Impact tech: Opportunities in Clean Meat and Cellular Agriculture by Liz Specht

Opportunities in Clean Meat and Cellular
Agriculture
Liz Specht
Senior Scientist at The GFI

Opportunities in clean meat
and cellular agriculture
Liz Specht, Ph.D.
Senior Scientist
The Good Food Institute
October 10, 2018

gfi.org
Today’s roadmap
1) What is the problem we’re trying to solve? Why is this so urgent?
2) What market trends are driving interest in – and development of –
alternative proteins? And who’s involved?
3) What opportunities are there for technological solutions to pressing challenges
in cellular agriculture and clean meat?
4) The ultimate question: Can it hit price parity?
2

gfi.org
The Good Food Institute
3
SCIENCE AND TECHNOLOGY
Director of Science and Technology David Welch, Ph.D.
INNOVATION
Director of Innovation Brad Barbera
CORPORATE ENGAGEMENT
Director of Corporate Engagement Alison Rabschnuk
POLICY
Director of Policy Jessica Almy, Esq.
UNITED STATES
BRAZIL
INDIA
ISRAEL
EUROPE
CHINA
Fall 2018
Our programmatic departments
INTERNATIONAL ENGAGEMENT
Director of International Engagement
Nicole Rawling, Esq.
Managing Director (Israel) Yaron Bogin, Ph.D.
Managing Director (India) Varun Deshpande
Managing Director (Brazil) Gus Guadagnini

gfi.org
Global demand for meat is on the rise,
despite increasing consumer awareness of its
environmental burden
2005 vs. 2050 (in tons)
Source: Food and Agriculture organization of the United Nations, ESA Working Paper No. 12-03, p. 131
4

gfi.org
We cannot continue with business as usual
5
29% land 71% oceanEarth’s surface
71% habitable land
10%
glaciers
19% barren landLand surface
77%
livestock
23%
cropsAgricultural land
50% agriculture 37% forests
11%
shrubHabitable land
1% urban
1% freshwater
33%
Meat &
dairy
67%
Plant-based
food
Protein supply
Adapted from OurWorldInData.org and based on UN FAO statistics

gfi.org
Sustainable food systems require radically rethinking
meat – not incremental efficiency gains
6
Feed
(calories)
Movement;
thermal energy;
growing bone,
brain, feathers,
etc…
Food
(calories)
We have pushed animals to their biological limits.

gfi.org
Here’s another perspective: producing meat is the
most perverse food waste problem imaginable
7
0
20
40
60
80
100
120
Food waste by
consumers or in
supply chain
Food consumed
0
500
1000
1500
2000
2500
3000
3500
Food waste by
consumers or in
supply chain
Food consumed Food waste in
production
(chicken)
Food waste in
production (beef)

gfi.org
The majority of mammal biomass on earth is either
humans or our livestock
8XKCD; also see YM Bar-On et al., 2018

gfi.org 9
Animal agriculture is “one of the most significant contributors
to the most serious environmental problems, at every scale
from local to global.”
– Livestock’s Long Shadow, 2006, UN FAO
monocrops

gfi.org
Superbugs could cost the
world $100 trillion by 2050
THE TELEGRAPH
In their latest test, Consumer
Reports found bacterial
contamination on 97% of chicken.
Drug resistant infections kill
half a million people a year
THE GUARDIAN
Despite increasing
awareness that eating
animal meat is
harmful, consumption
continues to rise.

gfi.org
The solution: plant-based meat, clean meat, and
other alternative proteins
11
PLANT-BASED
MEAT
CLEAN MEAT

gfi.org
Today’s roadmap
12

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“If we can grow the meat
without the animal, why
wouldn’t we?”
— Tom Hayes, Tyson Foods CEO, 2018

gfi.org
Big Meat companies are rebranding as
“protein companies”

gfi.org
Strategic Investors and Partners

gfi.org
Visionaries agree — the future of food is animal-free
“What I was experiencing [Beyond
Meat’s chicken] was more than a clever
meat substitute. It was a taste of the
future of food.” -Bill Gates
“I believe that in 30 years or so we will no longer
need to kill any animals and that all meat will either
be clean or plant-based, taste the same and also be
much healthier for everyone.”
– Richard Branson

