Controversy: Bioeffect EGF Serum
This is our first controversy, a carryover from a discussion that began on truthinaging.com. It deals with products that contain a single cytokine (epidermal growth factor) as an active ingredient. it is being sold by Sif Cosmetics of Iceland (www.bioeffect.co.uk). Absent from the web site is any reference to scientific studies documenting the safety or efficacy of the products, or the active ingredient. The actual concentration of EGF is not listed for the product. The controversy has two parts. 1) The use of transgenic plants to produce drugs and biochemicals has been a subject of scientific debate for some time. 2) The wisdom of applying EGF without counterbalancing cytokines to human skin is examined in light of extensive scientific evidence as to it’s known effects.
What is transgenic pharming?
Transgenic pharming refers the use of genetic engineering to cause plants to create drugs or biochemical that are not native to that plant. It is akin to genetically modified animals and microbes. The purveyors of the transgenic EGF product under consideration have labeled this author as “completely unscientific” for suggesting that there is any danger whatsoever to transgenic pharming. As it turns out, I am not alone. In fact there are prominent scientists all over the world (experts in the field, which I am not), proclaiming the dangers of transgenic plants. The Institute of Science in Society is a nonprofit) has published a statement signed by 136 scientists, which you can find here: http://www.twnside.org.sg/title/world-cn.htm.
There are multiple dangers cited; the most common is the risk of transgenic plants sharing their altered DNA though pollination with other “wild” plants, potentially devastating agriculture across a wide area. Proponents say it can be contained. Yet there have already been incidents where contamination has occurred. In Iceland, where the company making this is located, there has been trouble for the company. It turns out that barley is the only crop grown in Iceland. While they currently have their government’s approval, there has been discussion of shutting this down. In fact, many in Iceland want to ban the import of foods made from transgenic crops, which is already banned in Europe. In the U.S., the USDA and FDA have a zero tolerance policy when it comes to security around experiments with plants. In Iceland, the company growing ECF-producing barley was sabotaged by food safety activists when it was discovered that they were growing their genetically modified barley outdoors (NOT in a greenhouse).
Because this is not our primary field of study, we do not wish to state a strong opinion on either side of this controversy. Rather, we point you to a just a few places on the internet where you can gain further insight.
http://www.saynotogmos.org/scientists_speak.htm
http://www.raw-wisdom.com/50harmful.
http://www.twnside.org.sg/title/world-cn.htm
http://www.twnside.org.sg/title/world-cn.htm
http://www.aaemonline.org/gmopost.html
http://www.responsibletechnology.org/
http://www.organicconsumers.org/gelink.cfm
http://www.saynotogmos.org/molecular_pharming.htm
http://geneticallyengineeredfoodnews.com/
What is EGF?
Epidermal growth factor (EGF) is one of many hundreds of chemicals that cells use to communicate with each other. Generally speaking, we call these cytokines. Cytokines can be broken down into families according to their principal actions (to the extent that we understand their function – sometimes they have multiple functions). EGF belongs to a family known as growth factors. There are about a dozen of them. As their name implies, they are involved with growth, development, and healing (damaged or dead tissues undergoing reconstruction).
EGF and Skin
Skin has multiple layers. The outermost layer is the epidermis, which itself can be divided into multiple layers. The outermost layer of the epidermis (stratum corneum) is about a dozen cells thick (on the face, thicker elsewhere). The innermost layer (basal cells) is only one cell thick. In between there are 2-3 layers of varying thickness.
Under normal physiologic conditions, EGF would reach the basal layer of the epidermis not from the outside in, but from the inside out (from the dermal layer, which is rich in blood vessels). In the case of skin damage, cell communication signals would have resulted in migration of a certain class of stem cells to the area, which would orchestrate a damage control strategy though a complex array of secreted cytokines, including growth factors. But they would do so in a carefully controlled sequence, as there are many steps involved in cutaneous healing. Toward the end of that sequence, EGF may predominate to stimulate basal cells to increase production of new cells which, as they mature, advance from inner to outer layers, and are ultimately shed.
When applied to human skin in the absence of other cytokines (that provide a synchronized set of signals to local cells, the outer layer of cells (the epidermis) proliferates. This is accomplished my increased mitosis (cell division) within the epidermis itself. Normally, new cells are formed by miosis at the basal cell layer, and work their way up to the surface over time. This normal progression may be bypassed with unbalanced EGF hyperstimulation. Cells that have already progressed from basal to midlayers may be stimulated to divide. These cells are more likely than deeper cells to have been stressed by free radical generation due to UV exposure and the like.
What does EGF skin proliferation look like?
The outer epidermal layers thicken, as more cells are produced. This can have positive cosmetic effects, as the skin “plumps up” not unlike what happens when a good moisturizer is applied to dry skin. But in this case it is more (surface) skin. Now the plumped up skin can help the contours of thinned (aged) skin to look younger, more rounded. However, problems may arise. The growth of new epithelial cells narrows the pore through which the hair grows. Over time the hair may become thinner and thinner until it become peach fuzz (vellus) hair. The follicle may be so smothered that it stops producing hair altogether. Eyebrows and eyelashes may start falling out, and your scalp hairline may recede. (It’s a superb depilatory – in fact EGF is used commercially to remove wool from sheep). This type of hair loss has also been reported as a side effect when EGF is taken internally. Skin texture may become less pleasing as well, as pores may become more prominent over time. Like other actives, a certain “dependency” can develop. Stopping the application of EGF may lead to a period of skin “hypoplasia” or slowed growth as a compensatory defense.
EGF and wrinkles
Wrinkles are defects in the dermal layer of the skin, where collagen precursors and elastin are produced by fibroblasts. During aging, collagen forms cross links that cause it to deform its shape and lose elasticity at points of stress. The process of removing old collagen and replacing it with new slows down.
Mitogenic cytokines that act in the dermis layer include basic fibroblast growth factor (bFGF), transforming growth factor alpha (TGF-α), and insulin-like growth factor-1 (IGF-1) along with transforming growth factor-beta 1 (TGF-b1). Companies that tout products with EGF as an active claim that it stimulates collagen and elastin to reduce wrinkles. But EGF, it turns out, has only a weak effect on fibroblasts.
