How the most common disease you've never heard of is unearthing our evolutionary roots
An ambulance rushed Dr. Malcolm Casadaban to a Chicago emergency department with labored breathing and three days of fever, body aches, and cough. He died twelve hours later as heart, lungs, kidneys, and liver failed under the burden of overwhelming infection. Bacterial cultures of his blood eventually revealed the characteristic rods of Yersinia pestis. Somehow, the MIT-and Harvard-trained scientist died of septicemic plague -- the Black Death -- in Hyde Park, Chicago, in September of 2009.
Investigators soon learned that Casadaban studied this organism in his laboratory at the University of Chicago, but they could not explain how the bacterium bit the hand that cultured it. Remembered as "one of the most creative and influential geneticists of our time," during his career he furthered our understanding of science and disease. Unexpectedly, he continues to do so in death.
Autopsy revealed that Dr. Casadaban unknowingly suffered from hereditary hemochromatosis, a genetic disease leading to a toxic accumulation of iron in his organs. A modern manifestation of an ancient DNA mutation, this disorder can be traced to a single unknown ancestor who lived millennia ago. This mutation allowed her (or him) to more readily absorb iron from food, which may have unexpectedly aided survival in lean times -- possibly at the expense of iron-overload in later generations. We know little about the disease's founder, but we do know that she survived long enough to pass one copy of the gene to her children, and eventually, to nearly one in ten individuals of northern European ancestry.
The mutation's surprising frequency and peculiar fondness for those of Irish, British, and Scandanavian heritage offers a unique opportunity for scientists and historians to study how the world of our ancestors may have shaped the landscape of modern disease. Researchers look to DNA analysis to solve a lingering biohistorical puzzle: Is the hemochromatosis gene common because it is an unintended consequence of natural selection, or because it is a relatively fresh glitch in the human genome with little time to spread to other regions?
Out of this tradition of sickness rises a story of medical progress -- and uncertainty -- involving an atom, the wanderlust of ancient peoples, the appetite of a caveman, and a possible legacy of the Black Death. Casadaban's tragic death at the hands of an infamous microbe challenges a theory that the hemochromatosis gene became common because it protected its owners from the plague.
In this search for the origin of one of the world's most common genetic diseases, emerging research in evolutionary medicine raises new questions about our history, development, and future as a species.
As elements go, iron is a fickle and mischievous companion. Essential to life, yet impulsive, promiscuous, and destructive when allowed to roam unescorted, it poses a tremendous engineering challenge to human tissues.
Iron readily exchanges electrons with other elements. Indispensable to oxygen transport and metabolism, this property may also cause disease if iron participates in unsanctioned electron exchanges that produce free radicals -- an evanescent and particularly hot-blooded family of compounds that damage cells and DNA. As a result, all organisms dependent on iron -- from primitive bacteria to mammals -- go to great lengths to safely transport and store this potentially poisonous payload. Under normal conditions, this meticulously coordinated system functions beautifully. However, in those who absorb more iron than average, the extra influx eventually overwhelms this transport and storage system. Eventually, rogue iron escapes its minders and chemical mischief ensues.
In spite of its proclivity for drama, we owe our lives to this metal. In fact, its value and scarcity over the course of human evolution may be reflected in the body's selfish tendency to hold on to it. The kidneys and gut are much less fond of sodium, potassium, calcium, and magnesium, as we can easily excrete these metals when they accumulate in excess. We have no such way to rid ourselves of iron. Some believe this may be a thrifty adaptation to an ancient world where meat from the butcher or blood from the hospital weren't a short car ride away.
