SBE Special Section: Industrial Biotechnology

Meeting the Needs

of the Cell-Based Meat
Industry
Elliot Swartz Commercialization of cell-based meat products
The Good Food Institute
at economically viable prices will require significant
innovations, presenting new challenges and
opportunities for industrial biotechnologists.

C
ell-based meat (also referred to as clean or cultured 77% of habitable land on Earth is used to raise and feed
meat) is genuine meat cultivated directly from animal livestock, this land use accounts for only 17% of the global
stem cells rather than by raising and slaughtering caloric supply (4). Industrial animal agriculture is the lead-
animals (Figure 1). The meat is created through a bioprocess ing cause of global deforestation and biodiversity loss (5),
in which stem cells are extracted, isolated, and proliferated and it is a major contributor to foodborne illness and zoo-
in bioreactors at high densities and/or in large volumes. notic disease outbreaks (6). The volumes of antibiotics used
These stem cells are subsequently differentiated, either in to produce livestock and farmed fish is at least equivalent to
the presence or absence of scaffolding materials, into the that used in humans, and antibiotic use is expected to rise,
principal cellular components of meat, including skeletal making industrial animal agriculture a significant contributor
muscle, adipocytes, and fibroblasts of the connective tissues. to antibiotic resistance (7).
The final product mirrors the structure, composition, and The public awakening to the urgency of climate change
nutritional value of conventionally derived meat. and the negative externalities associated with industrial
Advances in regenerative medicine and bioprocess
engineering have made the creation of palatable prototypes
relatively straightforward. However, scaling up the process
while lowering costs will require innovations in cell line
development, cell-culture-medium optimization, bioreactor
and bioprocess engineering, and scaffold biomaterials.

A growing problem
The United Nations estimates that by the year 2050 there
will be 9.7 billion humans on Earth. As this number grows,
the socioeconomic status of residents in developing coun-
tries will continue to increase, and global demand for meat is
expected to double (1). This appetite for meat from industri-
alized animal agriculture is not without consequence.
Animal agriculture accounts for 14.5% of global green-
p Figure 1. This meatball is formed from cell-based meat that was grown
house gas emissions (2) and is projected to account for 81%
in a bioreactor from bovine stem cells, eliminating the need for livestock
of the remaining carbon budget under the Paris Agreement and the associated ethical and environmental challenges. Photo courtesy of
by 2050 if current rates of production continue (3). While Memphis Meats.

Reprinted with permission from Chemical Engineering (CEP).

CEP October 2019 www.aiche.org/cep 41
Copyright © 2019 American Institute of Chemical Engineers (AIChE).
SBE Special Section: Industrial Biotechnology

animal agriculture, including animal welfare, has made con- Cell line development
sumers more accepting of alternative meat products, such as As starting material for cell-based meat, cells that can
plant-based and cell-based meat (8). self-renew and differentiate into the cellular components of
meat are isolated and selected. Companies in the cell-based
A potential solution meat space work with embryonic, induced pluripotent,
Growing crops to feed animals to produce meat is a mesenchymal, and adult stem cells such as myosatellite
vastly inefficient process, as most calories are expended for cells. The starting cell type ultimately influences many of
metabolism rather than creating edible meat. In 2013, Mark the downstream variables of the bioprocess, such as timeline
Post revealed the first cell-based hamburger, demonstrating and differentiation strategy. Cell selection should be weighed
that the animal could be cut out of the equation altogether. alongside cost models and design requirements for the
Since then, more than three dozen cell-based meat compa- intended products.
nies have formed across the world, aimed at dramatically Considerable work has been done using these cell types
reducing negative externalities of meat production while from bovine and porcine species, but substantially less work
taking a bite out of the more than $1 trillion global market. has been performed on the range of other species humans
Preliminary projections estimate large gains in land use consume, especially sea creatures. Publicly available bio­
and energy efficiency and reductions in eutrophication (i.e., repositories of cell lines from commonly consumed species
nutrient runoff from fertilizers and manure that cause algal are needed to accelerate research and generate -omics data­
blooms and water dead zones) (9), as well as curtailment of sets to facilitate development.
livestock-related biodiversity loss and zoonotic disease. At A variety of cell line engineering strategies can improve
scale, preventive controls and monitoring methods adapted upon or optimize the bioprocess. However, future regula-
from existing biopharmaceutical bioprocesses enable tory standards may dictate the extent to which engineering
antibiotic-­free cultivation, lowering global antibiotic use appears in final products. For example, strategies might
while simultaneously reducing the incidence of foodborne include the creation of immortalized cell lines and cells that
illness. These benefits make cell-based meat a potential solu- have high tolerance to shear stress, resistance to toxic metab-
tion to many pressing problems. olite buildup such as ammonia and lactic acid, suitability for
suspension growth, and low growth factor concentrations.
Critical technology areas Engineered biosensors can assist in signaling hypoxic condi-
To commercialize cell-based meat, four critical technol- tions, mechanical stress, or amino acid and glucose starva-
ogy areas require further innovation: cell line development, tion (11). Other strategies may be able to remodel metabolic
cell culture media, bioreactors and bioprocessing, and scaf- or differentiation pathways, making them more efficient or
fold biomaterials (Figure 2) (10). favorable to low-cost cell-culture-medium ingredients, rather
than expensive growth factors.
Cell Line Development Cell Culture Media Researchers may pursue cell lines that inherently exhibit
many of these properties, such as insect cell lines that are
adaptable to suspension growth, tolerate nutrient starva-
tion, and readily immortalize in vitro, or fish cells that
can be grown at room temperature (12, 13). Companies
and researchers with experience in strain optimization or
high-throughput genome editing are needed to support
these efforts.

