Losing Conner’s Mind
The race to save a child from a genetic death sentence.
The lightning hit on a sweltering and stormy June afternoon. It thrashed through the chimney of the Beishes’ two-story home in Denton, Maryland, a rural community, before ripping into the basement. There it arced into the gas line, setting off an explosion that shook the walls of the house.
Jeff Beish, a truck driver, was often away for extended stretches of time. That day in 2016, however, he was in the living room with his three-year-old son watching television. “It was the loudest boom I’d ever heard. Then I saw smoke spring up through the wall,” Jeff said. “I grabbed Conner, booked it, and called 911.” While they stood outside in the yard, the fire surged through the living room floor.
“Thank God it happened during the day and not while we were asleep,” Hollie, Jeff’s wife, added. She and the Beishes’ other son, seven-year-old Jaxon, had been out running errands. By the time they got home, firefighters had extinguished the flames. The house was salvageable, but electrical wiring needed to be rerouted, and floors and walls required structural repairs. The Beishes spent the next month at a nearby hotel.
Which would have been fine, except that Conner was sick. He had been for months, and the cause was a mystery. He got worse at the hotel. The Beishes hoped that the elusive condition wasn’t serious and they’d find the right treatment soon. Certainly, they reassured themselves, it was nothing catastrophic. After all, the cliché is that lightning never strikes the same place twice.
Born in August 2012, Conner had been a healthy infant. He was prone to colds and had “baby asthma,” but the doctors said that would go away. By the time he turned one, he had a full head of wavy blond hair that Hollie kept long. Sometimes it fell down his forehead, meeting the long brown eyelashes that framed his blue eyes. He had a wide, mischievous smile. He started walking at 13 months and two months later was chasing Jaxon around the house dressed as a lobster for Halloween.
Words came slowly to Conner. By his second birthday, he’d mastered about ten of them; at that age, the number should have been at least 50. “I assumed it was because Jaxon would always speak for him,” Hollie said, something big brothers often do. “Sometimes I thought maybe he was just shy.” The Beishes’ pediatrician said not to worry, that some children gain words in bursts. Family and friends were also reassuring. “They would joke that once he started talking, he wouldn’t stop,” Jeff recalled. Months passed and Conner’s progress was still glacial. The Beishes took him to a speech pathologist.
Hollie was in her late twenties then, five-foot-three with green eyes and a silver hoop through the inner cartilage of one ear. Jeff was a few years older, was much taller, and liked to wear baseball caps backward. They’d met ten years prior at a Walgreens, where she’d worked as a clerk and he’d made regular drop-offs driving a Coca-Cola delivery truck. Hollie had decided to be a full-time mom, which suited her “strict and structured” personality, she told me. It also meant that she was the person who adapted the most to Conner’s limited communication.
“Eat! Eat!” he would yell when he was hungry. Hollie would take him to the pantry or fridge and point to various food items. He would nod or gesture at what he wanted. “It was a bit like negotiating,” Hollie explained. If Conner didn’t know a word, he would make a sound instead—imitating the sucking of liquid through a straw if he was thirsty, for instance. Some words he understood but couldn’t quite say: Jaxon was “Bubba,” Jeff was “Da,” and Hollie was “Me.”
Conner started preschool at three. When picture day rolled around, on October 1, 2015, Hollie dressed him in khaki pants and an OshKosh collared shirt with white and beige stripes. She noticed that he seemed tired. At school, Conner sat for his picture against a blue background that matched his eyes, offering the photographer a measured, close-lipped smile.
Then, as he made his way across the classroom to return to his seat, Conner suddenly went limp. He crumpled onto the carpet. His teacher rushed him to the nurse’s office. His forehead felt warm, and soon he began convulsing. Conner’s seizure, his first, lasted six minutes.
When the school called Hollie, she jumped in her dark purple Ford SUV and resisted the urge to speed. “I even put the car on cruise control,” she said. She also forced herself to stop crying, because the tears were blurring her vision. She didn’t want to get into an accident.
At the hospital where Conner had been rushed in an ambulance, doctors ruled out an infection like meningitis. Then they sent him home. “It could happen again, or it might not happen again,” one of them told Hollie. If it did, she shouldn’t worry. About 470,000 children in the United States have epilepsy, according to the Centers for Disease Control and Prevention, but an underlying medical condition isn’t the only cause of seizures. High temperatures can also trigger an episode in a developing brain. The doctor told Hollie that Conner had likely experienced one of these so-called febrile seizures and instructed her to give him Tylenol.
Jeff was “scared to death” when Hollie called to tell him what had happened. He thought back on their families’ medical histories and couldn’t remember anyone who’d experienced seizures. Hollie, though, was comforted by what the doctors had said. When Conner had more seizures—after his nighttime bath, while playing in his room—she imagined that she and Jeff would one day look back on these episodes as they did Conner’s baby asthma: They would remember them as part of a passing phase.
Two months later, the Beishes took Conner to a clinic in Baltimore for an electroencephalogram, which measures brain activity through electrodes attached to the scalp. The results were abnormal: He endured multiple seizures during the procedure, some so small that his body never visibly moved. Conner was prescribed a low dose of an anti-seizure medication, which seemed to work. By the time of his follow-up appointment in February 2016, he’d been seizure-free for three months. He was even able to ride a scooter, a Christmas present from his parents, in the backyard with Jaxon.
The good news didn’t last long, however. During the February appointment, Conner had an MRI. The test revealed that his cerebellum, the part of the brain responsible for balance and coordination, was unusually small. “Some doctors said it could be a normal thing, like some people just are born with a small cerebellum,” Hollie said. “Another doctor said it could mean it had changed and had become smaller as he got older.” They would need to run more tests.