gfi.org 17Source: Nielsen custom defined data set, xAOC + WFM, 52 weeks ending 8/11/18.
-10%
0%
10%
20%
30%
40%
50%
60%
70%
Creamer Yogurt Cheese Ice
Cream
and
Novelty
Meat Milk Butter
$%ChgYA
Plant-based Animal-based
Plant-based products are exploding across all categories

gfi.org
27% 57% 61%
The plant-based meat market is booming
18
Year-over-year growth

gfi.org
Millennials are driving this trend, and it will accelerate
• 30% eat meat alternatives every day
• 50% eat meat alternatives a few times per
week
• “These numbers, coupled with the size and
spending power of Millennials, indicates a
strong potential market for meat alternatives
in the future.”
- Billy Roberts, Sr. Food & Drink Analyst, Mintel
Source: Mintel’s The Protein Report – Meat Alternatives - 2017

gfi.org
Consumers choose alternative proteins for many reasons

gfi.org
But in the end… it’s always about taste!
“Plant-based
protein eaters swear
it’s about taste” -
Mintel
New research from the research firm Mintel revealed taste
as the top reason U.S. adults who eat plant-based proteins
do so (52%), outranking concerns over diet (10%), animal
protection (11%), the environment (13%) and even health
(39%).
The research was based on responses from 1,876 U.S.
internet users aged 18 or over that eat plant-based
proteins. The study also indicated that 46% of Americans
agree that plant-based proteins are better for you than
animal-based options. Whether a desire to avoid
processed foods (39%), manage weight (31%) or promote
muscle growth (16%), many plant-based protein
consumers are motivated by maintaining or improving
their health and well-being, according to the Mintel survey.
Souce: Mintel - Plant-based proteins report. January 2018.

gfi.org
Desired attributes vs. product claims don’t always align
“Meat Alternatives Report”, Mintel, June 2017

gfi.org
Source: Datassential, PLANT + CELLULAR 2017 Report
Why pursue clean meat when plant-based is booming?

gfi.org
Today’s roadmap
24

gfi.org
Protein alternatives fit into four categories from a
production/cost/infrastructure perspective
25
ANIMAL CELL
CULTURE
NON-ANIMAL
CELL CULTURE
RECOMBINANT
PROTEINS
PLANT-BASED
PROTEINS

gfi.org
Protein alternatives occur along a spectrum
Fully
plant-based
Fully
cellular ag.
Tofu,almondmilk
Clara,PerfectDay
(eggs,milk)
Cleanmeat
hybridproducts
ImpossibleBurger
Processed
plant-basedmeats
Geltor(gelatin)
Cleanmeat

gfi.org
Basic infrastructure requirements for all single-cell
growth exhibits cross-platform similarities
27

gfi.org 28
Lots of room for enzyme adaptation, prospecting,
or engineering to improve ingredient functionality
or biomaterial properties.
Recombinant protein production can be used for
high-value ingredients, materials, and enzymes

gfi.org
Now we can find the best biology has to offer — or
engineer something bespoke to the application
29

gfi.org
Clean meat is emerging in the context of
developments in all of these parallel industries
30
ANIMAL CELL
CULTURE
NON-ANIMAL
CELL CULTURE
RECOMBINANT
PROTEINS
PLANT-BASED
PROTEINS

gfi.org
The cell culture medium is a nutrient broth
containing the vitamins, lipids, sugars, and
amino acids cells need to grow.
It also contains signaling molecules called
growth factors.
The core components of the nutrient feed and scaffold
for clean meat are derived from biomass
31
The scaffold can be
made of a number of
plant- or fungal-derived
polymers or gels.

gfi.org
What is Clean Meat?
32
Clean meat is genuine animal meat that can replicate the
sensory and nutritional profile of conventionally
produced meat because it’s comprised of the same cell
types arranged in the same three-dimensional structure
as animal muscle tissue.

