Eighty years ago, Jack Strominger, Higgins Professor of Biochemistry, began his “tortuous journey to immunoland.” En route, he discovered how penicillin kills bacteria and how the immune system fundamentally works. Now he explores autoimmune diseases, the “enigma” of pregnancy, and natural killer cells.
“He’s highly prolific and has made lots of discoveries,” comments Alex Rich, Professor of Biophysics at MIT, a friend since their Harvard undergraduate days. Born in 1925, Strominger entered Harvard in 1942, as World War II was raging. He joined Harvard’s Navy V-12 program and majored in psychology. “I wasn’t much interested in biology,” he recalls. He became “hooked” on research while at Yale Medical School and published the first of his 967—and counting—papers.
While he was clerking at the Yale–New Haven Hospital, doctors treated the first infectious disease patient with a new drug, penicillin, with “miraculous results.” When strange circumstances handed him a fully funded, independent NIH laboratory at age 26, Strominger began tackling the miracle behind penicillin. How could it work selectively on many different types of bacteria? While still in his thirties, Strominger showed that penicillin prevents bacterial enzymes from building the cell wall (animal cells have membranes, not walls), causing bacteria, but not host cells, to die. Recent research has validated his further hypotheses about the biochemistry of penicillin’s mode of action.
In 1967, Harvard University invited Strominger to join a new department, today’s Department of Molecular and Cellular Biology. Nobody expected he would become an immunologist who would galvanize the field. By then, basic antibiotic research became less exciting, while heart transplants—and their immune rejection—took center stage. Looking for a new challenge, Strominger began studying why the body rejects tissue grafts.
Scientists knew that MHC (major histocompatibility complex) proteins displayed on a cell’s surface vary significantly from person to person, causing the rejection. But they didn’t know what MHC proteins were, what they normally do, or why they have so many variations (polymorphisms), which did not evolve simply to reject surgical grafts.
By 1987, Strominger (and Don Wiley, an MCB professor until his tragic death in 2001) isolated , crystallized, and determined the 3D structures of two classes of MHC proteins. The resulting crystallography images were “a bombshell,” he recalls. “All you have to do is look at the pictures and you know what they’re for.”
The pictures showed that the proteins have a pronounced cleft packed with antigens, the cell’s nametag. The cleft exhibits antigens to the immune system’s killer T cells. “If it is a foreign peptide, the T cells proliferate to attack the invader. Essentially, we solved the problem of how the adaptive immune response is initiated,” says Strominger. The Journal of Immunology recently republished Strominger’s 1987 paper (with Wiley and lead author Pamela Bjorkman, then a graduate student and now a professor at the California Institute of Technology) describing the work as the first of its “Pillars of Immunology.”
Intended to help fight infectious organisms, MHC proteins also attack implanted tissue—and, in autoimmune diseases, the body’s own tissues. Strominger’s lab is investigating how normal self-tolerance is established, why it is broken in a disease like multiple sclerosis, and particularly how to counter its loss. “One goal is to understand how an existing MS drug (Copaxone) works and use the structural information on MHC proteins to develop a better version,” he says. “We did that for mice. But mice are not men! It will take five to ten years to test the new version in humans.”
Strominger’s newest research concerns the immunology of pregnancy, which involves natural killer cells. “The fetus is a foreign graft because it has paternal MHC proteins. It should be rejected.” He hopes to characterize the normal system for fetal tolerance to understand why some women lose that tolerance, causing multiple miscarriages.
With 30 awards to his name, including the Lasker Award and Japan Prize (both shared with Don Wiley), Strominger is proudest of how many former lab members have had stellar careers worldwide. Nine are Harvard professors, four are National Academy of Science members, and one is a Nobel laureate.
Why is his lab so successful? “I’m very permissive. I believe you must find your own way in life,” he says, adding that originality is the hardest part of discovery. He also keeps an open door, visits each of his 14 lab members every day, and knows what each is doing, say graduate student Xi Chen and lab manager Tatiana Murnikova.
To others, Strominger is brilliant, devoted to science, inspiring—and fun and humorous. “He’s very optimistic about life and has endless energy,” says Chen. “He jokes about what he will research at 100. I tell him that as long as he is willing, he’s capable of doing anything.”
“There’s no way Strominger can retire yet,” Murnikova says. “Running the lab is too much fun for him. I don’t know whether he would ever give it all up. It’s always challenging and fun here. There’s never a dull moment.”
Read “Breaking the Age Barrier“, an article in the 8/11/05 Nature Magazine featuring Jack Strominger.