Ralf Paus Discusses Current Hair Growth Research
In this article, Follicle Thought talks “all things hair science” with one of the most prolific hair biology researchers in the field, Dr. Ralf Paus.
Dr. Ralf Paus Of The Monasterium Laboratory
A recent publication from The Guardian featuring several of the latest technologies being developed to treat hair loss included some interesting remarks from Dr. Paus. Coincidentally, I had conducted a brief interview with the esteemed researcher before The Guardian article was published and I thought now would be a perfect time to share. For those unfamiliar with Dr. Paus’ work in the hair industry, he is currently appointed as Professor of Cutaneous Medicine at the University of Manchester, Professor of Dermatology at the University of Miami Medical School, Founder of the Monasterium Laboratory, and he also serves on various Scientific Advisory Boards for biotech companies such as Follicum.
For the Q&A, Dr. Paus preferred to answer questions pertaining to his recently published journal articles, however, I did manage to ask him which prospective treatment seemed the most promising for hair restoration. It is a rare opportunity to get this perspective from one of the most knowledgeable hair researchers on the planet. You’ll be surprised to hear his answer. Also, make sure to read through the entire section, there may be an update about a popular hair loss drug that is “way” interesting.
Q&A With Dr. Ralf Paus
FT: Many are familiar with the “Sandalore” OR2AT4 research published late last year. Would you say there is potential to develop a more powerful compound to stimulate OR2AT4, perhaps a drug?
RP: In principle, yes. However, one main charm of focusing on olfactory receptors and available cosmetic ligands (i.e. odorants used e.g. in perfumes) is to be able to avoid the staggeringly high costs of developing and FDA-licensing a regular drug – not to mention the adverse effects that, sooner or later, almost invariably turn out to be associated with most drugs.
FT: Are there potentially other olfactory receptors to target besides OR2AT4?
RP: Yes, there are additional olfactory receptors expressed and functionally active in human scalp hair follicles, which are under ongoing investigation at Monasterium Laboratory (www.monasteriumlab.com). Some of this work is funded again by Giuliani/Milano. However, I can not share any details until this work is published, hopefully by the end of next year.
What I can say though is that, based on related findings in Cheret et al. Nat Commun 2018, we are also particularly interested in Sandalore-mediated stimulation of OR2AT4 as a means to up-regulate the intrafollicular production of antimicrobial peptides, e.g. in the context of protecting the hair follicle from bacterial infection (bacterial folliculitis).
FT: You recently published the study “Hair growth control by innate immunocytes: Perifollicular macrophages revisited.” Do you think any groups will pursue targeting pfMACs or immunopathology for hair growth therapies in the near future?
RP: Exactly, targeting pfMACs could indeed become a new paradigm in clinical hair growth modulation (see also Castellana et al. PLoS Biol 2014 & Hardman J et al. JID 2019), quite likely also in the context of inflammatory hair loss disorders, e.g. frontal fibrosing alopecia (FFA). The – as yet unmet – key challenge, however, is how to accomplish this with sufficient selectively for pfMAC by reasonable safe, yet effective topically applied agents. The latter are likely to be drugs. Predictably, this will protract R&D and drives up cost for this line of research until any product can be introduced into the clinic. Therefore, it would be most intriguing to identify cosmetic agents that are capable of modulating pfMACs in a well-targeted manner, depending on whether one wishes to promote hair growth in alopecia/effluvium or inhibit undesired hair growth. (Editor: hint, hint)
FT: You are the founder of one of the most advanced hair labs in the world and review many research projects. Out of topical compounds, stem cell/growth factor injections, or engineered hair follicles, from your perspective which do you see as the most promising area to bring new solutions over the next few years?
RP: For what my (limited & fallible) perspective on this may be worth, even though this technology may actually work in clinical practice one day in the future, I am unenthusiastic about “engineered hair follicles”.
Main reason: even a completely bald scalp probably still has something around 100,000 hair follicles.
The challenge here is to retransform vellus into terminal HFs. To achieve that, cell-based therapy with autologous inductive (!) hair follicle fibroblasts from the dermal sheath or dermal papilla strikes me as efficient & pragmatic. Yet, to become commercially & clinically viable, the above (likely expensive!) cell-based therapy approach is challenged with having to generate results that are significantly better and longer-lasting than current standard therapy with combined topical minoxidil and oral finasteride – a very tall order!
