by Ian Brown
This was a common sentiment among parents of CFC children; what made it more remarkable in Angie Lydicksen was that six months before she expressed that thought to me in May 2007, she had been diagnosed with lung cancer. But her health was less on her mind than her son’s value to the world.
“Oh God, he’s given us so much,” she told me that day, when she already knew she was dying. “He’s taught us how to accept life for what it is, to deal with it as it comes up. You can be either stuck in a bad rut, or you pick up the pieces and go on the best we can. Right then and there [after Luke was born], we just changed our ways. We bought a camper and went camping, because he likes that. One of the biggest things Luke has taught us is to accept being different, not to be afraid of him. It’s just so different from when we were kids. We always stayed away from disabled kids. But nowadays everybody plays with them.” Luke is known as the Mayor at his school. “The whole entire time I thought, if he can do what he did then I can do this.” She meant deal with her own cancer. Luke seemed to put things into perspective. When other mothers complained about a child who hadn’t slept through the night, she tried not to laugh. “Sleeping through the night! Oh my God! I haven’t slept through the night in nine years.”
She wanted to be around forever for him, and when she got sick became afraid that no one would be able to replace her in Luke’s life. But of late she had begun to think otherwise. “In the long run he’s very adaptable.” Her own grave illness only reinforced what Luke’s disability had already revealed. “Without him, I would have been more interested in material things,” Angie said. “Stuff. And now, it’s just like, you know, I can do without it. I don’t need it. Just having your health and people that you love and a family that’s strong …”
Talking to Angie Lydicksen was like talking to any parent who had experienced the ups and downs of raising a child—the steady low-key anxiety punctuated by explosions of fear and concern, the pride and frustration, the exhaustion and pleasure. The difference was that Lydicksen could not afford to succumb to the hyperbolic sense of isolation that can make a father or mother believe he or she is the only one to whom this or that is happening. “I don’t get the complaining thing,” Angie Lydicksen told me that day on the phone.
The following spring, she died of lung cancer. She was forty-two years old. Luke still lives with his father.
I was always looking for a context in which to make sense of Walker, in which his disorganized life (and my unavoidable devotion to it) might take on more meaning and purpose. I thought I might find it in the lives of other children with CFC, and in the example of their parents. To my surprise, while it was sometimes reassuring to know he was part of a larger community, and that I was not alone, the nature of that community—a hundred children and their parents, invisible in the greater world, desperately trying to quell their pain and rescue some semblance of normal life from an abnormal circumstance—was more complicated than it looked, sometimes as upsetting as it was reassuring. I now knew that “Walker and his ways,” as Johanna described them, were not unique. What I had yet to find out was why he was the way he was. And so I turned to science, to see if the laboratory could explain my boy Walker.
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These are the glossary terms that “help with understanding cardiofaciocutaneous syndrome,” as listed on the Genetics Home Reference page of the United States National Library of Medicine:
apoptosis; atrial; autosomal; autosomal dominant; cancer; cardio; cardiomyopathy; cell; cutaneous; differentiation; failure to thrive; gene; heart valve; hypertelorism; hypertrophic; hypotonia; ichthyosis; incidence; keratosis; macrocephaly; malformation; mental retardation; muscle tone; mutation; new gene mutation; nucleus; ocular hypertelorism; palpebral fissure; proliferation; protein; ptosis; pulmonic stenosis; RAS; seizure; septal defect; short stature; sign; stature; stenosis; symptom; syndrome; tissue.
The language of Walker’s strangeness held me captive. New words had been invented for a new creation, infused with the pretend exactitude of scientific nomenclature, as if all the labels said something helpful and useful, which of course in any comparative sense they did. The alluring multi syllabic complexity necessary to describe a simpleton, to use the old, once-scientific word for such a boy. Everything about Walker was complicated by something else, and there were many days when I appreciated that, when it deepened him, and gave me more to think about. Sometimes it was all there was to think about.
I was sitting at my desk at the Globe and Mail, the large daily newspaper where I work, the morning I read the scientific paper announcing that a geneticist named Kate Rauen had found a mutation in three genes associated with CFC. It was a Tuesday in April 2007. My desk sits out in the open: it’s a congenial place to write, as abattoirs go. But that morning I had to get up and walk outside. I couldn’t catch my breath. A gene that caused CFC: after eleven years of living with the mystery of Walker, the notion was exciting, but also terrifying. My relationship with Walker, after all, had been personal, and private; we operated by our own standards, by what worked between us. I “spoke” to him and he “spoke” to me, clicking our tongues back and forth to one another to let each other know that we were paying attention, that we knew the other was there, and listening. Now there was a gene, an impersonal scientific cause, at the root of his affliction. What would it tell me? And would it prevent me from believing any longer in what I told myself were my son’s secret capacities? Would I still be able to take comfort in our private language of click—to offer just one example—if the gene said it was pointless, that such a connection was beyond his capacities? So far I had already had to share my son with his other home. Would I now have to share him with the lab?
