Status of Hair Regeneration Today
Most people in the know believe that Drs Walter Unger and Jerry Cooley have stood at the doorstep for the emerging arena of hair regeneration. They have both spoken at various medical meetings on the subjects of hair regeneration and hair cloning and they have been kind enough to comment on the history and status of the field. Included are comments on the company Intercytex from England, the company which has generated a great deal of hype and excitement in the field today, the company I have previously commented on in various postings.
The following segment is written by Walter Unger, M.D.
-
Having been a consultant for various medical investigations over the years, I know that companies can misrepresent, in a variety of ways, the results of studies and your collaboration with them. We therefore shouldn’t think of the company’s promotional statements as necessarily scientific or formulated/agreed to by the medical consultants that are working with them. Some doctors also use exaggerations in their own promotional material so we probably shouldn’t be too harsh about a company’s promotional zeal.
To put in perspective the results of this company and others it may be worthwhile to remember: when I was doing the cell therapy studies, we could successfully grow the hair follicle cells that we were interested in, in 100% of the cases, growing millions of cells from a single cell with no problem at all. We also could successfully transfer those cells into athymic mice and in almost 100% instances, grow hair on the mice. I was very excited when we got to that stage because I thought for sure we could use the same cells in the human donor and grow hair on them if we could grow their hair on the mice. In fact this didn’t happen; we grew hair on 1 of the first 10 patients and 3 of the 13 in the second study. But the numbers of hairs and quality of hair was not nearly as good in the second group as in the first. It was at that point that we ran out of funding as the sponsor took ill and ultimately died from that illness. What I’m trying to say and what I think most investigators in this field will agree with is that it’s a huge step from laboratory studies to actually getting consistent hair growth in a human. There is some missing factor or factors. I’ve concluded that this project will require some luck rather than just knowledge and hence my relative disinterest in doing further studies at this time.
The following segment is written by Jerry Cooley, M.D.
-
“I have worked with Intercytex for the past five years. Everyone I’ve met from the company seems very reputable and has a sterling reputation; their staff includes almost 50 at this point and they’re very well funded. They have projects going for skin substitutes, soft tissue augmentation, and even renal failure. By the way, I am not a spokesman for Intercytex and have no equity in the company. My role is to offer clinical input for their product development.
A multitude of labs have consistently regenerated hair follicles in animals and there have been a scattering of reports in humans–Colin Jahoda, myself, Aderans, Walter Unger, PheonixBio in Japan, etc. There is a wide gulf between animal research and human experiments at this point in time. But that’s pretty typical for the biotech pipeline. That animal research is making definite and exciting headway, for example in showing that ‘cloned’ hair does cycle, and that multiplications of 100 fold are possible from third passage cultured human Dermal Papilla cultures.
Not being directly involved in running a biotech company, I can only imagine that there is tremendous pressure on these people to generate media coverage for their ventures to keep the public and especially investors interested. You don’t get very far by telling reporters, “I’m not really sure how all this is going to turn out”. Many pioneers in surgical procedures created exuberant publicity for their techniques even before they were perfected, and it often had its unsavory aspects. Nevertheless, that publicity led to greater public interest and ultimately acceptance of follicular unit transplantation and megasessions. Perhaps we will see the same pattern play itself out with cell therapy.
I don’t think Intercytex has claimed that they are getting consistent results. In fact, they state that only 5 our of 7 participants in their phase I trial had increased hair growth. From what I understand, they are starting efficacy trials very soon and at their conclusion the results the company is able to achieve will be more evident.
Unless Intercytex is lying, and I don’t believe they are, then they have achieved better success than Dr. Unger since they had growth in 5/7 of their patients and unger achieved only 3/13. The fact that progress has been achieved should encourage those who look forward to HM.
It also should be noted that Dr. Unger ran out of money. As Dr. Cooley pointed out, Intercytex is very well funded which gives them a greater likelyhood of success.