gfi.org
Clean Meat Production at Scale
Phase 2:
Tissue Perfusion
Phase 1:
Cell proliferation
CELL LINE DERIVATION
A small sample of cells is
obtained from an animal.
Medium Recycling
The cells are added to
a bioreactor along
with cell culture
media, which causes
the cells to proliferate.
CELL STARTER CULTURE
Scaffolding
Final Product
CELLS AT MATURATION
Primarily muscle, fat, and
connective tissue.
Fat
Cell
Muscle
Cell
Fibroblast
Cell
A change in culture
conditions pushes the
cells to differentiate
into muscle, fat, and
connective tissue.

gfi.org 34
World Firsts
^ 2013 Prof Mark Post
World’s First Clean Burger Patty
< 2017 Memphis Meats
World’s First Chicken & Duck
< 2016 Memphis Meats
World’s First Clean Meatball
^ 2017 Finless Foods
World’s First Clean Fish

gfi.org 35
The Competitive Landscape for Clean Meat
at the End of 2016

gfi.org 36
The Current Competitive Landscape For Clean Meat
Several more companies are in stealth mode or are
very recent entrants to the landscape.

gfi.org
Cell line development
38
Cells can be pluripotent, multipotent,
or specialized (such as adult stem cells).
Proliferative capacity: the ability to
continuously multiply.
Stability: exhibiting predictable
behavior generation after generation.

gfi.org
Opportunities in cell line development
Genome editing or cell
selection/adaptation for
higher metabolic
efficiency, greater genetic
stability, higher cell
densities
Cell banking,
characterization,
cryopreservation,
maintenance
Selection for more efficient
differentiation; engineering
trigger-induced responsesLive-cell reporter cell lines
for real-time monitoring

gfi.org
Synthetic biology and systems biology are
completely untapped
in this field
40Gao et al., Science, 2018
The more “heavy
lifting” you can ask the
biological system to do
itself, the more it
alleviates design
requirements (cost) for
all downstream
processes.

gfi.org
Cell culture medium development
41
Basal medium: the basic nutrients that cells need to
grow (salts, sugars, amino acids, etc.)
Growth factors: signaling proteins that can control
animal cell behavior (growth, differentiation,
attachment to scaffold, etc.)
Scaled Biolabs:
10,000 experiments in parallel

gfi.org
Media recycling will likely be necessary in some form
42
Cell proliferation
bioreactor
Tissue bioreactors
Media
recycling
New media
inputs
Media
recycling
New media
inputs
New media
inputs
Real-time analysis of media composition
with automated input adjustments
In-line monitoring of cell morphology

gfi.org
Opportunities in cell culture media
Drastically lower cost by
scaling production,
incorporating food-grade
materials, rethinking QA/QC
processes
Metabolic modeling and
highly-parallelized screening to
optimize formulations
Screening biological diversity
landscape for growth factor
variants with higher stability,
potency, etc.
Extracting high-quality amino
acids from agricultural or other
biological waste streams

gfi.org
Scaffolding biomaterials and fabrication
44
Scaffolds can be biodegradable or
integrated into the final product.
Porosity is a key trait for ensuring nutrient
access to cells in thick tissues.

gfi.org
Should we expect more from our scaffold?
45Mitchell et al., 2016

gfi.org
Opportunities in scaffolding
Integration of growth factors
into scaffolds for time-
controlled and/or spatially-
controlled release
Large-scale hydrogel
fabrication with tunable
properties, chemical handles,
microencapsulated factors
Expandable/contractible
scaffolds in response to
environmental conditions
Mimicking microvasculature

gfi.org
Bioreactor and process design
47
Stirred-tank bioreactors are
widely used in large-scale
suspension animal cell culture.
Tissue perfusion bioreactors
will require additional
engineering for scale-up.
Yan et al., 2011

gfi.org
Process design will inform the challenges of scale-up
and bioreactor design, and vice versa
48
?
Proliferation Differentiation
?

gfi.org
Opportunities in bioreactor design
Automation: harvesting,
downstream processing,
closed containment
In situ fabrication of
scaffolds for sterility
Sensor development and
filtration for media monitoring,
recycling, metabolite
scavenging
Up-scaling of perfusion
bioreactors: fluid dynamic
modeling, parallelized
platforms, etc.

