by Geeta Anand
“You can’t come, Daddy,” Megan chided, looking annoyed. “It’s girls only.”
John chuckled, kissed her, and said, “I know. I’ll be waiting at home with your brothers. Don’t rush too fast to get home to the boys.”
Megan’s six girlfriends—Sharon’s three granddaughters, Haley, Cara, and Taylor; two neighbors, Angela and Whitney; as well as Aileen’s friend’s daughter Alexa—scrambled in next. Nana (Aileen’s mother), Laurie, (Alexa’s mother), and Sharon’s daughter Misty followed. In the back, Aileen and Sharon took apart Megan’s red wheelchair and loaded it in the trunk, along with a backup battery and ventilator.
It took a half hour to get everyone and all Megan’s medical equipment inside the limo. But finally, with Megan and her giggling entourage of eleven, the vehicle sped up the New Jersey Turnpike into Manhattan. The group was late for their lunch reservation.
An hour later, the limo stopped on Central Park West in front of the entrance to Tavern on the Green, the famous garden restaurant in Central Park. John’s mother Barbara was waiting for them at the corner table for thirteen they had reserved in the greenhouse section. As they ordered their meals, Aileen’s brother Marty, who lived in the city, showed up with seven bouquets of roses, presenting one each to Megan and her friends. Megan accepted her bouquet excitedly and then looked at Aileen. “Boys aren’t allowed, you know,” she said. Uncle Marty laughed and said, “Not even boys with flowers?”
“Nope, it’s an all-girls party,” Megan said, shaking her head.
Uncle Marty stayed long enough to see Megan cut her white chocolate birthday cake and return to the limo. It drove next to the Lunt-Fontanne Theater, where the group watched the Broadway production of Megan’s favorite story, Beauty and the Beast.
“Can we come again tomorrow?” Megan said to her mom as they rode back at five o’clock that evening.
“You make sure to ask Daddy,” Aileen said, smiling and diverting the question, “because he planned all of this for you.”
They got home to find the kitchen and den decorated with pink and white balloons. John had taken Patrick and little John to the mall to buy decorations and a big cookie cake with a pink icing rose that read, “Happy Birthday Princess Megan.” Everyone stayed and sang “Happy Birthday” again; John grew tearful as his little princess blew out the five candles, thrilled with the attention, and entirely oblivious to the larger significance of the day.
That night, with the relatives and guests all gone, the deflated balloons and crumpled crepe streamers wadded in the trash cans, and the remains of the huge cake in the freezer, John read his precious daughter to sleep with the story “Beauty and the Beast.” Megan looked up at him, her eyes still sparkling, and said, “That was such a fun day, Daddy. Can we do it again tomorrow?”
It took most of December to design and begin what became known at Genzyme as the Mother of All Experiments. McKinney came up with that name at a Pompe leadership team meeting, reading down the long list of experiments planned and exclaiming, “Jesus, this is the mother of all experiments!” And the moniker stuck, despite the attempts of several serious-minded officials at Genzyme to give the experiments a more “appropriate” name.
Each drug development group—the one in Europe developing Pharming’s enzyme, scientists in Oklahoma working for Canfield, Chen’s team at Duke, and Mattaliano’s group at Genzyme—prayed their drug would “win.” Losing, everyone knew, meant marginalization of their research and, in some cases, wholesale layoffs.
To placate the various factions, the scientists decided to use several different methods to test the efficacy of the enzymes. These included a biochemical analysis, in which they ground up mouse tissue and added a chemical to measure how much enzyme had been taken in. In another biochemical analysis, they compared how much glycogen had been removed. They also performed a histological analysis, slicing up tissue, putting it on a slide, and staining it to see how much glycogen remained. They compared the enzyme activity and glycogen clearance in several different types of mouse tissue, including samples from the triceps, quadriceps, and hearts. They tested the enzymes at three different dosages. And they also performed experiments to compare the levels of antibodies produced in the mice to get a clue about which enzyme might be least foreign to the body. In all, they would analyze nearly five hundred tissue samples. They would be tested in Canfield’s lab in Oklahoma as well as Genzyme’s in Framingham.1
To make it a blind test, the formulations group color-coded the different enzymes whose identities were kept confidential. In the test, they would be known only as green, blue, yellow, and magenta samples.