I don’t think its fair to even allude to Intercytex as hyping up their product unreasonably, since they admit their work is still a thing in progress. No disrespect to the above doctors, I’m sure they have made great contributions to HM , but a new technology is rarely perfected by its pioneers.
Dr. Rassman, you post those two quotes by Drs. Unger and Cooley, but don’t even provide the dates on which the statements were made! “Scattering of reports”??? Is Dr. Cooley discounting the work being done RIGHT NOW by Aderans and Intercytex, which is at a very advanced stage?
Murray – Sigh. I realize based on your comment above and a comment that you made elsewhere on this site that you have a difficult time with reality when it comes to the hair cloning. The quotes from both Doctors were from emails (posted with permission) and were made within a few days of the blog posting’s date at top. Dr. Cooley’s words speak for themselves. If you have questions about his words or thoughts, you can pose them to him — I do not speak for anyone but myself.
StemceleX
Hair Restorative Lotion
http://www.stemcelex.com
Common baldness and alopecia has been a problem afflicting mankind and animals. A manuscript written in Egypt in 1200 B.C. provides numerous recipes for beauty which were in vogue thousands of years ago. There are remedies for moles, treatments for gray hair, and suggestions for overcoming baldness. More than 3000 years have passed and still hope springs eternal in the brain of the bald – headed man. There is no scientifically proved remedy, for example one compound currently in clinical use for treating alopecia is 2,4-diamino-6-piperidinopyrimidine 3-oxide (i.e.minoxidil) or its derivatives, topical application of minoxidil and other agents is only partially effective and suffers from a number of disadvantages and the exact mechanism of action of minoxidil is not known. Please see our webpage and click on the NEW ENGLAND JOURNAL OF MEDICINE.
Various compounds and extracts of a crude drug which have been conventionally known as a hair growth composition are employed as a hair growth stimulant. However, they do not always exhibit good effects for the hair growth, different forms of androgens have been tried to elicit hair growth without success. Many products may state “FDA approved†but may be for safety not for efficacy in hair growth. Bradbury & White (1954) listed over 50 species of plants reported to exhibit estrogenic activity, (see Agents affecting fertility C.R. Austin and J.S.Perry page no. 6-15) these plants helps only to prevent hair from falling out.
In many individuals, alopecia causes embarrassment, psychological problems, including depression, stress, and can affect one’s self image and feelings of sexuality. Alopecia has been hypothesized to have various etiologies in males and females, many of which involve gonadal steroids. Alopecia is more common in men (e.g., male pattern baldness or androgenic alopecia) than in women (e.g., female pattern baldness). Alopecia areata -like baldness may be the first sign of metastatic breast cancer.
(See Andrews Diseases of the skin, Clinical Dermatoligy, Eighth Edition Arnold, Odom,
James page no. 881).
Vera Price (Department of Dermatology, University of California, San Francisco, CA) has extensively reviewed testosterone metabolism in the skin, the 5a-reducase of testosterone is increased in the scalp of balding individuals yielding increased dihydrotestosterone. It has been suggested that high dihydrotestosterone levels in the genetically marked hair follicles initiate baldness by inhibiting adenyl cyclase. (See Andrews Diseases of the skin, Clinical Dermatoligy, Eighth Edition Arnold, Odom, James page no. 884). Pitts in J Am Acad Dermatol 1987 Mar: 16(3 Pt 1): 571-3 discloses that elevated levels of dehydroepiandrosterone sulfate in young men with male pattern baldness were found and since has suggested that adrenal hyperactivity may initiate alopecia in genetically susceptible men. The pathogenesis is centered around the lengthening of the telogen phase and the shortening of the anagen phase of hair growth. The shorter the anagen phase, the shorter the hair growth.
