christiano.jpgAfter battling hair loss, Angela Christiano, a
molecular geneticist at Columbia University,
has a passionate interest in the genetic
regulation of hair growth. More than 100
genes are thought to influence the
development of the hair follicle.


On a Friday morning last June, Efrat Fadida threw a denim jacket over her white summer blouse and caught a ride with her father from the small Israeli town of Gedera east to Jerusalem. Walking into Hadassah University Medical Center, the 25-year-old cut a striking figure: high cheekbones, a square jawline, and a scalp as bare as the day she was born. Fadida suffers from alopecia universalis, a genetically influenced autoimmune disease that can strike at any age, causing all the body's hair to fall out. She had come to Hadassah to meet a team of gene hunters.

"I've had this disease a year," Fadida told the researchers, speaking in simple declarative sentences and using her fingers to draw quotation marks around the word disease. "It started in small bald spots. It became very big, so I decided to shave my head. The only thing that bothers me is that I don't have any eyebrows or eyelashes. I've learned to love myself." What she didn't say was that she hadn't always been so accepting, although four others in her family have the same disorder. As Fadida's hair began to disappear, she grew skittish about shampooing. She worried that her boyfriend would leave her. For the first month she cried constantly. Today, living with supportive parents, she no longer dates her boyfriend and remains wary of others' reactions. "I put makeup on, but I still look like an ill person," she says. "When people see me, they think automatically that I have cancer."

Recently, geneticists have started closing in on clues that might lead to treatments for Fadida's disease. Their efforts are part of a larger push to study more than 300 known genetic hair disorders, which range from rare diseases detected in a few dozen families to male-pattern baldness, which affects hundreds of millions. What all these diseases likely share is a disruption somewhere in the complicated growth cycle of the hair follicle.
As Fadida spoke, one scientist in the group listened with particular interest. Angela Christiano, a molecular geneticist at Columbia University in New York City, presented a dramatic contrast to Fadida, mostly because of her hair. A veritable fountain of it rises high above Christiano's skull and cascades past her shoulders in bursts of onyx and bronze. Elaborately colored and curled, it is more sculpture than hairdo, and inescapably the first thing anyone notices about her.
Despite appearances, Christiano knew exactly what the young Israeli was feeling. Diagnosed in 1996 with alopecia areata, the geneticist lost 10 large clumps from her magnificent mane before symptoms finally abated.

Since then, Christiano has cracked the genetic code of three hair diseases. Now she wants to pin down the mutations that caused Fadida's hair loss, and in doing so, figure out what caused her own.

chassin.jpgTHEA CHASSIN: TAKE 1 An architectural lighting designer,
Thea Chassin of Briarcliff Manor, New York, leads the
Westchester Resource and Support Network of the National
Alopecia Areata Foundation (www.naaf.org), which sets up
discussion groups for people with hair loss.
"Knowledge is power," she says.


Although two of her relatives cut hair for a living, some of the women in Christiano's family had trouble retaining their own. As they reached menopause, both Christiano's mother and grandmother began going bald. They wore wigs in public and shied away from any activity like swimming that might blow their cover. And they were hirsute compared with Christiano's second cousin, whose alopecia universalis left her without a single hair anywhere on her body.


None of this history, however, led Christiano to her studies. That happened with remarkable serendipity. After she earned her Ph.D. from Rutgers University in 1991, she began an emotionally wrenching postdoctoral fellowship: hunting down the genetic basis of epidermolysis bullosa, a childhood disease that causes disfiguring and even fatal blisters. Every few months, Christiano collected blood samples from children at Rockefeller University Hospital in New York City to analyze their DNA. "These kids are covered from head to foot with blisters that are like third-degree burns. They have to be bandaged constantly. And to take those bandages off, you have to soak the children in warm water because if you just took the gauze off, you would take their skin off."

Christiano felt powerless because scientists knew so little about the disease. But over the next five years she isolated one gene, then another, and another, until more than 50 mutations on several genes associated with epidermolysis bullosa had been nailed. Not only did her research lay the groundwork for effective genetic counseling, but she also developed the first prenatal test for the disease. She was 30.

