Here Is a Human Being (24 page)

It was early December, the cusp of cold and flu season in Northern California. Hugh Rienhoff, a geneticist turned consultant, turned to his young, slight, Spider-Man-loving pixie of a daughter, Beatrice, and said, “Beazle, I really think you ought to get a flu shot.”

“No,” she said calmly. “I don’t like shots. But … if you want some of my blood for DNA, that’s no problem.”
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A few days later, Beatrice turned five, though at twenty-eight pounds she could pass for much younger.

I had met father and daughter seven months earlier at Penn Station in Baltimore, an enormous and beautiful old Beaux-Arts edifice defiantly standing over a part of Charm City that had seen much better days. I stood just outside the massive revolving doors and watched as a good-looking fiftysomething man in a dress shirt and wire-rimmed glasses carried a blond child in a bright yellow raincoat in one arm, umbrella in the other, through a cold May downpour.

Hugh had brought Bea here to see Hal Dietz, her doctor at Johns Hopkins. Hugh knew the landscape well: he came from a family of Baltimore doctors. His father, Hugh Sr., broke the line by becoming a metallurgist and wanted his son to resist medicine as well; Hugh Jr. could not. In the early 1980s he was a genetics fellow at Hopkins under the tutelage of the father of twentieth-century medical genetics, Victor McKusick.
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When Bea was born, Hugh had long since traded in his full-time clinical and lab-bench vocations for biotech entrepreneurship and business consulting. “Working as a consultant is another way of saying you’re unemployed,” he told me. His current venture was called FerroKin Biosciences, a start-up developing a treatment for iron overload in anemia patients who had undergone multiple transfusions. He had kept his medical license current and for a while did pro bono work at an HIV clinic in San Francisco; now he volunteered at the city’s Department of Public Health. But since 2004 his passion—his obsession—had been trying to figure out what was wrong with his daughter.
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When Rienhoff’s wife, Lisa Hane, was pregnant with Bea, their third child, she was forty-two and at higher risk for having a baby with a chromosomal abnormality like Down syndrome. Her chromosomes—pictures of chromosomes are a fairly crude view of one’s DNA—looked normal. Lisa’s doctor looked elsewhere: one of the common ultrasound tests obstetricians run near the end of the first trimester is a nuchal scan, which measures the amount of fluid behind the neck of the fetus. More fluid is associated with a higher likelihood of a chromosomal problem and/or heart defects.
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Bea’s scan showed a high level of fluid. At nineteen weeks the couple got an echocardiogram to look for major heart problems; the doctors did not observe anything unwarranted on the ECG.

But with Bea’s emergence from the womb came the first moment of recognition for her father. “I saw her feet,” Hugh said. “Marfan syndrome flashed through my mind.”
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Marfan syndrome is a connective tissue disorder that affects multiple organs; patients may have enlarged aortas, severe nearsightedness, cataracts, and a swelling of the sac around the spinal cord, among many other features, including the long feet that Hugh noticed on Bea.
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A person with Marfan is typically tall and thin; there has been speculation that Abraham Lincoln might have had it.
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Without surgical aortic replacement, Marfan patients’ aortas may eventually weaken and rupture, leading to sudden death.
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Bea had other physical peculiarities, too, though they didn’t look like Marfan. She was floppy, she had a port wine stain (a large red or purple vascular birthmark) on her face, and her fingers were contracted. “I knew there was something going on,” Hugh said. “Were these things isolated or part of a syndrome? Was it genetic?” He tried not to think about it.
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Lisa was mostly oblivious until the three-month visit to the pediatrician, who told the couple that something was up. Bea was still floppy and she was not gaining weight. She would nurse but would consume only tiny amounts at one time. There was discussion about inserting a feeding tube. Lisa’s lowest moment came when a friend visited. “I said, ‘Do you think she’s okay?’ My friend said, ‘She’s just …
really small.’
The way she said it made me think it was bad. When an ordinary person gave her true assessment of what she saw … Bea just looked so weak.”
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She did not appear to have classic Marfan syndrome: she lacked certain features, such as ocular problems. And she had others not typically associated with Marfan, such as severe muscle weakness, widely spaced eyes, and failure to thrive. The Rienhoffs went from specialist to specialist on the West Coast. Each one poked and prodded at Bea, ordered tests, and offered tentative diagnoses, none of which were satisfying to Hugh. One intriguing suggestion was that Bea had a form of Beals-Hecht syndrome, a rare Marfan-like condition characterized by crumpled ears, long fingers, contractures, and scoliosis.
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Hugh contacted Rodney Beals, who described the syndrome in 1971. But based on Bea’s hyperextensible limbs, he didn’t think she had it.
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Hugh reasoned like a clinician: his daughter needed a diagnosis. A diagnosis would suggest a management plan. A management plan would, he hoped, lead to weight gain for Bea and alert him and Lisa of what to be on the lookout for. Simply getting a muscle biopsy or ordering another round of tests was not a management plan. He was frustrated.

