SynBio in Supplements: A New Technology Brings New Questions

SynBio picOnce the stuff of science fiction, modern scientists are now using the techniques of synthetic biology to generate a vast range of useful compounds – including a growing number of ingredients and raw materials that end up in dietary supplements.

The fast-growing science of “SynBio” technology is enabling us to modify the genetic expression of living organisms—typically bacteria, yeasts, or other microorganisms—to meet our insatiable global demands for nutritional and medicinal compounds.

Many companies are already using custom-tailored creatures to produce vast quantities of consumable, bioactive compounds that up until the advent of SynBio had to be pressed, extracted, distilled or otherwise processed from plant or animal sources.

Whether we realize it or not, SynBio compounds already exist throughout the supply chain for foods, beverages, dietary supplements, cosmetics, essential oils, and many other consumer goods.

In almost all cases, these SynBio ingredients are not labeled as such, because there are currently no federal or state mandates to require labeling. The current position of federal agencies is that SynBio is a technologically enhanced form of fermentation—an ancient and natural method for producing comestibles.

The gene modifications involved in SynBio are mostly limited to tweaking the existing genome of a particular microorganism, and do not involve transfer of genes from one type of organism to another. Consequently, federal regulators do not consider this to be “genetic engineering.” And even if transgenic technology was involved, the US does not have any binding regulations requiring companies to label GMO-containing products.

That means many people are already consuming SynBio ingredients without ever knowing it.

Likewise, biosynthetic substances typically aren't considered "New Dietary Ingredients" by the FDA and, as such, are not subject to the same level of scrutiny that the agency would bring to a novel ingredient for use in foods or supplements.

GMO 2.0

Advocates believe that by putting microbes to work generating massive amounts of the raw materials we humans want, SynBio can drastically reduce costs and environmental impact.

But many other people are understandably wary. As with all new technologies—especially those that involve genetic modifications—SynBio raises many thorny questions.

It presents particular challenges for the supplement and natural products industries because many health-conscious consumers are suspicious of genetic modification, and they seek GMO-free products. But supplement makers may not always be aware that the ingredients they use were produced via SynBio.

The United Nations Convention on Biological Diversity defines SynBio as, "a further development and new dimension of modern biotechnology that combines science, technology and engineering to facilitate and accelerate the understanding, design, redesign, manufacture and/or modification of genetic materials, living organisms and biological systems."

Put simply, SynBio involves altering an organism's existing genetic information, causing it to synthesize a desirable substance. Typically, this means re-engineering the genomes of bacteria, yeast, or algae so they start to make a compound or compounds that they wouldn't normally produce -- or would make in far smaller quantities.

Compounds manufactured using synthetic biology run the gamut from vitamins, amino acids, and bioactive phytochemicals, to food flavorings, sweeteners, essential oils, and other fragrances. SynBio versions of Vanilla, Saffron, Stevia, Rose oil, Patchouli, Squalene and many other ingredients are all currently available or in development today.

Big Promises, Big Questions

Supplement industry watchers say that there are at least 13 SynBio versions of common supplement ingredients on the market already, including Astaxanthin, Resveratrol, various carotinoids, and Omega-3 fatty acids.

By engineering yeast to produce Resveratrol, a SynBio company like Evolva is--at least in theory--obviating the resource and labor-intensive processes of growing massive quantities of grapes (the natural source of Resveratrol), and then extracting and processing the desired compound into useable forms.

Evolva’s SynBio resveratrol is guaranteed to be free from pesticides or other agricultural toxins, as well as toxic solvents sometimes used in extraction of phytochemicals.

It also potentially makes an expensive ingredient more widely available for lower cost.

But the emergence SynBio ingredients begs the question, What is “Natural”?

Put another way, can an ingredient like yeast-generated Resveratrol be considered truly natural? After all, there is no form of wild, naturally occurring yeast that can synthesize this antioxidant without human “assistance.”

Consumer watchdog group SynBioWatch warns about "GMOs 2.0," characterizing synthetic biology as a risky new branch of genetic engineering that "produces artificial compounds that taste or smell like familiar substances but don't actually come from the natural source."

In the first wave of GMO technology, geneticists used transgenic editing or recombinant DNA technology to move genes from one type of organism into another -- for instance, genes from the soil bacterium Bacillus thuringiensis are introduced into maize, inducing pest resistance and creating a unique and patentable organism: Bt corn. 

