Thank you, Covalo!

https://covalo.com/ is a company that helps other companies bring goods to the market.

They invited me to a podcast that will be edited and published soon on Spotify. In the meantime, I wish to thank Anna Lorentz for her thoughtful questions. Here are my written responses to Anna’s questions, but the responses in the actual podcast will differ.

Questions by Covalo to Dr. Hannah Sivak:

For our listeners who might not be aware, what exactly are growth factors, and how do they function in the skin?

Growth factors are proteins in our body that stimulate cellular division and differentiation. They bind to specific receptors on cell surfaces and are essential for regulating various cellular processes. Different tissues have different receptors for growth factors and different growth factors that bind to them. The first growth factors were discovered by (winners of the 1986 Nobel Prize for medicine and physiology) Rita Levi-Montalcini and Stanley Cohen.

How do growth factors contribute to skin rejuvenation and anti-aging?
As we age, the epidermal turnover rate slows. The cascade of changes caused by slow cell turnover results in heaps of corneocytes on the older skin, which makes the skin surface rough. Many cosmetic dermatologists use products like hydroxy acids and retinoids to accelerate the cell cycle.

What they should do instead (or in addition to) is to correct the natural decline in growth factors that comes with age.

Growth factors initiate mitosis of dormant cells. Cofactors and nutrients are all required for metabolic processes, but only growth factors can initiate cell division. Using growth factors like EGF you can accelerate healing, decrease wrinkles, tighten skin, decrease sun spots, even help control acne. That’s not my research; it’s in the scientific literature in refereed journals.

How do growth factors differ from other popular skincare ingredients like retinoids or peptides?

The two you mentioned are very different.

Peptides are short chains of amino acids, too short and fragile to do much. Unless we discuss biomimetic peptides like Ozempic, most peptides do nothing and have no independent research backing them. They are used as label-value ingredients. The word “peptide” has a scientific sheen that publicists like (and they are cheap to boot!).

Conversely, retinoids work; they bind to the retinoic acid receptor on the nuclear membrane retinoic acid receptor and accelerate skin renewal. Most retinoids have side effects.
Growth factors and retinoids are different chemically and work differently. Retinoids are carotenoid derivatives, but they also increase skin turnover.

Growth factors and retinoids are very valuable in skincare, and it may be worthwhile to alternate them.

Can you explain the main growth factors used in skincare and hair care, and their benefits?

EGF was the first growth factor to be discovered and studied, but many more factors have been found since then. The great thing about growth factors is that when we use them, we only add to what is already there. There are no problematic side effects like with retinoids; we are pushing the skin back to “working young.”

EGF and KGF are the primary growth factors available for use on the skin and scalp. Both help with skin aging and healing, but KGF is especially useful for hair and nails.

What inspired you to focus on growth factors in your work and product development? When you founded Skin Actives Scientific, was there already a focus on Growth Factor products?

When I arrived in Arizona, I had already spent many years working with proteins. My background was in the expression and modification of transgenic proteins.

I could not get a job in academia (I was too old!), so I took a job in a cosmetics company. I saw interest in growth factors. At the time, none were available to the industry. Why? The FDA restricted the use of human-derived products because of the risk involved, although some adventurers were using animal products to mimic the effects of banned human-derived growth factors.

It seemed like a natural extension of my expertise to produce proteins that could be useful topically. Epidermal growth factor was the first protein we made, and it was great to see that our protein had activity like that of the EGF sold by Sigma, which was available only for research purposes. This was expected; they were, after all, the same protein, but now we could supply the cosmetic industry with real EGF! That was almost 20 years ago. And then we got active keratinocyte growth factor (KGF)!!!! We were over the moon!

Can you share some key findings from your research on growth factors, perhaps from your book “The Scientific Revolution in Skin Care”?

I read the scientific literature to find proteins that can be useful to the industry, and, most important, that are very safe. We make several proteins, and we add them to our catalog one by one. Expressing large quantities of a pure, active protein is not a trivial task.

Apart from the growth factors, I realized that antioxidant proteins could help prevent aging and alleviate the effect of pollution on the skin. We also added some antibacterial proteins, including a favorite of mine: defensin, the protein responsible for the healing effect of bee’s royal jelly. We no longer have to kill bees to get royal jelly healing activity.

How have Growth Factors in skin care evolved over the years?
It went from using crude animal homogenates (argh! That was at the time of mad cow disease) to having access to pure, active, bio-identical proteins at a cost compatible with everyday anti-aging products. Some old hacks are still using discarded growth medium containing animal serum; they are not saving money anymore; they are being silly!

Why should brands consider using proteins in skin care?

Because they work.
By using growth factors on the skin, you can avoid (or delay) blepharoplasty and face lifts. If you go the plastic surgery route, EGF will accelerate recovery and decrease scarring. This is the scientific revolution in skin care; why let it pass you by?

Are there any misconceptions about growth factors in skincare, or barriers to adoption, that you’d like to address?

There are primarily misapprehensions about cost, but you need only nanograms of the active proteins, so math is essential! When you work the math out, you add lots of anti-aging activity for cents! We will do the math for you and tell you how much pure protein to add.