The “cytokine context” of the dermis again is driven largely by specialized local cells, assisted by cells that migrate to areas of (acute and chronic) damage. Assuming that any topically applied EGF reaches the dermis, it would be a minute fraction of that applied, and thus not likely to affect collagen production. Also, wrinkle reduction requires not just the making of new collagen, but also the breakdown and disposal of old collagen. That is the role of a different group of cytokines, and their target cells, some of which are phagocytes (immune cells that gobble up debris and export it).
So, all in all, EGF as a lone cytokine applied topically is not likely to affect wrinkles at the dermal level. Epidermal plumping may temporarily alter fine lines, but is just as likely to exaggerate them (hills plump, riverbeds less so).
Absorption
The epidermis is a keratinised stratified squamous epithelium. The main function of the epidermis is to protect the body from harmful influences from the environment and against fluid loss. It is well designed for this task. Epidermal Growth Factor (EGF) is a 6.2 kDa polypeptide (protein) containing 53 amino acid residues, not huge by biomolecule standards , but too big to slide through the spaces between the stratum corneum brick and mortar wall. Like most proteins, EGF is a polar molecule, making it doubly difficult to breach the defensive barrier. Without a specialized strategy (e.g. stable liposome, solid lipid nanosome, or other such envelope) it is likely that very little will past the SC. Most will be denatured and leave protein debris on the skin surface. Which actually can be a good moisturizer when combined with water (albeit a relatively expensive one).
EGF and Cancer
While EGF is not mutagenic (it does not initiate cancer formation), it is mitogenic (it stimulates the proliferation of cells, including cancer cells). Inhibitors of epidermal growth factor signaling can slow and even stop proliferation of some tumors
Cells in the body, must ask permission to multiply and expand, thus restricting growth to the places and times when it is needed, e.g. for baby who is growing, or for an adult healing a wound. Normally that growth is precisely orchestrated; tissues communicate through a panoply of growth factors and cytokines, passed from cell to cell to control growth and ensure that cells behave normally and healthfully. Cancer cells, however, often acquire the ability to give themselves this permission, so they can grow without worrying about the consequences to their neighbors. Epidermal growth factor (EGF) and its receptor are one place where cancer cells short-circuit the normal controls. EGF is part of a complex network of growth factors and receptors that together help to modulate the growth of cells. EGF is released by cells, and then is picked up either by the cell itself, stimulating its own growth, or by neighboring cells, stimulating their ability to divide (mitosis). Many aggressive types of cancer have overactive signaling through the epidermal growth factor system. They either create excess amounts of the growth factor or develop mutant forms of the receptor that are unnaturally active. Many anti-cancer drugs target this very pathway to slow or stop the spread of tumors.
What does this mean for skin? It does not mean that you need to worry that ECF will cause a skin cancer. However, if you should have skin cancer in any stage (including one too early to detect), ECF will make it grow more quickly. So, who has skin cancer? Consider this – skin cancer is the most common form of cancer in the U.S. More than 3.5 million skin cancers are diagnosed every year. Who is at risk? Older people. If you are over 40 and have a history of sun damage, there is a pretty good chance you will experience skin cancer. Between 40 and 50 percent of Americans who live to age 65 will have either skin cancer at least once. Up to 90 percent of the visible changes commonly attributed to aging are caused by the sun. The more signs of aging, the higher your risk for skin cancer. So, who is likely to have skin cancer? The same people who seek products to counteract skin aging. There are also pre-cancerous lesions to consider. Basal cell carcinomas often arise in lesions previously diagnosed as actinic keratosis. There is some evidence that mitotic overdrive can move a pre-cancerous lesion to a cancerous one.
In Summary
1. Topically applied EGF, without counterbalancing cytokines, will cause epidermal cells to proliferate, plumping up the skin, but doing so in a non-physiologic, uncoordinated fashion.
2. The site of action is the epidermis itself, as most of the growth factor will be unabsorbed anyway, in the absence of a specialized transport vehicle. Even if it did reach the dermis, EGF has minimal effect on fibroblasts and thus has severely limited capability to alter the architecture of true wrinkles.
3. EGF is an effective depilatory agent, popular among sheep farmers as an effective way to strip wool from the hides of their animals. Watch your eyebrows and hairline!
4. EGF is a potent mitogen, but not a mutagen. As such it is not cancer causing, but once a cancer gets started, ECG can cause it to grow rapidly.
5. Whatever the source, EGF is relatively expensive to isolate or manufacture. When weighing the risks and benefits, you might also want to weight the costs.
6. Several companies are now marketing EGF derived from barley through a process known as transgenic pharming. This has its own set of concerns. We refer you to the links provided here for details.
Conclusion
EGF is a potent, natural biochemical. It clearly does what its name suggests. However, putting a single cytokine (cellular signalling molecule) on your skin, unbalanced by other cytokines that work in concert during growth and healing, may not create the cosmetic result you desire. And, it is not without potential unwanted side effects. Certainly if you are someone who has had skin cancer, or is at risk for skin cancer, or is at an age when undetected skin cancer is very common, you would want to consider carefully the potential of EGF to accelerate a cancer that might be forming but is not yet evident.
Your comments are welcome.
Selected References
Goodsell, D.S. (2003). The Molecular Perspective: Epidermal Growth Factor. The Oncologist October 2003 (8,) 496-497.
Yu L, Cho CH, Liu SW. (2011). Epidermal growth factor stimulates the proliferation of human esophageal squamous cell carcinoma HKESC-1 cells by increasing COX-2 expression. J. Southern Med. U. (8), 1323-6.
Soeda A, Inagaki A, et.al (2008). Epidermal growth factor plays a crucial role in mitogenic regulation of human brain tumor stem cells. J Biol Chem.18(16),10958-66
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Thank you for the explanation of how EGF’s work! If counterbalancing cytokines were being added to the skincare products, how would they be labelled? Are there any “natural” products in our environment which could mimick the counterbalancing act of ese needed cytokines? Also, would a product that restores elastin fiber production be more beneficial?
Generally, the products that are labelled with “conditioned medium of stem cells” or “conditioned medium of fibroblasts” contain a mixture of hundreds of different cytokines, some from each family. Skinmedica TNS serum is one. ReLuma Anti-aging Serum gets close with a product based on adipose derived human stem cells. Not my choice of stem cells (wrong cytokine recipe). And not sure whether they are isolating only a few (9 according to Marta).
