Saved by the Black Death?

O’Brien studies evolution in search of a different sort of weapon against HIV. Humans have evolved in response to parasites in the past, and it’s possible that some of those adaptations may be protecting some people from HIV today.

Since 1985 O’Brien has collected samples of blood from people who are at high risk for being exposed to HIV, such as homosexuals and intravenous drug users. He analyzed their DNA, comparing the genes of people who have become infected with HIV to those who haven’t, in the hopes of finding mutations that might defend humans against the virus.

By the mid‑1990s, after collecting more than 10,000 samples, O’Brien and his team were starting to flag. “We were beginning to lose our enthusiasm. We went through several hundred genes, one after another, and every one of them gave the same answer–that there was no effect” But in 1996 that finally changed. In that year, several different teams of scientists discovered that in order to enter a white blood cell, HIV has to pry open a receptor on the cell’s surface called CCR5. O’Brien’s team turned back to their thousands of samples and looked for mutations to the gene that makes the CCR5 receptor.

“We were stunned,” says O’Brien. They came across a mutation to CCR5: some people were missing a 32‑base section of the gene. The mutation ruined the protein that the CCR5 gene is supposed to create.

As a result, people who carry two copies of the mutant CCR5 gene have no CCR5 receptors on the surface of their cells (people who carry only one mutant copy of the gene have fewer receptors than average). O’Brien discovered a striking correlation between the mutation and HIV infection: people who carried two copies of the mutant CCR5 gene almost never became infected. “It was the first serious genetic effect we were able to discover,” says O’Brien, “and it was a big one.

Without CCR5 receptors, HIV’s doorway into white blood cells is bricked up. As a result, people who carry two mutant copies of CCR5 can be repeatedly exposed to HIV and yet resist it completely. Those who carry only a single copy of the mutant gene make fewer CCR5 receptors than normal; while they may get infected by HIV, the mutation slows down the onset of full‑blown AIDS for two or three years.

O’Brien’s team was also surprised to see who carries the CCR5 mutation. It is relatively common in Europe, with 20 percent of the population carrying one or two copies. It’s most common of all in Sweden, and as you move towards southeast Europe, the frequency of carriers tapers off. Only a small fraction of Greeks carry it; an even smaller number of Central Asians do. From the rest of the world, this particular mutation is missing altogether.

The only way the CCR5 mutation could have reached such high levels was if it was somehow valuable to the ancestors of northern Europeans and had been favored by natural selection. “It would have been a breathtaking selective pressure,” says O’Brien, “and the only thing that would fit would be some infectious disease epidemic that was killing off thousands, if not millions, of individuals, and favoring those who carried it.”

Whatever sort of event favored the gene among Europeans happened 700 years ago, according to O’Brien. He was able to determine its age by examining the DNA that surrounds the CCR5 mutation. Over time, variations have emerged, and O’Brien used that variability to estimate how long ago the gene arose. And it turns out that 700 years ago, something was putting Europe under massive natural selection: the Black Death.

The Black Death, which claimed over a quarter of all Europeans between 1347 and 1350, was only the most deadly of a long string of epidemics of bubonic plague that struck the continent for centuries. The plague acted like a human pesticide: any mutations that could help Europeans survive would become far more common in later generations. O’Brien suspects that CCR5 was just such a fortunate mutation, and with each plague outbreak its frequency ratcheted upward.

The bubonic plague is caused by Yersinia pestis, a bacterium that can live inside rats and spread to humans through the bite of a flea. Like HIV, Yersinia binds to white blood cells. Rather than invade the cells, it injects toxins into the cells to stun the immune system, allowing the bacteria to multiply without being attacked. No one knows exactly how Yersinia binds to white blood cells. O’Brien and his team are finding out. If his hypothesis is right, Yersinia needs to use CCR5. Europeans who were born without CCR5, he proposes, were protected during the Black Death; today, some of their descendants are protected from HIV.

If the CCR5 mutation does provide resistance to bubonic plague, it might turn out to be an extraordinary exaptation. Thanks to the gruesome natural selection of the Black Death, some Europeans may now be protected from a virus that depends on the same cell receptors. The fact that the AIDS epidemic has been far more destructive in Africa and Southeast Asia than in Europe or the United States might be due in part to the different evolutionary histories of the continents. O’Brien hopes that ultimately the benefits of the CCR5 mutation can be translated into a treatment for HIV. If medical researchers can invent a drug that can block normal CCR5 receptors, they may make people immune from HIV without causing dangerous side effects.