That night, after her family went to sleep, Hollie poured herself a glass of soda, sat down with her iPad, and Googled “small cerebellum.” The conditions that popped up were terrifying. There was Alzheimer’s, which she knew Conner couldn’t have, and fatal childhood brain disorders, which she couldn’t stand to think about. Then Hollie saw cerebral palsy listed. “I always thought that was something that happened at birth,” she said. “But one article I read said it’s hard to tell in some kids until they’re older.” If Conner had cerebral palsy, the Beishes could handle it. They knew a few kids with the condition. Her eyelids heavy, Hollie clicked off her tablet and went to bed feeling hopeful.
Conner didn’t have cerebral palsy. His doctors were able to figure out that much—but little else. By May 2016, the seizures were back and worse than ever. “He was standing beside his wooden train table and fell and smashed his face on it,” Hollie said of one attack. Then he threw up. His doctors increased his medication. It didn’t work.
By then the costs of Conner’s prescriptions, procedures, and visits to specialists tallied into the tens of thousands of dollars. The Beishes had private insurance that covered most of it; not every American family could say the same. Still, Hollie and Jeff were exhausted and frustrated. Conner’s life, and theirs, had been upended by a medical riddle.
The Beishes didn’t think the seizures had anything to do with Conner’s speech delay, which had remained static for months. He still had his small arsenal of vocabulary, and he could parrot what his parents and speech therapist said. He would answer his mom when she pointed at things, even if the words he used for them weren’t exactly right: “Moo” was cow, for example, and “meow” was cat. He knew his colors, too, especially red, green, and blue.
One day in August, a few weeks after lightning struck the Beishes’ house, Hollie and Conner were working on a puzzle. “What color is this?” Hollie asked, holding up a blue piece. Her son was silent. She asked again, this time more slowly. Conner stared at her and still said nothing. “He was looking at me like, What do you want me to do?” Hollie recalled.
Blue was the first word Conner lost.
Emily de los Reyes had two career choices. “All the women in my family were teachers or doctors,” she said. De los Reyes was born in 1963 and grew up in Manila. Her family was well off, so they didn’t feel the most acute effects of the Philippines’ widespread corruption and privation, the fallout of President Ferdinand Marcos’s dictatorship. When de los Reyes went to medical school, however, she witnessed social ills firsthand. On Sunday afternoons, following church, she sometimes assisted health workers caring for children in poor parts of the city. Hundreds of kids would queue up—some with parents, some on their own—and wait to be seen. The experience stayed with de los Reyes as she pursued a career in pediatrics.
Toward the end of medical school, in the mid-1980s, she joined her classmates in protesting the waning Marcos regime. When I met her at a busy Starbucks in Columbus, Ohio, more than 30 years later, it was hard for me to imagine her as a firebrand. At 54, she was the picture of precision. Her hair had been blow-dried into a neat black bob and showed a few streaks of gray. Nearly everything she had with her was a shade of pink: her laptop cover, her iPhone case, her zip-up sweater. Before I arrived, she’d been carefully finalizing a PowerPoint presentation. “I was so idealistic back then,” she said of her youth, a smile creeping across her face.
After graduating she decided to work in the United States, because its democracy was strong and medical care first-rate. She moved to San Francisco, where there was a large Filipino community, then to Charleston, West Virginia, where there was not. One day, while completing her residency at a local hospital, she rode in a helicopter to pick up a sick infant from a farm. When the mother saw de los Reyes’s dark skin, she hesitated before handing over the baby. Still, the young doctor found a community. Her residency class had several other foreigners—not uncommon in underserved parts of the United States—and she met an American doctor who soon became her husband.
In the early 1990s, West Virginia became a relative hotbed of an infectious brain disease called La Crosse encephalitis. Like Zika, the virus is spread by mosquitoes, and most cases occur in children. Dozens of patients came to the Charleston hospital where de los Reyes worked. Some presented with nothing more than a fever. Others arrived comatose, with terrified parents. “A day or two before, their child was fine,” de los Reyes said, “just running around in the woods.” Then the kid would struggle to wake up, have seizures, and become delirious before passing out. “We would give them anti-seizure medications and make sure they were ventilated,” de los Reyes said. “Most would do fine.” But some would not: They left the hospital with permanent neurological deficits.
De los Reyes decided to specialize in pediatric neurology, a field rife with harrowing conditions that degrade young brains. Many of those ailments are rare diseases, a legal designation that in the United States is generally reserved for illnesses afflicting fewer than 200,000 people. Nearly 7,000 maladies fall into the category. Most are complicated genetic conditions that pharmaceutical companies have never been inclined to gamble on. The industry prefers to focus its resources on widespread ailments with identifiable causes, an approach that requires less research investment and offers a larger stable of patients who will eventually pay for the pills, injections, and devices that companies invent. A U.S. law called the Orphan Drug Act, signed in 1983, offers tax breaks, subsidies, expedited approval, and exclusive manufacturing rights to companies that develop treatments for uncommon conditions. The law led to the creation of hundreds of new drugs in its first three decades on the books. Still, when de los Reyes entered pediatric neurology, 95 percent of rare diseases had no cure. Over the course of her career, that number would hardly budge.
After finishing her residency and a fellowship, de los Reyes was recruited to work as a neurodevelopmental specialist at the University of Arkansas at Little Rock. It was there, in 2001, that she saw a case unlike anything she’d ever treated. The patient, referred by an ophthalmologist, was a nine-year-old girl who’d been born healthy but was now losing her eyesight. Her family was from Guam. They’d traveled more than 7,000 miles for the appointment at the Little Rock hospital, which through word of mouth they’d learned had excellent eye specialists.
