in the military, and she’s very proud of what’s she accomplished.”
After three years Drennan resumed her studies, first at the University of Michigan, then Caltech. Along the way, she honed her skills at the specialty called crystallography.
FASCINATING
Crystallographers turn massive quantities of target molecules — usually enzymes and other proteins — into semi-solids, then probe them with X-rays. The resulting patterns can reveal in detail how the molecules are put together and what they’re made of.
The technique offers an unmatched window on the fundamental machinery of life, providing detailed depictions of molecules that may go back billions of years. It’s no wonder Drennan peppers her conversation with words like “fascinating” and “amazing” when talking about such molecules.
But crystallography isn’t for the fainthearted. One of Drennan’s interests is the all-but infinitesimal snippets of metals — iron, nickel, zinc — found in some key biological molecules. Those metals matter: the enzymes that harbor them couldn’t function without them. (Which means, if you think about it, that our bodies wouldn’t function either.)
But if you’re trying to prepare a metalbearing enzyme for study, a hundred things can go wrong. One example: the fragile metal infrastructure the molecules harbor can collapse, leaving no hope of figuring out their role in the enzyme’s workings.
Crystallizing a protein in a way that lets you really solve it, notes Drennan, “can take 10 to 15 years. It’s much more of an art than a science.”
She found this out the hard way. “I beat my head against the wall all the way through grad school and through my postdoc,” she says. But her success rate has spiked upward since.
Why should we care? Consider one of the molecules whose structure Drennan has largely worked out. It’s an enzyme called carbon monoxide dehydrogenase/acetyl-CoA synthase. But however much of a tonguetwister its name, this is a critical player in activities like regulating levels of certain pollutants.
Some bacteria, for example, use it to metabolize carbon monoxide (CO), an environmental pollutant and — at high concentrations — a lethal poison. It also has a role in metabolizing carbon dioxide, which is linked to the potential warming of our climate. Its mode of action, meanwhile, is similar to that our bodies use to break down homocysteine, a hormone linked to heart attack risks.
Solving CODH/ACS was a tour de force. “Enzymes with many metal atoms are especially difficult to deconvolute,” says Steven Lippard, head of MIT’s chemistry department. “Cathy’s insightful use of multi-wavelength X-ray diffraction and her knowledge of bioinorganic systems allowed her to deduce how this marvelous enzyme produces carbon monoxide at one metal center, shoots it down an internal tunnel to another, and then uses it to make acetyl CoA.”
Knowing such enzymes’ structures doesn’t bring immediate medical or environmental payoffs. If someone wanted to build a device for getting rid of atmospheric carbon monoxide, for example, having CODH/ACS’s structure would be a key step, but still only one.
As Drennan notes, though, such breakthroughs do help answer the critical question,“How does nature do it?” Which means that whether the issue is battling pollution, safeguarding heart health, or meeting some other basic challenge, “Eventually, you’ll be able to do some of these things pretty much the way nature does them.”