“That happens on Mondays, when the Cloisters is closed,” he said. He spends anywhere from a minute to an hour with the tapestries. “It can be an exceedingly frustrating experience. One ponders so many questions about the tapestries for which there are no more answers today than there were when I was in graduate school.” In some of the scenes, the unicorn may represent Christ. Alive and chained to the tree, after its apparent death in the hunt, it may speak of the immortality of the soul. Or the drops of blood may represent the pains of love. The truth is that the modern world has lost touch with the meanings in the Unicorn Tapestries. “Sometimes I come in here and try to pretend I have never read anything about them, never heard anything about them, and I just try to look at them,” Husband said. “But it’s not easy to shed that baggage, is it? And my other reaction, sometimes, is just to say, ‘To hell with it, someday someone will figure them out.’ And then there is a solace in their beauty, and one can stare at them in pure amazement.”
The Self-Cannibals
ONE DAY IN SEPTEMBER 1962, a woman who here will be called Deborah Morlen showed up at the pediatric emergency room of the Johns Hopkins Hospital, in Baltimore, carrying her four-and-a-half-year-old son, Matthew. He was spastic and couldn’t walk or sit up. As an infant, he had been diagnosed with cerebral palsy and developmental retardation. The hospital’s pediatric emergency room was in the Harriet Lane Home for Invalid Children, an old brick building that stood in the center of the Johns Hopkins complex. Deborah Morlen sat down on a wooden bench in the waiting room. Her son lay stretched across her lap. He couldn’t hold his head up, and his arms and legs thrashed around. His eyes were bright and restless. He was wearing mittens, though it was a hot day. Deborah Morlen had fastened the mittens tightly around his wrists with string, to keep them from falling off.
Eventually, a resident named Nancy Esterly saw Matthew in an examination booth, where she asked Deborah Morlen what was wrong.
Mattey was putting out strange-colored urine, Morlen told Esterly. “And there’s, like, sand in his diaper,” she said.
Nan Esterly removed the boy’s diaper. It was stained a deep, bright orange, with a pink tinge. She touched the cloth and felt grit. She had no idea what this was, except that the pink looked like blood.
She began asking questions of Deborah Morlen, getting the boy’s history. She eventually learned that Matthew had an older brother, Harold, who was also spastic and retarded, and also had had orange sand in his diapers. Harold was living at the Rosewood State Hospital, an institution for disabled children, outside Baltimore, while Matthew was living at home.
Since both brothers seemed to have the same condition, Nan Esterly thought it was likely that they had a genetic disease. A genetic disease is an inherited condition that runs in families, passing from parents to their offspring in their DNA. The human DNA, or human genome, is stored in the chromosomes, small elongated bodies in the nucleus of cells. Human cells contain two sets of twenty-three chromosomes (for a total of forty-six chromosomes in each human cell). The human genome contains a bit more than three billion letters of genetic code—enough letters to fill roughly a thousand complete editions of Edward Gibbon’s The Decline and Fall of the Roman Empire. A gene is a stretch of DNA that holds the recipe for making a protein or group of proteins in the body.
In 1962, not a whole lot was known about genes and the human DNA. Even so, by that time Johns Hopkins pediatricians had begun discovering many previously unrecognized genetic diseases. Some of the doctors, perhaps not very kindly, would occasionally refer to children with genetic diseases as FLKs, or funny-looking kids. The story around Johns Hopkins was that every time a kid with an unusual appearance showed up in the emergency room, a new genetic disease would be found. Nan Esterly noticed that Matthew Morlen was wearing mittens, even though it was a warm day. She admitted the little boy to the hospital.
* * *
ESTERLY TOOK a sample of the boy’s urine, and both she and an intern looked at it under a microscope. They saw that it was filled with crystals. They were beautiful—the crystals were clear as glass, and they looked like bundles of needles or like fireworks going off. They were sharp, and it was obvious that they were tearing up the boy’s urinary tract, causing bleeding. Esterly and the intern pored over photographs of various kinds of crystals in a medical textbook, trying to identify them by their shape. The intern asked if the crystals might be uric acid, a waste product excreted by the kidneys; however, cystine, an amino acid that can form kidney stones, seemed the more likely candidate. Esterly needed a confirmation of the diagnosis, so she carried the test tube upstairs to the top floor of the Harriet Lane Home, where William L. Nyhan, a pediatrician and research scientist, had a laboratory. “Bill Nyhan was the guru of metabolism,” Esterly told me.
