If we expect heterogeneity in genetic factors and environmental factors, that is, if we do not expect the factors to be common across families, we can still ask what factors are involved and how they act together. We would, however, expect investigations around this question to be difficult. That is the position where second installment in this series of posts ended.
One response to the difficulty is, putting aside the search for common genetic factors, to look for rare variants that have a large effect on some biomedical or behavioral condition (McClellan and King 2010). How can this approach be justified? Two ways: a) For those individuals carrying the rare variant—or for relatives among whom the variant is common—knowing about the genetics could lead to genetic counseling (about having children), screening and selective abortion of fetuses carrying the variant, screening of newborns and other relatives, or investigation of biochemical pathways that might eventually be modified by pharmaceutical treatment; and b) Investigation of biochemical pathways related to the rare variant might suggest mechanisms and pharmaceutical treatments to explore that might help others who have the condition but lack the particular variant.
Got the second possibility [b], notice that we have, as in the previous installments, slipped from family (i.e., sets of close relatives) to the population. This time the slip depends on a hope that the biology is amenable to investigation, intervention, and extrapolation/generalization. Perhaps that will turn out sometimes to be the case. If so, the resulting biomedical interventions or treatments won’t be based on screening for who has the original genetic variant, but for signs of the biochemical or related conditions that turned out to be amenable to intervention. That kind of screening, of course, dominates Western medicine already; there’s nothing especially genomic about that.
If we return to the family-based justification for searching for rare variants of large effect ([a] above), we can envisage, because it already happens, families with children possessing rare genetic variants of large effect agitating for more research on the mechanisms and possible treatments. Biomedical researchers have joined forces with such families in part because the hope of a treatment is important to people who they get to know personally. In part, also, because researchers benefit from such cases to the extent that they fuel the idea that genomics will lead to a revolution in biomedicine or, more recently, the idea that genomics opens up a realm of personalized medicine in which knowledge of one’s particular and not-necessarily-common genetic profile allows for customized and thus more effective therapies.
There’s no denying the emotional power of addressing the needs of families whose children suffer from conditions related to rare variants with a large effect. Notice, however, that it’s a retreat from the idea of a genomic biomedical revolution where, because all conditions would be linked back to their genetic basis, diseases could be better treated for everyone—for the population. That research on rare genetic variants that affect some members of some families could fuel genomics speaks again to the conflation of family and population.
The more recent tactical regrouping of genomics around the ideal of personalized medicine does not, however, escape lack of clarity about the distinct levels of family and population. The realm of personalized medicine is supposed to one in which knowledge of one’s particular and not-necessarily-common genetic profile allows for customized and thus more effective therapies. However, as I have discussed previously, genomics-based pharmaceutical research will generally depend on there being an advantage on average in some given population of a treatment—perhaps prophylatic—related to the effect of a genetic variant. At the same time, there will be variation of effects and responses to drug treatment around that average for the group or subpopulation who have the genetic variant. From this variation may emerge pressure to find ways to subdivide people who have the genetic variant into smaller subcategories so that the treatment can be made to fit each person better. Pharmaceutical companies, however, will not have an incentive to trim the potential market unless the side-effects of treatment for some people so outweigh the benefits or the treatment fails to help them and they push back strongly. In that case, negative publicity on those side-effects or failures could erode adoption of the drug even among those who might have benefited. In short, from the point of view of the pharmaceutical company, the pathway to personalized medicine goes through a phase in which carriers of the the genetic variant are treated according to the group they belong to. They may or may not be driven to move beyond that phase to a place where variation within the group or subpopulation are taken into account. Continued in next post.
McClellan J, King MC. Genetic heterogeneity in human disease. Cell. 2010 Apr 6;141(2):210-7. PubMed PMID: 20403315.