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The Boy Who Loved Too Much Page 4


  On the way home they stopped at a local diner for breakfast. They were regulars there, but everything now felt strange and foreign to Gayle. The waitress—their regular waitress, a hard-looking woman with a short, spiky hairdo and a rose tattoo on her forearm—seemed to read their distress. She frowned empathetically at Eli, who smiled at her and burbled a wordless greeting.

  “Can I pick him up?” she asked. Gayle handed Eli to her without answering.

  The waitress bounced Eli gently on her hip, looking intently at his parents. Alan’s eyes were dry but glazed over. Both of their faces drooped listlessly. We must look like zombies, Gayle thought.

  The waitress clearly sensed that something terrible had happened; maybe she could tell that it had to do with Eli. Normally, Gayle would have made small talk to cover for a bad mood. She would have pretended things were fine. But today she couldn’t muster the energy. She stared at the laminated tabletop, half seeing her own reflection.

  She felt the waitress watching her, though, and finally lifted her head. The woman looked her in the eyes, still holding Eli, and said, “Do you know how lucky you guys are?”

  Gayle was touched. She smiled weakly but couldn’t speak. She knew she would cry. The waitress held her gaze.

  “Do you know how special he is?” she asked.

  Gayle blinked back tears. She wondered what exactly the woman had seen in Eli to make her say that: the twinkle in his eyes, or the way he held his hands out to her even before she asked to pick him up? Or was it something she saw in Gayle: the shadow of grief and loss that suggested she needed to be reminded of what she had?

  The waitress had seen Eli before—they’d been there often enough with him—but she’d never paid him this much attention. Now it was as though she could see into his soul—and into Gayle’s.

  Her words startled Gayle out of her stupor. She got the message: Snap out of it and love this baby. She reached out her hands to take back her son.

  Three

  Putting Williams on the Map

  Every baby has roughly a one-in-10,000 chance of being born with Williams syndrome. The likelihood is the same across countries and cultures, classes and races; scientists have found no geographic or demographic variables that make people more or less susceptible to the genetic deletion that causes it. Unlike Down syndrome, for example, it’s not correlated with older mothers—or, like autism, with older fathers.

  The number of Americans with Williams—approximately 30,000—pales in comparison to those with Down syndrome, which affects one in seven hundred people, or about 400,000 Americans. That number is rising, despite the prevalence of prenatal testing and the fact that about 70 percent of expectant mothers who are told their child will have Down syndrome choose to terminate their pregnancies. The growing Down syndrome population, then, is partly due to a marked increase in older motherhood and partly to health care advances that have made it possible for people with Down syndrome to live longer, healthier lives than ever before. Some scientists have estimated that the number of Americans with Down syndrome will double by 2025 to 800,000.

  The number of Americans on the autism spectrum, meanwhile, is estimated at about one in sixty-eight, or more than two million people. Most of us have at least met someone with Down syndrome, autism, or Asperger’s. Many of us will never meet someone with Williams. But we all benefit from research on the disorder. Despite its low prevalence, Williams syndrome has led to groundbreaking advances in gene mapping and been singularly helpful in unlocking the connections between our genes and our behavior.

  It’s notable among genetic disorders in that it involves a small, specific group of genes—twenty-six to twenty-eight, by most geneticists’ counts—and generates symptoms that are so distinct and observable. (People with Down syndrome, by contrast, have an extra copy of chromosome 21, giving them an additional two hundred to three hundred genes. That makes tracing symptoms back to the contributing genes exponentially more complicated, since symptoms depend as much on the interplay between genes as on the individual genes themselves.) And people with Williams are in a unique position to educate researchers, thanks to their striking verbal abilities.

  The study of so-called microdeletions, like the one that causes Williams syndrome, provided geneticists with some of their earliest entry points into the human genome—the massive, dauntingly detailed blueprint for who we are as human beings. Although a road map of the genome has existed since 2001, when researchers working on the Human Genome Project published a rough draft of the three billion bases that make up a DNA strand, much of the map remains essentially undecipherable even today.

  What the researchers mapped was the sequence of chemical “letters” that make up human DNA: the bases adenine, thymine, cytosine, and guanine (which geneticists abbreviate as the letters A, T, C, and G), strung like beads in varying patterns along each of twenty-three paired chromosomes. But identifying the letters didn’t mean they could read the map in a meaningful way. Linking genes to the traits they code for remains a distant Holy Grail for scientists, since most traits seem to depend on multiple genes, or perhaps even hundreds. More recently, geneticists have concluded that the non-gene portion of DNA—which they had once written off as “junk” DNA despite the fact that it constitutes roughly 98 percent of the genome—may in fact play a pivotal role in regulating genes, perhaps by switching them off or on, or by controlling how much protein results from a given gene’s activity.

  There was a lot to work with—too much, at least in the early days of the Human Genome Project, which began in 1990. The impetus for the project—a massive, worldwide research effort funded in part by the U.S. National Institutes of Health—was to seek out the genetic roots of common disorders, such as cancer and schizophrenia, and to use those findings to develop more effective treatments. Instead, the project revealed that disorders like these involved more genetic variables than researchers had previously imagined. Most of the implicated genes accounted for only relatively slight increases in the risk of developing these disorders, some of them no more significant than environmental factors.I

  Meanwhile, rarer disorders with small, isolated genetic footprints—including Williams, as well as single-gene diseases like cystic fibrosis, sickle-cell anemia, and Huntington’s disease, a degenerative brain disorder—led to clearer revelations about human biology and evolution.

