Blood Matters

by Masha Gessen

  It may not always have been easy and obvious, and it was profoundly frustrating at times, but on the whole, genetic analysis as practiced at the Clinic for Special Children in Strasburg, Pennsylvania, represented a thorough demystification of the science.

  ***

  The P. family came in with two boys, ages five and six. Morton knew the Amish family well: Its four affected children had allowed him and Puffenberger to diagnose a disease that had not been named, and to find the mutation that caused it. The parents were both thin, very light-haired, very young, and very tired. They had had extremely poor genetic luck: Four out of four of their children were affected. Children with this disease are born apparently normal and develop well, with perhaps slight motor delays, until the age of eighteen months. Then they begin having seizures, their language ability disappears, and social skills deteriorate. “If they were somewhere else, they would probably be diagnosed as autistic,” Holmes Morton explained. He had as little regard for this possible diagnosis as for any umbrella term that he believed obscured the fact of a genetic abnormality.

  The two P. boys were beautiful, with large eyes and smooth light brown hair, cut roughly—clearly at home—and a little long. They wore maroon shirts and the usual thick black trousers with suspenders. When I came in, they were sitting quietly in their parents’ laps. Then Isra, the younger boy, stood up, stumbled over to me uncertainly, and poked his finger at the fly of my jeans, which was directly at his eye level. He then leaned with his elbows on a chair seat, stuck his head against the chair back, and pushed. His brother Nathan was doing the same in his father’s lap, butting his head against his father’s stomach insistently.

  Isra had noticeably better coordination than his brother. He had a vagal nerve stimulator—an electrical device that is implanted in epilepsy patients to help control seizures. His older brother, unfortunately, was not a candidate for this surgery, because he was having seizures on both sides of his brain. Isra’s seizures had stopped after his surgery. “We thought we had it licked,” said Morton. But after nine months the seizures returned, although they were apparently less frequent than before.

  Susie, the boys’ three-year-old sister, was affected a bit less severely. “She is talking more than the boys ever did,” said their mother. The boys were now both on the floor, Isra rolling around with his diaper sticking out the top of his trousers and Nathan sitting quietly. Their youngest brother, Ethan, may have been the luckiest: He was diagnosed early, because by that time Puffenberger had identified the mutation that caused the disorder. Dr. Morton put him on valproic acid, which is commonly used to treat seizure disorders and some other neurological conditions, and so far, at the age of twenty months, he had not had seizures. He was learning to talk.

  The boys had the clinic’s disease of the month. The clinic team’s article on identifying the mutation was coming out in the next issue of the New England Journal of Medicine. They had not only defined the disorder but had found a mutation that seemed to shed new light on a substance called contactin-associated protein-like 2, or CASPR2, which, they now suggested, influences brain development. The genetic mutation in these children meant they had less CASPR2 than is normal.

  “Maybe as they grow older we might still see changes?” asked the father. Ethan’s apparent health had made him hopeful that valproic acid might help his older sons, too. Morton nodded.

  “Interesting thing about valproic acid,” he began, and launched into a small lecture involving the spectacular qualities of a remarkably versatile drug, gene expression, and the small but valid hope that he still had for being able to help Isra, Nathan, and Susie. “These children are actually better off than Annabelle was,” he pointed out, referring to a girl from a different family. “She just seized until her brain burned out.”

  The father nodded. This was clearly not the first time he had discussed gene expression with Morton. But today the family had come in with a more pedestrian complaint: Both of the boys had earaches. Morton had given them ibuprofen, and as the visit went into its second hour, it became evident that the pain reliever was working. “What was the name of the medicine you gave them?” the father asked. Ibuprofen, said Morton, and added that Tylenol would also work. “Are they safe to take?” the father double-checked. “Are they available in drugstores?” Thanks to Morton and his colleagues, knowledge of gene expression was more common than ibuprofen and Tylenol in the very separate world of the Old Order Amish.

  Morton walked the P.’s to the waiting area, where he told the receptionist, “We had short visits.” The family had spent an hour and a half in the exam room. They had had time, too, to talk about other families with similarly affected children, and to agree to get one of them to come in to be tested for the newly discovered mutation. Morton had promised to do the test free of charge.

  ***

  On the evening of the second day I spent with Morton, I finally saw him eat. Lancaster, Pennsylvania, has a perfectly ordinary highway cutting through it, with discount shopping malls, Staples and Holiday Inns along it, as well as a roadside Waffle House. I sat in a booth with Morton, Puffenberger, Strauss, and Charles Hehmeyer, a medical malpractice lawyer who had driven the two hours from Philadelphia to help the clinic’s staff teach a class at Franklin and Marshall College, where we would all go after dinner. On the face of it, this was a clear case of overkill: Four grown, professional, even famous men teaching a two-hour undergraduate seminar was probably three men too many, even if the students were the sort most valued by Morton—unspoiled by medical school and the business of medicine as business. But I had already realized that resources around here were allocated very differently from anywhere else I had seen, especially anywhere else in the United States.

