TRIALS - A Desperate Fight to Save Kids & Change Science

By Amy Dockser Marcus

Chapter 1: The Children’s Crusade

In the beginning, Chris Hempel noticed the clumsiness. Her girls tripped over toys on the floor. Their grandfather said he couldn’t teach them to pedal their tricycles. At a neighborhood party, Ms. Hempel watched a younger child jump off a sofa and realized her own toddlers never tried such stunts. Something’s not right, she thought. Addison and Cassidy Hempel, her identical twins, shared a crib, sleeping side-by-side on star-and-moon sheets, in a room painted yellow, toys everywhere. Most mornings, Ms. Hempel and her husband, Hugh, woke to the girls chattering over the baby monitor. The twins loved pretending to talk on the phone. Addi sang “Twinkle, Twinkle, Little Star,” and Cassi liked “Mary Had a Little Lamb.” After the twins were born on Jan. 23, 2004, the Hempels bought land in Reno, Nev., to build a house—big enough, Ms. Hempel said, for the girls to bring all their friends. The winter the girls turned 2 marked an end to all that. The twins first had fevers and vomiting. The pediatrician found their spleens were enlarged, and she treated them for mononucleosis. After the mono was gone, their spleens remained abnormal. Their parents took them to a children’s hospital at Stanford University. Tests there found nothing. Friends tried to be reassuring: The girls were born five weeks early, they said, maybe they had a developmental delay. Or, they were taller than average, perhaps this explained their awkwardness. The twins got another virus when they were 3 years old. This time, their livers were enlarged, and the doctor suspected something called a lysosomal storage disease. Ms. Hempel learned these diseases included more than 50 inherited disorders, marked by the failure of cells to process and recycle waste. The materials accumulated in cells, eventually triggering a range of problems, including seizures and dementia. Tests, again, revealed nothing specific. Doctors ordered a skin biopsy to test for a particularly rare disease called Niemann-Pick Type C. There are an estimated 500 cases of NPC disease diagnosed world-wide, mostly children. It gradually steals mobility, speech, the ability to swallow. Patients who take ill as children rarely live beyond their teens. “We looked at the statistics of it all, and we said, ‘What are the chances?’ holding out hope that it wasn’t NPC,” Ms. Hempel said. “But in my heart, I knew.” The tests came back positive, and Ms. Hempel cried inconsolably. For three months, she needed pills to sleep. After the diagnosis, the couple spent more and more of their time online. They looked for experimental treatments, a potential drug in the pipeline, promising research, anything. Chris Hempel found condolences but little hope. The more Ms. Hempel learned, the more upset she became. Some labs were testing different compounds, but the work was at its very early stages. At this rate, she said, “there won’t be any drugs in time for the girls.’’ Until their twins got sick, Hugh and Chris Hempel knew little about science. But they knew how to work and how to win. As teenagers, they each pursued sports. Mr. Hempel lived in Denver, where he played hockey. He grew to 6 foot 4 inches and joined the University of Vermont team as a freshman. He quit to have more time to study engineering and business. Outside class, he waited tables to pay his way through school. Mr. Hempel’s view of medicine was shaped by his grandfather, a plastic surgeon. The older man would sometimes stitch up his grandson after games, and Mr. Hempel remembered the plaque on his grandfather’s wall: “You’re Welcome To Go Get A Second Opinion. Hah!’’ Ms. Hempel was the shooting guard on the basketball team at Mills High School in Millbrae, a Northern California town. Sports were a way out of a difficult childhood. Her parents married when Ms. Hempel’s mother was 17, and they divorced when Ms. Hempel, the youngest of four children, was 7. High-school friends recall Ms. Hempel as popular and pretty, with blue eyes and long, jet-black hair. She devoted her time to playing basketball and studying game tapes. Her obsession was winning a college scholarship. In high school, Ms. Hempel moved in with her father, who let her practice three-point shots at all hours. She made the all-state team and won a scholarship to the University of California, Berkeley. In college, she studied political science and broke records for three-point shooting. She joined Netscape in 1995, employee No. 132, a low badge number that carried status in Silicon Valley, along with generous stock options. Ms. Hempel helped run Netscape’s PR department, forging a tightknit group of women there. Selling the World Wide Web barely left time for lunch. When they had a break, the women ran “the Dish,’’ a hilly route above Stanford University named for the radio-telescope at the summit. Do something first, apologize later, was the Netscape way. Ms. Hempel’s colleagues said she was a good fit. When a new boss ordered an 8 a.m. starting time, Ms. Hempel refused, saying her morning workouts made her more productive. The boss agreed to 9 a.m. Mr. Hempel also joined Netscape in 1995—employee No. 161, in charge of electronic marketing. He sold one of the first banner ads on the Internet, a deal with Visa and MasterCard. They were only work acquaintances until a late-night party at the house of Mr. Hempel’s boss. Someone suggested hiring a limousine to take everyone dancing. In the hired car, they sat side-by-side. Ms. Hempel said she felt a jolt when they touched and was certain he felt it, too. They married in 1999, and a business magazine noted the couple sent their invitations by email. The Hempels didn’t know that they each carried a gene mutation that in their twins yielded the NPC disease. When the girls were diagnosed, “we were in a state of shock,” Ms. Hempel said. She was 39 years old; her husband was 49. The couple discovered online a small community of families, researchers and doctors linked by NPC disease. Ms. Hempel created a blog to post medical updates about her girls and to share scientific papers. She tapped into a stream of discontent flowing through chat groups and patient sites, complaints that science moved too slowly to keep up with the symptoms progressing in loved ones. The Hempels learned of people who called themselves citizen-scientists. Many shared research papers and their day-to-day experience. Some talked of their willingness to try any promising drug. Others sought a role as equal partners with researchers. Scientists, while sympathetic, generally believe their work should be left to experts. Families are encouraged to raise money if they want to help, but the traditional view is that amateurs can't shape research or find cures. The Hempels found a maddening gap between the search for scientific knowledge and the search for treatments. Scientists aren’t villains, Ms. Hempel said, but too many are hobbled by secrecy and rigid tradition. “The bottom line is their work does not translate fast enough to help Addi and Cassi and the other NPC kids,” she said. To change that, the Hempels needed to find allies. In October 2007, the Hempels flew to Minneapolis with the twins to see Marc C. Patterson, an expert in NPC disease at the Mayo Clinic. Many young patients and their parents had passed through his office in Rochester, Minn. Without a cure for NPC, Dr. Patterson said, doctors could treat only symptoms, prescribing medicine for seizures or asthma drugs to ease breathing. He told them about a doctor named Forbes D. Porter at the National Institutes of Health, who examined NPC patients each year to record their progress. The information would help researchers see if a drug was working in a future clinical trial, and his patients would be likely trial candidates. The Hempels wanted to sign up the girls. Chris and Hugh Hempel sat on a couch, the twins on their laps clutching stuffed dogs, as Dr. Patterson began speaking about the idea of scientists and families working together to accelerate the search for a treatment. Dr. Patterson told them he had joined forces with two scientists and a parent seeking to reshape traditional research. The men wanted to link the observations of families with the work of scientists. They named their collaboration SOAR—Support of Accelerated Research for Niemann-Pick Type C—and hoped others would join them. Dr. Patterson said the group and some of his colleagues planned to meet the next month with other parents to talk over their ideas at the NIH, the U.S. headquarters of publicly funded medical research. Lured by the promise of science, families of patients with rare diseases began making their way to the laboratory of Christopher P. Austin. He was director of the NIH Chemical Genomics Center in Rockville, Md., a state-of-the-art lab that used robots to search for treatments. Robots are the most eye-catching part of the lab’s $20 million, 30,000 square-foot system of refrigerators, automated incubators and computers. Machines work around-the-clock, testing hundreds of thousands of compounds against a variety of mostly rare diseases. One of the first parents to visit was a woman whose college-age son had a rare cancer. During a tour in 2006, Dr. Austin told her that instead of 17 years to develop a new drug, the new lab could cut the time to 10 years. “ ‘I love your technology,’ ’’ Dr. Austin recalled the woman saying. “ ‘I love your robots. I love this fancy stuff. But for my child and this disease, 10 years, 15 years, isn’t going to work. Isn’t there something else we can do?’ ’’ It was a question he would hear again and again. There are roughly 7,000 known diseases; about 500 have a treatment. Even with robots working day and night, Dr. Austin said, the arithmetic was discouraging. Pharmaceutical companies were the primary organizations with the resources to support large clinical drug trials, and Dr. Austin didn’t think they were doing enough for rare diseases. If the NIH didn’t do more, he said, many patients would be left to die. The idea was controversial. Researchers worried it would shrink the pot of NIH grants for basic science. Dr. Austin loved the elegance of lab work, but he believed basic research was too often removed from patients. As a medical student, Dr. Austin shuttled between the genetics department of Harvard Medical School and the New England Conservatory of Music, where he sang bass baritone. It was easy to lose sight of patients while working in the lab, he said, but not so in opera, which “is all about what makes humans human.” Now, as head of the robot lab, Dr. Austin wondered how science could build a better partnership with the sick. With that in mind, he hosted the meeting of NPC scientists, researchers and parents in November 2007. The room that day filled with the makings of a fragile alliance of parents and scientists. Chris Hempel sat next to Dr. Austin. Sitting nearby was Phil Marella, of Greenwich, Conn., another parent of two children with NPC. Dr. Porter, of the NIH, joined the meeting. Dr. Patterson was there with Daniel S. Ory, an NPC scientist and Harvard classmate of Dr. Austin’s, and Steven U. Walkley, a tall, bearded researcher who had worked on NPC disease since the late 1980s—all three men founders of the SOAR group. The meeting set the stage for six years of debate over which experimental drugs to pursue and whether any was safe to try on children. Scientists urged families to delay promising treatments until they learned more. Researchers worked under the pressure of helping young patients they knew by name. All sides faced risk and sacrifice. Despite the challenges, the group came to believe their work would one day yield a treatment, and, if successful, they just might steer a new course for medical research in the U.S. The 2007 meeting ended in a small victory. NIH officials agreed to use Dr. Austin’s lab to test drugs on skin cells from children with NPC disease. It was only a first step. But looking back, Dr. Austin said, “the discussion was one we never had before.’’ He thought these parents and scientists might be the right group to test his ideas about greater collaboration. During a break in the talks, Dr. Austin took the visitors to see the lab. When describing his work, he often referred to football. He grew up in Baltimore as a young fan of legendary NFL quarterback Johnny Unitas of the Colts. Modern science, Dr. Austin said, had evolved into a team sport. In drug development, he said, scientists were often stuck on their own 20-yard line. The robots might get them to midfield. In a traditional lab, workers deliver tear-size drops of chemicals into wells on plastic plates that contain cells from patients. Scientists then look for any successful attack on the cells. Robots perform this work in Dr. Austin’s lab, moving bright yellow arms in a synchronous choreography—untiring, faster than human hands. The mechanical arms scoop up plates filled with cells. When they bend over to lower the plates for the next stage, they look like they are bowing. The lab is one of the few places in the world where this mechanized screening technology is on display. Chris Hempel stopped Dr. Austin to ask whether the robot had a name. Her focus on science so quickly after her daughters’ diagnosis had surprised him. No, it doesn’t have a name, Dr. Austin told her, but a lot of people ask. “I think you should name the robot Hope,” she said.

