His Brother's Keeper

by Jonathan Weiner

  Matt During was Jamie’s gene therapist and he was pessimistic about Jamie’s gene therapy. Well, I thought, why am I so surprised? Why do I feel so burned? I know the odds. And yet I had begun to hope it would work.

  Matt had been called a maverick for his Canavan work. “I have a reputation as something of a cowboy,” he had said on the phone. But I could see that with this project, at least, Jamie was pushing the cowboy.

  Matt wished his Canavan critics would remember the development of chemotherapy for cancer. “No one was cured overnight there. That took years of experiments with sophisticated combined protocols,” he said. But with gene therapy there had been so much hype and expectation that people were primed now to react against it. “It’s always politically a smart thing for scientists to say, yeah, we need to slow down,” he said. “It helps your career because you sound balanced and mature. No one ever pats you on the back for doing things on the edge. They just call you a cowboy. It’s ironic but sometimes the less you do the more you’re commended for it.”

  I told Matt I was impressed by the size of his center, which was still expanding and—I could not help noticing—as disheveled as a new house on move-in day. He needed space, he explained, because he liked to change directions and charge toward the hot questions and the sudden frontiers. Here he spoke as grandly as Jamie. “I like to make a difference in as many aspects of medicine as I can. I always like to think of the provocative, the unexpected. I like to break dogma down. I have a lot of resources here at Jeff. Most of this research is not the sort of thing one can write grants on. You need something that is already far along before you can write a grant application. That kind of work is bread and butter. Ninety percent of science is bread and butter. Not very worthwhile. That’s not what I want to do.”

  Finally I asked Matt to tell me about the second plan he was working on with Jamie, the neurovaccine.

  Matt told me that he had just submitted a new draft of his paper to Nature, and he expected to hear back from the editors in about two weeks. He was racing a few other scientists toward neurovaccines. The month before, Elan, a company based in Dublin, Ireland, had published an account of an Alzheimer’s vaccine in mice. Nature had run the story on the cover, because it was the first experiment that had ever slowed Alzheimer’s disease—in mice. “Unlike complex procedures such as gene therapy,” the editors wrote, “this immunization treatment is one that should be testable in human patients in the near future.”

  Jamie and Matt were developing both the gene therapy and the neurovaccine for Stephen. When he met Jamie, Matt had been working on vaccines for stroke and epilepsy. Now he wondered if it would help with ALS, too. If glutamate floods were doing the damage in all three diseases, then maybe his vaccine could make a difference. Matt wanted to test it. But he would have to reengineer the vaccine and target it to a different type of glutamate receptor, one that is important in ALS, a receptor called AMPA. If the vaccine worked against ALS, that would be great news, Matt said. It was powerful. “But we know it can cause changes in behavior. The rats learned mazes faster.”

  “What?”

  “We did a crazy experiment here in Philadelphia,” he said. He told me about the vaccine that he and his team had made to help protect against brain damage after a stroke. They made the vaccine and gave it to rats. Matt ripped down a chart labeled “Figure One” from his bulletin board and showed it to me. “Multiple injections,” he said, making the gestures of an addict shooting syringes into the crook of his arm. Then he and his team had induced strokes in the rats. The injections had prevented seizures in more than seventy percent of the rats, and those that did suffer seizures were protected from brain-tissue damage.

  “An interesting story,” Matt said. “But like anything in biology, it gets more complicated. We did a screen for behavior. The rats were actually smarter,” he said again. In maze studies the neurovaccine had had the same sort of effect on the rats as his gene therapy for memory had done.

  “It’s pretty novel,” he said, with a smothered smile of satisfaction.

  The neurovaccine had many other innovative features, Matt went on. It broke ground at every step. The sheer amount of novelty made it revolutionary, in fact, which is why the editors at Nature had already rejected it once; but revolutionary research was the only kind that interested him anymore. Let other people worry about old stale dogma. Neurovaccines would transform medicine in the new century. They would be used to attack the plaques of Alzheimer’s disease and help the brain heal itself of prion diseases.

  “And Lewy bodies?” I asked.

  “Sure,” Matt said.

