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
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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: 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
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 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.
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
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
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.
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
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
“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
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.”