Since the l930s, it has been clearly established that suppression of the thyroid raises serum cholesterol (while increasing mortality from infections, cancer, and heart disease), while restoring the thyroid hormone brings cholesterol down to normal. In this situation, however, thyroid isn’t suppressing the synthesis of cholesterol, but rather is promoting its use to form hormones and bile salts. When the thyroid is functioning properly, the amount of cholesterol in the blood entering the ovary governs the amount of progesterone being produced by the ovary, and the same situation exists in all steroid-forming tissues, such as the adrenal glands and the brain. Progesterone and its precursor, pregnenolone, have a generalized protective function: antioxidant, anti-seizure, antitoxin, anti-spasm, anti-clot, anti-cancer, pro-memory, pro-myelination, pro-attention, etc. Any interference with the formation of cholesterol will interfere with all of these exceedingly important protective functions.
Study concluded that one of the signs of thyroid hormone deficiency, namely the thickening of the skin caused by the subcutaneous deposition of a viscid mucinous material. So it is clear that excessive growth to the skin around the hair follicles finally produces ordinary male pattern baldness.
Most evidence points to ward its being an autoimmune disease modified by genetic factors and aggravated by emotional stress. Many studies have documented abnormal cell mediated immune factors in alopecia areata. There is an increased suppressor T-cell function in patients experiencing re-growth. In the inflammatory perifollicular infiltrate seen in active cases, helper cells predominate. Stress has been regarded for years as a possible initiator and if it does play a role, it may be as an instigator of an immune mechanism
Hair is basically composed of keratin, a tough and insoluble protein; its chief strength lies in its disulphide bond of cystine. Each individual hair comprises a cylindrical shaft and a root, and is contained in a follicle, a flask-like depression in the skin. The bottom of the follicle contains a finger-like projection termed the papilla, which consists of connective tissue from which hair grows, and through which blood vessels supply the cells with nourishment. The shaft is the part that extends outwards from the skin surface, whilst the root has been described as the buried part of the hair. The base of the root expands into the hair bulb, which rests upon the papilla. Cells from which the hair is produced grow in the bulb of the follicle; they are extruded in the form of fibers as the cells proliferate in the follicle. Hair “growth” refers to the formation and elongation of the hair fiber by the dividing cells. As is well knows in the art, the common hair cycle is divided into three stages: anagen, catagen and telogen. During the active phase (anagen), the epidermal stem cells of the dermal papilla divide rapidly. Daughter cells move upward and differentiate to form the concentric layers of the hair itself. The transitional stage, catagen, is marked by the cessation of mitosis of the stem cells in the follicle. The resting stage is known as telogen, where the hair is retained within the scalp for several weeks before an emerging new hair developing below it dislodges the telogen-phase shaft from its follicle. From this model it has become clear that the larger the pool of dividing stem cells that differentiate into hair cells the more hair growth occurs. Accordingly, methods for increasing or reducing hair growth can be carried out by potentiating or inhibiting, respectively, the proliferation of these stem cells.
Follicular development relies on a series of messages between dermis and epidermis. During embryogenesis, the formation of hair follicles results from interactions between the epidermis and mesenchyme. The dermal components of the hair follicle (i.e., the dermal papilla and dermal sheath) are derived from aggregate of mesenchymal cells. Follicle initiation and development begin with the aggregation of dermal fibroblasts and epidermal keratinocytes. The epidermal cells proliferate and penetrate the dermis as plugs. Subsequently, the epidermally derived cells encircle a dermal aggregation and incorporate it into a pocket of tissue, the dermal papilla. It is generally understood that the population of hair follicles and dermal papillae is established during embryogenesis with no significant postpartum development ( P.L.Williams,et al.,â€Hairs†in Grays Anatomy, pp.90-94, P.L. Williams, et al., eds. (Churchill Livingston, 1989); D.H. C ormack, “Hairs†in Ham’s Histology, 9th Ed., D.H. Cormack, ed. (J.B. Lippincott Co.,1987).
One single molecule determines how stem cells in the hair follicle develop. This molecule is part of a complex signaling system known as the “Hedgehog pathwayâ€. This signaling system controls the development of many different organs and consists of chain reaction in which several proteins together control the behavior of cells.
Studies have shown that the Hedgehog system is responsible for stem cells in skin being the signal that allows them to develop into a certain type of cell. The molecule that has been studied is called “Smoothened†and it forms a link in the chain of information. If Smoothened is missing, the information never reaches the nucleus of the cell.