  Take congenital leptin deficiency, an exceedingly rare disorder that causes extreme obesity from infancy. In 1994, when scientists isolated the single-gene malfunction behind the disorder, it marked a milestone in understanding how weight is regulated by the brain. The gene (called OB, as in obese) codes for the production of leptin, a hormone that sends signals to the hypothalamus about whether the body has sufficient fat reserves. Low leptin levels set off a hormonal alarm bell, warning the brain that the body urgently needs to stockpile more fat, which triggers a corresponding increase in appetite. So people with a mutated OB gene can’t stop eating because their brains sense, incorrectly, that they are starving. (Following this discovery, drug companies quickly began exploring whether supplemental leptin might be a magic bullet for obesity in the general population. It isn’t.)

  The same year that geneticists pinpointed the OB gene, they traced the most common form of dwarfism, achondroplasia, to a mutation in a gene called FGFR3, short for fibroblast growth factor receptor 3, which plays a key role in skeletal development. FGFR3 is one of a number of genes involved in bone growth, and the hallmarks of achondroplasia—shortened limbs, a normal-size trunk, and an enlarged forehead—helped scientists pinpoint exactly what types of bones it affects and at which developmental stages. The discovery of FGFR3’s connection to short stature led to a flurry of identifications, some within a matter of weeks, of other bone disorders that could be traced to the same family of growth-regulating genes.

  This burst of interest in rare bone disorders was a boon for the medically neglected people who had them, many of whom had struggled to find doctors who could treat
or even diagnose them correctly. It also helped spur an increase in funding for research into rare diseases, which policy makers had largely ignored in favor of more prevalent disorders—with the justifiable intention of doing the most good for the most people. As researchers have pointed out, however, a single rare disease may only affect a handful of people, but, as a class, rare diseases are not so rare at all. In the U.S., a rare disease is defined as one that afflicts fewer than 200,000 people. But that definition applies to more than 7,000 disorders that collectively affect more than 25 million Americans.

  New incentives soon emerged to encourage the study of these disorders. In 2009, the National Institutes of Health established its Therapeutics for Rare and Neglected Diseases program, which provides government funding to facilitate research and drug development. And in 2011, the National Human Genome Research Institute established the Centers for Mendelian Genomics, a network of researchers from around the world charged with tracing the genetic root of every Mendelian, or single-gene, disorder. Three years into that ambitious effort, researchers reported having averaged an impressive three genetic discoveries per week, successfully linking Mendelian conditions to 375 genes not previously associated with health effects.

  The scope of this research is broader than treating the conditions themselves, of course. Aside from helping people who have them, studying these rare disorders has given scientists a more precise key to cracking the genetic code. It has allowed them to examine the effects of one altered gene at a time, linking it to observable symptoms with relative clarity and certainty—especially compared to the most common method of studying gene function, which is essentially the opposite approach: attempting to unravel complex genetic interactions while working backward from a trait to its corresponding gene or genes.

  Using that method, known as a genome-wide association study, geneticists compare complete sets of DNA across large numbers of people. To find the genes for blond hair, for example, they’d gather a group of blonds and analyze their genetic sequences alongside those of people with other hair colors, in the hopes of finding statistically significant commonalities within the blond group. These studies are cumbersome, costly, and time-consuming, however, and on their own they are rarely conclusive.

  Studying what goes awry when a gene is missing or mutated is an easier and more definitive way to determine its function. There simply aren’t enough known Mendelian disorders, however, to allow geneticists to solve the genome’s puzzle one gene at a time. And although the technology exists to disable single genes in the laboratory, scientists studying altered cells in a petri dish won’t get very far in understanding the role a gene plays in development, or in traits like cognition or social behavior. Much of this research is conducted instead on “model organisms,” such as mice, rats, and flies. But what happens in a mouse doesn’t always translate exactly to what will happen in a human.

  This is why Williams is so tantalizing to geneticists: it offers them the opportunity to study the curious DNA behind a dazzling array of features that no amount of lab research could illuminate. Mice missing the Williams genes could never demonstrate the unique language abilities or musical skills common to the disorder, for example. Only people can do that. People with Williams, furthermore, are some of the most valuable research subjects on the planet when it comes to one of the trickiest realms in genetics: personality.

  * * *

  WILLIAMS IS RARE ENOUGH THAT it isn’t one of the standard conditions included in prenatal screenings for pregnant women. And although it can be diagnosed with a simple blood test once an infant is born, many doctors just don’t know to test for it. Its constellation of strange, seemingly unrelated symptoms are often mistakenly attributed to various more common disorders, including autism.