It took almost two months to complete the almost five hundred experiments and one exhausting week to compile the results. And there was, indeed, a winner.
On January 31, John pulled up at Genzyme’s science center, a four-story brick and glass building that was part of a campus of a dozen buildings the company occupied in Framingham, an old industrial town about twenty minutes west of Boston. The science team, which included Canfield, Mattaliano, O’Callaghan, and several others—had met several hours earlier to discuss the results of the Mother of all Experiments and learn the identity of the winning enzyme. They were waiting only for him to arrive.
John found the scientists assembled in a small, cold, second floor conference room, occupying nine of the ten seats around the rectangular table. John took his seat, greeting everyone briefly. Mattaliano said the science team had spent several hours reviewing and analyzing the massive amount of data generated by the Mother of All Experiments, and that he would now present the most important of the conclusions. He launched into a PowerPoint presentation of the results. The first slides showed the results of a series of biochemical analyses, in which the muscle samples were ground up and a chemical added to test for the presence of the Pompe enzyme. In this test, the magenta enzyme was taken up best, outshining the others by far. But in the next series of slides, when numerous different tissue samples were studied to see which enzyme had cleared glycogen best, the yellow and green performed better than the magenta. And this type of analysis was considered the more relevant test in Pompe science because it indicated that the enzyme treatment had entered the lysosomes and done its job, metabolizing glycogen.2
“Of the top two, the yellow enzyme appears slightly superior in some muscles, but not by enough to be statistically significant,” Mattaliano said, as he clicked to change slides.
John, hoping Novazyme’s was the yellow or the green, snuck a look at Canfield, who hadn’t said a word yet. His arms were folded tightly across his chest, and he was brooding down at the grains of wood in the conference table. Novazyme’s must be the yellow, John thought, and Canfield looked upset because it didn’t perform significantly better than the second-place finisher.
“Now let me show you what these enzymes are,” Mattaliano said. “We were just unblinded ourselves to the color coding a couple of hours ago.”
For first place, there was a statistical tie between the top-performing yellow enzyme, Chen’s, and the green, the internally developed Genzyme enzyme, the one Mattaliano had helped develop for easy manufacturing. Novazyme’s, the magenta, came in third in the overall assessment, and Pharming’s a distant fourth.3
John was shocked and, to some degree, embarrassed. Even though he’d known Canfield was struggling to get his enzyme to work right, John had been sure it would outshine the others—or at least work as well.
“How is it that the Novazyme enzyme was so much better on the enzyme activity test and did so poorly in the glycogen clearance?” John asked, hoping there was some mistake with the final analysis.
Mattaliano smiled. “We were wondering the same thing,” he admitted. “We discussed it at length a few hours ago.” He said that the scientists’ best guess was that the Novazyme enzyme, with all the extra phosphates at the end of the sugar chains, was taken up by some other part of the tissue before it could get to the lysosomes of the muscle cells. Endothelial cells, in t
he linings of blood vessels, also had receptors with an affinity for the sugar chains. Perhaps the endothelial cells had taken up the Novazyme enzyme, leaving little or none remaining to enter the lysosomes and clear glycogen.4
John said it was time to poll the group to make sure there was agreement. Still sitting, he went around the rectangular table asking the scientists if they agreed with the conclusions. Mattaliano, O’Callaghan, and the rest of the Genzyme group nodded, smugly, and each gave a firm “Yes.”
Finally, John reached Canfield, hoping the man who was always so skeptical would challenge the way the experiments were conducted—that he would find something wrong with the conclusions.
But Canfield, not lifting his gaze, nodded almost imperceptibly and said, “The results speak for themselves.”5
“Are you sure, Bill? Is there anything else you’d like to add?” John pressed.
Canfield shook his head.
