Hair today, gone tomorrow? Teasing out details of hair growth.

From the strength-giving locks of the biblical Samson to the elaborate updo of a geisha and the neon, spiked styles of punk rockers, hair remains an important part of a person's self-image and one of the most obvious forms of self-expression.

People may cut their hair, dye it, perm it, and style it. But unless they resort to wigs and hair transplants, they are stuck with the quantity of hair that nature gives them--and takes away. That fact of life becomes especially vexing when people lose their hair to chemotherapy, diseases that attack hair follicles, or simply aging. And there are few options for hirsute women, who have an overabundance of hair and may even grow beards.

At the moment, scientists don't fully understand the molecular orchestrations that underlie hair growth. That hasn't stopped them from providing a few drugs for hair-related problems. The two medications now available to treat hair loss, known commercially as Rogaine and Propecia, were developed after researchers fortuitously observed hair growth as a side effect of drugs designed for treating hypertension and enlarged prostates. Likewise, the only drug on the market that slows hair growth came as a spin-off of a search for an anticancer drug.

In the past few years, however, researchers have begun to tease out the molecular signals that cause hair to grow and fall out. Unraveling such signaling, they hope, will lead to new ways of addressing the needs of people with either too little hair or too much.

"Hair disorders aren't necessarily important from a life-or-death situation ... but we are defined by how we look, in terms of gender and of youth," says Ricardo Azziz, a specialist in hair disorders at the University of Alabama at Birmingham. "Our job is not only to make people survive but to give them a better quality of life."

Whether it's the light, downy hair on a woman's arm, the short, curly hairs on a man's chest, or the longer hairs on either gender's head, each hair grows from a tiny, cell-lined skin indentation called a follicle. By adulthood, the skin hosts all of the follicles it ever will have naturally.

A hair follicle consists of three concentric cylinders. The central cylinder, the hair fiber, is created by the rapid growth and death of cells at the follicle base, which make proteins such as keratin (SN: 8/25/01, p. 124). The outermost cylinder is known as the outer root sheath, a structure that separates the hair follicle from the surrounding skin. The middle cylinder, the inner root sheath, shapes and guides the hair as it grows outward. A person's hair will be straight if this middle cylinder is round and will be curly if the cylinder is flattened.

An eyebrow hair grows slowly and falls out after just a couple of months. In contrast, a hair on a person's head can extend many feet long because the follicles there stay in the growth stage for 6 to 10 years.

One theory has it that such long-term growth cycles operate on an internal clock that's independent of the seasons or temperature. Some scientists suggest the timer is set by the dermal papilla, a structure containing dividing cells at the base of the hair follicle. Others argue that the clock controlling hair growth is part of a bulge lying just to the side of the hair follicle. Still others doubt whether this timer exists at all.

Over the past 50 years, scientists have pieced together the basic steps in the hair cycle anywhere on the body. The initial step, anagen, provides the active growth of the hair fiber, during which cells at the base of the follicle rapidly divide. In catagen, the hair follicle stops producing the fiber and regresses, shrinking dramatically. Telogen is a resting stage.

The process of shedding the hair is also a distinct stage, argue Kurt S. Stenn of the Skin Biology Research Center at Johnson and Johnson in Skillman, N.J., and some of his colleagues. They call it exogen. Stenn notes that "shedding is probably the most important aspect of hair growth from a patient's view." But other scientists aren't convinced that hair loss requires a unique step; most hold that hair falls out during telogen.

Normally, the hair cycle continues throughout a person's life. In most people not showing hair loss, about 90 percent of the hair follicles on the head are in anagen at any given time. Anagen can last for a few weeks to a decade, catagen for 14 to 21 days, and telogen for 1 to 3 months.

Even bald people have hairs on their scalp, but those hairs are unusually fine and short. Furthermore, the proportion of hair follicles in the regression and resting stages increases. Androgens, or male sex hormones, are behind much of such hair loss in men.

Unusual hair loss or growth may be a sign that something else is wrong. Loss of hair may signal thyroid disorders or lupus, an autoimmune disease. About half of women who have abnormal facial hair have higher-than-normal concentrations of androgens in their blood, a condition that may signal reproductive disorders like polycystic ovary syndrome (SN: 7/8/00, p. 31).

Hair disorders, though, don't always spring from underlying diseases. Many people suffer from transitory hair loss when they undergo cancer chemotherapy, which attacks the rapidly dividing cells found in hair follicles, as well as in tumors. Another common cause of hair loss is alopecia areata, an autoimmmune attack specifically targeting hair follicles. This condition, characterized by inflammation of the affected hair follicles, affects 4 million people in the United States.

To design treatments for hair disorders, researchers need to understand the pattern of molecular signals behind hair follicle cycling. People with too little hair, for example, might benefit from therapies that stimulate follicles into anagen or inhibit catagen. A person trying to get rid of hair might want compounds that drive hair follicles into catagen or telogen.

One approach that shows potential focuses on a natural product of hair follicles. It's called parathyroid hormone-related peptide, or PTHrP. Several years ago, Michael F. Holick of Boston University Medical Center demonstrated that a chemical that blocks PTHrP stimulated hair growth in mice. Injections of the PTHrP blocker triggered hair follicles in the resting state to switch to growth, and it also delayed the transition to follicle regression.

"There are lots of substances known to regulate the growth of hair and the differentiation of hair" from fine, light hairs to thick, dark ones, notes Azziz. "PTHrP seems especially promising because it is almost an on-off switch."