Nyhan, who was then in his thirties, had built some equipment that he was using to identify amino acids. He had been identifying amino acids in cancer cells while trying to find ways to cure cancer in children. “It was one of my impossible projects in cancer research,” he told me. Nyhan later became a professor of pediatrics at the U.C. San Diego School of Medicine. “I love working with kids, but dealing with pediatric cancer was depressing, saddening, and, in truth, maddening,” he said. Nyhan ran some tests on Matthew’s urine, using the equipment he had designed. The crystals weren’t cystine or any sort of amino acid. They proved to be uric acid.
A high concentration of uric acid in a person’s blood can lead to gout, a painful disease in which crystals of uric acid grow in the joints and extremities, particularly in the big toe. Gout has been known since the time of Hippocrates, when ancient doctors recognized that it occurs mainly in older men. Yet the patient here was a little boy. Nyhan had a medical student named Michael Lesch working in his lab, and together they went downstairs to have a look at the boy with “gout.”
Matthew lay in a bed in an open ward on the second floor of the Harriet Lane Home. The ward was filled with beds, and most of them were occupied by sick children. Matthew was a spot of energy in the ward, a bright-eyed child with a body that seemed out of control. The staff had tied his arms and legs to the bed frame with strips of gauze, to keep him from thrashing, and they had wrapped his hands in many layers of gauze. They looked like white clubs. Nurses hovered around the boy. “He knew I was a doctor and he knew where he was. He was alert,” Nyhan recalled. Matthew greeted Nyhan and Lesch in a friendly way, but his speech was almost unintelligible: he had dysarthria, an inability to control the muscles that make speech. They noticed scarring and fresh cuts around his mouth.
They inspected Matthew’s feet. No sign of gout. Then the boy’s arms and legs were freed, and Lesch and Nyhan saw a complex pattern of stiff and involuntary movements, a condition called dystonia. Nyhan had the gauze unwrapped from the boy’s hands.
Matthew looked frightened. He asked Nyhan to stop, and then he began crying. When the last layer was removed, they saw that the tips of several of the boy’s fingers were missing. Matthew started screaming, and thrust his hands toward his mouth. With a sense of shock, Nyhan realized that the boy had bitten off parts of his fingers. He also seemed to have bitten off parts of his lips.
“The kid really blew my mind,” Nyhan said. “The minute I saw him, I knew that this was a syndrome, and that somehow all of these things we were seeing were related.”
Lesch and Nyhan began to make regular visits to the ward. Sometimes Matthew would reach out and snatch Nyhan’s eyeglasses and throw them across the room. He had a powerful throw, apparently perfectly controlled, and it seemed malicious. “Sorry! I’m sorry!” Matthew would call, as Nyhan went to fetch his glasses.
The doctors persuaded Deborah Morlen to bring her older son to the hospital. Harold, it turned out, had bitten his fingers even more severely than Matthew and had chewed off his lower lip down into his chin, at the limit of the reach of his upper teeth. Both boys were terrified of their hands and screamed for help even as they bit them. The Morlen brothers, the doctors found, ha
d several times more uric acid in their blood than normal children do.
Nyhan and Lesch visited the Morlen home, a row house in a working-class neighborhood in East Baltimore, where Matthew had been living with his mother and grandmother. “He was a well-accepted member of his little household, and they were very casual about his condition,” Nyhan said. The women had devised a contraption to keep him from biting his hands, a padded broomstick that they placed across his shoulders, and they tied his arms to it like a scarecrow. The family called it “the stringlyjack.” Matthew often asked to wear it.
Nyhan and Lesch also discovered that they liked the Morlen brothers. Lesch, who became the chairman of the department of medicine at St. Luke’s–Roosevelt Hospital, in New York City, said, “Michael and Harold were really engaging kids. I really enjoyed being around them. I got beat up once by Matthew.” He had leaned over the boy and asked him how he was feeling, and Matthew had slugged him in the nose. Lesch had staggered backward holding his nose while Matthew said, “Sorry! I’m sorry!”