De los Reyes examined the little girl, who had a chubby, tamarind-colored face and short black hair—not so different from her own appearance when she was a child in the Philippines. The parents described a bizarre constellation of symptoms on top of progressive blindness: speech delay, seizures, and difficult walking. Together with the ophthalmologist, de los Reyes began testing for various illnesses. The doctors ruled out macular dystrophy, a genetic condition that destroys cells in the retina, and keratomalacia, a chronic deficiency of vitamin A that causes blindness. Could it be a problem with the little girl’s brain, like a tumor? Imaging came back negative for suspicious masses.
Stumped, de los Reyes called her mentor, Paul Dyken, one of the country’s foremost experts in childhood brain disorders. She spelled out everything she’d learned and asked if he’d ever seen anything like it. “Oh Emily…,” Dyken replied with a heavy sigh before delivering the news.
The little girl had a condition so rare that most pediatricians hadn’t heard of it. But Dyken had. He’d treated several patients with, and coauthored scientific papers about, the disease. He was one of the few doctors in the world who could say “I see this all the time” about the condition, because afflicted families sought him out. If she was lucky, Dyken said, the girl would live to be 20. De los Reyes could help her die a slow, inevitable death as painlessly as possible—nothing more.
Soon after the Beishes moved back into their home after the lightning strike, Conner was hospitalized twice for tonic-clonic seizures, marked by a loss of consciousness and violent limb contractions. Doctors diagnosed him with Doose syndrome, a form of childhood epilepsy that more often affects boys. “It was comforting to have an answer,” Hollie said. They told their worried families; everyone relaxed.
Conner had just turned four. As he headed into his second year of preschool, he took various combinations of anti-seizure medications as his doctors tried to find a cocktail that worked. Hollie and Jeff had never heard of the prescriptions, which had names like Keppra, Depakote, and Onfi. Sometimes Conner would scream when he couldn’t remember a word for something he’d once been able to name, which seemed to happen more and more often. His legs began trembling when he walked.
That fall, a blood panel came back with surprising results. Conner had two genetic markers indicating that he might be missing an essential enzyme called tripeptidyl-peptidase1 (TPP1). A second blood test would be necessary to confirm the discovery. If it came back positive, that meant Conner had a rare genetic disorder. “The doctor advised me not to look anything up on the internet,” Hollie said, “which of course I did as soon as I hung up.”
What she saw on her iPad was horrifying. Being born without TPP1 was a slow death sentence. There was no cure and no treatment. Hollie saw videos of kindergarten-age children in wheelchairs, unable to speak or control their limbs. She began to sob.
More blood was sent off to the lab, and for what felt like the millionth time, Hollie and Jeff waited for the results. As fall turned to winter, Conner stopped running around with his brother, and he could barely speak. “It was like he wanted to say things and would open his mouth, but nothing came out,” Hollie recalled. He developed tremors in both hands, like an elderly man with Parkinson’s. He had trouble feeding himself, taking longer to use a fork and struggling to bring the utensil to his mouth. Hollie had to hold his cup when he drank.
Grasping for any shred of comfort, the Beishes kept reading about TPP1 deficiencies and looking for differences between the doomed children who appeared on their computer screens and their own son. They realized that in each case they read about, the afflicted kid was blind. Conner’s vision was fine. It was something to hold on to.
That December was mild in Maryland. On days when snow fell, it melted as soon as it hit the pavement. Conner had to grasp one of his parent’s hands in order to walk. Otherwise he crawled. Hollie emailed the doctors and requested, if the news from the blood test was bad, that they not deliver it before Christmas. She wanted the holidays to be happy. As a gift for Conner, the Beishes adopted a golden Labrador retriever, whom they named Joy. Jeff hid the puppy in the garage until Christmas morning, when Hollie put reindeer antlers on Joy’s head for the big reveal. Conner shrieked with glee when he saw the puppy, then stroked her back as she lay curled up next to him on the floor. His parents imagined a similar scene repeating itself as Conner and Joy got bigger. “It would be his dog that he would grow up with,” Jeff said.
When the doctors didn’t call after Christmas, Hollie thought they might have forgotten about Conner. Or maybe the news was good, so not a high priority. The Beishes didn’t nag, preferring instead to preserve a semblance of normalcy. “I wanted to know, but at the same time I didn’t want to know,” Hollie admitted.
Then, on January 19, 2017, she called to ask for an update. It turned out there had been an error: Someone had put Conner’s test results in the wrong part of his chart. A doctor would call with answers the next day, the Beishes were told, which happened to be the date of Donald Trump’s presidential inauguration. Jeff and Hollie had voted for Trump. “I didn’t like either candidate, but I picked the one whose policies lined up with me more,” Hollie explained. She and Jeff hoped that the ceremonies on TV would distract them while they waited for the call.
Hours passed. As the sun was setting, they turned off the inauguration feed. They sat side by side on the staircase in the foyer, Hollie’s iPhone clenched in her hand. Finally it rang.
“I’m sorry I couldn’t call earlier,” the doctor said. “But…” She paused before continuing. “The test results confirm things.” Conner was missing TPP1. “He has Batten disease,” the doctor said.
Hollie was standing on the steps, the phone to her ear. “OK,” she said weakly, the only word she could manage. Jeff was on the other side of the banister, unable to hear the doctor. He held his hands suspended in the air, palms up, in a gesture that seemed to plead, Tell me what’s happening.
Frederick Eustace Batten, a British physician of the late 19th and early 20th centuries, was one of the founders of the field of pediatric neurology. A “brisk, lithe figure” with “bubbling humor,” according to one medical historian, Batten was “practical and purposeful,” and “children loved him.” In 1903, he published research on two young siblings suffering from the same undiagnosed condition, in which their brain function and eyesight deteriorated rapidly. The disease was given the name juvenile amaurotic idiocy, which endured in the medical lexicon until the 1970s.