gfi.org
Which stages could
be single-use?
Which stages could
be batch processes?
…semi-continuous?
(Operational for how
long?)
…continuous?
50
Meyer et al., 2017

gfi.org
Process elements to define
Cell line
derivation
Seed train Proliferation
Scaffold
integration
Tissue
perfusion
Harvesting

gfi.org
Process elements to define
Cell line
derivation Seed train Proliferation
Scaffold
integration
Tissue
perfusion Harvesting
What
types of
cells?
Modificat-
ions?
Character-
ization?
Banking?
How many
steps?
Single-use?
Max density
and split
density?
Suspension?
Single-cell
suspension?
Adherent?
Microcarriers?
Aggregates?
Together or
separate?
Seed onto solid
scaffold?
Mix with cells
and polymerize?
(how?)
Material?
Biodegradable?
Fabrication?
Thickness?
Together or
separate?
Type of
bioreactor?
How to
differentiate?
Downstream
processing?
Wash steps?
Formulation?
Food safety
validation?
Raw material sourcing and validation?

gfi.org
Economic viability depends on scale, cost, and product
53
Cost
Production volume
Pilotscale
Large
scale
Bench
scale
Bluefin
tuna
Chicken
nuggets

gfi.org
Today’s roadmap
54

gfi.org
Media cost modeling exercise: assessing long-term
scaling implications
Basal media: contains 52 components, mostly amino acids, salts, sugars, etc. – all shelf
stable and relatively inexpensive, approximately $3/L for a powdered mix
7 additional components:
- AA2P (vitamin C precursor), 64 mg/L
- NaHCO3 (buffer), 543 mg/L
- Sodium selenium, 14 ug/L
- Insulin (growth factor), 19.4 mg/L
- FGF-2 (growth factor), 100 ug/L
- TGF-B (growth factor), 2 ug/L
- Transferrin (transport protein), 10.7 mg/L $418/L

gfi.org
Cost estimate of Essential 8 from individual components
Component Cost and
volume
Final conc. Amt. needed for
20,000 L
Cost per 20,000 L
batch
Basal medium $156, powder for
50L
-- 20,000 L worth $62,400
AA2P $392 for 50g 64 mg/L 1280 g $10,040
NaHCO3 $220 per metric
ton
543 mg/L 10860 g ~$0
Sodium Selenite $100 per 1kg 14 ug/L 280 mg ~$0
Insulin $17,000 for 50g 19.4 mg/L 388 g $131,920
Transferrin $2,000 for 5g 10.7 mg/L 214 g $85,600
FGF-2 $2,005 for 1mg 100 ug/L 2 g $4,010,000
TGF-beta $809 for 10ug 2 ug/L 40 mg $3,236,000
Cost per L $377

gfi.org
Scenario A: Reduce concentration of all four GFs to a tenth of their current levels by engineering higher
stability/potency, adapting cell lines, etc.
Scenario B: Produce FGF-2 and TGF-B at larger scales and higher efficiency, putting cost per gram on
par with insulin and transferrin.
Scenario C: Pursue Scenarios A and B simultaneously. These affects are additive, as they target
different routes to reducing cost.
Scenario D: At the original formulation, produce all four GFs at $4 per gram (industrial scale
recombinant protein production).
Influence of seven technology development/scaling scenarios

gfi.org
Base case Scenario A Scenario B Scenario C Scenario D Scenario E Scenario
F
Scenario G
Basal medium $62,400 $62,400 $62,400 $62,400 $62,400 $4,600 $4,600 $2,456
Vitamin C $10,035 $10,035 $10,035 $10,035 $10,035 $10,035 $4.48 $4.48
NaHCO3 $2.39 $2.39 $2.39 $2.39 $2.39 $2.39 $2.39 $2.39
Sodium
selenium
$0.03 $0.03 $0.03 $0.03 $0.03 $0.03 $0.03 $0.03
Insulin $131,920 $13,192 $131,920 $13,192 $1,552 $1,552 $1,552 $1,552
Transferrin $85,600 $8,560 $85,600 $8,560 $856.00 $856.00 $856.00 $856.00
FGF-2 $4,010,000 $401,000 $800.00 $80.00 $8.00 $8.00 $8.00 $8.00
TGF-beta $3,236,000 $323,600 $16.00 $1.60 $0.16 $0.16 $0.16 $0.16
Total per
20,000 L
$7,535,958 $818,790 $290,774 $94,271 $74,854 $17,054 $7,024 $4,879
Cost per L $377 $41 $15 $4.71 $3.74 $0.85 $0.35 $0.24
All scenarios assume 20,000 L batch size.