* * *
TWO YEARS AFTER meeting Matthew Morlen, Nyhan and Lesch published the first paper describing the disease, which came to be called the Lesch-Nyhan syndrome. Almost immediately, doctors began sending patients they suspected of having the disease to Nyhan. Very few doctors had ever seen a person with Lesch-Nyhan syndrome, and boys with the disease were, and are, frequently misdiagnosed as having cerebral palsy. (Girls virtually never get it.) Nyhan himself found a number of Lesch-Nyhan boys while visiting state institutions for developmentally disabled people. When I asked him how long it took him to diagnose a case, he said, “Seconds.” He went on, “You walk into a big room, and you’re looking at a sea of blank faces. All of a sudden you notice this kid staring at you. He’s highly aware of you. He relates readily to strangers. He’s usually off in a corner, where he’s the pet of the nurses. And you see the injuries around his lips.”
* * *
WILLIAM NYHAN was eighty-one, a tall, fit-looking man with sandy-gray hair and blue eyes. He ran marathons until he was about seventy, half marathons after that; he was now the top-seeded tennis champion in his age class in southern California. He had a laboratory overlooking a wild canyon near the U.C. San Diego Medical Center. One day when I visited him, the Santa Ana wind was blowing in from the desert, and the air had an edgy feel. Two red-tailed hawks were soaring over the canyon, tracing circles in the air. The distinct movements of the hawks revealed a pattern of flight engraved in the birds’ genetic code.
In the years since he had identified Lesch-Nyhan, William Nyhan had discovered or codiscovered a number of other inherited metabolic diseases, and he had developed effective treatments for some of them. He had figured out how to essentially cure a rare genetic disorder called multiple carboxylase deficiency, which could kill babies within hours of birth, by administering small doses of biotin, a B vitamin. Lesch-Nyhan, however, had proved to be more intractable.
Decades after the discovery of Lesch-Nyhan syndrome, it is still mysterious. It is perhaps the clearest example of a change in the human DNA that leads to a striking, comprehensive change in behavior. In 1971, William Nyhan coined the term “behavioral phenotype” to describe the nature of diseases like Lesch-Nyhan syndrome. A phenotype is an outward trait, or a collection of outward traits, that arises from a gene or genes—for example, brown eyes. Someone who has a behavioral phenotype shows a pattern of characteristic actions that can be linked to the genetic code. Lesch-Nyhan syndrome seems to be a window onto the deepest parts of the human mind, offering glimpses of the genetic code operating on thought and personality.
* * *
H. A. JINNAH, a neurologist at Johns Hopkins Hospital, has been studying Lesch-Nyhan syndrome for more than fifteen years. “This is a very horrible disease, and a very complex brain problem,” he said to me one day in his office. “It is also one of the best models we have for trying to trace the action of one gene on complex human behavior.”
A child born with Lesch-Nyhan syndrome seems normal at first, but by the age of three months has become a so-called floppy baby, and can’t hold up his head or sit up. His diapers may have orange sand in them, and his body begins a pattern of writhing. When the boy cuts his first teeth, he starts using them to bite himself, especially at night, and he screams in terror and pain during these bouts of self-mutilation. “I get calls in the middle of the night from parents, saying, ‘My kid’s chewing himself to bits, what do I do?’” Nyhan said. The boy ends up in a wheelchair, because he can’t learn to walk. As he grows older, his self-injurious behaviors become subtle and more elaborate, more devious. He seems to be possessed by a demon that forever seeks new ways to hurt him. He spits, strikes, and curses at people he likes the most—one way to tell if a Lesch-Nyhan patient doesn’t care for you is if he’s being very nice. (He wishes you would go away, so the Lesch-Nyhan part of him tries to keep you near him.) He eats foods he can’t stand; he vomits on himself; he says yes when he means no. This is self-sabotage.
A few hundred boys and men alive in the United States today have been diagnosed as having Lesch-Nyhan syndrome. “I think I know most of them,” Nyhan said. A boy known as J.J. whom Nyhan found in a state institution, where he’d been considered spastic and mentally retarded, ended up living in Nyhan’s research unit for a year. He was a lively, gregarious child whose hands seemed to hate him with a demonic precision. Over time, his fingers had gotten into his mouth and nose, and had broken out and removed the bones of his upper palate and parts of his sinuses, leaving a cavern in his face. He had also bitten off several fingers. J.J. seemed happy most of the time, except when he was injuring himself.
