Closing the Circle

I grew up in New York City during the Sputnik generation, a time when every kid wanted to be a scientist. I recall reading Microbe Hunters by Paul de Kruif when I was 8 or 9 years old, and decided that I, too, wanted to be a scientist and spend my life as a medical researcher. As a Yale undergraduate, working with Don Crothers in the biophysics of nucleic acids, I discovered what it really meant to do academic research in the sciences, and it was clear that was going to be my career path. Don had a wonderful attitude about science that I have tried to emulate. He believed you needed to have a killer instinct for the important problems and go after them with passion, but not be overbearing with the people around you. The environment in his laboratory was terrific, I couldn't wait to finish classes and get back to the lab. I spent four years working in Don's lab and published my first paper while I was there. I took most of my classes in chemistry, biochemistry, and biophysics, always planning on picking up biology along the way. I thought medical school was a way to get grounding in biology, so I applied to M.D./Ph.D. programs.

I chose the newly established program at Rockefeller University, and I'm still here. Rockefeller is a very special place with a wonderful tradition and great history. Each laboratory is an independent unit, free from the constraints of departments, free to pursue its own course. I moved from chemistry to bacteriophage genetics, working with Norton Zinder and Peter Model, then into molecular biology. I did a postdoc at the National Institutes of Health (NIH) with Phil Leder, got involved with structure and function of antibodies and have stayed with that problem, in one way or another, since then.

I eagerly returned to New York and started my own group at Sloan-Kettering in 1982, focusing on an obvious question, “Why do antibodies have an Fc region?”, a question that many would have argued was solved by 1982. I was unsatisfied with the solution and decided to clone the receptors that bound the Fc region, in part because of the challenge of cloning genes for rare messages. Cloning of rare messages was still a big deal then, and this receptor family had no known function. The Fc receptors opened up a whole new approach to the regulation of the immune response, establishing global concepts of inhibitory signaling and balanced responses. It's been a very slow battle to get the medical community to accept the fact that antibodies work by engaging specific receptors on the cell surface, and the regulation of those receptors controls not only inflammatory processes, but tolerance pathways as well.

Sometimes choosing a research problem comes from a paradox. If IgG antibodies mediate the pathogenic effects in autoimmune diseases, why are we using high doses of IgG as a therapeutic to treat these same diseases? After 10 years of work, we have come up with an answer—differential glycosylation of IgG antibodies is an important switch controlling whether IgG is going to be a pro- or anti-inflammatory molecule. When sialic acid is incorporated into the Fc, the IgG is an anti-inflammatory molecule. When exposure to an antigen occurs, pro-inflammatory IgGs are generated that have reduced sialic acid content and can activate their Fc receptors. That leads to a new therapeutic application, fully recombinant forms of intravenous immunoglobulin that will be much more potent than the current material. It's the first extension of our basic research into a clinical program. It's exciting, it's closing the circle. There was always this childish hope that someday I could say I studied a disease, understood how it worked, developed a therapeutic, and showed how it altered the course of the disease. We're finally getting there.

I've discovered how difficult it is to translate a basic finding in the lab to a clinical experiment. The reality is that if, as an academic scientist, you want to do a clinical trial you will need to manufacture the test compound in a way that's acceptable to the FDA, and that's expensive and not usually accessible. Satisfying regulatory concerns requires significant expenditures in time and money. Where are the budgets and the infrastructures to do those experiments? Only pharmaceutical companies, and a few very special foundations, have that capacity. The majority of us have to appeal to pharmaceutical companies to take on the project. Then the questions are financial more than anything else. It prevents simple, scientific inquiry into basic questions of the human immune response. I'm pushing to recapture the academic component of therapeutic development. We can't lose the opportunity to ask questions about basic human biology. Unfortunately, I don't see government funding for research improving anytime soon. I fear that we have several years of very hard times ahead of us. As our approaches become more sophisticated and more in vivo oriented, the questions that you ask can take years. If you don't have continuity in funding, those projects can't reach fruition. Long-term approaches are in danger right now.

When I was an undergraduate at Yale, I had a double major, in molecular biophysics and biochemistry, and in English. I maintain a passionate interest in poetry, particularly modern American poetry. I'm an avid weekend gardener, an interest that has extended into the laboratory. We have a large collection of orchids we grow in the lab and enter in competitions. Last year at the New York Orchid Show, one of our orchids (Paphiopedilum philippinense) took best in class with two blue ribbons. I've tried to make my lab interesting and exciting, an environment you never want to leave. Everything you want in life is in your laboratory, where I'd spend all my time if I could. Scientists are still kids, curious about everything, who never really grow up.