If these efforts succeed, they could revolutionize the nature of drug discovery and medical treatment. In the ultimate manifestation of this technological dream, no hypothesis of disease causation is necessary. Medical researchers need not speculate first about what biochemical pathways are involved or what proteins are at fault, which is the laborious way that medicine now makes progress. Instead, they would simply compare databases of genetic samples and disease records, employing computerized data-mining operations to find the causative genes and gene variations at work. Pinpoint the genes that predispose individuals to disease and you have a clue to what disease mechanisms are at work and how to prevent or repair them.The same kind of research would also provide clues to what your own medical future has in store for you-what afflictions are more or less likely to do you in; what treatments, pharmaceuticals or preventive measures will most likely ward off disease or cure it; and perhaps even how you personally should lead your life to maximize the chance of surviving to a ripe old age. Are you genetically predestined, for instance, to fall dead of heart attack in your 50s or fade slowly away with heart failure in your 90s? Will breast cancer or Alzheimer’s be your fate? Schizophrenia or depression? Diabetes?
This endeavor is what Stanford University geneticist Neil Risch, for one, calls “the endgame of human genetics.” Certainly it is the best shot of geneticists to identify the genes at play in the common ills of mankind. Should it work, it “will herald a new era of information-based targeted care, in which genetic profiling will identify the disease predisposition risks faced by individuals and, if disease occurs, will make it possible to tailor therapy based on individual patient needs,” wrote George Poste, former chief scientist for SmithKline Beecham (now GlaxoSmithKline), in the journal Nature. And even if it doesn’t achieve such lofty goals, it may still provide new understanding of the nature of common chronic disease.
In the jargon of genetics, the search for disease-causing genes is a search for the genotype that explains the phenotype. Genotype is the individual variations in the three billion base pairs of DNA and the tens of thousands of genes we all share; it’s our actual genetic makeup. Phenotype is how that DNA physically manifests itself-in this case, as the susceptibility to disease, or the progression of disease, or the susceptibility of the disease itself to treatment, all of which likely have a genetic component. Genotype goes into a black box of human biology and phenotype comes out. Occasionally this connection is excruciatingly deterministic, as it is, for instance, with Huntington’s disease or cystic fibrosis, in which a single mutation in a single gene means you have the disease or will get the disease. In the vast majority of human ailments, however, the connection is excruciatingly vague-as it is with personality or intelligence or athletic excellence or any other complex trait. When geneticists use the word “complex,” they mean that more than one gene is responsible for an individual’s condition, and probably quite a few.
The challenge for the geneticist is, depending on how you look at it, a signal-to-noise problem or a needle-in-a-haystack problem. With tens of thousands of genes in the haystack of the human genome, how do you identify those one or two or 10 that play a role in any particular disease?
This is where large families come in handy. Because all the members share a common genetic inheritance, it’s highly likely that any disease that runs in the family is caused by the very same genes and the very same mutations slipped into the family gene pool by a distant ancestor. If you can find a few hundred family members with the disease and a few hundred without, you can be pretty confident that eventually you’ll find the mutation that is present in the DNA of the afflicted members and absent from the DNA of the healthy ones. For researchers, this is much simpler than the situation where the afflicted are unrelated, since in that case the genetic causes may also be unrelated, and the overall variation in the DNA so bewildering that the signal from any disease-causing genes is overwhelmed by the background noise of genetic variation.