Now, you need to know that products claiming to contain plant stem cells don’t contain human cytokines, and in fact are really just ground up plant bits. These products are based on pseudoscience, and should be avoided. They do not pass the BFT truth test. We will do a detailed report on that whole scam soon. Products like Juice Beauty Stem Cellular Repair and Hydropeptide Hydrostem+6 are perpetuating this marketing myth.
In terms of “natural”, we consider the cytokines from human stem cells to be quite natural, because they are the exact same ones your own body makes (just makes a lot more of them when you are younger). You won’t find these cellular messenger molecules in plants (unless you transfect them with human DNA), because plants share very few cytokines in common with humans (they are called cytokinins in plants, and they are different). For instance, a plant tends to deal with a wounded limb by killing it off and growing a new one. Until we figure out how humans can grow new limbs, we should probably not try to dose up on the plant limb killer chemicals.
Elastin is under cytokine control. Transforming growth factor-β (TGF-β) is the best known of these. The problem with elastin (some of the oldest proteins in your body) is not lack of production, but the problem of glycation leading to stiffness. If it gets broken down, it gets replaced. So a better strategy is to undo cross links, clear out old collagen and elastin, then make new, fresh fibers. We will do a collagen & elastin physiology primer soon.
Apart from the many parabenes, do you really think the tns essential serum is safe for long term use?…: http://www.beautypedia.com/Brand/SkinMedica/254.aspx
The review you linked to must be very old, as it ignores a good deal of evidence in favor of the efficacy and safety of so-called “conditioned media”, not just from SkinMedica but from many sources, around the world, including soiid academic centers . It also presents a number of errors in interpreting the biochemistry of CM. Whoever wrote is not expert in cell biology. I recognize it is a fast moving field, and the terminology has changed, adding confusion. Most scientiosts in this area look to stem cells as superior sources of these cytokines and growth factors. SkinMedica sticks to fibroblasts. The fact is this stuff has been extensively researched, and has been around for about a decade without reported safety issues. They should dump the parabens.
hi,
it is very exciting to see others thinking about long-term effects of stem cell-based cosmetics. I have brought it up to Marta’s attention in the past in r/t ReLuma serum; unfortunately this subject never became a discussion (the comments’ thread is no longer available for review). Regranex gel used in care of diabetic foot ulcers was the first red flag. The end-result of growth factors’ use in some of the trials of therapeutic angiogenesis in coronary artery disease was malignancy. We simply have no control over these powerful “signals” of cellular growth. There is no end-result research either to prove safety. It is sad to see that vanity takes over common sense so easily.
Growth factors are indeed potent molecules. Regranax does work, but carries a significant warning label. You are right that signalling proteins in general are very powerful, and they work on just about every cell/system, and thus have a high potential for unintended consequences. Platelet derived growth factors are quite similar to epidermal growth factor (same family). They do the same thing (stimulate mitosis, or cell division, growth, and proliferation). It makes total sense that if a potent mitogen meets up with a tissue that has undergone mutagenesis (DNA altered to be come cancerous) … tumor proliferation could occur. Some cancers deviously figure out how to amp up their own growth factors (or receptors for same). I suppose if we feed a tumor some unopposed growth factors, we would be saving them the trouble.
disagree about Regranex – look at the Warning box. as far route of administration – we don’t know enough about the variations in the effect depending on the route. so, who really knows?
BOXED WARNING: An increased rate of mortality secondary to malignancy was observed in patients treated with 3 or more tubes of Regranex Gel in a post-marketing retrospective cohort study. This means that it didn’t cause any cancers, but if you had one it grew / spread faster, leading to earlier mortality.
This is consistent with what we have been saying — Regranex, like EGF, is not a mutagen, but a really potent mitogen. Some cancers thrive on growth factors. Thanks for reminding us of that.
I like this post, enjoyed this one thanks for putting up.
I think you should call it carcinogenic. According to Mirriam-Webster dictionary, carcinogenesis is defined as “the production of cancer”. It seems that production has several parts – 1) initiation 2) growth 3) spread. While EGF may not initiate, it sure is part of growth, which leads to spread. If 50% of older people are going to get skin cancer, then half of those women who put this on their face are going to produce (grow, spread) their cancers by their own hands
You make a good point. The FDA says Regranax is “linked to” cancer, not “causing cancer”. Here is a review:
Diabetes Gel Regranex Linked to Cancer
Regranex Users Have 5 Times More Cancer Deaths
By Daniel J. DeNoon
WebMD Health News
Reviewed by Louise Chang, MD
June 6, 2008 — Diabetes patients who use Regranex gel to treat dangerous foot and leg ulcers may have a fivefold higher risk of dying from cancer, the FDA today warned.
The FDA will ask Regranex maker Ethicon (a division of Johnson & Johnson) to put a “black box” warning label on the drug. The black-box warning is FDA’s highest warning level.
“In announcing this label change, FDA still cautions health care professionals to carefully weigh the risks and benefits of treating patients with Regranex,” Susan Walker, MD, director of the FDA’s Division of Dermatological and Dental Products, says in a news release. “Regranex is not recommended for patients with known malignancies.”
The cancer finding comes from an FDA review of a postmarketing survey that suggested there might be a link between Regranex and cancer.
“FDA has now completed its review of the study and has concluded that the increase in the risk of death from cancer in patients who used three or more tubes of Regranex was five times higher than in those patients who did not use Regranex,” the FDA reports.
Despite this fivefold increase in risk, the finding is based on only four excess cases of cancer, according to an Ethicon news release.
“We remain committed to the safety and efficacy of this product when used according to its label,” Ethicon spokeswoman Jackie Jankewicz tells WebMD.
Regranex is a medicine that is a genetically engineered form of a human growth factor that helps wounds heal faster. It is a huge benefit to diabetic patients with slow-healing wounds on their legs or feet that often result in amputation of the affected limb.
Because Regranex makes cells grow faster, there has been concern that it will also make cancer cells grow more quickly. That’s why Ethicon has monitored patients since the drug was approved in December 1997.
