(R)evolutionary Rheumatology

I spent most of my senior year in college in the basement of the science building, in a room the size of a closet, watching (and videotaping) fish having sex. I was studying pipefish, a relative of the seahorse in which the males get pregnant. I was interested in learning how this unusual quirk of evolution affected the sex roles of the fish, asking questions such as: which sex is more promiscuous, bigger, and more aggressive? Evolution was at the heart of my biology major, and its existence was palpable in every biology class I took—from Genetics sophomore year to a senior seminar on Ecology. It was clear during my undergraduate education that “nothing in biology makes sense except in the light of evolution.”

So It surprised me that the topic of evolution was never adequately addressed during my medical school, residency, or rheumatology fellowship. As if, in the study of medicine, humans no longer obeyed the rules followed by the rest of the animal kingdom. After millions of years of evolution, I wondered why we didn’t evolve stronger and smarter immune systems, protecting us from malaria and the flu while avoiding autoimmunity? I was interested not only in learning about health and disease but in understanding why diseases exist in the first place.

During my pediatric rheumatology fellowship, I developed a clinical interest in autoinflammatory diseases. More accurately, the interest was forced upon me during a Passover Seder, when a distant relative asked me to write a review for pediatricians about this group of illnesses. I didn’t know whether to receive this assignment as a blessing or a plague, but it eventually opened a sea of opportunities and helped to carve a career path for me.

I quickly became fascinated by Familial Mediterranean Fever (FMF), a syndrome that causes self-limiting, recurrent episodes of fever, serositis, arthritis, and rash due to mutations in MEFV, a gene that codes for the protein pyrin. Untreated, FMF can lead to amyloidosis and death. Despite the severity of the disease, the prevalence of mutations in MEFV can be as high as 1 in 3 in some populations. In fact, it seems that mutations in MEFV have developed independently, at various times in history, in multiple locations, and may actually have been selected for.

But how could a disease mutation persist with such a high frequency in several populations? A recent study in Nature provides us with some clues: pyrin was found to be an intracellular sensor that detects bacterial toxins such as those from Clostridium difficile. It is hypothesized that people with mutations in pyrin may have had an evolutionary advantage by being better able to combat infections prevalent along the Mediterranean despite the potential harm caused by autoinflammation, similar to the protection of sickle cell trait against malaria.

Trade-offs such as these are common in our evolutionary history. We and every organism on earth are not “machines whose designs have been optimized. Instead, we are bundles of compromises shaped by natural selection to maximize reproduction, not health.” Therefore, evolutionary pressures have to work under specific constraints, making trade-offs along the way. For instance, when early humans became bipedal, they did not acquire a new body optimally designed to stand upright but adapted the body of their four-legged ancestors. With that change came many of the problems we see today including hernias, herniated disks, and hip and knee osteoarthritis.

During my adult rheumatology fellowship, I began seeing a lot of patients with rheumatoid arthritis (RA), a condition with significant morbidity and disability if left untreated. Recent studies have linked the development of RA to the citrullination of peptides in the mouth by Porphyromonas gingivalis, leading to the formation of antibodies which may cross-react with epitopes on the joints. Many other diseases in rheumatology are known or suspected to be linked to pathogens such as polyarteritis nodosa (hepatitis B), cryoglobulinemic vasculitis (hepatitis C), Lyme disease (Borrelia burgderfori), and giant cell arteritis (varicella zoster), to name just a few. But why did evolution leave us so vulnerable to infections?

The problem is that we are not the only ones evolving; pathogens are evolving as well, much faster and more efficiently than we are. Thus, when we develop new defenses against pathogens (through adaptations of our immune systems or with the synthesis of new antimicrobial agents in the lab), they are under enormous evolutionary pressures to circumvent our defenses. This never-ending arms race explains why we get sick with the common cold and other infections.

Finally, we need to turn our attention to the Disease of Kings. Until relatively recently, it was not possible for humans to eat a high-purine diet, wash it down with a beer, and top it off with an ice cream sundae. Western diets put our bodies under stress that they never were designed to handle, leading to hyperuricemia and gout. Disease occurs when the environment in which we spent most of our evolutionary life differs significantly from the stuff that surrounds us today.

But the story of gout is more complicated, also reflecting trade-offs and compromises. Most organisms have uricase, the enzyme that converts uric acid to allantoin, a readily soluble compound. Several million years ago, the gene for uricase was turned off in early humans and in several of our close relatives. Uric acid is a powerful antioxidant and scavenger of oxygen radicals, and it may have protected our developing brain from these toxins. Uric acid may have helped us to maintain our blood pressure and perfusion to the brain once we became bipedal. Could we be harming patients by lowering uric acid levels beyond a certain point?

Throughout millions of years of evolution, the human body and mind have developed remarkable features that allow us to think, compose symphonies, dunk a basketball, and apply for grants. Unfortunately, evolution has been unable to provide us with a disease-free existence—it has focused its energies on enhancing our ability to reproduce. Trade-offs and constraints, the never-ending arms race with pathogens, and the mismatch between our current environment and that in which we evolved are responsible for most of the diseases that affect us today. Application of evolutionary medicine to rheumatology may provide us with a better understanding of disease and provide opportunities for novel treatments in the future.


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