Chapter 2: Home Remedy

Chris Hempel wasn’t waiting for science. She ordered 100 grams of a white powder that arrived in a plastic bag from a Florida distributor. It looked like sugar and tasted like it, too. She mixed a few teaspoons in water and drank it. After trying the concoction every day for a few weeks and feeling no ill effects, Ms. Hempel put the drink in sippy cups for her 4-year-old twin girls. Ms. Hempel had reason to hope the sugary drink might help. A month after the November 2007 meeting at the National Institutes of Health, scientists in Texas published a startling discovery: a single dose of cyclodextrin injected into mice with NPC disease markedly extended the animals’ lives. Cyclodextrin, a sugar-based molecule, was the anti-odor ingredient in Febreze air freshener. Food makers used it in chewing gum and cholesterol-free mayonnaise. In labs, it was a tool to dissolve and deliver drugs. Researchers “were no more thinking about cyclodextrin as a possible therapy than they were thinking about the pipettes they were using as a therapy,” one NPC scientist said. Ms. Hempel began giving cyclodextrin to the girls in early 2008. "I am posting this message to the entire world to let everyone know that Hugh and I will not sue any doctor, scientist, researcher, hospital or non-profit if anything happens to Addi and Cassi as we embark on trying experimental treatments to save them from Niemann-Pick Type C disease," she wrote in her blog. From the beginning, scientists said drinking cyclodextrin wasn’t likely to help because not enough of the drug could reach the brain and other organs. In December 2008, the Hempels’ doctor applied to the Food and Drug Administration for permission to give the girls intravenous infusions. The scientists were alarmed. No one knew how cyclodextrin worked. No one knew effective dose levels. And no one was sure if it was safe. The planned collaboration of parents and scientists was moving forward. But Chris and Hugh Hempel wanted to set the pace. Ms. Hempel and other parents were parked on a sofa in a New York City office in late February 2009, waiting to meet with scientists to discuss the joint effort that took shape in the robot lab two years earlier. The scientists were talking privately in a conference room before meeting with parents. Next to Ms. Hempel sat Cindy Parseghian, president of the Ara Parseghian Medical Research Foundation—set up by the family of the famed former Notre Dame football coach. Ms. Parseghian had lost three of her four children to the disease. She buried 16-year-old Marcia in 2005, following the death of a son and another daughter. Ara, her surviving child, was born without NPC. Ms. Parseghian held a special place with both sides, families and scientists. Researchers had shared in more than $40 million raised by the foundation over the years, money that supported discovery of the gene that caused most NPC cases. After 20 minutes, a young woman led the parents to their own conference room. As the others headed to the elevator, Ms. Hempel picked up her bag and followed. They walked past a glass-walled room filled with the scientists. Ms. Hempel lingered a moment to look inside. One of the men stood with a pen at a white board. Others watched from a table strewn with paper plates and coffee cups. Ms. Hempel couldn’t hear anything; the glass was too thick. For a moment, she was tempted to barge in, grab a chair and refuse to leave. The other parents beckoned from the elevator, holding the doors open. “I wish I knew what they were saying,’’ Ms. Hempel said. Then she looked away and joined the others. Scientists in the room were stunned when they first heard the Hempels were trying to get special permission to give intravenous infusions of cyclodextrin to Addi and Cassi. NPC was fatal, but an untested drug might kill children sooner than the disease, said Forbes D. Porter, the NIH scientist tracking symptoms. “You can make things worse,” he said. “As a physician, I have to account for that.’’ His colleagues also worried about parents trying experimental treatments. “There is a huge gap between what you find one day in the lab and what is a safe compound to put in a person,” said Daniel S. Ory, the NPC researcher at Washington University in St. Louis. The Hempels, he said, weren’t heeding that gap. Such concerns were one reason scientists preferred to keep their work behind closed doors. Another was practical. Experiments took months or longer. It was slow work to verify results and prepare them for publication. Sharing information too early might make it harder to have work published in a scientific journal, potentially jeopardizing funds scientists need to keep labs running. Parents, in their own meeting room, also were divided over the Hempels, who blogged about giving cyclodextrin drinks to the twins. “What the Hempels are doing, pushing the envelope furthest, has added value to the community because they are the engines driving things,” one parent said. But Phil Marella was worried. Other parents would be tempted to follow the Hempels when too little was known about cyclodextrin. Mr. Marella’s daughter Dana had advanced NPC, and even a common over-the-counter drug like ibuprofen could cause problems. Some parents might try cyclodextrin, he said, and end up hurting their children: “You can cause more harm than good.’’ Chris Hempel told the others she opposed the secrecy of medical researchers and would keep posting every bit of information she learned from the twins. “The process does not move fast enough,’’ she said. “But the process doesn’t accelerate because we tell other parents that some compound might be promising,’’ Mr. Marella said. Ms. Hempel stood her ground. “I have an ethical obligation to tell parents I’m doing it.’’ Mr. Hempel acknowledged that he and his wife had no idea of what was a safe and effective dose. “We’re guessing,’’ he said. For Mr. Marella, that was reason enough to wait for science. “It’s too easy to guess wrong,’’ he said. Ms. Parseghian also worried about families trying drugs on their own, but she understood. A few months after her children were diagnosed, she and her husband went to a family support meeting, where “I saw my first very impaired NPC child with a feeding tube,’’ she said later. “I told my husband, ‘I will never put a feeding tube in my child.’ But when it got to that,” she said, “we put feeding tubes in two of my children. It made me realize I cannot judge other families.’’ When parents and scientists finally gathered, Dr. Porter announced there was a compound he thought might be a candidate for a drug trial, and it wasn’t cyclodextrin. Dr. Porter wasn’t ready to reveal the name because it was so easy to buy. He didn’t know whether parents would wait for an NIH trial, or give it to their children immediately. “My obligation has to be to the community, not to individuals,’’ Dr. Porter told parents, expressing the traditional view of medical research. Few of the scientists personally knew more of the children than Dr. Porter did. He had examined many of them over the years, boys and girls who gave him high-fives when they saw him or ran into his arms. But he would be in charge of any future NIH drug trial and would need about 30 patients healthy enough to enroll. There were only an estimated 200 to 300 diagnosed cases in the U.S. If too many children took an experimental drug on their own, it might be impossible to confirm results in a formal trial. Dr. Porter immediately understood the dilemma posed by the Hempels’ aggressive use of cyclodextrin because he had seen something like it before. He had directed research on a rare genetic disorder called Smith-Lemli-Opitz Syndrome, or SLOS. Children with the condition can’t properly make needed cholesterol. Some live into old age. Others die early. Dr. Porter’s work led to a 2005 clinical trial of a common dietary supplement. He wanted 40 children to enroll. But by then, parents were already giving the supplement to their children. The trial got only 13 participants. Statisticians later said there weren’t enough children to know whether the trial results were tied to the drug or to chance. Dr. Porter closed the trial, never proving parents’ claims the supplement helped their children. Dr. Porter turned to NPC that year. Researchers had reported a brain steroid prolonged the life of mice with the disease, and NIH scientists started talking about a drug trial. One knew of Dr. Porter’s work with SLOS and tapped him to help. The first question Dr. Porter asked colleagues was how they measured whether a drug worked. “There was silence around the room,” he said. Scientists didn’t know enough about NPC to say if it was progressing or arrested. Instead of a drug trial, Dr. Porter launched what researchers call a natural history study. Every year since 2006, he has gathered medical data from patients to answer basic questions: How quickly did the disease progress? What were the key symptoms? Dr. Porter examined dozens of children. He took blood and urine samples and collected spinal fluid with a large needle. After the exams, he watched his young patients slide across hospital hallways in their socks. Families stayed about a week at the NIH for their children’s annual visits, and Dr. Porter talked with parents for hours. In the evenings, he stopped by to play air hockey with the children. He played catch on a patch of grass outside the clinical center. Privately, he worried the children got little in exchange for the discomfort of the annual exams. “Nothing I am doing in there will have a direct benefit to the child himself,” he said. “And so I have to step back and realize what I do to these kids, and there are things that I do that will hurt, I can’t get away from that. The only way I can justify it is we’ve thought it out, and we think it has the potential to help kids with NPC in general.’’ He sometimes escaped aboard an 18-foot fishing boat on the Chesapeake Bay. For two or three weeks in spring, when trophy rock fish were in season, he scheduled appointments around fishing trips. During these early mornings, when the water was still and clear as glass, his mind relaxed, he said. Other times, Dr. Porter’s lab manager joined him, and the two men dropped fishing lines from the back of the boat and talked about the next experiment. A month after the meeting in New York, the FDA approved the Hempels’ request for the twins to receive infusions of cyclodextrin, and, in March 2009, Addi and Cassi got catheters surgically implanted in their chests. Five months after the meeting, Dr. Porter announced a clinical trial of the compound he had kept secret—an antioxidant sold in nutritional stores. Enrollment began in September 2009, and the families of 35 children signed up. Two children suffered liver complications during the five-month trial. In the end, the drug didn’t appear to work. Through the year, parents turned to Dr. Porter for advice about trying supplements or different drugs. Some asked about the Hempels and cyclodextrin. When parents sought a medical opinion about heading into such uncharted waters, Dr. Porter always answered with the latest research findings. Sometimes they simply asked: “What would you do if you had a child with NPC?’’ Dr. Porter expressed empathy, as well as his deepest consideration. But the glass wall still separated them. “I don’t know,’’ he would say. “I don’t know.’’

