While there have been hundreds of human gene therapy trials since 1990, none of which has yet resulted in approval by the U.S. Food and Drug Administration, that prospect appears to be getting closer. One leader in the race to bring gene therapy to market is a Philadelphia biotech firm that, in 2015, successfully restored vision to twenty-one patients suffering from a rare genetic eye disease—with no apparent immune system reactions or other serious side effects. Other contenders for FDA approval include genetic treatments for hemophilia, cystic fibrosis, and sickle-cell disease.
One of the field’s biggest constraints has long been a financial one. Large pharmaceutical companies have been reluctant to invest in gene therapy for rare genetic diseases, since even successful treatments for these disorders aren’t likely to turn a profit, owing to the small number of people who would use them. But the increased pace and promise of recent advances has prompted a corresponding increase in investment. In 2015, biotech companies developing gene therapies—about seventy of which were in late-stage testing—raised $10 billion globally, according to the Alliance for Regenerative Medicine. And in 2016, when European regulators approved a new gene therapy for SCID that does not cause cancer, it marked an industry milestone as the first approval granted to a major multinational drug company: GlaxoSmithKline, which also plans to seek U.S. approval for the therapy.
This newly robust interest and investment in gene therapy is a game changer for the researchers who study rare genetic disorders, including Williams. Dr. Pober, the geneticist who diagnosed Eli, believes that gene therapy trials could be possible for Williams syndrome within the next decade. So far the research related to Williams has been conducted in petri dishes, not people, but some of the results have been promising.
“This is mind-boggling for a geneticist,” Pober says. “Twenty-five years ago it was ‘Yup, this is what you’ve got. Good luck to you.’ We were jealous of our colleagues who had something you could treat.”
She sees particular hope in the elastin gene’s involvement in Williams, since a decline in elastin production is what causes our skin to wrinkle as we age. With limited elastin, people with Williams are prone to develop wrinkles earlier than the rest of us. (They also get gray hair at a much younger age, although geneticists aren’t exactly sure why, since graying hair isn’t connected to elastin. Mice missing the Williams genes also turn gray earlier than their genetically intact counterparts.) And although elastin-related cardiac problems are of greater concern to Pober, she half-jokingly deems the quest for youthful skin a golden ticket to future research.
“If we design a study that could lead to a cure for wrinkles,” she says, “the funding will be unlimited.”
In fact, researchers at Yale recently succeeded in tricking the elastin gene into producing more elastin than normal, a step they hope could help prevent the narrowing and rigidity of the aorta and arteries in people with Williams—and lead to healthier hearts for the rest of us. George Tellides, a professor of cardiac surgery and the lead researcher on the Yale team, believes that curing the heart problems inherent to Williams could help prevent similar problems in the general population, especially among the elderly.
“In older people, wrinkles are the visible effect of the underlying loss of elastin, but it’s also affecting the arteries, including the aorta,” he says. “So the lessons we learn about Williams can be applied to everyone.”
Because people with Williams are missing only one copy of the twinned elastin gene, they aren’t devoid of elastin altogether; they just produce about half as much as they should. If the existing gene could double its protein production, the deficiency would disappear. At least, it should. But just because something works in a lab doesn’t mean it’ll work in a human being, Pober warns. There it becomes a matter of releasing exactly the right amount of elastin at exactly the right time during blood vessel development. That kind of fine-tuning will take time, if it can be done at all.
In the meantime, the treatment of Williams syndrome, especially its behavioral and social symptoms, remains a murkier matter. This generation must make do with the treatment options that exist in our time, none of them specifically geared to the unique symptoms of Williams. Many of the behavioral therapies used for Williams were initially developed for children with autism. Most drugs on the market for anxiety, attention-deficit/hyperactivity disorder, and low impulse control were developed for the general population, and some have very different effects on people with Williams, whose brain chemistry is just different enough that doctors are sometimes surprised by their reactions to common medications.
Dr. Pober describes the pharmacological approach to treating the symptoms of Williams as trial and error. Some medications work fine. Others have unexpected side effects. SSRIs, the most common treatments for anxiety and depression, frequently make people with Williams worse instead of better, and often exacerbate their social disinhibition. One drug Eli took for anxiety helped with those symptoms but annihilated what little self-control he had when it came to hugging strangers. Eli’s psychiatrist shuffled his prescriptions several times throughout his preteen years, trying to find a cocktail—which at different times combined varying amounts of Celexa or Abilify for anxiety, plus Ritalin and Intuniv for ADHD—that would help more than it hurt.
Researchers estimate that more than half of all children with Williams have ADHD. While the class of drugs that includes Ritalin is usually effective in reducing their symptoms, it also causes different side effects than in the general population, most notably mood changes. One study found that two-thirds of children with Williams experienced sadness and malaise after taking Ritalin, as opposed to less than a quarter of Ritalin takers in the general population.
Of course, parents would prefer an approach that didn’t require a prescription. All drugs have side effects, after all. And neither the parents nor the doctors of people with Williams want to risk overmedicating to the point of eclipsing their radiant personalities.