Idiocy is no longer considered appropriate terminology, and Batten disease is now known by the name of the man who identified it. Still, Alfried Kohlschütter, a pediatrics researcher at the University of Hamburg and an authority on the condition, uses another controversial label. “I always say it’s a form of childhood dementia, though people don’t like me using that term,” he told me recently. Dissenters claim that it oversimplifies the condition and suggests a link to adult memory loss, which has different underlying causes. To Kohlschütter, though, the progression of the diseases is strikingly similar. “It’s like these children are melting in front of you,” he said.
Batten disease is a glitch in the body’s nervous system. Whenever the brain completes basic cellular and metabolic processes, its cells produce waste. Batten disease sufferers lack certain enzymes or proteins required to process this waste. As a result, brain cells are forced to store it internally. (See figure below.) Eventually, the cells become clogged and die. One parent of a child with Batten disease compared the condition to “your kitchen filling up with garbage” because no one ever takes it out, to the point that the room is no longer usable. Along the way, patients’ motor, verbal, and emotional capacities diminish.
In the United States, according to the National Institutes of Health, between two and four of every 100,000 children are born with Batten disease. They can get it if both their parents are genetic carriers. There are 14 subtypes of the disease, each affecting a different gene, involving a different deficiency, and decreeing a different life span. Conner was diagnosed with subtype CLN2, distinguished by the absence of TPP1. Symptoms initially appear around the age of two; a speech delay is often the first noticeable sign of disease. After that come seizures, language regression, motor dysfunction, and blindness. Patients die between the ages of eight and twelve.
The first Batten disease case that de los Reyes saw was the little girl from Guam. Her subtype was CLN3, indicated by a protein missing from cellular membranes. Her family was stoic when de los Reyes delivered the diagnosis. By then she had young children of her own. Explaining a fatal illness to parents who'd come thousands of miles to Little Rock, armed with faith in doctors’ abilities to help their daughter, “was one of the hardest things I’ve ever had to do,” de los Reyes recalled.
The family flew home a few days later. De los Reyes communicated with the girl’s local doctors for about two years. But eventually the calls from Guam stopped. “We lost touch,” de los Reyes said. “I have no idea how long the girl lived.”
Like her mentor, de los Reyes fashioned herself into one of the world’s few experts in Batten disease. She diagnosed several more cases in Arkansas before being recruited to Nationwide Children’s Hospital in Columbus, Ohio. As the head of the neurodevelopmental department, she took on the project of turning Nationwide into a hub of Batten disease research and patient care. Families traveled from around the world for appointments with her.
De los Reyes was proud of her work, but the script she was forced to recite to parents was excruciating: There is no cure. Your child will die. People reacted in different ways. Some turned numb and silent, like the parents from Guam, dumbstruck by the futility of feeling or doing anything else. Others put the blame on de los Reyes, because she was the messenger of the devastating news. Or they lashed out at loved ones, their disappointment channeled into anger.
De los Reyes advised parents to spend as much time as they could with their sick kids. She promised to support them while they did, with medication, physical therapy, and walking aids. “I can’t tell you how many funerals I’ve been to,” she said in the Starbucks, her gaze shifting to the floor. She hoped that things would be different one day.
Science is almost never done in a vacuum. Given Big Pharma’s historical indifference to rare-disease research, finding a treatment or cure almost always requires a scrappy army of academic researchers, patient advocates, and bold financiers. Collectively they must be willing to endure years of painstaking, costly investigation and the litany of failures that typically precede even marginal gains. The quest to unravel Batten disease was no exception.
While de los Reyes was delivering tough news in Little Rock and Columbus, Peter Lobel and David Sleat were hard at work in a lab at Rutgers University in New Jersey. During the late 1990s, the scientists isolated TPP1 and demonstrated its role in processing cellular waste, a breakthrough in knowledge of CLN2. Their research led to a new hypothesis: If children with CLN2 are sick because they’re missing TPP1, they should get better when given the enzyme. The proposition was straightforward enough, but testing it wasn’t.
Lobel and Sleat’s first step was replicating CLN2 in mice, so that the animals could be used as experiment subjects. “This part was really, really hard,” Sleat told me in a mildly accented voice, a remnant of his native England, which he left 30 years ago to work in the United States. It took about two years to genetically engineer the TPP1-deficient stem cells needed to produce a mouse that showed signs of Batten disease at around seven weeks old. “You could pick them up and feel them shaking,” Sleat said. “As they got older, the shaking got worse, and they would have difficulty walking, dying at around four months.” (Healthy lab mice live two or three years.)
The next phase of research involved administering lab-made TPP1 to the mice through the spine. Remarkably, at just a fraction of normal TPP1 levels, young mice didn’t develop signs of Batten disease. Older subjects with severe symptoms experienced only mild gains. Early treatment, the research confirmed, was crucial.
Other labs around the world began using mice that had been genetically altered using Sleat and Lobel’s method. Some researchers experimented with cerebral shunts, which worked at least as well as the spinal route in terms of reducing seizures and cellular waste. But inserting a device into the brain left severe scarring, and the subjects died within a few months.
Meanwhile, at the University of Missouri, ophthalmology professor Martin Katz was studying dogs’ brains for clues to help solve neurodevelopmental problems in humans. In 2005, a man in Pennsylvania had grown worried about his longhaired dachshund, Frodo, who at a few months old had started having seizures, then ceased walking and eating on his own. His owner took him to several vets, none of whom had any idea what was wrong. When Frodo died at just one year old, the owner offered his body to the veterinary lab at the University of Pennsylvania, which packed it in ice and sent it to Katz, widely known for his research.
Katz was intrigued. He extracted tissue samples from Frodo’s brain and examined them under a microscope. He compared the samples to research texts, which led to a surprising match: Cellular waste that had accumulated in Frodo’s brain was essentially identical to that found in autopsies of human subjects who’d died of CLN2. Both had a distinctive curvilinear pattern. “If you imagine a bowl of alphabet soup with all C’s and very little liquid, that’s what it looked like,” Katz told me.