Cell culture media

The cell culture medium is the most important factor
in maintaining cells ex vivo. Since the 1950s, virtually all
basal cell culture media have consisted of variable buffered
solutions of glucose, inorganic salts, water-soluble vitamins,
and amino acids tailored to specific cell types. To achieve
Bioreactors and long-term maintenance and proliferation, insulin, transferrin,
Bioprocessing Scaffold Biomaterials
selenium, lipids, antioxidants, and other growth factors are
p Figure 2. To reach price parity with conventionally derived meat,
included, typically in the form of animal sera such as fetal
engineering of cell lines and bioreactors is needed alongside smart bovine serum (FBS).
selection of raw materials for cell culture media and scaffolding. FBS has been a mainstay in mammalian cell culture

42 www.aiche.org/cep October 2019 CEP

Copyright © 2019 American Institute of Chemical Engineers (AIChE).
because it is rich in growth factors and hormones, which components could be recycled using size-exclusion dialysis
supports a proliferative fetal-like state. However, FBS is not filters to reduce costs while simultaneously removing waste
viable for use in cell-based meat because: (19). Efforts by the biopharma industry to move toward per-
• it varies by region and batch fusion culture and continuous bioprocessing have driven the
• it is a potential source of contamination development of continuous monitoring systems and adaptive
• it is misaligned with animal welfare control with concentrated feeds, which could also help lower
• not enough of it is available to supply the industry (14). the cost of cell-based meats.
While serum-free alternatives exist, they are expensive None of these strategies are technologically infeasible
and often optimized for human cells in clinical settings or require large scientific leaps. Rather, the demand being
or cell lines used in production of biologics under current established by the ultra-large-volume cell-based meat
good manufacturing practice (cGMP) guidelines. Estimates industry is driving the effort to rethink the composition of
suggest that 55–95% of the marginal cost contribution of a cell culture media. New business opportunities abound for
cell-based meat product will come from the medium. Thus, those equipped to scale recombinant protein production and
the cell-based meat industry will likely require optimized rapidly iterate media formulations.
serum-free formulations for a variety of cell types, at price
points below $1.00 per liter to become economically feasible Bioreactors and bioprocessing
at industrial scales (15). In order to scale beyond taste tests toward market readi-
Several strategies could help achieve this goal. For ness, standard 2D culture or miniaturized stirred flasks
example, protein-rich hydrolysates from plants, such as soy, must be replaced by bioreactors capable of supporting
wheat, pea, or organisms such as yeast and cyanobacteria, high-density and/or large-volume cell cultures. Production
can support a proliferative environment for cells at low cost of biologics using suspension-adapted cells in stirred-tank
(16). Machine learning or differential evolution algorithms reactors has reached volumes of 20 m3. But, the production
could be used in tandem with in silico modeling or high- of therapeutic off-the-shelf mesenchymal stem cells typi-
throughput microfluidic systems to accelerate the pace of cally uses volumes less than 0.25 m3, as these cells must be
formulation discovery (17). cultured on microcarriers or another solid surface to avoid a
Production of commonly used recombinant proteins, form of programmed cell death known as anoikis (20). Cells