“Treating Williams is a matter of coping with the disabilities enough to let the abilities shine,” Dr. Pober says. “The parents of these kids can see their potential. Unlocking it is the mystery.”
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MANY CLINICIANS SEE THE LANGUAGE skills of people with Williams, especially their proclivity for storytelling, as a valuable tool to help them manage the syndrome’s disabling effects. Compared to people with other forms of intellectual disability, people with Williams are much more responsive to talk therapy. The researchers Eleanor Semel and Sue R. Rosner, coauthors of Understanding Williams Syndrome: Behavioral Patterns and Interventions, reported that many people with Williams who suffered from phobias found it calming just to discuss a fearful situation rationally. For example, a child afraid of thunder felt soothed when an adult explained that thunder was caused by a clash of hot and cold air, and that it followed lightning but couldn’t hurt anyone itself. (Talking through a fear typically only helped temporarily, however, and some people found that it made their anxiety worse instead of better.)
Interactive games—for example, having everyone in the room clap their hands along with the thunder—are also prominent in behavioral therapy for people with Williams, drawing on their love of socializing to trump the power of phobias. Stories and role-playing have proved useful as well: children afraid of going to the doctor often felt less fearful after acting out the parts of the doctor and the patient in a more familiar setting.
Since music has such a profound emotional effect on people with Williams, and because it holds their attention better than almost anything else, it has become another popular therapeutic tool. Kids with Williams learn exceptionally well when a lesson is set to music, retaining phrases more consistently even if they simply rhyme or can be said in rhythm. Music is also deeply soothing to most people with Williams, which makes it a powerful ally in battling anxiety and phobias.
Many parents have developed their own unorthodox treatments for some of the problematic behaviors common to Williams. A
tendency to wander off, especially in pursuit of a stranger to greet, is one of the disorder’s more alarming traits. After all else failed in preventing one child from routinely disappearing, her parents tied a small bell around her ankle to make her easier to find. Some parents, like Gayle, curb their kids’ unstoppable impulse to wander after strangers by almost never letting them out of their sight.
The problem of indiscriminate hugging is a complicated one to treat, partly because several factors contribute to the urge. Neuroscientists have found evidence of anomalies in the frontal lobe—the part of the brain that controls impulsivity and helps us evaluate the consequences of our actions—which may explain why people with Williams can’t stop hugging strangers even when they know they shouldn’t. Additionally, some researchers point to a developmental dysfunction in the way young children with Williams form (or don’t form) preferential emotional bonds. One study found that people with Williams didn’t differentiate between types of relationship—say, between an uncle and the school bus driver—the way the rest of us do from a very young age. They approached and interacted with each person the same way. This is one of the heartbreaking hazards of raising a kid with Williams: your child loves you intensely and unconditionally, but he feels the same way about his bus driver.
Like many Williams parents, Gayle felt the sting of this discovery when Eli was still a baby and nearly leapt from her arms into the arms of strangers, cooing tenderly to them. Of course, he had always been effusive in his love for her, too. Even now, at an age when most kids had stopped being so affectionate toward their mothers, he overflowed with warmth and gratitude, routinely telling her, “Mom, you’re the best!” But there were moments when even his warmth troubled her. It was so automatic that she sometimes thought, Is this real? Or is he just programmed to say “I love you”?
It sometimes seemed like Eli had little choice in whom to love—that free will didn’t factor into the matter. You’d have had to go out of your way, by being intentionally cruel or abrasive, to get him not to love you. This could be hurtful to Gayle and the rest of Eli’s family, who had earned the love that was so freely doled out to strangers. But it didn’t mean that his love wasn’t as real as anyone else’s. All social bonding is predicated in part on the release of oxytocin, as Korenberg and other researchers have shown. We all respond to the same brain chemicals when we feel or express love. People with Williams just do so more often.
The fact that he loved nearly everyone didn’t make Eli’s love for Gayle any less authentic. And although she occasionally questioned this, she could tell his feelings were genuine just by looking into his eyes. The earnest emotion she saw reflected back was anything but programmed.
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WHILE IT’S LARGELY IMPOSSIBLE TO stop people with Williams from caring about everyone they meet, it’s essential—both for safety and for social acceptance—to reinforce that different relationships entail different levels of intimacy. Many teachers use a “circles” curriculum, sometimes represented visually as a series of different-colored concentric circles and drawn on the floor to give kids the physical experience of moving between them. In the center is the “you” circle. Children are reminded that this is a private bubble and that no one else is allowed to touch them without their consent (and correspondingly, that they should respect the private bubble around other people). The circles move outward from there: the “close hug and kiss” circle, the “faraway hug” circle, the “handshake” circle, the “wave” circle, and finally the “strangers” circle. The people who fall into this circle require no acknowledgment at all, teachers explain. The curriculum insists: “Some people stay strangers forever”—a phrase that’s anathema to the Williams worldview.