Chapter 3: Do No Harm

On an island in the middle of the kitchen, Chris Hempel mixed a pungent concoction of more than 25 herbs and supplements that her twin girls, Addi and Cassi, drank three times a day. Ms. Hempel wasn’t betting on cyclodextrin alone. She came up with a makeshift recipe from ingredients she hoped would stave off symptoms of the fatal disease diagnosed in her girls two years earlier. Ms. Hempel added the ingredients to small porcelain mixing bowls, squeezing tubes to the last drop, measuring each teaspoon of powder. There was sesame oil, an egg-yolk yellow supplement called CoQ10, a teaspoon of mushroom, a dash of garlic and grapeseed extract. The color of the mixture changed with each ingredient—from blue to green to red to muddy brown. The family logged the doses on a printout hanging in the kitchen. Each girl, now 5 years old, got a piece of candy before, and handfuls after, as a reward. After their morning dose, the twins were fed and their limbs stretched to keep them limber. Their long hair was combed and tied in ribbons. Diapers were changed, and the girls were dressed in fresh clothes. Once a week, the girls got infusions of cyclodextrin at a local hospital. With the girls’ symptoms advancing, Chris and Hugh Hempel had decided against waiting for a government-approved drug trial that might be years away. The girls were getting more difficult to understand. They had stopped singing. Caring for the twins left the couple little free time. “Everything I thought I once believed was important, I don’t believe anymore,” Chris Hempel said. That included keeping up appearances. Since going gray in her early 20s, Ms. Hempel regularly visited a hairdresser for the three-hour process to color her long hair a glossy black. Now, the visits seemed a waste of time. It had been weeks since her last salon visit when she and her husband shared a rare night out at a friend’s 50th birthday party in August 2009. A wide gray streak ran down the middle of Ms. Hempel’s scalp. She wore a hat and didn’t take it off until she returned home. Shortly before two o’clock in the morning, Ms. Hempel stood in front of her bathroom mirror with scissors in one hand and a curtain of hair in the other. The couple had shared two bottles of wine at the party, which wasn’t far from the Reno property the Hempels bought to build their dream house with their Silicon Valley winnings. In 2000, two years after AOL acquired Netscape, they cashed in stock options for a comfortable fortune and quit work. When they decided to start a family, Ms. Hempel got pregnant right away. The first cut of the scissors was the hardest, Ms. Hempel said. Her hair had cascaded past her shoulders for as long as she could remember. Shorn hair piled up on the counter next to the sink. In the mirror, she saw her husband behind her. He looked shocked. “I’m cutting my hair,’’ she said. He was silent for a moment. Then he said, “Let me help you.’’ Hugh Hempel retrieved hair clippers and began cutting, as his wife leaned over the sink. When he was done, she looked in the mirror. She saw a bristly, quarter-inch of gray fuzz, like an Army recruit. Ms. Hempel got a plastic bag and collected the hair on the counter. She still felt a little tipsy from the wine. The next morning, she asked her husband why he hadn’t tried to stop her. “How can I stop you from doing anything?’’ he said. As Addi and Cassi continued their cyclodextrin infusions, scientists advanced their work on lab animals. Steven U. Walkley, of the Albert Einstein College of Medicine of Yeshiva University in New York City, gave the drug to younger and younger mice, testing different doses. Untreated mice died. Mice that received the drug not only lived longer, but the cholesterol stored in many of their neurons cleared. Dr. Walkley couldn’t explain how it worked, but he had never been so excited about a drug. Its potential surfaced in a lucky accident. Dr. Walkley and others had set out to replicate experiments from the University of California, San Francisco, that found mice receiving the brain steroid allopregnanolone lived significantly longer than those without it. While trying to duplicate the finding, scientists gave cyclodextrin as a placebo to a control group of NPC mice. Cyclodextrin had been used for years in the medical industry as a so-called excipient—an inactive substance used to stabilize and dissolve drugs in a solution. Dr. Walkley and other scientists were surprised when mice in the control group lived as long as those receiving allopregnanolone, which was administered using cyclodextrin. No one believed cyclodextrin had its own pharmacological power. Scientists revised that long-held view in articles first published by John Dietschy’s lab at the UT Southwestern Medical Center in Dallas, and then in papers from Dr. Walkley, Daniel S. Ory and others. In September 2009, shortly after Ms. Hempel’s haircut, Dr. Walkley and his colleagues published a paper showing that regular infusions significantly increased the life span of mice with NPC, an advance suggesting that cyclodextrin could be an effective ongoing treatment. Later that month, the Hempels invited him to an Oct. 3 fundraising gala. Dr. Walkley wanted to attend to support the family’s efforts. He also needed to pass on some disturbing news. For years, Dr. Walkley had little contact with parents of children sick with the diseases he studied. He had trained as a veterinarian to sharpen his research skills. In his career, he first worked with cats and dogs—animals that also develop lysosomal storage disorders like NPC. But he eventually switched to mice. New technologies made them available with a wider variety of genetic diseases. He also wasn’t as emotionally attached to sick and dying mice, as he had been with dogs and cats. Dr. Walkley and his wife lived in upstate New York, in the former summer home of a movie producer. The house, built in the 1800s, had fallen into disrepair when the couple first saw the property. They counted 18 broken windows. The Walkleys replaced the windows and cleared the garden. Dr. Walkley planted blackberry, blueberry and gooseberry bushes. He picked the berries and made jam. He kept fish heads in the freezer to prepare spicy dishes from his childhood in Mobile, Ala. The house became a refuge. But even there, Dr. Walkley was preoccupied with his work. Over the years, he had grown frustrated with the slow progress of understanding NPC and similar disorders. Children were dying, and scientists were no closer to finding a treatment. Dr. Walkley met Chris and Hugh Hempel at the robot lab and was a founder of SOAR, the parent-scientist collaboration. He appreciated the emotional connection he formed with young patients and their parents. He kept a picture of the Hempel twins and another child on his office door. His wife had a view of Dr. Walkley’s relationship with the families. Both sides needed something from the other, she said: “We rise to greet what meets us.’’ The personal ties also made Dr. Walkley uncomfortable after the Hempels decided to try an untested drug on their girls, partly based on his work. When Ms. Hempel first asked about trying cyclodextrin, Dr. Walkley begged her to wait, even six months, until he learned more. “It could take 20 years,” Ms. Hempel told him. “We don’t have 20 years.’’ A mouse brain is the size of a thumbnail. A child’s brain is bigger than a softball. Extrapolating information from a mouse to a child was too big a leap, Dr. Walkley said. He was now particularly interested in how cyclodextrin worked in cats. Their brains measure about three-quarters the size of a human fist. A child’s brain was larger, but researchers could make good guesses from cats about doses that might work in children. Since the early 1990s, Dr. Walkley had been closely following a colony of cats with NPC disease that a New York family had first brought to a veterinarian at Cornell University. The animals had tremors and fell trying to play. Skin-tissue samples confirmed NPC, giving scientists a new way to study the disease through the cats and their offspring. The cat colony was eventually housed at the University of Pennsylvania, where Charles Vite, associate professor of veterinary neurology and neurosurgery, began giving the animals cyclodextrin in 2008, the same year the Hempel twins began taking the drug. The results startled Dr. Vite. Cats that were usually dead by 24 weeks appeared normal. But two of the cats died from a pulmonary disease that persisted even after stopping the drug. Researchers didn’t know why. And at very high doses, cats went deaf. Still, Dr. Vite was convinced some of the animals would survive the fatal disease for a long time with cyclodextrin. He started experimenting with different ways to deliver the drug to the brain, hoping to avoid the worst side effects. A few hours before the fundraising dinner, Dr. Walkley told the Hempels and other parents that two cats on cyclodextrin had died. A similar toxic reaction might not only harm the Hempel twins, it also could cause the Food and Drug Administration to halt cyclodextrin use by anyone else. A potentially beneficial treatment might be lost before scientists determined safe, effective doses. Dr. Walkley knew he couldn’t steer the Hempels from cyclodextrin. But he didn’t want to leave Reno without pressing the importance of monitoring the girls’ lungs. “It’s potentially a very serious issue,’’ he told parents before the gala. The Hempels quickly arranged for doctors to examine the twins. Some of the parents listening to Dr. Walkley’s news were deciding whether to ask permission from the FDA to give cyclodextrin to their own children. “It’s about trade-offs,’’ a parent told Dr. Walkley. “Will the kids develop a lung disease that is treatable as opposed to a neurological disease that is untreatable?’’ Or, he asked, could cyclodextrin have fatal side effects? That evening, Ms. Hempel seated Dr. Walkley and the other scientists at a center-stage table. She introduced them to cheers from the hundreds of people there. When the spotlight turned to Dr. Walkley, he seemed embarrassed by the attention. He stood, raised a hand and waved. “We don’t know how we would get through this without you,’’ Ms. Hempel told the scientists. A meeting of parents and researchers was planned for November 2009 at the NIH, a month after the Hempels’ fundraiser. Dr. Walkley would speak about his lab’s mice studies; Ms. Hempel would give an update on the twins; and Dr. Vite was invited to talk about his cats. In Philadelphia, Dr. Vite compiled a short video. He didn’t have all the answers. But he knew one thing for sure, he said: People are going to want to see this. Chris Hempel brought no charts or video. During her presentation, she instead described “the carpet test.’’ Before her twins started on cyclodextrin, the Hempels planned to install wall-to-wall carpeting because the girls kept falling. But they canceled an appointment with the carpet store, she said, because the girls walked a little better. They also had more control of their head movements, were more expressive. They laughed. “It’s not a miracle,’’ Ms. Hempel said. “They didn’t start talking. They didn’t start running again. It’s subtle.’’ She argued it was time for scientists to submit a proposal for a grant to study cyclodextrin in children. But even the researchers most excited by the drug thought it was too early. “This is not going to make scientific sense,” Dr. Ory said. Scientists didn’t know why the two cats had died suddenly. And they were no closer to understanding how cyclodextrin worked. The improvements Ms. Hempel saw in the twins might be due to chance. There was still no reliable measure to see if the drug worked. Parents were frustrated at how long it was taking to retrieve information that scientists insisted was needed to launch a drug trial. By the time they were ready, one parent said, “some of our kids may not be around.” The lights were dimmed when it was time to show Dr. Vite’s video. Small white cats filled the screen, their tiny faces almost human. The cats that hadn’t received the drug couldn’t stand. They trembled and shuddered. The cats that received cyclodextrin walked and played normally. Parents stared at the screen. The room went silent. It wasn’t hard to make the leap from kittens to children, to imagine the possibilities. Ms. Hempel left the meeting and boarded a flight back to Reno. Once airborne, she pulled down the tray in front of her and crossed her arms to use as a pillow, immobilized by disappointment. A few weeks later, her frustrations erupted in an email to Dr. Ory. “I am finding that after two years of being involved in the NPC community, there continues to be little sense of urgency and a terrible amount of secrecy and apathy,’’ she wrote. “I get this sinking feeling that most researchers and doctors simply feel that NPC kids are going to die anyhow.’’

