His Brother's Keeper

by Jonathan Weiner

  I felt a creator’s pride in my idea. I was experiencing firsthand the glamour that even a very ugly thought can acquire when that thought is your own. For a few days, I understood what the atomic scientist meant at Los Alamos when he spoke of the “technically sweet.” I sat up late into the night scribbling until the nearest Homo sapiens sapiens rolled over and murmured, “My husband, Doctor Frankenstein.”

  A few days later I thought I found a fatal flaw in the plan. When I got out a few genetics textbooks and looked up chromosome translocations, I saw that moving chromosomes around is dangerous. Some people who make babies with Down’s syndrome have a piece of chromosome 14 on chromosome 21. People who die of Burkitt’s lymphoma have a piece of chromosome 8 on chromosome 14. People with still another misfiled fragment are born with a syndrome called cri du chat, the cry of the cat. They have tiny heads and thin, high-pitched wails, and they die in infancy. If you chopped up human chromosomes and moved them around, you might hurt the babies, and you might not know the damage until they grew up.

  Suppose you changed only a single gene in the sperm and a single gene in the egg to alter one of the chemical signals by which they recognize each other. Then the sperm of your Adams could meet only with the eggs of your Eves. But you might not know what other kinds of work that particular signal does in the human embryo or in the adult brain. You could not know with certainty what your little project might destroy in your progeny, until you tried the experiment. Who knows? You might even alter the moral sense, as Dr. Jekyll altered Mr. Hyde’s. You might change something that is deeply and subtly human, so that the adult who sprang from that altered egg would give everyone near him a sense of obscure inner deformity, as Hyde repelled everyone he passed in the fogbound streets of London.

  I stopped by Silver’s office to tell him that the Adam and Eve project could not work—but he dismissed my objections. He said one did not need to understand the evolution of reproductive isolation in order to engineer it, any more than one needed to understand the evolution of flight in order to build an airplane, or the evolution of the brain in order to build a computer. He thought it would be straightforward to avoid harmful translocations, for instance, and to make only benign ones. “Millions of translocations and rearrangements happen all the time,” Silver said. “Most of them do absolutely nothing.” In fact, he said, in many infertility clinics, men and women are checked for these chromosome translocations as a matter of routine.

  He pulled down a book from his shelf, Infertility in the Male, by Anne M. Jequier, and opened it to chapter nine. According to the book, men walking into infertility clinics are eight times more likely to have translocations than men who are fertile. In most cases, there is nothing else wrong with them, nothing at all. They are as healthy as the mice in that Swiss valley. As I stared at the page of statistics, it dawned on me that there would be virtually no guesswork involved in choosing translocations for the Adams and Eves.

  “You could copy the translocations from the records at an infertility clinic,” I said.

  “You’re right! I didn’t think of that!” Silver said. “You actually have the experiment in hand.”

  We both laughed tight little laughs.

  “This is scary,” Silver said. “This is very scary.” In a way, he said, it reminded him of 1975, when molecular biologists were so unnerved by genetic engineering that they called a moratorium. “They thought they were playing God back then!” Silver said. “But now we’ve reached another point. They were fooling around with human genes. They weren’t fooling around with human beings.”

  The creation of a new human species is one of the many strange possibilities that are now in our hands. It could be done. In the end, the only ineradicable problem in the project may be the one that Shelley and Stevenson both foresaw from the beginning, the flaw that gives their novels power: the pathos of the creatures themselves. No matter how well you made your fifty Adams and Eves, they could never mate with anyone but each other—breeding in a bottle, like fruit flies, with no escape. They would have every right to be furious. They might gnash their teeth at their creators. They might cry out as Adam does in Paradise Lost, in the lines that Mary Shelley chose as the epigraph to Frankenstein:

  Did I request thee, Maker, from my clay

  To mould me Man, did I solicit thee

  From darkness to promote me?

  Part Three

  The Construct

  Who is strong enough to rule the sum of the immeasurable; who to hold in hand and control the mighty bridle of the unfathomable?

  LUCRETIUS

  Nineteen

  The Cowboy

  I thought I would leave you alone until I got something done.”

