|FEATURES Spring 2002|
A University microbiologist seeks the answer to preventing and treating leishmaniasis, one of the world's most neglected diseases.
Writer James Thurber once wrote, "It is better to know some of the questions than all of the answers."
For Stephen M. Beverley, the Marvin A. Brennecke Professor of Microbiology at the School of Medicine, good science always begins with good questions. And Beverley's interest in pursuing challenging questions has earned him the distinction of being the foremost microbiologist studying a protozoan parasite called Leishmania.
Leishmania parasites are spread to adults by the bite of infected sand flies, which contract the parasites from first biting contaminated rodents or dogs. People in nearly 90 tropical or sub-tropical countries, including Brazil, India, Nepal, Sudan, and Bangladesh, are at risk of being exposed to Leishmania infection, known as leishmaniasis. Leishmaniasis takes several different forms, but the most common are cutaneous leishmaniasis, which causes skin sores, and visceral leishmaniasis, which affects internal organs, including the spleen, liver, and bone marrow. Both forms of the disease, when not fatal, can take years to heal and leave disfiguring scars and lesions throughout the body.
People in nearly 90 tropical or sub-tropical countries are at risk of being exposed to Leishmania infection.
"I have traveled enough in endemic countries and seen enough of the real disease to understand that we cannot ignore the need for good vaccines or good chemotherapy for the treatment of these diseases. That is why I have spent a significant amount of my research and study trying to further things in that direction," says Beverley, who also heads the Department of Molecular Microbiology and is the director of the Center for Infectious Diseases Research at the University.
At present, there are no efficient vaccines or drugs for preventing Leishmania infection. Beverley and his laboratory team are working to change thiseven though leishmaniasis is virtually unknown in the United States.
So how does a man born and raised in Southern California come to be involved with an infectious disease not found in his native country? The answer begins, as do so many things about Beverley and his work, with a good questionand a good amount of serendipity.
Back in second grade, Beverley and his classmates wondered, "What would happen if we sprinkle some water on a piece of bread and put it in a cabinet overnight?" As most grade-school scientists know, the answer is that mold forms.
"That experiment was my earliest recollection of doing science. It was foreordained that I should be a microbiologist; it just took me a while to realize it," Beverley says. "I knew that I wanted to be a scientist since elementary school, yet I was never quite sure what kind of science. I was always interested in microbiology, but I actually never worked in this area until I was a postdoctoral fellow."
When Beverley was a junior in high school, a teacher invited him to attend a science show-and-tell day at California Institute of Technology. Watching presentations on the sciences, including geology, physics, and biology, he felt like "a kid in a candy shop." Because he did not know which discipline he wanted to study, he decided a university that offered them all would be his best choice.
Beverley started off as a physics major at Cal-Tech but soon realized he liked biology and chemistry better. During his undergraduate years, he worked in a laboratory that allowed him to pursue independent projects while learning the skills and techniques of research. As graduation loomed in the spring of 1973, Beverley began to read the scientific literature, searching for something that would give him direction in his post-graduate studies. Some papers written by Allan Wilson, a researcher at the University of California, Berkeley, piqued his interest.
"Wilson was one of the pioneers in the use of molecular techniques for working out evolutionary relationships, and then using those techniques to ask interesting questions about biology," Beverley says.
Beverley received his doctoral degree in biochemistry from Berkeley in 1979. His work during that time involved investigating how organismsespecially fruit fliesadapted to new stresses in their environment. In particular, he studied pesticide and drug resistance.
This was an exciting time to be doing research, Beverley says, because it was the beginning of the recombinant DNA era. This new methodology, commonly called "gene splicing," was allowing scientists to join disparate pieces of DNA together to see the effects.
After receiving his Ph.D. in 1979, Beverley went to Stanford University as the Walter Winchell Postdoctoral Research Fellow. He chose Stanford after attending a lecture from a researcher there who was working with another new process called gene amplification, a process that encourages cells to generate hundreds and sometimes thousands of copies of a genea boon for researchers.
"I carried on what I thought were a lot of very intensive studies related to drug resistance, but they just never worked out. I kept doing what I thought were the right experiments, but nature had a different idea about how things worked. After a year and a half of that, I was a little bit frustrated," he says.
Then, in stepped serendipity in the form of Dr. Robert T. Schimke. "He [Schimke] said that he had selected a parasite called Leishmania that showed behaviors that were suggestive of drug resistance mediated by gene amplification. He went walking down the hallway, pitching this to various people, and I was the susceptible person," Beverley says.
Beverley immersed himself in parasitology and discovered the field was wide open and poised for rapid progress using the techniques of recombinant DNA and gene amplification.
"At the time, very, very few people were working on protozoan parasites like Leishmania and malaria. In fact, the Rockefeller Foundation formed a network of scientists to study what they called the 'Great Neglected Diseases of Mankind.' I was part of that movement, but it was sort of an accident. But for me, it was a fortunate one," he says.
Beverley could finally call himself a full-time microbiologist.
In 1984, he published his first of many new findings. In the prestigious journal Cell, he described how the parasite responded to a drug by making nonchromosomal circles of DNA. In layman's terms, Beverley had taken the first step into genetically manipulating Leishmania.
"The organism is very interesting. How can a fairly primitive, unicellular creature manage to survive and resist at the molecular and biochemical level all the tough defenses that tough hosts like humans can throw against them? The overall question in terms of how this fits into the biology of disease is quite interesting," he says.
Beverley further enhanced his research after relocating to Harvard Medical School, where he was both the Hsien Wu and Daisy Yen Wu Professor of Biological Chemistry and Molecular Pharmacology and acting department chair.
In 1997, Beverley came to Washington University School of Medicine to continue his research. He was named head of the Department of Molecular Microbiology and was installed in the newly endowed Marvin A. Brennecke Chair in Molecular Microbiology.
Between his time at Harvard and at Washington University, Beverley and his laboratory teams have continued to make discoveries about the genes and proteins that allow Leishmania to begin its life cycle in the sand fly and continue in human white blood cells. Understanding the complexities of these discoveriesdescribed in the more than 130 peer-reviewed scientific articles he has writtenis extremely difficult. But suffice it to say that each discovery takes him one step closer to developing a vaccine or other treatment to alleviate the suffering of millions of people worldwide.
"In the field of Leishmania, there is no single investigator who has done more to change and further the field," says David Sacks, a longtime collaborator with Beverley and head of the Intracellular Parasite Biology Section of the Laboratory of Parasitic Diseases at the National Institute of Allergy and Infectious Diseases. "Stephen really is responsible for generating tools to create specific genetic mutations. He has fundamentally altered how virtually everyone works in the field of infectious parasites."
Beverley's accomplishments have taken on a staccato cadence in recent years, as he has developed "designer parasites" that include certain "interesting" molecules or that have certain genes "knocked out."
"We are still in the phase of identifying and characterizing the good targets. We clearly have some really attractive ones now and are looking into validating the best targets for chemotherapy or immunotherapy," Beverley says.
These accomplishments have led Beverley to yet another question that he will some day have to answer: What happens once a vaccine or other therapy is finally created?
"Though we do all this wonderful stuff in the laboratory, we are going to face certain challenges in terms of real-world treatments," he says. "Getting the funding to do field testing in endemic countries will be much harder than the science for making them. This is something that, like many ivory tower scientists, I tend to ignore, until all of a sudden I can't ignore it anymore.
"If we develop these therapies, we are also going to have to deal with the political, social, and economic issues for bringing them out to the people. This is a question that many people are wrestling with not just concerning leishmaniasis but other diseases as well."