  How hard it was to speak up and identify myself as not only a reporter but a family member in need. I felt hope, dread, and shame. Speaking meant dragging myself up and over a stone wall. I tried to keep my voice under control. Thinking about that moment later, I understood better why Jamie had hesitated to tell his news to his office mate and to the director of the Neurosciences Institute. For me this conversation was the beginning of a whole new appreciation for what Jamie was about. What a world of difference there is between asking questions as a professional and professing a desperate need. You stop being a doctor or an engineer, an entrepreneur, or a reporter. Suddenly you are just a human being who is very frightened and trying not to beg.

  “The reason I asked you about Lewy body,” I said, “is that my, ah, mother has that, unfortunately.”

  “Oh, she does? I’m sorry.”

  “We’re watching a rather rapid decline right now,” I said. “Of course—” I went on, trying to keep my voice calm, but finding myself trapped in sentences that were strangely hard to finish, “of course, it’s very different from watching your kid brother—my mother is in her mid-seventies—but still, you wonder whether something like this—”

  “Well, yeah,” Matt said. He looked at me. He had been through many conversations like this one. “It certainly could be done,” he said. “I mean, if I had the resources, we could do something that would be worth considering there. One of the key proteins in the Lewy bodies is alpha-synuclein. Alpha-synuclein is found in all sorts of amyloid deposits, including Alzheimer’s and Parkinson’s, and, from my understanding, Lewy bodies. And that would be a good protein to target with the immune system, I think. If I had the resources, I could do something.”

  I had stopped making notes. I let my tape recorder roll while I watched Matt sit with his fingers to his chin and read the screen of the computer on his desk. He was engrossed in the same kind of PubMed search that I had often heard Jamie Heywood make when we talked late at night on the phone. Matt, too, seemed to have a way of losing himself in the monitor.

  “Hey, this is interesting,” Matt said, and fell silent again. I waited, listening to the clicks of his mouse and the clicks of the computer. If I had taken two steps I could have looked over his shoulder, but it did not occur to me to move.

  “The key is, if they have a model,” Matt said, half to himself. To test a vaccine, he would need a Lewy body mouse—the equivalent of the ALS mouse.

  Matt glanced up. He would need ten thousand dollars from me for the animal tests, he said.

  My eyes must have widened.

  “It sounds a lot, but it isn’t, really! It would be consistent with what we’re doing,” he went on, judiciously. “I would be happy to get involved. The research is straightforward. The red tape is harder. But alpha-synuclein may be a good target for Lewy body, and Alzheimer’s, and Parkinson’s. We would target the immune system to the plaques, and clear the debris.”

  Matt was telling me why he would to do this for me. Alpha-synuclein would be a huge prize. The very same vaccine that he developed against Lewy body dementia might work against Alzheimer’s and Parkinson’s. I was offering him another ship of opportunity.

  He told me that he could get special permission from the FDA, the kind of emergency permission called “compassionate use,” in order to immunize my mother against Lewy bodies, just as he would get compassion
ate use to try an ALS neurovaccine on Stephen. The bureaucracy makes allowances for special cases in which individuals need to move quickly: Out of compassion for desperate people in medical crises, the red tape is cut to a minimum. First Matt would need a brain biopsy for confirmation of the diagnosis, he said, staring at the screen. Then he and his team would genetically engineer a vaccine. The vaccine might induce my mother’s immune system to clear her brain of the deposits that had progressively impaired it. Matt and Paola could get rapid approval from the FDA on the basis of Elan’s Alzheimer’s vaccine, which the FDA had already approved for a safety trial. Immunization might help clear up the Lewy bodies. As we both knew, Matt went on, there was no other treatment, and the disease was progressive and fatal.

  “If it was my mother, I’d be doing that. It’s certainly worth doing. We could move quickly.”

  I told Matt the names of my mother’s neurologists. There was Stephen Salloway, and there was the man she had seen at Harvard—a doctor with a name like Seltoe, I said. Why could I not remember that name? It was a peculiar experience pronouncing these names from our family’s secret saga—as if I were dragging them with me over the stone wall, too.