There’s no evidence that Regranex causes new cancers, although the follow-up study has not gone on long enough to rule out this possibility.
I just wanted to thank you doctors for taking the time to educate us about these products. It really makes you think about how easy it is to believe the false science and product claims, I guess because we so much want it to be true. Keep up the great work.
Hey Dr John,
I’m a bit perturbed by point no 3 in your summary list, where it says that EGF is an effective depilatory agent. This because Reluma, in their hair growth products, use the Human Adipose Derived Stem Cell Conditioned Media as a primary ingredient. Isn’t that kind of counterproductive? I would be more than grateful if you would explain this to me. Thank you.
,
Hi Arandiel. They are two different things. Conditioned media of stem cells contains a cocktail of cytokines derived from stem cells in culture, including low (physiologic, natural) levels of multiple growth factors. EGF is a single growth factor and is derived by transgenic pharming (in this case). It is present in non-physiologic (not natural) concentrations. EGF in this application has NOTHING to do with stem cells (another science error at truthinaging.com where they lump it in with stem cell products; it’s nothing of the sort).
I came across this study while delving into crosstalk between various cytokines and their cellular receptors. What it points out is that UV radiation works just like EGF on growth factor receptor (EGFR). Both lead to the activation of c-Jun, the activator protein involved in photoageing. It suggests that downregulation of the EGF-EGFR pathway could be exploited to prevent UV-induced skin aging. The obvious valid antithesis is that upregulation (by putting pure unopposed EGF on your skin) does the opposite – it would promote photoageing.
————–
Cell Signal. 2010 Feb;13(2):139-44.
EGF receptor crosstalks with cytokine receptors leading to the activation of c-Jun kinase in response to UV irradiation in human keratinocytes.
Wan YS, Wang ZQ, Voorhees J, Fisher G.
Abstract
Ultraviolet (UV) irradiation causes photoageing through induction of matrix-degrading metalloproteinases (MMP), which are upregulated by activator protein-1 (AP-1) (Jun/Fos). The c-Jun kinase activity proves to be critically important in the regulation of AP-1 activity. Our previous studies showed that UV irradiation activates epidermal growth factor receptor (EGFR) and cytokine receptors leading to the activation of c-Jun kinase in cultured human skin keratinocytes in vitro and in human skin in vivo. However, the mechanism of UV-induced cell surface receptor activation and the crosstalk among growth factor receptor and cytokine receptors were not fully investigated. This study showed that UV (30 mJ/cm(2))-induced EGFR tyrosine phosphorylation in a manner similar to EGF (100 ng/ml), or IL-1beta (10 ng/ml) in cultured human keratinocytes. In all cases, EGFR tyrosine phosphorylation was completely inhibited by pretreatment of PD153035 (100 nM, 1 h). Also observed was that UV induced autophosphorylation of interleukin 1 receptor associated kinase (IRAK) in a manner analogous to IL-1beta or EGF. In both UV and EGF cases, the phosphorylation of IRAK was inhibited by pretreatment of PD153035. However, IL-1beta-induced IRAK activation was not affected by PD153035. In vitro kinase assay using GST-c-Jun as a substrate revealed that pretreatment of PD153035 completely inhibited UV- and IL-1-induced c-Jun kinase activity in cultured keratinocytes. Taken together, the above data suggest that EGFR plays dominant role in the crosstalk among growth factor receptor and cytokine receptors leading to the activation of c-Jun kinase upon UV irradiation, and that EGFR could be one of the targets for clinical and cosmetic prevention of UV-induced skin aging.
Hi Dr John,
This may be like trying to force black or white in an issue that clearly defines many interim shades, but from your articles about EGF would I be correct in surmising that usage of Bioeffect (or any othe EGF based product) is likely to introduce a faux anti-aging process? By this I mean that mitosis of the skin cells in the upper dermal layers is encourgaged but ultimately the root causes of aging are not addressed (Fibroblast reconstruction, collagenation of damaged tissue etc). In effect; cells multiply and produce a nice ‘plumped’ look – which would account for the subjective accounts posted on the internet by users – but the process is not actually ridding the subject of wrinkles or laying down any beneficial framework to retard or reverse the aging process?
Please forgive me if I’ve misunderstood any of the processes involved – it’s not an area I have any previous knowledge in.
Thanks!
Yum
PS. Fantastic site by the way.
Yum, your summary is spot on. Plumping the epidermis with EGF, without providing the other cytokines & growth factors needed for coordinated rejuvenation, leads to pleasing but superficial effects.
Analogy: your house is ageing, the foundation is slumping, wood has rotted in some places, and it just plain looks old and tired. A guy comes along and sells you aluminum siding (remember Tin Men?), pocketing $20,000. The house looks pretty on the outside, at least for now. On the inside, the structure has not changed. The foundation gets worse, and the siding starts to bulge in places. The old wood can no longer breathe, and begins rotting (like those pores getting clogged). Now you could try taking off the offending siding, but things would by then look even worse! In the end, nothing short of a major renovation will fix the situation.
I am not against plumping as part of an overall renovation project, but not with unopposed EGF. The best moisturizers are also “plumpers” because skin is retaining more fluid (matrix, not just H20). Soy isoflavones stimulate receptors way upstream to stimulate skin to add additional layers (coordinated, not a single cytokine).
Thanks for your excellent comment, Yum.
Thank you for all the work you put into this site. I feel quite well informed. Keep up the good work. Did you ever find an affiliate site to do product reviews?
Hi Dr John and Dr George – I have a question on another EGF called rh-oligopeptide-1. Is this EGF oncogenic also and/or would it cause a “faux anti-aging process” referenced by Yum’s comment above? How do we know if a product contains the necessary cytokines to work in conjunction with the EGF? I am getting better at understanding the science talk (esp Stem Cell Part 2 article), so I hope this is not a dumb question. BTW, this is an ingredient in Skin Nutrition Cell CPR.