Chapter 4: Living Proof

Near the end of kindergarten, Dana Marella’s teachers asked her parents for a meeting. Dana was having trouble remembering things, the teacher said, and she wasn’t keeping up with the other kids. At home, Dana’s parents had noticed speech problems and had her tested. She’ll grow out of it, the specialists said. Dana also was a bit clumsy. One of her feet turned in. Orthopedists said not to worry. But after the meeting at school, Dana’s father, Phil Marella, said he began to think that maybe something more serious was going on with his little girl. Dana lived with her parents, an older sister and younger brother, in Greenwich, Conn. Her mother was pregnant with a boy they planned to name Andrew. The family sailed for fun. On Sundays, they went to church. Three years after the meeting with Dana’s kindergarten teacher, a neurologist suggested they see Marc Patterson, then at Columbia University Medical Center. “Marc knew in three minutes what it was,’’ Mr. Marella said. At age 8, Dana was diagnosed with NPC disease. In 2004, two years after her diagnosis, the Marellas took Dana to the National Institutes of Health to see if she qualified for a trial Dr. Patterson was helping design for Zavesca, a drug approved for a form of Gaucher disease, another lysosomal disorder marked by the accumulation of fats and other materials in cells. Doctors told the couple that Dana’s disease was too advanced for her to join the trial. “It was like someone yanked the heart right out of your body,’’ Mr. Marella said. He and his wife, Andrea, drove home in silence. The couple came to two decisions. Since Dana couldn’t be in the trial, they would ask Dr. Patterson to write her a prescription for Zavesca. It would be a so-called off-label prescription—when doctors prescribe medications approved for particular illnesses that show promise in treating other diseases. They also would test their youngest child, 5-year-old Andrew. Unlike Dana, he had shown no neurological symptoms. But as an infant, he had an enlarged spleen, the same as his sister. Andrew tested positive for NPC. He was early in the disease. Dana, 11 years old, was already in a wheelchair. Soon, both children started Zavesca in a family trial that began with high hopes. Shortly after Dana’s diagnosis, the Marellas started raising money for research, sponsoring walks and other small events in Greenwich, Conn. After Andrew was diagnosed, they started thinking bigger. Mrs. Marella had seen TV personality Regis Philbin in town. She wrote him a letter that described her hopes for Dana and Andrew. Mr. Philbin offered to help. The Marellas put up posters at local shops for a fundraising event, advertising Mr. Philbin and his wife, Joy, as special guests. Another celebrity, Frank Gifford, also lived in Greenwich and saw a poster. He and his wife, Kathie Lee Gifford, had a daughter the same age as Dana. They offered to host the 2005 event and proposed dinner at their house for 10 people as an auction prize. The Marellas raised more than $250,000. They turned it into an annual event, later presenting such entertainers as Natalie Cole and the Beach Boys. Mr. Marella had been talking for years with other parents about finding ways to get drugs out of the lab and into trials more rapidly. He had already joined the parent-scientist collaboration when he met the Hempels at the robot lab. Like the Hempels, Mr. Marella felt that observations of parents treating their children should be considered by scientists. He kept records of medications and doses for Dana and Andrew that he believed could help. After his children were on the drug for six years, Mr. Marella got his chance. He agreed to argue on behalf of Zavesca before an advisory panel of the Food and Drug Administration reviewing whether the drug should be approved to treat NPC. At the time, the couple’s oldest child, Julia, was at college in California. Their teenage son, Philip, was a football player. Dana, 16 years old, couldn’t walk or talk. Andrew still had only mild symptoms. The 10-year-old boy struggled with math, but he played flag football in a town league. Mr. Marella believed Zavesca was one reason Andrew had so far escaped the debilitating symptoms of his older sister. He saw the limits of Zavesca. But he believed he was an expert on living with NPC. Mr. Marella sometimes checked on Dana at night, he said: “She wakes up a bit. She opens her eyes. She gives you a big smile. She reaches out a hand to hold your hand.’’ He believed science needed that kind of context. The FDA panel convened in Silver Spring, Md., on Jan. 12, 2010, to weigh evidence from a trial of 41 children, adolescents and adults. Dr. Patterson concluded the drug was beneficial for some patients, but the trial results were clouded by statistical doubt. He believed it was going to be difficult to overcome FDA skepticism and hoped parents would help. The FDA typically, though not always, accepts the recommendation of advisory panels, which are made up of doctors, scientists and a patient representative. Hearings aren’t uncommon for trials with uncertain results. Traditional drug development usually involves three steps for drug approval: a Phase 1 trial to test the drug’s safety; a Phase 2 trial to see if the drug works at safe doses; and a large-scale Phase 3 trial to show its benefits. Since NPC was such a rare disease, with as few as 200 diagnosed patients in the U.S., the FDA agreed to consider medical data from 41 patients. The Marellas drove their van to Maryland for the hearing. They planned for Mrs. Marella to take the four children sightseeing during the morning session and return in time to hear Mr. Marella speak. As a lawyer, Mr. Marella specialized in TV production and distribution. He had little experience that prepared him to argue before doctors and researchers. He called it “the most important speech of my life.’’ The conference room filled early. Mr. Marella sat with other parents. Forbes D. Porter from the NIH was there. He wanted to support the families, and he hoped for insight into FDA thinking. The hearing might help him steer his own efforts to get NPC drugs approved. Prospects for using Zavesca as a treatment for NPC surfaced in the late 1990s, at Steven U. Walkley’s lab in the Albert Einstein College of Medicine in New York City. Mice and cats with NPC lived about 30% longer on the drug. It wasn’t a cure. The animals eventually died. But after the study was published, a drug company approached Dr. Patterson about a trial. “We asked, ‘Is there something we can measure to show the drug is working?’ ” Dr. Patterson said. The researchers decided on rapid eye movements because they could be measured and they appeared to correspond with an NPC patient’s growing disability. The advisory panel seemed skeptical. Early in the hearing, scientists asked about height measurements that suggested the drug may have stunted growth among younger participants. Children with the most severe form of the disease often don’t survive to adolescence, Dr. Patterson told the panel in his Australian accent. For parents, he said, “there is really not a major concern that children may be a little shorter than they might be otherwise under these circumstances.’’ As he waited for his turn to address the panel, Mr. Marella grew frustrated. “Would I rather have a dead child or a short child?’’ he thought. Midway through Dr. Patterson’s presentation, Mr. Marella jumped from his seat. “I have to get out of here,’’ he said. He needed to rehearse. Parents were scheduled after the next break. Mr. Marella ran upstairs to his hotel room with a thought forming. The FDA wanted medical data. But he could see each day how the drug was working. It wasn’t enough for his children to be in the room. They needed to stand next to him as he spoke. The panel needed to see living proof. When it was the Marella family’s turn, Mrs. Marella wheeled Dana to the podium. Andrew stood next to his sister and rubbed Dana’s arm. She reached out a hand to her brother. Their two siblings were beside them. “The last six years have not been easy,’’ Mr. Marella said, “but the one truly bright spot has been that Andrew, now going on 11, is stable.’’ Mr. Marella told the panel how differently the disease had progressed in his two children. Dana attends school and still laughs when the family watches a comedy, he said, but she relies on a feeding tube. “And Andrew, well, he is nearly perfect,’’ Mr. Marella said, good at spelling and writing essays. Weighing a recommendation to approve Zavesca had a financial consideration. The drug cost $100,000 a year or more with off-label prescriptions. If the FDA approved Zavesca for NPC patients, more insurers would likely pay. The panel’s first vote was to decide if the trial provided substantial evidence that Zavesca was working in NPC patients. It failed, 7 to 6. One panelist said the benefits reported by parents were “hard to ignore, but that is not science.’’ During the hearing, Mr. Marella thought about cyclodextrin and the debate over launching a drug trial. The hearing helped him better understand Dr. Porter’s insistence on gathering enough scientific evidence. “You can’t just sit there and say, ‘My kids are better,’ ’’ Mr. Marella said. The panel arrived at the last question: Should they recommend the FDA approve Zavesca for NPC? Mr. Marella closed his eyes. He clenched his hands in his lap. A parent sitting behind him leaned forward and put his arms around him. When Mr. Marella opened his eyes, he saw the final vote: 10 yes, 3 no. There wasn’t substantial evidence the drug worked, the panel said, but there was a “suggestion of benefit.’’ The panel concluded that Zavesca should be approved to treat NPC, given that it was a rare disease with no therapies. After the vote, Dr. Porter and the families met at the back of the room. Mr. Marella was exhausted. The conference room emptied until there was only the cleaning crew and the families. Parents huddled around Dr. Porter as he spoke. “The three who voted no, voted on the science,’’ he said. “The 10 who voted yes, voted on the parents.’’ He turned out to be right. Two months later, the FDA rejected the panel’s recommendation and Zavesca.

