The Gene: An Intimate History - Siddhartha Mukherjee Page 0,122

instance, is regulated through a variety of genetic circuits, and abnormalities in one or many of these circuits all result in the same disease—hypertension. It is perfectly accurate to say “hypertension is a genetic disease,” but to also add, “There is no gene for hypertension.” Many genes tug and push the pressure of blood in the body, like a tangle of strings controlling a puppet’s arms. If you change the length of any of these individual strings, you change the configuration of the puppet.

McKusick’s third insight concerned the “penetrance” and “expressivity” of genes in human diseases. Fruit fly geneticists and worm biologists had discovered that certain genes only become actualized into phenotypes depending upon environmental triggers or random chance. A gene that causes facets to appear in the fruit fly eye, for instance, is temperature dependent. Another gene variant changes the morphology of a worm’s intestine—but only does so in about 20 percent of worms. “Incomplete penetrance” meant that even if a mutation was present in the genome, its capacity to penetrate into a physical or morphological feature was not always complete.

McKusick found several examples of incomplete penetrance in human diseases. For some disorders, such as Tay-Sachs disease, penetrance was largely complete: the inheritance of the gene mutation virtually guaranteed the development of the disease. But for other human diseases, the actual effect of a gene on the disorder was more complex. In breast cancer, as we shall later learn, inheritance of the mutant BRCA1 gene increases the risk of breast cancer dramatically—but not all women with the mutation will develop breast cancer, and different mutations in that gene have different levels of penetrance. Hemophilia, the bleeding disorder, is clearly the result of a genetic abnormality, but the extent to which a patient with hemophilia experiences bleeding episodes varies widely. Some have monthly life-threatening bleeds, while others rarely bleed at all.

The fourth insight is so pivotal to this story that I have separated it from the others. Like the fly geneticist Theodosius Dobzhansky, McKusick understood that mutations are just variations. The statement sounds like a bland truism, but it conveys an essential and profound truth. A mutation, McKusick realized, is a statistical entity, not a pathological or moral one. A mutation doesn’t imply disease, nor does it specify a gain or loss of function. In a formal sense, a mutation is defined only by its deviation from the norm (the opposite of “mutant” is not “normal” but “wild type”—i.e., the type or variant found more commonly in the wild). A mutation is thus a statistical, rather than normative, concept. A tall man parachuted into a nation of dwarfs is a mutant, as is a blond child born in a country of brunettes—and both are “mutants” in precisely the same sense that a boy with Marfan syndrome is a mutant among non-Marfan, i.e., “normal,” children.

By itself, then, a mutant, or a mutation, can provide no real information about a disease or disorder. The definition of disease rests, rather, on the specific disabilities caused by an incongruity between an individual’s genetic endowment and his or her current environment—between a mutation, the circumstances of a person’s existence, and his or her goals for survival or success. It is not mutation that ultimately causes disease, but mismatch.

The mismatch can be severe and debilitating—and in such cases, the disease becomes identical to the disability. A child with the fiercest variant of autism who spends his days rocking monotonously in a corner, or scratching his skin into ulcers, possesses an unfortunate genetic endowment that is mismatched to nearly any environment or any goals. But another child with a different—and rarer—variant of autism may be functional in most situations, and possibly hyperfunctional in some (a chess game, say, or a memory contest). His illness is situational; it lies more evidently in the incongruity of his specific genotype and his specific circumstances. Even the nature of the “mismatch” is mutable: since the environment is constantly subject to change, the definition of disease has to change with it. In the land of the blind, the sighted man is king. But flood that land with a toxic, blinding light—and the kingdom reverts to the blind.

McKusick’s belief in this paradigm—the focus on disability rather than abnormalcy—was actualized in the treatment of patients in his clinic. Patients with dwarfism, for instance, were treated by an interdisciplinary team of genetic counselors, neurologists, orthopedic surgeons, nurses, and psychiatrists trained to focus on specific disabilities of persons with short stature. Surgical interventions were reserved to