Q&A with Dr. Aaron Gardner

[PinotQ]

Dr. Gardner since it's known that injecting cells can prompt hair to grow using the follicles that already exist in the skin, wouldn't it be better to focus on how to produce hair cells with good inductivity and then injecting those cells into the skin so they can prompt hair to grow through the existing follicles rather than focusing on how to grow whole follicles and then having to implant the whole follicle into the skin?

If you inject the cells instead of whole follicles then you are able to grow the hairs through the follicles that are already in the skin which would solve a lot of problems that come up when you inject whole follicles into the skin.

I agree that this sounds like the quickest most direct route to the goal line. Assuming that the lack of success by Aderans and Replicel to date has been due to the lack of inductivity, and given that it is now know how to obtain as much as 40% inductivity, it sounds like the Taiwan clinical trial is testing whether this will rejuvenate miniaturized follicles. I would appreciate Dr. Gardner confirming this and possibly supplying a link or 2 regarding this trial.

[hellouser]

I agree that this sounds like the quickest most direct route to the goal line. Assuming that the lack of success by Aderans and Replicel to date has been due to the lack of inductivity, and given that it is now know how to obtain as much as 40% inductivity, it sounds like the Taiwan clinical trial is testing whether this will rejuvenate miniaturized follicles. I would appreciate Dr. Gardner confirming this and possibly supplying a link or 2 regarding this trial.

Gremlin pointed out something particularly interesting on the topic of Replicel with respect to the availability of treatments after a Phase I safety trial:

The title of Replicel's post about their Japanese expansion is "A new course of action" - I do not think anyone, besides the people who are in the company, can guess what that means besides that they are moving down another path hence the phrase "new course of action." Furthermore, as to my understanding of the Japanese Regenerative Medicine Law, according to Market Watch - "Conditional approval by no means implies that regulatory approval process is over. It simply allows the therapy to be made available to patients earlier in the process, and for the sponsor company to begin commercialization and obtain reimbursement." Conditional approval can be obtained after completing phase 1 - so Replicel has completed phase 1, hence I believe that they are eligible to apply for conditional approval. They can continue doing trails but my understanding is that it will enable them to start administering it to patients during this process.

[sdsurfin]

Follicle creation question

Dr. gardner, I just thought of this, and was wondering if you could shed some light:

Aren't our follicles induced and created as embryos? Even in babies the hairs are vellous for a while, so don't our follicles develop and grow with the rest of our bodies? When Jahoda/Christiano grew that hair in foreskin, they say that it was smaller etc because of gene expression. But what if the DP cells are simply doing a perfect job, and inducing the type of follicle that would grow on an embryo? In other words, maybe the DP cells, having been disassociated from each other and the rest of the body/follicle, now "think" that they are at their most basic form, in an early stage of human development, and create a follicle germ that is appropriate for an embryo/baby and not a full grown human, as dictated by the age information of all the surrounding tissues.

Is it possible that the DP cells have a certain amount of information regarding hair induction, but that the type of hair produced is based on signaling that is age/development linked, and comes from a number of different cells that surround the DPs? In my mind, there is a time-based aspect to baldness that is being overlooked, and must carry to the cellular level. what makes hair cells suddenly decide to start miniatuirizing? we know the triggers, but what cells or signals are dictating the biological clock? It would seem to me that the inductivity and type of hair induced by any one given cell would depend on the information stored in that particular cell, and that in order to grow a hair that is more globally correct for a grown human, you would need more global information. Not only that but if you were to use epithelial or fat cells to help trigger proper induction and gene expression, wouldnt those cells need to be from the right place -ie and area of the scalp that produces good hair?) Is this stupid?