In terms of growth factor injection, I personally find the strategy most appealing & safer to not inject potent growth factors directly (if one applies these repeatedly & long-term, there always is a slight theoretical risk that this might overstimulate e.g. some resident stem cells and thus become tumorigenic in the long run), but rather to down-regulate the intrafollicular production of potent inhibitors (such as SFRP1) of key hair growth factors (such as Wnt or Shh), thus increasing the activity of locally generated potent hair growth promoters like Wnts whose levels remain essentially unchanged. That’s exactly the reasonably safe & effective principle we have shown to work in our Hawkshaw et al. PLoS Biol 2018 study.
I have long felt that the role of epithelial stem cells in re-transforming a vellus into a terminal HF in AGA tends to be overrated, and I doubt that injecting these stem cells will be a game changer in AGA management. Rather, we’d be well-advised to work harder on topically applicable agents that enhance the (reduced) capability of resident bulge stem cells to generate progeny in AGA-affected vellus and intermediate HFs, and, probably even more important, that attract the immigration of resident, inductive fibroblasts from the dermal sheath into the dermal papilla (whose size and inductive power (i.e. secretion of “papilla morphogens” determines hair follicle volume, type, anagen duration, and hair shaft diameter & length).
FT: What is the current status of the WAY-311606 project? It was announced in a Guardian article that Guliani was moving forward with clinical trials for the drug.
RP: If the Guardian did indeed announce that Giuliani was moving forward with clinical trials for WAY-316606 (i.e. a drug that is currently not FDA-approved for clinical application), they must have been ill-informed and mistaken. Instead, to the best of my knowledge, Giuliani is in the process of preparing the clinical testing of certain WAY-316606 analogs as potential cosmetic anti-hair loss agents.
The above image is taken from the famous PLOS study on WAY-316606, displaying how the drug was able to increase human hair follicle length and diameter. Following my discussion with Dr. Paus, I also spoke to a representative from Guliana Pharma who confirmed Paus’ comments about the development of WAY-316606. I’ll have a new article with more information on this subject and quotes from Guliani in the coming week.
Posted in Hair Growth Treatment, Ralf Paus
I thought Ralf’s sentiments about potential therapies/cultured follicles was very interesting. It doesn’t mean that the issues of spacing and cosmetic outcome cannot be solved. This is of course, his own perspective but interesting to hear. What’s nice about it is other researchers will solve those issues, we’ve even heard about scaffolding being created to solve this issue, and Ralf will focus on his preferred line of research which involves regenerating miniaturized hairs back into terminal hairs – this would actually be the ultimate “Holy grail” even beyond creating unlimited follicles. Of course, this still needs work and likely that the first incarnations of this approach will not restore a full head of hair, but only a % of follicles. But in my opinion it’s one of the most fascinating techniques to pursue. For now, engineered follicles still seem to be the most promising treatment option on the horizon.
Also, thought everyone would enjoy the WAY pre-announcement as a bonus to the technological discussion.
But these results wouldn’t be permanent, right? You would either have to keep taking a drug or getting injections? Although TissUse thinks they’ve gotten around this problem?
You mean the theoretical treatment to reactivate dead/dormant follicles? If it’s from a topical most likely yes you would have to keep taking the drug to continue results. Injections would also be continuous but might not be such a rigorous schedule, for example potentially once every few months, or a few times a year. But this is still likely somewhat far away.
I’m not sure what you’re referring to with TissUse? Did you mean TissUse? I think the neopapilla from TissUse would work for a longer period of time but not be a permanent solution.
Interesting discussion, had never heard of the pfmacs before.
Did you know which research line is focused on bringing back the dead follicles?
Yes, the WAY-316606 research is the beginning of this type of research by un-inhibiting the Wnt pathway so it can perform as usual. Paus mentions this will not add more growth factors which could become an issue if too high a level is reached, but will establish the normal level for healthy hair. I’m hoping he would have already identified other gene targets like SFRP1 to promote hair regeneration by now. The original WAY paper was published in May 2018.
So he thinks that fibroblast cells from the dermal sheath or papilla is the best bet for cell therapy. Is any company currently use dermal fibroblasts? Hairclone?
i like the way that turned around quick. “guardian was mistaken about way trials”…
“actually it’s coming out as a cosmetic!” quicker release time is good thing. Nicely done!
Do you have an indication of how long it will take for the way cosmetic to be developed?
I don’t know how long until a product comes out, however, I heard a snippet of a potential timeline to see human results from the Guliana representative, I’ll wait until the dedicated article comes out, but I would say most people including myself would be happy with the timeframe.
If Joseph is happy, I’m happy too! 🙂 Nice article, a testament that this stuff ain’t easy. Sure, we’d all like new treatments yesterday, however in the overwhelming majority of cases it’s not due to incompetence or some grand conspiracy that we don’t.
So DHT-resistant follicles will be a permanent result if it works?
