Perspectives Online

College Profile - Dr. John Cavanagh shows that in scientific collaboration - as in a community of  molecules - the product is more powerful than the sum of its parts.

Dr. John Cavanagh
Photo by Daniel Kim

Synergy has been on Dr. John Cavanagh's mind these days. The College of Agriculture and Life Sciences professor sees it when he studies communities of disease-causing, antibiotic-resistant, sum-is-greater-than-the-parts microorganisms called biofilms.

And he lives synergy through a partnership he's forged with a fellow scientist who shares his interest in finding ways to destroy biofilms - or at least render them harmless.

Their research, Cavanagh said, has implications not just for overcoming infectious and neurodegenerative diseases but also for making paint last longer, boats go faster and Stealth bombers, as he put it, "stealthier."

A professor in the Department of Molecular and Structural Biochemistry, Cavanagh focuses his research on how the structure and flexibility of proteins influences how they carry out their roles. That understanding is vital when it comes to developing drugs that target particular receptors involved in diseases. The drug needs to fit the receptor involved in the disease, and to do that, it needs to have specific shape, he said.

"I hate using the phrase 'lock and key,' because it's not quite that simple, but something that is a ball shape is not going to recognize something that's flat. It's going to recognize something that's kind of cupped - that will accommodate it," he explained. "So we need to know shapes of molecules very accurately. I'm interested in the precise shapes of proteins and how flexible they are, which will tell me how they interact with all their targets."

Cavanagh and other scientists have found that it's not just enough to understand the precise shape of individual molecules: They also need to understand how that shape influences the ability of harmful microorganisms to come together and function as a community.

Cavanagh (center) shares the enthusiasm of his students as they seek to determine the shapes of proteins and learn what those proteins do.
Photo by Daniel Kim
"You take a single bacterium that's swirling around, and it doesn't have a very good defense mechanism. It has only a few things it can do to defend itself. That's why drug companies design antibiotics to go against the single-cell bacterium," Cavanagh said. "But when they get together - it's the same kind of bacteria, but they all stick in a film - they are able to actually generate different responses.

"They actually act as if they know more about what they are doing: They can assess the environment more efficiently, and they can have different protective strategies. It's amazing: Two of what you think are identical things come together but act in a way that the effect is greater than the sum of their parts. They can actually do different things."

Cavanagh uses the same greater-than-the-sum-of-parts analogy when he talks about his research with Dr. Christian Melander of the College of Physical and Mathematical Sciences' Chemistry Department. A few years ago, Cavanagh recalled, the two were "talking about what he does and talking about what I do."

Cavanagh was talking about quorum sensing, a process through which "bacteria decide to come together to make these communities," he said. "I know relatively a lot about that because I've been working on it for so long, and he was talking about these molecules he had that seem to inhibit that process. But he didn't know why or what to do with it.

"And I was doing my things and didn't know what to do with it," Cavanagh added. "But we became greater than the sum of our parts. That's what science is really about-doing your stuff and sharing it with the right people."

As their shared understanding has grown, Cavanagh and Melander have made sweeping connections in their work - and a possible application of Melander's biofilm inhibitors.

Biofilms, they know, are pervasive, deadly and costly, complicating such deadly diseases such as cystic fibrosis and cancer. They can also cost billions of dollars annually in energy loss, equipment damage and product contamination.

While his main concern is finding ways to fight antibiotic-resistant biofilms, Cavanagh rattled off a few of many uses he and Melander envision for their technology: Put the chemical on a ship's hull, and you could keep away barnacles and, thus, make the boats go faster and use less fuel. Put it in paint cans, and you keep the paint from getting watery. And put it on the Stealth bomber, and it could keep the airplane off enemy radars.

Right now, Cavanagh explained, "the plane gets covered in biofilms, and as it flies low it gets covered in dirt. The dirt sticks to it, and suddenly the radar can pick it up."

Given the possibilities, Cavanagh and Melander are looking into licensing the technology or commercializing it themselves through a company they've formed. But first they need to figure out why the molecules work, because that understanding is crucial to making them more efficient.

