As the partner of a 40-something male, I’m acutely aware of the hair-loss horizon looming large in our house. With the first signs of a receding hairline come furtive glances in the bathroom mirror, then throwaway remarks about shaving it all off.
Pretty soon, we’ll be stocking up on scalp cream and hats. Going bald is no joke, though, as the now-retired American body-image expert, Prof Thomas Cash, showed in a 2001 study. Cash convinced 145 customers of Virginian barber shops and hair salons to visit his lab, where he checked the extent of each man’s hair loss and asked them how they felt about it.
Men who had more severe balding were less satisfied with their hair, but also with their overall appearance, admitting to feeling self-conscious and unattractive, while actively coping by restyling their hair, trying to dress better and embracing the aforementioned hats.
And while Cash’s study focused on men’s hair hang-ups, plenty of women have to confront hair loss too. In fact, according to Dr Christina Weng, a dermatologist in Boston, Massachusetts, and chief medical officer at Los Angeles-based company Pelage, which is developing a new drug to treat the condition, the majority of patients she sees for hair loss are women.
“Hair is obviously a big part of identity so it’s really distressing and the treatments are very limited for female patients,” she says. In contrast to men, who lose their hair in the classic pattern we’ve come to expect (the receding hairline and bald spot) women are more likely to have thinning across the whole scalp.
Either way, the widespread psychological impact of hair loss makes it a condition deserving of better solutions. Existing hairloss medications have been around for years and don’t benefit everyone who tries them.
Meanwhile, hair transplants may be a great solution for the celebrities of the world, but they’re not affordable for most of us. All of this means that scientists are still seeking new ways of saving our scalps.
In the genes
As with many conditions, treating balding depends on knowing what causes it. That’s something scientists are still working on. What we do know is that it’s a complex picture involving ageing hair follicles, hormones and stress – as well as whatever genes our parents passed on.
More than 380 sites in the human genome are known to play a part, although this large collection doubtless boils down to fewer mechanisms that could be targeted to develop new treatments.
“That will somehow merge into a number of pathways and maybe a number of main regulators and switches,” says Dr Stefanie Heilmann-Heimbach from the University of Bonn in Germany, whose work focuses on the genetics of hair loss.
Since the human genome was sequenced, scientists have uncovered strong links between balding and genes on the X chromosome that influence the body’s response to testosterone.
Evidence for a hormonal link emerged much earlier, however. In 1960, the anatomist Prof James Hamilton noticed that mentally disabled men castrated in American prisons (a shockingly common practice associated with the eugenics movement) didn’t go bald.
Moreover, those who had a family history of balding started to lose their hair if they were given testosterone. The role of testosterone became even more intriguing in the 1970s when a rare ‘gender-switching’ condition was discovered in families in the village of Las Salinas in the Dominican Republic.
Children with the condition are initially brought up as girls, but develop male genitalia during puberty. As adults, however, their prostate glands remain small and they don’t lose their hair like other men.
When US scientists studied how these people metabolise testosterone, they appeared to have normal testosterone levels while, crucially, lacking the enzyme needed to convert the hormone into its more potent form: dihydrotestosterone (DHT).
It’s DHT that’s responsible for the development of male sex characteristics in the womb and, later, acne and hair loss. Both DHT and testosterone stick to receptor molecules, called androgen receptors, whose production we now know is housed in the same region of the X chromosome that links to balding.
The triggering of these receptors all over the body (including in those associated with hair follicles) mediates the hormones’ effects. DHT binds more tightly to the receptors than ordinary testosterone and people whose genes make them more sensitive to DHT, or who convert more of their testosterone into it, face a greater risk of going bald.
DHT accumulating in hair follicles is considered key to the chain of events that eventually leads to a bare scalp. This process centres on the ‘shrinking’ of hair follicles, as they spend less time actively growing and more time in the resting phase between one cycle of hair growth and the next (see ‘The hair growth cycle’, p64).
“Usually the new hair cycle is switched on and there’s a regrowth of the hair,” says Heilmann-Heimbach. Whereas in balding, she says, the follicles spend more and more time resting between cycles, becoming shorter and shorter, until eventually they fail to breach the scalp at all.
A few decades back, the enzyme that converts testosterone to DHT – 5-alpha-reductase (5AR) – became a target for pharma companies as it was presumed that suppressing it could treat men with conditions like an enlarged prostate and hair loss.
In 1992, these efforts led to the approval of the first 5AR blocker, finasteride, which remains one of only two widely approved hair-loss treatments – the other being minoxidil, a drug whose action isn’t fully understood.