J.J. died in his late teens; in the past many Lesch-Nyhan patients died in childhood or their teens, often from kidney failure. (Both Morlen brothers died young.) Nowadays they may live into their thirties and forties, but they often die from infections like pneumonia. Occasionally, a man with the disease flings his head backward with such force that his neck is broken, and he dies almost instantly.
A Lesch-Nyhan person may be fine for hours or days, until suddenly his hands jump into his mouth with the suddeness of a cobra strike, and he cries for help. People with Lesch-Nyhan feel pain as acutely as anyone else does, and they are horrified by the idea of their fingers or lips being severed. They feel as if their hands and mouths don’t belong to them, and are under the control of something else. Some Lesch-Nyhan people have bitten off their tongues, and some have a record of self-enucleation—they have pulled out an eyeball or stabbed their eye with a sharp object such as a knife or a needle. (The eye is a soft target for the hand of a Lesch-Nyhan person.) When the Lesch-Nyhan demon is dozing, they enjoy being around people, they like being at the center of attention, and they make friends easily. “They really are great people, and I think that’s part of the disease, too,” Nyhan said. Some Lesch-Nyhan people are cognitively impaired and others are clearly bright, but their intelligence can’t be measured easily. “How do you measure someone’s intelligence if, when you put a book in front of him, he has an irresistable urge to tear out the pages?” Nyhan said.
J.J., one of the earliest Lesch-Nyhan patients diagnosed by William L. Nyhan. His fingers pulled out the bones of his upper palate and sinuses, while his teeth removed several fingers. The bumps at the top of his ear were caused by gout; they are deposits of uric acid crystals known as tophi. J.J. was an outgoing child, very popular with his caregivers. He may be smiling in this picture, and he seems to have closed his eyes in anticipation of the camera flash.
William L. Nyhan
* * *
IN 1967, J. EDWIN SEEGMILLER, a scientist at the National Institutes of Health, and two colleagues discovered that in Lesch-Nyhan patients a protein called hypoxanthine-guanine phosphoribosyl transferase, or HPRT, which is present in all normal cells, doesn’t seem to work. The enzyme is especially concentrated in deep areas of the brain, around the brain stem. The job of this enzyme is to help recycle DNA. Cells are constantly b
reaking DNA down into its four basic building blocks (represented by the letters A, T, C, and G, for adenine, thymine, cytosine, and guanine). This process produces compounds called purines, which can be used to form new code. When HPRT is absent or doesn’t work, purines build up in a person’s cells, where they are eventually broken down into uric acid, which saturates the blood and crystallizes in the urine.
In the early 1980s, two groups of researchers, one led by Douglas J. Jolly and Theodore Friedmann, decoded the sequence of letters in the human gene that contains the instructions for making HPRT. It includes 657 letters that code for the protein. Researchers also began sequencing this gene in people who had Lesch-Nyhan. Each had a mutation in the gene, but, remarkably, nearly everyone had a different one; there was no single mutation that caused Lesch-Nyhan. The mutations had apparently appeared spontaneously in each affected family. And in the majority of cases, the defect consisted of just one misspelling in the code. For example, an American boy known as D.G. had a single G replaced by an A—one out of over three billion letters of code in the human genome. As a result, he was tearing himself apart.
The HPRT gene is found on the X chromosome, which is the female sex chromosome and carries information that makes the person female. Women have two X chromosomes in each cell, and men have an XY pair. Lesch-Nyhan is an X-linked recessive disorder. This means that if a bad HPRT gene on one X chromosome is paired with a normal gene on the other X chromosome, the disease will not develop. A woman who has the Lesch-Nyhan mutation but carries it on only one of her X chromosomes doesn’t develop the syndrome. Any son she has, however, will have a 50 percent chance of inheriting the syndrome (if he gets the bad X chromosome, he will have the disease; if he gets the good one, he won’t), and any daughter will have a 50 percent chance of being a carrier. (Examples of this type of X-linked recessive disease include hemophilia and a form of red-green color blindness. Queen Victoria was a carrier of the hemophilia gene, but she didn’t have hemophilia. Some of her male descendents had it.)
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