Unlike the Rutgers mice, Frodo was a natural subject for Batten disease research. If there were more dogs like him, they could be used to test treatments. Katz quickly traced him to a breeder, to whom he explained that Frodo’s parents could produce puppies that might help sick children get better. The breeder agreed to let Katz adopt the two adult dachshunds, Captain and Autumn. “Captain and Autumn were very attached to each other,” said Katz, who has a soft voice and a head of thick, wavy chestnut hair, not unlike the coat of some dachshunds. “It was nice to have them around.” Both dogs were perfectly healthy; the genetic mutation that causes CLN2 was recessive in their DNA. They produced several litters in Katz’s lab, each bearing a few puppies with Batten disease.
Here an unusual player in rare-disease research entered the scene. BioMarin is a Northern California pharmaceutical company that develops treatments for uncommon genetic disorders. Founded in 1997, it has a risky business model: Pour money into research for orphan drugs, then profit from large price margins and limited competition. Relying on a handful of willing investors and the provisions of the Orphan Drug Act, the company’s path has been anything but smooth. After posting disappointing revenues, BioMarin laid off a third of its staff in 2005, the same year its second rare-disease drug went to market. That proved to be a turning point: Within a few years, the company’s first two proprietary treatments would reap more than $500 million annually through licensing and medical coverage of just a few thousand patients. By 2017, the company would finally reach the edge of profitability.
Around 2009, building on Lobel and Sleat’s research at Rutgers, BioMarin began producing purified TPP1 in vats. When it heard about Katz’s dachshunds, the company suggested collaborating on trials to determine how enzyme injections affected dogs. Katz agreed, and together they launched a pilot study. Three dogs with CLN2 received injections at the base of the spine, a procedure that lasted a few minutes. After only the second round of treatment, they mounted an allergic response. After the third, they went into anaphylactic shock. Ultimately, they were euthanized.
Rather than declare failure, Katz brainstormed new approaches. “I always tell my students that it wouldn’t be called research if it worked out all the time,” he explained. His team spaced out the injections and tried administering the enzyme to the dogs’ brains through the cranium, even though complications with that approach had previously killed lab mice. Finally, Katz hit on a method that worked. Two puppies named Waylon and Lulu had shunts surgically inserted into their brains. (A pathologist would later find no scarring as a result of the procedure.) Compared with injections, the shunts gave researchers more control over the rate at which TPP1 entered the dogs’ bodies—and slower delivery minimized the risk of allergic reaction.
Waylon and Lulu received infusions every other week for a few hours at a time, then were observed alongside sick subjects that weren’t given treatments. For a couple of months, Waylon and Lulu behaved like healthy dogs. They were attentive and playful with the scientists, they didn’t wobble when they walked, and they didn’t have seizures. When Batten disease symptoms finally appeared, they progressed slowly. Ultimately, Waylon and Lulu lived 50 percent longer than the dogs that didn’t receive TPP1 infusions.
A BioMarin researcher presented the study’s results in the summer of 2012, at a meeting in Charlotte hosted by the Batten Disease Support and Research Association, a network for families affected by the condition. De los Reyes, who by then sat on the BDSRA’s medical advisory board, perched in a chair at a table in the dimly lit room, absorbing Katz’s PowerPoint presentation. Katz ended the slideshow with split-screen video footage. On one side, Waylon and Lulu were running; on the other, two dogs of the same age struggled to walk.
“The whole room gasped,” de los Reyes said. No one had ever seen anything like it. Accustomed to brutal disappointment when it came to Batten disease, de los Reyes initially considered Katz’s findings too good to be true. When her skepticism subsided, however, her thoughts turned to the obvious question: When can we give this to kids?
Standing on the stairs, Hollie could barely hear what the doctor on the phone said next about Conner’s diagnosis. Shock had quickly morphed into anger. First it had been febrile seizures, then Doose syndrome, now Batten disease. Why had it taken so long—nearly 16 months since Conner’s first seizure, even more since the onset of his speech delay—to get the right answer?
“We’d like for you to come into the office to discuss it further, and moving forward we’d like…”
“That’s OK,” Hollie interrupted the physician. “I’m not interested. I’d like to find a new doctor.” She demanded that Conner’s medical records be sent to their house. Then she hung up and told Jeff everything. Together they cried at the bottom of the stairs.
The next day, Hollie found herself strangely invigorated. “I felt a weight had lifted. All of our questions and the wondering were just gone,” she said. “Now it became, What can we do to help Conner?” The clock was ticking. The longer it took the Beishes to find their son the right care, the more muted his short life would be. And maybe—just maybe—there was something out there that might save him: a medicine, or a miracle.
The Beishes read about various hospitals and specialists. “It was time to find a doctor who knew what this disease was,” Hollie said, “someone who could give us answers.” She kept careful notes about everything she learned. The Beishes told their families, who began doing research, too. Jeff’s mother read about the BDSRA and called its director. “Please speak with my daughter-in-law,” she begged.
The director phoned Hollie soon after. “You should give Dr. Emily at Nationwide a call,” she said, referring to de los Reyes. “She’s the Batten disease guru.” Not only that, but Nationwide had a clinical trial under way that Conner might be able to enroll in.
Delivering an enzyme directly to a child’s delicate brain had never been done before, and it was a scary prospect. “The knowledge translation is difficult,” de los Reyes said. “We know mice are not men.” Nor are dachshunds. BioMarin tested the infusion method on monkeys, which are genetically more akin to humans, to screen for complications and determine the safest dosage level (300 milligrams every two weeks). Then, in 2013, the company launched human trials of the treatment, cerliponase alfa, which it gave the trade name Brineura.
