Biology Is Hard

Many years ago, after finishing my residency, I decided to become a researcher. Around the same time, I went home to India for a visit. In those days, one of the standard accoutrements found in the living room of a Tamil Brahmin home was a wooden swing. My grandfather was still alive then and would occupy the swing each night. I remember once sitting by his side during this postprandial ritual. We sat swinging peaceably, no doubt immersed in our own thoughts, when he turned and asked, in his

By | October 6, 2003

Many years ago, after finishing my residency, I decided to become a researcher. Around the same time, I went home to India for a visit. In those days, one of the standard accoutrements found in the living room of a Tamil Brahmin home was a wooden swing. My grandfather was still alive then and would occupy the swing each night. I remember once sitting by his side during this postprandial ritual. We sat swinging peaceably, no doubt immersed in our own thoughts, when he turned and asked, in his typically bellicose manner, "So what are you doing in America?" "Research on the molecular biology of the mouse major histocompatibility antigens," I replied. "Research!" he bellowed. "Research? How old are you now?" I was about 24 then and told him so. "Nonsense," he said. "You are too old to be doing the research."

As I get closer to the age he was when he told me that, I look back ruefully to that conversation. My Tamil Brahmin family had an arrogant, narrow outlook towards intelligence and ability. The only kind of acumen they accepted as valid was mathematical ability, and I, who lacked that aptitude, was always regarded as intellectually suspect. Within that particular frame of reference, my grandfather's conviction regarding age and research was valid. It seems an accepted wisdom that most of the best work that mathematicians and physicists conduct occurs before they are 30 years old.

In contrast, we biologists still seem to be going strong in our 50s and 60s. When I ask my peers about their work, they invariably tell me, with much excitement, that their research is going better than ever.

I find it difficult to believe that the truths in biology are more profound or challenging than those in physics or chemistry, or that biologists are less intelligent. Surely the rules governing individual phenomena in mammalian systems are as simple and as easily described as any reaction in any other discipline. Is it just that biological systems seem to have such an infinite number of these relatively simple reactions going on at the same time, at the same place, that complexity emerges from their interactions, as Stephen Wolfram has averred?1

Whatever it is, nature seems very chary of yielding its biological secrets; I sometimes wonder whether reductionism is a fundamentally flawed approach to biology. I do not pretend to understand physics or chemistry, but I suspect that these disciplines have paradigms, which some universal laws apply within defined categories. For instance, Boyle's Law seems to be true of all gases, on all continents, and perhaps everywhere in the known universe.

This does not ever seem to be the case in biology. Consider, for instance, the work of my colleague, Fred Finkelman, who has painstakingly worked out the mechanisms by which mammals protect themselves against gastrointestinal nematode parasites. You might think that this is a very small universe of creatures with a universal biology. He has demonstrated that a particular class of T lymphocytes, called Th2 cells, is critically important in achieving host protection. Here then seems to be the magical paradigm that seems so dear to the historians and philosophers of physics and chemistry. But, if you look deeper into this small and obscure universe of creatures, you realize that the paradigm falls apart quite quickly. The precise tissue, cell type, or molecule that plays the critical role beyond the Th2 lymphocyte in achieving host protection is very different, even among this small group of organisms!

The French geneticist François Jacob once wrote, after discovering the mechanism of operon regulation in bacteria, that what is true of Escherichia coli is true of the elephant. Research over the last 30 years has shown that the two have precious little in common, at least in terms of gene expression regulation. Thus, paradigms, if they exist at all in biology, seem to do so only in broad-brush strokes.

All of this is good for us aging biologists: None of our questions ever seems to reach a complete solution. What more can an aging biologist ask for? We can legitimately say that more research is needed before any clinical application can be devised based on our findings!

Sometimes I fancy a repeat of the conversation I had with my grandfather, now long dead. If he was skeptical then as to whether I was young enough to do research, I can only imagine how much more dubious he would be now. The irony is that then, I was vaguely and momentarily discomfited by his attitude; I wondered whether it might not be an expression of intolerable hubris for me to pretend that I could conduct research at the age of 25.

Thirty years later, I feel comfortable knowing that I was not too old then, and I'm not too old now. It has taken me this long to convince myself that biological problems require slow, painstaking, methodical, accretive work. I wish sometimes that I could tell my grandfather that.

T.V. Rajan is a professor of pathology at the University of Connecticut Health Center in Farmington.

References
1. S. Wolfram, A New Kind of Science, Champaign, IL: Wolfram Media, 2002. 2. J.F. Urban Jr. et al., "Cutting edge: IL-4 receptor expression by non-bone marrow-derived cells is required to expel gastrointestinal nematode parasites," J Immunol, 167:6078-81, 2001.

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