Not to say there wasn’t huge hope in the discovery. If I knew what genetic misstep had caused Walker’s troubles, I would have a hook to hang those troubles on. I might even have a cure for them. There would be a firm and unassailable cause, something to blame and something to fix—a shrimpette of concrete fact in the sea of speculation and vagueness that constituted his life, and ours.
Two weeks later I flew out to San Francisco to interview Dr. Rauen. At the airport, I rented a car with a GPS unit. It was my first time. Until then, I’d always used maps. I liked maps, liked the way they let you get used to the overview of somewhere new and unfamiliar, in plan form, before the place became details, close up and unavoidable.
With GPS, I could fly into a vast complicated confusing city after dark, rent a car and plug in the address of where I was supposed to end up. The GPS unit told me to turn left out of the rental lot and spat me instantly onto a chain of highways, a speedy tube of lights that ran for a long time until finally the tube dumped me out into a hotel parking lot. GPS made me feel like I was getting somewhere fast. The downside was that I never knew where I was in the bigger picture. GPS took you right where you already knew you wanted to go, and cut out the less efficient side trips. Just like a CFC gene, it turned out.
The genetic research labs at the Comprehensive Cancer Center in San Francisco, where Kate Rauen worked, were lit like the inside of a refrigerator and cluttered with textbooks and tubes and stoppers and scales and micro-array scanners.
The scientific papers the geneticists wrote—largely for one another—had titles that were incomprehensible to a layman, such as “Keratosis pilaris/ulerythema ophryogenes and 18p deletion: Is it possible that the LAMA1 gene is involved?” The geneticists themselves bore the slightly startled air of soldiers who had just emerged from the deep jungle, only to be told that the war they had been fighting had been over for twenty years. They were fond of unusual, non-human screen savers: a photograph of a cat, say, asleep in a tiny log-cabin cathouse. (I once stepped into an elevator full of young geneticists leaving work. It was Hallowe’en. Two of the female geneticists in the elevator were wearing devil horns on their heads. “Going out tonight?” one of the guys ventured. The women shook their heads. I can’t say I was surprised.)
The morning I showed up at Raue
n’s lab, her colleague, Anne Estep, was feeding liquid medium into Petri dishes. The Petri dishes contained clones of twenty-nine different mutations of one gene that Estep and Rauen had isolated in the DNA of people with CFC. Rauen had yet to show up for work, so Estep, a personable, blond-haired woman in her thirties who openly admitted her love of lab work, undertook the challenge of explaining the complicated genetics of CFC to me.
She saw the entire process from a scientific height, as evidence of the elegance of human biology. “There are just so many things that can go wrong in conception,” she said. “The majority of pregnancies are spontaneously aborted, or miscarried very, very early in the pregnancy—it’s just nature’s way of allowing only the right combination to come to term. Even to be born, you are already one of a minority of conceptions—so much has had to go right to get to that point.”
This was a new way of understanding Walker—instead of broken, he was simply slightly flawed, like a discounted but perfectly wearable pair of shoes at an outlet mall. He was still “a genetic configuration,” as Estep put it, “that is compatible with life, is a living, breathing human being. So there’s a wide variance. They all have two arms, two legs. Most of the children have a range of emotions. They’re human.” Two weeks before I met her, Estep had been introduced to Emily Santa Cruz—her first encounter with a breathing embodiment of the CFC genes she had been studying in a dish in the lab for eight months. She found the encounter “very moving,” although she had been surprised, she said quietly, “by how severe her delays were.” Even for a dedicated scientist such as Estep, there was a gap between the life she studied in the lab, and the life itself.
Kate Rauen was in her early forties, short, blonde, vastly energetic. She kept an office at UCSF Children’s Hospital across the city, where she ran a clinic, as well as another at the Comprehensive Cancer Center. She was good at clarifying complicated genetic processes. “Here’s your chromosome,” she told me later that afternoon, as she drew circles on a piece of paper to explain how a cell operates. “On this chromosome, here’s your DNA. On this DNA are genes, kind of, maybe, next to one another. That gene makes an RNA, and then that RNA makes a protein. And proteins actually are the ones that float around in the cell and do the work.” There are roughly 25,000 protein-making genes in the human genome, and another 35,000 regulatory genes. Some proteins fold up in complex patterns (again, according to instructions from the genetic code) and form cells, which in turn form human tissue. Other proteins operate as group managers, controlling other enzymes. (Bureaucracy is everywhere.) The RAS family of proteins and enzymes (for rat sarcoma virus, which was involved in its discovery) are managers—specifically, molecular on–off switches for a group of signalling pathways that communicate between a cell’s membrane and its nucleus, to control cell growth. “The nucleus is the brains of your cell and the only way it gets instructions is from outside of the cell,” is how Rauen put it. “And the instructions come in the form of signal transduction, or molecules talking to one another, which will actually end up telling the nucleus what to do.” The entire process operates like a game of telephone. An enzyme or protein sidles up to the outside wall of a cell, and tells it to do something; an enzyme on the other side of the cell wall passes the instructions along to another series of enzyme systems within the cell, and so on through the body of the cell until the message reaches the nucleus—which does what it thinks it has been told.
