His Brother's Keeper

by Jonathan Weiner

  Then the Daughters of Rhea, Melinda and her sister Piper, danced out with finger cymbals. Melinda did her candles routine, and Piper whirled and reeled with a scimitar balanced on her head. Robert announced, “Tonight only, all belly dance tips are tax deductible.” And crowds of Heywoods and their friends stuffed checks and bills into the sisters’ sequined girdles. Then Melinda and Piper led the whole crowd in a chain and they snaked around and around through the brick arches of the restaurant.

  Stephen leaned back in his chair against the white brick wall, holding Wendy’s hand, and watched the chain of dancers. He looked almost foreign that night at the edge of the festivities, as if he had traveled such a long way to be there and brought such a different world of emotions and associations from his own country that now just being there was all that he could manage. His expression was somber, pale, serious, and spent.

  Twenty-One

  Birds Suddenly Appear

  With the tips the Daughters of Rhea collected in their girdles, and the checks that came in the mail the next week, including a generous donation from Alexander d’Arbeloff, the First Annual Belly Dance Extravaganza raised $240,000. That was a pittance in a normal research setting, but it was close to the amount the family of the Canavan baby Jacob Sontag had donated to Matt During’s Canavan research, and Jamie hoped it would be just enough for him to begin his mad dash in the style he had in mind. A quarter of a million would go further for him than it would for any medical research charity he could think of, because Jamie would not give the money to anyone in a lump sum. He would parcel it out. Now that he had put together a dream team, and a little money, he planned to run the show.

  In Matt’s office he sat in on the lab meetings and more and more often he ran them with Matt. Like gene therapists all over the world, Matt and his team were struggling with tough engineering questions. A gene has to work as part of a system, like a gear in an engine or a sentence in a paragraph. To make it work, a gene therapist has to engineer what is called a promoter sequence, which sets in motion the reading of the gene. Otherwise the gene will get into the nucleus and sit there unread. The gene therapist also has to provide a stop codon, like a period, to get the cell to stop reading the gene when it comes to the end of the message. And a gene therapist also tries to include a switch that can be turned on and off from outside. That way, if the gene they have injected is hurting the patient, they can turn it off before it does too much harm. In experimental gene therapy on flies, temperature has been used as a switch. The new gene turns on only when it is very warm. At room temperature the gene turns off again. In human beings, certain antibiotics can serve as the switch.

  Taken together, all this DNA—a long strand containing the promoter sequence, the gene itself, the stop codon, and the switch—is called the DNA cocktail. It is the elixir of the gene therapist. To get it into a patient’s cells, the gene therapist engineers a virus that will carry the elixir instead of its usual load of DNA. A single virus is like a syringe. It has evolved to be very efficient at injecting its DNA into a host cell so that the DNA will snake through the cell and find its way into the nucleus and insert itself into its host’s DNA. With the standard tools of genetic engineering, it is now a simple job to take a sample of viral DNA and cut away much of it, and put back the harmless bits that give the DNA the ability to snake into the heart of the cell. It is also simple to splice in a new ribbon of DNA—the elixir, the DNA cocktail. But the head of a virus, even a hollowed-out virus, is a very small syringe. Gene therapists usually find that they have more DNA in their cocktail than they can stuff into the virus.

  Essentially, a virus is a Trojan horse. Its contents are DNA that tricks its way inside the city of the cell, and once there, gets in through a nuclear pore to the DNA in the center and takes over. Then the cell makes more of that viral DNA. Once a cell has been infected, it literally explodes and hundreds of syringes spill out to infect cells around it. What a gene therapist does is to scoop out some of the Greeks from the Trojan horse—remove all of the most dangerous ones—so that the horse really becomes a gift to the city. The trouble is that viral DNA, after innumerable generations, has evolved an exquisitely compact force inside the horse. That is why there is so little room in there, and that is why the potions of gene therapy tend to be too big to fit inside that tiny hollow space.

