Hair Today, Gone Tomorrow?

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.”

Hair follicles

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: Chemistry of Colors and Curls). 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.

Promising approach

One approach that shows potential focuses on a natural product of hair follicles.

It’s called parathyroid hormonerelated 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.

Specialized cells

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: Telltale Heart). 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 beta-catenin. 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 beta-catenin 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.

Molecular signals

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.”