The stem cells at the hair follicles normally lie in special small niches in the tissue, but the transgenic mice used in studies lack these protective niches. The stem cells that should have become hair develop instead into cells from the mammary gland.
Previous work has shown that intensive Hedgehog signaling can lead to cancer. The new study shows that raised signaling activity can also prevent the formation of mammary glands. It is Hedgehog signaling that determines whether hair or breast tissue is formed. Also study shows in the American Journal of Pathology, 2003; 163; 2173-2178 that the hedgehog signaling regulates sebaceous gland development. Hedgehog pathway activation led to a striking increase both in size and number of sebaceous glands. Remarkably, ectopic Hedgehog signaling also triggered the formation of sebaceous glands from footpad epidermis, in regions normally devoid of hair follicles and associated structures.
The sonic hedgehog pathway may also play an important role in male- and female-pattern baldness. In the skin, sonic hedgehog (shh) is required for hair follicle morphogenesis during embryogenesis and for regulating follicular growth and cycling in the adult. Recent studies indicate that topically applied hedgehog (Hh)-agonist can modulate follicular cycling in adult mouse skin. The Hh-agonist stimulated the transition from the resting (telogen) to the growth (anagen) stage of the hair cycle in adult mouse skin, suggesting that topical application of Hh-agonist could be effective in treating conditions of decreased proliferation and aberrant follicular cycling in the scalp including androgenetic alopecia (aladimi et al, Journal of Investgative Dermatology-2005; Volume 125 Page 638)
Study shows that when hair follicles in adult mice are induced to make a cell signaling protein called Wnt, during the resting telogen stage, the follicles shift prematurely into the hair-producing, anagen stage. Thus sonic hedgehog can stimulate dormant follicles to begin producing hair.
Cyclopamine Inhibits Medulloblastoma Growth. Cyclopamine is a teratogen, a compound that can cross the placenta and cause defects in a developing fetus. It was first discovered in extract from the Veratrum californicum (corn lilly). If a pregnant sheep eats the plant, the fetus develops with cyclopic feature- same defect that is caused by inadequate Hh activity in people and mice. It turns out that cyclopamine can block the activity of Smoothened (Smo) an intracellular protein that activates genes in response to the Hh signal. By affecting the Hh pathway, cyclopamine has the potential as anti-cancer drug.
Elaine Fuchs discussed the WNT signaling pathway and how it controls cell proliferation, transeription and adhesion and attachment. WNT signaling is important in stem cell development, in hair follicle determination, and in committing hair matrix cells to formation of hair keratins. The details of how such signaling pathway link cell attachment, proliferation and differentiation will provide fundamental understanding of the molecular control of hair follicle development and cycling. In the context of alopecia areata, such knowledge may make it possible to maintain hair follicle growth even in the face of immune attacks in alopecia areata.
Another finding that Silencing of Wnt signaling and activation of multiple Section of Molecular Signaling and Oncogenesis, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255, USA. To investigate the transcriptional program underlying thyroid hormone (T3)-induced cell proliferation, cDNA microarrays were used to survey the temporal expression profiles of 4,400 genes. Of 358 responsive genes identified, 88% had not previously been reported to be transcriptionally or functionally modulated by T3. Partitioning the genes into functional classes revealed the activation of multiple pathways, including glucose metabolism, biosynthesis, transcriptional regulation, protein degradation, and detoxification in T3-induced cell proliferation. Clustering the genes by temporal expression patterns provided further insight into the dynamics of T3 response pathways. Of particular significance was the finding that T3 rapidly repressed the expression of key regulators of the Wnt signaling pathway and suppressed the transcriptional downstream elements of the beta-catenin-T-cell factor complex. This was confirmed biochemically, as beta-catenin protein levels also decreased, leading to a decrease in the transcriptional activity of a beta-catenin-responsive promoter. These results indicate that T3-induced cell proliferation is accompanied by a complex coordinated transcriptional reprogramming of many genes in different pathways and that early silencing of the Wnt pathway may be critical to this event.metabolic pathways in response to thyroid hormone-stimulated cell proliferation. by Miller LD, Park KS, Guo QM, Alkharouf NW, Malek RL, Lee NH, Liu ET, Cheng SY.
