Introduction
In 2003, the first ever tissue-engineered steak was eaten by Australian artists, Oron Catts and Ionat Zurr. This was for their “Disembodied Cuisine” artwork where they used a tissue of Xenopus cells to grow frog skeletal muscle over biopolymers. The steak was three-dimensional, but it had the texture of jellied fabric. According to the artists, “…we decided to use frogs as a comment on the disgust that many French people express towards engineered food, a disgust that parallels the reaction of some non-French people towards the idea of eating frogs’ legs” (Catts and Zurr, 2004). Since then, consumer interest has evolved to the point where alternative and more environmentally friendly protein sources are being developed and now, commercialized. Pea protein and cell-cultured meat (also known as cultured, cultivated, cell-based, and clean meat), in particular, are showing the most promise for market growth based on an analysis of online search query data from 2004 to 2018 (Bashi et al., 2019). While plant-based meat has come remarkably close to replicating conventional meat, meat grown from animal cells is identical to conventional meat products (Forgrieve, 2020). This is because cell-cultured meat is produced by the in vitro culture of animal cells from species and breeds that are routinely farmed for meat (e.g., livestock, poultry).
According to the Food and Drug Administration (FDA) (2020), “there are currently no food products made from cultured animal cells in the U.S. market.” However, cell cultures have been used for years to create enzymes, oils and transgenic proteins for use as food ingredients (Wayne Labs, 2019). Similar to other products produced from cell lines, it is crucial that meat products grown from animal cells are evaluated for safety before reaching consumers. To establish a safe intended use of a cell-cultured meat product, the chemical characterization and specifications, as well as the intended use levels and manufacturing process must be assessed according to FDA’s premarket approval of a Food Additive Petition (FAP) or a Generally Recognized as Safe (GRAS) dossier (which does not require FDA input). Discussed below are the regulations, as well as the safety concerns associated with cultured meat including the introduction of adventitious agents, and the safety of substances during production.
Brief History
The first lab-grown burger was created by Mark Post in 2013. The burger had a texture close to meat but not as juicy due to lack of fat. Mark Post used the term “cultured meat” to describe the patty (BBC News, 2013), maybe in attempt to replace the clinical-sound of “in vitro meat”. As shown by Siegrist et al. (2018), nontechnical descriptions of cultured meat that emphasizes the final product and not the production method, results in increased consumer acceptance.
With the continual improvement of cell culture technology and increased consumer interest, by the end of 2019, 40 companies are making finished cell-cultured meat products. Seven of the 40 companies are creating seafood (e.g., salmon, tuna), and 33 companies are focused on creating meat (e.g., traditional beef, chicken) (Forgrieve, 2020).
Regulatory Oversight
Under a joint agreement accounted in March 2019 (USDA and FDA, 2019), U.S. FDA and the U.S. Department of Agriculture’s (USDA) Food Safety and Inspection Service (FSIS) agreed to jointly oversee human food products incorporating cultured cells from livestock (including Siluriformes fish i.e., catfish) and poultry. FDA is responsible for overseeing cell collecting and cell culturing, and conducting premarket consultations on production processes. The transition to FSIS (USDA) oversight occurs during cell harvest stage. FSIS oversees processing, packaging, and labeling of harvested cellular material. FDA and FSIS share oversight of harvesting of live cellular material (FDA, 2020; FDA CFSAN, 2020)(Table 1).
Adventitious agents
Introduction of adventitious agents during production is the primary potential hazard of cell-cultured meat. This includes bacteria, fungi, and viruses which can come from the serum used in cell culture media, persistently or latently infected cells, or the environment (e.g., human workers, food packaging) (FDA, 1991). U.S. regulations (21 CFR § 200 et seq., 21 CFR § 600 et seq., 21 CFR § 610.18 et seq.) require that the final product is uniform, consistent from lot-to-lot and free from adventitious infectious agents (FDA, 1993). Cell-cultured meat, by definition, is produced in a controlled and sterile environment, and therefore does not have the same chance as conventional meat to encounter intestinal pathogens such as Escherichia coli, Salmonella or Campylobacter during slaughter (Chriki and Hocquette, 2020). Also, cell cultures can be monitored continuously and immediately treated or aborted if contamination is detected (Specht et al., 2018). FSIS has identified controls to mitigate against hazard related to producing conventional meat which are comparable to certain hazards for producing meat from cell-culture (e.g., microbiological contamination) (see 9 CFR § 417.2 (a)).
