AS THE nurse inserts a wide-bore needle into the vein on my arm, I settle back and look forward to my juice and cookies. Like millions of people worldwide I am a blood donor. There is something different about my blood, though, that makes it highly sought after: it is overflowing with iron. In fact, if it were not for my regular blood donations, I would risk rusting to death.
I have a condition called iron overload, or haemochromatosis, which means that my body mistakenly thinks it lacks iron and absorbs too much from my diet. Initially the excess can be stored in organs such as the liver, but over time the metal builds up and damages other tissues, such as the joints, and can even cause cancer.
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Iron overload was once thought a very rare condition 鈥� a medical curiosity. But since the first genetic mutations for haemochromatosis were discovered in 1996, it has turned out to be much more common than we realised among those whose ancestors come from north or west Europe. The current estimate is that 1 in 200 of this population may have iron overload, but the real figure may be much higher as doctors do not often do the requisite tests and may put the symptoms down to other causes. When patients do get diagnosed, a surprising number turn out to have been conscientious blood donors, having unwittingly found a remedy for their aches and pains.
The most surprising finding, though, was that the number of people who carry a single haemochromatosis mutation and usually have just slightly raised iron levels is as high as 1 in 3 in some parts of Europe. Why are so many people walking around with these mutations, and why only in this part of the world?
My colleagues and I have developed a theory that iron overload mutations must have conferred some kind of benefit in our recent evolutionary past (Medical Hypotheses, vol 59, p 325). We believe the mutations may have been shaped by the most awesome selective force the European population has faced in recent history 鈥� the Black Death.
How could such a mutation offer a benefit? The explanation lies in its complex effects on the body, which we are still unravelling.
Haemochromatosis was probably first recorded in 1865 by the French doctor Armand Trousseau. He called it bronze diabetes, for the tanned appearance it can give the skin and because many patients have symptoms of diabetes from damage to the pancreas.
The mutations found in 1996 affect a protein called HFE, which is thought to help regulate iron absorption in gut cells. People with two copies of the most severe mutation, called C282Y, are usually at much higher risk of iron overload, and people with one usually have moderately raised iron, but levels are also affected by other HFE gene mutations, other genes, and iron in the diet.
Iron is essential for almost all forms of life. It also gives your blood its red colour; iron forms a part of haemoglobin, the pigment in red blood cells that transports oxygen round the body. Many enzymes, which catalyse metabolic reactions, also contain iron, because it is a very reactive element and so helps forge and break chemical bonds.
Most bacteria and fungi are desperate for iron, and their success at infecting us often directly relates to how much is available to them. So you might think that to bacteria, people with all that extra iron in their system, should act like, well, magnets.
Except they don鈥檛. Apart from those with severe late-stage iron overloading, most people with haemochromatosis mutations do not appear to be more prone to infections (with one or two rare exceptions). So what鈥檚 going on?
There seem to be several explanations, but so far the best-understood one concerns a type of cell called macrophages 鈥� the front-line soldiers of the immune system. Their job is to keep an eye out for infections and marshal other forces to head off the invaders. They also gobble up bacteria and destroy them, as well as absorbing any free iron they come across to keep bacteria or fungi from accessing it.
With that in mind the following might sound counter-intuitive. Macrophages from people with haemochromatosis mutations actually lack iron. The exact reasons are unclear, but the HFE protein is known to be present in macrophages so perhaps that plays a role in this unexpected twist.
Some human pathogens actually use macrophages as a sort of Trojan horse to get inside the body. They can multiply within macrophages, using the iron to get a leg up. Because the macrophages of people with iron overload lack iron, they should be relatively resistant to these bacteria, and those who carry one copy of the HFE mutation should lie somewhere in the middle in terms of resistance.
Current estimates pin the arrival of the C282Y mutation to some time around AD 800. So we were looking for a selection factor in the form of an infectious disease, preferably a bacterium that multiplies within macrophages, that has affected Europe some time in the past 1200 years.
Enter the Black Death. The most lethal known pandemic in history, it is thought to have burst onto the European scene in 1347 (although it may have made earlier less deadly forays). After arriving in Italy on a fleet of Genoese trading ships, the death march continued over the next few years. Somewhere between a third and a half of the population is thought to have succumbed.
鈥淚f the Black Death organism needed iron, people with the iron overload mutation would have had some protection鈥�
There were recurring outbreaks of what was probably the same disease in Europe until the 18th or 19th century, although it gradually lessoned in severity. This is usually put down to increasing resistance in the population or the microbe growing less virulent, or both.
