Troubling. Troubling, indeed.

provoque-post-draftShakespeare famously wrote “a rose by any other name would smell as sweet”. BFT sadly wilted-rose-2cannot agree. This post discusses a new product and marketing ploy that can only be described (in BFT’s opinion) as  deceptive, or at least misleading. It is also certain to disturb some of our readers. This “rose” stinks, not because of what is said about it, but because of what is deliberately left unsaid.

In order to hawk their wares, marketers are notorious for telling half-truths, even outright lies. The world of beauty and skincare may be the most flagrantly abused market of them all. Just think of the outrageous promises you have seen and heard, only to be disappointed when you tried the product.

Cheap products contain cheap ingredients. Just as one doesn’t expect a four-banger econocar to outperform a V-12 Ferrari, cheap skin products do not contain sophisticated (read: expensive) active ingredients that have scientifically proven skincare benefits. Cheap products can’t perform. They’re cheap for a reason. Feel good / smell good does not equal efficacy. Nothing new there.

Most of the time the damage wrought is financial, purloining cash from unsophisticated consumers who add another disappointment to their growing list of promises unfulfilled. Predictably, these products usually have short market lives and are priced low enough to not cause too much damage to the pocketbook. It’s easy to say “oh, what the hell, I’ll give it a try” when the downside is not too steep. Low-priced disappointment, one might say, is only a modest assault on the consumer.

HIGH SCIENCE – WITH A TROUBLING TWIST

We’re not talking about such a product. This product is a “high science” offering in the same human cell culture derived product space that we BFT authors operate. Likewise, it is priced in the “lux” tier, that part of the pricing ladder where one finds sophisticated products, usually but not always, with sophisticated science to back up their claims.

We, in our humble opinion, offered a better, more scientific mousetrap, and wrote and lectured about it to gain credibility. We told the truth, the whole truth, and nothing but the truth to earn legitimacy and loyal customers. Provoque® is a different story: to many we feel it will be a disturbing story.

truthhurtsAs our readers know, one of our missions at BFT is to be truth tellers and watchdogs, roles we take seriously. Someone has to be a whistle-blower in an industry where fast bucks drive many products. Having launched our own product line into the lux market, we certainly have to be careful about where we throw stones. Nonetheless, we feel compelled to say something.

PROVOQUE® (SHOULD THAT BE SPELLED PROVOKE?)

Our problem with today’s topic product, Provoque®, has to do with the ethics and morality of its underlying science, specifically what is not said about it, or, as one might say, what is hidden from view, and the consumer.

Some readers might shrug their shoulders and say “so what?” If you are one of those people, that’s fine. We are each entitled to mad-black-woman-mph1a6mv41k9bbnlk2fggzwkoiw16sexjgkvjttwbsour opinion. Not giving a hoot is just as valid a giving a huge hoot. For those who care, however the woman-asking-question-20genesis and evolution of Provoque® may be troubling. For some, it may approach being unconscionable – in other words, a HUGE hoot.

Let’s cut to the chase. Provoque® contains conditioned media derived from laboratory culture of true, real, actual human embryonic stem cells. These are the types of cells that were the crux of the political brouhaha of several years ago when President George W. Bush outlawed the research use of new human embryonic stem cells. What he did permit, however, was the continued use of the then already established human embryonic stem cell lines which were being actively studied as possible sources of medical cures and treatments for serious illnesses and injuries. Anti-aging skincare hardly fits that profile. More about that in a bit.

HIDING THE BALL

hiding-the-ballNot surprisingly, nowhere has BFT found any mention of human embryonic stem cells in the published articles, marketing materials, or websites that describe Provoque® or the science behind it. The only cells mentioned anywhere are CSC14 cells.

Everything is hunky dory if the conversation is about CSC14 cells, right? Who can have a problem with CSC14 cells? Potentially, a lot of people…when they learn what CSC14 cells actually are.

Google them – you’ll have your answer, right from the National Institute of Health, where they are registered as one line of human embryonic stem cells grandfathered in as OK for continued study following the prohibition against destruction of new embryos for stem cell research signed by President George W. Bush.

Dig deeper and one can read the several different consents signed by the parents of the CSC14 cells (their identities are well hidden as their names are thoroughly blacked out on the documents.) The last of a series of consents (approved in March, 2014) stipulates: “California Stem Cell, Inc. will use the CSC14 to proceed with their therapeutic program in Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis and possible use CSC14 in future research programs.”

IS BETTER LOOKING SKIN THE MEDICAL MIRACLE THE DONATING PATENTS CONSENTED TO?

