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The Bea Project
Date: September 1, 2012
With the air of a mini-docent, Bea Rienhoff stops short in front of a prehistoric shark’s jaw at Baltimore’s National Aquarium. “A whole family can fit inside!” she declares. She and her older brother MacCallum have spent all day touring Charm City as their dad, Hugh Rienhoff ’82, met with former colleagues, research collaborators, and Bea’s doctor, Hal Dietz, the Victor A. McKusick Professor of Genetics at the School of Medicine.
Later, as they walk along the Inner Harbor, Hugh keeps an eye on his slight daughter, who’s clearly losing steam. “Do you want a ride, Bee Bee?” he offers, effortlessly sweeping her up. Off her feet—clad in black sneakers to anchor the orthotics that support her arch and stabilize her ankles—she perks up and Rienhoff regales the kids with tales of his adventures in the neighborhood in the early 1990s. Back then, Rienhoff worked as a venture capitalist for New Enterprise Associates, whose offices overlooked the docks nearby.
With her contemplative manner, punctuated by bursts of enthusiasm, it’s easy to imagine Bea wrapping any adult—not least her father—around her little finger. What’s not so obvious on meeting this pint-sized yellow belt in kung fu is the role she and her father have played in promoting DNA-based personalized medicine.
It would take a trained clinical geneticist—her father, for example—to detect the subtle traits that suggest that Bea’s slight frame and wide-set hazel eyes owe to a mutation among the genes that program some of the earliest steps in embryological development.
In his ongoing quest for a definitive diagnosis for his daughter, Hugh Rienhoff has taken a page from each of the careers he’s pursued since he earned his MD at Hopkins—incorporating a dash of do-it-yourself genetic diagnostics, a healthy dollop of Internet-based crowdsourcing, and the insights of a widely distributed team of academic experts. His approach has garnered criticism as well as praise, and there have been plenty of dead-ends.
But Rienhoff is circling ever closer to insights about the biology behind Bea’s low muscle mass and the resulting weakness and fatigue—information he hopes will provide clues to how her condition will play out over time.
Building a Gene Trust
Bea was born in December 2003, a few months after her father’s 51st birthday. Yet even before she left the delivery room, the pediatrician flagged some subtle indicators of genetic trouble: Bea had a port-wine stain on her face (since faded), poor muscle tone, disproportionately long feet, and tightly clenched fingers and toes. The constellation looked a lot like Marfan syndrome.
If anyone was equipped to make sense of Bea’s symptoms, it was her father, by then a Silicon Valley-based biotech entrepreneur and venture capitalist at the leading edge of the move toward consumer-oriented genomic sequencing.
As a fellow in clinical genetics at Hopkins in the late 1980s, Rienhoff had trained at the elbow of the legendary Victor McCusick ’46, founder of Hopkins’ Division of Genetic Medicine and an early expert on the molecular underpinnings of Marfan. During training, Rienhoff himself had examined dozens of adults with the condition, which is caused by an anomaly in the transforming growth factor-ß pathway responsible for connective tissue and musculature.
When Rienhoff left Hopkins in 1992, it was for a stint as a managing partner at the Baltimore office of New Enterprise Associates, a life sciences venture capital firm. There, he combined his insights into clinical practice and a knack for business with a vision for how the Internet could empower patients and improve health care. Along the way he forged connections with physician-entrepreneur Seth Harrison and worked closely with James Clark, founder of Netscape and Healtheon (now WebMD).
A voracious reader, Rienhoff steeped himself in issues related to intellectual property, clinical trials, and trends relevant to the emerging biotech sector. It took him just a few years to come across the technology that would anchor his own first startup.
In 1998, he moved to California’s Bay Area to found DNA Sciences, based on a high-throughput device to speed large-scale genomic sequencing in the lab. By recruiting volunteers from around the world who would provide both medical histories and DNA samples, DNA Sciences sought to create a “gene trust” for use by scientists seeking the precursors to disease, as well as pharmaceutical and other life sciences companies developing diagnostic tests and treatments based on the genome.
The $3 billion Human Genome Project had passed its midpoint that year and the promise of personalized medicine—the notion that both prevention and cure could be tailored to a person’s unique genetic predispositions—had become something of a holy grail. Funded by Harrison’s venture capital fund, DNA Sciences boasted an all-star board of directors including Netscape’s Clark and James Watson (with Crick, of double-helix fame). “The knowledge we gain from the gene trust has the potential to change medicine forever,” the company’s site promised in 2000. “But we can’t do it without your help.”
It was a grand vision. By that time the company had raised more than $100 million and grown to nearly 200 employees. But when the dot-com bubble burst in 2001, DNA Sciences’ bottom line went with it. The day before the twin towers fell in Manhattan, the board announced a lay-off of half the firm’s employees; Rienhoff stepped down as CEO. Three years later, the company filed for Chapter 11. “The tech wreck happened right as we were going public,” says Harrison. “It was literally a plane crash.”
