Here Is a Human Being (25 page)

But could they also prevent lung disease? This was an obvious follow-up experiment, but Dietz wanted a more clinically relevant way to suppress TGF beta. Like, say, with a drug. One of his postdocs did some digging and learned that several blood pressure medications also inhibited the growth factor. Dietz then went to Google and typed in “TGF beta antagonist, FDA-approved.” Losartan was at the top of the list. At six months, Marfan mice given a placebo or a traditional beta-blocker had severe aortic aneurysms; they were in bad shape. The losartan-treated mice, on the other hand, looked completely healthy. The drug had actually
reversed
the aortic damage and had positive effects on lung tissue and skeletal muscle.
⁶²
“It was beyond anything I could have anticipated or hoped,” Dietz told
Science.
⁶³

In some cases, discovering that a drug has profound effects in mice might be sufficient to get a grant funded or drive a stock price up, but rarely does it have immediate ramifications for patients. Losartan was different: it was already FDA-approved and had been used safely and effectively in millions of people, including children, for nearly two decades. On top of that, it was used to lower blood pressure, which was already known to be a good thing in Marfan patients. Dietz and his colleagues began offering losartan to a small number of Marfan kids with severe aortic problems who had not responded to other drugs. A preliminary study by the Dietz group on eighteen kids with Marfan looked promising: once on losartan, their rate of aortic enlargement slowed dramatically. A fullblown clinical trial began, but it would be years before definitive results were in; meanwhile the buzz about the drug was so strong in the Marfan community that some patients opted not to participate for fear that they would be assigned to the control group and not receive losartan. Some obtained losartan prescriptions from their own doctors.
⁶⁴

For the Rienhoffs, even though Bea did not have Marfan, losartan offered hope. “Two things were compelling to me,” Hugh said. “First, we had not ruled out that Bea was at risk for vascular disease. She will be getting echocardiograms for a long time to come. Losartan actually
arrested
the vascular disease of the Marfan mouse! Second, I looked for cases where people taking this family of drugs had an increase in skeletal muscle mass; I found a bunch of papers supporting that. It seemed to me that, with this drug, Bea could get prophylaxis [prevention of aortic problems] on one hand, and therapy [an increase in muscle growth] on the other.”
⁶⁵

Dietz, who tended to err on the side of caution, was somewhat lukewarm to the losartan-for-Bea idea, but he was prepared to go along with it given Hugh’s research and rationale. But it wouldn’t have mattered: Hugh had already made up his mind. “I didn’t ask for Hal’s permission. I only asked him for the correct dose.”
⁶⁶

I drove to Hugh and Lisa’s place about thirty miles south of the San Francisco airport in San Carlos, a bedroom community with Spanish street names and two-story houses on windy culs-de-sac. Their old farmhouse seemed more Virginia than California—hardwood floors, high ceilings, and a wraparound porch. They had three kids: Colston, then age ten; MacCallum (“Mac"; age seven); and Beatrice. When I showed up in December right before Bea’s fifth birthday, no one was home; a neighbor let me in with little to no suspicion. Inside, amid the artwork, children’s furniture, and tasteful decor, stuff was strewn everywhere: books, toys, mail. I felt right at home.

An hour later Hugh showed up wearing a bow tie—his doctor outfit, I reckoned, though he only saw patients a couple of days a month. He greeted me warmly, kicked off his shoes, and insisted on carrying my bag upstairs. We retired to his carpeted office in the attic: the Bat Cave, he called it. Piles of paper, notebooks, journal articles, and books littered the floor. Pro-Obama and anti-Bush stickers adorned the wall; Lisa had been a socialist labor organizer when she and Hugh met in the 1990s. Another sticker said, “Evolution is God’s Intelligent Design.” The room featured two computers. One was for all of the mundane business of being a serial entrepreneur. The other was for “My Daughter’s DNA,” as Hugh called it, or what I will call, for the sake of brevity, “Project Bea.”
⁶⁷