Twenty-one children were enrolled to receive infusions at one of three participating hospitals in Italy, Germany, and England. BioMarin also wanted a small research cohort in America. Nationwide was a natural fit, and de los Reyes was adamant that the hospital participate. “I’m an impatient person,” she told me with a smile, the same one I’d seen when she talked about her time as a student protester in Manila. The hospital’s ethics board and research coordinators were concerned that the treatment might expose children to infection or cause injury. “Even with rare diseases where children are dying, we don’t want to hasten their death,” de los Reyes explained.
She had a plan: De los Reyes invited the hospital’s decision-makers to her clinic to meet children with Batten disease. Some of the top brass had never seen an afflicted patient; they’d only read about what the illness did to young bodies. By the end of the tour, one of the research directors was crying. “Emily, we want to help,” she said. “Let’s do this.” Need was weighed against risk, and Nationwide’s participation in the trial was approved.
Due to funding limits and the trial’s protocol, which capped the number of participants at 24, only three children could be enrolled at the Ohio site. They came from various locations, referred by physicians in their home states. The plan was for them to fly into Columbus every other week for treatment. “They had no alternative,” de los Reyes said. “The alternative for them was death.” One by one, starting in December 2014, the participants had catheters and ports inserted into their skulls by neurosurgeons at Nationwide. No infections or injuries occurred. After that, de los Reyes used the surgical implants to administer the enzyme infusions. (See figure below.)
Weeks passed, then months. None of the three children got sicker. They maintained their motor skills or even made gains. Some saw their speech improve. “They didn’t go from single words to sentences, but they were acquiring new words, which is so important,” de los Reyes said. “They could tell their family what they wanted.” Juice, snacks, a hug.
The first trial results weren’t released until March 2016. By then de los Reyes was bursting with excitement over what she knew: On average, participants’ clinical decline was 80 percent slower than expected during the first 48 weeks of treatment. In nearly two-thirds of cases, the disease stabilized. The most common side effects—hypersensitivity, fever, vomiting—were generally tolerated. Batten disease effectively had been halted in its tracks. That the stalling had happened so quickly was all the more remarkable.
News of the clinical trial’s early results spread quickly through the tightly knit community of families coping with Batten disease. It reached the Beishes, through the BDSRA director, in late January 2017. Hollie immediately called de los Reyes and left a message. Her request was simple: She wanted Conner in the trial.
When de los Reyes called Hollie back, she offered to evaluate Conner as soon as the Beishes could get him from Maryland to Ohio. While she could talk to them about Brineura, however, the trial was limited to its original participants. De los Reyes hoped the treatment might be available to more children soon.
Hollie looked at her son. He seemed both too young and too old, his mind and body slipping away before they could really develop. How could anyone deny him help? “I thought maybe if the doctor met us and Conner, she might get us into the trial faster,” Hollie told me—an idea similar to the one that de los Reyes had acted on to convince Nationwide to study Brineura.
Hollie made an appointment for March 13. That day friends and family in Denton wore T-shirts emblazoned with the words “Fighting for Conner.” Jaxon had one, too; he wore it to school while Hollie, Jeff, and Conner piled into the family’s SUV. It was an eight-hour drive through snow and slush to Columbus.
The Beishes had never explained Conner’s condition to him. He was too young to understand. All he knew as his parents led him into the huge glass building that is Nationwide Hospital was that he was going to see another doctor. In the exam room, he sat on a narrow green table, a sippy cup in one hand. When de los Reyes came in, Hollie was struck by how tiny she was—scarcely five feet tall.
“Hi, Conner,” de los Reyes said. “You’re holding that cup very well!”
She was soon joined by several specialists: an occupational therapist, two physiotherapists, and a speech pathologist. They examined Conner, watching him take a few assisted steps and listening to his strained speech. They peppered Hollie with questions about his medical history. The entire process took more than four hours, much longer than the Beishes had expected.
When the examination ended, de los Reyes repeated what she’d said on the phone: The trial was closed. Hollie’s heart sank. De los Reyes explained that the Beishes would have to wait for the treatment to get approval from the Food and Drug Administration. Then Brineura would be available commercially. The doctor was hopeful that that would happen soon, but there were no guarantees.
Normally, drug approval moves at a sluggish bureaucratic pace. But in 2016, BioMarin had filed for rapid assessment of Brineura. On one hand, the enzyme-replacement study had a small number of participants and a limited time frame. No one had any idea how TPP1 infusions would affect a child two or five or ten years into treatment. The FDA was tasked with avoiding a nightmare scenario in which a drug is approved too early and adverse side effects appear down the road, requiring a recall and possibly leading to lawsuits. On the other hand, the FDA might agree to fast-track Brineura, given that it targeted a fatal disease and had positive early results. The BDSRA was pushing hard for that to happen, providing the agency with families’ testimonials. Some of them had children who would never benefit from Brineura—kids who’d already died or were nearing the age when they would. Still, their parents felt compelled to speak up.
The FDA would weigh all these factors in its ruling, de los Reyes told the Beishes. “It’s a horrible feeling having to ask a family to wait,” she told me. “They know their child is dying, and I’m sitting there saying, ‘I don’t have access to the medicine.’” In the meantime, she prescribed Conner leg braces, a gait trainer, and adjustments to his seizure medications. The Beishes went home to wait and hope for good news—yet again.
Hollie kept de los Reyes updated on Conner’s condition. She shot videos on her phone, including one recorded in April at a party themed around the Star Wars movies, some of Conner’s favorites, thrown by the Make-A-Wish Foundation at his school, where he’d been able to return since the appointment in Columbus. Flanked by volunteers dressed as stormtroopers and Darth Vader, Conner stood in the frame of his customized walker, equipped with a saddle that held him upright. He was able to move haltingly, with a plastic red light saber in one hand. Jeff wore a black shirt that read, “I am your father.”