  “Selkoe is very famous,” Matt said, suppressing a smile, like a psychoanalyst whose patient has just mispronounced the name of Sigmund Freud. “He’s a world expert on Alzheimer’s. He may be too established to get.” Of the two doctors, Matt thought Salloway was the better choice for our purposes. I should call him and ask if he would sponsor a trial of the vaccine. I should tell him that Matt would consider generating the vaccine. We would need Salloway to sponsor it as my mother’s doctor. There would be a reasonable amount of work from Salloway’s side, Matt said. “The procedure is quite involved, unfortunately. One needs a gift for politics, too, to ease the wheels. This would be only one case. We couldn’t use it for publication.” So we would need a physician who was motivated, like Salloway. “If it hits a roadblock, Selkoe may be overextended.”

  On reflection, Matt said, we would not want to wait for an animal model. We would do a toxicology study. I might have to put up ten thousand dollars for that instead.

  Suddenly it was Matt who sounded nervous. He said he was worried about telling competitors what he was doing with his neurovaccines. If I told anyone that he was working on vaccines to the brain, I might jeopardize the paper he had submitted to Nature. He was more nervous about Selkoe than Salloway. (I realized why later. Selkoe was involved with Matt’s competitors’ work on an Alzheimer’s vaccine at Elan.) On second thought Matt preferred that I say nothing about the work even to Salloway. I should ask Salloway to call him directly.

  We stood up, and Matt gave me a tour of his vast maze of a lab. I was preoccupied. I had never felt so hypnotized and so distracted. Though I had my reporter’s notebook in my hand, and kept scribbling away out of habit and reflex, my imagination kept leaping ahead to my mother, my father, and my brother. It was remarkable how that brief exchange with Matt in his office had transformed the look of the situation for me. There was a chance that my work as a science writer could save my mother and clear up whatever had fouled her inner weather for the last dozen years. What would my family say? Would we try it? Would it work?

  Matt led me on through the hodgepodge maze of rooms. On a laboratory bench, a white rat lay in a pool of light, attached to a micro-injection pump. The rat was lying on the stage of a stereotactic apparatus: a dissecting scope with binocular eyepieces. Two young scientists had drilled holes in its skull. Now they were pumping in DNA. As I looked at the rat, I did not picture Stephen, or my mother, lying there on the table, because the thought was unimaginable, but I could not help staring at that rat. It was alive. Its whiskers were twitching.

  In another room, Matt showed me where he and his postdocs were growing bacteria and manufacturing DNA for his gene therapy projects. A young postdoc by the vats introduced himself and told me that he was getting over a mysterious flu. He was just back from New Zealand. He gave me a wet handshake.

  “Don’t worry,” he said. “Just washed my hands.”

  In still another room, Matt showed me a cage full of mice that Jeff Rothstein had sent up from Johns Hopkins. Then Matt introduced me to another postdoc, Dave Poulsen, from Montana. Dave was using a gene gun to inject genes into mice. He put it in my hand. It looked and felt like a plastic ray gun, made of computer-case gray plastic. The spent shells on the laboratory bench were plastic, too. The gun fired tiny gold particles, one micron in diameter coated with DNA. The gun shot the gold into the skin of a mouse, a rat, or a human patient with a burst of helium gas. The gun was armed and ready to fire. Dave demonstrated the procedure. The gun produced a high-pitched beep as it fired into the rat’s skin. It was nowhere near as painful as getting a shot, Poulsen said, but he anesthetized the animals anyway.

  Poulsen had shaved the bellies of the rats before the injections. He demonstrated again and I could see a hint of gold where the shot went in: a faint gold spot that looked enormous to me but was about the size of a dime.

  This was the postdoc Matt had assigned to handle the preparations for Jamie’s gene therapy. He was in his mid-thirties, a bit stout, with a red-and-white-striped polyester shirt, brown hair, a beard almost as short as stubble, and the kind of aviator glasses that were in fashion back in the 1980s. The postdocs I had just met all looked as if they felt they were on a vertical expedition together, as if they were all hands on a climbing rope. Dave Poulsen looked like a man who would rather be someplace else: A decent guy, but even with a gene gun in his hand, he was not a bolt from the future.

  “I have a lot of rats here,” Matt During told me, with a little laugh, as we went on with the tour. A few of them were pets from the memory-enhancing gene therapy and the memory-enhancing neurovaccine. “I kept Jeremy. He has a 190 IQ.”

