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.
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.
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.
Shortly afterward, Christiano attended a lecture at a meeting of the Society for Investigative Dermatology. She heard about a mouse with a mutation on a recessive gene nicknamed hairless. A slide show illustrated how, over the course of four days, the mouse's hairline migrated from its nose toward its tail, until the animal was nearly bald. As Christiano viewed the slides, she realized the pattern resembled that of the young Pakistani girl. She decided to explore whether the mouse and the girl had the same condition. Because mice and humans share many of the same genes, Christiano's lab was able to isolate the human equivalent of the hairless gene. To everyone's delight, it was located on chromosome 8. Then the team compared the DNA sequence of an affected patient with that of a healthy control. Sure enough, the hairless gene from the bald Pakistani family contained a mutation.
"This was a landmark achievement," says Ralf Paus, a professor of dermatology at the University of Lübeck and an expert on hair-follicle biology. The matching of human and rodent phenotypes—observable characteristics—to find human mutations was a novel idea among hair researchers. "We had been pestered by clinicians saying, 'What does the mouse say about human hair growth?'" Paus says. "This proves that what you can do with mice you can extrapolate to the human situation."
Christiano's paper, published in the journal Science in 1998, did, however, contain one notable misnomer. Using the original Pakistani diagnosis, she suggested that the family was suffering from a form of congenital alopecia. It turned out that the patients had a much rarer disorder called papular atrichia, which destroys the hair follicle. That made her discovery "biologically fascinating but clinically of limited relevance," Paus says.
(Worldwide, there are only about 30 documented families with papular atrichia.) Still, by identifying the human hairless gene as an important master switch in regulating cell death in a hair follicle—a discovery that could lead to gene therapies for unwanted hair growth—Christiano emerged as a new star in the field, and a glamorous one.
"The first talk she gave, people thought: 'Who the hell is this? How did she get in here?' " Paus recalls. "With her flamboyant hairdo, no one could believe this was one of the world's foremost skin researchers. But she has vitalized the hair field like no one before her. Some people get a little taken aback by her flamboyance. I just love it—and if you look at her work, no one can compete with that."
When Christiano made the switch to hair research from skin blisters, some of her colleagues in the epidermolysis bullosa field wondered if her research had turned trivial. "Hair?" she remembers their asking. "How could you go from working on this life-threatening thing to hair?" But as the news of her research spread, Christiano was deluged with correspondence from people suffering from all sorts of hair abnormalities. Some wrote that they never left their homes. Others had considered suicide. "I am frustrated and scared and feel hopeless," wrote a midwestern woman with little hair left. "I don't know what it will do to me if I keep losing my hair."
Psychologist John Rooney of La Salle University in Philadelphia has found that women so prize their hair that most students surveyed during a classroom exercise said they would not shave their heads for even $1 million. The roots of such a strong emotional attachment may well lie in natural selection, says evolutionary psychologist David Buss of the University of Texas: "Hair quality—fullness, texture, color, and even length—are strong correlates of youth and health. They signal high mate value. Loss of hair signals loss of mate value, hence it is psychologically upsetting."
"It wasn't until those letters started pouring in that I realized that, even though people didn't die from this disease, a part of their soul died," Christiano says.
Not long after her discovery, Christiano was giving a lecture at Harvard University when a dermatologist approached to tell her about two sisters in Acerno, a mountaintop village outside Naples, Italy. Both girls were born with compromised immune systems. One had died around her first birthday. The other had received a bone-marrow transplant at five months, enabling her to survive into childhood, but without scalp hair, eyebrows, or eyelashes. "I think this might be related to the nude mouse," the Harvard scientist suggested. Mice with mutations in what is called the nude gene don't fully develop the thymus, a small organ in the chest cavity that plays a key role in the maturation of infection-fighting T cells. For reasons unrelated to the thymus, the rodents also have immature follicles and are completely bald.
Christiano contacted Claudio Pignata of Federico II University of Naples, who informed her that a handful of children in Acerno die each year of the same immunodeficiency. In most cases, the children are so ill and die so young that their baldness goes unnoticed. Pignata sent blood samples to New York. Christiano's lab found that the sisters had a common mutation on chromosome 17, right in the area of the human nude gene. A deeper analysis confirmed her hunch, linking nude to the sisters' condition. Pignata now offers genetic counseling based on blood tests of prospective parents in the Italian village, where one resident in 15 carries the mutation.
Meanwhile, more letters arrived. Christiano heard from a Texas pediatrician whose Pakistani-American family had sparse hair that broke easily and sometimes coiled beneath the skin because it was too weak to penetrate the surface. By now she had set up a system: Find a mutant mouse with a similar phenotype and see if the human patient had a mutation on the equivalent gene. "This is our hat trick," she thought. But when she tested one candidate mouse with a known mutation, the trick failed.
Frustrated, Christiano turned to a colleague, who suggested she look at a lanceolate mouse, a rodent with sparse, stubbly hairs but no identified mutation. It took five years of gene hunting to find the source of the mouse's strange hair patterns. In 2002 a student in Christiano's lab was studying the Human Genome Project database and noticed an unnamed region where Christiano had predicted the human version of the lanceolate gene would reside. The gene proved to be severely mutated in both the Texas family and some lanceolate mice. "This one took a little bit longer," Christiano says, "but only because we had to wait for the genome project to catch up and point us in the right direction."