RAS in turn activates other “downstream” signalling systems, such as the mitogen-activated protein kinases (the MAPK pathway) that control even more specific cell functions. RAS is an infamous route among medical researchers: 30 percent of cancer tumours display some form of RAS deregulation, where either cell growth has run out of control or cell death has stopped, because of an incorrect instruction, or signal transduction.
“I’m just a dumb old medical geneticist,” Rauen told me. “I just see patients and try to diagnose what they have. Meanwhile I’m with all these smart biochemists that studied signal transduction. And I just remember looking at these pathways and thinking, oh my gosh, one of these days they’re going to find genetic syndromes that are involved in these signal transduction pathways, part of this alphabet soup.”
One of the genes associated with Noonan syndrome had already been found to have a role in the RAS pathway. So had a gene for neurofibromatosis. The physical traits of both syndromes, give or take a few details, were remarkably similar to the symptoms of Costello syndrome and CFC. It made sense that genes responsible for CFC’s genetic mutations might lurk in the RAS pathway as well.
To fund a study of a syndrome that might affect three hundred people worldwide, however, was another matter. Fortunately—at least for Rauen’s purposes—the RAS pathway had a known role in producing cancerous tumours, which are themselves the result of unstoppable cell growth. Costello, Noonan and neurofibromatosis all produced tumours, whereas CFC did not. To Rauen, those known facts looked like a research opportunity. Three out of the four syndromes found in the same cellular pathway produced cancer; the fourth did not. What made them different genetically? Would that knowledge provide clues to why tumours formed? By way of analogy, say 100 kids grow up on the same street, but only 75 of them get the same kind of cancer. It follows that if you can figure out what was different about the 25 who don’t get cancer, you might have a clue as to its cause and cure.
“That,” Rauen continued, wrapping up the tour of her logic, “was the basis of a National Institute of Health grant.” Rauen was no longer investigating a mutation that afflicted a mere three hundred unfortunate kids. She was investigating a potential cause of cancer, via their handy DNA markers. “We are going to learn so much from these kids,” she told me. “We are going to learn how to treat them better from knowing their genes…. We are going to learn so much about cancer treatment from these children that this is a huge discovery on multiple levels.”
That, at any rate, was the theory. The practice was another matter. Rauen was working simultaneously on both Costello and CFC, trying to find the genes responsible. She needed thirty subjects with each syndrome, their consent and their DNA. Rounding up thirty Costello subjects took five years. By the time she completed her research—and the Costello gene was right where she predicted, in the RAS pathway—a team of Japanese researchers led by Yoko Aoki at Tohoku University in Sendai, Japan, had beaten her to it by a month.
She had better luck with CFC, thanks to the blood samples Brenda Conger and Molly Santa Cruz had been gathering at their CFC conferences since 2000. What had taken five years to find for the Costello experiments took mere weeks for CFC. “I was handed a cohort of CFC subjects in days—in days. I had DNA within that week. It was amazing.”
In January 2006, three decades after cardiofaciocutaneous syndrome was first described, Kate Rauen published her findings. The mutations associated with CFC occurred in at least three genes: BRAF, MEK1, MEK2. Independent research in Japan had added another gene. Costello syndrome showed mutations in the HRAS gene, whereas Noonan syndrome showed up in the PTPN11 gene. All of them were found in the RAS pathway, and all of them influenced cell growth and cell death.
The genes and their complicated acronyms (most of which related to their chemical composition) sounded like newly discovered planets to me, as baffling and rarefied as genetics itself. But I didn’t have any trouble following Rauen when she gave me her best guess of what had gone wrong in Walker. The dinner hour was approaching, and outside the windows of her office, San Francisco was washed in its standard impossible end-of-day gold.
The sequence of four paired nucleotides that, combined and recombined, make up the genes of a human being is three billion base pairs long. Each nucleotide is represented by a letter. “This mutation,” Rauen said, referring to the one that caused CFC, “is one letter change in the entire gene. Yup. One letter in the entire gene, which causes one amino acid to change—one amino acid, one tiny building block of the entire protein. That’s what causes CFC.” That i
n turn had caused the snaggle of Walker’s life.
“Does anyone know why that letter changes?” I asked.
“DNA replicates, right? DNA replicates, but it doesn’t replicate with extremely high fidelity. If it replicated and never made a mistake, we would all look the same, right? The good news and the bad news is if it does make a mistake, it makes a mistake about once every million times. One in every one million base pairs has got a mistake in it. Now, you’ve got all kinds of proteins and enzymes and stuff that go back and try to find this mistake and correct it. So a lot of mistakes you never know about. But sometimes the mistake’s not corrected. And when that mistake’s not corrected, it causes a change in protein. And that protein behaviour might make our immune system better. It might make our muscles stronger. It could have beneficial effects called evolution. You know, survival of the fittest. But you can also have a genetic change that makes a deleterious effect, where it causes a hole in the heart, it causes your immune system to be weak. It might be a beneficial effect, it might be a deleterious effect.”