Also, I was looking at the anatomical structure of the human head, and the fact that the male bald zone correlates to basically exactly the part of the head that has no muscle on it, and where the galea is (the "safe" zones have underlying muscles) seems like more than a coincidence, and makes me think even more that the hair follicle cells themselves might not be the biggest players in triggering hair growth/baldness. Except for the areas related to sexual development, our bodies seem to be most hairy in areas where there is lots of bulk muscle, and I guess thus also more fat (upper thighs, calves, stomach, pecs, etc). Women's bodies seem to be similar, but generally maybe sexual selection made them less hairy as a whole. Maybe having hair on parts of the skin that do not overlie muscle/fat/orifices (and the MPB zone of the scalp seems to be one of the most un-muscular and fatty parts of the body) is the most unnatural, and MPB is basically the body's general reaction to hair in areas where it is not needed to keep complex networks of blood vessels and muscle thermoregulated? The fact that other primates with similar muscle structure to ours also go bald might suggest this is true. is it then possible that the chemical signals for baldness might begin in the underlying tissues, and hormones and other age dependent chemical signals trigger the communication between the different tissues to give off the "lose hair now" signal? If this is the case, is it possible that gene expression and inductivity is more dependent on a communication chain/loop between say muscle, fat, blood, and hair cells than it is on just the freshness of a DP cell or other hair cell? In other words, maybe when the DP cells lose their inductivity upon culture, maybe it's not just because they are separated from each other, but also from an entire time-related feedback loop between all the body tissues that reinforces genetic expression. In other words, maybe it's not the conversation between two DP cells, or two DP cells and two epithelial cells, or the conversation between all the hair cells, but the conversation in that region of the body as a whole that is dictating the nature and behavior of each DP cell. sorry I know this was a very long question/ramble, and I don't really know if it's nonsense or not, but if you get a chance to read it I'd love to know if there's anything valid here. thanks!


PS I was reading an article today about how physicists now posit that things (ie a cup of coffee) lose their heat over time because they are increasingly entangled at the quantum level with other particles in the room, and essentially become more like the "whole." In other words, the entanglement dictates the arrow of time. (this would explain why a cup of cold coffee doesn't suddenly become hot in a cold room that was once hot) The idea that structures become less and less unique based on their exposure to their environment and increasing entanglement got me thinking about DP cells too-
If when you take DP cells out of the body their particles are becoming increasingly disentangled from each other and also from the particles in the surrounding native scalp tissue, would it not make sense to try to keep as much of these connections in proximity throughout the entire process? Maybe all of the cells in the follicle and surrounding tissue need to be cultured together in order to retain that amount of entanglement/uniqueness. When a hair is transplanted traditionally, it is kept within an environment of its native scalp. for a few thousand cells, this surrounding plug is relatively vast. however, these hairs eventually falter also, begging the question of where those signals to die off are coming from. maybe there is no direct signal, but the plug as a whole is slowly sharing chemical signals or even just becoming entangles at the quantum level with the surrounding balding tissue. Now I might be getting really silly, but trying to think outside the box

[Armandein]

A hair as a whole

Very good dissertation sdsurfin
Embryo have hormones around all tissues, different that prepubertal childrens
Hormones can be make in the sebaceous gland from cholesterol
BTW Note that a transplanted hair have also a sebaceous gland attached.

Excuse me Desmond Morris, but We are not the naked ape but the miniaturized body hair ape. It is a great difference. We all born with all our surface covered with hairs, exception palms of feet and hands etc., only the scalp hairs grow in the early months, why? Is it possible that these scalp hairs have an operative sebaceous gland attached at the hair? We have not androgens circulating in the blood before puberty, body hairs only star to grow with androgens, sebaceous glands are functionally only with hormones, interesting,,,,,
I have the hunch that sebaceous gland and sebum play a pivotal and key role in order to make the miniaturized hairs to terminal hairs. I am talking about chemical signals, etc. Call me fool but I imagine sebum as a nutrient of hair, ask you why sebum travel downward to the inner part of pilosebaceous unit?, and more important, take note that is a closed road if it don’t sprout with the same physical hair shaft.

[Sogeking]

Hello Dr. Gardner. You answered all of my questions already. So I just want to sincerely thank you for coming here and educating us. And good luck with your work.