To figure out that part, Cavanagh will use a number of techniques. He literally wrote the book on how to use one of the most painstaking of those techniques, nuclear magnetic resonance (or NMR), to look at proteins. It's a process through which a nucleus, hit with a radiofrequency pulse, resonates a noise. The frequency at which the nuclei resonate after being hit with a pulse is specific to their position in the protein. Cavanagh was the lead author of Protein NMR Spectroscopy: Principles and Practice, now in its second edition.

Cavanagh now uses an NMR spectrometer in Dabney Hall, but he'll soon have access to an even bigger, one-of-a-kind machine being built for the developing N.C. Research Campus in Kannapolis. As part of the campus' core lab, the instrument will be available for use by researchers from N.C. State, as well as other organizations that are part of the 350-acre life sciences campus.

Billionaire David H. Murdock, the driving force behind the campus and the owner of Dole Food Co., is buying the 950 megahertz superconducting magnet, which he intends to donate to the non-profit research institute. The two-story, eight-ton machine will let researchers see with greater clarity than ever before the three-dimensional structures of molecules. They'll even be able to figure out how far apart one atom of a molecule is from another.

Having such tools opens new ground for scientists and speeds their work. And for Cavanagh, it's part of what makes his work exciting.

"I've got my students working on the magnets over here in Dabney, and ... that's what I still love to do more than anything else. I don't get as much time as I should (to do) it any more, but I can still do it better than the rest of them!" he said with a big laugh. "I just get into it."

Why? For the thrill of it.

"You know, my students will make these proteins, and we need to then determine what shapes they are. But the real excitement is that none of them have been looked at before, even though we know kind of what they do and what they are involved in," Cavanagh said, pointing to primary-colored squiggly pictures on the bright pink walls of his office in Polk Hall.

"That's a protein that the brain kicks out that tries to stop Huntington's disease developing. That's the main way that the brain protects itself - by using that protein. And no one knew what it looked like," he said. "So we made it, and we went over to the magnet, and we popped it into the magnet, and then we get a picture of it.

"And I'm the first person to see a picture of this!

"I never want to lose that," he said. "If you start losing the excitement of seeing these pictures of what these proteins are going to look like, then you shouldn't be doing it."

Cavanagh wasn't always so enthusiastic and all-consumed by science and discovery. At one point in high school, in Manchester, England, he was one of the worst science students in his school, he said. But a chemistry teacher, David Moss, offered to tutor him, and after hours of working together, Cavanagh suddenly began to get it.

"Maybe it was just (because) I wasn't frightened of doing it any more. Some kind of epiphany happened, and I don't know what it was, but I know that if it hadn't have been for him it wouldn't have happened," he said.

From then on, Cavanagh's passion for science has had him hop-scotching around the Western world - and around scientific disciplines: In his undergraduate work at the University of Surrey in the United Kingdom, he focused on theoretical chemistry, and then he earned a Ph.D. at the University of Cambridge in 1988. From there, he went to La Jolla, Calif., as a post-doctoral fellow at the Scripps Research Institute.

Then it was back to Cambridge to serve on the faculty, to Scripps again to run one of the world's biggest NMR labs, and over to Albany, N.Y., where he directed the state health department structural biology program. He spent a year in the chemistry department at Purdue University before being lured to NCSU in 2000.

"I wanted to be in a place where there was a huge student population and also where there's a big technological hub," he said about his attraction to the Research Triangle.

Cavanagh's moving around has been an effort to take what he has been doing and make it useful to other scientists. "So every time you do that, you have to make a little jump. I've just made a lot of jumps," he said.

Making those cross-disciplinary jumps has made Cavanagh a crusader for helping undergraduate and graduate students bridge the divide among scientific fields. He's set up a Structural and Integrative Biosciences Initiative to expose undergraduate students to multidisciplinary projects "to see how science works these days," he said.

"We have to have the big picture," Cavanagh explained. "So we are trying to expose the students at an earlier age to that kind of breadth that they need to be successful."

Making them successful, he said, is his way of honoring the chemistry teacher who got him started with his career in science.

As for what kinds of career successes he would like to achieve, Cavanagh names two: "I would like to have been part of the development of a therapeutic (agent) that impacts infectious disease. That would be my main thing," he said.

"And I'd like it if there was just one student that said, 'You know what - if it hadn't have been for Cavanagh, I wouldn't have done this.'"