When Mark Davis looks back for the moment when he knew he would study the immune system, he sees a meandering path rather than a decisive instant. Sure, his childhood fascination with human origins, fostered by visits to the American Museum of Natural History, played some role in his choice—so did using his chemistry set to make chlorine gas in the basement. But these incidents alone didn't determine a career path that has included cloning T cell receptor genes and creating precise, quantifiable videos of T cells in action.
"I guess for some there is this 'road to Damascus' moment when they have an epiphany that they are going to study a particular aspect of science for the rest of their lives," Davis says. "That really isn't my story. I was just interested in learning about new things. And research keeps you thinking and getting continuous stimulation from colleagues and students."
As an undergraduate at the Johns Hopkins University, he entertained biology and economics as career paths. A capricious economics professor inadvertently cut off one of those avenues. "He called me in at the end of the semester and said, 'You're right between an A and a B. I think I'll give you a B,'" Davis remembers. "That experience cured me of wanting to be an economist!"
A series of gigs in several organic chemistry labs provided stimulating research experiences for an undergraduate because organic chemistry delivers results so quickly. Still, Davis grew somewhat bored with the work and drifted toward biology. "As a senior I worked with Michael Beer who was trying to sequence DNA using a high-powered, fancy microscope," he says. "It didn't work, but the experience did get me interested in what you could do in biology if you had a DNA sequence."
After a summer hitchhiking around Europe, Davis entered graduate school at the California Institute of Technology to focus on nucleic acid chemistry and gene expression in Eric Davidson's lab "just before the recombinant DNA era" and later in Leroy Hood's lab, cloning antibody genes and uncovering the chromosomal rearrangements behind class switching. But while great progress was being made in understanding how antibodies confer immunity, the cellular, or T cell, side of the adaptive immune system remained mysterious. Davis set out to explore it in William Paul's lab at the National Institutes of Health. "He gave me a remarkable amount of freedom, and I was able to lead a small group there that cloned the first T cell receptor gene," he notes.
After setting up his lab at Stanford, Davis and his colleagues isolated several more T cell receptor genes and pinned down their biochemistry. Then he asked the question: "What more do we want to know about this?"
As he sees it now, the question stemmed from a realization that he had as a senior in college. "I took a physical chemistry course," Davis recalls. "I remember thinking this is what a mature science looks like. You could ask very precise questions about what would happen in a particular situation and predict very accurately what would happen."
Seeking to approach this mechanistic level in biology is very challenging, but Davis decided to focus on the cell—particularly interactions between T cells and the cells that present foreign antigens. Biochemical means, however, offered no way to observe such interactions in real time. Using advanced imaging techniques that became available in the mid-1990s and have been advancing dramatically ever since, Davis decided to try to observe the interactions directly. Through imaging, he and his colleagues showed that T cells are able to recognize single molecules of antigen and that fleeting interactions with antigen-presenting cells are sufficient to activate the T cell. "The T cell is really the sixth sense," Davis says. "They are a sensory system that can recognize a single molecule, just like the retina, which detects the presence of a single photon."
Davis is also focused on developing a broad understanding of the human immune system. Mice, which can be important animal models for some human diseases, have proven to be poor models for human immunological diseases. As a result, Davis and his lab are using high-throughput screens to catalog a host of cellular parameters. Ultimately, Davis hopes to develop benchmarks of health for the immune system and a systems biology type of understanding of stimulus and response.
"There isn't any coordinated information about what a healthy immune system looks like," Davis says. "It's important to know how the whole system fits together. It will really require a systems biology approach because there are so many moving parts."
Developing such a view of the immune system may provide important new avenues for combating other diseases, such as cancer. "Cancer therapies usually target rapidly dividing cells," Davis says. "That buys time in the short term, but because the same therapies damage the immune system, it can leave people susceptible to deadly infection."
More reliable human immunological data may also lead to clues that can explain confounding scientific results, Davis says. "Too often you see a therapy work miraculously in mice while only one in 10 people end up with a miraculous cure."
Developing measures of immunological health that physicians can use in the clinic will require extensive work with computational scientists. It's a challenge Davis relishes. "You can really do interesting things with the tools of bioinformatics. It's fun to learn new things about new things—it's sort of adult education."
And, it's an education that Davis doesn't see ending soon. "The fun of modern biology is that there is so much to discover. It's a very rich field. If you are interested in a question, you can look at it in many different ways across a spectrum of information."