Nature v. Nurture

CHW LogoThe mention of funding for additional research in “precision medicine” attracted applause from both sides of the aisle in a State of the Union address that was notably thin in bipartisan appeal.  But it was hard for me to bring my hands together over the concept.  When I hear about the promise of the “genetic revolution,” I think of Carly (not her real name).  I took care of Carly, an 8 year old with sickle cell disease, a few years ago when she came to the emergency department with a massive stroke.

In medical school, in 1983, a professor told us with great authority that within 15 years, sickle cell disease would be an historical relic.  Because it was known to be caused by a single mutation coding for a single amino acid in the hemoglobin molecule, it was an obvious target for the emerging field of gene therapy – it would be the simplest genetic disease to cure.  If that professor had been correct, Carly wouldn’t have sickle cell disease, much less a crippling stroke.  I think everyone knows that sickle cell disease is still very much with us.  Carly’s family certainly does.

Now, I know “precision medicine” isn’t about gene therapy.  As described by the White House, the initiative is designed to “provide clinicians with new tools, knowledge, and therapies to select which treatments will work best for which patients.”  The concept is appealing.  Therapies have different effects on people depending on their genetics.  Rather than a “one size fits all” approach, drugs can be targeted to people whose genetics suggest they would be more likely to benefit, and dosages can be adjusted according to genetic differences in metabolism.

But as Mayo clinic anesthesiologist and physiologist Michael Joyner points out in a recent New York Times op-ed, it’s never quite as simple as it seems.  First, most diseases, and certainly the most common ones, turn out to be genetically very complex.  In sickle cell disease, 100% of the risk is associated with a single gene mutation.  For most conditions studied so far – diabetes, heart disease, autism – multiple genes account for at most a few percent of the variability.  Environment and behavior remain far stronger risk factors.  And of course there is an interplay between genes, environment, and behavior that increases the complexity further.

Another “straightforward” example provides further caution.  Metabolism of many drugs is affected by a genetic variants in the cytochrome p450 complex.  The presence of certain alleles alters drug metabolism in predictable ways.  Knowing a patient’s cytochrome p450 alleles should allow a clinician to adjust drug dosages without the need for trial and error – giving more to people known to metabolize more readily, or less to those who are slow metabolizers –  potentially maximizing benefit while avoiding toxicity.  Warfarin (Coumadin®), an anticoagulant commonly prescribed to prevent blood clots in patients with a variety of heart and other conditions, is one of the drugs metabolized in this way.  Moreover, it has a narrow therapeutic index, meaning there is a relatively small zone of appropriate dosages: too little is ineffective, too much is dangerous.    The usual way to find the sweet spot is to start with a given dose and monitor blood tests to check clotting, making frequent adjustments until the desired effect  if achieved.  This can take many weeks, during which time the patient is at risk for either blood clots or excessive bleeding if the dose is too low or too high.  And people can vary in the necessary dosage by a factor of almost 20, in large part due to known variants in the p450 genes.  So when these variants were identified, it was appealing to think that prescribing based on knowing a patient’s p450 genotype would be safer and more effective.  There was a lot of hype about the coming “pharmacogenetic revolution,” and in 2010, the FDA actually changed the labeling on warfarin to recommend that  physicians choose the dose based on p450 genotype.

They appear to have jumped the gun.  A recent study, a meta-analysis of 9 clinical trials comparing genotype-based dosing of warfarin with standard “trial and error,” found no advantage to the “precision” approach in terms of any laboratory or clinical outcomes.

No doubt as our understanding of disease improves, we will be able to target treatments more effectively.  Some things we consider a single condition will turn out to be a cluster of many different conditions, based at least on part on genetic differences, each with a different optimal treatment.  Cancer chemotherapy is already a step in this direction.  But we shouldn’t get overly distracted by this latest shiny object.  The more we learn about the human genome, the more we realize that external factors – environment and behavior – remain the primary determinants of disease and the keys to prevention.  The single biggest advance in the 40+ year “war on cancer” has not come from the lab; it was the reduction in smoking.

Diet, exercise, and other behavioral and environmental factors aren’t very sexy, and they are not the stuff on which academic careers are built, but in the end they are what will make us healthier.  We can’t let the allure of precision medicine threaten support for these mundane but proven strategies.  Gene therapy sounded pretty cool, but it didn’t help Carly.

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