  Walking back from Jefferson Medical College to the train station at Market East, I was amazed at the way the names of my mother’s doctors, Salloway and Selkoe, were transforming themselves. So were the words of the diagnosis, Lewy body dementia. Up until that moment, the names and the terms had all been gray and heavy as lead, synonyms for despair. Now that there might be something we could do, it was almost as if the lead was turning to gold. There is something anesthetic about resignation, and I felt suddenly as if a painkiller and a tranquilizer were wearing off. After that dark talk with my mother by the coatrack at the foot of the back stairs—Hold on—maybe I had found help after all.

  At the train station I called Deb from a pay phone to tell her that I was catching the 1:47. Then I could not resist telling her what Matt During had said, although as I talked I realized how wild it all sounded.

  “A brain vaccine!” she said.

  The more I explained, the wilder it sounded to me, too.

  “Don’t miss your train,” she said.

  In a seat by a window I pulled Matt’s stack of papers from my briefcase, and found the manuscript of his unpublished neurovaccine paper. I underlined the phrase “neurodegenerative disorders” in the abstract. But after one page, I put it down. Again I felt the weight of what Jamie was doing for Stephen.

  In the window of the train, the leaves of trees rushed by backward. A single sparrow hopped in a bush. I stuffed Matt’s papers back in my briefcase. What I was feeling at that moment was what Stephen and Jamie had felt when Jamie set up shop outside his Cave: the collision of resignation and defiance. After a while it is almost comfortable to let an illness progress, even a fatal illness, if you are absolutely sure there is nothing that anyone can do. And in that dull anesthetic comfort it can be painful to let yourself hope again. Stephen had lost some of that comfort when he decided to support Jamie in his fight. He had to give up something. Each brother had given a gift to the other.

  Again I thought how level Jamie’s head was that first evening, the evening of the diagnosis, back at the Neurosciences Institute. My emotions on the train were only to be expected. But Jamie’s level head and his ability to decide and com
mand—that was something rare.

  My eyes felt tired. I did not want to rub them, because I had not washed my hands since the lab. Walking with Matt During in a borrowed white lab coat past all those vats had not bothered me: I was used to laboratories. But now I stared out the window and worried about that wet handshake. Well, it was a distraction from what really worried me.

  Twenty-Four

  Thunder and Lightning

  Put the right people in a room, stir, let simmer, bring to a boil,” Jamie exulted to me on his cell phone from the car as he left one of his lab meetings at Matt During’s. It was mid-August 1999. Jamie was back from Paris and he was doing a lot of that—calling me from his cell phone to check in and whoop at how well things were going. He and Matt were meeting with scientists and the vice presidents and presidents of biotechs. “I swear to God!” he exulted after a lunch in Philadelphia. “This is the cheapest way to buy people’s time there is. You get five people talking about ALS for two hundred bucks? It’s a deal!” After one dinner in New York, he told me that he had just dropped $900. “Not holding back. Which is actually my philosophy on how to do everything.”

  He was very happy with Matt and Paola. “These are aggressive people. They’re not…” He hesitated—I think he was trying not to put down the pure scientists I usually write about. “I think it’s so easy in science to not do it. Matt really wants to make science happen in the real world. I think he just cares about that a lot.” I heard what Jamie was not saying, and felt indignant and annoyed on behalf of scientists. Without them, Jamie would not have his EAAT2 project. Without people like Jamie, Matt, and Paola, it would not be happening either—not this soon and this fast. On the other hand, scientists were telling me almost unanimously that this EAAT2 project was too soon and too fast. When Jamie put down scientists, I felt as exasperated with him as he was with scientists. I challenged him on this once, later on. Jamie said, “To say scientists are slow or lazy is not accurate. Most of them work very hard. But in modern medicine, scientists are reluctant to jump from researching in yeast or mice or rats to trying to treat humans. In desperate diseases, they should be able to move quickly from the lab to patients. They could do that fifty years ago—we were much freer back then. But I think medicine today has a culture that is overprotective and makes it very difficult for researchers to make those leaps. I think their caution is hurting us as a society and we’re not moving forward as we should. There are complex reasons for this, and some are valid, but I think as a whole we’re just way too reluctant to treat people with new ideas. Somehow too many scientists lose themselves in the question of what goes wrong in ALS and lose sight of the fact that twenty people die of it in this country every day.”