Viruses like influenza or measles kill cells when they infect them. But when retroviruses like HIV infect a cell, they often let the cell live and splice their genes into its DNA. When the cell divides, both of its progeny carry the retrovirus’s genetic code in their DNA.
In the past few years, geneticists have pieced together an account of how Perron’s retrovirus entered our DNA. Sixty million years ago, a lemurlike animal—an early ancestor of humans and monkeys—contracted an infection. It may not have made the lemur ill, but the retrovirus spread into the animal’s testes (or perhaps its ovaries), and once there, it struck the jackpot: It slipped inside one of the rare germ line cells that produce sperm and eggs. When the lemur reproduced, that retrovirus rode into the next generation aboard the lucky sperm and then moved on from generation to generation, nestled in the DNA. “It’s a rare, random event,” says Robert Belshaw, an evolutionary biologist at the University of Oxford in England. “Over the last 100 million years, there have been only maybe 50 times when a retrovirus has gotten into our genome and proliferated.”
But such genetic intrusions stick around a very long time, so humans are chockablock full of these embedded, or endogenous, retroviruses. Our DNA carries dozens of copies of Perron’s virus, now called human endogenous retrovirus W, or HERV-W, at specific addresses on chromosomes 6 and 7.
If our DNA were an airplane carry-on bag (and essentially it is), it would be bursting at the seams. We lug around 100,000 retrovirus sequences inside us; all told, genetic parasites related to viruses account for more than 40 percent of all human DNA. Our body works hard to silence its viral stowaways by tying up those stretches of DNA in tight stacks of proteins, but sometimes they slip out. Now and then endogenous retroviruses switch on and start manufacturing proteins. They assemble themselves like Lego blocks into bulbous retroviral particles, which ooze from the cells producing them.
Endogenous retroviruses were long considered genetic fossils, incapable of doing anything interesting. But since Perron’s revelation, at least a dozen studies have found that HERV-W is active in people with MS.
By the time Perron made his discovery, Torrey and Yolken had spent about 15 years looking for a pathogen that causes schizophrenia. They found lots of antibodies but never the bug itself. Then Håkan Karlsson, who was a postdoctoral fellow in Yolken’s lab, became interested in studies showing that retroviruses sometimes triggered psychosis in AIDS patients. The team wondered if other retroviruses might cause these symptoms in separate diseases such as schizophrenia. So they used an experiment, similar to Perron’s, that would detect any retrovirus (by finding sequences encoding reverse transcriptase enzyme)—even if it was one that had never been catalogued before. In 2001 they nabbed a possible culprit. It turned out to be HERV-W.
Several other studies have since found similar active elements of HERV-W in the blood or brain fluids of people with schizophrenia. One, published by Perron in 2008, found HERV-W in the blood of 49 percent of people with schizophrenia, compared with just 4 percent of healthy people. “The more HERV-W they had,” Perron says, “the more inflammation they had.” He now sees HERV-W as key to understanding many cases of both MS and schizophrenia. “I’ve been doubting for so many years,” he says. “I’m convinced now.”
Torrey, Yolken, and Sarven Sabunciyan, an epigeneticist at Johns Hopkins, are working to understand how endogenous retroviruses can wreak their havoc. Much of their research revolves around the contents of a nondescript brick building near Washington, D.C. This building, owned by the Stanley Medical Research Institute, maintains the world’s largest library of schizophrenic and bipolar brains. Inside are hundreds of cadaver brains (donated to science by the deceased), numbered 1 through 653. Each brain is split into right and left hemispheres, one half frozen at about –103 degrees Fahrenheit, the other chilled in formaldehyde. Jacuzzi-size freezers fill the rooms. The roar of their fans cuts through the air as Torrey’s team examines the brains to pinpoint where and when HERV-W awakens into schizophrenia.
New high-speed DNA sequencing is making the job possible. In a cramped room at Johns Hopkins Medical Center, a machine the size of a refrigerator hums 24/7 to read gene sequences from samples. Every few minutes the machine’s electric eye scans a digital image of a stamp-size glass plate. Fixed to that plate are 300 million magnetic beads, and attached to each bead is a single molecule of DNA, which the machine is sequencing. In a week the machine churns out the equivalent of six human genomes—enough raw data to fill 40 computer hard drives.
The hard part starts when those sequences arrive at Sabunciyan’s desk. “We got these data right around New Year’s 2009,” Sabunciyan said one day last August as he scrolled through a file containing 2 billion letters of genetic code, equivalent to 2,000 John Grisham novels composed just of the letters G, A, T, and C (making the plot a great deal more confusing). “We’re still looking at it.”
Sabunciyan has found that an unexpectedly large amount of the RNA produced in the brain—about 5 percent—comes from seemingly “junk” DNA, which includes endogenous retroviruses. RNA is a messenger of DNA, a step in the path to making proteins, so its presence could mean that viral proteins are being manufactured in the body more frequently than had been thought.
Through this research, a rough account is emerging of how HERV-W could trigger diseases like schizophrenia, bipolar disorder, and MS. Although the body works hard to keep its ERVs under tight control, infections around the time of birth destabilize this tense standoff. Scribbled onto the marker board in Yolken’s office is a list of infections that are now known to awaken HERV-W—including herpes, toxoplasma, cytomegalovirus, and a dozen others. The HERV-W viruses that pour into the newborn’s blood and brain fluid during these infections contain proteins that may enrage the infant immune system. White blood cells vomit forth inflammatory molecules called cytokines, attracting more immune cells like riot police to a prison break. The scene turns toxic.
In one experiment, Perron isolated HERV-W virus from people with MS and injected it into mice. The mice became clumsy, then paralyzed, then died of brain hemorrhages. But if Perron depleted the mice of immune cells known as T cells, the animals survived their encounter with HERV-W. It was an extreme experiment, but to Perron it made an important point. Whether people develop MS or schizophrenia may depend on how their immune system responds to HERV-W, he says. In MS the immune system directly attacks and kills brain cells, causing paralysis. In schizophrenia it may be that inflammation damages neurons indirectly by overstimulating them. “The neuron is discharging neurotransmitters, being excited by these inflammatory signals,” Perron says. “This is when you develop hallucinations, delusions, paranoia, and hyper-suicidal tendencies.”
The first, pivotal infection by toxoplasmosis or influenza (and subsequent flaring up of HERV-W) might happen shortly before or after birth. That would explain the birth-month effect: Flu infections happen more often in winter. The initial infection could then set off a lifelong pattern in which later infections reawaken HERV-W, causing more inflammation and eventually symptoms. This process explains why schizophrenics gradually lose brain tissue. It explains why the disease waxes and wanes like a chronic infection. And it could explain why some schizophrenics suffer their first psychosis after a mysterious, monolike illness.