The intention of the donating parents concerning use of CSC14 cells in medical research and possible commercialization of medical-miraclemedical miracles is clear. Their use as a source ingredient in anti-wrinkle cosmetics? Not mentioned, and in BFT’s opinion, highly unlikely. We looked but saw no mention about their use in anti-aging skincare products anywhere in any of the consents signed by the donors of the CSD14 line of cells.

That’s why we think the manufacturer “misspelled” the product name. It should more rightly be spelled “Provoke”, because that is what BFT expects to be the reaction when some customers learn they are slathering a product that contains ingredients derived from human embryonic stem cells onto their face.

While some consumers will consider this no big deal, BFT expects others to feel they are doing something morally and ethically unacceptable, perhaps even committing a sin. We expect some consumers to be provoked to anger, and some perhaps into action. BFT can envision avaricious litigators licking their chops over this; emotional damage and deceptive marketing has in the past resulted in hefty damage awards and fines.

SO WHAT ARE HUMAN EMBRYONIC STEM CELLS AND HOW ARE THEY HARVESTED?

blastocyst_diag_no_bkg_4-preview

Embryonic stem cells, such as CSC14 cells, are harvested from very early “embryos”, literally only a few days post conception. At this stage the mass of cells has no resemblance to a fetus or a baby. At six days post conception, the time when embryonic stem cells are typically harvested, there is a round and hollow structure called a blastocyst which has a cluster of approximately 100 cells at one side. These are the embryonic stem cells that have the potential to develop into a living anatomically complete functioning human infant.

 

DRJOHN WAS LESS THAN IMPRESSED WITH PAPER; DRGEORGE ECHOES THAT SENTIMENT

“Really Bad Paper”, that was the subject line of Drjohn’s email to Drgeorge on May 7th, 2016.  He was referring to an article not-impressedpublished in the May issue of the Journal of Drugs in Dermatology that described a “revolutionary cosmetic ingredient”, specifically fetuin-A, also known as Alpha 2-HS Glycoprotein. This ingredient was derived from the laboratory culture of CSC14 cells.

articlejddDrjohn’s troubling observation from the outset was that nowhere in the article is it mentioned that CSC14 cells are human embryonic stem cells. He learned what they are when he did a simple internet search. The failure to mention this fact now extends (to the best of BFT’s knowledge) into the marketing materials available online and likely in printed product sheets and brochures. The use of human embryonic stem cells is not mentioned anywhere. It is BFT’s opinion that this was not an oversight, it was intentional. But that’s not the only problem.

FAULTY SCIENCE & CONCLUSIONS (in BFT’s humble opinion)

BFT considers the science faulty for several reasons.misleading

1. In reading the article, speculation about the important role of fetuin-A in fetal skin is made from observations that have no proven cause-effect relationship. In other words, the statement that fetuin-A is a “revolutionary cosmetic ingredient” is not supported by the experimental model described in the paper. The topical application of formulae in which a 5% ingredient is conditioned media from CSC14 cells is utterly inconclusive as to what role fetuin-A plays in skin changes since conditioned media also contains dozens if not hundreds of other molecules produced by these cells in culture. To claim it is fetuin-A that is playing the major role is sheer speculation.

From the article:

“The mammalian fetus has the remarkable ability to heal dermal incisional wounds with no signs of scarring.  Proteomic analysis by mass spectrometry identified fetuin-A as a major component of fetal skin and this was verified by western blotting using a fetuin-A antibody. After birth, fetuin-A expression was significant, indicating that the high levels of fetuin-A are intrinsic to fetal skin. Moreover, it shows regional localization during skin development and wound healing, thus providing direct evidence that fetuin-A may contribute to scar free wound healing.”

One should note that use of the word “may” opens the possibility that it also “may not.” With this ambiguous wording, the declarative statement in the title of “a revolutionary cosmetic ingredient” is far from definitive, and certainly not supported by the experimental design of the study.

Fetuin-A functions in the fetus is ways that are analogous to how the protein albumen functions in post-gestation humans.  Just as albumen can be found throughout the post-fetal human, it is not surprising to find fetuin-A within fetal tissues including the skin. Again, imputing a cause and effect relationship cannot be proven just because fetuin-A is present. Futuin-A and albumen are both produced by the liver into the blood, each during a different period of the human organism’s life – fetuin-A predominantly during fetal development, albumen after birth. Because albumen is found in all tissues, including the skin, does that mean albumen “may” contribute to wound healing with scars after fetal life? As you can surmise, it’s MUCH more complex than that, so the declarative description of fetuin-A as “a revolutionary cosmetic ingredient” is sheer nonsense.

