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A Unified Theory of Complex Disease

An added quirk is that there likely are mechanisms that ensure that as few individuals as possible exceed the threshold, even when they have more than their fair share of the risky alleles. This phenomenon is known as canalization. It says that not only do species evolve so that most individuals resemble one another, but they have also evolved buffering that ensures that everyone is “normal” despite the slings and arrows of outrageous fortune that life throws at them.

Next time you trap a mouse, count the number of whiskers: Almost certainly there will be 17 or 18 on each side of the snout. Actually, my dogs also have this number of whiskers, but that may just be coincidence. This number of whiskers is very stable, unless the mouse happens to have a Tabby mutation, in which case on average it will only have a dozen or so whiskers. The catch is that the “or so” can be as few as 7 and as many as 20. Observations such as this are often seen when developmental circumstances are perturbed. Not only does the average appearance change, but it also becomes much more variable.

It seems than that normal buffering mechanisms fall apart when the genetic system is pushed too far away from the optimum. Translated into the realm of disease, the idea is that the modern environment that humans have constructed has taken us out of the buffering zone, and left us more susceptible to perturbations that result in disease. It is, however, much easier to describe what canalization is than the mechanisms that produce it. This is partly because we don’t really understand the mechanisms, and partly because they are usually addressed in mathematical and statistical equations.

The essence of these equations is that stability arises through the deeply interconnected web of interactions among genes. If I were to give you 100 pieces of string and ask you to make a carrying bag, the simplest thing you could do would be to tie them all together at both ends, resulting in a sling. This would be fine for carrying around tennis balls, but somewhat disappointing if you tried to use it to carry your loose change. A slight improvement would be to divide the strings into two groups, and lay two slings perpendicular to one another. If you had time, you could weave the strings into a cross-hatching cloth, and by adding reinforcing strings at different angles you could make this web even stronger. Such a cloth would be able to hold heavy objects that distort it and to absorb breaks in a few of the strings.

Genetic networks are similarly structured as interacting linkages that together form a tighter, more coherent whole than would be produced simply by adding together bits and pieces. But the whole inevitably has holes, particularly when stressed, and these holes lead to disease.

Now think about some recipe you used to love to make as a child. Let’s say your favorite ham and cheese omelet, or if you were unusually adept in the kitchen, a soufflé. When you were a child, you probably stuck pretty close to the recipe, knowing that so long as you balanced the amount of ham and cheese you added, the omelet would turn out nicely. Then you went away to college and went through a phase of not eating breakfast or stopping for a McBiscuit on the way to work, and now you’ve forgotten the exact recipe. You think you have it right, but every other time you make one, the kids get a pained look on their faces and spit it out. There’s probably something wrong with the number of eggs you are using or the amount of milk. Or maybe it is because you are using an electric stove instead of gas, or the eggs where you live now are a different size than those where you grew up. It’s frustrating, but you just can’t recapture the magic of the old combination.

In this metaphor for the origins of complex disease, the recipe stands for the genetic program for healthy development, growing up and changing the recipe stands for genetic evolution, and switching cooktops stands for environmental change. The key is that tens of millions of years of genetic evolution devised canalized systems for regulating the amount of glucose in our blood; the balance of immune response to bacteria, viruses, and parasites; and the way the chemicals signal in the brain. These systems were well able to absorb normal fluctuations, without exposing too many individuals to disease. But humans are an incredibly young and rapidly evolved species, and we have completely changed our environment in the past century. This pushes us—as well as many of our domesticated companion animals that get similar diseases—out of the buffered zone, exposing genetic variation that may never have had an effect in the past.

So while it is convenient to assume that humans are close to some optimal design, we have not actually been around for long enough to allow the genome to make fine adjustments that ensure that most people are buffered from disease. Humans are without a doubt a long way from any such equilibrium. We shared a common ancestor with chimpanzees just five million years ago, and with Homo erectus cavemen just a million years ago. As a species, Homo sapiens has been in existence for just 140,000 years, somewhere around just 10,000 generations. The flies sitting on the fruit salad at your barbecue have likely been around as a species for 100 times as many generations.

Perhaps it wouldn’t matter so much, except that we’re also a really, really different species in so many ways. We’re just beginning to explore our novel world. From the Arctic to the Antilles, and from Newfoundland to New York, humans are re-creating their niche, putting pressure on the gene pool to deal with all kinds of extremes. We live longer than our close ancestors, consume strange diets, walk upright with a funny pelvis, have babies with big heads, share our homes with a menagerie of animals, and cope with really complex social settings. If you feel stressed at times, imagine things from the perspective of the genes that helped us get here.

The point is that recent human evolution has required substantial changes in our genetic makeup, disrupting genetic relationships that had evolved over millions of years. These changes have left us exposed. Like an adolescent still growing up and trying to come to terms with a constantly changing world, we’re just a little uncomfortable with who we are. Presumably we’ll get to a more comfortable genetic place, but not for a few more hundred thousand generations.

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