such as insulin, transferrin, FGF2, TGFβ, and platelet- used in cell-based meat are also anchorage-dependent and
derived growth factor (PDGF), must be scaled to match face similar challenges. Thus, significant developments are
production costs of food industry enzymes such as pec- needed to scale cell-based meat to affordably and reproduc-
tinase and cellulase, which can be purchased for less than ibly produce batches upward of 1012 to 1015 cells.
$5.00 per gram. This may require additional host or protein Scaling up can require large capital expenditures and
engineering, as certain growth factors, such as TGFβ, are time. To increase scaling efficiency, miniaturized bio­
typically produced in mammalian expression systems rather reactors or microfluidics can produce predictive models of
than microbial host platforms. The growth factors them- process parameters. Once the process works at larger scales,
selves may also be engineered to create synthetic proteins development of real-time, online sensor systems can help
with multiple bioactive domains or more-stable isoforms. enable continuous and/or perfusion bioprocessing methods
Recent demonstrations focusing on the optimization of that save money. In silico modeling of nutrient utilization
growth factor production suggest that stem cell medium and the buildup of inhibitory or stimulatory paracrine factors
costs can be reduced by 97% or more (18). Lower puri- and/or toxic waste can inform feeding strategies, timelines,
fication demands for food-grade production of basal and and perfusion rates (21). The implementation of automation
recombinant components may reduce costs further, but may from the ground up, as opposed to retroactively replacing
also require new, nonpharmaceutical-grade manufactur- manual steps, can unlock additional cost savings. Dynamic
ing facilities. It is unclear whether regulations or the need cost-of-goods models can help identify bottlenecks that can
for reproducibility will require chemically defined medium be prioritized for automation or future research and develop-
formulations; the answer may dictate the exclusion of ment (R&D) efforts as the industry matures.
medium constituents such as hydrolysates, which are chemi- Proliferation of cells in a semi-continuous or continu-
cally undefined. ous process can minimize processing times or increase the
Additional methods to reduce costs include the develop- productivity of seed train processes. In a seed train process,
ment of small molecules that can mimic the bioactivity of cells are grown and used to inoculate sequentially larger,
more-expensive growth factors. However, the safety profile higher-volume vessels, capturing the greatest efficiencies
of any residuals within a final product should be consid- at later cell doublings. For example, productivity can be
ered for this approach. Water and nonmetabolized medium increased by using a percentage of cells from the highest-

Copyright © 2019 American Institute of Chemical Engineers (AIChE).

CEP October 2019 www.aiche.org/cep 43
SBE Special Section: Industrial Biotechnology

t Figure 3. Seed train

Embedded processes may be semi-
Scaffolding continuous or continuous.
In this process, cells
are grown and used to
inoculate sequentially
Harvest some cells, larger vessels in higher
regrow remaining
cells, and repeat
volumes. Productivity can
be increased by using a
percentage of cells from
Cryovial the highest-volume vessel
in the proliferation stage
Seed Train Maturation Perfusion to directly inoculate a final,
Proliferation Bioreactor
large-volume maturation
perfusion bioreactor.