  One boy was diagnosed as a baby with fetal alcohol syndrome. Only when he was nineteen did a new doctor check for Williams. Suddenly the dichotomy between the boy’s math skills (abysmal) and his verbal abilities (nearly normal), and between his spatial skills (so bad he couldn’t draw a simple stick figure) and musical talents (which included perfect pitch and the ability to play some instruments by ear), made sense. Williams explained them all.

  A woman who recently celebrated her ninetieth birthday had been known throughout her life for her love of music, her radiant warmth, and her ability to bond instantly with people she’d just met. But she wasn’t diagnosed with Williams until she was eighty-three. And one high-functioning woman with Williams wasn’t diagnosed until she had a baby—who also had Williams. The DNA deletion that causes Williams is random, but once it has happened, it can be passed down. Having one parent with Williams gives a child a 50 percent chance of inheriting the syndrome. With two Williams parents, there’s a 50 percent chance of Williams, a 25 percent chance that the child’s DNA will remain fully intact, and a 25 percent chance that both copies of chromosome 7 will have the Williams deletion, in which case the pregnancy isn’t expected to be viable.

  Given the odds of running into someone who recognized Williams syndrome just by looking at him, Eli’s diagnosis in infancy was a fluke. Babies with Williams tend to be diagnosed primarily when their doctors notice signs of SVAS, the narrowing of the aorta that Eli was lucky to have in its mildest form. It’s such a rare condition, except among people with Williams syndrome, that it tends to be a giveaway for cardiologists. In fact, it was a cardiologist, John C. P. Williams, who first identified the syndrome in 1961, when he noticed that four children being treated for SVAS at his New Zealand hospital also shared similar facial features and intellectual disabilities. Dr. Williams published a paper on the similarities, suggesting that they might constitute a syndrome. A year later the German physician Alois J. Beuren arrived independently at the same conclusion, noting that three of his patients with heart defects both looked and behaved similarly. He wrote, “All have the same kind of friendly nature—they love everyone, are loved by everyone, and are very charming.”

  For a time, the disorder’s unique facial features became its defining trait. After Williams published his 1961 paper, it became known as “elfin face syndrome” (or “elfin facies syndrome”), but “Williams syndrome” eventually caught on instead—although “Williams-Beuren syndrome” is more common in Europe.

  Dr. Williams, however, was not interested in pursuing his namesake syndrome further. He returned to his regular cardiology studies, never to publish anything more on the subject. The following year he left New Zealand for a job at the Mayo Clinic, where none of his colleagues were aware of his research into the disorder or later recalled him ever mentioning it, according to the biologist Howard Lenhoff. In 1966, Dr. Williams moved to England, where he worked with Nobel Prize–winning physiologist Andrew Fielding Huxley at University College London. And in the early 1970s he simply vanished, leaving his colleagues, friends, and family to search for him in vain. It was a mysterious end for a mysterious man, whom colleagues described as “private” and “odd,” according to Lenhoff.

  In a biography of the New Zealand writer Janet Frame (a close friend of Williams) the historian Michael King describes Williams as an awkward, standoffish man, who once proposed to Frame by saying “Why don’t we formalize our relationship?” She declined. That was a year or so before his disappearance; Frame never heard from him again. Williams’s sister enlisted Interpol’s help to search for him, but they could find no trace of the wayward cardiologist. In 1988 the High Court of New Zealand declared him missing and presumed dead, although King claimed that Williams contacted him “indirectly” in 2000 and asked not to be mentioned in Frame’s biography. According to Frame, who died in 2004, Williams’s work at the Mayo Clinic had involved classified research for NASA into the effects of weightlessness on blood pressure and heart function, and the top secret assignment had led some of his friends to postulate conspiracy theories about his disappearance. If he were alive today, he would be in his nineties.

  John Williams may have had more in common with autistics than with those who h
ad the disorder that came to bear his name. He certainly didn’t invest much time in getting to know them. Perhaps a man whose marriage proposal sounded more like a legal document than a declaration of love was uncomfortable around people who might declare their love for anyone at any time.

  * * *

  I. Promising inroads have been made, however, and even partial genetic links have led to groundbreaking advances in individualized treatment for diseases such as cancer.

  Four

  Milestones

  For the rest of the year after that first genetics appointment, while Gayle contemplated Eli’s diagnosis, he remained in a kind of developmental limbo: not talking, not walking, barely crawling. Then, on Christmas Eve, two months before his second birthday, he was playing on the floor by the Christmas tree, festively attired in red footie pajamas. Gayle noticed a red blur out of the corner of her eye and turned to see Eli up on his feet, bobbling toward the tree. Despite her religious skepticism, she couldn’t help but consider this a Christmas miracle. Unwilling to believe that Eli’s life would turn out the way Dr. Pober had predicted, she’d clung to the dim but real hope that he would be an exception to the Williams syndrome rules. Now she felt that hope flare up again as she watched Eli take his first unsteady steps across the carpet. Maybe the developmental delay was behind them, and he was back on track—a little behind the curve, but catching up.

  Gayle started a scrapbook to commemorate the stages of their life together as a family. She bought heavy art paper and fancy pens. She made elaborate borders for Eli’s baby pictures, capturing the classics: Eli in his high chair, making a mess of spaghetti, and at bath time, swaddled in a towel. She wrote captions in careful block letters.