The Prodigy's Cousin

by Joanne Ruthsatz

  From the day Joanne met Garrett James and his cousin Patrick, she has been tackling one particular piece of the prodigy puzzle: Does the cousin’s autism have something to do with the prodigy’s talent? The answer seems to be yes. Many of the prodigies have autistic relatives. Brothers. Sisters. Uncles. Grandmothers. Some have autism in every twig and branch of the family tree. The prodigies themselves—all of them—have autistic characteristics, such as extraordinary attention to detail and a tendency toward obsession. They draw on these traits to rocket to the top of their fields; these attributes are essential to their success. Prodigies and autists may even have a genetic link in common, a mutation on chromosome 1 that some prodigies and autists (but not their non-prodigious, non-autistic relatives) share.

  This connection is fascinating; it offers an unexpected perspective on the riddle of the prodigies’ talent and an intriguing take on what drives children to hone their skills with laser-like focus and intensity. But understanding child prodigies’ abilities is only the first step; the next is to find out whether this connection could improve our understanding of autism. Doing that requires investigating why it is that the prodigies have the strengths associated with autism but not the challenges.

  The answer may be in the prodigies’ genes. The prodigies and the autists appear to share genes on chromosome 1—a common foundation. But what if the two also have critical genetic differences? What if there is something about the prodigies’ genes that protects them from autism’s social and communication deficits but leaves the heightened attention to detail, astounding memory, and passionate interests of autism in place? If the prodigies and the autists share a genetic mutation and have important genetic differences, maybe studying the prodigies could unlock a piece of autism’s infamously complex genetic architecture. It could mean that a breakthrough in autism research will come not from studying autists, but from studying child prodigies.

  This sort of thinking has recently lit other areas of medical research on fire. For decades, scientists sought to learn more about conditions ranging from diabetes to heart disease by studying those who have diabetes or heart disease. Scientists rooted through the underlying biology of those with various medical conditions to try to understand what, exactly, was going wrong.

  But recently scientists have begun looking in the other direction as well. Instead of focusing solely on those who are sick, they’ve taken a keen interest in those who are well—especially those who are at high risk for a particular disease, due to genes or lifestyle or both, but don’t develop it. The idea is that if the scientists can isolate whatever it is that protects these inexplicably healthy individuals from the disease in question, perhaps they can use that knowledge to help those who actually have the disease.

  HIV research is a good example of how this works in practice. To explore the potential implications of this strategy, it’s worth taking a detour through the history of HIV research and considering whether a similar road map could lead autism research in an interesting direction.

  Not long after AIDS was identified in the early 1980s, scientists began studying individuals with a high likelihood of contracting the virus: homosexual men with many sexual partners; prostitutes in Kenya and Gambia; adults with a history of intravenous drug use. As these studies progressed, the scientists found something unexpected. Even among these extremely high-risk groups, there were pockets of people in whom the virus never took hold.

  Take Erich Fuchs and Stephen Crohn, for example. Erich had been exposed to HIV multiple times through unprotected sex with HIV-positive men. Stephen’s partner, Jerry Green, was one of the first people in the United States to die of AIDS. Both men fully expected to contract HIV. They thought it was only a matter of time. But it never happened.

  Mystified by their inexplicable luck, Erich and Stephen separately contacted research institutions and doctors, volunteering themselves as subjects. Eventually, both men crossed paths with Bill Paxton, then a postdoc at the Aaron Diamond AIDS Research Center in New York, who was seeking out a group of high-risk, uninfected individuals. “It was clear the minute I met Erich and Steve—these people should be HIV positive,” Paxton recalled.

  Paxton and his colleagues included Erich and Stephen in a group of twenty-five high-risk, HIV-negative individuals and homed in on their underlying biology. The idea was to extract their blood, infect their cells with HIV in the lab, and then figure out how they managed to shut down the virus’s ability to replicate. But it was difficult to study virus replication in Erich and Stephen; their cells were nearly impossible to infect with HIV in the first place. The scientists used ever-increasing doses of HIV, but still the infection didn’t take hold. “We repeated and repeated and repeated because we were throwing very high dosage of virus on these CD4+ cells, and we did not see infection,” Paxton said. “We never thought for a minute that would be the outcome.”

