The mice were born in January of 1999. All but the one with the antidote was dead. Now it was September and that mouse was still alive.
“Dad, drive Jon over here!” Jamie said.
As we drove through the dark suburban streets, John was still just as quietly and sturdily skeptical as he had been back in the den. His son was not a biologist, he said, and these mouse models were notoriously unreliable predictors of human cures.
In a minute we had parked outside the Victorian. Inside we could hear Jamie, Stephen, and Robert yelling.
This was the property that Peggy had bought the boys while John was out of the country. She had bought the boys the house knowing and trusting that he would support her completely. I asked John how he had felt when he got home and saw the place. He gave me a wry tilt of his head, and a shrug. He had accepted it. I loved that gesture in the suburban dark, part smile, part grimace, part shrug, man to man, reticent and candid. It said more than a speech.
The ground floor of the old house was full of shouting and maniacal laughter. When we walked in, we saw Jamie and Robert each sitting at a desk and staring at the screen of a computer and jiggling a joystick. Stephen was off in his computer room with the door open. Jamie had wired all the computers in the house into a network and the three of them were playing Starcraft.
“So that’s exciting,” John said quietly.
“That’s very exciting,” Jamie said. “Dad! It’s totally awesome!”
John gave me a level look across the room. “One mouse,” he said.
“One mouse,” said Jamie. “The oldest mouse in the history of ALS.”
John Heywood smiled. He had been through enough experiments and team projects to know that they had many ups and downs. He let Jamie shout and explain. Then he said good night and left. He had to get up before dawn to bicycle to the Sloan Automotive Laboratory.
Since Jamie had called me over, I assumed that he wanted to talk about the mouse. But he was too elated and distracted by the game. The three of them, Jamie, Stephen, and Robert, kept shouting as they played. They looked like my kids.
I wandered through the open door into Stephen’s room. Jamie and Robert played with one hand on a joystick, but Stephen’s right hand was too weak for that. He had worked out a way to play with a mouse and a keyboard. He was afraid that soon he would not be able to do that. But Jamie told him that if the gaming equipment got too hard for him to use, he would drag Stephen down to MIT’s Media Lab and say, Fix it, guys!
Stephen tried to explain the game for me while he played, but Jamie took advantage of his distraction and attacked. “So I think what I’m gonna do—no, it’s OK, Jamie is clueless—I’m going to—oh, fuck. Jamie just killed me. That’s a huge army. That’s a big army. OK.” He exhaled through his mouth. “I guess at this point it’s a bit of a race. Soon it will be a massacre. And one of us will go quickly.”
The phone rang. It was Ben, in L.A., returning Stephen’s call about the mouse. Stephen told Ben the story. Listening to his answers to Ben’s questions, I could tell that Ben already knew all about the background of the Sutherland experiment. Like everyone else in the family, Ben was following Jamie’s project closely enough to appreciate what the news might mean.
I wandered over to watch Jamie’s monitor. He was so obsessed with his race to save Stephen that TV shows did not engage him anymore. But computer games still worked. He did not leave the battle when I walked up. “I can see this scene is going right into the story,” Jamie said, and groaned. But he did not look up from the screen.
Rothstein had picked up another piece of news at the conference, but he had not told Jamie. It was about Jesse Gelsinger, the young man who had entered an OTC gene therapy safety trial in Philadelphia on September 9. It was a Phase 1 clinical trial, a safety trial, to see how big a dose a human body might tolerate comfortably.
Rothstein had spared the Heywoods the story. He let them have a celebration. They would hear about it soon enough. The story was very bad, and the whole world was going to hear about it.
Wilson was using cold virus, adenovirus. Matt During was using a virus he thought was safer, called adeno-associated virus (AAV). Unlike cold virus, AAV in its pure form does not replicate in human beings and does not trigger an inflammatory response. Unfortunately, AAV is also a much smaller virus—a smaller syringe. There is less room in it for the cocktail of DNA.