Management plan or not, Hugh had not been able to let go of Project Bea. Since I’d last seen him he had resumed his molecular detective work in a massive way. Sequencing three genes was nothing. Now, loaded onto his computer, he had tens of thousands of gene sequences from himself, Lisa, and Bea. Each had given blood. From those samples, someone at Illumina, the market leader in the new DNA sequencing technology, had isolated white blood cells and from those extracted RNA and enzymatically converted it to its DNA form known as complementary DNA, or cDNA.
^*
The resulting collection of genes from Bea and her parents were their three transcriptomes: the sets of all of the
active
genes (transcripts) produced in a particular type of cell, in this case white blood cells. Transcriptomes were easier to work with than whole genomes because 1) they represent only 1 to 2 percent of the genome, “only” 60 million plus base pairs instead of 3 billion; and 2) they include much if not most of the “business end” of the genome: the parts that instruct the cell what proteins to make.

So now Hugh had a set of sequence data from all of the genes that were expressed or “switched on” in Bea’s white blood cells.
^*
In this case, that meant about fifteen thousand distinct bits of RNA, about two-thirds of which coded for protein. And he knew to
what extent
any given gene was expressed in those cells. “Why would that matter?” I asked. Hugh pointed to the glowing computer screen where he had aligned his, Lisa’s, and Bea’s data—a seemingly infinite series of colored peaks and valleys measuring gene expression. In most cases, the peaks were of similar height in all three. Although the conventional wisdom at the time was that humans’ gene expression profiles would vary widely, Hugh’s family suggested otherwise—the diagonal lines showing levels of gene expression were almost identical for the three of them, even though he and Lisa were not related—certainly not closely. But the patterns were not perfectly correlated, either: Hugh pointed to a variant in a gene he was scrutinizing that had two versions (alleles), G and C. He and Lisa both had one of each: they were both genotype G/C (heterozygous). Bea, on the other hand, inherited a C from each parent: she was genotype C/C (homozygous). So what, I thought. “Ah,” Hugh said, anticipating my skepticism. “Look at the difference in expression between the two alleles.” The peak representing the G allele towered over the tiny peak representing the C allele; the G version was expressed tenfold more strongly than the C version. Bea, therefore, appeared to make a tiny fraction of this particular protein compared to the amount her parents made.
⁶⁸

Hugh would have to chase down this lead as he would thousands of others, one gene at a time: checking for differences in expression levels, looking for new mutations that neither he nor Lisa carried (he had found several possibilities), looking for known pathogenic variants, trying to guess whether variants he saw that had not yet been reported might be capable of causing Bea’s condition, and all the while enlisting pro bono help from academic scientists who analyzed gene expression data for a living. And there was a
mountain
of data: instead of setting his computer’s sequence analysis filters to be extremely stringent, Hugh kept his filters loose and inclusive, lest he miss anything among the millions of base pairs scrolling by. It seemed like an impossible long shot.

He smiled. “That’s why I call it hand-to-hand combat.”
⁶⁹

As we sat in the Bat Cave, Hugh picked up a child’s acoustic guitar and began to play a sure-handed version of “Fly Me to the Moon.” Later we harmonized on “I Will” by the Beatles. As the kids ate dinner in the kitchen, Hugh sat on the floor munching carrot sticks and telling me about his decision to become a conscientious objector during the Vietnam War. I reckoned I liked him because he came across as a smarter, better-looking version of what I imagined myself to be on my best days: a dedicated father, an enthusiastic dilettante, an iconoclast, and a bit of a troublemaker.

A couple of years earlier, at the National Marfan Foundation Annual Conference in Palo Alto,
⁷⁰
not far from his home, Hugh went to a workshop intended for people and families who had Marfan-like features but lacked a diagnosis. He saw it as an opportunity to represent Bea’s point of view and to learn something. There were a fair number of patients and a doctor, Dianna Milewicz of the University of Texas Health Science Center in Houston, who served as interlocutor.
⁷¹
Each patient told his/

her story, many of which involved frustration with the medical system. Many went something like this: “I have long fingers, a heart murmur, and the insurance company won’t pay for the echo.” Or: “I have a high arched palate and narrow feet, long fingers, my father died at age thirty-five, and my physician will not order the genetic test for Marfan.” Hugh found it heartbreaking to encounter so many people stuck in the same netherworld of not knowing what their symptoms meant, and without his financial and scientific resources.
⁷²