Hi Kris Ann. rh-oligopeptide-1 is EGF. The name on the label is an INCI (International Nomenclature of Cosmetic Ingredients) name. So why not just put “EGF” or “epidermal growth factor” on the label, since it is such a well known biochemical? Good question. Could it be a marketing ploy? Turns out anybody can petition INCI to get their own ingredient name in the database. Which is odd, since the whole reason for the database is to comply with regulations that state that ingredients need to be ‘clearly” stated on the label. This does not clarify, it obfuscates. Further, it is a total misnomer. By definition an oligopeptide has 20 or fewer amino acids. Since EGF has 156, it is not an oligopeptide. But hey, this isn’t about science, right? It’s about selling products. Peptides are good, right? So oligopeptides sound good.
Now to answer your other question, I would to know how much EGF is in the product you mention. However, if i try to go to their website, I get this from my computer protection system: REPORTED ATTACK PAGE. This web page has been reported as an attack page and has been blocked based on your security preferences. Attack pages try to install programs that steal private information, use your computer to attack others, or damage your system.Some attack pages intentionally distribute harmful software, but many are compromised without the knowledge or permission of their owners. Yikes! Stay away.
Your question about other cytokines is a complex one. I don’t think anyone has done the kind of work required to answer with surety, since there are hundreds of cytokines, and the combinatory permutations are therefore in the millions. But I can tell you a few basic principles that we use as guidance. The first is called primum non nocere. It’s a Latin phrase that means “First, do no harm”. If there is any doubt about an ingredient, go back and do the research to make sure it’s safe. The second principle is one called biomimicry. The best way to discover natural cures or benefits is to study the natural, and try to mimic or replicate it. We know that groups of cytokines secreted by human cells under certain situations are aimed at healing and restoration. We know that if you take a single cytokine and apply it, it may do something powerfully, but that is not the same as physiologic. Not natural. Pure EGF is not natural — your cells are far too clever to rely on a single signal to effect repair. Cytokines can be inflammatory or anti-inflammatory. EGF can be either, depending on the context or ‘milieu”. If it meets the wrong milieu and is not balanced by other cytokines, it will became an inflammatory agent. It will lead to growth, but not necessarily coordinated growth. More like scarring growth — fast but ugly. But when part of a coordinated, balanced cocktail of cytokines it can play an important role in growth and healing.
One of the cytokines that is definitely missing is fibroblast growth factor (actually a family of 22 different cytokines). This at least would generate more collagen synthesis. But again, all these growth oriented (mitogenic) cytokines have to be balanced with other cytokines that prevent the wrong kind of growth. We should post a list of the various families.
Here’s a board exam question. If you see this constellation of symptoms & signs in a male body builder, what do you think? Acromegaly, fluid retention, carpal tunnel syndrome, diffuse painful joints, gynecomastia (enlarged breasts in males), and liver damage … what is your diagnosis? That’s right, he has been injecting himself with human growth hormone. Some of the effects are quite similar to EGF, only systemic. Excess hGh is also inflammatory.
Sorry for the long answer. You got me started!
Is it OK to use product with both EGF and FGF?
They belong to the same family, and have some receptor crossover. I would want to be cautious.
Would this caution extend also to a product using FGF1 as its sole growth factor?
Yes, any cytokine or growth factor in isolation holds risks, because it upsets a complex interplay of cell signals. Especially growth factors, as cancers are famous for exploiting them for their own nefarious purposes. There need to be a physiologic balance. Don’t try to fool mother nature – she has ways of getting even.
Dr John,
I am a biochemist. A couple of points.
1. I respect your position on GMO, which is shared by some others. But it is a huge topic for discussion. Since the ingredient we are discussing is extracted and purified, the source of the molecule is irrelevant except for a moral debate. Insulin is produced by transgenic e.coli bacteria and has a blemishless safety record, being injected by millions of people everyday. The e.coli or barley is just a biological machine to produce a chemical which is extrated. The transgenic organism is not consumed in any way.
2. Dealing with the cynical remarks on the ingredients list – i feel your comments are unfair. They imply a cosmetic company is deceiving the public by hiding the name of the ingreident. I think they would actually like to do the reverse but are required under law to adhere to the INCI naming system. This is regulated by the FDA. They must list the ingredients of a product in order of concentration using a designated name for each ingredient. The PCPC issues names based on a chemical naming rationale.
3. Can I ask if you have any interests to declare? You seem to be in favour of Skinmedica as a conditioned media of balanced cytokines but you do not mention that this media is derived from humans (banned in the EU) because of the danger of using human derived products. The potential for prion transfer is significant leading to CJD is considered a risk meaning a blanket ban on all human derived produce. This apart from much larger ethical questions in my view, such as using Human baby foreskins as a source for cosmetics rather than plants.
4. I would need to more time to respond to your other main points about the dangers of using a single ingredient rather than a complex. To give a considered reply will take an entire day collating evidense and research that would paint a different picture. I am sorry but i do not have the time to do that. But I think that your argument could be used to say that there is no point taking vitamin C supplements without a thousand others to ensure the right mix. We may end up drinking the blood of other humans if we were to be literal.
5. EGF does NOT cause cancer. You said it yourself. It is a massive leap to say that a product which increases proliferation (as many cosmetic active ingredients do) may therefore potentially speed up skin cancer if someone has it, from saying it causes cancer. We do not confuse alcohol’s ability to induce procreation as proof alcohol can create human beings
Hi mandyM,
Welcome to the debate. We are grateful that you would take the time to visit and for your very thoughtful comments. Please allow me to respond.
1. When transfected e.coli are employed within bioreactors under highly controlled conditions to create proteins via a transfected DNA-altering process, there is little or no risk that that same e.coli will find its way into the environment and spread that gene to the wild type. With transfected barley, not so safe. This company already got in trouble with the Icelandic authorities when it was discovered they were growing their genetically altered barley in an open field, rather than a controlled greenhouse. Their comeback was that Icelandic barley has such a short growing season the risk was small. Small comfort. If the GAO barley cross pollinates with wild barley, the risk is that the whole barley crop in Iceland could contain the EGF gene. Now recall, it is orally ingested EGF that strips the wool right off sheep. So imaging some sheep, some barley, you’ve got yourself a wooly mess. So, as you can see, the issues are not so much moral as public health, and economic.
2. The FDA requirements state a requirement for INCI naming, but it was based on the Second Edition of the INCI database, which uses common names, not chemical names. So, by law, they could have used Epidermal Growth Factor and been perfectly compliant. And since the regulations have as their stated purpose to make things clear to the consumer, I think that would have been a better choice than rh-oligopeptide-1.
