CCR5 Delta32 Gene's Black Death & AIDS Mystery

CCR5 Delta32 Gene's Black Death & AIDS Mystery

PBS: Secrets of the Dead

Frequencies of the CCR5 allele

EPIDEMIOLOGICAL STUDIES OF PERSONS WITH THE CCR5 DELTA-32 MUTATION

The delta-32 mutation of the CCR5 receptor gene is present in up to 20% of the white population worldwide.8 Persons who have 2 copies of this mutant gene have been shown to be highly resistant to HIV infection; those with a single copy can be infected but experience an attenuated course of disease.9
-- The AIDS Reader

Plaque commemorating Black Plague

CCR5: Evolving hypotheses

When the CCR5-delta32 mutation was first discovered — and when its restriction to European populations was identified — scientists hypothesized that the mutation had been favored because it offered resistance to an intense epidemic largely restricted to Europe: the bubonic plague pandemic of the Middle Ages. However, when scientists studied ancient DNA from 2900-year-old skeletal remains, they found that the mutation was common in European populations long before the plague epidemics. Further research and several lines of evidence suggested that smallpox may have been the more likely culprit. New research has offered yet another hypothesis. The genetic variation associated with the mutation is similar to the genetic variation associated with neutral mutants. Perhaps, the CCR5 mutant drifted to high frequencies in Europe through nothing more than luck. Researchers continue to investigate the possibilities — but meanwhile, there is little doubt that the CCR5 mutant offers a significant survival advantage to those at risk of HIV infection.
-- Understanding Evolution

Plague Boils on Human Skin

No one knows exactly why, but in the late 1320s or early 1330s, bubonic plague broke out in China's Gobi desert. Spread by flea-infested rats, it didn't take long for the disease to reach Europe. In October of 1347, a Genoese ship fleet returning from the Black Sea -- a key trade link with China -- landed in Messina, Sicily. Most of those on board were already dead, and the ships were ordered out of harbor. But it was too late. The town was soon overcome with pestilence, and from there, the disease quickly spread north along trade routes -- through Italy and across the European continent. By the following spring, it had reached as far north as England, and within five years, it had killed 25 million people -- one-third of the European population.

Spread of Bubonic Plague

The bubonic plague is caused by a bacterium called Yersinia pestis and is characterized by chills, fever, vomiting, diarrhea, and the formation of black boils in the armpits, neck, and groin. Though the disease was originally called the "Great Mortality" and the "Great Pestilence," the name "Black Death" was eventually adopted because of these black boils, which derive their color from dried blood under the skin caused by internal bleeding. In certain cases the bacterium spreads to the victims' lungs, causing them to fill with frothy, bloody liquid. This derivation of the disease is called pneumonic plague, and can quickly spread from person to person through the air. It is almost always lethal.

Eyam, England

The plague first spread to Britain in 1348, travelling from Bristol to Oxford and London in several days. More than three hundred years later, in 1665, perhaps the worst of the English epidemics broke out in London. That summer, the nobility and clergy fled the city, as some 7,000 people died each week. As many as 100,000 lives were lost before winter killed the fleas and the epidemic tapered off. Contemporary medicine could provide no explanation for the sickness, and most doctors were afraid to offer treatment. In an attempt to keep from being infected, the few physicians who did risk exposure wore leather masks with glass eyes and a long beak filled with herbs and spices that were thought to ward off the illness. Even one person in a household showing plague-like symptoms was enough to mandate a 40-day quarantine for the whole home -- a virtual death sentence for everyone living in it.

Hilltop View of Eyam, England

In September 1665, George Viccars, a tailor in the small, central-England village of Eyam, received a parcel of cloth ridden with plague-infected fleas from London. Four days later, Viccars died. By the end of the month, five more villagers had succumbed to the plague. The panicked town turned to their rector, William Mompesson, who persuaded them to quarantine the entire village to prevent the bacterium from spreading throughout the region. It seemed like suicide. A year later, the first outsiders ventured into Eyam, expecting a ghost town. Yet, miraculously, half the town had survived. How did so many villagers live through the most devastating disease known to man?

John Clifford examining the Eyam parish register

Local Eyam lore tells befuddling stories of plague survivors who had close contact with the bacterium but never caught the disease. Elizabeth Hancock buried six children and her husband in a week, but never became ill. The village gravedigger handled hundreds of plague-ravaged corpses, but survived as well. Could these people have somehow been immune to the Black Death?