  The topic of that night’s Franklin and Marshall class was newborn genetic screening. The team’s basic policy suggestion: test all babies for all diseases, including rare ones. Morton had successfully campaigned to add some rare disorders to Pennsylvania’s newborn screening panel. Charles Hehmeyer had been suing hospitals across the country for malpractice in cases where children died of or were disabled by genetic disorders that could have been diagnosed and addressed at birth. A few unlucky undergraduates were assigned to defend the opposing view, and they had done the best they could to advance the argument that the diseases were so rare that testing children for them was, on a large scale, a waste of money. This reasoning, standard for health-care bureaucracies, was indefensible under the circumstances. First, adding disorders to the existing testing panels barely increased the cost of the procedure. Second, by Hehmeyer’s count, in the United States a thousand children a year were killed or injured by the preventable effects of undiagnosed genetic metabolic disorders. And third, these four remarkable men had come to tell the students that, basically, everyone should be tested—for everything, if necessary.

  The intoxicating sense that anything was possible, which pervaded the work of Morton and his associates, was natural and integral to his thinking. Within perhaps half an hour of meeting, he and I had engaged in a discussion about the pros and cons of testing children for adult-onset diseases. Conventional wisdom, professional consensus, and general policy were all clear on this much: Genetic testing of minors should be performed only if it is of immediate medical benefit. My own mutation was often used as an example of a mutation for which it would be counterproductive and possibly dangerous to test a child. The arguments were that the child would come of age some years before she was likely to develop cancer and could make her own decision about testing then—by which time effective treatments might have been developed—and that informing her parents might result in fragile-child syndrome and otherwise complicate relations. But just a week earlier I had heard Stephen Narod, billed as the world’s most-cited expert on breast cancer, tell a conference audience that the course of breast cancer in mutation carriers seemed to be determined in adolescence. For example, a girl with a BRCA1 mutation who had her first period after the age of fourteen was less than h
alf as likely to develop premenopausal breast cancer as a girl with the mutation who had her first period at eleven or earlier. This, said Narod, seemed to suggest that whatever ultimately set off the cancer started happening at puberty. My mind rushed: It was entirely possible to affect the age of onset of menstruation through exercise and diet. Should I have my daughter, who was four and a half at the time, tested for the mutation and then decide, say, whether to encourage her dream of becoming a professional figure skater? Professional-level athletic training would give her a good shot at delaying the onset of periods, thereby cutting her risk of cancer in half. Granted, choosing a demanding and dangerous sport was a complicated decision and I was not certain I would ever really encourage it, but now it seemed there was an important unknown in the equation. Following his talk, I asked Narod whether his study results suggested that prepubescent girls should be tested for BRCA1 mutations. To my surprise, he adamantly defended the professional consensus, saying children should not be tested.

  Morton, on the other hand, was in favor of genetic testing, period. His arguments, too, were unassailable. First of all, knowledge was power, and diagnostic knowledge meant the power to heal, or at least to treat. In the case of incurable and untreatable diseases, the right genetic diagnosis would at least save parents tens or hundreds of thousands of dollars that they might otherwise spend trying to figure out what was wrong with their children—something that had happened to a number of Amish and Mennonite families—and might bring a kind of peace, as it clearly had for Susie, whose children Morton had diagnosed when it was too late to help them. Attempting to help even a hopelessly sick child might ultimately yield treatment for others with the same diagnosis—provided there was a diagnosis. The same was true for adult-onset and late-onset diseases, Morton argued. Take Huntington’s. Studying people believed to be presymptomatic would yield a better understanding of early symptoms, which would ultimately lead to treatment or prevention. The same argument held for hereditary cancers. Fundamentally, he believed, the more you knew, as a patient or as a doctor, the better. Sure, one had to be honest, caring, and ethical, but special rules created to insulate people from genetic tests in particular seemed only to irritate Morton and his team.

  I came to think that the difference between those at the Clinic for Special Children and other doctors, geneticists, and genetic counselors I had met was that here in Lancaster, Pennsylvania, people really believed that treatments, cures, and other breakthroughs were just around the corner. The rest of us talk about living in an age of unprecedented medical progress; these people were actually living in it. Most medical researchers have had the experience of spending several years working on a failed treatment—or even just a failed idea for a treatment that was never so much as tested. Morton, despite his grudge over having been beaten out for a grant two decades ago, had never experienced the sort of devastating failure that irreparably alters a person’s sense of time, progress, and his own utility. In fact, he had to be one of the luckiest doctors on the planet. He had built his own clinic. He had revolutionized health care in two populations, the Amish and the Old Order Mennonites. He had developed effective treatments for diseases that used to cripple and kill universally. By all accounts, his less-than-total success with glutaric aciduria type 1 troubled Morton terribly, but on the whole he had one of the most creative and rewarding jobs in all of American medicine. What for other doctors, those anchored in traditional research centers, might have been career-making events were for Morton virtually daily occurrences: identifying new diseases, inventing new approaches to treatment, running experiments at will.

