Editing and disrupting the MC1R gene can give your future child a shock of bright red hair. But disrupting this gene can also dispose you to a higher risk for melanoma. There are several genetic variants that are “risk factors” and provide a strong predisposition to disease, such as the e4 variant of the APOE gene, which increases risk for Alzheimer’s disease. But the e4 allele exists at about a 25 percent frequency in the population, a surprisingly high frequency for a genetic variant which is perceived to be so risky. The reason that nature has not selected against it, may in part be explained by the fact that e4 helps in maintaining higher levels of Vitamin D, which many adults have trouble getting enough of from sunshine in northern climates – my doctor recently told me to take Vitamin D supplements, for instance. Few genetic variants are completely harmful or beneficial in all people, and most come with evolutionary trade-offs. Higher expression of the gene PCSK9 degrades a receptor called LDLR and increases bioavailable LDL “bad cholesterol,” thus contributing to a heightened risk of a cardiac event and ischemic stroke. Drug makers are therefore pursuing drugs that can disrupt the expression of PCSK9 and sell PCSK9 inhibitors. In the summer of 2017, a drug named Inclisiran had just completed a Phase 2 trial. It makes use of RNA interference to disable the RNA molecule of the gene, preventing it from turning into a protein. The downstream effect of inhibiting the product of the PCSK9 gene in the cell is a reduction of LDL cholesterol. Of course, the next best thing might be to use CRISPR-Cas9 to disable the DNA of the PCSK9 gene. But we don’t know if disrupting this gene to lower cholesterol will contribute to strong health benefits in the long term for most people. It’s an open question. In fact, it turns out that genetic variants that contribute to elevated levels of PCSK9 have even been described to be under positive selection, suggesting, ironically, that raising
the levels of this gene product may have some beneficial effect. In evolution, nothing comes for free. In fact, having LDL that is too low can contribute to heightened risk for another kind of stroke, hemorrhagic stroke. Such trade-offs mean scientists rarely best evolution. Problems for drug-makers don’t stop there. In the spring of 2017, in The New England Journal of Medicine, Pfizer reported that of 30,000 patients taking their PCSK9 inhibitor in a trial it had stopped responding to it. Pfizer had invested billions but pulled the drug from the trial. PCSK9 inhibitors are often monoclonal antibodies that target the product of the gene, but those antibodies can themselves provoke immune system reactions. Steve Danehy, a Pfizer spokesman, told The New York Times that up to 87 percent of patients taking monoclonal antibodies will develop antibodies of their own that block the drug. Scientists might want to deactivate PCSK9 with a gene modification system such as Crispr-Cas9, but Cas9 is a foreign protein that can also elicit an immune reaction. A genetic variant may confer a risk for one type of phenotypic effect, but often may provide another genetic advantage. Genetic variants in a gene that cause people to have sickle cell disease also provide protection against mosquito-borne malaria, and thus, many people in sub-Saharan Africa have at least one copy of the gene variant for sickle cell disease, since it also protects against malaria. Similar tradeoffs are probably in play in regard to the larger brains that provide us with deep memories and higher order intelligence, but also dispose us to a higher risk for psychiatric disorders or neurodegeneration. Myelination is a coating on the axons and improves the speed of synaptic connections between neurons, and it turns out that “late myelinating regions” of the evolutionarily newer parts of the brain, which receive these sheaths later in life are also those that break down the soonest and put us at risk for neurodegenerative disorders due to their high metal content.