Ralf Paus, Dept .of Dermatology, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany, described in his research that, while the significance of androgens as much less is known on the exact follicular functions of other nuclear hormone receptor ligands (e.g. endogenous estrogens, thyroid hormones, retinoids, calcitriols, glucocorticoids) and on non-steroidal, peptide hormones and neuropeptides (e.g. ACTH, aMSH, CRH, prolactin, P, catecholamines, melatonin). This introductory synthesis begins by summarizing important relevant findings from the old endocrine literature ( mostly in rodents) that serve to highlight many of the most intriguing open questions on the hormonal controls of hair growth, both in an endocrine and in a paracrine/autocrine signaling context, which the overly dominant androgenocetric view of the hair follicle has tended to obscure. This is followed by a discussion of more recent findings that the hair follicle to be both a source and a target of numerous hormones, neuropeptides and neurotransmitters, whose expression (along with that of their cognate receptors) underlies tight, hair cycle-dependent regulatory controls. In particular, the hypotheses are explored that the hair follicle exploits several locally generated and/or metabolized hormones for controlling its own growth, innervations, immune functions, perfusion and/or pigmentation and that the hair follicle has established a miniature equivalent of the hypothalamic-pituitary-adrenal axis, possibly as part of a complex, local stress response-system.
Article of J Clin Invest, October 1999, Volume 104, Number 7, 855-864 described that the ability of AdShh to accelerate the induction of anagen in a background of telogen skin invites the interesting speculation that transient expression of Shh could activate the hair growth cycle in disease conditions where the extent of these functions has been reduced. In this regard, the observations in this study may be relevant to a new approach to hair loss therapy, in which a gene-transfer vector provides localized, transient overexpression of activity of the Shh pathway, resulting in acceleration of hair follicle cycling to anagen, and thus hair growth. For example, such a strategy may be beneficial in treating some forms of alopecia associated with chemotherapy, in the same fashion as hematologic growth factors are used to accelerate the development of hematologic progenitors . These observations also suggest that the expression of other genes in the Shh pathway, such as Ptc and Gli1, could also be targets for therapeutic induction or inhibition of hair growth, using gene-transfer, antisense, or small-molecule therapeutic strategies. Whether modification of the expression of the Shh pathway is applicable to common androgenic alopecia (male pattern baldness) will have to await further study.
Richard L. De Villez, MD Associate Professor Division of Dermatology, University of Texus Health Science Center San Antonio, Texas desribed in his investigation the effects of androgens on sexual-hair growth and scalp-hair loss might be mediated through changes in intracellular concentration of cyclic AMP (cAMP). The “Second messenger†theory of cAMP states that the first massenger (a hormone) is carried to the plasma membrane of its target simultaneously, a catalytic subunit of adenyl cyclase produces cAMP which initiates a specific physiologic function.
The effects of various sex hormones on the activities of adenyl cyclase in the follicles of scalp hair
indicate that dihydrotestosterone produces inhibition by that testosterone dose not. Increased adenyl cyclase activity is observed when estrone is added to hair follicles. However estradiol (an active estrogen) does activate adenyl cyclase. The intracellular concentration of cAMP is determined by the relative concentrations of synthetic enzymes, such as adenyl cyclase, an degenerative enzymes, such as cAMP phosphodiesterase ACTH acts via adenylate cyclase and a protein kinase to increase the amount of free cholesterol that enters mitochondria and is converted to pregnenolone . The cyclic AMP also acts in some way to increase the synthesis of or possibly to phosphorylate, a protein that increases the conversion of cholesterole to pregnenolone. ACTH acts in a similar fashion on the cells in the zona glomerulosa that secrete aldosterone, but angiotensin II and K+ stimulate aldosterone secretion without affecting cyclic AMP.