  That same spring, for instance, while Jamie began meeting with Matt to plan the EAAT2 project, a parallel project was in the works at the University of Pittsburgh. There a gene therapist named Xiao Xiao was working on gene therapy for a form of muscular dystrophy—the most common form, Duchenne muscular dystrophy, which afflicts about one in every 3,500 male children. Their muscles waste, they are confined to wheelchairs by the time they are thirteen or fourteen, and they are dead by their early twenties. Doctors had no treatment to offer, and no cure. Biologists knew the complete sequence of the gene that causes the problem—the dystrophin gene. Inside a human cell, in the form of messenger RNA, that gene is about 14,000 letters of genetic code. Gene therapists had been looking at that gene for a long time, but they could not fit so much DNA inside the head of a virus. There was room in the viral capsule for only about 4,000 letters of code.

  In Pittsburgh Xiao Xiao and his colleagues studied the shape of the molecule that is manufactured by a muscle cell with a healthy dystrophin gene. It is a long semirigid molecule: a rod with sockets at either end. The sockets are important. They are known in the jargon as functional domains. One socket binds to the plasma membrane of the muscle cell, and the other to the cell’s cytoskeleton. Without them the membrane is not properly attached to the cell’s skeletal scaffolding. A muscle cell gets a lot of wear and tear whenever the muscle flexes. Without those rods, the membrane comes unstuck and the cell falls apart.

  The rod consists of twenty-four protein subunits like twenty-four LEGO pieces, all about the same size and shape. It also has four hinges, spaced along its length, which give it flexibility. The rod has to be flexible because it has to give gracefully every time the muscle flexes; otherwise it will be torn apart and the cell will die.

  The gene for this simple piece of molecular hardware is on the X chromosome. Girls have two X chromosomes. Since they can make these rods even if they have only one good copy of the dystrophin gene, they do not get Duchenne muscular dystrophy. But boys have one X chromosome and one Y chromosome. The Y chromosome is small and atrophied, and it has lost its copy of this gene—and many other genes, too. That is why boys inherit more genetic diseases than girls. If a boy inherits a defective copy of the dystrophin gene on his X chromosome, he will make none of these rods, and his muscle cells will slowly fall apart.

  This is a natural project for a genetic engineer. Why should a boy die for lack of such a simple piece of hardware? The rod is not much more complicated than those braces they sell at Home Depot to screw into freestanding bookcases and keep them from falling down. If the boy’s DNA has forgotten how to make those rods, why not teach it how?

  Xiao Xiao considered the rod: a long and and more or less featureless repeated assembly of sections, with the four hinges for flexibility and the sockets at the ends. Then Xiao engineered a radically abridged version of the gene, cutting it down from 14,000 letters of genetic code to 4,000. The abridged version of the gene made a shorter rod. It had the same sockets at either end, so he thought it could still attach the membrane to the cytoskeleton, as if holding Sheetrock to the frame of a house. And it was still flexible, because Xiao Xiao had kept two of the four hinges, so it might still have enough play in it to last. In diagrams, the object that a cell made with this reengineered dystrophin gene looks like a prosthesis, like an artificial arm or leg, not as flexible as the original but better than nothing, a thing worth having if you need it.

  Xiao Xiao knew that nature had already tried this engineering experiment. There are boys born with mutations that give them short rods. The rods hold that membrane to the muscle cell cytoskeleton, and those boys develop only mild forms of musc
ular dystrophy. Other researchers in the field of Duchenne muscular dystrophy had found short rods in the muscle cells of a man who had lived for decades with a mild form of muscular dystrophy. He was in his late sixties, and he could still walk.

  So Xiao Xiao inserted his abridged gene into a viral capsule. He and his colleagues cultured their engineered virus in vats. From Jackson Laboratories in Maine they ordered mice that had been genetically engineered to get muscular dystrophy. The mouse dystrophin gene is defective and makes no rods. At around three weeks old these mice begin to suffer, their muscle cells degenerating in great sick waves of trouble.

  When Xiao Xiao and his colleagues were ready, they filled a syringe (a real, life-size syringe) with a milky solution containing more than 5 trillion virus particles per milliliter. They injected these 5 trillion virus particles into the hind-leg gastrocnemius muscles of forty mice with the defective gene.