  It was Jamie Heywood. He was calling from a cell phone in his car. “We’re feeling good,” he said. “Things are going.”

  Jamie sounded level and confident. When I heard how much he and his family had done since we last spoke, I was amazed.

  It was summer now, the summer of ’99, and from what Jamie told me, the Heywoods were all having a hectic ride. I had to watch. I pitched the story to my editor at The New Yorker, and went to work.

  Just after our dinner at Paganini in April, Jamie had been sitting at his door-desk in the basement with Melinda and their friend Robert Bonazoli when the phone rang. It was one of the gene therapists on his long list, returning his call. The name of the scientist, Matthew During, meant nothing to Robert and Melinda, but Jamie knew that he was one of the boldest and most controversial young doctors in the field. He was also the one whose work came closest to the genetic engineering project that Jamie had invented for Stephen.

  Matt During had been trying for a few years to develop gene therapies for neurodegenerative diseases, including Alzheimer’s and Parkinson’s. The project that had made him famous, or notorious, had begun in 1995 when he was a young, ambitious doctor at Yale, still in his thirties. He was working there with another neuroscientist, Paola Leone, and she was young and ambitious, too. The parents of a baby with a rare and grotesque neurodegenerative disease, Canavan’s, had approached the two of them and persuaded them that Canavan’s would make an ideal disease on which to try out and refine the tools of gene therapy. If During and Leone could figure out how to get the right piece of DNA into the nerve cells of the dying baby, they would know right away by certain simple diagnostic signs whether the DNA was working—even if they did not save the baby. Then they could do the same thing with different DNA injections for patients dying of many of the other more common horrors like Alzheimer’s and Parkinson’s. They could use the Canavan baby for a Phase 1 safety trial: a first step toward a treatment. But of course the baby’s parents, a doctor and a psychologist in New Fairfield, Connecticut, hoped that by some miracle the experimental treatment would do more than help these young doctors refine their tools.

  Matt During and Paola Leone had thrown themselves into the design of a gene therapy for Canavan’s. The clock was ticking because a Canavan baby is born healthy and then becomes rapidly paralyzed, blind, and retarded, and begins to suffer from seizures. Such babies die by the time they are five, ten at most, but they are gone long before that. During directed the science on the team and Leone was one of his postdocs. Their project would have to get the approval of review boards at Yale and then in Washington. In Washington they would have to get their proposal past the RAC, and then the FDA. But if they were to help that baby, they had no time.

  During and Leone believe that gene therapy will cure these incurable diseases and many others. They dream of revolutionizing the practice of medicine. Like Jamie, they have the outlook of outsiders, rebels with a cause, partly because they are young and ambitious and partly because they each come from islands far from the centers of the biomedical empire: During from New Zealand and Leone from the island of Sardinia. During was being courted at the time by the University of Auckland in New Zealand, and he decided to leave Yale and carry out the Canavan experiment there.

  At Auckland,
he injected DNA into two Canavan babies from America, one of them the baby from Connecticut. By now, parents of many other Canavan babies in America were besieging the young doctors to inject DNA into their babies. So even before the first round of gene injections, During and Leone had begun planning a second round, this time for eight American children with Canavan. This round, like the first, was designed to test whether the procedure was safe.

  The work made Matt During instantly famous in New Zealand as the first pioneering geneticist there to do gene therapy. Back in the United States, a member of the RAC happened to read about the trials in a newspaper, and decided that During and Leone had gone around Yale’s ethical review board, and the RAC, and the FDA, to treat these American babies in Auckland. A story about this accusation appeared in the British medical journal The Lancet. During protested. He said he had gotten approval for his plan from authorities at Yale and in New Zealand. But The Lancet quoted someone on the RAC as saying that his claim was “inaccurate to put it politely.” An ethicist at Otago University in New Zealand charged that since the babies could not give consent and since the trial could not cure them but was purely for the future, During and Leone were “using children in a manner which is not acceptable under any international criteria.”