Gayle saw Eli’s indiscriminate displays of affection as the biggest obstacle to his successful social life. She became a one-woman police force in the fight against hugging. But therapists who treat Williams say this battle is often futile. Not only do they question whether people like Eli can muster the self-control to stop hugging, but some therapists question whether they should. Physical contact is, after all, one of the primary joys of their lives. This impulse is hardwired into who they are. To hold them back from hugging would be to deny a central part of their personality.
Karen Levine, the Harvard psychologist who specializes in Williams, sees hugging as a gray area in treatment: it can be problematic, but it can also enrich the lives of people for whom social contact is paramount. Her first priority is to treat the anxiety, phobias, and fixations of the disorder because they are universal burdens: people with Williams agree that they’d be better off without them. Overfamiliarity, on the other hand, is more a question of degree, and she cautions against crossing the border between treating pathology and reprogramming a personality.
“People with Williams love people; they want to touch them. As long as they’re not putting themselves in danger, or making someone else uncomfortable, I don’t think there’s really a right or wrong amount of hugging,” Levine says. “Everyone’s comfortable with a different level of physical contact. At some point, it falls to other people to either accept it or to say they don’t want to be hugged.”
Advocates of neurodiversity take Levine’s point further, arguing that we should focus less on treating neurological conditions such as Williams or autism and more on broadening our own understanding of what constitutes normal or acceptable social behavior. The neurodiversity movement takes issue, fundamentally, with the classification of these conditions as illnesses rather than as identities. Some of its proponents oppose any effort to cure them, arguing that doing so would amount to stifling the quirks and creativity that give the world its richness. And they tend to overlap, ideologically, with the opponents of prenatal testing that could lead to the abortion of fetuses carrying similar disorders. Since Williams is too rare to be included on the standard panel of prenatal tests, and since there is no test for autism, that debate doesn’t currently apply to either condition. (That could change soon, however—at least for Williams—thanks to rapidly evolving technologies such as cell-free fetal DNA testing, which analyzes tiny fragments of free-floating fetal DNA in the mother’s bloodstream, and could increase the scope of prenatal screening.) Lawmakers in some states, including Indiana and North Dakota, have already proposed or passed legislation prohibiting abortion because of genetic abnormalities—which, for now, primarily affects the prospective parents of children with Down syndrome.
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AS A WHOLE, WESTERN CULTURE is relatively tolerant of the Williams personality. We value gregariousness and admire people who show no social fear. We celebrate icons like Oprah Winfrey—who routinely hugs strangers and asks them personal questions—for their warmth and openness. Of course, Oprah manages her warmth with more sophistication than most people with Williams possess. She can turn it off when needed. Still, she represents an ideal inherent to our culture and not to others. In a collectivist culture like Japan’s, where conformity and self-control are prized above the assertiveness and self-expression of our own individualistic society, the Williams personality elicits more stigma and is seen as more dysfunctional. The same tendency to greet and touch strangers that Americans describe as endearing gets a darker gloss in Japanese culture, where it is more often described as intrusive and offensive—as another disabling symptom of the disorder, rather than its silver lining. Carol Zitzer-Comfort, who led a cross-cultural study comparing children with Williams in Japan and the U.S., noted the different tone of aphorisms about attracting attention: in the U.S. “the squeaky wheel gets the grease,” while in Japan “the nail that stands out gets pounded down.” Her study found that Japanese parents considered the overfamiliarity of Williams syndrome to be more disabling than did American parents. People with Williams were much more likely to be institutionalized in Japan than in the U.S.
Zitzer-Comfort’s study found that while people with Williams were more social than their non-Williams peers in each culture, both groups were less soci
al overall in Japan. In fact, American children without Williams showed the same level of social behavior as Japanese children with Williams, whose behavior was considered wildly inappropriate by Japanese standards. Zitzer-Comfort concluded that the disorder was at least somewhat moderated by cultural norms, even as it tended to violate those norms.
Even outgoing Americans have boundaries, after all. We prize extroversion to a point, but we tend to flinch when someone violates our personal space, no matter how charming they are. This sets us apart from close-talking, communal cultures in which platonic friends, male and female, hold hands and kiss cheeks. In Greece, for example, a survey of parents whose children had Williams syndrome found that they did not consider their kids’ outgoing, affectionate behavior to be pathological, although they did list other traits as disabling, including anxiety, impulsivity, and low frustration tolerance. Greeks with Williams are hardly ever institutionalized; researchers concluded in a 2011 study that no Greek psychological services specialized in treating the disorder. The bulk of treatment for Williams came from geneticists, who focused almost exclusively on its medical symptoms.
Short of moving to Greece, though, Gayle believed the best way to give Eli a shot at social acceptance was to get him to conform to American standards of conduct—by giving strangers their space. For as much as people with Williams love everyone else equally and indiscriminately, the corollary is decidedly not true. They might show the same affection to their bus drivers as to their mothers, but even the most compassionate of bus drivers will never muster a mother’s love for someone who is, at best, a casual acquaintance. No one else, anywhere in the world—Greece included—could possibly have treasured Eli’s love like Gayle did.
The Boy Who Loved Too Much Page 18