Thursday, May 12, 2005

Nature, nurture, cancer

One of the problems that bedevils environmental health is the question of the relative contributions of genes versus environment in producing disease, especially cancer. In many ways it is a false problem. Even diseases we consider "purely genetic" (e.g., the inborn error of metabolism, phenylketonuria) has an environmental component: if the infant is given a diet free of phenylalanine they remain healthy. Thus calling a disease "genetic" is a misnomer. There is always at least some kind of gene-environment interaction.

Ah. Gene-environment interaction. Another buzz word in environmental health. It represents an extremely active area of research, looking for "susceptibility genes": gene variants that make the person more susceptible to environmental agents. There are such genes, so the idea isn't at all crazy. The problem for me is that this area of research has a strong tendency to locate the blame and the cause of disease within the individual rather than the environment. Having participated in many grant reviews where entire research centers are proposed to work on this problem, the argument usually goes something like this.

You smoke three packs of cigarettes a day and live to 90 and die in a pedestrian accident. I seem to be just like you and smoke three packs a day but contract lung cancer age 60. What's the difference between us? Obviously our genes our different. What else could explain this tremendous difference in outcomes?

Given what we know about molecular biology and toxicology this is not at all an implausible story. But let's examine it further. Suppose you and I go to a movie and you hate and I love it. Is it because I have the XYZ movie loving gene and you don't? Suppose we each flip a coin and yours comes out heads and mine comes out tails. Is it because you have the "heads" gene?

I'm not saying that genes are irrelevant to disease susceptibility or disease outcome. But I am saying it is easy to be seduced by this idea to develop a research agenda that looks away from the actual causes of disease in the environment and toward those factors within individuals that may increase risk once exposed. To use another analogy, if you are doing something risky like walk along the edge of a cliff and someone comes along and pushes you off the edge, it is still the one that pushed you that caused your fall. I don't think a defense of "contributory negligence" would keep the assailant out of prison.

And while the notion of cancer susceptibility is scientifically attractive and plausible, it may not be so very important. A paper recently published in the journal Biometrics looked at prostate, breast and colorectal cancer in three Scandinavian twin registries for concordance in identical twins and same-sex non-identical twins. Thus these are pairs that share much or all of their genes. Using sophisticated statistical modeling techniques the researchers concluded "genetic susceptibility makes only a small to moderate contribution to the incidence of prostate, breast, and colorectal cancer."