The bad news: It’s the 10th biggest killer in the country, it has no effective treatment except for risky surgery, and it affects a rapidly rising demographic. The good news: Alan Daugherty’s groundbreaking research may lead to prevention—or even a cure.
Daugherty, a professor of medicine and physiology, received a University Research Professorship to continue his study of aortic abdominal aneurysm (AAA), a disease that predominantly affects males over 55. Few people have heard of the disease, and even fewer study it—making Daugherty’s work all the more important.
For reasons that are still unknown, AAA begins with a bulge in the aorta; the bulge eventually ruptures, causing massive internal bleeding. “At the moment, it’s a disease that you usually don’t know you have until the thing bursts and you bleed out into your belly,” says Daugherty, who wears, appropriately, a heart-shaped pin to attach his medical center name tag to his shirt pocket. “It can be picked up by vague symptoms of lower pain.” Most of the time, he says, it’s discovered when a patient goes into an exam for something else.
Part of the reason so little is known about AAA is that most biomedical research depends on information from animal models, and there was no widely accepted animal model for AAA until 2000—when Daugherty accidentally created one. Daugherty and Lisa Cassis, director of the Graduate Center for Nutritional Sciences, were researching atherosclerosis (hardening of the arteries) when they made a fortuitous discovery.
“Lisa and I were doing studies in which we infused angiotensin, a very common substance that controls blood pressure, into this specific strain of mice,” he says. “And we began to notice these big bulges in their abdomens.” The bulges turned out to be AAA. When Daugherty and Cassis published their finding, the scientific community adopted their animal model as a way to study the mechanisms of the disease.
The research professorship funding will help Daugherty, who also serves as the Gill Foundation Chair in Preventive Cardiology and the director of the Cardiovascular Research Center, to conduct the expensive genetic manipulation required to study the disease in mice. “Our project is based mostly on the fact that your aorta has several different cell types that respond to angiotensin II,” he explains. “We’re trying to determine the type of cell in the aorta that is responsible for starting this disease, as well as those responsible for the progression of the disease.” Daugherty’s lab has narrowed down the possible cell types to macrophages, endothelial cells and smooth muscle cells.
Daugherty uses the word “serendipity” when he talks about the discovery of the animal model. “A very unusual set of circumstances came into play here, and we simply capitalized on our good luck.”
Daret St. Clair was only five when she heard the story that would determine the course of her life. Her school teacher in Bangkok, Thailand, had assigned the class to read a story about Marie Curie, the first woman to win a Nobel Prize. “The story really fascinated me,” says St. Clair, who speaks with a strong Thai accent. “Even as a very young girl, I realized there was a future for girls in science.”
For St. Clair, the future has come. A professor in the Graduate Center for Toxicology, she received a University Research Professorship to continue her trailblazing work in cancer treatment. Unlike most cancer researchers, St. Clair focuses on protecting healthy organs, particularly the heart, during treatment. “Generally, the focus is on how best to kill the cancer, not usually on what happens to the non-cancerous organs,” she explains, as sunlight pours into her UK office. “We are unique in that sense.”
The problem is clear: When a drug is powerful enough to kill cancerous cells, it often destroys healthy tissue in the process. St. Clair’s research will potentially provide a way to avert this complication—with the help of an enzyme called MnSOD.
MnSOD, or manganese superoxide dismutase, is a crucial component in the respiration process. “When we inhale air, we make energy, and that energy activates the mitochondria,” St. Clair says. But this process also generates a toxic substance called superoxide. To combat superoxide, humans need MnSOD. “Without it, we cannot live,” she says.
Her study of this enzyme began to pay off when she discovered that MnSOD suppresses the growth of cancerous tumors. That finding drew the attention of the National Cancer Institute, which awarded her a $600,000 grant in 1998.
Not only does MnSOD suppress the growth of cancer, but it may also lower the risk of heart problems that result from cancer treatment. St. Clair is researching the possibility that cancer drugs destroy too much MnSOD, thereby triggering heart disease. Her observation: MnSOD resides in the mitochondria—and 40 percent of a heart cell’s volume consists of mitochondria. “It’s extremely important that the heart has this enzyme.”
If the amount of the enzyme decreases during cancer treatment, the already-strained heart may be pushed to its limit. In contrast, if the amount of the enzyme increases, the heart could be protected during treatment. “Can we make the body create more of this enzyme? And how?” St. Clair asks. “If we cannot make more of this enzyme, can we prevent it from being destroyed by the drug?”
Using the professorship funding as seed money, St. Clair will work to answer these questions by developing a program that will expand her research into other tissues, such as the brain. “This expansion is a team effort that will include Dr. Mary Vore in toxicology, Dr. Allan Butterfield in membrane sciences, and several oncologists in the Markey Cancer Center. We’re excited about the opportunity to translate our basic research into patient care.”
Some people associate the George Clinton song “Atomic Dog” with early 1980s rhythm and blues, others with the hip-hop artists who sampled it a decade later. Jonathan Phillips associates the song with chaos analysis in earth surface systems. The song happened to be on the radio when Phillips had a Eureka moment. “To this day, I think of the paper that resulted from it as ‘The Atomic Dog Paper,’” says Phillips, a professor in the Department of Geography.