Dr. Stephen O'Brien of the National Institutes of Health in Washington D.C. suggests they were. His work with HIV and the mutated form of the gene CCR5, called "delta 32," led him to Eyam. In 1996, research showed that delta 32 prevents HIV from entering human cells and infecting the body. O'Brien thought this principle could be applied to the plague bacteria, which affects the body in a similar manner. To determine whether the Eyam plague survivors may have carried delta 32, O'Brien tested the DNA of their modern-day descendents. What he found out was startling. ...

Joan Plant, tracing family tree

For a disease-causing microorganism to infect the human body there must be a gateway or portal through which it enters into human cells. The plague bacterium works this way, hijacking the white blood cells sent to eliminate it. Traveling inside the white blood cells to the lymph nodes, the bacteria break out and attack the focal point of the human immune system. Dr. Stephen O'Brien felt that the mutated CCR5 gene, delta 32, may have prevented the plague from being able to enter its host's white blood cells.

Eyam provided O'Brien an ideal opportunity to test this theory. Specifically, Eyam was an isolated population known to have survived a plague epidemic. Everyone in the town would have been exposed to the bacterium, so it's likely that any life-saving genetic trait would have been possessed by each of these survivors. "Like a Xerox machine," says O'Brien, "their gene frequencies have been replicated for several generations without a lot of infusion from outside," thus providing a viable pool of survivor-descendents who would have inherited such a trait.

Dr. Bill Paxton examines Steve Crohn's DNA.

Knowing who died and who lived through the early years of the plague is somewhat problematic. Deaths among the general English population were not recorded in the 14th Century -- the height of the Plague -- and most communities did not begin recording parish registers until around 1538. Fortunately, Eyam began keeping a parish register in 1630. Thus historian John Clifford began by examining the register, noting everyone who was alive in 1665, the year the plague came to Eyam. He searched for evidence of life through the year 1725 -- marriages, baptisms, burials that took place years after the plague had left the village. Deleting the names of those lost during the plague period, he was able to determine who the survivors were.

DNA samples could only be collected from direct descendents of the plague survivors. DNA is the principal component of chromosomes, which carry the genes that transmit hereditary characteristics. We inherit our DNA from our parents, thus Eyam resident Joan Plant, for instance, may have inherited the delta 32 mutation from one of her ancient relatives. Plant can trace her mother's lineage back ten generations to the Blackwell siblings, Francis and Margaret, who both lived through the plague to the turn of the 18th century. The next step was to harvest a DNA sample from Joan and the other descendants. DNA is found in the nuclei of cells. The amount is constant in all typical cells, regardless of the size or function of that cell. One of the easiest methods of obtaining a DNA tissue sample is to take a cheek, or buccal, swab.

Crohn's blood, resisting infection.

After three weeks of testing at University College in London, delta 32 had been found in 14% of the samples. This is a genetically significant percentage, yet what, really, did it mean? Could the villagers have inherited delta 32 from elsewhere, residents who had moved to the community in the 350 years since the plague? Was this really a higher percentage than anywhere else? To find out, O'Brien assembled an international team of scientists to test for the presence of delta 32 around the world. "Native Africans did not have delta 32 at all," O'Brien says, "and when we looked at East Asians and Indians, they were also flat zero." In fact, the levels of delta 32 found in Eyam were only matched in regions of Europe that had been affected by the plague and in America, which was, for the most part, settled by European plague survivors and their descendents.

Spread of the Plague

Meanwhile, recent work with another disease strikingly similar to the plague, AIDS, suggests O'Brien was on the right track. HIV, the virus that causes AIDS, tricks the immune system in a similar manner as the plague bacterium, targeting and taking over white blood cells. Virologist Dr. Bill Paxton at the Aaron Diamond AIDS Research Center in New York City noticed, "the center had no study of people who were exposed to HIV but who had remained negative." He began testing the blood of high-risk, HIV-negative individuals like Steve Crohn, exposing their blood to three thousand times the amount of HIV normally needed to infect a cell. Steve's blood never became infected. "We thought maybe we had infected the culture with bacteria or whatever," says Paxton. "So we went back to Steve. But it was the same result. We went back again and again. Same result." Paxton began studying Crohn's DNA, and concluded there was some sort of blocking mechanism preventing the virus from binding to his cells. Further research showed that that mechanism was delta 32.