Those were the trade-offs. AAV was safer but it was so small a syringe that it gave Matt the awkward engineering problem of trying to fit all the essential DNA in, a problem he still had not solved. Instead James Wilson and his group had injected Jesse Gelsinger with a cold virus. A cold virus is bigger, so it is easier to put a DNA package into it; but of course a cold virus is recognized as an enemy by the human immune system, which is why we get rheumy eyes and runny noses and mucus-filled lungs when we are infected by it. In short, a cold virus is efficient but risky.
The primary reviewer of Wilson’s proposal, Robert P. Erickson, a geneticist at the University of Arizona, warned the RAC in 1995 that Wilson’s plan, delivering the genes directly into the liver through a catheter, might be dangerous because it would expose the liver to such a high dose of viral particles that it could trigger an inflammatory response. He thought it might be safer to inject the virus into the bloodstream through an ordinary IV and let the circulation of the blood bring it to the liver. He also questioned whether it was right to subject relatively healthy volunteers to such a risky trial. But the FDA thought it was safer to inject directly into the liver rather than expose the whole body to the genetically engineered virus.
Wilson and his team had engineered the cold virus to be less infectious than the wild type. It still had that risk but they judged it an acceptable risk and so did the regulators in Washington. There were about 400 gene therapy trials under way at that time and about 100 of them used that cold virus. It had been approved for that purpose by both the FDA and the NIH, and of course the common cold is not usually a killer.
Because the mechanics of gene therapy are so badly understood, the whole effort is horribly inefficient. To get the genes into the patient, gene therapists inject trillions of virus particles, which is a much more massive infection than anyone suffers with an ordinary cold. The therapists inject trillions of viral syringes, and hope that at least a few of them will go on to inject their load of DNA into the right cells and that a few of those injections will make it through to the cell nucleus and insert themselves in the cellular DNA.
Unfortunately, at such high doses of infection the immune system may react vigorously to the attack. That is what had happened in animal studies of the cold virus. Some monkeys given high doses of the virus had suffered such a strong inflammatory response that they had gone into shock and died. A human patient with cystic fibrosis who had volunteered for a gene therapy trial had a toxic reaction, too, though it was not fatal.
Gelsinger was the eighteenth patient in the OTC gene therapy trial. Wilson and his team had already treated seventeen volunteers with their gene therapy, gradually increasing the dose. One of the volunteers had a grade 3 reaction. Blood tests showed that some of that patient’s liver enzyme levels were elevated. A grade 3 reaction is significant. By the agreement they had with the FDA, Wilson and his team reported it and stopped the study while they waited for a ruling. The FDA told them to go ahead. A second patient had a grade 3 reaction. Again the team reported it, and the FDA told them to go ahead. When another patient and yet another had a grade 3 reaction, Wilson and his team did not bother to call the FDA. They did include those data in their next formal progress report to the FDA, but they did not highlight those incidents, and the FDA said nothing about them. The team went ahead with the tests, trying to find the point at which the dose was too great, testing the edge.
Wilson was testing three patients with one dose, then increasing it and trying it out on the next set of three. So, Gelsinger got a dose bigger than the last set of volunteers, and much bigger than the firs
t set. In the body, small increments of change can lead suddenly to catastrophically new reactions. The volunteer just before him got the same dose and lived. But Gelsinger already had elevated ammonia levels when he showed up for the test. When he had enrolled in the study three months before, in June, just after his eighteenth birthday, his ammonia level was within acceptable limits, 47 micromoles per liter. On September 12, the day before he was due for his gene injection, his ammonia level was 91. That should have been high enough to stop the test according to the rules set down by the FDA. But Wilson and his team reasoned that the rules said nothing about ammonia levels at the time of the injection, only about levels at the time the patient enrolled in the trial. The team gave Jesse a drug to lower his ammonia level and went ahead.