Finally it was his turn. “I have a daughter,” he began, “and she has some of the important features of Loeys-Dietz, but she doesn’t have any evidence of vascular disease. I reasoned that maybe she had a TGF beta problem, or that she had a problem in some other member of that gene family. So I sequenced a few of her genes.”
⁷³
At that point, according to Hugh, Milewicz stopped him, turned to the rest of the participants, and said that none of them should ever attempt this—it was just too difficult.
⁷⁴

Hugh was taken aback. “Who the fuck is this person?” he thought, shocked at the paternalism of a fellow doctor, especially given the current, pre-reform state of health care. “I’ve never seen a better example of a physician being contemptuous of a patient’s own initiative. I live in a world where the patient-doctor relationship is a
collaboration.
That’s how I was trained. These people need a diagnosis. Without a diagnosis they can’t get coverage. And sometimes once they do get a diagnosis they’re screwed anyway because suddenly they have a preexisting condition. But getting a diagnosis is the foundation of everything else: prognosis, management, reimbursement … and understanding.”
⁷⁵

It was an epiphany. People had no idea what genetics and genetic testing were about and the medical establishment didn’t seem all that interested in telling them. Hugh was. He went home and wrote down everything he’d done for Project Bea. And he began talking. “If you can make a good soufflé, you can sequence DNA,” he told the
Economist.
⁷⁶
He and Bea graced the cover of
Nature.
⁷⁷
They appeared in
Make,
the do-it-yourselfer magazine.
⁷⁸
In 2009 they were in
Wired.
⁷⁹
A presentation Hugh gave showed up on YouTube.
⁸⁰

And he launched MyDaughtersDNA.org, a website that pointed visitors to various accounts of Bea’s journey and invited parents, patients, and physicians “to describe for the other users of the site a case that needs some help.” A few of them have told their stories and shared their expertise.
⁸¹
A geneticist in St. Louis read a description that a Bulgarian man had posted of his twelve-year-old daughter who lacked the ability to cry and suggested that she might have an extremely rare endocrine disorder known as Triple-A syndrome. She did; shortly thereafter she began hormone therapy. “To see a complete stranger solve another person’s problem,” said Hugh. “That was nice.”
⁸²

But the broader goal was to inform. Everything he’d written down went on the website: how to do PCR, how to pick primers, where to get something sequenced, how to navigate genomic databases. “I felt that just understanding what the steps were would demystify the process. Maybe no one would actually go from beginning to end, but people could understand every little step along the way. A lot of people don’t have the benefit of seeing a geneticist, let alone know what it is a geneticist does.”
⁸³

But just as Milewicz considered the Rienhoff approach a bad idea, so too did Bea’s own doctor, Hal Dietz. “I could imagine some parents diverting financial resources away from physical therapists and other health-care professionals in order to access the great promise of genomics and sequencing. I could imagine tragic consequences to that decision. I think Hugh is uniquely prepared to understand and deal with the complexities of his daughter’s situation. But I can’t imagine parents with no scientific background really knowing what to do with the information they would get.”
⁸⁴

Hugh deferred to Dietz. “When the discouraging word came from Hal, I immediately switched from being the ‘bad boy of genetics’ to being Bea’s dad who did not want to jeopardize her relationship with her doctor, which at that time was tender and new. I’m not condemning Hal. I just decided that maybe I wouldn’t tell the world how to make an A-bomb and blow up academia. And besides, it’s all out there already anyway, right? I was just consolidating the information. And putting a human face on it.”
⁸⁵

Eventually Dietz came around … at least somewhat. When Hugh and Bea came to Baltimore in 2009, Dietz fully endorsed keeping her on losartan. And when Hugh brought him reams of transcriptome data, Dietz did not roll his eyes; Hugh hoped that this would be the beginning of yet another collaboration on Project Bea. He speculated that his “Tom Sawyer” approach to science might finally be working.
⁸⁶

When Hugh called from his cell phone the following summer, he was still pursuing any number of hot candidate genes. But he was even happier that Bea was thriving, if not putting on weight. Her echocardiograms continued to come back clean. She was being a champ about remembering her losartan pill and taking it on her own.