Rienhoff retrenched, investing in other biotech startups, serving on the boards of directors for a handful of them, and tending his growing family with wife, Lisa Hane. Son Colston was born in 1998 and MacCallum in 2001. In the delivery room with Hane and their new daughter in 2003, Rienhoff was all father and husband. Back home, though, his clinical training spurred him up the stairs to his attic office, where he devoured his former mentor’s papers on Marfan. Bea was 10 days old when an orthopedist suggested that she had Beals, also associated with mutations in the TGF-ß pathway. Rienhoff did his reading, then sent Bea’s records to Rodney Beals himself, an orthopedist in Oregon. Not a fit.
By the time Bea was five months old, her symptoms were more alarming: She still had poor muscle tone and while her limbs were all growing at a healthy clip, she wasn’t gaining weight. “For a mother, the most important thing is that you’re feeding your child, that she’s getting enough to eat,” says Hane. The two undertook an evaluative 36-hour inpatient hospitalization to determine whether Bea would need supplementation with a feeding tube. “At the end of it,” says Hane, “they concluded that she was feeding properly, she was getting nutrition, she just wasn’t growing at the normal rate.”
Specialist after specialist examined the infant, offering up a potpourri of diagnoses: amyoplasia congenital, cystic fibrosis, metabolic syndromes, a mitochondrial defect. Rienhoff dived even deeper into his reading, putting out the word among friends and former colleagues on both coasts, seeking referrals to someone expert enough to name his daughter’s condition.
When Bea started standing, another clue emerged. She had to use her arms, bracing them against her legs for extra leverage, to push herself erect. Rienhoff recognized the tactic as a classic indicator of Duchenne’s muscular dystrophy, a fatal condition caused by a recessive gene. “I needed a comprehensive, old-fashioned assessment of her symptoms,” says Rienhoff, who called his former colleagues in Baltimore. “I needed to come back home—Hopkins is really grounded in the clinical arts and that’s really the big message of my Hopkins education: Lay your hands on, get a good history, and most of the time you’ll get the diagnosis.” In March 2005, Bea had a comprehensive exam with a team of pediatric clinical geneticists at Hopkins’ Institute of Genetic Medicine. They suggested a particularly terrifying TGF-ß anomaly—now known as Loeys-Dietz for the two Hopkins professors who described it in a January 2005 Nature Genetics article. People with the mutation develop such profound aortic warps and arterial convolutions that they rarely live beyond their mid-20s.
Bea underwent an echocardiogram just days after her return home. Rienhoff watched the entire procedure like a hawk. As with each sonogram that Bea has had since, it showed no sign of vascular disease. A subsequent genetic test confirmed that the Loeys-Dietz diagnosis didn’t fit either.
Rienhoff breathed a sigh of relief, but he was far from satisfied—plagued, he recalls, “by the unanswered question” of whether Bea was at increased risk for the ticking time bomb of vascular disease.
The Bea Project is Born
How do you mark the launch of a quest? Is it the first time the vision is spoken aloud? The bottle, smashed against the hull of a ship when the craft is christened?
For Rienhoff, the journey to understand Bea’s biology happened in stages. By the time Loeys-Dietz was off the table, Rienhoff knew that uncovering Bea’s diagnosis would require more than just literature reviews, clinical exams, and consultations with experts. Someone was going to have to analyze each of the genes implicated in Bea’s TGF-ß pathway, looking for the unique mutation at the heart of her symptoms, including the one most complicating her life—an inexplicable dearth of muscle growth.
What happened next has made Rienhoff a minor celebrity in the do-it-yourself biology world and a lightning rod in the debate over personal genomics. Rienhoff launched “The Bea Project” by contacting scientists investigating the TGF-ß pathway to ask if they’d sequence that part of Bea’s genome. Hopkins’ Se-Jin Lee, MD/PhD ’89, a professor of Molecular Biology and Genetics and an expert in the TGF-ß gene responsible for curtailing muscle development, was among many who declined to participate.
What Rienhoff was proposing was technically an experiment, Lee pointed out. For any academic scientist to touch so much as a hair on Bea’s head—let alone start sequencing her genes—an institutional review board (IRB) would have to give its blessing.
Rienhoff felt he didn’t have the time to wait for IRB approval, and back then, consumer-targeted whole genome sequencing cost $350,000. Even more than cash, this dad had connections—to used equipment, to labs for hire, to help and guidance from the cadre of experts, many of them personal friends, with whom he’d been consulting.
Rienhoff decided to sequence his daughter’s DNA himself.