  And three months later, the muscles in those mice had not degenerated. Nor had their immune systems attacked the virus, or the rods, or the muscle cells. They sacrificed the mice and put tissue samples under the microscope. The muscles looked normal. Apparently the rods had attached properly at both ends and anchored the plasma membrane to the cytoskeleton.

  Time would tell if the short rods would hold. Like artificial hip joints, they could pop out when mice or men tried to do something eccentric and frenetic. But this was the kind of hopeful new experiment that inspired Jamie in the spring of ’99. There were many genetic engineering successes to study that year—in mice. Many treatments and cures that heal mice fail to heal human beings, so researchers with a success in a mouse lab can never be sure how hopeful to feel. Still, there really were some reasons for hope. A team at Boston’s Children’s Hospital and Harvard Medical School tried using stem cells to cure mice with muscular dystrophy. They injected bone marrow cells with the healthy dystrophin gene into a tail vein of the mouse, about as many cells as Xiao’s team had injected viral particles into the gastrocnemius muscle. That experiment seemed to help. This was the very approach that Martin Cline had tried and failed with back in 1980, in the world’s first attempt at gene therapy.

  Jamie’s plan was real now, and Peggy felt the need to honor it. From her years practicing psychotherapy in Newton she knew how many families fall apart around troubles like these, and she was determined to hold hers together. And the foundation was beginning to mean as much to her as it did to Jamie. Jamie was always putting her to work. For a time he had Peggy cold-calling people on their mailing list for donations. But she was getting turned down, and she said, Every no is like a nail in Stephen’s coffin!

  Jamie switched her to something else: writing thank-you notes to donors and well-wishers.

  That month, a white, peeling, slightly dilapidated Victorian went on the market in Newton Highlands, just a few minutes’ drive from the Heywoods’ house on Mill Street. Stephen had long since given up his dream of renovating a house in Boston. But the house and its garage, a ruined carriage house, was just the kind of Boston fixer-upper he had dreamed of. “I looked at this place and, suddenly, bang!” Stephen told me. “I’d assumed I wouldn’t work anymore. But now this—it was perfect.”

  Peggy knew that buying the house would mean mortgaging the house on Mill Street and cutting into their retirement savings. And then there were the expenses of Stephen’s illness itself to consider: The expenses were bound to grow exponentially in the next few years. But Peggy wanted to give that house to her sons. She knew that Jamie and Melinda needed a place to live outside the house where Jamie had grown up. And the foundation that Jamie was putting together needed a way to get out of the basement. And the carriage house might be right for Stephen and Wendy someday, though it was hard to plan ahead that far since they did not know how long Stephen had to live and since Stephen and Wendy were not even engaged.

  The house—even dilapidated as it was—would not be on the market long, and John Heywood was out of town on one of his consulting trips.

  Peggy thought, and, with contributions from Jamie and Stephen, she bought it.

  “Thank God I’m not married to a flaky man,” she says. “Thank God John’s John.”

  It was characteristic of John Heywood to take this in stride. Sometime after he got home, he mentioned his book Internal Combustion Engine Fundamentals, and said he hoped to bring out a new revised edition someday. “A retirement project.”

  “If you ever retire,” Peggy said. “You may never retire now.”

  So Jamie and Robert moved the door-desk out of the basement and installed the new foundation on the ground floor of the Victorian. They set up their desks in the living room, and their computers, and homemade inspirational signs and slogans. Jamie tacked a sign up on his bulletin board: “Depression is merely anger without enthusiasm.” On a bookshelf he propped a saying of Melinda’s in a little gold frame: “I’m halfway between euphoria and falling on my head. Melinda Heywood 6/2/99.” Jamie and Melinda moved into the second floor of the house. Someday they hoped Stephen would fix up the carriage house. Jamie would save and restore Stephen from the main house, and eventually Stephen would restore the Victorian from the carriage house.

  In July, at the Heywood family retreat in North Carolina, Stephen’s right arm and right leg were so weak that he was forced to sit out the annual basketball game. Jamie tried to hide his feelings from Stephen. This was the loss he had dreaded in the first hour of Stephen’s news. By now Jamie could see that giving up basketball would be the least of it. Stephen was even having trouble eating.