BUT, seeing this statement published in a peer-reviewed journal may be sufficient to prime the pump of a marketing campaign to convince the world a panacea to skin aging has arrived.

2. The article lists a large number of cytokines and growth factors produced by CSC14 cells, inferring the complexity of the bio-signals produced by CSC14 is somehow unusual. Nothing is further from the truth. Regardless of the cell type cultured to produce conditioned media intended to be used as a cosmetic ingredient (fibroblasts, adipose derived stem cells, bone marrow stem cells, umbilical cord stem cells, embryonic stem cells, etc.), there are scores, if not hundreds, of molecular bio-signals produced in culture. What is apparent from the list, however, is a large number of the identified bio-signals promote an inflammatory response. Readers of BFT are well aware of the pro-aging effect of inflammation on the skin, and all other tissues. That is why we chose to focus our work on the pro-healing anti-inflammatory benefits of conditioned media from culture of bone marrow mesenchymal stem cells. On balance, conditioned media from CSC14 cells appears to be significantly pro-inflammatory.

3. While fetuin-A is the primary blood borne protein in the fetus and albumen is the primary one in post fetal life, fetuin-A continues to be found in blood throughout life, albeit at much lower concentrations. The articles below discuss the effects fetuin-A can play in adults. You will see repeated references to the participatory role of fetuin-A in inflammation, insulin resistance and even possible tumorigenesis. BFT has written extensively about the role of inflammation, particularly chronic smoldering inflammation, and aging elsewhere in BFT. This collection of articles brings into question the laudatory conclusion that fetuin-A is a revolutionary cosmetic ingredient.

(Snippets are provided; the full article reference is provided for those interested in delving deeper.)

FINALLY: THE INTERESTING IN-BREEDING IN PROVOQUE’S FAMILY TREE

Provoque® is being marketed by a company that has as one of its board of directors a gentleman who just so happens to be the bofdchief author of the paper published in the Journal of Drugs in Dermatology, and the CEO of the company that developed and produces Provoque®. His participation on that board predates the publishing of the article by three years. From what we have learned, it also appears to predate the final consent addendum signed by the donors of the CSC14 cell line. (The details have not been fully fleshed out.)

From conversations with one of the founders of the company marketing Provoque®, it appears that CSC14 cells may not have been disclosed as actually being human embryonic stem cells. Perhaps other executives of the marketing company knew this, it is clear this highly placed executive did not. Troubling. Troubling, indeed.

 

Inflammatory Markers in Obese Adolescents with Type 2 Diabetes and Their Relationship to Hepatokines and Adipokines.  J Pediatr. 2016 Jun;173:131-5.

Increased inflammatory markers are associated with T2DM in adolescents. Because CRP was related to FGF-21 and TNF-α was associated with leptin, these findings suggest a link between increased levels of these adipokines and hepatokines  (fetuin-A and FGF-21) and chronic inflammation.

 

Hepatokines: unlocking the multi-organ network in metabolic diseases. Diabetologia. 2015 Aug;58(8):1699-703.

Liver-derived proteins known as hepatokines are now considered attractive targets for the development of novel type 2 diabetes treatments. This commentary presents examples of three leading hepatokines: fetuin-A, the first to be described and correlated with increased inflammation and insulin resistance; angiopoietin-like protein (ANGPTL)8/betatrophin, initially proposed for its action on beta cell proliferation, although this effect has recently been brought into question; and fibroblast growth factor 21 (FGF21), an insulin-sensitising hormone that is an appealing drug target because of its beneficial metabolic actions

 

Implication of hepatokines in metabolic disorders and cardiovascular diseases BBA Clin. 2016 Jun; 5: 108–113.

High levels of serum fetuin-A are predictable marker for the incidence of T2DM after adjusting for risk factors. Stefan et al. demonstrated that serum fetuin-A concentrations are positively associated with hepatic steatosis measured using magnetic resonance spectroscopy (MRS) in humans. Fetuin-A plays an important role in palmitate-induced hepatic lipid accumulation in hepatocytes. Fetuin-A stimulates inflammatory cytokines in monocytes and adipocytes, and suppresses adiponectin, which is an adipokine with anti-inflammatory properties. Fetuin-A induces an inflammatory response and insulin resistance, which may result in the development of T2DM.

 

Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med. 2012 Aug;18(8):1279-85.