Safety of substances during the culture process
Cell culture medium is required in all cultured meat production because the cell culture medium provide cells the nutrients needed to reproduce. An advantage of cultured meat over industrial meat is that their nutritional composition can theoretically be tailored to best meet the needs of human health (Oxford University, 2019). This could be done by adjusting fat composites used in the medium of production. However, control over the nutritional composition remains unclear, especially for micronutrients and iron (Chriki and Hocquette, 2020).
According to the Good Food Institute (GFI) (2018), a U.S. based nonprofit that promotes meat alternatives, the cell culture medium will contain ingredients that are widely used in the food industry and their safety is well understood and documented including salts, sugars, and amino acids. The cell culture medium may also contain recombinant proteins and/or small molecules present at low concentrations that are expected to be produced through methods currently used to make enzymes and other food processing aids routinely used in the food industry (GFI, 2018). According to Specht et al. (2018), recombinant growth factors are identical proteins and hormones that are naturally found in meat and therefore would not pose a novel protein risk.
Scaffolds, which provide a support structure to help the cells create a desirable, meat-like texture, are comprised of edible materials, such as alginate, chitin/chitosan or cellulose (Campuzano and Pelling, 2019). Therefore, without a scaffold, the final cell-cultured meat product might look more like mush than conventional meat (Parkinson, 2020). But unlike culture medium, scaffolds are not required in cultured meat production (GFI, 2018). For instance, companies that are using cultured animal cells as ingredients for incorporation into predominantly plant-based products have little need for scaffolding (Specht et al., 2018). Similar to cell culture medium, scaffolds may also contain recombinant proteins and/or small molecules present at low concentrations (GFI, 2018).
Within large bioreactors, the process of cell proliferation and differentiation will likely take place. The integrated, closed systems with increasing automation of large-scale bioreactors reduces errors and contamination risk associated with human handling (Specht et al., 2018). Outside the animal body or bioreactor, meat cells do not survive longer than a few minutes or, at most, hours and therefore are safe even if they are never cooked or frozen (Specht et al., 2018). However, bioreactors might cause cells to create substances at levels different from those in an intact animal. These substances may include the following: growth factors and other molecules produced by intra- and inter- cellular signaling; unintended or abnormal levels of metabolites; genetic and epigenetic drift that could alter protein expression levels; and endogenous retroviruses or other species-specific viruses (GFI, 2018). However, the frequency of contamination of cells and harvests by viruses is low for products of biotechnology (Merten, 2002). As with components of cell culture media and scaffolds, documented controls and assays, such as polymerase chain reaction (PCR) and chromatin immunoprecipitation (ChIP) assays, can be used to detect abnormal levels of substances and ensure such deviations are brought back to suitable levels (GFI, 2018). If done correctly, the cellular and molecular composition of the final product of cell culture meat could be identical to the composition of industrial animal meat, with the exception of the bacterial load and very low-abundance cell types like nerves and white blood cells (Specht et al., 2018).
Overall, the substances used during production and the final composition of the cell-cultured meat product is important in determining safety. For instance, a cell-cultured meat product composed of a mixture of cell-cultured meat and other ingredients such as binding, flavoring ingredients, and plant-based materials used in conventional food products, will need to be evaluated for safety for each ingredient. The Federal Food, Drug, and Cosmetic Act (FD&C Act) Section 402 considers a food adulterated if it bears or contains any food additive that is unsafe within the meaning of section 409 of the Act. A food is also considered adulterated if it has been prepared, packed or held under insanitary conditions whereby it may have become contaminated with filth, or whereby it may have been rendered injurious to health (21 CFR § 117.1). To ensure that adulterated or misbranded human food products derived from animal cells do not enter or are removed from commerce, FSIS will conduct enforcement actions, as necessary (FDA CFSAN, 2020).
