The Prodigy's Cousin (26 page)

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.

These beneficial mutations would never have been discovered, and the associated treatments likely wouldn't have been developed, if scientists hadn't scoured the DNA of people who were well, despite being at high risk for various diseases. The at-risk but inexplicably healthy subjects of the CCR5-Delta32 studies are the prodigies of the HIV world; researchers studied them in an effort to help their “cousins”—those who contracted the virus.

Now, let's not get too far ahead of ourselves. These efforts to better understand those who are well have produced some spectacular results—but
autism is not HIV, type 2 diabetes, or heart disease. There are a couple of important reasons why autism is different.

First, not everyone agrees that you ought to think about “curing” autism in the same way you think about curing diabetes or heart disease; there's real debate about how best to support autists and their families.
Some advocates argue that we should view conditions like autism as neurological
variations,
not neurological disorders. Autism then is a distinct combination of strengths and weaknesses and a part of the individual's personhood. As Jim Sinclair, one of the founders of Autism Network International, an autism advocacy organization run by the autistic, put it in his 1993 essay, “Don't Mourn for Us,”

Autism isn't something a person
has,
or a “shell” that a person is trapped inside. There's no normal child hidden behind the autism. Autism is a way of being. It is
pervasive;
it colors every experience, every sensation, perception, thought, emotion, and encounter, every aspect of existence. It is not possible to separate the autism from the person—and if it were possible, the person you'd have left would not be the same person you started with.

From this perspective, focusing on the search for autism's genetic roots could be misguided (as could efforts to develop pharmaceutical treatments, which are often tied to this sort of work). Autists may not view their autism negatively. Autists also can and do make great contributions to society, and as Jacob Barnett observed, they may be able to do so not in spite of their autism but
because
of it. And every dollar spent on analyzing genes is a dollar not spent on accommodations, support, and efforts to increase sensitivity that could help autists now. As Julia Bascom, deputy executive director of the Autistic Self Advocacy Network, put it, “
The biggest barrier the autistic community faces is not our autism, but a society which is ignorant, unaccommodating, and often actively hostile to people who are different, people with disabilities, and autistic people.”

Others are equally adamant about the necessity and urgency of finding effective ways to treat autism.
It's a disorder, they believe, and parents should do all they can to help their children fight against it. Those who argue for acceptance over intervention, they often claim, are “high functioning”: they don't appreciate the difficulties faced by those with more severe autism.

The second challenge with using this approach in autism research involves both the methodological difficulties and the heterogeneity of autism genetics. Child prodigies are rare, so scientists attempting to study their genes are stuck with a small sample size. Similar work
has
been done in genetics studies involving siblings of autists (the autists' genes are compared with those of their non-autistic siblings), and while this approach has helped identify autism-linked genes, it hasn't yielded any genetic variants that seem beneficial. Autism has such complicated, knotty underlying genetics that it may not be possible to tease out anything useful. “So far, none of these single-gene studies has given us anything that's in some sense actionable to say
okay,
we can take this, block that gene, or further goose up the effect of that gene, and it's gonna get us somewhere,” Bruce Cuthbert, the acting director of the National Institute of Mental Health and the director of the Research Domain Criteria project (which we'll get to shortly), said. “That just hasn't proven to be the case.”