  It became one of the celebrated cases at the edge of medicine. Matt During was forced to delay the second round of injections. He went back to Yale, and parents in America found senators to pressure the university to approve the experiment. The board of Yale’s biosafety committee met again and again, and could not agree to allow it. The babies were doomed and their parents were desperate; but gene therapy had never saved one human being. An article in Nature that fall reviewed all of the gene therapies that had ever been tried. That year, doctors were injecting their patients with genes to treat or cure cancer, heart disease, and dozens of rare genetic diseases. “Although more than 200 clinical trials are currently under way worldwide with hundreds of patients enrolled, there is still no single outcome that we can point to as a success.”

  Which was true, unless you counted the babies that Jacques Cohen had brought into the world by cytoplasmic injection. But gene therapists did not know about that.

  Eventually the Canavan controversy made both 60 Minutes and the cover of the New York Times Magazine. The article in the Sunday Times was written by the reporter Michael Winerip. He said Paola had shouting matches with one of their older, more conservative colleagues at Yale, a doctor with the lovely name of Margretta Seashore. The magazine’s cover was designed to grab and shock. It showed a snapshot of one of the Canavan babies whose parents wanted him in the second round of injections. He was a toddler named Jacob Sontag, a very little boy with a face pathetically thin for his oversize, thick glasses. The text read:

  Their 19-month-old boy was deteriorating, and Richard and Jordana Sontag had come to Yale, desperate and angry. An experimental gene therapy was their only hope, but the scientists were not sure it was safe. The couple spotted Dr. Margretta Seashore in the lobby. “Look at him,” Richard said, thrusting Jacob in her face. “You tell him why this protocol is delayed while he’s dying…. You look at my son dying. Tell it to him.”

  Pressure built at Yale. Jacob Sontag received the injections of DNA on January 22, 1998, and a second round of injections that September. By now the boy was two and a half. He and the other babies who got the injections continued to decline, although some of the parents believed they saw a few subtle improvements. So did Paola, a passionate scientist who often fell in love with Canavan babies and their families. A paper that Matt and Paola published later on in Annals of Neurology presents evidence that their gene therapy had made the slight but measurable differences in brain chemistry for which they had hoped.

  The two young scientists left Yale. They were given a large laboratory and a generous welcome at the Jefferson Medical College in Philadelphia, which is a strong medical school but one tier down from Yale. To attract them, the school allowed Matt to set up his own center there, the CNS Gene Therapy Center (CNS for central nervous system). The school allowed him to keep his appointment in Auckland, where he still ran a large laboratory.

  Jamie Heywood knew all of this, having done his homework. He was electrified when he heard Matt During’s name on the phone. So far, of course, Matt and Paola had saved no one with gene therapy. Still, they had carried out the world’s first gene therapy for a neurodegenerative disease of the brain. And best of all, from Jamie’s point of view, they were fighters and fast workers. From the day that Matt and Paola were approached by the first parents of a baby with Canavan’s to the day they were injecting DNA into that baby’s brain was only twelve months.

  Down in the basement, when Jamie took the phone to speak with During, Melinda and Robert could see that he was on. He was projecting his confident voice, highly caffeinated and candidly seductive at the same time. And Jamie did feel very sure. He was ready. After pitching his gene therapy idea to more than sixty people, he had learned the lingo. He knew enough to engage Matt During properly.

  When he hung up the phone, he looked at Robert and Melinda.

  He said, We’ve got the guy.

  On April 23, 1999, Jamie met Matt During for lunch at Jefferson in Philadelphia. From their phone talk, Matt had gotten the impression that Jamie was a biologist. Even so, the two of them sized each other up and clicked immediately. They are both pragmatic, urgent men with adventurous grins. In fact, they look like brothers: boyish and very fit, with short-cropped brown hair and sharp cleft chins. Matt was forty-two that year, but he looked only slightly older than Jamie. Like the three Heywood boys, he is an athletic dreamer with an air of slightly raffish competence, a sort of impatient willingness to dare.