Riding on success, she accepted an appointment at Columbia University in 1995. In her new job, she was expected to break away from her old postdoctoral studies and establish herself as an independent scientist with new research interests. In her first academic year, she seemed to be spinning without direction. Then one day she got her hair cut.

It was May 9, 1996. Christiano was at her favorite salon in Metuchen, New Jersey, when the beautician casually mentioned a small bald spot: "What happened? Did you have a biopsy back here?" Christiano assumed she had merely tied her hair too tight, but later that day she asked a colleague for a second opinion. With the office door closed, immunologist Monica Peacocke parted Christiano's hair. When Peacocke saw a bald patch the diameter of a coffee cup, she let out a scream. "It's not small!" she cried.

Doctors diagnosed the problem as alopecia areata, a genetically determined autoimmune disease in which the body's T cells identify hair-follicle cells as foreign invaders and try to destroy them. Healthy scalp hair follows a staggered process through three phases: a growth period, which can last up to eight years; a two- to three-week degeneration period; and a two- to four-month resting period, during which the follicle weakens and the hair falls out. The periods can vary in length in different people, but in patients with alopecia areata, all the hair in a single area enters the phases of degeneration and resting at the same time, causing hairs to fall out all at once.


chassin2.jpgTHEA CHASSIN: TAKE 2 When she lost all of her hair nine
years ago, Chassin was at a loss about what to do. She
needed to learn about makeup and wigs. "It's not like going
out to buy a car or a TV," she says. Now she says she doesn't
always wear hair. "This summer I was the bald chick."

."Doctors told Christiano the only treatment was to undergo a series of painful cortisone-derivative shots in her scalp to blunt the immune-cell attack. Over the next year and a half, she developed nine more bald spots. As soon as hair in one corticosteroid-injected patch began growing back—as colorless as rice noodles at first—another would appear.


Christiano lived with perpetual fear: "You wake up every morning and before you lift your head off the pillow, you think, 'Is it all there? Is it gone?' And then you get angry at yourself for being so vain. You think, 'I just spent five years working on these lethal skin diseases. I should count my blessings that this is all I have.' And that doesn't work." The answer, she decided, was to throw herself into figuring out what was happening to her.
As she learned more, she was surprised that so little was known about a condition that plagues 5 million Americans. What genes are responsible for normal hair, she wondered. And what at the molecular level causes those cycles to go awry?

Because alopecia areata was believed to result from more than one altered gene, Christiano knew it would be daunting to decipher. The completion of the Human Genome Project was almost a decade away. Instead, she decided to seek out a simpler form of the disease, one regulated by a single gene. She knew what to look for: a family in which a large number of people had extreme hair loss but whose other members had perfectly normal hair. That pattern of inheritance would suggest the strong effect of a single gene mutation, and it would most likely crop up in families that had a lot of shared genes through the intermarriage of first cousins.

She found what she was looking for in a remote part of Pakistan.

Less than two weeks after her alopecia was diagnosed, Christiano read a clinical report about a family in a small Punjabi village. Many of its babies were born with hair, but they soon lost it, even their eyelashes. The problem did not appear to be related to more complex skin disorders: Their teeth were fine. Their nails were fine. They sweated normally. "It was exactly what we were looking for," she says.

Christiano sent a letter to researchers in Islamabad, suggesting a collaboration and enclosing a snapshot of her own bald spot. Five months later, 30 blood samples arrived, followed by Pakistani researcher Wasim Ahmad, who remained at the New York laboratory for two years. Christiano and her team chose several of the samples, analyzed the DNA, then compared the bald patients with relatives with normal growth. She identified a region on chromosome 8 where the affected family members had distinctly different genes.

She was ecstatic: "Oh, my God, it was like heroin." But she was still a long way from isolating a gene. "Let's put it in simple terms: We went from the whole of the United States down to a zip code. Maybe a county," she says. Within that region, there were hundreds of genes, few of them mapped. When it came to further narrowing, the Columbia team was stalled.

A photograph of a young family member finally helped crack the problem. Typically, the family followed the Muslim practice of shaving the heads of its infants. Once the hair was shaved, it never grew back. One mother, however, did not shave her daughter's head. Ahmad obtained a picture of the girl at age 6. Partway through the balding process, she retained a fringe on the back of her head, much like a 50-year-old man with male-pattern baldness.