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.
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).
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.
Addendum: since the original publication of this article in 2011, we have fielded many questions regarding the safety of EGF. Since the discussion below is now quote lengthly, we decided to add right here a firm statement of opinion on that topic. We do not believe that EGF causes cancer. Period. There is much research about how cancers use EGF and other growth factors and their receptors to further their agenda of growth at all costs. But the same can be said of the ability of cancers to beg, borrow, or steal blood, oxygen, nutrients, and everything else they need for growth, often at the dire expense of tissues, organs or the whole organism. In short – that is the very nature of cancer and why it is dangerous – but that is not the nature of EGF. To blame EGF would be like blaming amino acids, carbs, fats, vitamins, minerals, hormones, etc. (cancers use them all). But you should think of EGF as the stolen object, not the thief. To the extent that cancers may co opt EGF, well then so does healing tissue after a surgery, or skin after damage by the sun. There is no scientific evidence that EGF applied to skin in any dose causes cancer. But then you don’t want to apply it to known skin cancers either. That is common sense. Knowing your own skin, and the signs of skin cancer, and promptly presenting to your doctor if you perceive any changes is the reasonable caution there.
We hope this message is clear. We can defend it with a huge body of knowledge in the published literature literature. We will present that for you soon.
1. Topically applied EGF, without counterbalancing cytokines, will cause epidermal cells to proliferate, plumping up the skin, but it may do so in a non-physiologic 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.
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. Tissues, normal and otherwise, will grow under its influence. This does not mean that EGF causes cancer. (see above addendum)
5. EGF is relatively expensive to isolate or manufacture. That may change in the future.
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 are not experts. We refer you to the links provided here for details.
EGF is a potent, natural biochemical. It clearly does what its name suggests. However, putting a single cytokine (cellular signaling molecule) on your skin, unbalanced by other cytokines that work in concert during growth and healing, may not create the best cosmetic result.
Your comments are welcome.
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