Yes if the follicles are dht resistant they would be permanent result. If they can achieve good density it is all you need, but most likely other future treatments that could revive dead follicles may not work. But for now that would not be biggest of issues. Every solution comes with its own challanges until something better comes around.
Thanks for this FT.
It’s always interesting to hear a specialist talk in general terms on an industry. For me, as a non expert, most of the proposed treatments, in some shape or form seem to be based on creating new follicles, whether that be engineered outside the body and transplanted or by the appropriate cells combining in side the scalp to formulate new follicles. So even though the theory that every bold head has it’s follicles, just no hair growing has been around for years the more realistic potential treatments seem to be around creating rather than reactivating. In my opinion the reactivation theory obviously points towards the silver bullet cure which most people who follow research will probably not believe has been proven possible yet and there’s far more advanced research substantiating that the most likely cure (5-10 years) will be in the form of creating new follicles in some shape or form. The potential cosmetic result issue raised in this article around engineered follicles, there’s nothing to back that up other than the assumption that the results will be comparible to a conventional hair transplant. Organ Technologies have covered this in 2016 and 2017 and don’t feel this is an issue and can obtain a density comparable to the head of hair you previously had. I think it’s important to state that as this comment will discourage your readers. FT, if you have any future contact with a company maybe you can ask them their thoughts on the achievable density of their engineered follicles. By the way, I hope the reactivation theory comes to fruition as it would be the miracle cure. But not enough practicle evidence that this can be done yet.
I agree,
There are plenty of examples of transplants where the density is great and indistinguishable from the native hair.
Look at Elon Musks hair, you wouldn’t know if you didn’t know.
Density issues occur when you’re trying to cover large areas and are limited by the no. of grafts available.
Surely with an unlimited supply of cloned follicles and several procedures, density is not an issue
Welsh (Cymro), do you have any interest in Hairclones pending treatment?
Hi Mattt,
I have one eye on it but not really holding out for it. I made a Frank comment on that by saying if they had the most significant hair growth technology at their disposal they would have raised 3m never mind the 300k they wanted. It’s strange that even though the UK has the legislation to get stem cell therapies through quicker there doesn’t seem to be the same appetite as Japan in this area for any stem cell therapies let alone hair related. There should be 4 or 5 companies fighting to get to the finish line first but there isn’t ?
yes that is true, but right now no one knows if it’s worth 3k or 300M. If this was case there is no such thing as failed drug, no one would invest forthright. That’s what the human experiments will be for. It’s possible the technology is better than replicel etc. Investors don’t know, but it takes a daring one to find out.
So how much did you invest in the crowd fund?
so what does that mean for way316, — that its efficacy is not as promised, and if its going cosmetic route does that expedite release date quicker than clinical trials? how long it would take you think to be released. it seems they are downplaying way 316 effectiveness ??
Yes cosmetic route really expedites things. If it was going to be a drug it would take 4 years. A cosmetic product could potentially be out Q4 next year. The efficacy is fine as reported in the published study they are looking for a cosmetic analog alternative to the drug route. The mechanism of WAY-316606 is as promising as anything else known for hair growth right now.
A couple of new videos on YouTube of the guy using NGF. The latest video actually has an extract from this site. He has reported a bit of shedding but not as bad as what you would potentially get with minoxidil. He is convinced small hairs are coming through not previously there. But I think shedding is to be expected with these sort of treatments. I think you would have to give this a good 6 months to see if it works for you. Plus this guy isn’t dermarolling with this. We have probably all seen the results people are getting using dermarolling with minoxidil. We’ll see.
Thanks for pointing this out. I too am watching for results for the product and have seen other vids from the guy. I also wonder how the response could be improved with dermaroll. I think next vid from guy should start to show a result one way or else.
Frankly, I don’t see anything significant and monumental in the above article. It is just hot air from a luminary in the field of tricholology. All I give a toss about are whether or not these prospective “cure” are going to be effective and affordable.
C,
I think your comments would be echoed by most who come to sites like this. However, this guy mentions WAY and that is FT’s next article. So watch this space. May have some positive news soon.
Great effort, as always FT, but he didn’t say anything groundbreaking here.
Also, regrowth vs cloning debate is pretty much settled and Mr Paus is on the wrong side. We are far far away from even conceiving all the pathways and molecular dynamic in hair fall/growth process. THERE IS NO VALID HYPOTHESIS THAT WOULD TAKE US INTO PRECLINICAL STAGE FOR ANY DRUG DEVELOPMENT ATM.
Cloning skips that part almost completely. They KNOW how to clone HF (multiple companies) growth direction-solved, spatial differentiation-solved. Only problem is price and mass production.
