Deadly illnesses such as AIDS and cancer may one day be wiped out when researchers find and control the molecular "doors" in the structure of cells that permit the agents of disease to enter. Each path to a new doorway, whether literal or figurative, presents what U of L scientist Stephen C. Peiper views as an exciting challenge.
In these roles, Peiper is creating new opportunities for scientific discovery and fresh connections for clinical application. His studies of what may be the gate-keepers of AIDS are opening new doors in research at U of L and adding to a rich and growing fund of knowledge in the fight against cancer.
Peiper emphasizes the necessity for research across a broad spectrum in order to eventually focus in on any individual disease. There is a delicate balance between the importance of wide-ranging research, he notes, and the need to apply research findings to specific clinical treatments. He points out that when you begin cancer research, you don't really know where the answers will lie. In fact, the correlations important in understanding cancer have come from several different research areas.
"That will always be what makes the process interesting," he says. "It will always be the challenge of a university to have a broad, robust (research) base, so that you can bring a lot of different (scientific) areas to bear on a problem."
As part of the process of building programs at the cancer center in such areas as molecular biology, U of L wanted a scientist with a broad range of experience in basic research. "They also wanted somebody who could have an impact on diagnostics, and bring technology to the bedside," a process known as translational research, explains Peiper. "That was an attractive opportunity. Usually one gets a chance to do a couple of those things, but not all three."
Arriving at U of L from the University of North Carolina, Peiper brought his background in molecular biology and genetic engineering to Terence Hadley's ground-breaking research, and Peiper and Hadley began working together to try to understand how chemokine receptors work. Hadley, professor of medicine, was involved in research on a cytokine receptor responsible for permitting cells, and therefore human beings, to become infected with malaria. People with receptors for this group of cytokines, called chemokines, can become ill when exposed to the disease. In contrast, people lacking one of these receptors, who are typically of African ancestry, have, in effect, a natural immunity to one type of malaria because the parasite that causes the disease can't get into their red blood cells.
At this point, recalls Peiper, "the initial word emerged (from the scientific community) that there was a similar process for AIDS, and the specific receptor we were working on is... a first cousin of the one used by HIV."
Peiper's lab began to focus on the group of normal chemokine receptors that is pirated by HIV to infect human cells. The studies included their normal function, how they're involved in the development and progression of AIDS, and whether, as with the chemokine receptor related to malaria, their absence is associated with a natural immunity to HIV. They found that individuals who lack one of the receptors (called CCR5) have a high degree of resistance to infection following exposure to HIV. "It's like having a door without a doorknob," Peiper explains. AIDS is effectively "locked out."
As the data began to emerge, AIDS researchers at the University of Pennsylvania invited Peiper and his research team to become part of a joint effort to find out whether manipulating chemokine receptors might be an effective approach to block HIV infection, or slow the progression of AIDS.
U of L successfully competed in the first round for major funding in this area of research. As they enter their second year, says Peiper, the goals are to understand how receptors are used by HIV to gain entry into cells, and to use that understanding to guide approaches to therapy. Peiper and his team are also collaborating with Duke University AIDS researchers and with Columbia University to study the virus that causes Kaposi's sarcoma, a form of cancer that develops in some patients infected with HIV. This virus actually carries genes that code for chemokines, which are unusually effective in blocking the high-jacking of chemokine receptors by HIV. The research looks promising, Peiper says, for scientists trying to discover how to block infection by denying HIV access to the receptors that it needs for entry after an individual is exposed to the virus.
"If you can block its ability to enter new cells, you can potentially blunt the attack (of the virus)," Peiper explains, "so there's a lot of interest in trying to change the course of AIDS by blocking its access to co-receptors." Indeed, Peiper was invited to share his findings at the 1997 meeting of the Institute for Human Virology, hosted by Robert Gallo, one of the discoverers of the AIDS virus.
The cancer center's research base is broad, with key clinical and research programs in areas such as carcinogenesis (factors responsible for transforming a cell from normal to malignant), the role of hormone receptors and environmental agents in malignancy, the mechanism of tumor blood supply, translational research studies on leukemias and lymphomas, and a unique program on photodynamic therapy, in which dyes activated by light are targeted to destroy tumors.
Under Peiper's leadership, the level of technology at the cancer center has advanced, facilitating the expansion of these and other research programs. A quarter-million dollar flow cytometry facility, through which cells can be sorted and typed, and two automated DNA sequencing instruments have helped make the cancer center what Peiper terms "the vanguard of technology" of the University Medical Center.
If keeping many doors open to solve problems is the challenge for Peiper and his colleagues at the cancer center, their motivation lies in the potential payoff in human terms. "One of the things that is exhilarating about the work is (that) we're working on a mechanism that is directly applicable to therapeutic intervention in the disease process," Peiper says. "That's really the exciting thing. Clearly, that's where we're positioned."
Peiper is optimistic that the 21st century will bring an acceleration in the application of research findings to the treatment and survival of cancer patients. As a medical doctor dedicated to research, Peiper keeps his eye on that goal. "There are times that I've sat down and looked in a microscope and seen the disease process," he says. But unlike researchers for whom disease can be abstract, Peiper says he has "actually seen the (human) face of this. It helps you with motivation and stamina, it gives you determination. For all of us who've seen the human side of this, it makes a difference.
"For a basic scientist, the perspective of people with disease should never be lost."
Louisville was the base for pioneering studies of the Pap smear in the 1950s, smoking and cancer in the 1960s, and mammography in the 1970s, yet there was no comprehensive central place in the city dedicated to cancer treatment, research, and education.
That changed after the National Cancer Act of 1971 (known as the "war on cancer") sparked communities nationwide to consolidate their cancer programs into centers. The University of Louisville Cancer Center was formed in 1972 to merge the school's programs administratively, yet there was still no central building to house the research. Renowned cancer researcher Condict Moore, center co-founder, former director of the surgical oncology division, and now professor emeritus of surgery, served as the director of this "center without walls."
Today, the center houses a diverse collection of researchers and serves as an education facility for medical students. As a regional treatment center, it also provides care and hope for thousands of patients.
Under U of L's Challenge for Excellence initiative, the center seeks to attain National Cancer Institute designation by the year 2008. Facility improvements and ventures into cutting-edge genetic research should help the center reach this goal. Recent renovation and equipment replacement has made the cancer center's radiation oncology department the most advanced of its kind in Kentucky. Among its new linear accelerators is a Philips SL25, a state-of-the-art model providing more powerful treatment of tumors that is actually safer for patients. Innovative research programs underway in the center's Henry Vogt Cancer Research Institute include the Hormone Receptor Laboratory and studies on chemokine receptors and the AIDs virus. The institute is supported by a grant from the Henry Vogt Foundation. Cancer center researchers are involved in about 50 studies a year.
Other notable programs at the center include:
Barbara Myerson Katz is a Louisville-based free-lance writer.