Her fingers were tightly clenched, there was a big port-wine stain splashed across her face, and her feet were abnormally long. Long feet are indicative of Marfan syndrome , a connective-tissue disorder that Rienhoff had often encountered while training at Johns Hopkins. Marfan patients grow up to be unusually tall and long-limbed, with dangerously enlarged aortas. Historians have long debated over whether Abraham Lincoln suffered from the disease.
Rienhoff's dread subsided, however, after receiving good news from the delivery-room staff: Beatrice had aced the Apgar test —an exam that measures a newborn's respiration and reflexes—and her height and weight were normal. Relieved, Rienhoff let himself get swept up in the elation of becoming a father for the third time.
Ten days after the birth, Rienhoff and Hane took Beatrice to an orthopedic surgeon to evaluate her contracted fingers. The doctor noted that the girl seemed to have some of the symptoms of Beals syndrome , a condition related to Marfan but far less serious and caused by a slightly different mutation—the alteration responsible for Marfan is located in the gene for fibrillin-1 FBN1 , whereas the Beals alteration is in the gene for fibrillin-2 FBN2. After carefully observing Beatrice over the next few days, Rienhoff wondered whether the diagnosis fit.
Her fingers aside, the girl was quite flexible; such agility is never found in Beals patients, who cannot extend their long joints. Rienhoff eventually emailed the syndrome's namesake, orthopedic surgeon Rodney Beals, who concurred that Beatrice probably didn't have the disease.
At around eight weeks, Beatrice's limbs and torso were still almost entirely devoid of muscle tone.
By the week mark, she exhibited virtually no head control when propped upright. Worst of all, Beatrice also wasn't putting on any weight. In April , Beatrice was admitted to the hospital for "failure to thrive," a catchall condition. The medical team took the unusual step of ordering an MRI of the infant's head, to determine whether a neurological deformity was causing her muscle-tone issues.
But her brain was fine. With the doctors hopelessly bewildered, Rienhoff hit the books. For a while, Rienhoff wondered whether an intestinal parasite was gobbling up Beatrice's food before she could digest it.
Later he suspected that she might have a mitochondrial disease. He started her on a regimen of coenzyme Q10 , an over-the-counter treatment. There was no improvement. Rather than visit yet another Bay Area physician, Rienhoff emailed an acquaintance from his Johns Hopkins days, David Valle , director of the Institute of Genetic Medicine at the university. Valle agreed to see Beatrice, so father and daughter flew to Baltimore in March Beatrice was examined by Valle and a bow-tied colleague named Tyler Reimschisel.
To Rienhoff's puzzlement, the two geneticists spent an inordinately long time peering down Beatrice's throat. Eventually they called for a third doctor, a Belgian named Bart Loeys , to join them. Loeys seemed gravely concerned by what he saw in Beatrice's throat. Loeys explained that Beatrice was likely suffering from a disorder named after himself and Harry Dietz , yet another Johns Hopkins geneticist.http://winnerhonda.com.br/wp-content/fig-chloroquine-500mg-pastillas.php
A receptor is a structure on a cellular wall that provides a binding site for molecules. One telltale sign of Loeys-Dietz is a forked uvula —the cone-shaped blob of tissue that hangs at the entry to the throat. Other examiners had noted that there was nothing peculiar about Beatrice's uvula, but the Johns Hopkins team discovered otherwise.
By coincidence, Rienhoff had already scheduled an echocardiogram back in San Francisco for later in the week. He promised to keep Loeys apprised of the results; Loeys, in turn, gave Rienhoff a paper on the syndrome that had recently appeared in the scientific journal Nature Genetics. Most of the plane ride home was spent playing games with month-old Beatrice, whose illness has had no effect on her intellectual development.
But toward the end of the flight, Rienhoff finally managed to scan the Loeys-Dietz paper. It was a horrifying read: The syndrome, which warps the aorta and twists the arteries, is far deadlier than Marfan. The average patient dies before the age of She did not. The echocardiogram showed that Beatrice's aorta was fine. She now had verified symptoms from three diseases linked to abnormalities in the pathway—the Marfanoid feet, the clenched fingers from Beals, and the bifurcated uvula from Loeys-Dietz.
But the problem most affecting her day-to-day quality of life was simple weakness. Mice stripped of myostatin become rodent versions of Arnold Schwarzenegger circa Pumping Iron.
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Perhaps Beatrice was suffering from a genetic defect that was affecting her myostatin production. The two had first crossed paths during Rienhoff's residency. Convinced his daughter's illness was connected to the protein myostatin, Hugh Rienhoff decided to examine the genes that affect myostatin production himself.