Both offer limited benefits and neither come without side effects. In finasteride’s case, the side effects can’t be glossed over: erectile dysfunction, depression and suicidal thoughts. The drug is also not prescribed for women, largely due to risks to unborn babies (though benefits for postmenopausal women are being explored).
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New approaches
Testosterone may be essential to the balding process, but as Heilmann-Heimbach notes, interfering with testosterone is “not the ideal option” for treating the condition, precisely because of the hormone’s widespread effects.
So, alternative solutions targeting other, or multiple, biological pathways are in demand. One increasingly popular experimental treatment is platelet-rich plasma (PRP) therapy, in which a whole bunch of components with restorative potential are concentrated from the patient’s own blood and then injected into their scalp.
But while the therapy has shown promising results and is safe for men and women, it’s not clear exactly how it works or what the standard treatment regimen should be. Plus, it’s impossible to predict who it’s going to work for – a problem for such an expensive treatment.
As Weng points out, “[You might pay] $800-plus (around £600) a pop for a series of six injections and then maintenance injections thereafter. So the cost really adds up and you don’t know if you’re going to be one of the folks who respond until six treatments in.”
Platelet-rich plasma (PRP) therapy is one of a growing number of new ‘regenerative’ treatment approaches intended to stimulate hair regrowth through growth factors and other components, which experts think may tackle inflammation, reduced blood supply and the altered hair growth cycle in thinning hair.
Many regenerative approaches use stem cells, either in an attempt to freshen up ageing hair follicles’ stores of stem cells, which are supposed to generate new hairs, or as a source of molecules with the desired regenerative effects.
“We think that by providing stem cells we could restore the population that has been diminished,” says dermatology chief Dr Eduardo López Bran from the Hospital Clínico San Carlos in Madrid, Spain, who believes that stem cells could offer longer-lasting benefits than existing medications.
In August, López Bran and colleagues at Complutense University of Madrid published a study outlining the latest advances in regenerative hair-loss therapies, highlighting several examples where stem cells were collected from patients’ excess fat tissues, which offer more accessible stores than sources like bone marrow and teeth.
These therapies can essentially use fat from your bottom to regrow the hairs on your head. In 2020, plastic surgeons and dermatologists in the US treated a group of 71 men and women with stem cell-enriched fat, collecting the fat via liposuction, processing it to concentrate the stem cells and then injecting it back into the participants’ scalps.
The treatment increased hair growth over 24 weeks (albeit with a possible need for repeat treatment after a year) and is now being developed by US company Bimini Health Tech under the name Kerastem.
Simple methods, better results
However, it’s becoming clear that what stem cells produce when they’re cultured in the lab – their so-called ‘secretome’ – may be more practical for treatment purposes than whole stem cells, which have to be kept alive.
Recent trials suggest such secretions can increase both hair density and thickness, with better results the longer treatments last. In one trial, patients receiving laser therapy for hair loss also got a preparation made from stem cells (or a placebo) applied to their heads.
Those who received the rejuvenating elixir grew an extra 14 hairs per cm2 compared to two per cm2 with the placebo. So what’s the secret of the secretome? Essentially, it’s a collection of molecules that scientists hope can manipulate key biological pathways involved in hair growth.
One such pathway is the ‘Wnt’ pathway, which Heilmann-Heimbach’s genetic studies have linked to hair loss. “Wnt signalling is an important regulator of the hair growth cycle,” she says.
“And what genetic studies show is that men who are balding more frequently have particular genetic variants in or near genes involved in Wnt-signalling.”Intriguingly, it’s thought the Wnt pathway may also interact with testosterone-related pathways.
As well as individual molecules, many cells (including stem cells) also release bigger bubbles of molecules, seemingly to communicate with cells elsewhere in the body and to transfer useful cargoes to them.
These ‘exosomes’ were only discovered around 40 years ago and thought of as cellular ‘garbage’, but some scientists now see them as potential treatments for everything from Alzheimer’s disease to bone cancer.
Exosomes from the stem cells of healthy human hair follicles have been shown to alter the hair regeneration cycle in mice by teasing follicles out of their growth phase and delaying the shedding phase, a neat trick apparently accomplished by hair-growth-regulating molecules – including those in the Wnt pathway.
Dr Mert Ersan, a plastic surgeon at Yeditepe University Hospitals in Istanbul, Turkey, has just completed a trial aiming to treat baldness using exosomes from stem cells in foreskins. While Ersan couldn’t divulge anything more about the trial before the results are published, he confirmed that it’s “one of the first in a clinical context.”