But happy moments were sporadic. Conner struggled to react emotionally to external stimuli like smiles and friends saying his name. Before long he would lose one of the last words his brain had managed to hold on to. “We had this routine where, when I picked him up from school, he would say, ‘Me! Me! Me!’” Hollie explained. As his disease worsened, he had stopped repeating his word for her so many times. Then he got to the point where he would chirp it only once. Finally, in the spring of 2017, he stopped entirely.
“I picked him up, and he smiled. But he didn’t say ‘Me.’ He was just silent,” Hollie recalled. “He never said it again.”
On the morning of April 27, Hollie was in her car, getting ready to pull out of the parking lot of a deli in Denton, when her phone rang. It was de los Reyes. “I have some really good news,” the doctor said. “Brineura was just granted approval.”
It was the first time the FDA had given its blessing to any sort of Batten disease care. The rapid decision was based largely on trial data showing improved ambulation—that is, kids with CLN2 who received Brineura were able to walk better. The agency said that it couldn’t make a call on how the treatment affected children’s emotional or verbal development. But the motor-skills gains, coupled with minimal side effects, was enough. If the Beishes wanted, de los Reyes said, she could treat Conner in Columbus, following the same protocol as her earlier trial participants: surgery, then infusions every two weeks. He would be part of an expanded research cohort, monitored for long-term safety implications.
“Tell us when we need to be there and we’ll be there,” Hollie replied.
Then she called Jeff, who was driving a tractor-trailer and didn’t immediately pick up. When he noticed several urgent notifications on his screen, he pulled over and called his wife back. “I cried my eyes out,” Jeff recalled. “You have no hope. Then you get the call.”
That night, sitting at their kitchen island, the Beishes plotted a plan of action. Money wouldn’t be an issue, they hoped. As part of the trial, Conner would be eligible for 90 days of Brineura infusions, after which Jeff’s insurance would be responsible for coverage. (According to BioMarin, the wholesale cost of a single Brineura infusion comes to $27,000.) Then there were the logistics: driving to Ohio every other week, for instance, because flying was too expensive. But what if they got in a car accident? “My mind went into overdrive,” Hollie said. “Anything could happen.” After airing out every worry they could think of, they contacted de los Reyes and scheduled Conner’s surgery for May 22.
In Columbus, the Beishes stayed at the Ronald McDonald House, a fixture at most children’s hospitals that offers families of sick kids free or low-cost lodging. The morning of the procedure, Hollie reassured Conner, who seemed scared of going into a big, cold room without his parents, even though he couldn’t say so. “You’re going to go to sleep, and when you wake up, you’ll see us,” Hollie said, giving her son a kiss. “Everything will be OK.”
A surgeon used a blue permanent marker to make a cross on the right side of Conner’s forehead, just above the hairline. Conner didn’t feel the marker; he was already under anesthesia. Around the cross, the surgeon clipped away the little boy’s soft, caramel-colored hair, then used a scalpel to make a shallow, crescent-shaped slice through the first layer of skin. Next came antiseptic, followed by a local anesthetic, and the surgeon made a second, deeper cut—this one through muscle. There was a lot of blood. The scalp is incredibly vascular; arteries, veins, and arterioles crisscross it like spiderwebs. The surgeon called for suction.
Once the blood was cleared away, the surgeon saw bone. He drilled through it, then penetrated the dura, the thin gray layer of tissue that envelops the brain. An errant cut could prove fatal. The surgeon double-checked anatomical landmarks, making sure he was in the right place. Then he picked up the device he would insert into Conner’s brain.
It was shorter than a No. 2 pencil and looked like a spindly mushroom, with a small ivory-colored dome made of plastic attached to a thin tube containing a catheter. The surgeon guided the tube into Conner’s brain, threading it like a needle until it neared his third ventricle, the midline cavity that sits between the brain’s hemispheres. At that point, the plastic dome was flush with Conner’s skull. This was the port where TPP1 would be injected every other week. From there the enzyme would flow through the catheter and soak Conner’s brain.
When the procedure was done, a doctor stitched Conner’s scalp back together. Slowly, the little boy was brought out of anesthesia. Hollie and Jeff were allowed to see him. “Hi, buddy,” Jeff said softly at his bedside. Then the Beishes climbed up on either side of their son, where they stayed while he slept. Jeff stroked Conner’s head carefully, so as not to disturb the incision. In the coming weeks, hair would grow back over the surgical site.
Conner was discharged three days later and went home to Denton. After less than two weeks of rest, during which a fever sparked fears of infection—it turned out to be a stomach bug—Hollie bundled him back into the car to ferry him to Columbus for his first infusion. Her father, Bruce, went with them. Jeff stayed behind to throw Jaxon his eighth birthday party. As ever, the Beishes tried to keep their lives normal.
The infusion was supposed to take three and a half hours, followed by a 45-minute saline flush to minimize risk of infection. When the medical staff attempted to access the reservoir in Conner’s scalp with a needle, there was still swelling from the surgery. The little boy began to cry. Finally, they got a needle into the port, then wrapped his head in gauze to hold everything in place. TPP1 began to flow through an IV drip. Conner settled down, intermittently napping and watching movies. First it was Frozen, then Moana. His legs were covered with his favorite Star Wars blanket. Occasionally, he sipped a vanilla-flavored nutrition drink.
Two weeks later he did it again. And again two weeks after that. Conner tolerated the long trips and infusions well, but nothing about his health seemed to improve: His mobility, his speech, and his emotional intelligence stayed the same. “It was frustrating and hard,” Hollie said. “I had to tell myself to keep going.” De los Reyes explained that the enzyme could take a while to have an effect. If it were the garbage truck pulling up to the metaphorical kitchen overflowing with trash, it would need to haul out a couple of loads before the space became usable again. Or it might not work at all. Failure was always a possibility.