  “We have our gene therapy,” he told me, laughing. The promise of gene therapy, which had in the 1990s seemed like the imminent and obvious result of all the advances in genetic research, had been receding for nearly a decade. In 1999, at the University of Pennsylvania, an eighteen-year-old man named Jesse Gelsinger died four days after receiving an experimental gene therapy treatment aimed at curing his ornithine transcarbamylase deficiency, a metabolic disorder that had required him to stick to a low-protein diet and a drug regimen. His immune system went into fatal overdrive in response to the adenovirus used as the vector to deliver the therapeutic gene. He died of inflammatory shock: His blood developed clots, and many of his organs failed. The Food and Drug Administration reacted by shutting down a number of gene therapy trials around the United States; several research centers shut down their trials voluntarily. The University of Pennsylvania disciplined the director of its gene therapy program, James Wilson, by restricting him to animal experiments.

  The first human gene therapy trial considered successful was performed at the Hôpital Necker-Enfants Malades in Paris in 2000–2002. It involved eleven boys affected with the “bubble boy” disease, the severe genetic immune deficiency. (The patients were all boys because their particular mutation was X-linked.) Nine of the boys were considered cured. Within two years of the trial, however, three of the patients developed leukemia. One died, while two others were helped by chemotherapy. As soon as news of the first case of leukemia got out, the Paris hospital halted its trial, and similar trials were stopped in the United States. The leukemia was subsequently shown to have resulted from the gene transfer—in yet another in a long line of setbacks showing that routine gene therapy is probably decades away.

  In 1995 the Wall Street Journal predicted that a gene therapy product would be on the market within a year. That may have been hype, but certainly by June 2000, when President Bill Clinton and British prime minister Tony Blair stood side-by-side to announce the completion—technically the near-completion, at that point—of the sequencing of the human genome, gene therapy seemed at hand. This was the basic promise of the era of medical genetics. It would allow doctors to dig down to the root causes of disorders and body responses. It would then allow doctors to calculate the best course of action for treating a particular individual. Best of all, it would allow doctors to tinker with the mechanism itself, treating not the symptoms of a disease or even the disease itself, but the cause of the disease.

  This has already happened, in a way. Eight of the boys from that Paris trial, including the two who survived leukemia, were alive and basically healthy at the time of this writing. Normally, children with this disorder could not survive more than a year without a bone-marrow transplant. In fact, the very first gene therapy attempt, performed on a four-year-old girl from Cleveland in 1990, was successful: Ashanthi DeSilva, who suffered from an adenosine deaminase deficiency, another cause of severe immune deficiency, was cured. Gene therapy trials in patients with lung cancer, pancreatic cancer, and malignant melanoma have all shown promise. Several lives have been saved. The difference between the promise of gene therapy and its practice to date is scale. The initial vision, even if no one quite articulated it, was that of an assembly line: All of us become reduced to a long line of letters, all of which can be examined, the causes of disease pinpointed and fixed. It would be like doing a check on a problematic computer hard drive, combing through every byte of information to identify and, if possible, to correct each error.

  That may happen eventually, when we learn much, much more about the mechanisms by which genes cause disease. But it may never happen. It may turn out that the uniqueness of each human body exceeds all the computing power humans are capable of developing: There will always be too many variables and unknowns.

  The clinical trial that ended with the death of Jesse Gelsinger involved seventeen other people—none of whom suffered a reaction like Gelsinger’s. There was talk that if the young man’s own treating physician had been involved in his care following the gene transfer, the complications could have been handled better. Knowing his patient, he might have used his experience and his informed intuition to help him. It seems obvious, but in a basic sense it goes against the very premise of gene therapy: that a single genetic condition will have a single genetic cure, which can be administered almost automatically.

  What Morton meant when h
e said “We have our gene therapy” was actually referring to the use of liver transplants. He had figured out that maple syrup disease can be cured by liver transplant. Even though the patients’ bodies were genetically programmed to lack a necessary enzyme, the insertion of a healthy liver would fix the problem. Several of Morton’s patients—some who had problems that exacerbated their symptoms, and one who had had enough of drinking formula—had opted for the operation. In a particularly exciting experiment, a team in San Diego transplanted a healthy cadaverous liver into a maple syrup patient and the maple syrup patient’s liver into a man who was dying of liver cancer. The maple syrup liver was healthy, and the recipient’s body managed to provide the enzymes to make it function normally. “That’s actually the neatest thing about transplants—what we call ‘domino transplants,’” said Morton, and then repeated his almost-joke about already practicing gene therapy.

  He was right, as usual. Gene therapy, like genetic medicine in general, will be practiced one patient at a time. And this was exactly what was already happening at the Clinic for Special Children. Erik Puffenberger was already isolating mutations one patient at a time. Holmes Morton and Kevin Strauss were inventing treatment protocols one patient at a time. This was the handmade version of the imagined assembly line of the future. That future may or may not happen, but until then, we all will want a kindly country doctor tinkering with our genes, which he can navigate like they were his own.