He started with a visit to a phlebotomist—Rienhoff has never drawn Bea’s blood or performed any other medical procedure on her, citing both the Hippocratic oath and his duties as a father. Vial in hand, he went to the Stanford lab of Nobel laureate Andy Fire, who provided access to tools for extracting Bea’s DNA. And then with a collection of used equipment purchased for less than $2,000 and installed in his basement, Rienhoff amplified the DNA in his daughter’s white blood cells, harvesting enough genetic material from the phlebotomist’s sample that a for-profit lab could sequence the strands associated with the TGF-ß pathway.
When the results came back, Rienhoff copied the entire sequence into a Microsoft Word file, then painstakingly reviewed each string of letters looking for diversions from the associated sequence published in the Human Genome Project. With Lee’s guidance, Rienhoff started with receptors for myostatin, the gene to which Lee has devoted his research. When he found nothing there, he expanded his search to the rest of Bea’s TGF-ß pathway. The work was slow and painstaking, a process he’s described as “hand-to-hand combat.”
“There’s so much data and no good software to analyze it,” he says. “When you’re talking about 20 million [base pairs], you need a collaborator to look at it.” With that, Rienhoff took the Bea Project public. Nature put a photo of Hugh and Bea on its cover. Wired and Discover ran stories. He penned a feature-length, do-it-yourself article for Make magazine, and gave talks at Google, Cold Spring Harbor, and at UCLA, for a conference on “outlaw biology.”
“I’m definitely outside the establishment, whether it’s big pharma, biotech, or academia,” he says. “I’m a gypsy and I prefer that—there’s so much more freedom to work with different kinds of people in industry, academia, in different companies.”
Rienhoff also took to the Internet, launching MyDaughtersDNA.com, intended as a forum for parents of children with undiagnosed congenital conditions and the clinical geneticists who might be able to help. Ideally, he would find another Bea, and if nothing else, he could empower other parents like himself, looking for answers.
Duke University’s Misha Angrist, who had his own DNA sequenced and published for the Personal Genome Project, is author of Here Is a Human Being: At the Dawn of Personal Genomics. In the book, he writes extensively about the intellectual property and privacy issues associated with genetic material, as well as Rienhoff’s work at DNA Sciences and on the Bea Project.
“Hugh knows what he doesn’t know, and he’s constantly looking for advice and support and insight,” says Angrist. “For him, it’s not an academic reputation or publishing papers or getting grants or winning prizes. He wants to save his daughter’s life and that dwarfs every other consideration. There really is no other consideration.”
Having failed to discover the explanation for Bea’s symptoms by comparing her TGF-ß pathway to that of the Human Genome Project reference, Rienhoff turned to his longtime friend and colleague Jay Flatley, the CEO of Illumina, a giant in the world of consumer, agricultural, and medical sequencing technology.
In 2008, a team at Illumina sequenced all the expressed genes of Bea, her brothers, and their parents. Rienhoff took the results to his attic office, poring over the files in search of variants in Bea’s file. In late 2009, he narrowed in on a likely candidate, the gene on Chromosome 20 responsible for producing copine-1, a remote element of the TGF-ß signaling cascade. With help from a Harvard scientist, he developed an assay to detect Bea’s copine-1 mutation in samples from 400 anonymous donors. Forty of them shared the mutation. “Even though we knew nothing about those 400 people, we knew it was very unlikely that 1 percent of the population around the world would be like Bea,” says Rienhoff. “That told me we had to cast the net further—we had to start looking at the whole genome.” He went back to the drawing board, getting Illumina to sequence the entire family’s genome.
Alan Beggs, PhD ’88, a professor of pediatrics at Harvard and director of the Manton Center for Orphan Disease Research at Boston Children’s Hospital, consults regularly with Rienhoff on the genetic pathways associated with the inherited muscle weaknesses he investigates. Beggs notes that while he works with hundreds of parents grappling with “orphan diseases”—conditions so rare they attract minimal attention from scientists and pharmaceutical companies—Rienhoff is unique both in his scientific training and access to resources.
While Beggs calls Rienhoff’s degree of involvement an “extreme case,” he also believes the quest to understand Bea’s biology promises new insights into other facets of both muscle weakness and orphan diseases—the intellectual legacy of Victor McKusick, who emphasized the insights to be gleaned from studying singular conditions.
Says Beggs, “[Bea] may have a mutation in a gene that’s of interest to a lot of people, and reveal things about muscle that would be useful to people with many different conditions. Learning about her has the potential to inform us about something much more common.”
Based on his latest research, Rienhoff now believes that the structural heart and circulatory defects that kill many people with TGF-ß anomalies—including those with Loeys-Dietz and Marfan—are less likely to afflict Bea.
“The biochemistry that we’ve done suggests a different mechanism of disease.” More likely, he believes his daughter’s long-term health challenges will involve orthopedic issues: While her limbs are as long as those of any other child her age, her scant muscles tire quickly.