Scientists studying HIV first learned about the gateway-blocking capacity of the CCR5 mutation in 1996. Several drug companies, then, quickly began exploring the possibility of developing pharmaceuticals that would mimic delta 32 by binding to CCR5 and blocking the attachment of HIV. Previous methods of treatment interfered with HIV's ability to replicate after the virus has already entered a cell. This new class of HIV treatment, called early-inhibitor -- or fusion-inhibitor -- drugs seek to prevent the virus from ever attaching at all. These pharmaceuticals are still in relatively early stages of development, but certainly stand as a hopeful new method of approaching HIV treatment.

Source: PBS: Secrets of the Dead

Ecologically-minded liberals should also heed Dr. Salter’s work, for only when Third-World populations are made to bear the consequences of their own reproductive irresponsibility will they, and the world as a whole, establish population policies that protect the environment. Closing off the “safety valve” of Third-World immigration to the West should be as attractive to the sincere left as to the racial right.

CCR5 Delta32 Gene's Black Death & AIDS Mystery

Interview with Dr. Stephen O'Brien

Dr. Stephen O'Brien

You may possess a genetic mutation. Most people would probably be aghast to learn that one of their genes is malformed. But before you start asking, "What does that mean? Will it make me sick someday? Will I pass it on to my children?" bear in mind that a mutation of the CCR5 gene -- called "delta 32" in its mutated form -- has no adverse effect on humans. In fact, possessing delta 32 could save your life, and the lives of your children.

"It's highly unusual," says Dr. Stephen J. O'Brien of the National Institutes of Health in Washington D.C. "Most genes, if you knock them out, cause serious diseases like cystic fibrosis or sickle cell anemia or diabetes. But CCR5-delta32 is rather innocuous to its carriers. The reason seems to be that the normal function of CCR5 is redundant in our genes; that several other genes can perform the same function."

"The non-mutated form is what's called a chemokine receptor," he says. Chemokines are protein distress calls released by an injured region of your body. "The normal function of the CCR5 gene is to act as a retriever of the chemokine distress signal from these bruises, which will then be alleviated by the chemokines."

This may not sound exciting, but delta 32 is a powerful mistake. HIV, the virus that causes AIDS, attacks the human immune system, infecting the white blood cells sent to destroy it. The delta 32 mutation, however, effectively blocks the crucial gateway into human cells the virus needs. In the case of Steve Crohn, whose partner was the fifth person to die from AIDS, possessing the CCR5 mutation has prevented him from contracting the virus.

O'Brien explains further, "In order to have total resistance to HIV, you have to carry two doses of the mutated gene -- one from each parent. If you get only one dose, you will not be resistant to infection. However, you may be able to delay the onset of HIV once you become infected. That's because, in patients with one copy of the mutation, the amount of 'portals' or 'doorways' that HIV can use is reduced by about 50 percent. That slows down virus replication, which is the most important factor in AIDS progression."

O'Brien's work on AIDS led him to another disease that delta 32 could prevent, the plague. "They both, upon entering the body, infect the macrophages, which are the first line of defense against bacterial infections," he says. "Over the course of evolution, many bugs and pathogens have become extinct because the body learned how to defend itself against them. So the ones that are around today, like HIV and the plague, are pretty savvy -- HIV, for example, specifically attacks and kills the very cells that are designed to kill it. Both these pathogens have developed very clever ways around our immunological defenses."

Eyam Plague Cottage

The results of the Eyam study suggest that delta 32 may have helped save Europe from the bubonic plague pandemic. It seems logical, then, that this could be confirmed by an experiment in which the plague bacterium is injected into the cells of someone possessing the delta 32 mutation. "We have attempted to design experiments that allow us to expose the plague to the lymphocytes of different people, including Steve Crohn," O'Brien says. "But so far we haven't been able to design that kind of experiment ... to do that experiment, you would need to isolate that particular kind of cell. You would need to isolate the exact strain of the plague, and you would need to expose them together."

Nevertheless, delta 32 seems to be a formidable defense the human body has developed in response to ages of pathogenic exposure. And though we may just be getting acquainted with it, delta 32 has been protecting humans for ages. O'Brien suspects the mutation has been around since long before the Black Death. "There have been human remains dug up from graves in Scandinavia -- bodies 3,000 and 4,000 years old -- in which they actually found the mutation, through DNA typing. So there are all kinds of pieces in this puzzle that are coming together."

Source: PBS: Secrets of the Dead
DNA Test for CCR5/Delta32