volume vessel in the proliferation stage to directly inoculate engineering, considerations of the porosity of the scaffold,
a final, large-volume maturation bioreactor (Figure 3). mechanical properties, and biocompatibility are paramount;
Perfusion bioreactors, such as hollow-fiber bio­reactors, in creating cell-based meat, the use of cost-effective edible
can achieve higher cell densities in lower volumes and or biodegradable materials is just as important. However,
operate continually over months, making them an attractive cell-based meat does not require the same microscale preci-
conduit between proliferation seed-train stages. Additionally, sion as functional tissue. It merely needs to represent tissue
larger-volume reactors can be directly inoculated using high- structure sufficiently to replicate the appropriate texture
density cryobanking at greater than 108 cells/mL, lowering and mouthfeel.
the time to achieve desired cell densities or numbers in Further exploration of plant- or fungal-derived polymers
seed trains (22). as scaffolds is needed. These organisms may be engineered
Innovations such as cell-laden core-shell hydrogels to express key cell adhesion domains used by vertebrates to
can achieve remarkably high densities of 5×108 cells/mL, boost biocompatibility (24). Alternatively, a polymer-based
permitting cellular proliferation in 3D microenvironments scaffold could be enzymatically modified or embedded with
shielded from shear stress (23). Creative approaches that growth factors to temper the dynamic cellular behavior fol-
entail thinking beyond what has worked for cell therapy may lowing seeding. Chemical modifications can create a tunable
prove to be a valuable strategy for those moving into the scaffold that is responsive to simple external stimuli such as
cell-based meat space. light or temperature (25). These or other forward-thinking
While cell therapy and cell-based meat both share the strategies related to preferred materials and how they may be
cell itself as the end product, the final stages of cell-based sourced via existing or new supply chains can help encour-
meat — differentiation and harvesting — will likely look age the development of cell-based meat.
quite different. Although unstructured meat products could Methods pioneered by tissue engineers can be adopted
themselves be composed of pressed cells, cells as additives, for the assembly of cell-based meat scaffolding but will
or even cells on edible microcarriers, structured products need to be expanded upon. For example, extrusion and
will require the use of a scaffold. Computational fluid stereolithographic bioprinting are promising candidates, but
dynamics (CFD) models are needed to understand how these processes must be able to be run economically at large
fluids in a perfusion bioreactor with embedded scaffold- scales in parallel. Use of electrospinning and decellulariza-
ing behave. Online sensors can be used to adjust flowrates tion techniques can be informative from an R&D perspec-
as the scaffold becomes cell-laden to protect the cells and tive, but may be difficult to implement at scale. Databases
scaffold itself from fluctuating shear forces. Bioreactor and with information on plant, fungal, and microbial biopolymer
bio­process engineers are needed to create new bioreactor mechanical properties, biocompatibility, anisotropy, viscos-
models that can support this culture strategy while integrat- ity, and other parameters can inform the selection of the
ing straightforward harvesting and sterilization processes. most promising candidate methods and materials.

Scaffolding biomaterials Looking forward

A scaffold for cell-based meat ideally permits cells to Cell-based meat is a nascent but rapidly growing field
attach and differentiate in a specified manner that mimics the that may significantly benefit human, animal, and planetary
3D cytoarchitecture of an intended meat product. The cyto- health. It is a highly interdisciplinary field that presents fas-
architecture must allow for continuous perfusion of media, cinating scientific challenges, as well as potentially lucrative
analogous to the vascularization of real tissue. In tissue new market entry points. Challenges for cell-based meat are

44 www.aiche.org/cep October 2019 CEP

Copyright © 2019 American Institute of Chemical Engineers (AIChE).
not problems to be faced by the industry alone, but problems
to be tackled in collaboration with other fields, such as cell ELLIOT SWARTZ is a senior scientist at
The Good Food Institute (GFI) (www.
therapy, regenerative medicine, and fermentation products, gfi.org), a global nonprofit organiza-
as the solutions will have a rippling effect. tion accelerating innovative strategies
toward creating a healthy, humane, and
To have the greatest impact on solving the world’s sustainable food supply via plant-based
toughest challenges, scientists, engineers, and biotechnolo- and cell-based meat, egg, and dairy
technologies. He focuses on analyz-
gists should consider cell-based meat as an opportunity to ing core technology areas and driving
apply their skillsets. An influx of talented scientists from key GFI-sponsored research projects in
cell-based meat, educating scientists and
across these fields will be needed to further drive the the public, and expanding awareness of
success of the industry. CEP career opportunities in the plant-based
and cell-based meat fields. He also has
experience consulting for startups in
the biotech industry related to drug discovery for neurodegenerative
Acknowledgments diseases. Swartz has a PhD in neuroscience from the Univ. of California,
The author would like to thank Christine Dvorak of The Good Food Institute Los Angeles (UCLA), where he worked with induced pluripotent stem
(GFI) for preparing figures for the article. cells to model neuromuscular disease.

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