John stood up and thanked the group, and then said, gravely, “God help us if we’re wrong.”
As John made the half-hour drive back to Genzyme’s Cambridge headquarters, his mind raced to absorb the enormity of the implications.
With the easy-to-produce Mattaliano enzyme coming in such a close second, John was almost certain it would be the chosen one. Pharming’s enzyme would have to be shut down. Who would tell those patients that development of their drug was coming to an end? Chen’s drug, which held so much promise, would also have to shut down. They would keep a sample in the freezer—just in case—but the multimillion-dollar contracts with manufacturers who were producing the enzyme would be canceled immediately.
Novazyme would be the hardest hit. Not only had the science that Canfield had worked eighteen months to develop—and nine years before that—been challenged and received a crushing blow, there would almost certainly have to be layoffs if the Novazyme enzyme was not going to be manufactured immediately. If Canfield viewed him as a traitor before, it was nothing compared to what he and others in Oklahoma would think of him now.
And there was a final, bleakly inescapable fact: because “his” drug had lost, John’s hope of exerting his influence over how the clinical trials were run, his hope of making sure Megan and Patrick were included, was lost as well. Since Genzyme’s drug would be picked, Genzyme’s medical and regulatory affairs department would run everything. As medical director, Landy would be in the driver’s seat for all clinical trials.
A few days later, John presented a drug development strategy to Henri and van Heek. John recommended investing $50 million to ramp up manufacturing of the Genzyme enzyme by building two new giant two-thousand-liter bioreactors in the company’s Allston plant. If all went well, they should have enough of Genzyme’s enzyme on hand by the summer to begin a clinical trial. He didn’t say it, but he intended to use every ounce of influence he had behind the scenes to persuade Landy and whoever else was in charge to get Megan and Patrick into that trial.
John suggested also that they find savings of $20 million a year by immediately canceling the outside contracts to manufacture Chen’s drug. He also recommended shutting down manufacturing of Novazyme’s enzyme, which would save several million. Eventually, he said, they ought to also close down Pharming’s manufacturing plant, but not until the next year—not until production of Genzyme’s internally developed drug had been scaled up. For the next year, Pharming’s rabbits would continue to supply drug to the nine patients on the treatment.
Instead of being moved into human clinical trials, Novazyme’s technology and experimental enzyme treatments were being sent back to the research labs. Still a believer in Canfield’s approach, John said he wanted to keep funding Novazyme’s research in the hopes of developing a second-generation treatment that worked better. John was convinced that Byrne’s and other results using an earlier version of Canfield’s enzyme had been accurate. He believed something had gone wrong in the rush to make it with human processing enzymes and the new inhibitor—and to add more and more phosphate molecules. Somehow, the latest versions were being taken up somewhere else before reaching their intended destinations. Finally, John told Henri, Canfield would have the time he needed to work out the problems.
Henri listened carefully, nodding in agreement. For a nonscientist, Henri had a way of absorbing and extrapolating the meaning of scientific information that surprised even the most egotistical scientists. When John had finished, Henri honed in on the risks of going with Genzyme’s enzyme.6
“We know how it works in animals, but we don’t know how—or if—it works in humans. This enzyme has never been tested in humans where the Pharming and Chen enzymes have. What if it doesn’t work? What happens if we’re wrong?”
“That’s our nightmare scenario, Henri,” John responded honestly. “But I think it’s reasonable to bet on the Genzyme product because it’s so much easier to manufacture. We’ll keep the Chen line in reserve. If the Genzyme treatment doesn’t work, we can go back to the Chen product and figure out what to do.”
Henri asked John to present the strategy to Genzyme’s board of directors the next day. “And then, John, your job is just to go and get this done.”