Chapter 5: Orphan Drug

Most of the people at the Food and Drug Administration workshop in Claremont, Calif., didn’t wear nametags. They didn’t say who they worked for. And, careful not to give an edge to competitors, they didn’t talk about the drugs that interested their companies. Then there was Chris Hempel. She chatted up scientists and researchers who waited for the shuttle bus to and from the hotel. She handed out denim-colored ribbons attached to a card that said, “Hope, it’s in our genes.” When people asked who she was, she said, “I’m a mom.’’ The February 2010 workshop was set up to increase the number of requests by pharmaceutical and biotechnology companies for something called orphan-drug designations. The designations can carry financial benefits from the federal government for companies that get approval for drugs to treat “orphan diseases,” illnesses that affect fewer than 200,000 people in the U.S. FDA officials scheduled appointments at the workshop to help with applications. Ms. Hempel had already done her homework. For months, she had worked with Ron Browne, a scientist hired by families in the SOAR group, the collaboration of parents and researchers seeking a treatment for NPC. Dr. Browne helped prepare a 50-page document seeking orphan-drug status for cyclodextrin. Even if the application was successful, doctors still couldn’t prescribe cyclodextrin because it wasn’t approved to treat any illness. But to Ms. Hempel, an orphan-drug designation would help her push NPC researchers to launch a clinical trial of the drug. The twins had for months received intravenous infusions of cyclodextrin. She was frustrated with arguments by Dr. Porter and others that the findings from her girls’ treatments weren’t rigorous enough to initiate a trial. Addi and Cassi were already on cyclodextrin, Ms. Hempel said, but an orphan-drug designation might make a difference for others. At the workshop’s opening session, Ms. Hempel asked Tim Coté, then-head of the FDA’s office of orphan products development, to explain the advantage of an orphan-drug designation, even without an interested drug company. “It signifies FDA has given a nod that this compound has promise and may be effective,’’ he said. That was what Ms. Hempel wanted to hear. Her phone rang at all hours with calls from as far away as Brazil, Spain and Japan—parents who also sought confirmation that cyclodextrin wasn’t just a reckless last resort. Ms. Hempel wanted to dispel the view of some scientists that she was only a “desperate mother on a mission to save her children’s lives, saying cyclodextrin is promising,” she said. “Now it will be the FDA saying it.’’ A month before the orphan-drug workshop, Ms. Hempel reached out to Charles E. Strattan of CTD Holdings Inc., the Florida distributor who had years earlier mailed her bags of powdered cyclodextrin. Mr. Strattan had also helped the Hempels when they sought FDA permission for the twins’ weekly cyclodextrin infusions. The FDA had asked Ms. Hempel for safety data before giving approval. Mr. Strattan told her a company owned by Johnson & Johnson, Janssen Research & Development, had studied cyclodextrin for years. The company used it in an antifungal medicine. Ms. Hempel called Janssen, but the company turned down her request. She wrote a blog entry titled, “Dear Johnson & Johnson, do kids really matter to you?” and illustrated it with a picture of the company’s baby-powder bottles. She called the company’s public-relations office to alert them to the blog post. Janssen executive Steven A. Silber soon phoned and offered to help. The company, which later said Ms. Hempel had reached the wrong person in her first call, eventually gave permission for the FDA to look at the data, and the agency cleared the way for Addi and Cassi to get the drug. To prepare for the orphan-drug workshop, Ms. Hempel reviewed a list of scientific papers that Mr. Strattan had sent. She stopped at a 2001 study he highlighted—a paper by University of Arizona scientists who had tested cyclodextrin as a possible treatment for mice with NPC. The results weren’t spectacular. But years before the breakthrough studies of cyclodextrin and NPC, the Arizona researchers had concluded the compound delayed neurological symptoms of the disease. The Arizona study was never followed up; Ms. Hempel tracked down one of its authors to learn why. Robert P. Erickson, a professor emeritus of pediatrics at the University of Arizona, said one reason the paper didn’t trigger more interest was that he didn’t attend many scientific conferences: “People are more aware of what they hear at talks than what is published.’’ Before their paper, the Arizona scientists had submitted early results of their cyclodextrin work to an international NPC workshop in 1999, but Dr. Erickson didn’t attend. “It’s one sentence in one abstract and the lead author was not there to push his story, so it was not visible,” said Steven U. Walkley, whose experiments with the drug Zavesca were generating excitement at the time. When Dr. Erickson and his colleagues sought further funding, there wasn’t any interest. “I have regrets that it languished,’’ he said. For Ms. Hempel, the Arizona story was painful: “This community probably had the perfect drug for years right under our noses.’’ While passing time in her hotel room before her appointment with the FDA reviewer, Ms. Hempel flipped through the pages of photo albums showing her twin girls. For most parents, childhood photos show progress. First, a baby crawls. Next, a toddler holds a grownup’s hand, learning to walk. Then, independence, a child running free. But the albums of Addi and Cassi reminded their mother of what was learned and what was lost. One photo showed Addi holding her sister’s head, both of them laughing. “They don’t interact now,” Ms. Hempel said. Another had the twins on a slide with their dad. “They can’t do slides now.” She turned a page. The girls pointed and waved at a dog across the street. They can’t wave now. Next, they were in a toy kitchen with plastic pots and pans. “They don’t do imaginary play,” Ms. Hempel said. As the pages turned, the girls’ faces seemed to go blank by Christmas 2006. There were more photos, but the baby books ended the following year. At the appointed time, Ms. Hempel and Dr. Browne crowded into a small room with an FDA official for the first of two sessions to review the application. The reviewer said the most challenging part of the application was showing there was enough science. “We have research papers,’’ Ms. Hempel said. “We have animal-model data.’’ The reviewer went through the documents: “This looks solid,’’ she said. The application was missing a required binder, so Ms. Hempel and Dr. Browne went to a nearby Staples store. Ms. Hempel picked a fluorescent pink binder. What about something more professional, Dr. Browne asked, like black or navy blue? “Pink is the only color they can be,’’ Ms. Hempel said. It was her daughters’ favorite. She felt it would bring luck. In a sea of black binders from pharmaceutical companies, she said, cyclodextrin would stand out. When they returned, Ms. Hempel pulled out a video camera and started recording the FDA reviewer take a final look at the application. Chris Hempel kissed the binder and then hugged Dr. Browne. “Your hard work is paying off,’’ the reviewer said. “I can't believe it’s in the pink binder.” Ms. Hempel said. She made a move to leave then realized she hadn’t used up all her time. Chris Hempel took out her phone and started scrolling through photos she kept there. She turned the phone toward the FDA official. “Let me show you some pictures of the girls.”