In 1865, Dr. Armand Trosseau described a previously unrecognized illness involving the peculiar triad of skin bronzing, cirrhosis, and diabetes. A French internist, Dr. Trosseau was a legendary diagnostician and educator. His name remains familiar to modern students of medicine, though not for this first case report of hemochromatosis. He is more famously associated with Trosseau's syndrome, a disorder of blood clotting found in patients with a lurking gastrointestinal cancer. Not long after giving the first lecture on hemochromatosis, Dr. Trosseau discovered a painful, pale, inflammatory rash on his own left leg, heralding an underlying blood clot. Ironically, it was the very phlegmasia alba dolens of his own eponymous syndrome. Shortly thereafter, he succumbed to gastric cancer -- having named, diagnosed, and suffered from its syndrome of inappropriate clotting. An ironic end for the first physician to study iron-overload.
Two decades later, the German pathologist Dr. Friedrich Daniel von Recklinghausen autopsied a series of patients dying of the mysterious "bronze diabetes." Mustachioed, bespectacled, and in dapper bow tie -- the very epitome of an academic pathologist, in the 19th or 21st century -- he appreciated that certain tissues were richly laden with iron deposits, prompting him to name the disorder hemochromatosis.
We now understand that years of unchecked iron absorption poison nearly every organ system --not just the liver, pancreas, and skin. The physician's challenge is to distinguish the initial symptoms of hemochromatosis -- which can include fatigue, arthritis, or erectile dysfunction in persons of middle age or older -- from common, unrelated mimics, before the irreversible consequences of organ failure occur: heart failure, massive hemorrhage, overwhelming infection, diabetic crises, liver failure, or cancer.
However, these outcomes are preventable. With prompt diagnosis and treatment, hemochromatosis patients can enjoy a normal lifespan. The remedy is simple, inexpensive, and a relic of the barber-surgeon: bloodletting.
The modern practice of therapeutic phlebotomy circumvents our inability to excrete excess iron. Every 500 milliliters of whole blood, roughly the size of a 16-ounce bottle of soda, contains up to 250 milligrams of iron. Patients generally begin with one phlebotomy session per week or two; it can take well over a year to normalize their iron levels. They must return a few times each year for maintenance therapy, as their small intestines stubbornly continue to absorb extra iron.
Nearly 150 years after Dr. Trosseau's initial report, researchers identified the genetic culprit: a mutated HFE gene encoding a tyrosine molecule instead of the intended cysteine at the 282nd position of the protein chain (a mutation abbreviated as C282Y by biochemists).
We are still exploring how this mutation ultimately causes hemochromatosis. A heterozygote, or carrier of a single copy of the C282Y mutation, will absorb slightly more iron than most. However, the patient will not absorb enough iron to develop the disease, as two defective copies of the gene are necessary. Afflicted individuals must inherit one mutated HFE gene from Mom and another mutated gene from Dad. But oddly enough, not all homozygotes, or those with two defective copies, will manifest the disease. For unknown reasons, only about 28 percent of male and 1 percent of female homozygotes will ever develop symptoms or organ damage. Iron loss through menstrual bleeding and childbirth may explain some of this gender discrepancy, but unfortunately at present, we have no way of predicting who will develop complications.
With 1 in 200 to 250 persons bearing the requisite double mutation, the C282Y form of hereditary hemochromatosis is among the most prevalent genetic diseases in the United States. Given its potentially fatal course, puzzling questions arise: why is a potentially dangerous mutation so common, and why does it favor people of Northern European descent?
Genetic analyses are answering historical questions and helping to distinguish whether natural selection or population isolation, or a combination thereof, propagated the European legacy of hemochromatosis. DNA testing shows that all individuals with this hemochromatosis gene descend from the same ancestor, and this may explain the geography of the disease.
If you randomly pluck two humans off Earth's surface and compare their genes, you would find they share, on average, 99.5 percent of the exact same DNA sequence, regardless of whether you are comparing Lou from the Bronx with Lucia from Brazil. This similarity reflects our recent common origin in Africa from the same small populations of ancestral humans; as a species, we have not been around long enough to grow different. On the time scale of evolution, we are the new kids on the block.