3. All my interests and biases have been stated repeatedly, e.g. here and here and elsewhere. SkinMedica is a competitor to my company. You may know that prion transfer cannot take place via an epidermal route. It takes place by ingesting infected nervous tissue (e.g. brains) or by a parenteral route (injection). There has never in the history of the world been a case of transfer via skin, nor airborne transfer. Never. The EU regulations don’t anticipate dermatologic products, as far as I am aware, and so the restriction is perhaps over-reaching. As far as making the case that EU regulations are out of step with the rest of the world (my view), let’s look at transgenic crops again. How far behind is the EU in allowing exceptions, and how long was a ban in effect? I wasn’t aware of moral issues of baby foreskin…you will have to enlighten me. They are the waste products of a procedure done for other reasons, just like using adipose stem cells from liposuction. Not pretty, but not all that morally controversial.
4. There are many examples throughout human biochemistry. Take the example of amino acids. They exist in harmonious balance in your circulation, largely regulated in the liver. If you give a bunch of one or several amino acids, they compete for transport across cell membranes with other amino acids in that group, leading to a functional deficiency of others. Something quite physiologic like cysteine can become a poison. Here and here are classical papers on the subject.
5. Yes, I said EGF does not cause cancer. Yes, I also said that cancers can and do exploit EGF to grow and enlarge and slip past the normal growth controls. Both are true. Also true that 50% of people who live to 65 get skin cancer. Starts small, before you can see it. I see risk there, don’t you? Shouldn’t we at least tell people about that risk, so they can make informed choices?
I thought for sure it was the alcohol!. I guess the old reassurance “don’t worry, as long as you don’t drink alcohol tonight, you won’t get pregnant” will now have to be modified.
Dear Dr John,
Thank you for your considered reply. If I may, i would like to respond. For ease, i will stick to the numbers we have been using.
1. I take your point on barley crops mixing with regular barley crops. I take your expertise that this would happen.. It is not the same with e.coli as you have stated. However, I wanted to be clear that you are not saying that the EGF extract in the Bioeffect product can have environmental effect.
2. I am sorry to disagree but while you can use common name, you cannot simply choose any name you want. You cannot say vitamin C for example but l-Ascrobic Acid. If you include Titanouim Dioxide, the name changes to a color reference if you are using the same ingredient to make it white/opaque. The name of the Bioeffect ingredient includes the words ‘transgenic barley’ as the PCPC presumably asked for that. The SH stands for synthetic human, as in not simply recombinent (RH). All these things were out of their control. Peptide and amino acid chains have taken this nomenclature for many years and in my experience, the PCPC have criteria for naming. As part of my work, i register INCIs and the USA is out of sync with international regulations in Europe, Australia, China and much of Asia. Bioeffect go to great lengths to promote their product containing EGF, it is only your suposition that they are being deceitful when in fact this could just be name-calling on your part.
3a. Thank you for the links. I was not clear from the blog entry who you were at the time of reading or that you were a skin care company. Skinmedica is definitely banned in the EU.
3b. There is debate over the viability of transcutenous transfer of prions. It is certainly not clear cut. One has to also consider mucousal membranes, people with cuts and of course most importantly the ingestion of product through people putting their fingers in their mouth or kissing their wife on the cheek. Also there is potential for children to ingest through misuse. It is surely without question that there is a real danger and if you are to be as rigorous about your product as you being about others, then it is right you acknowledge this, even if you wish to qualify that risk as being small. You simply cannot with any credibility rule out prion transfer from using human derived products. This is why the EU bans it outright. From my experience, the EU is ahead on these things and many other countries seem to be adopting the EU regulation in favor of FDA ones. One of the benefits of being a relatively new institution and able to look at things fresh with less industry arm twisting. Plus since the EU is not a nation, it has less patriotic slanted rulemaking and really is focused on science.
3b. I suppose morality is a personal thing, but for me, using a baby’s foreskin as the base for a cosmetic product is fundamentally wrong. Adipose tissue,if your own, is a different matter. I have no objection to people storing their own foreskin for future use but that would rule out most potential buyers!
4. I agree entirely and I think you are making the same point as me.
5. According to Bioeffect, there is no evidence of abnormal cell growth using EGF. The issue is to do with receptors. Ronald Moy, the (past-) president of the American Association of Dermatology says EGF is a breakthrough ingredient – the best he has seen in 30 years. You can see him saying these words on Youtube. There are licensed skin ulcer drugs containing EGF which have been through the FDA medicine approval process (much greater test for safety than any cosmetic company would ever do). Also genetically altered mice to over produce EGF showed no cancerous outbreaks etc. (sorry no reference but this is again from Bioeffect). I am no expert in this area of cytokines so it is difficult to know what to believe. Whilst you are a perfectly charming gentleman, I certainly cannot take your words at face value, any more than theirs. And since you are a competitor – you would say all this.
Mandy
Hello again Mandy,
1. I am saying that if EGF producing barley got into the human/farm animal food supply it could have effects, and that could be called an environmental issue.
2. I am not a regulatory expert. You can find them easily. Here is one (Marie Gale). Scroll down to Are INCI names required?. She says the same thing I did. Maybe the experts don’t agree – like all regulations, there is room for interpretation. However, BioEffect could have used the common name, or both common and obscure. They chose obscure. Perhaps they had no evil intent.
3a. If you want to look at the prion issue, do look at the only universally recommended precautions … “destroy all infected tissue”. How do you apply those sorts of “precautions” in a cosmetic marketplace. Further, by extrapolating from parenteral/enteral to topical risk for one substance (with zero data to support) you would have to do the same for every product. If anywhere along the way an animal (including human) substance touched any part of any product, it would be contaminated, and destroyed. If the glue on the label came from cow hide (as is common). You can see where this leads. It is not a reasonable extrapolation. No infectious disease authorities have even made this type of conjecture, as far as I know. The EU regs simply do not anticipate a human-derived product being used for topical purposes. I hear that may actually change in the future.
3b. I don’t like the foreskin idea myself. Whether or moral or intellectual, it lacks a compelling benefit to justify the concept in the first place.
