Questions and AnswersProf. Dr. Carl Nathan

How or why did you become involved in infection research, what fascinates you about this subject?
I’m fascinated by the ability of the immune system to destroy any tissue that the body thinks is infected. I want to find out how to train that power against metastatic cancer. This attracted me to tumor immunology. In the late 1970’s I chaired the Tumor Immunology Committee at NIH, but I became frustrated with the pace of the field at the time—the pregenomic era. I reasoned that to learn the rules and tools used by the immune system to kill, it would be profitable to study immunity in the setting that provided for its evolutionary selection-- infectious disease. Thus I turned to host-pathogen relationships as a detour in a lifelong commitment to tumor immunology. In retrospect this was perfectly reasonable, as long as the definition of “lifelong” includes the life of a line of inquiry, not of an investigator.

What are you working on at the moment?
Many of the challenges of tumor immunology can be recapitulated in a persistent infection like tuberculosis. It fascinates me that the only known natural host for Mycobacterium tuberculosis is humans. This implies an evolved, metastable equilibrium between the two species that occasionally leads to the death of one of them. What are the chemical and biochemical underpinnings of that relationship? It is privilege to work in an interdisciplinary lab and department where we can combine chemical genetics, microbial genetics, host genetics, biochemistry and immunology to try to answer that.

What were the turning points in science, in career, in life that influenced your decisions?
The late Lester Grant, MD, DPhil, addicted me to science when he hired me as an assistant animal handler at NYU Medical Center the summer after my freshman year in high school. I worked for Lester for 5 summers. Washing rabbit cages let me learn research from the bottom up. Lester loved students. He introduced us to the NYU greats, including Lewis Thomas, Jonathan Uhr, Chandler Stetson, Baruj Benacceraf, Sherwood “Jerry” Lawrence and Victor Nussenzweig. Watching neutrophils emigrate into inflamed sites in situ in real time ignited a lifelong fascination with phagocytes. At Harvard Medical School, I spent a year and half in John David’s lab, where my phagocyte interests broadened to macrophages and cytokines. It was a privilege as a student to introduce two great Harvard professors to each other—John David and Manfred Karnovsky—and to be given a key to each of their labs. One day during my oncology fellowship at Yale I was doing an experiment and the emergency room called. Reaching for the phone, I knocked over the tube of macrophages I was working on. I realized that despite my love for both clinical medicine and research, I was in the wrong specialty to combine them, given my personality, that is, my need to think quietly every once and a while for a few minutes at a stretch. I decided to go all-research. At Rockefeller, Zanvil Cohn taught me to think across disciplinary boundaries. It was an inspiration and an education to work in the same unit as Ralph Steinman and Sam Silverstein and to talk things over with Rene Dubos.

What was a single most important moment of your career?
Every new day is the most important-- except on days when I get “pink sheets” from NIH. Why aren’t they called “blue sheets”? If I have to narrow it down, then it’s those days when something entirely new has been discovered in our lab and we see it for the second time.

What was your most important scientific discovery?
Hasn’t happened yet. But with wonderful colleagues I learned that cytokines activate macrophages, that interferon-gamma is one of the most important to do so, that other cytokines deactivate macrophages, that TGF-beta and IL10 are among the most important to do so, and that activated macrophages kill tumor cells and pathogens in part through the production of reactive oxygen and nitrogen intermediates, the latter produced by an amazing enzyme, iNOS, that turns itself on by attaching calmodulin without an elevation in intracellular calcium. We discovered that iNOS is critical for control of tuberculosis in the mouse, and that Mycobacterium tuberculosis resists reactive nitrogen intermediates through its proteasome, its peroxynitrite reductase and its nucleotide excision repair pathway, among others. We found that some anti-infectives can selectively kill non-replicating bacteria, and that if you look for such compounds deliberately, you can find lots of them. I’ve become deeply concerned about inadequate anti-infective research and development and hope our work is illustrating new ways to approach the problem. I’ve equally concerned about inadequate access of poor people around the world to the drugs we do have and should have. I’m devoting some of my thinking, writing and teaching to that issue as well.

What drives you and carries you on? What do you love about your work?
As a teen I thought I was going to be an artist, unfazed by my obvious lack of talent, until the day I read a column by John Canaday, the art critic for the New York Times, that seemed to be written just for me. Only do that if you can’t imagine doing anything else, he advised. I applied that criterion as I went along, and only scientific discovery met it. What a great way to work and share with people from different backgrounds, to solve problems, to exercise freedom.

What influenced and impressed you and your life and therefore science?  Idols?
When I had the privilege of joining the editorial board of the Journal of Experimental Medicine as an assistant professor, I watched great people at work, including Zanvil Cohn, Ralph Steinman, Henry Kunkel and Tony Cerami. But the one who absolutely astonished me was Maclyn McCarty, a consummate scholar, gentleman, physician and scientific revolutionary. This gentle giant was much more interested in clarity of expression than personal acclaim.

What would you recommend to someone starting out in science? What would be your advice for young scientists?
Follow John Canaday’s advice, but don’t apply the test until you’ve experienced discovery.

What would have been your alternative plan (plan B) if science /your job had not worked out?
I majored in East Asian history in college and also became fascinated with South Asia. I had a Fullbright fellowship to go to India but my draft board promised to send me to Vietnam if I accepted it. So I went to medical school. Had that not happened, I’d probably be a history professor. If I had not had such a wonderful research experience in medical school, I’d be treating cancer patients. I would enjoy taking care of them but would be frustrated to be applying science I considered inadequate and had no part in developing.

What are your dreams for the future?
Another discovery, and another.

What do you think is important and should be worked on in the future?
What a funny question. The answer is what we’re doing today, the inadequacy of the answer is why we keep doing it, and to find a better answer is what we hope to learn.

What do you do when you are not working?
My wife and I love music, dance, theater, art, books, photography, our dog, the great outdoors and the astonishing adventures of our kids. Then there’s the Daily Show with John Stewart.

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