EuglenaEuglena, a genus of flagellated single-celled algae. Noblegen, a Canadian biotech company, has developed ways to regulate this algae's gene expression to produce medium chain triglycerides, oleic acids, and many types of protein useful in foods & supplements. (Image: Rogelio Moreno) Synthetic biology, on the other hand, changes the genetic code of living entities by editing portions of their own DNA. Rather than introducing genes from a distinct and unrelated organism, the new gene editing technologies -- like the widely publicized CRISPR -- add, remove, turn off, or rewrite sections of the DNA an organism already possesses.

Thus, an algae-like organism called Euglena can be induced to produce things like medium chain triglycerides, oleic acids, and a host of proteins that it normally could not produce, as has been achieved by Canadian biotech company, Noblegen.

There are dozens of small biotech firms worldwide getting into the SynBio game, and also some very, very big ones.

"What we're doing is basically boosting Mother Nature to a degree, just in a more efficient manner," Adrian Percy, head of agricultural research for German pharmaceutical giant Bayer AG, recently told the Wall Street Journal

An Unregulated Space

Despite using a form of genetic manipulation to alter an organism's function, SynBio ingredients are exempt from GMO regulatory policies –such as they are--in the US.

"This type of genetic modification is largely unregulated -- not currently subject to special regulations or oversight, no testing is required in order to market -- and it is not tested for safety," said Bethany Davis, Director of Industry and Regulatory Affairs for the popular supplement brand, MegaFood, and it’s practitioner-only cousin, Innate Response.

"A great example of how safety is a back-burner issue for synthetic biology companies is the Impossible Burger," she continued. "Here, a company is making vegan burgers using SynBio 'heme,' the red oxygen-trapping compound found in meat. They are successfully making heme from SynBio; however, they are also making 40 other unknown proteins that have never been in the food supply before."

In order to obtain approval from the FDA's optional GRAS (“Generally Recognized as Safe) program, FDA requires that a company submit all new ingredients in a product to thorough safety testing to ensure that they're not allergenic to humans.

Davis points out that Impossible Burger withdrew its application for GRAS status, but continues to sell its burgers, which are currently available nationwide.

"We see that these ingredients can pose a safety risk, and the low bar to market entry is of concern," Davis said.

Ordinary consumers and healthcare professionals alike may be unaware of how many SynBio ingredients -- like canola oil, for instance -- have already made their way onto supermarket shelves.

SynBioWatch estimates that at least 350 total SynBio ingredients exist today; 150 of these are in some way relevant to the supplement industry.

"Companies marketing ingredients and other 'solutions' that employ synthetic biology are working very hard to convince people that these newer types of genetic modification are not GMOs, as there is much concern and resistance to traditional GMO crops worldwide," Davis noted. "They are hoping to avoid stigma that exists around GMOs."

All "Natural"?

Since the production of SynBio ingredients depends on the naturally occurring process of fermentation, many SynBio companies—or brands that use their ingredients-- claim that these products are completely natural.

For example, Stevia, a popular sweetener extracted from the leaves of the stevia plant, now has a SynBio counterpart. Earlier this year, global agribusiness, Cargill, launched its "EverSweet" product, a SynBioWatchSynBio sugar substitute made from a baker's yeast genetically engineered to produce a compound found in stevia leaves.

According to SynBioWatch, EverSweet may be labeled as "natural" or "fermentation derived."

Similarly, Evolva—the Ontario company that uses algae to produce oils and proteins—has been working with flavor maker International Flavors & Fragrances (IFF) since 2014 to create a "natural" SynBio vanilla flavoring agent.

In this single product, one can see all the pros and cons of SynBio.

Conventional production of natural vanillin-- the main component of vanilla bean extract -- is highly labor and land-intensive. That makes truly natural plant-derived vanillin very expensive, and more rare than most people realize.

Most commercial vanillin is synthetic, generally derived from petrochemicals or chemically derived from lignin. Evolva's vanillin, on the other hand, is fermented, a production route the company says is far more sustainable than traditional cultivation of vanilla beans, and more natural than synthesis of vanillin from petroleum.

Like artificial vanilla extract, many common food and supplement ingredients are entirely synthetic—they’re the products of highly-controlled, industrial scale chemical reactions, not extracts from fruits, vegetables or herbs.

Nearly all vitamin C products on the market contain synthetic ascorbic acid, not naturally occurring vitamin C from oranges or berries.

SynBio advocates say their products are far closer to “natural” than are the entirely synthetic options. That logic, however, certainly stretches the definition of the word “natural” to its limit.

Unknown Risks

From a personal health standpoint, it is still unclear whether or not SynBio-containing foods or supplements are biologically and physiologically identical to their nature-made counterparts. Large-scale clinical trials comparing synthetic biology to naturally-sourced compounds like curcumin are sorely needed to determine if their effects on humans are truly comparable.