Chapter 6: Gathering Force

Four months later, scientists spoke over slides and PowerPoint presentations in a conference room of a hotel in Silver Spring, Md., for a National Institutes of Health conference on NPC disease. Questions stretched presentations well past their allotted time. Caroline Hastings waited her turn. She was the doctor treating Addi and Cassi Hempel with cyclodextrin. After hearing only about cats and mice, she was certain scientists wanted to hear about the drug’s effect on children. When it was time, Dr. Hastings stood to speak. Immediately after infusions of cyclodextrin, the twins were more alert, she said. They swallowed more easily and walked better. The improvements wore off quickly. In the days between infusions, symptoms returned. The disease was still progressing. The girls had CT scan imaging of their lungs to warn of any respiratory disorders, which had killed two of the NPC cats. After the FDA raised concerns about cyclodextrin’s effect on kidneys, the Hempels collected urine each morning from the girls’ diapers for analysis. The twins’ blood was drawn and analyzed; cholesterol levels were monitored; height and weight recorded. So far, Dr. Hastings said, the drug seemed safe. The Hempels, she added, “offered the twins so we could learn something to help Addi and Cassi and, altruistically, to help other kids.’’ Hugh and Chris Hempel worked full time caring for the girls and searching for ways to accelerate drug development. When Dr. Hastings finished, she waited for questions. There was silence. She remained standing. Finally, a hand went up. “What scares you the most from the data today?’’ she was asked. “Sudden death,’’ Dr. Hastings said. “This is new territory, for all of us.’’ She sat down. Her turn was over. Forbes D. Porter, the NIH scientist, later said the findings from families using cyclodextrin were hard to assess, in part, because many of the children also took other medications. Addi and Cassi also took antiseizure medicine, supplements and vitamins, for example. If there was improvement, Dr. Porter said, it was nearly impossible to determine the cause. “Unless you set this up in a controlled way with formal outcome measures,” he said, “the data is anecdotal and the strength is weak. Does that balance the risk you’ve put these kids at? That’s the direction I have to come at it. The parent does a different equation.’’ Dr. Porter said he wasn’t against taking risks. But in the case of cyclodextrin, he wanted to better understand the risk before launching a drug trial. He didn’t want children dying suddenly, as two of the cats had. Mr. Hempel saw it differently. “They’ll say, ‘The Hempels’ kids are dying, and they’re desperate, and this desperate schedule isn’t good for all children,’ ’’ he said later. “That’s absurd. The Hempels’ children are paving the way and should be informing the process. Instead, everyone treats it as a side thing that has no relevance to what is going on.’’ That night, Mr. Hempel and some of the other parents joined scientists for dinner. Phil Marella said his daughter Dana, who had been in the hospital for weeks with pneumonia, was finally home. His son Andrew turned 11 that day. Most people couldn’t tell Andrew had the disease. Dr. Porter’s natural history study found that the age when symptoms first appear varies widely. Genetics, environment, or some unknown factor allowed some children to live for years relatively untouched. But once the decline began, abilities fell away at a steady pace. For parents of children with few symptoms, every birthday was weighted with worry. “We’re counting on you,’’ Mr. Marella told the scientists. “I hate to put that pressure on you, but we’re counting on you.’’ “Call Andrew,’’ one of the parents said. Mr. Marella dialed home. He put the phone on the table and pressed the speaker button. “Happy birthday to you,’’ sang the parents and scientists. “Happy birthday, dear Andrew. Happy birthday to you.’’ Parents and scientists at the June 2010 conference later met at Dr. Austin’s robot lab. He told them the NIH had selected NPC disease as one of five pilot projects for a new program to speed drug development for rare diseases. Millions of government dollars would be available to NPC scientists for a clinical trial when they finally settled on a drug. “I made a huge bet on you,’’ said Dr. Austin, who had added the title of director of Therapeutics for Rare and Neglected Diseases, leading a new program for collaborations among scientists, researchers and patient advocates. Continued government funding depended on showing success, which meant a clinical trial of a drug headed to FDA approval and into patients’ hands. Talk among parents had started to veer toward the possibility of two trials: a formal one run by Dr. Porter and a second, parent-driven trial composed of children like Addi and Cassi, who were already taking cyclodextrin. Scientists worried that if too many parents followed the Hempels’ example, there may remain too few eligible patients for an NIH trial to show government regulators if cyclodextrin was effective. During the meeting, Dr. Porter reminded people of how the FDA’s rejection of Zavesca illustrated “the difficulty of proving something works. The majority of parents believe it works, but getting data to prove it is another issue.’’ The Hempels wanted the twins’ experience to advance NPC research. “We can talk about all these hypotheticals and all these mice models and the cats and the hearing issues and this and that, but the bottom line is we won’t know until we try it on the kids,” Chris Hempel said before the meeting, “and some kids are going to have to go first.’’ One parent asked if there was a way for Addi, Cassi and other children taking cyclodextrin to provide clinical information without derailing an NIH trial. There was silence in the room. No one wanted to raise their concerns out loud. Then Mr. Hempel spoke. He and his wife planned to request FDA permission to administer the drug directly into the girls’ spinal fluid. The disease was still progressing, and they wanted to get more of the drug past the body’s natural barriers into the brain. Other parents were likely to follow, he said. Traditional science would have to find a way to incorporate the results of family-directed treatment. Mr. Hempel acknowledged the experiment might harm Addi and Cassi. He said he also saw how “a catastrophic adverse event can impact everyone.’’ If a child died, they all knew, cyclodextrin might never be approved for treatment. During the meeting, it was clear the scientists hadn’t made up their minds about which drug to pursue, even if some parents had. Dr. Austin said tests found a form of vitamin E had a bigger effect on cells than cyclodextrin. That fall, more parents were swayed by a Brazilian teenager named Marcela Pessoa, who began getting cyclodextrin infusions after her parents read the Hempels’ blog posts. Marcela’s mother emailed the Hempels copies of two letters the teen wrote. The first was barely legible. It was from May 2009, when Marcela was 15. The second was easy to read; it was dated in September 2010, eight months after starting cyclodextrin. “I am a very beautiful girl,’’ Marcela wrote, her handwriting marching neatly across the page. The family—and their Brazilian neurologist—attributed the change to cyclodextrin. Dr. Porter was intrigued but said it wasn’t proof. Yes, the girl had taken cyclodextrin, but there might be other explanations. Parents saw it differently: What was a test in cells compared with handwritten evidence? For many, Marcela’s letters confirmed the mounting evidence in favor of cyclodextrin; that, plus the video showing the stark difference between cats that got cyclodextrin and those that hadn’t. By December 2010, six months after the conference, the experiments with vitamin E had reached a dead end. The mice weren’t getting any better. Scientists at the NIH finally narrowed their interest to cyclodextrin in a trial that would require putting the drug directly into the brain or central nervous system of children. “One reason we could make the decision to investigate cyclodextrin was the parents themselves told us they were willing to be our partners in this very unconventional approach,” Dr. Austin said. The scientists committed to testing cyclodextrin in a drug trial but they debated everything else. They had no idea what dose might work, or how best to deliver it to children’s brains. Each had facts to back a view. “Scientists are like Steelers fans,’’ Dr. Austin said. “They are passionate about their position. Scientists love acting that it’s not the case, they’re just going with the facts, but Steelers fans do the same thing. They cite offensive-line percentages to tell you why the Steelers are the greatest team.’’ While scientists debated, the delays worsened tensions among parents. On a conference call in April 2011, Ms. Hempel’s heated criticism of NIH scientists led one parent to hang up in anger. In July 2011, at the annual National Niemann-Pick Disease Foundation meeting, Dr. Porter told parents his goal was to start a trial by the end of 2012. Chris Hempel, brought to tears by the news, sent an email to Dr. Porter: “I almost literally fainted I am so happy.’’ Now, parents needed to decide if they were willing to wait a year or more for the NIH trial to begin. Not all the children would be able to enroll: Dr. Porter and his team would choose.

Chapter 7: Crossroads

Hugh Hempel found solace in his garden over the summer of 2012. There, he briefly escaped the health troubles of his twins and all the back and forth with scientists. His wife, Chris, had pushed him to start digging in the desert soil of their Reno backyard. Mr. Hempel planted rows of grape trees, hoping one day to make wine. He built wooden boxes, protected with mesh, to grow vegetables. By watching YouTube videos, he learned there was a science to growing tomatoes. He wasn’t sure which method to choose, one that allowed tomato plants to grow wild or another that called for forceful pruning. It was here, too, that an idea began to grow. Mr. Hempel wanted the parents who were already giving their children cyclodextrin to agree on a standardized method of collecting patient medical data. A coordinated method, he said, would give parents a choice. Let them pick, he said, between waiting for the National Institutes of Health or going on their own. That way, families that acted alone could also help scientists. His children were already on cyclodextrin, and there were days when he thought, “I’d rather play golf’’ than keep working to make the drug more widely available. “But I feel this almost obligation, not sure to whom,” he said. “I feel like it’s almost more to Addi and Cassi, and their legacy.’’ He knew his girls weren’t going to recover. Scientists believed early treatment was essential. If neurons were damaged, cyclodextrin could potentially help them function more normally again. Even after symptoms started, there was hope that treatment might stabilize the disease. But once neurons died, cyclodextrin could not restore them. The drug, Mr. Hempel said, was “not going to give me the opportunity to have a relationship with them, other than changing diapers and getting the love I get.’’ Mr. Hempel said he argued on behalf of cyclodextrin because he felt it was the best drug available to fight NPC. “If anybody ever suggests that somehow my agenda is less than altruistic, I politely will tell them to go to hell.’’ He decided against pruning the tomatoes and let them grow wild. He said he felt a measure of joy each time he went to the garden and saw the plants spreading their vines, refusing to be contained. That summer, Daniel S. Ory, one of the SOAR scientists, was confident the National Institutes of Health would launch a drug trial to determine the safety of cyclodextrin. The trial would employ a new test the Ory and Porter labs had developed to measure oxysterols in the blood—molecules derived from cholesterol. The test would help determine the best dosage, as well as see if cyclodextrin was as effective as hoped. Everyone’s body produces oxysterols, but people with NPC disease have higher levels of some oxysterols and lower levels of others. The test measured one of the oxysterols that was distinctly lower, using it to monitor the release of cholesterol trapped in brain cells. In cats and mice, researchers were able to see within 24 hours of administering cyclodextrin whether this oxysterol level temporarily increased, a sign the drug was working. Some credit for the new test went to parents. Early in their collaboration, families had asked scientists how they could help. Forbes D. Porter had collected blood samples from patients with NPC disease in his long-term study of symptoms. But to see if the oxysterol test worked, he told families, scientists needed samples from healthy children, which weren’t easy to get. Laura Hadley—who has three children, two with NPC disease—helped organize drives in 2008 and 2009 to collect saliva, urine and blood samples from more than 70 healthy children. When Ms. Hadley saw parents and their children lined up, she said, it was a reminder that “we are doing this all together.’’ Drs. Porter and Ory later acknowledged the family’s help in the paper they published about their new test. As the trial approached, help came from unexpected quarters. Chris Hempel’s provocative blog post when she first applied for FDA permission to use cyclodextrin had triggered a conversation years earlier with an executive at Janssen Research & Development. That relationship led to a collaboration with the NIH team in the trial; 60 people at the company were now helping. Janssen also made cyclodextrin and gave it free to the NIH and to families with permission to treat their children. Once the company decided to help the Hempels and the NIH, Janssen executive Steven A. Silber said, the only ethical choice was to supply the drug to everyone who had approval to use it. The company’s involvement likely accelerated the trial by at least a year, NIH officials said. On Friday, Jan. 11, 2013, Dr. Porter was at a meeting at the NIH when his phone vibrated with an incoming call. He didn’t answer. Another call shortly after finally sent Dr. Porter into the hall to check his messages. The Food and Drug Administration had approved the cyclodextrin trial. Dr. Porter raised a fist in the air, “Yes!” Families were told the first patient would enroll in two weeks. Back in his office, Dr. Porter called some of the parents, including Phil Marella. Dr. Porter wrote to Dr. Ory, “It’s a go!’’ Dr. Ory, who enjoyed an evening run after a day in the lab, saw the way forward. It looked a lot like his jogging route. Starting was the tricky part. His run began on a stretch of road without a sidewalk or shoulder. Each time he set out, he knew he could get hit by something unexpected.

