Is It Your Karma--In New Clothes?

In the National Institutes of Health initial review group (IRG) on which I serve, we are now reviewing at each session a handful of proposals that seek to analyze the genetic basis of susceptibility to the infectious diseases that afflict great masses of the world's population. There is much excitement among my peers about these proposals, and by and large they have done reasonably well, in that they usually receive fundable priority scores. This trend in the Tropical Medicine and Parasitology study section is a microcosm of widespread excitement about quantitative trait analysis using microsatellite and other markers to determine the influence of genetic makeup on human health and disease. On the one hand, these studies are at the forefront of biomedical science. Clearly, the biological and statistical technology exists to decipher in great detail and with reasonable confidence allelic constitution(s) at loci that might play a role in the susceptibility to or outcome of infection among a population exposed to the causal agent(s). We know that individuals exposed to the same pathogen exhibit very different clinical outcomes, and it is quite likely that their genetic constitutions account for at least part of this variability. In addition, the determination of allelic variations in genes that determine these differences could well yield valuable information on the biological determinants of host-parasite interactions. So the proponents of these studies have the weight of mainstream scientific thinking on their side. On the flip side, the proponents of these studies seem to overlook the embarrassing reality that our ability to correlate genotype with phenotype is woefully deficient. To take just one example, there are a number of disorders that are clearly the result of a single gene deficiency. Nonetheless, the manifestation of disease in a given individual as a consequence of mutations in this single gene can range from a complete lack of symptoms to debilitating or lethal illness. If the correlation between genotype and phenotype is so incomplete in single gene disorders, could one confidently make any correlation between genotype and phenotype when the latter is the consequence of interactions between multiple alleles at several different unlinked genes, each of which contributes a small portion to the totality of the clinical manifestation? After all, in almost no disease are identical twins, genetically similar to each other in every base pair, 100 percent concordant for disease. Similarly, inbred mice that are also genetically identical differ from each other in almost every parameter you may wish to study. While hard-core genetic fanatics may disagree, both genetic components and environmental influences seem to play roles in complex phenotypes, and the knowledge of the much-vaunted genetic blueprint may leave us far less enlightened than we are sold. Ethical Concerns I also wonder whether many of the candidate genes that are unearthed will turn out to be quite banal--such as the major histocompatibility complex or various cytokine genes. But that is a subjective and personal bias and does not negate the validity of the studies themselves. These concerns get expressed in great detail and with adequate fervor at study sections. This is as it should be, and the outcomes, favorable or otherwise, fall within the guidelines of IRGs. There are, however, some ethical concerns that do not get discussed during the evaluations of these proposals that deserve airing. At one extreme of this mania for genetic description of individuals is the frightening possibility that all babies or fetuses will be subjected to genetic fingerprinting at birth, and their allelic constitution at all loci stored in some digitized format. In the most "benign" scenario, such information may be provided to the parents so that they can determine whether they wish to face the risks of all possible disorders in their potential offspring. Here is a problem in itself. While it may well be that a certain combination of alleles at certain loci predict that an individual may be prone to alcoholism, is it possible that the same genes or some subset of them may make one musically gifted? Creativity springs from the immense diversity of the human species. Are we willing to sacrifice this if future parents are given the latitude to choose the "ideal" combination of genes? Do we actually know what an ideal human being is? More malignantly, this information can be readily misused by "big brothers" in insurance companies or potential employers. The former may suggest that "unfavorable" allelic constitutions at several genetic loci can justify either charging exorbitant amounts or completely denying coverage. Potential employers may choose not to hire individuals who seem prone to any of a number of diseases, such as alcoholism or mental illness. The problem here is that this is, whether we want to accept it or not, a form of racism. Thus, we find it abhorrent when we hear that taxi drivers will not accept as riders black men of a certain age group. They do so based on their "probabilistic" determination that the risk of personal injury from that particular phenotype is such that they do not want to take a risk. Would it be different if employers or insurance agencies used similar probabilistic determinations in making their decisions? Just as any given African American male can be a fine, upstanding person, someone with the most unfavorable combinations of genes, say for alcoholism, may never become an alcoholic. Are we setting ourselves up for a system in which there will be a new type of racism, one based on genetics? Humans and Biological Determinism The inherent biological determinism implicit in purely genotypically based explanations of health and disease is troublesome. Implicit in any liberal, humanistic approach to life is the belief that human beings are changeable, even in our adulthood. If we are merely robots, more or less under the control of genetic programs that are determined at the moment of fertilization, there seems little hope that individuals can be bettered through intervention. Thus, if alcoholism or other deviant behaviors are the result of interactions of multiple, specific alleles at disparate loci, one is doomed to a lifelong addiction. Such biological determinism also jeopardizes the fundamental concept of Judeo-Christian belief, namely the existence of free will. How can free will exist if most choices are dictated by strings of the letters A, C, G, and T? Sometimes I fear that these "scientific" doctrines will have the same stultifying impact as the Hindu doctrine of karma, which conveys the same deadening message--you are the result of the actions of your past lives (read: the alleles you have inherited from your forebears), and you are doomed to your fate. As noted earlier, quantitative trait analysis proposals get a fair hearing in terms of their scientific merit. My concern is not this, but whether we as scientists should not also be paying attention to the long-term effect of our endeavors. There is a certain inexorable, inevitable quality to the scientific enterprise. If I were to view the future dispassionately, it seems to me that within the next few decades our grandchildren or their children will be handed CD-ROMs (or whatever is the preferred medium of storage at that time) with their fine-structure genetic map at or near the moment of birth. To raise objections to this progress often marks one as some kind of know-nothing Luddite. But I cannot help wondering whether there are not some lines of inquiry where the potential for harm is so great that the question is not whether we should stop, but whether we should pay attention to some of these implications carefully before the rush ahead, as we tend to do. Sometimes those who hesitate may be saved. T.V. Rajan, M.D., Ph.D. (rajan@cortex.uchc.edu), is Boehringer-Ingelheim professor and chair of the department of pathology, University of Connecticut Health Center in Farmington.

Is It Your Karma--In New Clothes?

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Tv Rajan

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February 2000

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