Another is the “size rule,” a silly idea with no research evidence backing it, which proclaims that growth factors can’t penetrate the skin. But the skin is not an impenetrable wall. It’s not enough to propose a theory; you need evidence to support it. Cartoons are not sufficient!
Growth factors enter the skin and reach the cell surfaces where the receptors are.

What are the challenges in formulating skincare products with growth factors? I’m also curious how your background in biochemistry has influenced your approach to skincare formulation.

The first rule is to look at the data and eliminate advertising and misinformation. I discard myths and check the research in independent journals.

Make sure you know how much protein you have in hand. The number of molecules will determine how many receptors will be activated. Do not short-change your customers!

Primarily, have respect for proteins: many of them are fragile.

What are some formulation “tips & tricks” that brands and formulators should keep in mind?
1) Start with the right amount of active protein and
2) add the proteins at the last stage, not to a hot mix.
3) Stay around a neutral pH.
That’s it.

How important is the source of growth factors (e.g., human-derived vs. plant-based)?

This is clear: for excellent reasons, the FDA does not allow the use of human-derived proteins in cosmetics. In the industry, we are not allowed to use EGF extracted, say, from human urine and use it in cosmetics.

Genetic engineering provides an alternative. A protein identical to the human is expressed in a system that may be bacterial, fungal, plant, or even animal. Almost any organism can be made to express a foreign protein. The key is to choose the best system for the protein you want. Don’t think of what is “cool”; think of what is best.

If you do good work, the proteins will be identical to the human protein in structure and function, regardless of the system used to express them (some organisms modify proteins post-translation).

The expression system used to make the protein may be different, and the choice should be made on the basis on cost, convenience and safety.  You can use bacteria, plants, fungi, insects and even human cells in culture.

Each system has its problems but the system of choice, unless you have a “difficult” protein, is bacteria. In a couple of days we can get bacteria to make grams amounts of our protein because the system directs the protein to make our protein and practically nothing else. Bacterial cells are broken, and the protein is then purified in a few steps.

It’s possible to modify plants genetically, and the methodology has been used to produce crops that are resistant to herbicide or to insects or to increase nutritional value.
The fact that you can do something doesn’t necessarily mean that you should do it. Plant genetic manipulation is immensely useful in increasing yields and food quality in times of changing climate. But, to express human proteins, plants have a bad system (compared to bacteria): very expensive because plant cells grow more slowly, making it much harder to purify a foreign protein (plants make Rubisco, the most abundant protein on earth), and environmentally tricky. By the time you get to express a foreign protein, the plant cells are dying, and then you have to remove huge amounts of endogenous plant proteins.
Expression of EGF in plant cells has been possible for several decades: DNA coding for EGF is inserted in the genome of a bacteria capable of infecting a particular plant species. Infection with the modified bacteria is followed by the expression of the human protein by the plant. As you can imagine, the plant is not particularly happy and often the infection results in the death of the plant cells. After a lot of effort, you may end up with a miserly amount of protein. I argued this point with a colleague 15 years ago, and here I am arguing the same point yet again!

Plants have unique problems as an expression system, including the abundance of Rubisco and environmental risks. One advantage of being my age is that I was there from the beginning, and I have seen how people rediscover the wheel repeatedly and eventually learn. It is easier to read the literature!

As a plant biochemist, I was involved in this type of research. Many of us gave up on the idea of inserting foreign genes in plants outside of a research lab setting. Some governments ban the use of this methodology outside the lab. I am not opposed to risky stuff, but I want the need and the benefits to be commensurate with that risk. If there are easier and safer means to an end, I go for those

What exciting developments do you foresee in growth factor technology for skincare?
Mostly, this involves adopting what already works instead of looking for a new, non-existent “miracle” that will look good in advertising. Here, we have proteins whose importance has been shown by Nobel prizes given to their discoverers and thousands of scientific papers, and you are looking for a silly peptide? Think about it: having the power to peoduce a pure protein that is identical to our own growth factor, that’s a miracle! It’s not magic, it’s science and it works!

We are already working on the production of other growth factors. They should be available for use in cosmetics in 2025. The priority is always “first, do no harm.” I look for beneficial growth factors for healing and rejuvenation and pursue those. I leave alone the pleiotropic proteins that have multiple effects and are unpredictable.

Lastly, I always like to end with some actionable advice to our community or brands and formulators. Other than formulation stability and ease, two other factors that come up are cost and sustainability. Can you speak to these two aspects as they relate to growth factors?

Cost comes first. Why? Otherwise, an ingredient ends up as “label value,” used in such tiny concentrations that its only effect is to motivate the buyer to spend money. I am afraid that many companies use this loophole.

The formulator should look carefully and critically at the COA: what is the concentration and total amount of PROTEIN you are getting? You need enough to bind to receptors and produce an effect.

Don’t be distracted by words. Look at how many milligrams of the active protein you are getting. Whatever additives they use as fillers, they are just that: fillers.
As for sustainability, protein expression in bacteria is probably the least costly biotech process in terms of environmental costs AND monetary cost. We already use bacteria to produce many ingredients, and for good reason.