National Jewish Health
Dr. Marrack is also a senior faculty member in the Integrated Department of Immunology at National Jewish Health and a professor in the Departments of Biochemistry and Molecular Biology, Immunology, and Medicine at the University of Colorado Health Sciences Center, Denver.
Philippa Marrack jokes she decided to become an immunologist almost 40 years ago because of alcohol, a handsome scientist, and genetics.
Born in the United Kingdom, Marrack had just obtained her in B.A. in biochemistry from Cambridge University, and was about to start graduate work at 22 years old. But she attended an academic cocktail party, became slightly inebriated, and met Alan Munro, an up-and-coming immunology researcher who, she said, was "better looking" than her chosen mentor, whose lab investigated a different subject.
Munro chatted her up, discussing her great uncle John, an immunologist who had discovered an aspect of antibody function. Munro told her he thought it would be interesting to have a relative of John Marrack in his laboratory.
Kidding aside, Marrack concedes she decided to work with Munro because he was starting a laboratory at the prestigious Medical Research Council's Laboratory of Molecular Biology in Cambridge. The MRC then housed four Nobel Prize winners and was known for its free exchange of scientific information. Indeed, Marrack routinely lunched with Nobel Prize winner Francis Crick, the codiscoverer of DNA's structure, when she was there.
At the time, though, Marrack says there really was no way to predict that immunology would prove to be so rewarding to her professionally and personally. T cells, which would become the focus of her research, had only recently been discovered and little was known about their biology. How was she also to know that immunology would allow her to meet another important person in her life—John Kappler?
The two met as postdoctoral fellows in 1971 at the University of California, San Diego. Two years later they married, moved to the University of Rochester, established a joint laboratory, and have collaborated doing research about T cell biology ever since. They came to Denver in 1979 and have appointments at both the University of Colorado Health Sciences Center and National Jewish Health.
T cells are a group of white blood cells made in the thymus that mediate the body's cellular response against infection from viruses and bacteria and provide immunity against repeated exposure from foreign invaders. In their time together, the couple has elucidated many fundamental aspects about how T cells work, are activated, and survive.
In 1982, for example, they revealed that a T cell, in order to fight an infection, must simultaneously recognize on an infected cell parts of the microbe released to the surface and another molecule, called MHC. Before their finding, it was unknown if the T cell recognized the microbe component and MHC separately. Their finding implied the T cell had a single molecule on its surface—a receptor—that was able to respond to an infection.
Soon after, in 1983, the couple identified that molecule: the definitive T cell receptor. Other scientists, Marrack said, had found the protein but were unsure of its function.
Although the characterization of the T cell receptor gave scientists a clue about how the immune system addresses a foreign antigen (a substance that may produce an immune response), why the trillion or so T cells did not attack antigens intrinsic to the body remained a mystery. In 1987, Marrack and Kappler published findings that explained the mechanism T cells use to tolerate the inherent antigens of mice and men.
They showed, in mice, that if a T cell receptor in an immature T cell in the thymus can bind to any antigens present in the thymus, the young cell dies. The only cells that mature and leave the thymus are those that do not react to self-antigens but can respond to foreign antigens.
"It is a continual process of making, screening, and escaping T cells, depending upon what is in the thymus at any given time," Marrack explained. "Ultimately what will get out of the thymus are randomly generated T cells that can recognize foreign antigens." In autoimmune disease, such as rheumatoid arthritis and diabetes, though, some self-reactive T cells emerge from the thymus and the body cannot keep their activity in check.
The duo's understanding of T cells also led them to reveal why certain so-called superantigens in the bacteria that cause toxic shock syndrome and food poisoning spur T cells to grow uncontrollably and cause death.
These days Marrack and her husband continue to work on T cells, including investigating why they need the MHC molecule. But they also pursue independent projects. Marrack, for example, is focusing on improving vaccines by improving T cell response to a foreign antigen upon re-exposure. Kappler works on autoimmune diseases.
Both acknowledge they have dissimilar scientific styles—she favors in vivo experiments; he is more detail and biochemically oriented. But they say their differences have given them a complementary approach to solving problems and finding answers to important questions in immunology.