  Jamie, with his strategy of WIIF’M, had decided exactly what assets he brought to Matt During. He had his connections at the Neurosciences Institute and even stronger connections at MIT, through his father and Alexander d’Arbeloff, chairman of the board of trustees of MIT. Matt had studied at Harvard and MIT and worked at Yale; anyone who met him at that time could see right away that he was feeling slightly defensive about his new berth at Jefferson Medical College. Jamie also had his connection with Bob Brown at Harvard, and the enthusiasm of Jeff Rothstein at Johns Hopkins, who had promised to help if Jamie could find a gene therapist. Besides these assets, Jamie could offer his own skills as a project manager and entrepreneur. He could also offer a patient who would risk a dangerous treatment if he gave the word.

  An explorer is always looking out for ships of opportunity, and this looked like a good ship to Matt During, who was used to talking with families of desperate people. He could see that Jamie had studied the disease and the playing field, and he liked the offer. Over their lunch he told Jamie that he was interested in exploring Jamie’s idea for a gene therapy, and if they decided to proceed together, he had the resources to help. In Auckland, where he spent part of every year, he had sixteen or seventeen people in his lab; and that year he had fifteen at Jefferson, along with three PhD students from Auckland who worked with him there. All this was true, although Jamie could see that Matt’s center at Jefferson was still new and raw, a meandering and disheveled maze of half-furnished rooms and crowded hallways lined with opened and unopened crates and stacked boxes of surgical latex gloves, even a lost-looking couch. The place felt as if the movers had just trooped through and were about to come back.

  With their colleagues in Philadelphia and Auckland, Matt and Paola were now developing gene therapies for Canavan’s, Parkinson’s, diabetes, epilepsy, Huntington’s. Matt was preparing a paper about the improvement of memory through gene therapy. That year one of the thrillers on the big screen was Deep Blue Sea, about super-smart sharks. Matt was tickled by the movie because his gene therapy project had strikingly improved the memory of laboratory rats. He liked to say that their IQ scores were 170 or so. Very, very smart. A close-on genius rat.

  Matt was working on still other research projects so new and novel that
he was having trouble getting the results published, he told Jamie. He thought Jamie might want to consider not only the EAAT2 gene therapy idea but also at least one or two of Matt’s other, more unconventional ideas. There was one in particular about which Matt was very excited, a radically new approach to incurable brain diseases. He was developing a brain vaccine. It was extremely exciting—revolutionary, he said. He was preparing a paper about it. The vaccine was an idea that he had developed in New Zealand. In a way, it fit with the zeitgeist. There was so much interest everywhere now in the power of the brain and mind to control diseases. Most of that sort of therapy was soft science. But he had gotten interested two years before in teaching the immune system a few new tricks. He and his colleagues were looking for a way to train it to generate an immune response to a brain protein. The immune system can be very specific: That is, it can recognize a highly restricted range of targets, and attack only those targets. That is appealing, Matt explained, because in diseases of the brain it is difficult to find drugs that are so specific. Psychiatric drugs, for instance, are notorious for their side effects. So Matt and his collaborators had decided to teach the immune system to try to treat what the immune system normally ignores.

  This idea is radical, and most of the early reviewers of Matt’s paper thought it was impossible. For one thing, the brain is immuno-privileged: It is normally ignored by the immune system. And normally the body generates antibodies against foreign invaders, not against its own molecular machinery. But Matt’s brain vaccines would have to generate antibodies against molecules that the brain itself had made, such as neuroreceptors or bad EAAT2 pumps.

  However, Matt believed that he could do this. He could teach the immune system to interact with a problem protein in the brain and either clear it away or stop it from doing more harm. He had already tried this on rats, in an experimental vaccine against stroke damage. It is well known that when the brain suffers a small stroke, the body switches on genes that help protect it against the damage. The body is now preconditioned and can deal better with damage from the next stroke. Much of the damage is caused by a local flood of glutamate—the same problem that Rothstein argued was central in ALS. Matt and his team had devised a vaccine against a set of brain receptors that are sensitive to glutamate, the NMDA receptors. They had vaccinated the rats and then given them drugs to induce strokes. The vaccine seemed to have preconditioned the rats and helped protect them against the damage.