John wanted to bring the same sense of urgency to Genzyme that he had cultivated at Novazyme by inviting patients to talk to his employees. So in February, with Henri Termeer’s go-ahead, he held what he called the Pompe Summit—bringing patients and their families to a luncheon at the Charles Hotel for all employees working on Pompe disease. Henri overruled members of the medical and regulatory affairs groups who paraded into his office worrying that their objectivity would be compromised, agreeing not only to attend the Summit, but also to give a speech. Like John, Henri believed in the power of inspiration to drive people to achieve the seemingly impossible.7
In the morning, before the patients arrived, about two hundred employees involved at all levels in the Pompe program—from machine operators to secretaries—heard Genzyme’s senior scientists and regulatory officials present the drug development strategy developed by the Pompe leadership team. Mattaliano, in a PowerPoint presentation entitled “In Vivo Veritas”—or “the truth revealed in animal testing”—presented the results of the Mother of All Experiments. The title was a muted but obvious dig at Canfield, who had been so insistent prior to the experiments that his approach and his enzyme were superior.8 It had been six months since the Novazyme acquisition, but tension still ran high between the Genzyme and Novazyme scientists. When the title slide came up on screen, John saw with a pang, Canfield winced and looked away.
Landy stood up and presented a plan to rush the Genzyme enzyme into clinical trial as soon as they had enough enzyme in storage to supply the trial patients for one year. Bill Fallon, the Novazyme manufacturing guru, gave an overview of the efforts under way to scale up production of large volumes of the enzyme by refurbishing a bioreactor in Framingham and building two new large reactors in Allston. Canfield, in his turn at the podium, explained Novazyme’s scientific approach and held out the promise of a better second-generation treatment.
The patients, their families, and Henri arrived in time for lunch. John had strategically placed his own family at Henri’s table. Beside Henri, Megan sat in her new pink wheelchair, which had just replaced the red one she had outgrown. Megan used the pink one inside the house and in crowded places like this where she couldn’t bring her electric chair. John, Aileen, and Sharon filled out the same round table; Patrick, who didn’t like crowds and grew agitated and fussy at attention, had stayed at home with a nurse.
Henri, in his dapper tweed sport coat and bright orange tie, leaned over to speak to John’s daughter. “I’ve heard a lot about you, Megan,” he said. “It’s great to have your dad here.” As John watched, Henri then rose and went from table to table, spending at least five minutes talking to each of the patients and their families. Seeing this, John told himself he’d made the right decision in selling Novazyme to Genzyme, despite his frustrations with the bureaucracy and his own lack of authority.
After an initial session of seating and mingling, John took to the floor to introduce the patients. “How many of you have ever met a patient?” he asked the assembled Genzyme group. Only a handful of the two hundred employees in attendance raised their hands.9
“Well, you are all going to meet some very special patients and families today,” John said, beaming. “I myself know the first speaker very well. Greg Assink has flown here all the way from Michigan with his wife Deborah and their new baby Megan, who, I’m proud to tell you, is named after my own daughter. Greg and Deb have been strong supporters of the Children’s Pompe Foundation. They are among the most committed parents I have ever met, and I am proud and pleased they have made the trip today.”
Greg stood up, carrying four-month-old baby Megan in his arms, his wife smiling from the seat beside him. He told the assembled group that he had two daughters with the disease—the one in his arms and another at home. Kelsey, now eight years old, was too weak to travel. Their youngest had been tested and diagnosed only weeks after she was born. She was still able to hold her head up, but her mouth hung open and her tongue poked out a little, the telltale sign of the disease.
“I cannot tell you what it means to us to have all of you working on a cure for our children,” Greg said, choking up. “Deb and I want to thank you from the bottom of our hearts—and for you to know that we know you’ll be successful. We know Kelsey and Megan will be saved because of your work.”
After several other parents spoke, it was Aileen’s turn. “I think you all know who my husband is,” she said dryly, drawing laughter and some scattered applause. “This is Megan here, our daughter, and Sharon, our nurse. We want to thank you all for your hard work. We’re counting on you.” Megan waved from her seat as the audience applauded.
Finally, Henri rose to address the patients. He gave a long and rousing speech, ending with an emotional declaration of his commitment. “I don’t know how much better we can make your children,” he said. “But I promise with every fiber of my being that we’ll do our best to make it happen.”