The organism that is generally held responsible for the Black Death is the bacterium Yersinia pestis. This organism just so happens to be one of those that multiplies happily within macrophages 鈥� just as long as there is an ample supply of free iron.
Y. pestis can hijack the macrophages for a free ride to lymph nodes in places like the armpits and groin. There they escape, multiplying rapidly to form painful swellings, or buboes, that can burst through the skin; hence the name, bubonic plague. Spread through fleas on rodents such as rats, bubonic plague kills about a third of those infected.
If the bacterium is inhaled, it triggers a different form called pneumonic plague, which kills 9 out of 10 of its victims. If that鈥檚 not bad enough, it is even more contagious than the bubonic form as it can pass directly from human to human.
In the past few years, Susan Scott and Christopher Duncan, two epidemiologists from the University of Liverpool, have been championing the theory that the plagues of medieval Europe were caused not by Y. pestis, but something else, possibly even a virus (New 杏吧原创, 24 November 2001, p 34). They say the way the Black Death moved through Europe does not match modern-day bubonic plague: for example, it spread too fast, sometimes in the absence of rats.
Critics, however, point out that some of the infections may have been the pneumonic form, which spreads faster and from human to human. Plus, the original Black Death may have changed its characteristics over time.
Whether the guilty party was the Y. pestis we know today, an older form, or some other organism, there are two factors that suggest the Black Death played a big role in perpetuating the iron overload mutation. The first is that unlike most infectious agents, which tend to prey first on the very young and the old, an unusual feature of the plagues of medieval Europe was their preference for young adult men. Records show, for example, that in St Botolph鈥檚 parish in London in 1625, adult men between the ages of 15 and 44 dying of plague outnumbered women by two to one.
Why is that relevant? Because young men tend to have the highest iron levels. Women of child-bearing age lose iron through menstruation, pregnancy and breastfeeding. Children haven鈥檛 had time to build up good stores, and the elderly lack iron because they don鈥檛 absorb it well from their diet. If the Black Death organism needed iron, people with the iron overload mutation and hence low-iron macrophages would have had some protection.
The second reason is that some researchers think the Black Death and the later outbreaks hit north Europe hardest, possibly because the colder winters kept people crowded together indoors, thus helping to spread the infection. Today the C282Y mutation is more common in north-west Europe (see Map).
Our idea is not just supported by historical records. Another group of researchers, at the University of Cincinnati, recently showed that in the lab Mycobacterium tuberculosis, the bacterium responsible for TB, acquires iron less efficiently from the macrophages of people with haemochromatosis. This suggests that people with haemochromatosis mutations should be less vulnerable to TB.
Ideally, we would repeat this experiment using Y. pestis, or even better, see if an animal with the HFE mutation is less susceptible to infection. This may not be feasible, however, as research with the plague bacterium is highly restricted because of the possibility that it might escape the lab.
If it was not Y. pestis that shaped today鈥檚 distribution of people with iron overload, what did? The TB bacterium is thought to have caused up to 20 per cent of deaths in Europe between 1600 and 1900, so that is another suspect. Or it may have been the bacterium that causes typhoid fever, Salmonella typhi, which has killed countless numbers of people in European history. All three bacteria are particularly contagious in overcrowded living conditions and multiply within macrophages, using their iron. Perhaps more than one organism is to blame.
鈥淪omewhere between a third and a half of the European population is thought to have succumbed to the Black Death鈥�
Whichever bacteria are involved, it would not be the first time a harmful genetic mutation has been found to have a beneficial side (see 鈥淲hy we need disease鈥�). Perhaps the best-known case involves the mutations that cause sickle-cell anaemia, which give some protection against malaria. I believe that many genetic diseases may have been selected for as evolutionary compromises that helped human survival.
Perhaps I am more aware than most that evolution can dole out complicated blessings. At the blood clinic I feel that familiar sting as the nurse pulls the needle out of my arm. All bandaged up, and eating my cookies, I can鈥檛 help reflecting on my genetic heritage. It has its downsides, but it may be the reason that my ancestors survived, allowing me to be here in the first place. Looking at it like that, I鈥檒l take a bleeding any day.
This article was updated on 17 January 2019 with a new headline. The original headline was 鈥楽urvival of the sickest鈥�
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