Chapter 8: The Trials

Dillon Papier was patient No. 2 in the cyclodextrin drug trial that began in January at the National Institutes of Health in Bethesda, Md. The Papier family lives about an hour away in Frederick, Md. The 10-year-old boy didn’t like hospitals, but he was always excited to see Forbes D. Porter, who was in charge of the trial. Dillon enrolled early in Dr. Porter’s ongoing study of NPC disease. At appointments, Dillon shouted down hallways, “Paging Dr. Porter,” and ran into the doctor’s arms. Dillon carried his bat, ball and glove everywhere. His father, Mark Papier, a high-school social-studies teacher and baseball coach, had shared his passion for the sport. As the disease progressed, Dillon lost coordination but his Little League teammates asked that he stay on the team. At the start of games, the coach pitched to Dillon and the boy ran to first base. In 2007, the Baltimore Orioles heard about Dillon’s story and invited him to spring training. Over the years, Dillon grew close to second baseman Brian Roberts. They sometimes sat in the dugout together and talked. After Dillon’s diagnosis, the family started raising money for NPC research, work that gave them a sense of some small control over the fatal disease. The owner of Foster’s Grille, a family restaurant in town, had a suggestion: A portion of the dinner proceeds one night could go to the National Niemann-Pick Disease Foundation. The first dinner was in 2008 and it turned into a regular event on the first Monday of the month. High-school baseball players brought their girlfriends. Friends from Little League showed up with their parents. Neighbors and classmates stopped on the way home from work or from after-school activities. The surgery to implant a catheter in Dillon’s head to deliver cyclodextrin was scheduled a few days after the first Monday in February this year. Dr. Porter’s wife suggested some of the scientists meet at Foster’s for dinner. Charles Vite, who ran the NPC cat colony, drove from Philadelphia with his wife. A baby sitter stayed late with the couple’s three children. Steven U. Walkley, the scientist from the New York City lab, drove five hours, ate dinner, then drove five hours home to be at work the next day. No one knew if the drug would have the same remarkable effect on Dillon as it had on lab animals. The evening, Dr. Walkley said, was “a gut-check moment, for the parents and the scientists.” Eight days later, on Feb. 12, a medical team crowded into a hospital room at the NIH to give Dillon his first dose. Nurses wore two pairs of gloves and dressed head-to-toe in surgical gowns and caps. They cleaned the skin that covered the catheter on Dillon's skull. A line of stitches on Dillon's partially shaved head marked where the boy’s scalp was opened to implant the sterile plastic tube. Dillon, dressed in a red, long-sleeve T-shirt and black sweatpants, was awake. He watched a video of “High School Musical,” and talked with Dr. Porter and his parents. Cards from classmates hung on the walls. A friend named Brad sent a drawing of a baseball diamond and a scoreboard: Dillon 100, Brad 0. The cyclodextrin came as a clear liquid in a vial that was drawn with a syringe and injected into the tube that went to Dillon’s brain. “Starting the medication,” a nurse said. The Hempels also received permission from the FDA for Addi and Cassi to get the same type of catheter used in the NIH trial, a device known as an Omayya reservoir. The catheters were implanted by surgery in the first week of April. Four days after arriving home from the hospital, Cassi started vomiting. She stopped drinking and eating. At a hospital emergency room in Reno, a CT scan showed bleeding in her brain. A helicopter prepared to airlift Cassi to a hospital in Oakland, Calif. Chris Hempel asked one of the paramedics if she could fly with them. She couldn’t; more weight would make it difficult to navigate over the Sierra Nevada range. The Hempels left by car without packing a suitcase and arrived four hours later. Ms. Hempel’s sister in California drove to Oakland to meet Cassi at the hospital’s helicopter pad. Dr. Porter heard the news and sent the Hempels an email: “Thoughts and prayers are with you and with Cassi.” Cassi was bleeding where the catheter was inserted, and the growing clot was preventing brain tissue from receiving oxygen. She couldn’t move her left side. Doctors removed the catheter in emergency surgery. Hugh and Chris Hempel stayed with her at the hospital for six weeks. A friend packed a bag with clothes and drove it to Oakland. Ms. Hempel’s parents stayed with Addi in Reno. The Hempels took turns going home to visit. Doctors were baffled. Implanting the catheters, frequently performed by neurosurgeons, is a relatively low-risk procedure. Cassi’s doctors considered several possibilities. Children with NPC often have low platelet counts, which might have contributed to the bleeding. Cassi also took drugs that children in the NIH trial didn’t. A combination of drugs could have made her more vulnerable. This was the kind of medical emergency that had worried scientists about uncontrolled experiments. Dr. Porter reached Caroline Hastings, the girls’ doctor, to find out what happened. Even though Cassi wasn’t in the NIH trial, he was obligated to report anything about the drug’s risks to an NIH review board and to the FDA. Dr. Porter’s drug trial had also run into trouble. Patient No. 1, a 13-year-old girl, developed an infection. Bacteria normally found on the skin and scalp had grown in the surgically implanted catheter. After two weeks of antibiotics, the bacteria remained. The catheter had to go. Then the catheter in patient No. 3 showed signs of infection. Tests later found no infection, but the family, after consulting with doctors, had it removed. Dillon became the only patient left in the NIH trial. A few days after Cassi fell ill, the Papiers hosted a charity baseball game featuring the Bowie Baysox, a minor-league team of the Baltimore Orioles. “Dillon was on,’’ his mother, Darrile Papier, said. The boy threw out the first pitch and headed to the dugout to talk to his favorite players. He hugged friends in the stands. After the game, the family spent the night at the Children’s Inn at the NIH. The next morning, April 15, Dillon received his third infusion of cyclodextrin and then took a nap. When he woke up, he didn’t feel well. He vomited. His fever spiked. Additional samples of his blood and spinal fluid were examined for infection. Doctors were alarmed. They showed the results to the Papiers. “The numbers were crazy,’’ Ms. Papier said. Doctors worried that Dillon’s fever and vomiting signaled bacteria had spread from the catheter to the brain. Ms. Papier badly wanted Dillon to continue receiving the drug. Since the trial started, she said, Dillon’s walk was more steady. The boy seemed better able to understand and was more articulate. But the doctors didn’t want to risk a brain infection. The catheter had to come out right away. The Papiers agreed. An operating room was prepared. At 11:30 p.m., nurses wheeled Dillon into surgery. Dr. Porter understood the trial required difficult choices—which children to enroll, as well as who might be disqualified because of declining health. He knew all the NPC children in his study and their parents. In many families, he also knew siblings and grandparents. Every drug trial requires tough decisions. But with rare diseases, he said, the consequences aren’t theoretical: “You know the faces that attach to those consequences.” The Marella family of Greenwich, Conn., had for a year debated whether to seek special permission from the FDA to administer cyclodextrin to their children—as the Hempels had—or wait for a spot in the NIH trial. Their 13-year-old son Andrew was a good trial candidate, but their 19-year-old daughter Dana was too sick to enroll. She had respiratory infections and other health troubles that landed her in the hospital. She needed a ventilator. Andrew’s symptoms were growing more noticeable. His speech was getting tougher to understand and his gait was awkward. But he looked forward to attending Greenwich High School in the fall with his brother Philip. Mr. Marella understood that if families didn’t enroll in the drug trial, cyclodextrin might never get approved by the FDA. But it was difficult to wait. “As long as things seemed to be moving along at a pace where we weren’t sacrificing Andrew’s health, that was OK,’’ he said. When the family learned that Andrew was accepted into the trial and would start cyclodextrin in July this year, Mr. Marella made plans for the trip to the NIH. But the day after Dillon got sick, Dr. Porter told the NIH review board he was suspending the trial. In a conference call with parents, Dr. Porter said he would ask the FDA for permission to restart the trial but they would have to administer cyclodextrin in a different way. Dr. Porter hoped the trial could resume in the fall. Mr. Marella was dejected. Andrew had been next in line. In June, the Marellas held their annual benefit. The Beach Boys played and the event raised more than $400,000. Soon after, Dana got sick again. At the hospital, doctors found her kidneys weren’t functioning properly. They made plans for dialysis. On July 9, tests showed Dana’s liver had stopped working. Three days later, she died. The funeral Mass was at St. Catherine of Sienna Church in Riverside, Conn., a few miles from the Marellas’ home. One speaker, the Rev. Drew Williams, recalled how Dana sang Broadway songs at the top of her lungs, and that she still went to summer camp after she couldn’t walk. The Rev. Mr. Williams, of the Trinity Church in Greenwich, singled out the work of scientists and families to find a treatment. As a community, he said, “We have to be honest and say that this is not the ending that we hoped for.” Parents of children with NPC joined the long line of mourners for a turn to console Dana’s mother, Andrea. “All these parents, we knew each other,’’ Mrs. Marella said. “And one by one, we lost our children.’’ Dana’s death made the Marellas reconsider their decision to wait for the NIH trial. They wanted Andrew on cyclodextrin right away. In late August, while Andrew was at his first day of high school, Mr. Marella said, “This is a rough awakening for all of us. We know it’s a fatal disease. We tell people it’s a fatal disease, but there was faith it wouldn’t affect this family.’’ Shortly after Dana’s funeral, Andrew started having seizures. “To lose your child and then 11 days later have this happen?’’ Mrs. Marella said. “We have strong faith, but even we said, ‘Enough.’ ’’ The neurologist said he wasn’t sure if the seizures were caused by the progression of NPC disease or if they were a reaction to Dana’s death. A family friend was at the Marella house when Andrew had a seizure. Afterward, the boy asked her, “Am I going to die from this?’’ Andrew hadn’t yet asked his parents that question. “We always maintain that he will be fine,’’ Mr. Marella said. When they discuss NPC with Andrew, now 14, they tell him the Zavesca is helping and more drugs are on the way. Since Dana’s death, Mr. Marella worries the assurances ring hollow. A few weeks after Dana’s funeral, Mr. Marella went to Baltimore to attend the annual meeting of the National Niemann-Pick Disease Foundation. A small memorial was set up at the front of the hotel conference room. Photos of Dana and others who died in the past year rested on tables that lined the way to the podium. Candles illuminated each child’s face. “It’s not just about science,’’ Mr. Marella said of the memorial. “It’s about life.’’ After the morning presentations, Mr. Marella ate lunch and left. There were still two more days in the conference, but Mr. Marella headed home. Even with the prospect of the trial restarting, Mrs. Marella didn’t want to wait any longer for Andrew. “Why are other families getting their kids on cyclodextrin, and why are we sitting back and letting the disease take hold?’’ she asked. “We’ve waited and waited. We’ve lost one. All the more reason to hurry it up.” Mr. Marella took steps to apply for FDA permission to get Andrew on cyclodextrin. He didn’t withdraw his son from the trial. He said he would follow whichever route was the shortest. Mr. Marella had already set up a college fund for Andrew and planned to use it. “I just assume we’re going to get there,’’ he said. Mrs. Marella doesn’t look that far ahead. “I take each day,’’ she said.

