Rare diseases and rare opportunities

From www.sciencemag.org

By Esther Landhuis

On 24 October 2014, after a daylong meeting to plan a rare disease clinical trial, Raymond Wang hopped into a cab and pulled out his cellphone. Months earlier, the 38-year-old physician had applied for a National Institutes of Health (NIH) K08 grant, an early-career award for people with clinical training who want to pursue research. Wang knew the study section had reviewed proposals that afternoon. Scanning the web portal, his anticipation turned into dismay when he saw his poor score. He wondered if his research career was over.

Not getting the grant might have been the last straw, but there was other writing on the wall. Two years of 60-hour work weeks and grueling rush-hour commutes had taken a toll. A debilitating bout of gastritis and vertigo several months earlier had jolted the physician-researcher to reconsider his workload. Nevertheless, the thought of hanging up his lab coat weighed heavily as Wang pondered his career in the taxi that evening.

“My body said ‘no more.’ … It felt like somebody was strangling my stomach every time I swallowed.” Raymond Wang

Two years earlier, in late 2012, Wang had been struggling to care for a month-old preemie named Galya, who was clinging to life in the neonatal intensive care unit at Children’s Hospital of Orange County (CHOC) in California. Her liver and spleen had bulged to more than four times their normal size, but “no one could figure out what was going on,” recalls Wang, a biochemical geneticist who directs the hospital’s program for a group of rare inherited metabolic disorders that are notoriously difficult to diagnose. After a grueling year of tests and hospital stays, exome sequencing finally confirmed Galya’s diagnosis: Niemann-Pick type C (NPC), sometimes called “childhood Alzheimer’s.”

Hospital staff told Galya’s father, Brian Chan, that she would be mentally disabled, Chan remembers. Even worse, he learned from Wikipedia that many children who get NPC when they are very young “won’t even live to school-age.”

But there was a glimmer of hope. The Wikipedia page also linked to stories about twin 5-year-old girls who in 2009 had become the first Americans to fight NPC with an experimental treatment called cyclodextrin—but only after their parents had spent years pressing for “compassionate use” of the investigational drug outside of a clinical trial. Chan emailed the twins’ mother, who told him what to do to get Galya on the treatment, and then asked Wang if he’d be willing to apply on his daughter’s behalf for compassionate use of cyclodextrin.

Wang said yes, even though he knew it would add to his already busy work schedule. Thanks to Wang’s efforts, in June 2014 20-month-old Galya became the youngest NPC patient to receive cyclodextrin therapy—and it appears to be helping.


Six feet tall with a youthful smile, Wang—who speaks slowly, with warmth and authority—seems as though he’d be equally comfortable consoling parents at the bedside of their sick child or hunched at his desk scouring scientific papers. He decided he wanted to be a doctor when he was 10 years old, in part because he liked how his pediatrician had his own practice in a little cottage. “He knew you and you knew him,” Wang says.

But as a biology major at Stanford University, Wang got interested in research. An undergraduate honors thesis investigating a cellular signaling component offered his “first real taste of research,” Wang recalls. “Whenever I wasn’t in class or writing papers … I basically lived in the lab.” Upon discovering how much he enjoyed research, he seriously considered M.D.-Ph.D. programs. But 20-year-old Wang couldn’t bring himself to commit 8 years to a single course of study. So in 1997, he stuck to his initial plan and enrolled in the M.D. program at the University of California (UC), Los Angeles, School of Medicine.

There, Wang noticed medical genetics among the third-year electives. “I had a lot of fun with that rotation,” he says. The genetics he’d learned in the classroom was “suddenly made real. I thought, ‘Hey, this is an interesting way to blend my scientific curiosity with my interest in medicine.’”

Wang went on to a residency at nearby Cedars-Sinai Medical Center, where he trained jointly in pediatrics and medical genetics in a program that also allowed some time for research. There, he began focusing on metabolic disorders, a specialty that is particularly demanding in both compassion and brainpower. It was a perfect fit. Not many doctors want to memorize all those multisyllabic enzyme names and the pathways and structures of chemical intermediates, Wang says. “Being super nerdy, I loved that stuff.”