His research, which proposes that there is no single, stable, “natural” landscape toward which nature is tending, may one day help humans plan for sudden changes in their environment. In the meantime, his work has added a new recipe for the geosciences. To follow the ingredients, you start with geomorphology—the study of processes occurring at or near the earth’s surface. Then you add a dash of chaos theory, which emphasizes the influence of initial conditions on the end product of a process.
“In other words, the tiniest variation in initial conditions can lead to much different outcomes further down the line,” says Phillips, who came to UK in 2000 from a faculty position at Texas A&M. “But chaos theory runs right into a major problem with the geosciences—the initial conditions are unknown and unknowable. We can’t rewind the clock and see what was there 10 years ago, much less a hundred or a billion.”
But Phillips has overcome that obstacle. “In the earth sciences, we often deal with what’s called ‘partially specified systems,’” he begins. We know the qualitative relationships between two things—relationships of width, depth, velocity, or friction, for example. But quantitative relationships are another matter. “You can’t really come up with a number or a specific equation that will apply to changing conditions in a tobacco field in Kentucky, a pine forest in South Carolina, or a desert in Libya. All you have are the qualitative relationships.”
For a concrete example of such a relationship, imagine a hillside. Though many geographic factors are interacting simultaneously to determine the hillside’s characteristics, Phillips knows that if vegetation increases, soil erosion decreases. And in general, a wetter climate means lots of trees, a dryer climate means grassland, and a very dry climate means desert. There is no specific equation to determine how climate affects landscape, but qualitative relationships help Phillips understand the results of nature’s interactions. “Basically I figured out a way to analyze the presence of ‘chaos’ based on just those qualitative relationships,” he says.
With his research funding, Phillips will examine such relationships to detect evidence of abrupt environmental changes at sites such as the Cumberland Plateau and Red River Gorge in Kentucky, the Ouachita Mountains of Arkansas, and the Texas Coastal Plain. At each location, he will study various features of the landscape to discern how it has responded to changes in climate, land use and sea level. “If we can find the clues or signatures that abrupt environmental change leaves behind, this would enable us to better prepare for abrupt changes in the future.”
Despite the esoteric language on his chalkboard, Phillips occasionally hints of a simpler time his career. “Almost every kid likes to play in the mud and play around in streams,” he says, smiling. “I found a way to make a living at it.”
How do you get teenagers to say no to drugs?
Michael Bardo envisions a new approach: using virtual reality games to prepare adolescents for face-to-face encounters in the real world.
“I imagine a high-risk adolescent donning a virtual reality helmet and walking through a series of ‘trials,’” says Bardo, professor of psychology at UK and director of the Center for Drug Abuse Research Translation. “In this walk through a virtual city, there’s the gym, the laundromat, the convenience store. And there’s the alley—where a guy is selling illegal substances. What do you do?”
If teens practice saying no in Virtual World—and are rewarded for it, by moving up to a more challenging level of the game, for instance—they are more likely to say no in a real-life situation, according to Bardo. “Just as your arms become stronger from lifting weights, your brain’s inhibitors become stronger with exercise. When you’re out in the real world, having done these virtual exercises, you presumably would be able to tap into that inhibitory control more easily.”
The reasons why adolescents choose to use drugs vary, he says, but biology plays a significant role. Some people are prone to enjoy things like eating unusual foods, climbing mountains, and parachuting from airplanes; these teens are high-novelty seekers or high-reward seekers. Studies have shown that this group tends to find drug use more satisfying. Some of them, due to their biological makeup, also have trouble exercising restraint. These high-novelty seekers are the focus of Bardo’s research, which he continues to carry out with Tom Kelly, scientific director of the center, Don Lynam, former professor of psychology at UK, and Nancy Grant Harrington, associate professor of communication.
To learn more about these traits in humans, Bardo studies animals. “You can’t really get down to the detailed, precise neuromechanisms without using animal models,” he says, pointedly.
“Rats, like people, vary in their preferences. You can expose a group of animals to a drug, but they don’t react the same,” he says. “Some are apparently biologically prepared to find the drug more rewarding than other rats we test. We’re interested in individual differences in the brain that we can use to predict which animals will be the high responders and which animals will be the low responders.”
By using microdialysis (extraction of chemicals from the brain) and microinjection (injection of chemicals into the brain), Bardo can perform specific experiments on rats to identify the mechanisms at work in novelty-seeking and inhibition. He can then translate the findings to humans by targeting the analogous parts of the human brain.
If we can understand the biological connection between novelty-seeking and inhibition processes, argues Bardo, we can identify adolescents who are most at risk for substance-abuse disorder—before their first drug experience. “And then we can intervene.”
The UK Board of Trustees first awarded University Research Professorships in 1977. The goal of these $35,000, one-year professorships is to enhance scholarly research and awareness of UK's research mission by recognizing outstanding faculty.