Conclusion
Advancements in cell culture technology are enabling food developers to use animal cells obtained from livestock, poultry, or seafood in the production of food (FDA, 2020). Companies may face regulatory and safety hurdles before launching their food product comprised of or containing cultured animal cells to market. Burdock Group can help companies overcome these hurdles in order to bring safe and compliant products to market.
References
Bashi, Z.; McCullough, R.; Ong, L. and Ramirez, M. (2019) The market for alternative protein: Pea protein, cultured meat, and more. McKinsey & Company. https://www.mckinsey.com /industries/agriculture/our-insights/alternative-proteins-the-race-for-market-share-is-on# (site visited on September 7, 2020).
BBC News (2013) World’s first lab-grown burger is eaten in London – BBC News. https://www.bbc.com/news/science-environment-23576143 (site visited on September 13, 2020).
Campuzano, S. and Pelling, A.E. (2019) Scaffolds for 3D cell culture and cellular agriculture applications derived from non-animal sources. Frontiers in Sustainable Food Systems. 3:38.
Catts, O. and Zurr, I. (2004) Ingestion. Disembodied Cuisine. Issue 16. The Sea. http://www. cabinetmagazine.org/issues/16/catts_zurr.php (site visited on September 13, 2020).
Chriki, S. and Hocquette, J.-F. (2020) The myth of cultured meat: A review. Frontiers in Nutrition. 7:7.
FDA (1991) Biotechnology Inspection Guide (11/91). https://www.fda.gov/biotechnology-inspection-guide-1191 (site visited on September 15, 2020).
FDA (1993) Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals. https://www.fda.gov/media/76255/download (site visited on September 15, 2020).
FDA (2020) Foods Made with Cultured Animal Cells. https://www.fda.gov/food/food-ingredients-packaging/foods-made-cultured-animal-cells (site visited on September 25, 2020).
FDA CFSAN (2020) FDA and USDA Roles and Responsibilities for Cultured Animal Cell Human and Animal Food Products – YouTube. https://www.youtube.com/watch?v=j4DCAx0EhYM (site visited on September 25, 2020).
Forgrieve, J. (2020) Is the world getting close to its first taste of cultured meat? SmartBrief. https://www.smartbrief.com/original/2020/08/world-getting-close-its-first-taste-cultured-meat (site visited on September 25, 2020).
Merten, O.W. (2002) Virus contaminations of cell cultures – A biotechnological view. Cytotechnology. 39(2):91–116.
Oxford Martin School, O.U. (2019) Meat: the Future series Alternative Proteins. White Paper. https://www.weforum.org/whitepapers/meat-the-future-series-alternative-proteins (site visited on September 13, 2020).
Parkinson, A. (2020) From Mush to Meat: Scaffolding to Structure Cultured Meat Products. Medium. https://medium.com/@averyparkinson23/using-scaffolding-to-structure-cultured-meat-products-a8c992ba8a03 (site visited on September 26, 2020).
Siegrist, M.; Sütterlin, B. and Hartmann, C. (2018) Perceived naturalness and evoked disgust influence acceptance of cultured meat. Meat Science. 139:219. Abstract.
Specht, E.A.; Welch, D.R.; Rees Clayton, E.M. and Lagally, C.D. (2018) Opportunities for applying biomedical production and manufacturing methods to the development of the clean meat industry. Biochemical Engineering Journal. 132:161–168.
The Good Food Institute (GFI) (2018) Docket No. FSIS-2018-0036 for FSIS-USDA and FDA Joint Public Meeting on the Use of Cell Culture Technology To Develop Products Derived From Livestock and Poultry. https://www.gfi.org/files/usda-fda-written-comment-on-clean-meat.pdf (site visited on September 15, 2020).
USDA and FDA (2019) Formal Agreement Between the U.S. Department of Health and Human Services Food and Drug Administration and U.S. Department of Agriculture Office of Food Safety. https://www.fsis.usda.gov/wps/wcm/connect/0d2d644a-9a65-43c6-944f-ea598aacdec1/Formal-Agreement-FSIS-FDA.pdf?MOD=AJPERES (site visited on April 22, 2019).
Wayne Labs (2019) Cell-cultured meat concerns. Food Engineering. https://www.foodengineeringmag.com/articles/98296-cell-cultured-meat-concerns (site visited on September 15, 2020).