About 12 years ago, Gary Glick and his wife noticed something wrong with their son, Jeremy. He seemed to be lagging behind his twin sister, recalls the immunologist and chemical biologist at the University of Michigan in Ann Arbor. "They were growing in unison, and he sort of stopped." Jeremy, who was 9 or 10 at the time, also looked sickly and pale and began complaining of nagging pains in his stomach and elsewhere.
Rachel Lipson Glick, a physician, was stumped by their son's mysterious ailment. So were other doctors. It took about 3 years to rule out myriad cancers, endocrine malfunctions, and other potential causes and to determine that Jeremy had Crohn disease, an inflammation of the digestive tract stoked by misbehaving immune cells, Science Magazine says.
The diagnosis made life harder for Jeremy, now 22 and a senior at college. To control the symptoms, he injects the antibody drug adalimumab (Humira). He will likely need it, or another immune-inhibiting treatment, for the rest of his life.
By coincidence, one of those alternatives might stem from his father's work. Gary Glick, like an increasing number of other researchers, is convinced that the immune cells driving conditions such as Crohn disease share a feature that could be their undoing: their metabolism. He has spent the past 2 decades searching for drugs that target metabolic adaptations of immune cells. Clinical trials by Lycera, a company Glick founded, are now assessing the first of those drugs for psoriasis and ulcerative colitis, an intestinal illness related to Crohn disease.
Drug companies are working to develop other candidates. Researchers are also looking to deploy existing drugs that tamper with metabolism, such as the diabetes treatments metformin and 2-deoxyglucose (2DG). "It's a very exciting time," says immunologist Jonathan Powell of Johns Hopkins University's School of Medicine in Baltimore, Maryland. "Potentially, all immunologic diseases are targets for metabolic therapy."
Cancer researchers have also tried to disrupt cell metabolism, even testing some of the same drugs immunologists are investigating. But many scientists are convinced the strategy will work better for immune diseases than for tumors because drugs to treat those illnesses need only to suppress a relatively small number of overexuberant cells, not eliminate them. And whereas existing drugs that restrain immune cells, such as adalimumab, can compromise our defenses against pathogens, Glick and other scientists think that drawback won't affect their strategy. Focusing on the metabolism of overactive immune cells, he says, offers "a way to directly target these cells while sparing immune function."
In the 1920s, the German doctor and chemist Otto Warburg was the first to realize that immune cells have a distinctive way of fueling themselves. To power their activities, cells need to produce the molecule adenosine triphosphate (ATP). They can make it directly through glycolysis, a biochemical pathway that dismembers glucose. Or they can generate ATP through a more involved process called oxidative phosphorylation, which requires energy-laden molecules produced by glycolysis but also enlists other biochemical reactions that break down fatty acids and amino acids such as glutamine.
Normal body cells typically rely on oxidative phosphorylation for most of their energy needs, but Warburg discovered that cancer cells ramped up glycolysis. He also noticed that some healthy cells depended on glycolysis: immune cells.
Warburg was on the right track, but researchers now know that when immune cells aren't fighting pathogens, they set their metabolism to low and produce ATP mainly through oxidative phosphorylation. The arrival of a threat, such as a flu virus reproducing in the lungs, activates the cells, galvanizing them to combat the invader. At that point, "they undergo these massive metabolic changes," says immunologist Erika Pearce of the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, Germany. The stimulated cells don't just require more energy, she notes. An activated T cell can divide several times per day, quickly spawning an army of millions of descendants. To sustain that mobilization, the cells also require large amounts of raw materials, such as the precursors of DNA, proteins, and lipids.
How exactly an activated immune cell satisfies its massive demand for energy and molecular material depends on what type of cell it is. Activated helper T cells, which serve as immune commanders, seem to follow Warburg's paradigm. They guzzle glucose and crank up glycolysis, although they also boost the rate of oxidative phosphorylation by a lesser amount and consume more glutamine. Cytotoxic T cells, which kill tumor cells and cells commandeered by viruses, take a similar tack. In contrast, immune-suppressing regulatory T cells continue to get most of their energy from oxidative phosphorylation, even after they swing into action, and they prefer fatty acids to amino acids and glucose.
Immune cells also make different metabolic choices depending on whether they are memory cells, which persist for years and protect us from getting sick from the same pathogen more than once, or shorter-lived effector cells specialized to attack microbes immediately. Memory T cells, for instance, typically favor oxidative phosphorylation and consume fatty acids. Effector T cells, by contrast, turn up glycolysis and are heavy glucose users—a difference reflected in their mitochondria, the organelles that serve as cellular power plants, Pearce and her colleagues reported 2 years ago.