  When the team later investigated the basis for this resistance, they stumbled onto a gem of a finding: Erich and Stephen shared a genetic mutation. Both had two copies (in scientific terms, they were homozygous) of what became known as CCR5-Delta32. This genetic “defect” prevented these individuals from producing a protein, CCR5, that usually sits on the outside of an individual’s T cells and serves as a main entry point for the HIV virus. CCR5 isn’t essential to every strain of HIV—some varieties rely upon other means to enter the cell—but for those strains of HIV that rely on CCR5, a double dose of the mutation makes patients’ cells essentially impenetrable to HIV; the virus washes right through their bodies.

  A search for this mutation in other HIV research subjects yielded some lopsided statistics. Across three studies, scientists found a few dozen HIV-negative individuals with two copies of this mutation. But no one infected with HIV—not a single one of the 2,741 HIV-positive individuals in these studies—had a double copy of CCR5-Delta32. It seemed that what Paxton and his colleagues had found in the lab was no fluke; the mutation was protecting its carriers from the virus.

  Critically, as far as the scientists could tell, there was no price to be paid for this mutation. It resulted in high resistance to HIV, but it wasn’t associated with any obvious defects or deficits. It was a genetic gift, no strings attached.

  The treatment possibilities were explosive. In the aftermath of CCR5-Delta32’s discovery, scientists set to work creating pharmaceuticals that could mimic its function. In 2007, the FDA approved maraviroc, the first of these drugs. It binds to CCR5 and blocks HIV from using it as a cell entryway.

  But pharmaceuticals were only the beginning; identifying CCR5-Delta32 had even more astounding implications. Perhaps no one knows this better than Timothy Ray Brown, the first (and, so far, only) person ever cured of HIV—a status he would never have assumed if scientists hadn’t taken the unusual step of studying a disease by zeroing in on those who don’t have it.

  Timothy was a twenty-nine-year-old American expat living in Europe when he was diagnosed with HIV in the mid-1990s.

  At first, he was terrified; a former partner predicted he probably had only two years to live. But Timothy’s timing was lucky. New pharmaceuticals that effectively managed HIV were coming onto the market around the same time that Timothy was diagnosed. He took the new drugs, his symptoms never really worsened, and he soon realized that HIV might not be a death sentence after all. Timothy continued building his life in Berlin. He got a job translating documents from German into English, and he hit the town at night. His health seemed almost normal.

  In June 2006, when Timothy was forty, he flew to New York for a friend’s wedding. He made it through the weekend’s events—the party the night before, the wedding itself, the dim sum brunch the next day—but he felt exhausted the entire time. That Monday, after he returned to Berlin, he rode his bike ten miles to work, as he often did. The ride took much longer than usual, though. At lunchtime, Timothy tried to ride his bike to a restaurant half a mile away, but he made it only halfway be
fore he was overcome by fatigue.

  Timothy was soon diagnosed with acute myeloid leukemia, a rapidly progressing form of cancer. His oncologist contacted a Berlin hospital, where, by chance, he got Dr. Gero Hütter on the phone. Dr. Hütter said to send Timothy in, and he started him on chemotherapy.

  In the meantime, Dr. Hütter initiated a search for a potential stem cell donor in case a transplant was necessary. A large number of potential matches turned up; there were eighty matches at the German Bone Marrow Donor Center alone.

  Dr. Hütter, who was thirty-seven at the time, specialized in cancer, not HIV, but he remembered learning about CCR5-Delta32 in medical school. The surprisingly large number of matches led Dr. Hütter to wonder if they should perhaps be picky about the donor. Did any of Timothy’s potential matches have two copies of CCR5-Delta32? Could stem cells from such a donor cure Timothy’s leukemia and his HIV?