In the August JOURNAL OF INVESTIGATIVE DERMATOLOGY, Holick reports that in mice, injections of PTHrP blockers before chemotherapy increased the number of hairs that grew properly after chemotherapy. The treatment also accelerated regrowth of cells within damaged follicles.

The blockers delayed hair loss and limited it to 20 percent of the loss in mice treated with a placebo.

In contrast, injections of a PTHrP mimic shunted hair follicles into catagen, making them more sensitive to chemotherapy. However, the compound also sped the hair cycle through catagen and into anagen. So, mice receiving the PTHrP mimic did lose hair but then grew their normally pigmented fur coats back faster than did a control group treated with chemotherapy and a placebo.

"PTHrP could very well be the master switch for regulating hair growth," Holick says. "I'm hoping this will be a major new approach that will be helpful for treating hair growth abnormalities, both too much and too little."

At a meeting of the Endocrine Society in Denver last June, Holick reported that topical lotions of a PTHrP mimic and of a PTHrP blocker work as effectively as injections in mice. Because they're applied locally, lotions like these decrease the likelihood of side effects, he says.

Holick and his colleagues plan to examine the effects of PTHrP and a PTHrP blocker on hair growth in people. They have to be cautious, however.

In one of its normal roles, PTHrP prevents skin cells from dividing too quickly. Preliminary work suggests that topical PTHrP slows painful, unsightly skin overgrowths in people suffering from the skin disease psoriasis, Holick says. Therefore, blocking PTHrP function in healthy people to stimulate hair growth might permit cells to grow unchecked, potentially provoking cancer.

So far, however, no malignancy has been observed in the mice treated with PTHrP blocker, Holick reports.

Although PTHrP is intriguing, it's not the only compound involved in the regular cycling of hair follicles. For example, without a compound known as beta-catenin, the progenitors of the keratin-producing cells can't specialize, George Cotsarelis, a dermatologist at the University of Pennsylvania School of Medicine in Philadelphia, and his colleagues reported in the May 18 CELL. A strain of mice that lacks this compound never grows hair.

Other researchers are exploring a family of proteins known as Wnts, which was originally identified in studies of development in the Drosophila fruit fly (SN: 7/7/01, p. 13). Hair follicles grown in laboratory dishes require these proteins to keep growing as they do in anagen, say Bruce A. Morgan and his colleagues at Harvard Medical School in Boston.

Elaine Fuchs of the Howard Hughes Medical Institute at the University of Chicago and her colleagues had previously demonstrated a role for Wnts and beta-catenin in the initial growth and development of hair follicles in embryos. It's as if the layers of embryonic cells need to "carry on a telephone conversation [to develop into a hair follicle], and the wires carrying the message are Wnt signals," Fuchs says.

She's shown that Wnts bind to specialized receptors on a cell's surface, thereby preventing proteins inside the cell from breaking down beta-catenin. This compound then joins with other molecules to activate specific genes. The proteins that they encode cause the cells to initiate hair formation--for example, by producing keratin.

Further evidence for the importance of the Wnt pathway emerged when Fuchs' group created genetically engineered mice that couldn't degrade betacatenin. This essentially made the cells behave as though they were constantly bombarded with Wnt signals. These mice developed new hair follicles as adults and so sported lush coats. As the mice aged, however, they also developed benign lumps resembling human scalp tumors.

Fuchs and her colleagues have altered different factors in the Wnt signaling pathways to coax precursor cells in hair follicles to specialize into either skin cells or the cells that make up the hair follicle and a nearby gland. The researchers described these findings in the July 1 GENES AND DEVELOPMENT. The implication, Fuchs says, is that Wnts play an important role in hair cycling, as well as in the development of hair follicles.

The same caution must be applied to potential treatments based on Wnts and beta-catenin as to those based on PTHrP. Animal studies have linked Wnts and abnormal amounts of betacatenin to the growth of malignant tumors of the colon, liver, breast, and reproductive tract.

To develop treatments for hair disorders while minimizing cancer risk, Fuchs suggests supplying Wnts in a pattern that mimics nature's precisely controlled delivery. Alternatively, effective treatments might come from interfering with steps in the Wnt cascade other than beta-catenin.

New molecular signals for hair growth and cycling are being uncovered on a regular basis. "We're living in a golden age of hair research," says Cotsarelis. "We know so much more than we did 5 years ago ... but there are still many unanswered questions."

The connections between cancer cells and hair cycling may not be surprising since both involve systems of rapidly dividing cells, notes Barbara M. Mathes of Bristol-Myers Squibb in Princeton, N.J. Mathes ran the clinical trials of Vaniqa, a drug that slows hair growth by interfering with the formation of amino acids needed for cell growth. The drug was originally developed as an anticancer treatment.

"If we can figure out the molecular links [between cancer and hair cells], we can learn a lot about manipulating cell cycles ... and the consequences of such manipulation," she says. That could be useful in developing safe, new drugs for hair disorders.

Meanwhile, on a more fundamental level of science, a growing number scientists are beginning to look at hair as an accessible model for various biological processes, such as organ development and communication between different kinds of cells.

Fuchs predicts that within a few years, despite the complexity of molecular signals involved, researchers will understand what compounds control the regular progression of hair follicles from growth to regression to rest and back again.

"It's like putting together a puzzle," she says. "In the early stages of trying to understand a molecular process, or put together a thousand-piece puzzle, it seems hopeless because there are so many pieces. But as you put together more of the puzzle, it actually gets easier to see patterns."