4. Agree to agree.
5a. Interesting that you cite Ronald Moy, who has a direct and compelling commercial interest in EGF products, without questioning his bias, yet you call me a competitor to BioEffect and tell me you therefore cannot take me at face value. Honestly, your logic here totally eludes me. Seems a double standard.
5b.The mission at BFT is not my company’s mission. Noneltheless we recognize the contaminating effect of bias, and disclose all the relevant variables. That aside, let me say also that we like EGF, our products contain EGF. But balanced by a plethora of other cytokines to create a concerted physiologic effect. So, it’s not like we are some anti-EGF force at all. Rather, it’s that we recognize risk/benefit, and find unopposed EGF as deserving of a risk discussion. Which you should appreciate as someone who wants to calculate the risk of prion contamination via dermal contact for which there is zero evidence, ergo infinitesimally small if any risk). As we have pointed out, there are known examples of risk associated with the application of single cytokines in a wound healing context (read the comments above on Regranex and what earned its black box warning). You can call me to task for extrapolating from one cytokine to the whole slew, which is fine, because we are now in the realm of theory, and the evidence base is not sufficient to argue with ironclad conviction. But again, I bring up your prion concerns. If you are really so risk adverse as to want to make that leap (again – to remind – never in the history of the universe-despite much investigation-has there ever been a documented case), they why do want to relax your standards when it comes to something like this (e.g. Regranex, single cytokine, statistical association with excess death). Excuse me for saying it, but again I musty call double standard.
Thanks again for the thoughtful discussion. How about sharing with us your disclosures – why so interested in EGF/BioEffect? Any connections direct or indirect between you and them, or transgenic pharming, or any of this? Do you work in industry, or academe?
Dr John,
1. So we agree that there is no risk to the environment from using Bioeffect. The debate on transgenic farming is a red herring.
2. I think there is some confusion here. You said before that Bioeffect could have chosen any name they wanted but as I stated, the nomenclature is determined by prior art and the vagaries of the PCPC decision. The manufacturer does have input but they cannot simply state what the ingredient is called. The rules for labeling are different all over the world. In Europe, the law states clearly that the INCI name must be used. For a small cosmetics manufacturer, like Bioeffect, they will have wanted to produce one label to cover all markets. Therefore it is entirely plausible that with no bad intent whatsoever, the company used the INCI name on the pack so the product can be sold worldwide. In my experience, it would be unusual if the company made a change for the USA. On double-standards, you would be right to alleged in this case that they had changed things in the USA simply to talk about EGF rather than use the accepted INCI name.
3a. I really have no time or Medline access to properly address this points, but here is just one article from the FDA. I cite this solely to demonstrate that this is not as clear cut as you make it sound. http://www.fda.gov/cosmetics/productandingredientsafety/potentialcontaminants/ucm137012.htm
One of the reasons, if not the main reason, why cosmetic companies around the world use single GF ingredients is because there is a ban on human-derived produce that is set to expand internationally. I accept that a physiological blend of GFs rather than a single GF would be preferable, but given the former is not possible for companies selling in the EU, the single vector is more conservative that adding other GFs to a cocktail which if poorly thought through could end up with one GF blocking another. The rationale for using a single GF eg. EGF is sensible.
5a. I apologize if you feel there was a double-standard. I know that Ronald Moy has a financial interest in EGF and tried to state in my reply to you that i was not sure who to believe as both doctors have opposing financial interests. As a leading dermatologist, president of the world’s most important dermatologist academy which over 22,000 visitor last year to the San Diego conference, it would seem odd that he is not concerned about EGF in the same way as you are. Equally I would say the same to him about why you as a professional physician and researcher are not worried about prion transfer.
5b. Regenrex is a PDGF product. Different cytokine. The relevance of it being a single vector is overshadowed by the difference of action. Further and more importantly, this product is a medicine which has the scrutiny of multiple phases of FDA regulated clinical trials.The patients (with leg ulcers) are almost always very elderly people who are susceptible to side-effects, have by definition a poor immune system. The product is applied to an open wound. If your product was applied to an open wound, you have already conceded that this would result in possible prion transfer. If your product was registered as a drug and went through clinical trials, who knows what would come up. We have no data on your product or its long term effects. It not a fair fight.
I do appreciate your repsonses and also that you are big enough and professional enough to host this debate on your site – both sides of the debate. I would trust your position less if you were not transparent which i think you are being.
I have no involvement with Bioeffect but work in the cosmetics industry as a consultant – my interest is bringing product to international markets and claim substantiation. I have met the team from Iceland at various trade shows. There is another excellent company from England that makes EGF without proteases that they say is safer or more stable. Both the aforementioned are proper scientist-backed operations – real PhDs etc. But every other company I have seen on the circuit either uses adulterated EGF, blends of GFs that counteract each other or worse, they include the apple stem cells or plant stem cells nonsense. I dont know if you know about this junk circulating the industry but this is what we should be getting mad at. I guess I want to support science. If i was on their blog, i would be representing you just as robustly. I dont like one-sided arguments.
Mandy
Hey Mandy,
Back to #1.
2012-01-19 News report …
Greenhouse of GM barley damaged in storm in Iceland
The Environment Agency of Iceland is investigating an incident where a greenhouse run by the plant nursery Barri on behalf of ORF Genetics, where genetically-modified barley is grown, was damaged in the storm in east Iceland on Tuesday night. Biology professor Kesara Jónsson commented to ruv.is that it was lucky the greenhouse was damaged in the winter, otherwise the barley’s seeds could have spread beyond the nursery. The Environment Agency has issued ten licenses to breed genetically-modified animals and plants in Iceland, including flies and mice. The cultivation of genetically-modified barley has been authorized in five locations in the country; one of which is in the open.
In other words, the only reason this wasn’t an environmental emergency is because it happened in winter, not the pollination season. This is the parent to the cosmeceutical company, I am pretty sure, from other press reports. So not only is environmental contamination (e.g. spread to cultivated non-modified barley, the only cash crop of Iceland) and/or crittters a theoretic possibility, there seems to have been a near miss involving the same folks in Iceland. This company is also growing their GAO barley in open fields. What do you think of that?