[KJ1982]

Dr. Gardner, I was wondering if there was any information that you could provide concerning application for participation in clinical trials regarding your work.

For example, do you know when "Team Jahoda" would consider volunteers for involvement in trials?

I myself live in the UK and would be very interested in any possibilities concerning this matter.

Many thanks,

KJ.

[JJJJrS]

Hi Dr. Gardner. Thank you for taking the time to respond to all of our questions!

I have a general question. Over the last few years, there's been a number of discussions on hair doubling techniques. I'm not an expert in hair science by any stretch, but at the most basic level the claims are that different parts of the hair follicle contain cells that can induce hair growth and that by splitting the hair follicle at these points, you can in effect, double or even multiply the follicle.

Can you comment on the viability of such a treatment, both now and possibly in the future? How does the theory hold up in your eyes?

Once again, thanks for talking time out of your busy schedule to answer our questions! It's greatly appreciated.

[534623]

Hi Dr. Gardner. Thank you for taking the time to respond to all of our questions!

I have a general question. Over the last few years, there's been a number of discussions on hair doubling techniques. I'm not an expert in hair science by any stretch, but at the most basic level the claims are that different parts of the hair follicle contain cells that can induce hair growth and that by splitting the hair follicle at these points, you can in effect, double or even multiply the follicle.

Can you comment on the viability of such a treatment, both now and possibly in the future? How does the theory hold up in your eyes?

Here you can find THE "comment" by Gardner ...

A mature [and complete] follicle is made up of tens/hundreds of thousands of cells. We don't need this many cells to make a follicle, we are trying to replicate the early induction events by implanting a relatively small number of cells ~2-8,000 into the skin, that can induce the surrounding tissues to form a follicle. If you think of hair follicle formation in the embryo then it is coming from a tiny number of cells.

*lol*

[nameless]

It’s not that 40% of the cells have reclaimed in vivo DP character, rather that the spheres have reclaimed 40% of the character of the DP. There is a group in Taiwan that are undertaking this work as a clinical trial but I don’t know anything about that beyond what is readily available.

What does this mean?

[agardner]

I'm highly interested in your multi-cell models, specifically the models that involve fat cells. I know you said you can't talk about those at the moment but please tell us when you can talk about those because I think that the signaling from the fat cells to the follicles could be part of what creates the hair inducitivity with hair cells. And since the fat cells are reduced in thinning areas that seems to mean that you will have to get more fat cells into the recipient area along with the hair cells.

I can't talk about specifics of the model, however, Prof. Jahoda has (relatively) recently published a paper looking at the development of various adipose tissues in the mouse, the conclusions/further work shows his thinking about fat in the role of follicle development.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0059811

[agardner]

Who is the Lendl group. I have not of them before you mentioning them. How far along are they at restoring inductivity?

http://research.mssm.edu/rendl/index.html

They are attempting to induce DP character in dermal fibroblasts that have never had inductivity. From the conference they are just about to start inductivity assays in a mouse model, so by next year I would imagine they will announce their findings on this.

[agardner]

Dr. Gardner since it's known that injecting cells can prompt hair to grow using the follicles that already exist in the skin, wouldn't it be better to focus on how to produce hair cells with good inductivity and then injecting those cells into the skin so they can prompt hair to grow through the existing follicles rather than focusing on how to grow whole follicles and then having to implant the whole follicle into the skin?

If you inject the cells instead of whole follicles then you are able to grow the hairs through the follicles that are already in the skin which would solve a lot of problems that come up when you inject whole follicles into the skin.

We, as a group, are not actually attempting to grow follicles in the lab. Rather, we are attempting to use small populations of cells that will interact with the existing tissues in the scalp to form a follicle in situ. It is possible that these cells would interact with already existing miniaturised follicles, but that data will come from others clinical trials.

[agardner]

Other than funding through methods like crowdfunding, is there any way in which the hair loss community, people like us from the forums and all around the world, can do to help speeding up the process for the 'holy grail' ?