Even if the evolutionary research of scientists like O’Brien and Hahn should lead to a cure for AIDS, there may be many more new diseases to grapple with in the future. The AIDS epidemic came about as nine different primate lentiviruses leaped from primates to humans. There are 24 other known primate lentiviruses, all related to HIV, that may be poised to make the jump as well. The modern world, with its frustrating mix of wealth and poverty, of intercontinental airplane flights and secondhand needles, is primed for their entry.

Plague Tamers

With so many diseases emerging, doctors may have to try a new way of controlling parasites: by taming them. When a disease‑causing parasite invades a host, it faces a trade‑off. On the one hand, it can breed like mad in a person’s body, feeding on its host’s tissues and spewing poisons until its host dies. While it may make many trillions of copies of itself in the process, it may risk extinction if it kills its host before it can infect a new one. On the other hand, a parasite might take a much gentler approach, multiplying so slowly that its hosts don’t even realize that they are sick. It may have a much better chance of spreading on a fork or a handshake, because it keeps its hosts alive long enough to transmit it. But if it lives alongside a more aggressive strain that can also breed faster, it may get outcompeted and driven to extinction.

Paul Ewald, a biologist at Amherst College, has been exploring how different parasites negotiate these trade‑offs. As a rule, he finds that if a parasite depends on a mobile host to get transmitted, it will be gentle. Rhinoviruses, which cause colds, can be transmitted only by sneezes or skin contact, so they depend on healthy hosts who can mingle with other people. “So, not surprisingly, the rhinovirus is one of the mildest viruses that we know about” says Ewald. “In fact, nobody has ever been known to die from a rhinovirus, and that’s not true for almost any other disease organism of humans.”

On the other hand, if a parasite doesn’t depend on the health of its host to get to a new one, it can afford to be more vicious. Malaria, for example, uses mosquitoes as its ferry, and its brutal fevers often leave its victims bedridden.

Not every pathogen follows this rule, Ewald points out. Smallpox, for example, has no vector like a mosquito to carry it to a new host, so it has to find new hosts on its own. And yet it is one of the most lethal diseases known. It can afford to be virulent because, unlike cold viruses and other benign diseases, it can survive outside a host for a decade, waiting for a person to pick it up. When it does get into a new host, it breeds madly until the host dies, and then waits for its next chance.

All of these parasites are continually evolving in response to their surroundings, and Ewald has predicted that if it becomes easier or harder for parasites to spread, they will adapt. He has tested his prediction with several different diseases, including cholera. Cholera spreads by releasing toxins that give its hosts diarrhea, allowing it to escape their body. Another person may then pick up the bacteria in a bathroom, handle some food, and infect someone else. On the other hand, cholera can also spread if sewage contaminates supplies of drinking water. The first route depends on a healthy host that can come into contact with other people; the second depends only on bad water supplies. According to Ewald’s theory, cholera should evolve to be more toxic in places where the water supply is contaminated.

That’s exactly what Ewald found during a 1991 cholera outbreak in South America. “Cholera came into Peru and then quickly, within a couple of years, spread all throughout South and Central America,” he explains. “When the organism invaded countries with clean water supplies, it dropped in its harmfulness.” In Chile, a country with clean water, it evolved into a mild form; in Ecuador, where water supplies are much worse, it became more dangerous.

Instead of eradicating diseases, Ewald argues, we may have more luck trying to domesticate them. It wouldn’t be the first time we’ve domesticated natural enemies. “Wolves have been harmful to us throughout our evolutionary history,” says Ewald, “but we’ve been living with some wolves which have evolved into dogs. Instead of harming us, they now actually help us. I think we can do the same thing with these disease organisms.”

Domesticating parasites is not as hard as it may sound. To domesticate Plasmodium, the parasite that causes malaria, people may need only to put screens in their windows. Unable to sail through open windows, the mosquitoes that transmit Plasmodium cannot bite as many people in a given night, slowing down the transmission rate. If a strain of Plasmodium is adapted to kill its hosts quickly, window screens will put it at an evolutionary disadvantage, because its hosts will die before it can infect someone else. Gentler strains will outcompete the harsher ones, and fewer people will die of malaria.

When it comes to disease, evolution has been working against us for millennia. It’s about time we harnessed its powers.

Ten

Passion’s Logic