On September 13, he got a two-hour infusion of the drug into his hepatic artery, which runs straight into the liver. For reasons that are still unclear, the coat of the virus seems to have caused problems in Jesse’s body almost immediately. That night his temperature rose to 104.5°. A high fever is very dangerous for someone with OTC. Jesse became jaundiced. His lungs got badly inflamed. He went into acute respiratory distress. One after another, his organs began to shut down. On September 17, the doctors told Paul Gelsinger, Jesse’s father, that they could not save his son. The father made the decision to remove his son from life support, and Jesse Gelsinger died.
If Rothstein had shared this news, Jamie, Stephen, and Robert would not have spent Boys’ Night Out whooping, hollering, and celebrating in their old, echoey Victorian. There was maniacal laughter from all three rooms. It was like listening to the banter of fighter jocks in a flight simulator. Stephen attacked Robert, and Robert yelled, “Oh, you slut!”
“We’re all dead in the end, Rob.”
“That’s a good point, Stephen.”
Rob counterattacked, and now it was Stephen’s turn to howl. “Did that seem right to you, Rob?”
“How much in this world is truly right, Stephen?”
Jamie played in rapt, dead earnest, like one of his science-fiction heroes. It was like watching Luke Skywalker when all the other space soldiers have fallen away and he is racing for that one weak spot in the Death Star, and the whole audience is rooting for him: “Luke, remember the Force! Use the Force, Luke!”
In basketball, when the hero on the court takes an impossibly long shot to win the game just as the buzzer is about to sound, there is often one mad, wishful moment when you are sure, you are convinced, you believe as it reaches the top of its parabolic arc that the ball is going in. The ball is going in!
Twenty-Nine
Grace Church
When your quick and dirty experiment comes out positive, it’s exciting,” John said judiciously, the next morning. He and I were slicing bagels for brunch. John was still steady and solid. “It’s only one mouse,” he said. “But it’s positive stuff that keeps people rolling forward.”
Jamie burst in the back door, even more electric than he was the night before. Already that morning he had been on the phone again with Jeff Rothstein in Baltimore.
“That mouse—they thought it was born in January,” Jamie said. “It was born in November! It’s lived seven months longer than it should. This validates the whole idea! Jeff was bouncing. Jeff was just bouncing.”
“What was the news?” asked Peggy, coming into the kitchen from the solarium, where she had been setting the table.
Jamie explained it all to Peggy. Then he added something else he had not known the night before. “There are some neural complications,” he told his mother. “It doesn’t learn.”
“A stupid mouse?”
“A stupid mouse.”
“How do you tell?”
“Well, the scientists don’t say stupid or smart.” Jamie described the mazes that neuroscientists use to test the ability of mice and rats to learn and remember new things. Apparently the mouse, with too little glutamate between its synapses, was not able to learn and remember very well. That made sense. Although too much glutamate can kill nerves, it is, after all, the messenger by which most nerves communicate. If you take away too much of the stuff, the nerves are less able to talk with each other.
Because experimental treatments for neurodegenerative diseases have to treat the brain, they often do risk transforming the minds and personalities of the people they seek to help. The risks of gene therapies for brain diseases are likely to be terrible, as the philosopher Philip Kitcher writes in his book The Lives to Come. The operation could be a success, but even so, he writes, “relatives and friends would wonder if their loved one had survived the genetic therapy.” Just as we have come to doubt the value of frontal lobotomies and certain kinds of electroshock treatments, Kitcher writes, “we might reject some forms of gene replacement because they failed to preserve—and therefore to cure—the person with whom we began.”
I tried not to look up at Stephen as I sliced the bagels. There was no class warfare in the Heywood house as far as I could tell. Stephen was following in the honorable tradition of his mother’s father and brother back on the farm in South Dakota. The Heywoods all admired people who knew how to do things, people who were interested in the things of this world. Still, in the American caste system, carpenters ranked lower than engineers and entrepreneurs. Stephen was blue-collar, or trying to be. Jamie and John were white-collar engineers, and until she retired Peggy had been a white-collar psychotherapist. Ben was trying to become a producer in Hollywood. I thought there was something creepy in the notion of the carpenter being saved but rendered stupid by the engineer.