You can contribute to a charity/organisation that is funding researchers. There are several alopecia charities that give out grants to researchers, that would be my recommended option as you are less likely to get ripped off going through an existing organisation that has review procedures in place.

I would recommend donating to the various hair research societies to encourage early-stage researchers to move between labs, attend conferences etc. as this is vital to encourage interactions between group and also widen peoples knowledge. You could also perhaps ask for representation on their various boards so that you are able to keep up with what is happening more easily, not sure how open they would be to this but it is worth a try.

With crowd funding I would be careful. It's an investment, and as with any investment you might get nothing. You would need to be very careful choosing who to invest in, and also very careful in nailing down what the outputs must be. E.g. that you hold any data generated, data must be published in open access journals etc... that way even if your funding doesn't immediately result in a cure, the work can help other groups develop.

[agardner]

Thanks dr.
I know you said you were against funding one researcher, but would it really be unrealistic to crowdfund your team or another top team? Not sure if you guys are lacking funding at all. What do you make of follica not being able to secure funds? Do you think that it is because their technique isn't good enough? Or do you think that dr cotsarellis was just angling for more money?

Also, I'm very curious, is someone intensely looking into what makes mouse and human DP cells act differently? It seems like the mysteries of regeneration lie in these disparities. Might it be possible to sequence the genes in a mouse and a human DP cell and at some point actually alter the DNA of DP cultures for each patient? On a perhaps more simple level- is it maybe a possibility to select out the DP cells that are better are aggregating and inductivity, and keep culturing them in order to perfect the cells that are to be used for implantation? Like selective breeding?

It seems that the two issues that have to be perfected are the mix of cells used, and the design and chemical nature of the culturing environment. I'm happy that so many teams are working on both parts. Are an embryo's or fetuses or babies dp cells more prone to induce hairs? I wonder if even the DP cells in our donor zone lose this characteristic over time. In mice hair is so crucial to survival that maybe their cells are programmed to lose this capacity at a slower rate(and they also live short lives). I wonder if making New DP cells from IPs cells will result in them having better inductivity...

There are some research groups that would happily accept crowdfunding, I personally wouldn't. There is nothing wrong with accepting crowdfunding as long as the group is reputable and the funders accept that they can lose their money for no gain. I wouldn't directly like that responsibility. I'm not sure about Follica, I guess the investors didn't fancy the risk:reward ratio.

We do know the differences in gene expression between mouse and human both in vivo and in culture. So that has given us several targets to investigate, in my talk/poster I mention attempting to restore gene expression to DS, several of these genes were identified as being different in mice/humans.

As to why they are different, I don't know.... you idea is as good as any I've heard but a question like that is almost impossible to answer It is important that we know they are different and that these differences may hold the key to restoring inductivity.

Embryonic/neonatal skin is more receptive to having follicles formed within it, whether the actual DP of young hair follicle is more inductive or not.... I don't know. It's not something that I'm aware anyone having looked at it, I guess most groups are focused on adult patients and so it is the differences between inductive/non-inductive tissues that receives the most focus.

[agardner]

Dr. Gardner, i'm not sure if i understood the part with epithelial cells correctly.
you say epithelial cells are tricky because they differentiate and do not multiply.
does that mean you have a method to overcome this problem or are you not able to multiply them actually? if you're able to expand them, do they also lose gene expression or is gene expression no issue here with this cells?

i just tried to understand if Dr. Xu's breakthrough (creating unlimited epithelial cells by converting from iPS cells) is required for us now or if you are anyway able to already expand them with your own methods.

Epithelial cells are easy to isolate and culture initially. However very rapidly they differentiate and stop multiplying (2-3 weeks), as opposed to DP, DS and DF cells which continue proliferating for much longer (2-3 months). For us gene expression in the epithelial cells is not important as we think the interaction with the dermal cells is key, and is restored as soon as they are cultured together.

Also I don't think this would be a limiting factor clinically, it's just an annoying quirk of the cells we're using in our experiments when we have limited donor tissues available.