#2. I accept your thesis. They were trying to do the right thing. Especially since i now know you are a pursuer of truth in regards such things as adulterated EGF, and plant stem cells nonsense. Seems we share some views. The enemy of my enemy is my friend (or whatever the PC version of that would be).
#3. ” Transmission of the BSE agent to humans through intact skin is believed to be unlikely; however, cosmetics may be ingested or applied to cut or abraded skin or to conjunctival tissues that can provide direct routes for infection.” Theoretically unlikely, actual measured incidence zero. Let’s just call it “highly unlikely”. In a relative odds ratio lets say it’s about the same as being struck by lightning 72 different times in 72 different places over 7.2 years. Theoretically possible, but statistically zippety-nada. Maybe we should put warning labels on – do not apply to open wounds or drink this stuff.
#3b I can accept your argument for the EU, but speaking for the rest of the world we don;t want to be limited to a single cytokine at a time, when nature clearly demonstrates that cells put these out in complex arrays, and that the net effect is not the same as a one off. Look at it from information theory (we are talking cell-to-cell communications) – suppose you were writing me a note but could only use key on your keyboard. Or if on my end I stripped out every word except those beginning with ‘C”. Further hint – I base a lot of my work in biomimicry. How did nature design it? How close to that can I get? How can I exploit that complexity therapeutically? I accept your economic argument (can;t sell into EU), but that can be said for a lot of things. Which could explain some of the current economic difficulties over there.
#5a There was only a double standard when you failed to point out that he had interests while pointing my own. Now that you acknowledge it, its no longer a double standard. Yeah!
#5b. It’s not a fight at all! It’s different perceptions on the balance between risks and benefits (science), regulations vs consumer choice (politics), and the realities of big companies vs small lean startups (I was a medical director for the big PDGF company, BTW). We continue our testing, and will likely apply for registered drugs in the not-too-distant future. Maybe even on open wounds. There may even by a cytokinal therapy for CJD!
I bet we could work this whole thing out in a evening over a few pints. Oh, and if you would like to test some AnteAGE (lab or face trials) we know a smuggler
I am 23 going on 24, with previously VERY youthful skin and a baby face, and about 9 months ago under the effects of doxycycline, got UV induced oxidation on my face, specifically the under-eye area, and it destroyed my skin. I was off balanced psychologically and googled how to get rid of wrinkles, and retin-a came up. I immediately went to my general physician and begged her to prescribe me it and applied it every day, and all of a sudden noticed I could see veins and I had MORE wrinkles. I look back and if I had just applied a nice moisturizer like jojoba oil or grape seed oil and kept hydrated, and consumed natural cancer fighting foods/oils, I would be fine. However I look sad, the skin is sallow and dark because it THINNED the epidermis and up close there are tons of lines and without frequent moisturization it is super ugly and a huge blow to my confidence and identity. In desperation I also purchased a very expensive cold laser that said the word “stem cell” in the marketing so I thought in my irrationality that it would fix everything. Here I am, 10 months later, really seeking answers, obviously wishing I never used the harsh chemicals under my eyes, but knowing I was not thinking clearly. I just want real advice on how I can re-thicken the epidermis and recover its hydration if possible, so I don’t have to lather oil on it every 10 minutes. Desperately seeking help, if someone could help me, I know the science is complicated but I am really seeking to fix the EPIdermis right now, and help my skin out with good food, sleep, exercise and home-made serums- wondering how I could harness EGF or niacinamide or peptides, etc. If anyone knows someone I could talk to I would pay for your consultation. I know our skin and bodies have tons of interactions going on at once and it would be bad to just put one thing on without complementing it with other things, etc- I just want my skin to recover itself to be able to reproduce in a healthier state. Much much much appreciated… It’s affecting me greatly and has emptied me of resources and taken away my trust of profit-based skin care companies wiling to prey on people. My situation is unique though as I am so young and the “wrinkles” are jagged cuts in my skin from oxidative stress. It’s been a process of becoming more clear eyed and understanding of holistic health. Please help anyone if you can. I could make my own serum or if anyone can recommend me a way to just get this improved, including red light therapy etc, if that works too. Regretting using retin-a, but can’t go back in time. Please help me with present and future. AMAZING THAT YOU ARE PUTTING THIS INFO ON. MUCH APPRECIATED AS THE TRUTH IS HARD TO FIND, WITHOUT UNDERLYING MOTIVES AND CONFLICTS OF INTEREST.
NAMASTE.
Sorry you are experiencing all this. Suggest you consult a dermatologist if you have concerns. The sallow/dark comment suggests some post-inflammatory hyperpigmentation, or solar hyperpigmentation, both of which can be associated with retin-a. If you are looking for a really good DIY formula, or kit, we suggest http://skinessentialactives.com. SeaKinNiaNAG serum (http://stores.skinessentialactives.com/-strse-93/Kinetin-DIY-kit%2C-SeaKinNiaNAG/Detail.bok) addresses both issues, may be all you need, and you can make it yourself inexpensively.
Uff. That was an embarrassing post. I am just seeing your reply now. I am definitely in the process of seeking integrative/naturopathic/holistic dermatologists, but I live in the U.S. and in Chicago. All the dermatologists offer are injections and chemical peels, and other treatments that induce short term inflammation, etc.
My main question is how to re-thicken and re-hydrate the epidermis (MAIN priority- the lines due to dehydration and thinning, and subsequent need for constant hydration is frustrating and saddening). I know I will need an integrative treatment. If anyone can engage in a brief email exchange with me that would be great, as I have a quick list of questions about copper peptides, soy isoflavones, red light therapy, sound therapy, and crystals with regenerative properties).
Another thing is to possibly regenerate the subcutaneous fat around the outer edges under my eye and whether or not peptides can do that.
Thank you for your response. It’s just very difficult knowing I compounded the damage to my skin (which could have been adapted to by smoothing some jojoba oil over it and going about my day).
You can get as scientific with me as possible, as I will comprehend it through my research and increased understanding and levelheadedness. Thanks again, and namaste.
It may take us a few days to get around to commenting on Michelle’s comments, so if any of you readers want to chime in, feel free. We know that many of you are quite knowledgeable, and we encourage open discussion & multiple viewpoints.
(And thanks for the lead on the kinetin DIY). Much appreciated, will look into it.