From there, Wang moved on to CHOC, where many patients come in with a laundry list of symptoms that defy explanation. Wang listens carefully and puts on his detective hat, combing through medical records, physical exams, lab tests, and imaging scans for clues. Unlike many doctors who are expected to see four or five patients an hour, “my specialty allows me the luxury of spending more time,” Wang says. “When you are talking with a family and they are telling you their child’s story, they’re opening up an important part of their life, maybe a very private part of their life. That time is precious.”

Yet as much as Wang treasures his patients and their families, he still craved more time for research. While trying to squeeze in bits of research amid mounting clinical responsibilities, the physician was often preoccupied, wondering when he would get to do this or that experiment—or whether he would get the NIH grant.

Lab rat

Ultimately, it was the desire to better serve his patients that pushed Wang to do more research. Week after week, Wang saw families bringing their children in for enzyme replacement therapy to treat a group of rare metabolic diseases called mucopolysaccharidoses (MPS). The treatments were working, yet the kids were developing progressive heart disease. Families asked why, and Wang got sick of saying, “I don’t know.”

So, in 2009, during his “spare” time, Wang designed and got funding for a pilot project to investigate.  The results—pre-teens with MPS had thicker arterial linings than other kids their age—helped Wang secure funding for additional studies, which revealed evidence of moderate to severe heart valve disease in kids with MPS. Wang went on to probe the mechanisms behind these cardiac abnormalities, striking up a collaboration with Jeffrey Esko, a biologist at UC San Diego who had engineered mice that model MPS.

But the research moved excruciatingly slowly—and Wang had to go to extreme lengths for it to progress at all. He was lucky to find time to make the 75-mile trip to UC San Diego for research once every other week. Occasionally he managed a 3-day stretch, and once he burned through a week of vacation time to do lab experiments. To sustain any sort of research momentum, “I would take an awful lot of work home—mostly grant and paper writing,” Wang says. He would come home late, often stressed and grumpy. When his kids wanted him to play or read a book with them, Wang was “more or less inaccessible.”

It took more than 2 years for him to acknowledge this workload was not sustainable. “My body said ‘no more,’” he says. In September 2014—after a busy stretch of travel, too little sleep, and too much caffeine—a horrible case of gastritis landed Wang in the hospital. “It felt like somebody was strangling my stomach every time I swallowed,” he says. “I was told I needed to slow down.”

Another wake-up call—vertigo—came just 2 days later. “My eyes were jiggling. If I spun my head too fast, I was on the ground,” Wang recalls. “I felt like the devil possessed.” Making matters worse, “here I was at age 37 with hypertension,” he says. “I was like, ‘Oh wow, is this where I really want to go?’”

During his 3-week medical leave, Wang made a decision. He would continue his research only if he secured NIH funding for protected time—research time during which junior investigators are relieved of their clinical duties. If he failed to get the grant, he would hang up his research coat.

So when Wang looked up his score during that cab ride in October 2014, he felt “disappointed but OK.” At least he would start taking care of his own health, even if it meant putting research aside.

An unexpected gift

Several months later, a few days before Christmas, Chan brought 2-year-old Galya in for her weekly cyclodextrin treatment. He asked Wang about the NIH grant. “It’s probably not going to get funded,” Wang told him. “I did what I could.” Chan asked how much the grant would have awarded—about $100,000 per year for 5 years—and then told Wang that the FightNPC initiative, which Chan and his wife launched after Galya was diagnosed, would support “whatever amount the NIH didn’t give.”

“I was floored,” Wang says. It was “a watershed moment in my research career.” With the foundation funds, Wang was able to negotiate a schedule adjustment. He now sees patients 2 days a week and spends the other 3 doing research.

When other families heard that Wang had protected time for research, they too started giving. “These families are trusting in me and investing in me to do research on behalf of their kids,” Wang says. “That’s very humbling.”

Since Galya started cyclodextrin therapy 2 years ago, her liver has shrunk and she can now sit on her own. She flips pages of books and breaks into tears upon seeing Wang—a sign that she “remembers me as the evil doc” who sticks her with needles, he says. Wang hopes to extend cyclodextrin access to other NPC families by serving as one of the investigators helping the Maryland-based pharmaceutical company Vtesse conduct a clinical trial of the compound.

On a personal level, the “saner work schedule has reminded me to take things slower,” Wang says. In the past he filled the “extra” time with medicolegal consulting and other work. However, these days, he says, “I treasure the games of Uno and chess I play with my son, the walks I take with my girls, and the date nights I have with my wife.”