Selective administration of Fetuin-A induced inflammatory signaling and insulin resistance. FFA-induced proinflammatory cytokine expression in adipocytes occurred only in the presence of Fetuin-A.

 

Fetuin-A induces cytokine expression and suppresses adiponectin production. PLoS One. 2008 Mar 12;3(3):e1765.

The secreted liver protein fetuin-A is up-regulated in hepatic steatosis and the metabolic syndrome. These states are strongly associated with low-grade inflammation and hypoadiponectinemia. We, therefore, hypothesized that fetuin-A may play a role in the regulation of cytokine expression, the modulation of adipose tissue expression and plasma concentration of the insulin-sensitizing and atheroprotective adipokine adiponectin.

 

Fetuin-A influences vascular cell growth and production of proinflammatory and angiogenic proteins by human perivascular fat cells. Diabetologia. 2014 May;57(5):1057-66.

Fetuin-A (alpha2-Heremans-Schmid glycoprotein), a liver-derived circulating glycoprotein, contributes to lipid disorders, diabetes and cardiovascular diseases. Fetuin-A may also influence angiogenic and proinflammatory proteins involved in atherosclerosis.The secreted liver protein fetuin-A induces low-grade inflammation and represses adiponectin production in animals and in humans. These data suggest an important role of fatty liver in the pathophysiology of insulin resistance and atherosclerosis.

 

Fetuin A promotes lipotoxicity in β cells through the TLR4 signaling pathway and the role of pioglitazone in anti-lipotoxicity. Mol Cell Endocrinol. 2015 Sep 5;412:1-11.

Fetuin A, a secreted glycoprotein, is known to promote inflammation and insulin resistance.

 

Adipocyte fetuin-A contributes to macrophage migration into adipose tissue and polarization of macrophages.  J Biol Chem. 2013 Sep 27;288(39):28324-30.

This was further confirmed by direct Fetuin-A addition to macrophages. Taken together, lipid-induced Fetuin-A from adipocytes is an efficient chemokine for macrophage migration and polarization. These findings open a new dimension for understanding obesity induced inflammation.

 

Fetuin-A: the missing link in lipid-induced inflammation. Nat Med. 2012 Aug;18(8):1182-3.

 

Facilitatory effects of fetuin-A on atherosclerosis. Atherosclerosis. 2016 Mar;246:344-51.

Fetuin-A is known to induce insulin resistance and suppress vascular calcification.

 

Alpha 2-HS glycoprotein (fetuin-A) modulates murine skin tumorigenesis. Int J Oncol. 2004 Aug;25(2):319-24.

To test our hypothesis that fetuin plays a causal role in skin tumorigenesis, fetuin-A null and wild-type mice were challenged using a two-stage chemically-induced carcinogenesis protocol with DMBA (7,12-dimethylbenzo(a)anthracene) as the initiator, followed by twice weekly treatments with the tumor promoter TPA (12-O-tetradecanoylphorbol-13-acetate). Our results suggest that fetuin-A contributes to early stages of skin tumorigenesis.

2 Comments

  1. Diya says:

    Hi Drs. John & George,

    You have an incredible blog here, thank you for this wealth of information. I had a few questions about the Ante Age system (Serum+Accelerator). What is the strength of retinol in the Accelerator? I currently use the obagi 1% retinol treatment, would I discontinue that if I switch to the Ante Age system? Is the system compatible to use with an acid toner/treatment? Would you use it before the acid or after? Also, any thoughts on the latest Nugene product, perhaps a review down the road? https://www.nugene.com/product/universal-serum/
    Thank you for your time and for this amazing blog!
    Diya

    • drgeorge says:

      Our accelerator was formulated with enough retinol to achieve clinical efficacy but not so much as to cause redness and drying. As far as whether or not you need to continue to use the Obagi product, a suggestion might be to stop and see what you observe in your face. There may well be enough in the Accelerator to meet the need for retinoids without having to spend for another product. As to the Nugene product, we are not fans simply based on our knowledge of what the cytokine pattern is produced by adipose (fat derived) stem cells in culture. Fat stem cell produce conditioned media that is laden with powerful pro-inflammatory bio-signals, which is something we don’t consider anti-aging in the least. While the edema (water accumulation) associated with inflammation, even chronic smouldering sub-clinical edema, can have the effect of reducing the appearance of fine lines, chronic inflammation from daily application of pro-inflammatory cytokines makes little sense to us. Because we know that inflammation has pro-aging effect in all tissues and organs, it is BFT’s opinion that it would be counterproductive to deliberately apply a product such as Nugene to one’s face on a daily basis.

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