  Over the course of four months, Dr. Hütter’s team tested potential donors for the CCR5-Delta32 mutation. On their sixty-first attempt, they found a match who was homozygous for CCR5-Delta32—just like Erich and Stephen. That individual agreed to donate if and when the time came. Timothy was already heterozygous for CCR5-Delta32 (meaning he had a single copy but not the magic-bullet double copy). It was a long shot, but the hope was that the transplant would leave him effectively homozygous for the mutation and potentially protected from HIV.

  As far as Dr. Hütter knew, it would be a first-of-its-kind trial. “We have no experiences of this,” Dr. Hütter recalled. “There were no cases published before, and there were also no animal results, and so we have totally no idea what will happen if we do this.”

  But Timothy was ambivalent about the procedure. After chemotherapy, his leukemia was in remission. Stem cell transplants are risky. His medication kept his HIV under control, and the idea of actually curing his HIV seemed far-fetched. Timothy initially refused the stem cell transplant. But when his leukemia returned at the end of 2006, he didn’t see any way around it.

  On February 6, 2007, eight months after he was diagnosed with leukemia, Timothy underwent surgery. He received the stem cells from the donor with two copies of the CCR5-Delta32 mutation. Just beforehand, he stopped taking his HIV medication. The operation went smoothly, and there were no serious complications.

  Early on, a couple of tests detected HIV in Timothy’s DNA. But soon all the tests were coming back negative; after a few months, there was no trace of HIV in Timothy’s body, even though he hadn’t taken his HIV medication since his surgery.

  Five and a half months after the transplant, the doctors performed a colonoscopy. There was no sign of HIV in Timothy’s rectal mucosa (the inner lining of the rectum), a potential hiding place for a viral reservoir. Twenty months after Timothy had stopped taking his medication, still no virus.

  Timothy went back to work for the translation company. He rode his bike. He started working out again and could finally develop muscles because he no longer had wasting syndrome.

  But his reprieve was short-lived. Timothy’s leukemia came raging back at the end of the year. The doctors decided on another transplant—which would, again, be a risky procedure—from the same donor, the one with the double CCR5-Delta32 mutation.

  As Timothy, who is chronically understated, put it, “That one didn’t go so well.” As he remembers, his blood platelet count plummeted. He began seeing black spots and temporarily lost his vision. During a conversation about a business venture, his words came out jumbled. The doctors suspected some sort of neurological disorder; they conducted an MRI and then biopsied Timothy’s brain. For a while, Timothy lost the ability to walk.

  Timothy began what would turn into more than a year of physical therapy. He eventually moved back to the United States, and his recovery is ongoing. His speech has returned to normal, though long conversations can still tire him. His condition improves daily, though he has residual balance problems and doesn’t walk quite as he did before the procedure. But as of the spring of 2015, it had been eight years since he took any sort of medication to control his HIV, and he’s still HIV negative.

  For a long time, no one used the word “cured.”

  Dr. Hütter wrote up Timothy’s case and submitted the paper to the New England Journal of Medicine. It was rejected. He applied to present Timothy’s case at the 2008 Conference on Retroviruses and Opportunistic Infections in Boston, but the conference organizers allowed him only a poster on which to describe his results. It didn’t create much of a stir.

  A few weeks later, an AIDS researcher read about Dr. Hütter’s work and invited him to present Timothy’s case to a small group of scientists in September 2008, over a year and a half after Timothy’s first stem cell transplant. Some of the audience thought that HIV had to be hiding somewhere in Timothy’s body; they agreed, though, that he was “functionally cured.”

  The New England Journal of Medicine reconsidered Dr. Hütter’s paper describing Timothy’s case and published it in 2009. But Dr. Hütter still didn’t use the word “cure.” Instead, he described Timothy as having “long-term control of HIV.”

  Even Timothy, at first, avoided declaring himself free from HIV. “I was actually afraid of using the word ‘cured’ for a long time because I felt like it might give people false hope. At that point, I didn’t really know for sure that I was cured, and I didn’t want it to come back that I actually do have HIV,” Timothy said.

