Craig Thompson didn’t set out to be a spokesman for the importance of bioenergetics in determining cell fate. Now a professor of medicine and chair of cancer biology at the University of Pennsylvania School of Medicine, he trained as a physician and became interested in research when he realized that “we really didn’t understand quite as much as we needed to about basic biology to develop effective therapies for patients,” he says. To pay for medical school, Thompson accepted a scholarship from the Navy and, following his training, he turned his attention to medical procedures that were of interest to the military – for example, bone marrow transplantation. The Navy planned to be prepared should such treatments become necessary to combat radiation injury on US soil.
In the early days, physicians were using bone marrow transplantation to treat patients, mostly with leukemias, who’d done poorly on standard cancer therapies. “The side effects were horrible,” says Thompson. Before the discovery of effective immunosuppressive drugs, “people got terrible graft-versus-host disease. These were some of the sickest patients you ever saw.”
As a naval officer at Seattle’s Fred Hutchinson Cancer Research Center in 1983, Thompson helped care for the first hundred patients to receive cyclosporine, a compound that would become the crown jewel of immunosuppression. “It was nothing short of a miracle,” he says. Patients still experienced some side effects, but after the transplant they fared remarkably well – too well, says Thompson. In particular, patients on cyclosporine seemed to be able to handle infections much better than those who had received less-effective immunosuppressants. “That just didn’t make any sense to us,” he recalls. If their immune systems were truly tamped down, the patients should have been coming down with infections left and right.
This mysterious lack of toxicity led Thompson and his colleague Carl June to search for the molecular pathway that the immune system might be using to circumvent cyclosporine to fight pathogens. That led them to the discovery of the CD28 receptor and the so-called costimulatory pathway. “We now know that T cells require two integrated signals to mount an effective immune response: Signal transduction through the T-cell receptor, and signal transduction through costimulatory receptors,” says Thompson. “So we started with a very clinical question and stumbled onto a signaling pathway that hadn’t been previously described.” The ability to make that leap from bedside to bench is not necessarily common. “Craig is a physician-scientist who, until recently, still saw patients. Yet his science has been right at the cutting edge,” says Martin Raff of University College, London. “In my experience, this is quite unusual.” June has gone on to harness the power of CD28 for growing large quantities of immune cells that can be given to patients to treat cancer and AIDS (see his Vision in The Scientist, May 9, 2005 issue). Thompson, on the other hand, “became a real science nerd” and decided to track down how CD28 works. The key insight, it happens, came from chickens.
While at the Fred Hutchinson Cancer Research Center, Thompson had become interested in studying cancer and immunity in chickens. Working with Paul Neiman, Thompson found that the oncogene myc promotes proliferation of chicken lymphocytes, but only when the cells are safely ensconced in the bursa of Fabricius, the organ in which the bird’s B cells mature. When he removed the cells from the bursa, “they died like stones,” says Thompson. “We thought, gee, if that’s true, there must be something in the bursal environment that keeps cells from undergoing apoptosis as long as they’re there,” he explains. “So we went looking for genes that would keep bursal cells alive.” And they found bcl-X, a relative of the bcl-2 gene that keeps programmed cell death in check. The discovery of this cell-death inhibitor “rocketed him to fame,” says Raff. “It made an especially big splash because cell death was just in the beginning of its exponential rise. So that made him one of the heroes in the field.”
Thompson then connected these two major discoveries, showing that CD28 stimulates production of bcl-X in mouse and human T cells, suggesting that the costimulatory pathway works by regulating cell survival during an immune response. Linking an extracellular signaling pathway with cell survival was not a major leap of imagination; most biologists now believe that animal cells are programmed to kill themselves if they don’t receive the proper signals from their neighbors, says Raff. These survival signals, acting through proteins such as bcl-2, keep the cell death program shut down. But Thompson then tossed metabolism into the mix.
“Craig argues that the bcl-2 family mainly regulates metabolism. So that what survival signals are doing is not regulating cell death directly, but regulating death indirectly by regulating metabolism – for example, the transport of glucose and amino acids across the plasma membrane,” says Raff. “That’s where he’s unique.” Indeed, Thompson hypothesizes that the function of extracellular signaling molecules is to give cells permission to take up sufficient nutrients to grow, maintain themselves, or reproduce. “We believe that in mammals, there’s a constant supply of nutrients – glucose and amino acids – but that cells need specific transporters and specific metabolic enzymes to utilize those resources,” says Thompson. “And those genes are under absolutely exquisite control by extracellular signal transduction.” In other words, cells need permission from other cells in the organism to be able to access the nutrients they need to live.
Derailment of the cell’s system, Thompson finds, can lead to cancer. The oncogene akt, for example, boosts glucose uptake in transformed cells by driving the recruitment of glucose transporters to the cell surface. The added fuel could power the cancer cell’s penchant for proliferation, and might explain something called the “Warburg effect.” In 1930, German biochemist Otto Warburg observed that most cancer cells undergo a shift in metabolism: they tend to scarf up and burn through loads of glucose because they rely more heavily than do normal cells on glycolysis to produce their ATP. Warburg believed that this reliance on glucose came about because cancer cells somehow lost the ability to carry out the more efficient ATP-generating process of oxidative phosphorylation, which coupled with glycolysis produces on the order of 30 ATP molecules per molecule of glucose, compared to the two ATPs produced by glycolysis alone.
But Thompson and others think that the shift occurs not because tumor cells can’t carry out oxidative phosphorylation, but because they gain the ability to take up and process as much glucose as they can – allowing them to make all the energy and the components they need to survive and proliferate. Although glycolysis alone produces less energy than oxidative phosphorylation, cancer cells crank up the activity of the pathway enough to more than compensate for the loss of efficiency. The theory makes sense according to oncologist Chi Dang of the Johns Hopkins University School of Medicine, who finds that myc also boosts the activity of enzymes involved in glycolysis. “In the paradigm we have now, oncogenes are like the accelerator and tumor suppressors are like the brakes. But basically what people forget about is the fuel source for the car.” And like any cells, tumor cells need fuel to grow. What’s more, by favoring glycolysis over oxidative phosphorylation, cancer cells can spare their pyruvate – the glycolytic product that gets carried into the mitochondria to produce ATP. Instead of burning its pyruvate, a cancer cell can save it to make the fatty acids needed to build new membranes, “which you have to do in order to make another cell,” says Lewis Cantley of Harvard Medical School.
Although the idea that this metabolic derangement is a necessary step in cancer formation is still somewhat controversial, more researchers are warming up to the idea. “We arrived at similar conclusions that the regulation of metabolism is going to be a major mechanism by which the PI3 kinase/Akt pathway is transforming cells,” says Cantley. Whether the conversion will be strictly required for all cancers remains to be seen. “But, yes, I think that it’s going to be very frequent in tumors and that one way or another something has to happen to turn on this pathway in order to get a tumor,” he adds. “One by one, all of our favorite oncogenes are going to tie into this story,” Cantley predicts. “I think it’s going to turn out to be incredibly important.” Thompson and Dang hope to take advantage of cancer’s metabolic Achilles’ heel to design novel therapeutics.
August 2, 2005
Original web page at The Scientist