Bill Bishai has had a career-long fascination with the pathogenic microbes that have evolved alongside humans to turn our own biology against us. In particular, he’s worked to solve why the organism that causes tuberculosis (TB), Mycobacterium tuberculosis (MTB), is so successful at hiding out inside human immune cells.
Originally, he didn't intend a career at the bench. Starting out, Bishai was drawn to study medicine because his physician uncles lavished him with the best Christmas presents. But during Bishai's first year of medical school at Harvard, a lecture given by microbiologist John R. Murphy captivated him. “He told us he was harnessing the power of microbial toxins to kill cancer,” recalls Bishai, “And how just one molecule of the diphtheria toxin could kill a human cancer cell." It was a turning point that drew Bishai into a research career for the long haul.
He spent a summer in Murphy’s lab studying diphtheria toxin. "And that sort of sealed my fate, because at that juncture I began to really focus on getting as much training as possible in infectious diseases and molecular biology."
He eventually switched to the MD./Ph.D. track to do a doctorate there as well. “I loved every minute of it—I couldn’t wait to get out of bed and in to work every day,” he says. “It was a captivating, energizing, and spectacular experience to see how you could take recombinant DNA, manipulate it, and build new protein molecules that had the potential to become therapeutic for cancer.”
Bishai moved to Johns Hopkins University in 1991 to do his medical fellowship training, followed by postdoctoral research in the lab of Hamilton O. Smith, who shared the 1978 Nobel Prize in Physiology or Medicine for the discovery and characterization of some of the first restriction enzymes—the key tools that allow molecular biologists to cut and paste pieces of DNA together. In Smith's lab, Bishai worked on Haemophilus influenzae, a bacterial pathogen that causes meningitis, epiglottitis, and severe infections primarily in children.
But, in the mid-1990s, when it came time for Bishai to decide on his own research focus, medical trends dictated another turning point. At first, he thought about continuing his Haemophilus work, but an effective vaccine was making its debut. His division director suggested he look elsewhere, asking him, “Have you read the papers?” It was sage advice. The headlines caught Bishai’s eye, proclaiming that TB rates were on the rise in the United States and New York City was grappling with a new beast—drug-resistant TB.
“I have always felt that the answers to controlling TB are first and foremost in understanding how the bacteria make humans sick,” says Bishai.
Today, TB is, along with HIV/AIDS and malaria, one of the top three infectious disease killers, but it is the least well understood. The bacteria invade immune cell macrophages and turn them into incubators for reproducing more bacteria. “But we don’t know how it makes the intracellular environment permissive for its own growth.”
In 2009, Bishai’s lab discovered that MTB secretes cyclic AMP into the macrophage. Cyclic AMP is a well-known messenger molecule used in a variety of intracellular signal transduction. Now, his group is working out how that bacterial cyclic AMP causes interference in the macrophage’s signaling networks. One idea is that it tricks the cell into secreting too much of another signaling molecule, TNF alpha. That may result in recruiting droves of other macrophages to the site of infection so they can be invaded, too.
In June 2009, he received a call from HHMI president Robert Tjian about the possibility of heading up a joint research center between HHMI and The University of KwaZulu-Natal in Durban, South Africa, called the KwaZulu-Natal Research Institute for Tuberculosis and HIV, or K-RITH.
“After I collected myself off the floor, I was extremely interested in this prospect because here in the U.S. there is almost no human TB around to study,” he says. “I’ve spent 15 years working on TB in vitro and in animal models, but it’s essential to use human samples to further the science.”
It was very easy for Bishai to fall in love with South Africa for its ethnic diversity, rich history, and what he describes as the “teenager excitement and enthusiasm” of a young, vibrant research community. It was also easy to appreciate the enormous need for biomedical intervention. The province of KwaZulu-Natal has been disproportionately affected by both HIV and TB, including what is called extensively drug-resistant TB, in which the disease has become resistant to at least four antibiotics.
In contrast to the United States, where “there are more scientists working on TB at Johns Hopkins than patients in a year,” active TB cases in KwaZulu-Natal number more than 1,000 cases per 100,000 people (the U.S. rate is about 4 per 100,000). He’ll have the opportunity to work with physician-scientists at the Nelson Mandela School of Medicine who know the disease and its treatment very well but need help building up the molecular biology tools to study human samples of the disease.
In July 2011, Bishai will move with his wife and three youngest children to Durban to direct K-RITH. The move brings together both family and career goals.
“Career-wise, it’s a chance of a lifetime to take what I’ve been working on and apply it to the actual patients who have the disease. And my wife and I wanted to offer our children the chance to live overseas,” he says. “A lot of attractive things came together in one fell swoop.”