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But Thompson was puzzled by something. The drug should also have kept the patients' immune systems from fighting infections, but that wasn't the case. The patients seemed to handle infections fine. Thompson's attempts to find out why launched him on a journey exploring molecular pathways in the immune system and immune-based therapies to fight cancer. His lab pioneered the study of a family of cancer-related genes and their role in regulating cell survival and was the first to demonstrate costimulatory pathways in the regulation of cytokine production by T cells. He has since made a number of other discoveries that have contributed to the understanding of immune-cell development and cancer mechanisms.
Some of his discoveries have been controversial. Even the way he approaches cancer research is different. Instead of wondering why people get cancer, he simply asks, "Why not? Why do most people not get cancer?" After all, there are almost a hundred times more cells in a human body than there are people on Earth, he points out. Yet those cells "live together as an effective colony to make you an organism." With so many things known to cause cancer, "it's just a miracle that one of [your] cells hasn't come down with cancer and killed you."
About six years ago, Thompson's lab proposed that the reason "collections of cells live together as a multicellular organism is because they have all given up the cell's autonomous ability to take up nutrients from their environment." Every cell in the body is constantly bathed in more nutrients than it would ever want or need—glucose, amino acids, other building blocks. Yet normal cells are unable "to take up those nutrients unless given permission by other cells" in a process called signal transduction. "A cell without those instructive signals will always starve to death despite the fact there's an embarrassment of riches outside," says Thompson. "A cell can't proliferate on its own because it can't even eat enough to actually survive." But in cancer cells, mutations control their ability to take up nutrients and allow the cells to grow and proliferate. Thompson and his research colleagues contend that increased glycolysis—the processing of glucose—is important for sustaining tumors but not necessarily for inducing them. Others disagree and say that the role of glycolysis is overestimated.
That's not the only controversial view Thompson holds. He also believes that cancer cells exploit autophagy—a process whereby cells eat themselves—in order to survive nutrient shortages, rid themselves of defective components, and even fight off chemotherapy. "We have found a variety of drugs that can intervene in that process that have never before been tried as cancer therapeutics, but are actually known to be safe and efficacious in patients," he says.
One such drug is chloroquine, an antimalaria medication that some suspect inhibits autophagy. When a mosquito injects the malaria parasite into the body, autophagy may help the parasite survive long enough to colonize its host. Thompson believes chloroquine interferes with that survival mechanism, killing the malaria parasite.
And he thinks cancer cells exploit autophagy in much the same way to protect themselves against chemotherapy. When "cancer cells metastasize, they move from a place where they can get enough nutrients to places where most of the mechanisms that have transformed them don't allow them to take up nutrients in a cell- autonomous fashion, until they've colonized a new organ." According to Thompson, when patients don't get better from chemotherapy it's because the cancer cells have used "autophagy to remodel themselves and to maintain themselves over the period of time of that treatment." He has shown that, in mice,
chloroquine inhibits autophagy and enhances their response to the chemotherapy drug tamoxifen. Now he is conducting clinical trials to see if chloroquine will work in human cancer patients, too.
Other researchers have found, however, that autophagy suppresses tumor development in animals. "Everything that we have enjoyed doing over the last 20 years has started out as a controversial idea," Thompson says with a laugh. "The fun thing for us is that occasionally it's turned out to be of interest to the broader community."
On a more serious note, he adds, "I think it's incredibly rewarding to contribute to research that ultimately ends up in the hands of physicians treating patients and makes patients better."
Thompson's theories may have critics, but he has been widely recognized for his work. He is frequently invited to give talks, has received numerous awards, and has been elected to prestigious professional societies. Last year, he was one of only four cancer scientists elected to the National Academy of Sciences. He also holds leadership positions in a number of other organizations. He is associate editor or on the editorial boards of several important journals, including Cell, Science, Immunity, and Cancer Cell. What's more, he holds a number of patents related to immunotherapy and apoptosis and is the founder of two biotechnology companies.
He has also mentored more than two dozen students and fellows who have gone on to successful careers in academic medicine. "In the end," he says proudly, "they will have much more influence on the practice of medicine than I ever will."
And as busy as he is, he also makes time for his family—his wife, Dr. Tullia Lindsten, who jointly runs his lab; and their teenaged daughter and son. And though he refused to sacrifice science for sports back in college, he never really gave up sports. In fact, he organizes a weekly Penn faculty basketball game. "We play the medical students once a year," he says. And he approaches that contest as avidly as he does his matchup with cancer. "They beat us the last three years, so we're honing up again to beat them finally this year."
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Laura Carter is the associate editor of Dartmouth Medicine magazine.
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