Jamie hurried back to the good news. “This is the oldest mouse ever! It’s perfect. It’s awesome.”
He and his parents were going to church that morning before brunch, and they invited me to join them. (Stephen never went.) John drove off early to join the choir, and I went with Peggy and Jamie. Peggy wore a floral silk dress. Jamie wore neatly pressed pants and a black turtleneck. He drove, speculating the whole way about the meaning of the mouse that lived. If EAAT2 saved the mouse’s life, then glutamate poisoning really must be what had killed all its brothers and sisters. He was right after all! He parked on Eldredge Street in Newton Corner, in front of a house about a block from the church. Stepping out the door of the car, he stood staring at the house. He seemed to expand as he stared at it.
“This is it, Mom. That’s what I want.”
Jamie was standing in front of a magnificent three- or four-story Victorian mansion. It was yellow with white trim, about a block before the church, just across from a park.
“Why don’t you buy that one?” his mother asked drily, but he did not seem to hear her. The mansion was shining in the Indian Summer morning sun.
“Maybe I’ll just make that one,” Jamie said. “And that’s just the size I want my porch.”
We walked a few steps toward the church and Jamie stopped to admire an even bigger place, a great white Victorian box with a slate roof. A plaque by the front door said, “The Honeywell Club.”
As we walked into the cool dark of Grace Church, the choir, in robes, was filing down the aisle, John Heywood among them. Grace Church had marble pillars. Flowers, candles, stained glass windows, a grand ceiling, large crosses. The pews were almost filled.
“It’s a Catholic form of service, but no pope,” Jamie whispered to me. He was afraid I might feel uncomfortable. “I always used to be embarrassed by how much Jesus Christ there is in the sermons,” Jamie said. “They’re always talking about Jesus Christ. But even though I hated coming here as a kid, when I come here now, I’m lifted. I love the ceremony, the robes, the songs. I don’t believe in a higher power, but I feel something here, even though the words often seem to fight against the meaning and the point.”
Peggy tried to put me at ease, too. “Because of the music and ritual I feel at home in Jewish synagogues,” she whispered. “There’s something evocative and emotional about it. Whatever that sets off in people, it’s very powerful. We jokingly say we’re fait
hful unbelievers. But obviously there’s more, or we wouldn’t be here every Sunday. If people don’t have it,” Peggy said, “I don’t know how they survive.”
Back in South Dakota, Peggy had gone to a one-room schoolhouse, where the town’s community club met in the evenings. Now she found Grace Church as warm and close as her old schoolhouse. “Here I moved to sophisticated Newton, and I’ve re-created the old village. That one-room school is Uncle’s machine shop now,” Peggy reminded Jamie. “He picked it up and moved it.”
“Beautiful tin ceiling,” said Jamie. He really was crazy about houses. Outside the great stone church I had almost expected him to say, That’s the one I want, Mom!
The choir sang a processional hymn: “When morning gilds the skies…” Then they sang, Gloria! The congregation recited together, according to their tradition, the Collect of the Day:
O God, you declare your almighty power chiefly in showing mercy and pity: Grant us the fullness of your grace, that we, running to obtain your promises, may become partakers of your heavenly treasure….
They listened to the words of the prophet Ezekiel:
Cast away from you all your transgressions, whereby ye have transgressed: and make you a new heart and a new spirit: for why will ye die, O house of Israel?
For I have no pleasure in the death of him that dieth, saith the Lord God: wherefore turn yourselves, and live ye.
Miriam, the new pastor, gave a sermon about turnarounds, changes of heart. “We all have a fear of the unknown. But we can turn our lives around. There is no one particular way. The key is to figure out what would give our lives more meaning. That’s not always easy. But God is right here to help us. The door is always open. A thirteenth-century mystic said you can come where you are. Come again wherever you are. Come again, come.”
His Brother's Keeper Page 25