It became part of Conner’s routine at every infusion to watch The Lorax, the movie based on the beloved Dr. Seuss story of the same name. The plot is a fable about the dangers of environmental destruction and humans’ responsibility to prevent it. “Unless someone like you cares a whole awful lot,” the main character says at one point, “nothing is going to get better. It’s not.” In de los Reyes’s clinic, it was a familiar mantra.
Around his fifth birthday, in August 2017, Conner was in a Maryland doctor’s office with Hollie and Jaxon. He’d been through about half a dozen infusions by then. The doctor he was seeing would be adjusting the prosthetics in his shoes, which helped him maneuver better with his walker.
The doctor was running behind schedule, so Hollie pulled out a book and began reading Conner a story. She pointed at various objects on the pages, naming them slowly. The method was supposed to help Conner gain words, but that hadn’t happened in almost two years. Hollie did it anyway.
On one page was a star, a word Conner had once been able to say but had lost. Hollie placed her finger on the yellow symbol and named it. She was about to move on when Conner raised his right hand and placed his own index finger on the page. There was a long pause. Then Conner spoke.
“Star,” he repeated.
The Beishes’ home is located in a quiet residential neighborhood in Denton. When I visited in October 2017, two pumpkins sat on the stoop, waiting to be carved, and the windows on either side of the front door were adorned with ghost and haunted-house decals. A wreath made of orange and red leaves hung on the door. “We’re all set for Halloween,” Hollie acknowledged with a smile when she greeted me.
She wore a sweater and sweatpants, with her hair pulled into a bun. We’d met once before, at an infusion appointment in Columbus, right after Conner started saying words again. Since then he’d made more progress. Hollie was eager to show me what he could do.
We settled onto a sofa in the living room. Nearby, above the doorway to the kitchen, I noticed a decorative sign that read, “Family… where life begins and love never ends.” Joy, the now huge golden Lab, lay across my lap. Conner was on the floor playing. At one point, he crawled across the room and hoisted himself up to stroke Joy, making eye contact with me before tumbling back down. He was more responsive, more interactive, and more deliberate than I remembered. At one point, after finishing a smoothie, he gestured to the flatscreen TV mounted on the wall. He wanted to watch cartoons.
In the coming weeks, Conner would learn to feed himself—yogurt was his first solo snack—and say “Bee,” his name for his grandmother. He would regain “choo-choo,” his word for train, when Hollie showed him a treasured family Christmas ornament in the shape of a locomotive. Then came “Da,” for Jeff. And the Beishes would soon stop traveling to Columbus every other week. A hospital in Washington, D.C., began offering Brineura treatments, so Conner could get his infusions there. Hollie said she would miss seeing de los Reyes, but staying close to home would be a relief.
The Beishes had found themselves on a lifeboat, along with the handful of other U.S. families with kids who’d started Brineura infusions. They didn’t know how long they could bob in the ocean—maybe forever, more likely not. No one had ever survived Batten disease. The Beishes would need to be cautiously optimistic. They shared stories with other families in their position and tried to think like scientists: incrementally, with judicious notions of progress. “I’ve heard of kids who can now walk 30 steps and kids that couldn’t sit up who can now sit up,” Hollie told me.
In our conversations, de los Reyes had described Brineura as “a treatment until we find a cure.” She told me that she was starting an extension study of the trial to examine the long-term safety and effectiveness of Brineura in children under three. The goal was to determine whether toddlers could be treated before they ever showed symptoms of CLN2. At Rush University in Chicago, researchers have been investigating therapies that could treat TPP1 deficiencies with pills already approved for addressing other medical conditions. For its part, BioMarin is hedging bets by scaling up production of Brineura. It’s also considering the treatment as a model for other direct-to-brain care, which could lead to breakthroughs for patients suffering from other rare neurological diseases.
There may be political hurdles. Congressional Republicans recently slashed the orphan-drug tax credit in half as part of the tax-reform package supported by the Trump administration. Meanwhile, legislators failed to renew the Children’s Health Insurance Program, which expands and supplements Medicaid for some nine million kids whose families otherwise don’t qualify. After short-term funding—a bandage, basically—for the program expires in March 2018, Batten disease experts worry that the CHIP lapse could hurt some families that need Brineura.
When I was in Denton, Hollie told me that her views on health care had changed drastically since her son’s diagnosis. “I used to think Obamacare should just be repealed, but there are things that come from Obamacare, like no lifetime maximum for insurance companies, that make a difference,” she said. “I wish [legislators] could see children like Conner and the impact these policies could have.” (As it happened, Conner would visit the White House in December 2017, as part of a holiday event for sick local children. Trump was in Florida playing golf at the time.)
Hollie said that she’d been using her trusty iPad less lately, resisting the urge to read about new data and prognoses for kids like Conner. She knew that uncertainty about his future was more terrifying than his current reality. She wanted to stay in the now. But sitting on the couch, she grabbed the device to show me some old home videos. There was Conner at age two running around the backyard, at three eating a cupcake and giggling as Jeff teased him. There he was at four hugging Jaxon. Then Hollie showed me a video from June 2016, when Conner was having seizures almost every day. When it was shot, he seemed to be doing well and was playing outside. “This was just before the lightning hit,” Hollie said.
I noticed just how much of the living room was new: the walls, the curtains, the TV on which cartoons were playing. Hollie, smiling with nostalgia, was already moving on to another video of Conner in a diaper. Then she looked up for a moment. “You know, sometimes, when the air-conditioning is on,” she told me, “it will blow, and for a few minutes the room will smell like a campfire.”