  As time went on and an ever-increasing number of tests failed to find HIV in Timothy, Dr. Hütter grew bolder. In a 2011 paper published three and a half years after Timothy stopped taking his HIV medication, Dr. Hütter and his colleagues declared it “reasonable to conclude that cure of HIV infection has been achieved in this patient.” Two months later, the San Francisco AIDS Foundation held a forum with what would have been, just a few years before, an unthinkable title: “Is ‘Cure’ Still a Four-Letter Word?”

  In June 2012, talk of a cure suffered a bit of a setback. At a conference in Spain, a researcher reported that his team had found traces of HIV in Timothy’s body using ultrasensitive tests; two other teams of researchers reported similar results. However, these traces didn’t match the HIV found in Timothy’s body before the stem cell transplant, and some of these researchers cautioned that it might have been a false positive due to laboratory contamination. Either way, it’s undisputed that in the eight years since Timothy’s stem cell transplant, he’s never taken his HIV medication, and there’s no sign that the virus is replicating in his body.

  Since Timothy’s transplant, the same method has been tried in a few other cases. So far, no second cure. But Timothy is convinced that his case is proof that curing HIV is possible, and he has taken up the cause of advocating for finding a cure that could work for more people. He has vowed not to stop until HIV is cured.

  Stem cell transplants aren’t a feasible option for most people living with HIV. But Timothy Ray Brown’s case was proof that a cure was possible, and scientists took note.

  Inspired by his eradication of HIV, some researchers tried to leverage his stunning CCR5-Delta32 results in another direction: What if, instead of merely developing pharmaceuticals, they edited the cells of those with HIV to mimic the effect of the mutation?

  In 2014, a group of researchers reported that they had tried. They had extracted blood from a group of HIV-positive patients and used zinc-finger nucleases (a sort of “molecular scissors”) to sever the T cells’ CCR5 genes. The idea was to dismantle both copies of the gene so that the patients’ treated cells would be immune to attack by the HIV virus and then return those cells to the patients.

  The modified cells could be detected in every patient. The modification, moreover, seemed to have worked: when the study participants stopped taking their HIV medication, the treated cells fared better than the nontreated cells.

  The scientists found something else, too: Patient 205.

  After Patient 205
stopped taking his HIV medication, it took six weeks for his viral load to increase. But then something unexpected happened. Without medication or any further intervention, his viral load began to decline. By the time the treatment intervention was over, a point at which the research protocol called for all participants to resume taking their HIV medication, his viral load was undetectable.

  Intriguingly, Patient 205 was already heterozygous for CCR5-Delta32, just like Timothy Ray Brown before his stem cell transplant. Patient 205’s built-in single mutation meant that he effectively received a bigger dose of treated cells; while the molecular scissors the team used to alter the patients’ cells might have disabled one or both copies of the relevant gene in each of the other participants’ cells, every time the scientists disabled one of Patient 205’s CCR5 genes, he already had an inborn mutated copy to match, giving him a double dose of the mutation.

  HIV isn’t an isolated case study of the power of studying those without a particular disease or disorder. By using this somewhat counterintuitive method, scientists have fine-tuned our understanding of other diseases and have even identified other beneficial mutations—the new holy grail of medical research. In one recent study, for example, scientists investigating type 2 diabetes compared the genes of those who had type 2 diabetes with the genes of those who were old and overweight but still (inexplicably) healthy. This led them to the SLC30A8 gene, which is related to insulin production. It turns out that those with a mutation that inactivates one copy of this gene have a 65 percent reduction in risk for developing type 2 diabetes. Scientists studying heart disease sequenced the PCSK9 gene in individuals with extremely low LDL cholesterol (the bad kind) and identified mutations tied to a reduced risk of coronary heart disease. The identification of beneficial mutations that reduce the risk of heart disease has the pharmaceutical industry salivating. So promising is this line of research that a team of scientists recently launched the Resilience Project, a program dedicated to identifying more such beneficial mutations.