The October 1999 issue of The Journal of Clinical Investigation
reports an interesting breakthrough by gene therapists, led
by Ronald G. Crystal at the Weill Medical College of Cornell
University in New York. The group reported that they have forced
resting hair follicles of mice into their growth phase by exposing
the cells to the activity of the Sonic hedgehog gene. Sonic
hedgehog, SHH for short, helps guide hair follicles from a resting
stage into growth activity. SHH is particularly important in
the embryonic formation of hair follicles.
Crystal along with collegues Noboru Sato and Philip Leopold
used an adenovirus, one of the viruses that cause the common
cold as a carrier of the SHH gene, to insert the Sonic hedgehog
gene into the mouse's follicle cells. Because viruses can penetrate
a cell and force it to make the products of the genes they carry,
these infectious agents are very useful vehicles for genes of
interest to gene therapists. Crystal's team stripped out the
genes that allow the virus to replicate and replaced them with
a copy of SHH. It is possible to use many other viral vectors
to carry genes into cells.
The virus plus SHH gene was injected into the skin of young
mice whose hair follicles had just entered their resting phase.
To distinguish any unusual hair growth, the team of scientists
dyed the mice's fur bleach-blonde. A few days later, vigorous
tufts of black hair, the mice's natural color, started to sprout
immediately around the sites where the virus had been injected.
Analysis of the follicle cells showed the Sonic hedgehog gene
was active in the injected areas where hair was growing but
Crystal's experiment seems to show that the cells infected
with Sonic hedgehog were forced into their growth phase ahead
of the surrounding follicle cells, which remained in a resting,
So what they have done is brought forward the natural hair
follicle cycle and induced anagen in hair follicles that were
previously in telogen. Presumably repeated application of sonic
hedgehog might keep hair follicles, originally forced into telogen
through disease, in an indefinite anagen phase. In theory this
may have application to hair loss conditions where there is
an increased number of follicles in a telogen state such as
telogen effluvium and early stages of androgenetic alopecia.
It does not have an apparent application to other hair loss
diseases such as alopecia areata, although it does show the
potential for using gene therapy to treat hair loss.
In some news reports they have stated that; "to apply this
therapy to humans, a person would presumably need to have multiple
injections over the scalp”. ..... and ....... "The injections
probably would not need to be repeated until the follicles next
cycle. Human hair follicles take roughly four years to pass
through one turn of the growth, regression, rest phases”.
However, this statement assumes healthy hair follicles with
a normal anagen duration. In hair loss the hair follicles may
be pushed into a telogen state by unknown factors. Sonic hedgehog
application may not remove those factors, so to maintain hair
growth and resist the factors telling the hair follicles to
rest, the gene would have to be applied regularly - just how
regularly is the question. I skimmed the paper and as far as
I could see the hair follicles stimulated into anagen did not
stay in that state. They entered telogen along with adjacent
Also for humans, hair grows in mosaic pattern - not as a wave
pattern as occurs in mice. This means not all hair follicles
are at the same stage - not all are in telogen at the same time.
So to keep different hair follicles at different stages in the
hair cycle all in anagen, there would have to be regular maintenance
injections. Given that humans have a mosaic pattern of hair
growth I expect that the response to SHH injection for humans
would be much less apparent than shown in the mouse study. In
the mouse study all hair follicles were in telogen at the time
of injection. In non-bald humans only 10% of hair follicles
are in telogen at any one time and so only 10% can respond to
At some point soon there will probably be development of a
vector to use in a topical application that will introduce whole
genes to hair follicles. This will be better than using injections
to apply a gene therapy. Recently at the European Hair Research
Society conference Dr Robert Smart reported introducing parts
of a gene to hair follicle melanocytes using a topical liposome
application. Right now, whole genes are too big to penetrate
the skin using the liposome preparation - but I expect they
are working to solve that problem.
Over activity of SHH can cause basal cell carcinoma – a common
skin cancer. So, I won't be volunteering to try this as a treatment.
What would be better is to find a gene regulator that switches
on the endogenous Sonic Hedgehog rather than adding extra sonic
hedgehog as the investigators have done here. Even then there
could be a risk of switching on Sonic hedgehog in the wrong
place and inducing carcinomas. Many problems remain to be solved
before any clinical trial could be contemplated.
This is a study that someone had to do sooner or later. Watch
over the next couple of years as copy cat papers using different
genes, known to be involved in hair follicle development, will