Again, they have problems but they are million miles ahead of you Mr Paus.
Thanks faust. Just to note, every article is not going to have a groundbreaking announcement in it. That would be impossible. There’s probably been a handful of groundbreaking announcements made in the hair growth industry in the last 10 yrs. But, of course the point of the blog is to continue to put out interesting and useful articles. If we stuck to only groundbreaking announcements or clinical trial results there would be maybe 4 articles published a year. I really appreciate your readership, perhaps you may just want to appreciate the article for what it is. Hair biology expert giving his opinion on ways to regrow hair, while describing the methods he’s working on.
It was a great article Joseph, some people are never happy and can always find a pile of crap under the pony. Plus, I’ll take the view on new generation of meds/topicals vs cloning of a longtime, well respected researcher in the field of hairloss over a self proclaimed expert on the internet. Really, all the comments were productive with that one exception. Another guy that leaves me scratching my head for reasons other than seborrheic dermatitis! 🙂
Thanks Yoda I appreciate your kind words and contributions as usual. I think there was some miscommunication in the previous comments and also some people may have been a little disappointed with Dr. Paus’ outlook on cultured follicles. It is only an opinion, though from a very respectable source. In the end, if he’s wrong about the cultured follicles it won’t be a big deal and will turn out great for everyone. I think we should not overlook all of the positive contributions and research he is doing now which could turn into useful cosmetic products e.g. sandalore + new olfactory compounds, pfMACS stimulators, WAY-316606 cosmetic.
Admin I also think Cosmetics will come in the very near future like till end of next year. To the Cosmetics you mentioned dont forget Medipost and Histogen/Allergan and finally we will have a proper drug as well with Polichem very soon.
You’re right. Thanks for reminding me about the Histogen/Allergan potential. I know some users here are also keeping an eye on medipost and the youtube user.
Personally I believe some people are getting a bit ahead of their skis in regards to cultured follicles. Not that it won’t possibly be a viable treatment someday, but when I read guys posts that think they’ll fly over to Japan next year for one time and come back with a full head of hair I believe they are setting themselves up for disappointment. But then again, what do I know, I’m also just some random guy on the internet with an opinion. However, I do my best not to portray opinion as fact.
Exactly, best case scenario here is the cultured follicle companies succeed like we think they would, and Ralf P is successful stimulating natural hair regrowth with the way drug or something better. All of this is good and useful. World needs more than just culture follicles, we need to stop hair loss as well.
has anyone tried sandalore? anyone know of reports of using this product? I am interested if there is a new version of this coming as well.
SO he Said that You Can get tumors of RCH-01 by Shiseido. Thats dangerous news…
He was talking about growth factors which would be more Histogen not RCH-01….but Histogen appears safe it does not seem like there is a chance to get tumors unless someone really over did it. He was just advocating for another way to do it which is the way he wants to do it, with WAY. blocking the things that lead to loss of natural growth factors.
No you can’t. Replicel from their first and only human trial confirmed that RCH-01 safety is indisputable. Biopsy taken from all trial participants over 4 years. No sign of tumours.
I would think with any of these treatments that don’t have long term studies behind it, there is the uncertainty of whether it may cause tumors years later. The exception would be a HL treatment using a drug already in use for another condition that has been thoroughly tested and with a long history of no known cancerous side effects.
This is the unsettling part of all these treatments. It is going to take prob 5 years before we get any type of good solution, but because it is new, we really don’t know with certainty there are no life changing side effects years later. Not a great choice we have to make because I and prob many others wanted a solution yesterday.
I think you make a good point. What I would say is regarding RCH-01 is that 4 year trial was finalised years ago. So they are well over 5 years. Even though Replicel would have stopped monitoring them I’m sure there would still be some kind of reporting process to continue to establish side effects. But in the case of Hairclone repeated treatments are needed. What effect will this have? I think it’s a great point and something everybody should be aware of. Having witnessed someone suffer and eventually die from a brain tumour being bald is by far the best option.
@ADMIN what do You think about The Danger getting Cancer of RCH-01?
I would say it’s unlikely. Replicel did do the 5 year follow up which showed safety and no serious adverse events were reported. https://www.replicel.com/news/replicel-s-phase-1-clinical-trial-for-hair-loss-succeeds-in-meeting-primary-endpoints Replicel also had done biopsies at injection sites after 24 months which showed no signs of tumors. Interestingly, this press release mentions taking some biopsies at 5 years which would be reported soon after, but I never do see the follow up for the 5 year biopsies.
So after 5 years it is unlikely that there could Come Tumor? Or would it Even be possible to get a Tumor Maybe 10 Years After Injektion of rch-01?