Unlike a disease such as hypertension, which follows a similar course in most sufferers, hair diseases come in many types. And while the most common disorders involve the absence of hair, some people grow too much. Christiano turned to a rare condition called hypertrichosis, whose sufferers are sometimes called wolf people. Instead of growing normal facial hair, they develop thick, pigmented scalp hair called terminal hair all over their faces. So unusual is their appearance that some people with hypertrichosis work as circus performers. The syndrome has different causes, but it can be inherited in families, and Christiano suspects it involves a single gene.
The problem of studying hypertrichosis is that so few people have the genetic form. So for the past six years, Christiano has been scouting research subjects all over the world. In 1998 she located two families in Europe. Then, in 2001, she flew to Monterrey, Mexico, where a colleague drove her to a rural open-air clinic. There she met a family with a quirky phenotype: those with excessive hair were also deaf and unable to speak. Many of them lived in shame, remaining inside and shaving constantly.
Meeting the family—especially an uncle and his young nephew—touched Christiano. "The uncle was just amazingly beautiful," she says. "I mean, I've never seen so much hair on one person. Others in the family were not as out about their disease, but he was very proud of his. He couldn't wait to take his shirt off and show me his chest.
"We could tell that the nephew looked up to this uncle as a guide to what his life was going to be like. In turn, the uncle looked at this kid as his responsibility. And they didn't even do sign language with each other. Even though they couldn't vocalize or hear each other, they had this bond that was just incredible."
Christiano took blood samples. She has not turned up any genetic clues yet, but if she succeeds, the impact could be staggering. Hypertrichosis is the mirror image of male-pattern baldness. With balding men, ordinary scalp hair is replaced by vellus, or peach fuzz. Among people with hypertrichosis, facial vellus is replaced by scalp hair. Unlocking the secret to hypertrichosis could lead to gene therapies not just for people with too much hair but also for some of those with too little.
Christiano is not a theorist. "Although she's a Ph.D.-trained scientist, she's always looking for the clinical relevance of her findings," says Hal Dietz, a researcher at the Institute for Genetic Medicine at Johns Hopkins University. "She's very emotionally attached to the patient populations. She's always looked for the relevance of her work to prenatal diagnosis of a condition, family counseling, and the development of new and rational treatment strategies."
Christiano's desire to connect with her research subjects was what brought her to Jerusalem last June. Hadassah University Medical Center claims the world's largest collection of patients with genetic hair diseases, including roughly half the documented cases of papular atrichia, the condition Christiano linked to the hairless gene. It also has many patients with alopecia, the disease that triggered Christiano's own hair loss and which remains unsolved. "It's extremely important not just to see the blood or the DNA but to see there are human beings behind this. And they suffer," says Hadassah dermatologist Abraham Zlotogorski, Christiano's principal Israeli collaborator. "It's very important for patients to see there's an international effort to find a cure for their problem." Conditions like papular atrichia are sometimes known as orphan diseases because they lack the frequency to merit much research. "But for patients, this is not an orphan disease," Zlotogorski says. "It's 100 percent of their problem."
When Christiano arrived at the clinic that Friday morning, the waiting room was already filling with the patients whose DNA she knew intimately. Several of the papular atrichia families had traveled from the West Bank and Jordan, braving bureaucracy and highway checkpoints solely for science's sake, as the disease still has no treatment. Emerging from the elevator, the geneticist saw two bald Palestinian girls, ages 3 and 8, who had come from the West Bank with their fathers, cousins in an intermarried family. Their heads were covered with kerchiefs. It was the first time Christiano had ever seen atrichia patients face-to-face. "Oh, my God," she whispered. "They're beautiful."
For the next five hours, the Hadassah conference room was a buzz of activity. Patients came and were examined. Most who were bald covered their heads with wigs or kerchiefs; their embarrassment was palpable. Zlotogorski pointed out the papules (tiny bumps) on the heads, elbows, and knees of the atrichia patients—subtle manifestations that help clinicians distinguish the disease from the autoimmune form of alopecia universalis. Questions and answers were translated into Hebrew, Arabic, and English. As lunchtime came and went, pastries disappeared from the middle of a long oval conference table.
Researchers took blood samples and skin biopsies and sketched out family pedigrees on scrap paper. Patients with alopecia universalis were given steroid shots in their eyebrows in hopes of revving up hair growth. As Zlotogorski injected a 14-year-old Israeli girl—who held her bald mother's hand and flinched at the needle—Christiano watched and winced with her. "It brings back so many memories," she said.
"But you're cured, right?" asked Basel Saad Edin, a Hadassah physician from the West Bank.
"You're never cured," Christiano said. "You wake up every morning and you feel . . ." The sentence trailed off as she patted the back of her head. "Too many memories," she finally said.
"In Arabic, there's a saying: If there's a crisis, sometimes it benefits other people," the Palestinian physician said. He reflected on the international effort fueled by Christiano's own disease—an effort that has brought scientists closer than ever before to finding the genetic basis of alopecia areata and its more extreme variants. "Maybe," he said, "it's a good thing you had this problem."