The vast majority of human genetic variation is neutral; it has no effect on an individual's ability to survive and have children. Our alleles, or individual genetic variants, are passed down to subsequent generations as we reproduce. It generally takes about one million years for one of these neutral alleles to "drift" through the population and become commonplace throughout the world.
However, some alleles become common over time as they help more individuals survive and reproduce: This is known as positive selection. Given our relative youth as a species, it can be challenging to distinguish whether a common allele is genuinely advantageous or neutral and still drifting. In hemochromatosis, both may be true.
Hemochromatosis, unlike many other hereditary disorders, is uniquely monopolized by one single defect: The C282Y mutation accounts for 80 to 90 percent of cases. Therefore, we suspect that all patients with this gene inherited it from the same distant ancestor. Known as a founder effect, this phenomenon may explain why the mutation is so common in Europe and North America and virtually unseen elsewhere: All persons carrying it belong to one large and relatively sheltered extended family that slowly dispersed through Europe, and eventually America, over the ages.
The genes surrounding the C282Y mutation bear other imprints of a founder effect. The clues lie in the genetic neighborhood, or haplotype, that encompasses the HFE gene on a strand of DNA.
Only a small handful of haplotypes carry the C282Y mutation; this can suggest that the disease-causing allele arose fairly recently and that there was insufficient time to spread the mutation throughout the population, as reshuffled maternal and paternal genes form new haplotypes in their offspring. However, natural selection can leave a similar footprint.
Haplotype analyses of hereditary hemochromatosis enable researchers to stalk the founder's identity and date of existence. The results are challenging popular conceptions of ancestry and ethnicity.
Given the surnames of the afflicted, physicians and patients long suspected that the "Celtic Curse" of hereditary hemochromatosis was an Irish export. However, in 1980, Marcel Simon proposed that the mutation arose in a central European population who carried the mutation to settlements in Ireland, Britain, France, and Iberia as they migrated west. This, too, would seem to explain the modern-day population distribution of hereditary iron overload. Yet its similar prevalence along the north Atlantic coast and Scandanavia more recently lead another group to propose another population of origin: Vikings.
Vikings emerged as wanderers -- and engines of alleleic dissemination -- in the late 8th century. In 793 AD, Norse raiders sacked the monastery on the English tidal island of Lindisfarne, igniting the Viking Age and an admixing of Scandanavian, Anglo-Saxon, and Celtic cultures. Norsemen later established settlements throughout the British Isles, including a stronghold at the mouth of the River Liffey now known as the city of Dublin. Trade, occupation, slavery, and intermarriage etched a Viking thumbprint into the native community, now reflected in modern English place and surnames ending in -thorp(e) or -by, or in words like "law," "husband," and "skull."
Advocates of the Viking theory argue that a Scandanavian founder better explains today's distribution of the C282Y allele along North Atlantic coastal areas, as Celts, unlike Norsemen, were not known for their seafaring ways.
In the midst of this debate, an elegant hypothesis emerged: a truly Celtic mutation exported from Ireland to Scandinavia aboard a Viking longship would appear on a greater number of haplotypes in Celtic lands than in Norse ones, as more time has passed for the mutation to spread throughout the Irish land of origin.
In a study comparing Irish and Swedish populations, researchers observed that the haplotype diversity in the two groups was actually identical. Provided the study was large enough, it suggests the culprit allele emerged prior to Celtic or Viking civilizations; perhaps the founder was a central European hunter-gatherer who followed melting ice sheets west and north to the Atlantic. His or her progeny now populate Scandanavia, France, the British Isles, and by immigration, the United States. If confirmed, this would further testify to our 99.5 percent genetic similarity and reinforce the lesson that modern perceptions of political, familial, even racial identities are constructs of culture more than biology.
But could factors other than geography and population migration explain the distribution of the disease? Many believe that the C282Y mutation and surrounding haplotype spread by natural selection: a single copy of the mutant allele may thwart iron deficiency or disease.