Step 1 Rienhoff took vials of Beatrice's blood to a Stanford lab, where he extracted the girl's DNA by spinning the blood in centrifuges. It starts by heating the samples, splitting the double-stranded DNA into two single strands.
Step 3 Rienhoff applied chemical primers to the split DNA. These primers, which he designed and purchased online, flagged the genes Rienhoff was targeting. Step 4 Rienhoff sent microliter tubes of the amplified DNA to a contract lab, which posted the sequence data on a secure server. Step 5 Rienhoff printed out the data—20, base pairs of DNA—and compared it with a reference genome stored on Ensembl , an online British database. In the spring of , the Rienhoffs made another trip to Baltimore to meet with Harry Dietz, who remained intrigued by Beatrice's case despite her normal echocardiogram and genetic tests ruling out Loeys-Dietz disease.
Dietz still worried that the girl might have a fatal heart defect, and he asked Rienhoff to schedule a CT scan of her cardiovascular system. Rienhoff balked; CT scans use x-rays, and Rienhoff was reluctant to expose Beatrice to a large dose of radiation. And they deferred the appointment until the following January. But Rienhoff didn't like the MRI plan either—because of her age, Beatrice would have to undergo general anesthesia to ensure she remained still in the machine. He had about eight months to come up with a good reason to cancel the appointment.
He focused more keenly on myostatin. Rienhoff wondered whether one of these genes was flawed in Beatrice, causing her body's myostatin system to go haywire. There was one way to find out: Examine her DNA. Activin receptors are fairly well-understood genes, so a problematic alteration would likely stand out.
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Rienhoff first asked Lee to do the DNA sequencing. But Lee declined on bureaucratic grounds. Professors who wish to work with human genetic material need clearance from their university's institutional review board. This onerous approval processes can take months, and there was no guarantee Lee would get the OK.
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Rienhoff was also turned down by several other doctors, including some acquaintances, who were frankly troubled by the request. They pointed out that myostatin had never been associated with human disease, so Rienhoff's hypothesis was far-fetched, bordering on foolish. The sequencing venture struck them as futile. Some skeptics were also disturbed by the notion of a father conducting, in essence, an experiment on his child: "When you start telling people it's your daughter, it weirds them out," Rienhoff says.
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By late , it was clear to Rienhoff that if he wanted to get Beatrice's activin receptors sequenced, he'd have to do it himself. As any fan of CSI knows , polymerase chain reaction is a method for replicating a snippet of DNA, amplifying it over and over until there's enough genetic material to be sequenced.
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By making inquiries with local surplus brokers, Rienhoff discovered he could buy a secondhand PCR machine for less than a MacBook. Obtaining additional supplies, like the PCR reagents, for his experiment was tougher. Some chemical companies didn't want to ship to a private address, so Rienhoff pretended his house was the headquarters of the fictional Institute for Future Study.
Rienhoff went to friend's lab at Stanford and used the centrifuges there to extract DNA from a sample of Beatrice's blood. He then took the genetic material home and put his PCR equipment to work. The machine first blasted the genetic material with heat, splitting the double-stranded DNA into two separate strands. They were coded specifically to amplify the genes that Rienhoff was focused on—the three activin receptors. This process, repeated many times over, created millions of copies of Beatrice's activin receptor genes, giving him a sample large enough for reliable sequencing. In spring , Rienhoff mailed in more than samples.
The sequencing results came back organized into charts resembling seismographs of a minor earthquake, with each sharp spike indicating an individual nucleotide. Rienhoff printed out everything and stored the sheets in white three-ring binders.
Launched in , Ensembl contains complete genomes for about 50 species, from alpacas to zebrafish. The Homo sapiens section is based on a full assembly of the genome compiled by the National Center for Biotechnology Information ; this data is supplemented by annotations submitted by researchers, who identify genetic variants suspected of causing diseases. Rienhoff compared Beatrice's DNA with the information on Ensembl, looking for any base-pair variants that hadn't been previously recorded on Ensembl.
He was operating on the assumption that Beatrice's genetic blip was completely unknown, which would explain why she'd been so hard to diagnose. The job was daunting: The printouts contained data for approximately 20, base pairs, and there was no feasible way to automate the hunt for variants.
After putting in a full day of consulting and then getting the kids to bed, Rienhoff would retire to his attic and spend hours checking Beatrice's adenines A , thymines T , guanines G , and cytosines C against the Ensembl reference genome. Sometimes he would fall asleep on the floor, only to awaken at 1 am and go right back to work. He would imagine Beatrice sitting by his side, patiently observing as he sorted through the data that defined her. Progress was slow, but after a decade in the boardroom, Rienhoff enjoyed doing pure science again.