  “We have a big crab fest at the beach,” Jamie says. “Bushels and bushels of crabs die for our family. And it was the height of brotherly love to actually crack open crabs for your brother and not yourself.”

  It was a big summer at Duck. Stephen smuggled a ring down for Wendy. He had sensed a dozen times that year that she was expecting him to propose, but he had not. “I think I may have been waiting to figure out if basically she didn’t have any choice in the matter,” he told me. By now he felt that their romance was beyond his control or hers. The choice was out of their hands. Their love life was rushing even faster than Jamie’s project. They were truly, madly, conventionally in love, only Stephen was dying.

  “It didn’t matter what I thought was best for her,” Stephen said. “We were gonna do it anyway. And then it was just a question of shopping for the ring.”

  He had some fun with that. Early that spring, Wendy had gone shopping with Melinda and found a ring she liked. She had told Stephen all about it. The price was $1,800. I hope that’s what you had in mind, she said.

  Well, actually, more or less double that.

  Oooh, said Wendy.

  Then the two of them had gone shopping for a ring together; and when Stephen was sure that he knew what she liked, he picked one out in secret. It’s an antique, platinum, it’s gorgeous, he told his friends. But he told Wendy, I’m still looking for a ring.

  Each summer at Duck, the Heywoods round up all the little kids in the family and hold a talent show on the beach. Stephen decided that he would get his brothers and cousins to sing a corny old song to her, “Why do birds suddenly appear…” While they sang, he would draw her up there with them, and in front of the whole family he would propose. Stephen had it all planned out, but an hour before showtime he realized that it might not be the best idea to do it like that. He decided that it was not a good idea at all to spring it on her in public. Next he thought they would go walk on the beach, and he would ask her down by the ocean. But it started raining, and they were trapped with a mob of friends and relations in the beach house that John and Peggy had rented that summer, a great three-story place with the seaward end on stilts. The talent show was only an hour away. How am I gonna do this? We can’t go for a walk on the beach, it’s pouring rain. Finally Stephen just led Wendy out the door and proposed right there, pulling her under the house to get out of the rain.

  They went inside and told his family. And later, at the tale
nt show, Stephen surprised Wendy when he dropped to one knee in front of his brothers, his cousins, and all that summer’s honorary Heywoods. He proposed to Wendy again, while Jamie, Ben, and a few of the others serenaded her, hamming it up and wavering way out of key.

  Why do birds

  Suddenly appear

  Every time

  You are near?

  Just like me

  They long to be

  Close to you!

  Twenty-Two

  Fizzy Water

  In one of Jamie’s late-night phone calls that August, I asked him if he felt more optimistic or pessimistic now that he had gotten the doctors to listen to him and work with him.

  “I alternate. I’ll give you a quick antidote,” Jamie said, without noticing his slip of the tongue. That past weekend he and Melinda had gone canoeing with Stephen in Newtonville on Crystal Lake. The three of them were carrying the canoe to the water, Stephen and Melinda in front and Jamie in the rear. Jamie was feeling terrific at that moment, he told me. He had yet to read of a single drug that had not taken six to eight years to get to clinical trials. Now he had a chance of getting his gene therapy into Stephen in a matter of months. He thought, My God, it’s unbelievable what we’ve gotten done!

  Then Stephen stumbled, dropped his end of the canoe, struggled ahead along the path in slow motion, and collapsed.

  “I—” said Jamie over the phone. We both waited while he recovered his composure.

  “This thing is relentless,” Jamie said. “You panic about hours. Sometimes you think: ‘This is unreal, the progress we’re making.’ Then you think, ‘It’s not real enough.’ ”

  Jamie dropped by my town, and we met at Paganini once again. What a difference. He and Robert Bonazoli were on their way home from another long day’s journey to Jeff Rothstein’s lab in Baltimore and Matt During’s lab in Philadelphia. In Philadelphia they had treated Matt During to a long, late lunch at the Striped Bass. From the way that Jamie said the name, I could tell that it was a hot place.