A Love That May Fuel a Miracle : A family’s fight to save a daughter with a rare disease has led to a discovery that exceeds their dreams--it may also aid cancer studies.
His daughter, Rebecca, was in seventh grade when George Smith arranged an informal meeting at school with her classmates. In four years, he says, “They’d seen Becca go from walking to a walker to a wheelchair. They didn’t know what it was--and they didn’t know how to ask.”
He explained that Rebecca has a rare and progressively disabling neurological disease called ataxia telangiectasia (A-T). Rebecca, at his side, put it this way: “I’m just the same as all the rest of you. It’s just that I have this balance problem.”
Rebecca’s disease had progressed to where she had to be accompanied to school by an aide. It was like throwing up a barrier between her and the other kids. Her father hoped to help tear down that barrier.
Rebecca, now 17 and a senior at Calabasas High School, doesn’t know what’s ahead--there is no cure for A-T and it claims its victims young--but she does know her parents are going to be fighting all the way for her and others with the disease.
In 1984, Smith, a real estate investment banker, and his wife, Pam, founded the A-T Medical Research Foundation, the first private foundation in the field. To date, it has raised $2.5 million for A-T research, $1.4 million of that out of their own pockets.
Their dedication has paid off. In June, an international research team isolated the gene that causes the disease after a 14-year search that reached from UCLA to Tel Aviv University.
There may be no big payoff for Rebecca and the 500 or more other young people in the United States afflicted with this cruel disease. A cure or treatment could be years away. “For us, a couple of years is a very long time right now. Or a very short time,” George Smith says.
But Rebecca and her family may not only have played a part in moving medical science one step closer to eventually conquering A-T--they may have helped researchers find answers to vital questions about cancer that could save thousands of lives.
Everyone carries two copies of the A-T gene--whose precise function is not known--but in ataxia telangiectasia carriers, one gene is defective. Those who inherit a defective gene from each parent will have the disease. There is a known link between A-T and cancer: 38% of the children with A-T develop cancers, primarily lymphomas and leukemia.
Doctors believe that this defective gene, known as ATM (A-T mutated), may be the largest single hereditary cause of breast cancer, accounting for as many as 8% of all cases, and may also increase the risk of developing lung, stomach, skin and pancreatic cancers. Studies of female relatives of A-T patients in the United States, Norway and the United Kingdom indicate that female carriers have a fivefold higher incidence of breast cancer than non-carriers.
This is significant in light of the fact that, of 250 million Americans, at least 1%--or 10 of every 1,000 people--are believed to carry one defective gene. Previously discovered genes that predispose one to breast or colon cancer affect possibly as few as one in 800.
Furthermore, the defective gene is known to cause extreme sensitivity to radiation, which is frequently used in cancer treatment. These patients’ skin may slough off at the site or they may develop skin cancers. One big question to be explored in the future: Should women with the defective A-T gene avoid diagnostic mammography?
Researchers also think the A-T gene plays a critical role in preventing cells from growing into tumors by directing those cells to make an enzyme that regulates cell growth. Children with two defective genes cannot make that enzyme, and otherwise healthy people with one defective gene may be highly susceptible to some cancers.
“Rebecca’s the seed that began this whole crystallization of effort,” says Dr. Richard A. Gatti, co-director of diagnostic molecular pathology at UCLA School of Medicine and lead member of the international team that isolated the gene.
Gatti, 58, considers the discovery of the ATM gene the highest achievement of his 33-year career in medicine. As a young doctor at the University of Minnesota in the late ‘60s, he performed the first successful bone marrow transplant, sibling to sibling, to cure a severe immunodeficiency. But, he insists, he was “just kind of following orders.” The long search for ATM was different: “This is my work, the most important scientific discovery that I can take credit for.”
The story of the Smith family’s crusade begins in 1980, when Rebecca was 2 1/2. Until then, says Pam Smith, “She’d seemed perfectly normal. But now she was still hanging onto the table and still wobbling” when she walked. The diagnosis: A mild case of cerebral palsy.
But two years later, when Pam was eight months pregnant with their son, Matthew, the Smiths were handed a different and devastating diagnosis: A-T. With luck, they were told, Rebecca might reach her late teens. “It was like we’d been hit by a 2-by-4,” George says.
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Little was known about this disease with the tongue-twisting name (ay-tack-see-uh teh-lan-jeck-tay-sha). Scientists weren’t even sure a single gene caused its multiple symptoms, which include motor control problems, slurred speech and immune system abnormalities. “We had never heard of A-T,” George says. “But we knew we had to learn as much as we could as soon as we could.”
The Smiths contacted the National Institutes of Health, but were told not to expect any help from the government. A-T fell into the category of “orphan diseases,” not prevalent enough to warrant big research grants.
Through a friend, the Smiths were introduced to Dr. Elena Boder, a retired Los Angeles pediatric neurologist who, with the late Dr. Robert Sedgwick, discovered A-T in the mid-’50s. She, in turn, introduced them to Gatti, who was then carrying on his research from a basement cubbyhole on the UCLA campus. Gatti had started studying the gene in the late ‘60s but “gave it up as too complicated, as did everybody else. We couldn’t figure out what one defect would cause all of these symptoms.”
In the early ‘80s, Gatti had moved to UCLA from Cedars-Sinai, where he had established the pediatric cancer program, to return to A-T research. Increasingly, there was evidence that this gene was implicated in cancer and he decided, “Maybe we should give it another shot.”