Chapter 9: Citizen & Scientist

At the Baltimore conference, Hugh Hempel stood at the lectern to address the parents, doctors and scientists he had come to know over the years, a select group linked by death and by hope. “Sometimes it might not feel like it,’’ he said, “but I assure each of you that you can play an incredibly powerful role in the cyclodextrin story.’’ Six years earlier, Mr. Hempel, and his wife, Chris, joined a fledgling movement to change medical science in the U.S. and gain a larger role in finding a treatment for their twin girls, Addi and Cassi. From the podium, Mr. Hempel saw the scientists and doctors: Christopher P. Austin, Daniel S. Ory, Marc C. Patterson, Forbes D. Porter and Steven U. Walkley. Parents and children he knew well were scattered around the room. For months, Mr. Hempel wasn’t sure he would attend this year’s conference of the National Niemann-Pick Disease Foundation. He didn’t like small talk. And watching children get sick and sicker each year upset him. But the Food and Drug Administration had an unusual suggestion. Agency officials wanted to talk with parents and scientists about getting cyclodextrin approved. Conference planners asked Mr. Hempel to speak, and he accepted. The Hempels’ view of citizen-scientists still separated them from professionals. Information collected by the parents giving cyclodextrin to their children didn’t seem useful to scientists, whose goal was FDA approval of the drug. Experiments outside the NIH trial “are not conducted with sufficient rigor or dispassion to get the data we need,” Dr. Ory had told a parent earlier. “It won’t help us get scientific approval. They should be honest and say we want drugs for our children. Don’t try to rationalize it and say it will help the greater good.’’ Mr. Hempel disagreed. His daughters’ doctors kept records of hearing tests, neurological and behavioral exams, as well as blood and urine analysis. “It becomes our collective responsibility to ensure that the data created by our participation in the clinical research is used to the benefit of our entire community,’’ he told the group, “not just the benefit of a few.’’ No one, including Mr. Hempel, argued that cyclodextrin was curing his daughters. The disease continued to progress. The 9-year-old twins no longer talked or walked unassisted. The girls’ doctor, Caroline Hastings, cited possible reasons. It could be that not enough of the drug was reaching their brain. Or, the girls had started the drug after too much neurological damage was done. But their hearing had improved. They were still able to eat and swallow. And they suffered no adverse reaction to the drug. More important, Mr. Hempel said, they were alive, which he hadn’t expected, given how aggressively the disease advanced in the twins. “The scientists seem to think our data is irrelevant because it doesn’t matter to the FDA,’’ Mr. Hempel said before the conference. But the government agency, in fact, was greatly interested. Shortly after Mr. Hempel spoke, an FDA official said families experimenting with cyclodextrin should standardize the way they collect information so it can be considered by the agency along with medical data from the NIH trial. Andrew E. Mulberg, a top FDA official, told the parents and scientists that findings from families alone were unlikely to lead the government to approve the drug. The data would be hard to interpret, he said, and subject to bias. But if patients and scientists agreed on a common way to collect and analyze medical information, Dr. Mulberg said, the family data would be “very important for us to consider,’’ especially regarding drug safety. The FDA wanted to give both parents and scientists a voice, he said. The FDA address marked an extraordinary moment, but one that would become more common, Frank J. Sasinowski, former chairman of the board of the National Organization for Rare Disorders, predicted after the conference. Patients and their views, he said, are becoming part of the system. Bolstering the change, President Barack Obama last year signed a law that called on the FDA to better integrate patients into drug development. Tim Coté, former director of FDA’s Office of Orphan Products Development, said debate would continue over how best to use information collected by families. It wasn’t that patients or families can’t perform useful research, he said, “But they have to be equipped and not give into the seductive alternative of, ‘Let’s just give the kids the stuff.’ ’’ A few weeks after the conference, Chris Hempel once more pressed against the glass wall separating scientists and parents. She began to create a protocol setting out the dose and frequency of cyclodextrin treatments, and the kind of medical tests families should seek if they wanted to strike out on their own. Sitting on a stool in her kitchen, she pushed away the girls’ medicine bottles and spread out more than 100 pages of documents from her own cyclodextrin research, along with procedures from the NIH trial. For several days, she studied and marked the documents. Problems got the pink highlighter pen—for example, tests that required medical equipment not available at every hospital or that required blood be drawn every day. Too burdensome, she said. What about children like Andrew Marella, who attended school? What about families who have to pay for the tests? “The NIH protocol is like a Mercedes with all these bells and whistles,” Ms. Hempel said, “when what we’re trying to do is get a car started and just drive.” Addi and Cassi had by summer received a total of 80 injections each of cyclodextrin into their spinal fluid. The family believed it had learned which tests were important and which were a burden. “We have a good idea how this should be working,” she said. “Someone who is writing up a protocol but isn’t living it every day, I think it’s hard for them to understand.’’ Dr. Ory had tried over the years, often shuttling between parents and scientists to explain each side. He bore some of the brunt of Ms. Hempel’s outbursts over the pace of NPC research. “It was hurtful,’’ he said. “I really felt that I was engaging with the families and working on trying to achieve the goals we had set out.’’ There were moments, Dr. Ory said, when he thought, “I don’t have to work on getting a clinical trial up and going. I’ll still stay a professor at the university. I’ll still continue to do my work.” He said he commiserated with colleagues, asking, “How much criticism do we need to really endure?’’ But two weeks before the August conference, Dr. Ory knew he couldn’t walk away from the alliance. “Do I think we will make this work?” he said. “I think so.’’ The view of citizen science by both sides was still evolving. Parents saw they had to collect useful medical information. Scientists had come a long way to help, offering to analyze blood samples and spinal fluid. There was still tension. The scientists wanted families getting cyclodextrin to follow the NIH protocol as closely as possible. The further the family’s medical data strayed, scientists said, the less useful it was. The Hempels wanted to post their own revised protocol. “What I care about most is there is a protocol that people can move forward with fairly quickly, and we don’t squander the opportunity to collect data,’’ Mr. Hempel said. Scientists agreed to collect the information from families, Dr. Ory said, but “whether we can use the data remains to be seen.’’ Parents need to understand, he said, “We have a trial to execute, we have a limited amount of resources, and I think we just have to keep our focus on what’s really important.’’ From the time the girls were diagnosed, Chris Hempel said, she often asked, “Why is this happening?’’ She came to believe that science might give some hope and purpose. In June, Ms. Hempel got an unexpected email from a researcher she had contacted years earlier about his study of mice with heart disease. The study found cholesterol crystals in arteries that played a role. Ms. Hempel thought there might be a link between NPC—the accumulation of cholesterol in cells—and atherosclerosis, the buildup of cholesterol in the arteries. She wondered if cyclodextrin could have a positive effect on the crystals or heart disease. If NPC opened a window into more common diseases—and cyclodextrin proved a drug with wider benefits—maybe the twins could help others. Ms. Hempel and another mother collected urine samples from their children and sent them to the scientist for study. The scientist conducted experiments based on Ms. Hempel’s idea and in the email asked her to read his paper before it was submitted for publication. On the first page, she saw her name listed as one of the paper’s authors. Chris Hempel called her husband to come see. Then she started to cry.

Chapter 10: Epilogue