Shifting the Paradigm
This fall, Bea Rienhoff started third grade. Her favorite subject is art, especially sculpture. At home, she helps with the dishes and takes turns feeding the family’s outsized rabbits. Other than her specially crafted orthotics and regular occupational and physical therapy, she’s pretty much just like any other kid, taking piano lessons and practicing her kung fu.
“There are some physical things she’s not strong enough to do,” says her mother, “but I’ve always tried to deal with her like I have with the boys. Bea has certain motor deficits still, but it’s just a daily part of our lives.” More powerful is the girl’s fearlessness and an independent streak. When the family was traveling in Ecuador this summer, Bea found a kid-sized tuxedo, as well as a perfectly fitted black fedora, trimmed with a peacock feather. She wore the combo for much of the remainder of the trip. “When her classmates see her and interact with her they recognize a physical uniqueness about her,” says Hane. “Instead of letting those physical distinctions get her down, she embraces them and takes them as her own, a sort of take-it-or-leave-it approach.”
Now free of the looming terror of an aortic blowout for Bea, Rienhoff has turned his attention to understanding the basic science of the TGF-ß pathway and its role in development. To do so, he’s begun integrating insights gleaned from a half dozen scientists at Harvard, Hopkins, and other academic medical centers. “I want to study TGF signaling in a whole animal,” he says. “There are multiple layers of regulation of the pathway.”
This fall, Rienhoff was submitting a case report about Bea to a peer-reviewed journal. “You have to be persistent, systematic, scientific,” he says, “but if you just follow the current paradigms, you’re likely to have to wait for a paradigm shift. That’s the nature of science, but I’m not content to wait for a paradigm shift. I want to be responsible for one.”
Already, the insights Rienhoff has gleaned from overseeing the Bea Project have infused his professional trajectory—and an emerging model in drug development—over the last five years.
In 2007, he launched Ferrokin BioSciences, a micro pharmaceutical company that is testing a chelation drug to counter the iron toxicity that accompanies frequent transfusions. The company owes its distributed research and development model to the experience Rienhoff has had working with TGF-ß experts around the country. Last spring, Dublin-based Shire acquired Ferrokin in a deal worth more than $100 million. Shire retained Rienhoff and four other of the company’s employees, as well as a few of the 60 contractors who had designed and executed the Phase I and II clinical trials of Ferrokin’s compound.
In addition to his new duties with Shire, Rienhoff continues his monthly pilgrimage to Harvard, where a Bea Project scientist has been analyzing the TGF-ß pathway’s influence on muscle development in embryonic frogs. Meanwhile, a team in Arizona has begun development on a knockout mouse with a mutation to its TGF-ß pathway that mirrors the one in Bea’s genome. Eventually, Rienhoff hopes to learn whether the “Bea mouse” develops vascular disease.
The mice and frogs are interesting, says Rienhoff, but in the end his daughter isn’t her disease. “Bea defines herself—and we all define her—in terms of what she can do and who she is,” he says, “not what she has.”
“She has so many adaptations that allow her to be herself,” says her father. Over the summer, while her older brother rehearsed for his part as Frederich in The Sound of Music, Bea banged out the tune to “Somewhere Over the Rainbow” for her father on the family piano. “It’s poignant,” Rienhoff admits, “but we’re out of the acute phase and dealing with something chronic now—our relationship is based on admiration.” *
Among the cadre of scientists who’ve helped Hugh Rienhoff, Se-Jin Lee stands out. He has furnished vital insights into the molecular cascade responsible for cueing muscle growth. “He thinks therapeutically about the TGF-ß pathway,” says Rienhoff.
Molecular Endocrinology published Lee’s description of the first gene in the pathway’s superfamily in 1990; biochemical details of the other genes followed. To reveal what each TGF-ß gene actually does, Lee created a series of knockout mice, deleting one gene from each strain, then meticulously analyzing the resulting litters to discover how the genes he’d eliminated had influenced embryonic development.
Most of the pups died, but one strain not only survived, they thrived. They had four times more muscle mass, no body fat to spare, extraordinary strength, and excellent health. Lee dubbed the gene responsible myostatin. Nature published the finding in 1997. Myostatin keeps our muscle growth in check; without it, Lee’s brawny knockouts rippled with definition befitting a bodybuilder.
Now a professor in Hopkins’ Department of Molecular Biology and Genetics, Lee has since found evidence of naturally occurring myostatin knockouts, including heavily muscled Belgian Blue and Piedmontese cattle and a super muscular German child.
Today, Lee investigates compounds that interrupt the TGF-ß pathway and block the effect of myostatin to enhance muscle development. Bea and her family aren’t the only ones with a stake in what he finds—people with muscular dystrophy, cancer, AIDS, and even those of us feeling the effects of the aging process could all benefit from compounds that promote musculature. ST