He sought an NIH grant, but was turned down--”You’re an immunologist, not a geneticist.” He was told, too, that tracking the A-T gene “is going to be a Herculean task and you’re not likely to succeed.”
And then along came the Smiths. Until then, Gatti says, “We were really nowhere. You just can’t do research without money.”
In 1984, the Smiths offered to fund him for $100,000 a year and established the A-T Medical Research Foundation, with Gatti as scientific director. He needed a proper lab to assemble a top-notch research team, so the Smiths went to foundations and to their friends, holding little parlor parties where Gatti would speak. They raised $540,000, some in five-year pledges, some in five-dollar bills, to build a state-of-the-art lab that houses the largest international A-T data base and a cell depository from more than 200 families.
By 1987, Gatti was also being funded by the Department of Energy, which was interested in the radiation link and how it might affect nuclear plant workers and others at risk. The first big pay-back came in 1988 when the Gatti team localized the A-T gene to the bottom third of the long arm of chromosome 11. It was, Gatti says, the genetic equivalent of narrowing the search from coast to coast to a single state.
About this time, Gatti introduced the Smiths to Dr. Yosef Shiloh of Sackler School of Medicine at Tel Aviv University, who had been studying A-T since the ‘70s. The foundation helped him establish a research laboratory and provided ongoing research grants.
Ultimately, it was Shiloh’s laboratory that isolated the gene, but that didn’t dim Gatti’s joy. He sees it as a team effort and, he says, “We were just afraid the gene would be discovered by a yeast geneticist who stumbled upon it. We wanted to get there before someone else did it based on our work--or totally independent of our work.”
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When doctors meet George and Pam Smith, they tend to be puzzled. A-T is known to be a disease that is particularly prevalent in small, clannish communities where there is a high incidence of intermarriage within families. Pam has to smile: “The first thing they’re always asking is, ‘Are we related?’ George is a Russian Jew from New York and I was born in Napa, Ida.”
The Smiths speculate that there might have been intermarriage among George’s ancestors living in small Russian villages, and within her father’s family, who were Mormons. In any case, each of them carries a defective gene, which means that there is a one-in-four chance that their children will have the disease. (Matthew, Rebecca’s brother, does not.)
Ironically, the Smith family’s efforts may not help Rebecca and other young people with A-T. Gatti points out that the muscular dystrophy gene was cloned in 1987, but there has been little progress in finding a treatment. But, he adds, the discovery of the A-T gene “opens up a tremendous logjam” that blocked the way to understanding the disease. Just the knowledge that a single gene is implicated in the disease opens the door to reliable identification of carriers and prenatal diagnosis.
For years Gatti has traveled widely to areas where A-T is most common--from Amish communities in America to small villages in Sardinia--educating people about the connection between intermarriage and A-T. There is a community of A-T families worldwide and, within this community, the Smiths are saints. Following their lead, A-T families in England, France, Italy and Florida have set up foundations.
George Smith says the front-page publicity over the gene discovery and its implications for cancer has lifted A-T out of the “orphan disease” category. When 1,000 people have a disease, there’s sort of a “So what?” attitude among the general population, he says, “but when you start talking about the gene maybe being a Rosetta Stone . . . “ (the journal Science made this analogy).
After years of arm-twisting for money, Pam Smith says, “I feel like I’m giving back to all the people who have given all these years.” Adds George: “It’s tough to keep asking . . . to say year after year, ‘We’re almost there. . . .’ ”
Each year, Pam Smith gives a women’s luncheon that raises $40,000 to $50,000. Gatti and Shiloh will be honored guests at this year’s event Nov. 1. Pam says it has been her friends who kept her going after Rebecca’s condition was diagnosed--”I could have come home and shut the door.”
Now, the Smiths carry on their fight with renewed energy. Their annual newsletter, which went out this month to A-T families here and abroad, finally had good news about the research. Rebecca, a bright teen-ager who loves music, designing clothing, poetry and horses, isn’t going to get her hopes up falsely. She is increasingly frustrated as her speech and motor problems worsen, and she must rely on her mother to help her dress and bathe. “I’d like to be able to do everything myself,” she says. But she rarely complains. She can still ride and, partially to encourage her and partially to escape city stress, the family has moved to Calabasas, which is horse country.
Her immune system is functioning well, she has not developed cancer, and dance therapy has kept her from developing disfiguring muscle contractions. In May, Rebecca was a bridesmaid in her half sister’s wedding. “I took my motorized wheelchair down the aisle.” Later, with help, she danced at the reception.
The cause gives Pam Smith strength. “I don’t have bad days,” she says. “I have bad moments. There’s a big difference.”
George tells himself that a cure will be found in time for Rebecca. “I’ve got to believe.” Still, he admits, “I cry a lot.”
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At UCLA, Gatti and his team carry on with refueled dedication. Will a therapy be found in time to help Rebecca? “Probably not,” Gatti says, but he is encouraged that victims are now living into their 30s, primarily as a result of better cancer therapies.
Says Gatti: “Things only happen in medicine when people say, ‘It needs to be done, and I’ll do it,’ like the Smiths did.”
Rebecca has found that one way to make friends is through her poetry. “She rides around in her wheelchair handing out poetry books,” her father says.
Her little bound volume, “Calling Out My Name”, includes this verse, titled “The Clock”:
The clock with thin hands of time
Stares boldly from the wall.
Numbers of the day and night
Are calling out my name.
The white face is laughing,
Telling me I’m late!
It sings a curious song
Calling out my fate.
