A college project studying how elephant seals' fat cells change after the seals are weaned triggered Vivien Cheung's long-time interest in how different human traits appear.

What began as a side project has become a primary focus for this physician researcher.

The children came to the clinic usually before the age of two. They had difficulty walking or even sitting upright. In some, angry red veins bulged in the corners of their eyes.

Vivian Cheung, then a pediatric neurologist at Children's Hospital of Philadelphia, recognized the signs of ataxia telangiectasia (AT), an inherited disorder. The good news was that it was rare; the bad news was that there was no cure. The AT gene defect normally rendered its victims wheelchair bound by the age of 10 and plagued them with respiratory ailments and cancers until they succumbed, often before turning 30.

Cheung had been on track for a medical career. “My dad was a surgeon,” the HHMI investigator says now, with a dutiful daughter's smile. But while working as a clinical fellow at Children's, a teaching hospital affiliated with the University of Pennsylvania School of Medicine, she began doing research in her spare time to unravel the mysteries of this heartbreaking disease.

It was a journey that would eventually make her one of the world's foremost experts on the genetics of DNA repair. In AT patients, a defect in an important repair-related gene leaves them vulnerable to a bewildering variety of bodily dysfunctions: balance and motor-control problems, spider veins in the eyes, diabetes and infertility, immune system defects, and—perhaps strangest of all—an extraordinary sensitivity to ionizing radiation.

“I had long been interested in how different traits appear,” Cheung says. As an undergraduate at the University of California, Los Angeles, majoring in microbiology, she had studied how fat-cell metabolism changes radically in young elephant seals to enable them, after weaning, to hunt fish at half-mile depths. Later, in medical school at Tufts University, she took part in a multiyear epidemiological project in Turkey to study the genetics of lipoprotein levels.

At Penn, Cheung set up a small laboratory to study the genetic havoc of AT, and she quickly focused on the radiosensitivity problem. Patients with the disorder have inherited two mutant copies of a gene known as ATM (ataxia telangiectasia mutated). The gene normally codes for an enzyme whose most evident role is to act as the foreman of a special repair crew—called into action after the gravest of cellular events, a double-stranded DNA break. The “ATM crew,” which includes several powerful tumor-suppressing molecules, must either attempt DNA repairs or trigger a cellular self-destruction process known as apoptosis, lest the damaged DNA lead to runaway cancerous growth. Cells that lack this repair capacity are much more susceptible to damage from radiation and are more likely to turn cancerous. “Even ordinary background radiation, from cosmic rays and radon gas, can contribute to cancers in AT patients,” says Cheung.

Photo: Jason Varney

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