New awakenings
If you don’t fancy fixing your hair with your own fat or other people’s foreskins, however, there may one day be regenerative options that resemble more traditional medications.
Pelage recently attracted investment to continue clinical trials of its topical treatment for hair loss, PP405, which Weng says delivered “fantastic” results in initial safety trials in humans.
The drug works by targeting stem cells already living in the hair follicles. In healthy hair follicles, these stem cells maintain a “mysterious lifestyle”, says Dr William Lowry, Pelage co-founder and stem cell expert at the University of California in Los Angeles.
“They wake up at the start of a new hair cycle to produce very rapidly dividing cells that go on to make a new hair and then they return to quiescence a couple of days later.”
In ailing follicles, however, they can get stuck in the resting phase of the cycle and carry on sleeping.
What Lowry’s team discovered is that the sudden awakening of hair follicle stem cells is associated with metabolic quirks that seem to be particular to stem cells, which can be manipulated by the right drug molecules to shake the cells out of their slumber.
While such drug molecules could also be used to activate stem cells in other areas of the body, Weng says PP405 has been specially engineered to penetrate the hair follicle. The drug can be incorporated into easy-to-apply gels or creams for home use – an advantage over injections that can only be given at a clinic.
Reviving the hair’s indigenous stem cells is easier than relying on stem cells that have to be cultured outside the body. “Cell-based therapy is just much more complicated logistically,” says Lowry.
“Maybe, one day it could be a way to restore follicles if you’ve lost all your follicles, but for most [regular male or female pattern baldness] the stem cells are still there and so our approach is just to wake them up.”
Meanwhile, tissue regeneration experts from other fields are exploring solutions that don’t focus on stem cells at all. At the COMSATS University Islamabad in Pakistan, Dr Muhamad Yar has devoted much of his career to finding better treatments for burns and ulcers.
One of the problems he has been trying to solve is poor blood supply to wounds, which can impair healing. Poor blood supply affects ageing hair follicles, too. So, when he came across a natural molecule that appeared to help restore blood supply, it occurred to him it might also be a good bet for hair regrowth.
This 2-deoxy-D-ribose (2dDR) molecule is a sugar that forms part of our DNA and is already available from companies stocking scientific supplies.
“We were very happy to see that we could buy this at kilogram scale from various companies,” says Yar. “So it was really easy for us to buy and use it.”
The implication being that it could provide a quick, and possibly cheap, option for a new treatment. Working with researchers at the University of Sheffield in the UK, Yar made a gel containing 2dDR that they tested on mice.
It turned out to be as effective as minoxidil and Yar suggests it should have fewer side effects, since it’s “already in our bodies anyway, so it’s not something strange.”
Still, it’ll have to undergo testing in humans before making its way onto pharmacy shelves. The question is, then, can today’s 40-somethings feel any more hopeful about saving their 50-something hairlines?
Well, López Bran expects some new stem cell-based therapies to reach the latter stages of clinical trials in the near future, while PRP, he says, is likely to be approved soon. Meanwhile, women’s options look to be expanding with companies like Pelage testing their products in both sexes.
For Heilmann-Heimbach though, the chances of finding a cure for balding increase along with each new gene and biological pathway we can link up in the chain of events that causes it. “Balding is something we see every day,” she says.
“Yet in biological and genetic terms, we’re still a bit in the dark – we have some clues, but it’s not the full picture.” In other words, if we’re going to stop hair loss, we’re going to have to get to the root of it.
About our experts
Dr Christina Weng is a dermatologist based in Boston, Massachusetts, and is Chief Medical Officer at Pelage and Dermatology Instructor at Harvard Medical School.
Dr Stefanie Heilmann-Heimbach is a male-pattern baldness expert working at the University of Bonn in Germany. Her work has been published in journals such as Nature, PLOS One and Experimental Dermatology.
Dr Eduardo López Bran is a dermatologist who works with the Hospital Clínico San Carlos in Madrid, Spain, and is the founding director of Imema Clinic in Madrid. His work has been published in Stem Cell Research & Therapy, Acta Dermato-Venereologica and Australasian Journal of Dermatology to name a few journals.
Dr William Lowry is the Pelage co-founder and a stem cell expert at the University of California in Los Angeles. His work has been published in the Journal of Investigative Dermatology, Neuron and Science to name a few journals.
Dr Muhamad Yar is an Associate Professor at COMSATS University Islamabad, Pakistan. He is an expert in finding better treatments for burns and ulcers. His work has been published in the Journal of Biomedical Materials Research Part B: Applied Biomaterials, International Journal of Polymeric Materials and Polymeric Biomaterials and International Journal of Molecular Sciences.
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