As is the case with GMOs, medical practitioners show a wide range of views and attitudes toward SynBio. Data from HPC's 2018 practitioner survey indicate that the majority are wary (see How Do Medical Practitioners Feel About SynBio?)

In the meantime, the fast pace of SynBio has already created a situation that will be hard to regulate, should real risks be discovered.

"Some companies are buying these ingredients, unaware that they are made from synthetic biology. Oftentimes the price of a SynBio ingredient undercuts the market by a significant factor from its natural equivalents," said Megafood's Davis.

The supplement industry—with its incessant need for low-cost, high-value, specialized, bioactive compounds--is an ideal market space for synthetic biology. And biotech companies have wasted no time getting in.

SynBio could potentially offer greater availability of rare or expensive supplement ingredients at lower prices.

Proponents say this technology will help solve major challenges, like achieving greater sustainability in the food production system. Growing, harvesting, and processing the crops used to make food and supplements requires significant quantities of water, land, and labor, while producing carbon emissions and creating waste.

SynBio requires less space, taking pressure off of the land, while leaving an arguably reduced environmental footprint, thus helping to combat climate change. It's also cheaper, more efficient, and more predictable, yielding highly consistent products than does traditional agriculture.

Is it Sustainable?

"Some brands tout [synthetic biology] ingredients as 'sustainable' -- because you can make unlimited amounts, where if you were harvesting an herb, say, to make an extraction for the same compound, it would be a limited resource," Megafood's Davis said.

But given how rapidly the technology is emerging, it is far too soon to fully measure the long-term impacts on environmental or human health. Skeptics point to the inevitability that new technologies will lead to unforeseen, unexpected consequences.

For one, SynBio food production is not entirely eco-friendly. Many of the microorganisms used rely on sugar as an energy source, while others depend on dirty feed-stocks like methane gas. Sugar is often obtained from chemical-intensive monocultures that require major land and water use and contribute to pollution and environmental degradation. This problem will only worsen if the demand for sugar to feed SynBio operations starts to increase.

SynBio food production also has social ramifications. Friends of the Earth, a non-governmental environmental advocacy group, argues that synbio foods "harm sustainable farmers and poor communities across the world." These new methods, the organization says, will displace traditional farmers especially in impoverished regions, taking away their livelihoods and undercutting small-scale, sustainable farming of plants like stevia, vanilla, and shea. 

Then, there are potential biohazard issues like environmental contamination. Genetic engineering is unpredictable, so it's hard to determine exactly what will happen to living organisms with altered genomes once they get out into the wild.

SynBio operations require vast quantities of growth media—typically sugar and nutrient-rich liquids. There are few regulations on disposal, and nobody really knows what will happen when industrial volumes of spent growth solution loaded with genetically tweaked yeasts or algae are introduced into the ecosystem.

It is also difficult to control what microbes grow on synthetic biology products. Some observers worry that SynBio organisms like modified yeasts or algae could easily escape into the environment, creating a kind of living pollution.

And what if those modified organisms weren't always used for good? In a report released last month, the National Academies of Science, Engineering and Medicine warned of potential "malicious applications of synthetic biology."

Going SynBio-Free

With so many questions yet unanswered, the debate around synthetic biology and its many applications won’t end anytime soon. For individuals unsure about sampling SynBio-derived ingredients, a few simple guidelines can help.

First, look for organic products. National organic certification standards prohibit the use of all genetically engineered foods (including SynBio), GMOs, and synthetic pesticides in certified organic crops and products.

Keep an eye out for the "Non-GMO Project Verified" seal on packaged goods as well. The Non-GMO Project conducts independent verification of non-GMO foods, taking the stance that items containing ingredients made with synthetic biology are not allowed to carry its voluntary label.

The Project's verification requirements specifically exclude all SynBio and and gene-edited ingredients. 

Where synbio ingredients are used, it's important to understand how the organisms that produced them were modified in order to make the desired end product.

GRAS status can also be a rough, though very imperfect guide. If a company does not provide information showing that its product's ingredients are GRAS, and you are concerned about SynBio, think twice before buying.

Advocates of SynBio claim that this technology holds great benefits for the health and wellbeing of the people and the planet. But, like all advanced agricultural technologies, it also has great potential to further consolidate economic power and control in the hands of massive multinational corporations that are very clearly motivated by profit.

The more we understand about where our food and our supplements come from, the better equipped we are to make healthy, informed choices.

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