“I thought she had something in the Marfan family. She had long fingers, long feet, and a caved-in chest. That was a place to start. But I wanted her to have a good old-fashioned physical exam. She had to be seen by someone of the old school.”
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He brought Bea to medical geneticist Dave Valle, someone he knew slightly from his Johns Hopkins days. Unlike the other docs they’d seen so far, Valle gave Bea what Hugh called “a great exam. He knows his syndromes. He knows that if the patient has inverted nipples, then he’d better check the fat on the bottom of the butt. Things like that. Dr. McKusick called clinical geneticists ‘the last generalists in medicine,’ and I think that’s true. That’s Dave Valle.”
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Valle brought in two colleagues, Bart Loeys and Hal Dietz. Loeys was a genetics fellow; Dietz had been at Hopkins since his pediatrics residency twenty years earlier. He was part of a group that had identified fibrillin-1 as the causative gene in Marfan syndrome in the 1990s and probably knew more than anyone on the planet about the genetic basis of the disease.
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Like Valle, Loeys and Dietz examined Bea for clues to her condition. They looked at her uvula, the small piece of flesh that hangs from the palate. Hers was split: a bifid uvula, something that occurs in anywhere from 1.5 to 10 percent of newborns.
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They examined her widely spaced eyes and listened to her heart. When they were done they told Hugh that Bea needed an echocardiogram as soon as possible. As it happened, Hugh had already ordered one, thinking that perhaps a defect in blood flow between the chambers of the heart was causing Bea’s failure to thrive.
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But Loeys and Dietz wanted an echo for a different reason. They were worried about Bea’s aorta, the largest blood vessel in the body. If she had a Marfanoid aorta that was enlarged and weakened, then it could tear and kill her.

Okay … but if it were agreed that Bea
didn’t
have Marfan syndrome, then why the urgency? Loeys and Dietz gave Hugh a paper they had just published on manifestations of a Marfan-like disease described by and named after them: Loeys-Dietz syndrome. Loeys-Dietz patients had mutations in a gene in the same biochemical pathway as the mutations that caused Marfan syndrome, the transforming growth factor beta (TGF beta) pathway.
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I asked Hugh how he felt at that moment, knowing that a possible diagnosis for Bea had been found. “Terrible,” he said. “I was depressed. I read the paper and saw that the average age of death was twenty-six or twenty-seven. Loeys-Dietz was
much
worse than Marfan. I wasn’t expecting that Bea might have catastrophic vascular disease. Sometimes you want a diagnosis … but really you just want your daughter to be okay.”
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Hugh brought Bea home and nervously watched the cardiologist perform the echo. It was completely normal … The family could exhale. Meanwhile, the Johns Hopkins team sequenced Bea’s copies of the two TGF beta receptor genes that had been associated with Loeys-Dietz syndrome. They were clean. Hugh pondered these data: a normal echo, no mutations in the Loeys-Dietz genes, and the presence of extreme muscle weakness, a feature not seen in Marfan or Loeys-Dietz. In his mind, all of this added up to three strikes against these two syndromes. The best news was that Bea did not have any signs of life-threatening vascular problems. The bad news was that Hugh was back to square one.