What about 12 years, 7 months, 3 days, 6 hours and 18 minutes after the injection? Could a tumor come right then? 🙂
Yoda, You don’t get The question and You Are Making jokes about a very very serious theme. It isnt cool.
The Point i make is: Sure we have 5 Years Safety data. But The question is:
It is possible to have no Signs of tumourgenesis within 5 Years After injection, But After 5 Years there could build a tumor?
I am not a scientist Thats why i ask experience member here.
@yoda: i would like to live more than 5 years But You Can Go on with your jokes If You want.
Dave, I hear what you are saying. It’s interesting because a lot of people on this site lament the FDA rules around trials and how it elongates proposed treatments getting to the masses. However, this is one of the reasons why to provide a safety assurance. Until these treatments live inside humans for a number of years no one will ever know. So from your perspective the best thing would be to wait before going for any proposed treatments to see what happens. But what is clear, stem cells are the medicine of the future for all diseases not just hairloss so like FT said below, tumours are unlikely but not he or even the scientists can guarantee this.
https://futurism.com/neoscope/hat-shocks-reverse-baldness
Welsh, a very sensible reply. As far as you Dave, I don’t worry about things that aren’t on the market yet, may never be on the market and if they are, have the data to back up safety and efficacy. To keep asking the Admin about different timelines until you get tumors seems a bit absurd to me. But if it makes you feel good, so be it!
Yoda, i just wanted to know whether it is possible to scientifically See no signs of tumors within 5 Years But later on it is possible to develop Tumors.
So could it be that after 5 Years The Cell will mutate without seeing any sign of adverse events Directly after injection?
I stumbled across the NGF-574h FB page. On 12 Sept they launched an early bird experience of the product, 300 bottles at a slightly discounted price ($70usd instead of $90usd). They said they would notify immediately when the 300 have gone. At the moment there is no notification on their FB page of this. They are only keeping it open until 6 Oct. Personally I will wait until the official launch but if any one else is interested: https://docs.google.com/forms/d/e/1FAIpQLSePlnSb2eremwaA6li2JSTzdYeoWIced1JBnTLvZNh4AdmhbQ/viewform
Already paid. Time to put this product to the test
Michael will you please keep us posted on your usage and progress when you receive the product?
Yes I will take high quality before and after pics
Update regarding an electrical device fitted into a baseball cap that stimulates hair growth. Could be interesting if it actually can support hair growth better than laser caps. https://folliclethought.com/updates/
Similar to the HairCell company concept or Teslabrush which is on the featured products page.
I hate to be a Debbie Downer but honestly, I’m 65 yrs old. When I was 18 I started loosing my hair. Talking with my dermatologist 47 years ago I said; “I can’t believe they haven’t come with a cure for baldness by now”. My dermatologist said, well they haven’t anything now, but in 10 years they will have it solved. I remember thinking, OMG, in 10 years I’ll be 28, I can’t believe it’s going to take that long. Since then, every year they say a cure for baldness is only 5, most likely 10 years away. And after every 10 years pass, they say again a cure is only 10 years away. That’s been going on for the past fifty (50) years – half a century. How many years have they tried to cure cancer? Imagine how many billions of dollars have been invested (worldwide) to find a cure for cancer, and where are we? Is there a cure for cancer – no. Think of the billions that will have to be invested to cure baldness. At this infancy stage of research, to find a cure for baldness, a multi-billion dollar investment would have to be made. The only entity that would even consider taking that on would be the government. But at this time, neither the government, or especially big business, neither are willing to invest billions toward a cure for baldness. Because of this, research will continue to move along at an impudent pace. Bottom line, a cure for baldness won’t be happening in the lifetime of anyone reading my post. Believing so is just mental masturbation. Is there a cure for cancer? What makes you believe they can cure baldness? Didn’t they just say in this very article, the silver bullet is (at least) 10 years away? Has a hauntingly familiar ring to it – sorry . . .
Steve, I realize at 65 you may not have much hope of seeing a hair loss cure in your lifetime, but I still think you will see a major treatment if not a cure in yours. Others who are in their 20s and 30s who are reading this will absolutely see a cure in their lifetime. The technological advancement from 1973 to 2020 is pretty vast. It is unfortunate that extremely wealthy people have not funded more hair loss cures in the past…
It’s also a misconception that billions of dollars need to be invested in hair loss to find a cure, I think it could be mostly solved with an investment of something like $50M given to the right people. I also didn’t see where it is mentioned that a silver bullet is 10 years away? Anyways, best wishes and I hope to share some meaningful news with you in the next 2 years.