He went into hypothesis-generation mode. He read everything he could about the TGF beta pathway. Perhaps Bea’s phenotype was also the result of something gone awry in TGF beta signaling. But whatever it was, it would have to account for her muscle weakness. Bea could certainly walk, but anyone could see that climbing stairs was a challenge—she would use her hands to help propel herself (to descend, she often opted to slide down the stairs on her backside). Bea’s underdeveloped musculature led Hugh to a biochemical pathway related to TGF beta and centered around a protein known as myostatin. Myostatin’s normal function is to limit the growth of muscle.
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Mice that have been engineered without a myostatin gene develop extremely large muscles: they are known as “Schwarzenegger mice.”
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A few champion athletes have been found to carry myostatin mutations.
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Hugh reasoned that if Bea’s muscles were
overproducing
myostatin or something like it, then that might explain her weakness. Moreover, myostatin shared at least one receptor with TGF beta. “The more I looked at it,” he said, “the more I thought this pathway was a credible way to get what Bea has.”
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He began asking around for help. He talked at length to one of the people who cloned the myostatin gene in the 1990s.
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This scientist thought Hugh’s TGF beta hypothesis was reasonable, but he was reluctant to sequence Bea without Institutional Review Board approval—Bea was a human, after all, and entitled to the protections offered all human research subjects, even if Hugh was her dad. This meant that research results from a lab that was not clinically certified could not be returned to research participants or their families. Other requests from other laboratories were met with similar polite refusals.

“I thought, well, shit, I’ll have to do it myself,” said Hugh.
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He found surplus stores in the Bay Area that sold used lab equipment. He bought a PCR machine. He ordered primers and began setting up PCR experiments to amplify the relevant parts of the activin receptor genes that were known to interact with myostatin (activin receptors receive signals that tell cells to grow, divide, differentiate, and/or die). He was just about to buy a cheap DNA sequencer when a friend stopped him and said, “You’re crazy. Just send the samples to a core lab at a university. They’ll do it for four dollars per reaction.” He did.
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Within a few weeks sequence data began coming back. Hugh transferred it all to Word files on his computer. He then went to every genomic database to find all the DNA variants that were known in the activin receptors. Did Bea have any that had not been reported? If so, did Hugh and/or Lisa carry them? And if they did, then why were he and Lisa healthy?

After scouring the three genes he’d had sequenced, Hugh found a variant in Bea that had not been reported in other published human genomes (of which, admittedly, there were few). But he had still not had himself or Lisa sequenced. It seemed like an obvious experiment—so why not do it? And why not sequence the myostatin gene itself?

“Because by that time I’d kind of lost interest,” Hugh said. “I had a management plan. Bea would get regular echocardiograms. And for treatment we had losartan.”
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Losartan is a generic, FDA-approved drug that is commonly used to treat high blood pressure. For the last few years, it has been used to treat Marfan patients
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thanks to a fateful Google search performed by Hal Dietz.

When I suggested this version of events to him, Dietz laughed. “That’s not the whole story.” He came across as a mild-mannered and affable guy; he wore a rumpled sweater and small rimless glasses and had a receding hairline. When I said that I thought he had devoted his professional life to Marfan syndrome, he gently corrected me again. “Certainly Marfan is an important part of what I do, but it’s not the majority. I would categorize [my work as being dedicated to] anyone who has a problem in the first three centimeters of his or her aorta.”
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In 2001, Dietz’s lab found that mice with Marfan mutations developed emphysema, something that occurred in about 10 percent of Marfan patients. The conventional wisdom was that the emphysema was the result of deterioration of the patients’ lung tissue over time. But Dietz’s team noticed lung problems very early in the Marfan mice’s development, which meant there must be another explanation. They suspected that too much TGF beta was the culprit. Dietz’s hypothesis was that fibrillin-1's normal function is to keep TGF beta in check in the extracellular matrix, the scaffolding that supports our cells and is a defining feature of our connective tissue. In Marfan patients, the thinking went, fibrillin-1 is disabled and TGF beta runs wild, leading to enlarged aortas and other problems in places where fibrillin normally keeps TGF beta tamped down, such as in the lens of the eye. The Johns Hopkins group showed that antibodies to TGF beta could prevent heart valve problems and aortic aneurysms in Marfan mice.
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