gfi.org
Scenario E: In addition to Scenario D, prepare the basal media in bulk from its constituent components
and allow food-grade materials.

gfi.org
Can the cell culture media components be sourced
as food ingredients?
60
INORGANIC SALTS
Calcium chloride, sodium
chloride, magnesium
sulfate, ferric nitrate,
magnesium chloride,
cupric sulfate, ferrous
sulfate, potassium
chloride, sodium
hydrogen phosphate, etc.
AMINO ACIDS
Alanine, glycine, leucine,
aspartic acid, proline,
valine, threonine, etc.
PROTEINS
Insulin, transferrin, FGF-2,
TGF-beta, etc.
OTHER NUTRIENTS
Glucose, HEPES (buffer),
linoleic acid, lipoic acid,
sodium pyruvate, etc.
VITAMINS
Biotin, riboflavin, folic acid,
citric acid, thiamine,
pyroxidine, vitamin B12,
pyroxidal, etc.

gfi.org
Scenario E: In addition to Scenario D, prepare the basal media in bulk from its constituent components
and allow food-grade materials.
Scenario F: In addition to Scenario E, substitute AA2P with ascorbic acid.
Scenario G: In addition to Scenario F, substitute HEPES with another pH buffer, TES, which operates in
the same physiological range and exhibits similar properties (solubility, etc.)

gfi.org
Base case Scenario A Scenario B Scenario C Scenario D Scenario E Scenario F Scenario G
Basal medium $62,400 $62,400 $62,400 $62,400 $62,400 $4,600 $4,600 $2,456
Vitamin C $10,035 $10,035 $10,035 $10,035 $10,035 $10,035 $4.48 $4.48
NaHCO3 $2.39 $2.39 $2.39 $2.39 $2.39 $2.39 $2.39 $2.39
Sodium
selenium
$0.03 $0.03 $0.03 $0.03 $0.03 $0.03 $0.03 $0.03
Insulin $131,920 $13,192 $131,920 $13,192 $1,552 $1,552 $1,552 $1,552
Transferrin $85,600 $8,560 $85,600 $8,560 $856.00 $856.00 $856.00 $856.00
FGF-2 $4,010,000 $401,000 $800.00 $80.00 $8.00 $8.00 $8.00 $8.00
TGF-beta $3,236,000 $323,600 $16.00 $1.60 $0.16 $0.16 $0.16 $0.16
Total per
20,000 L
$7,535,958 $818,790 $290,774 $94,271 $74,854 $17,054 $7,024 $4,879
Cost per L $377 $41 $15 $4.71 $3.74 $0.85 $0.35 $0.24
All scenarios assume 20,000 L batch size.

gfi.org
Assessing the culture media cost contribution per kg meat
500ml
10 days to grow
to saturation
100L
10 days to grow
to saturation
20,000L
10 days to grow
to saturation
Harvest and
seed onto
scaffold
200-fold replication
(~8 division cycles)
4 x 107 cells 2 x 107 ml 5 x 103 μm3 10-18 m3 = 4 m3
ml reactor cell μm3 reactor
A cubic meter of ground meat weighs about 881 kg =>
7769 lb in a batch [minimum]

gfi.org
500ml
10 days to grow
to saturation
100L
10 days to grow
to saturation
20,000L
90%
Harvest and
seed onto
scaffold
10%
10-fold replication
(2.3 division
cycles)
Assessing the culture media cost contribution per kg meat

gfi.org
There are multiple ways to achieve costs approaching
parity with wholesale conventional meat
$0.00
$2.00
$4.00
$6.00
$8.00
$10.00
$12.00
$14.00
24 26 28 30 32 34 36
Mediacostcontributionperkgofmeat
Proliferative capacity (number of doublings per production run)
Multiple variables can be
adjusted to fall within
range of economic
viability:
- Cost of medium per L
- Meat yield per batch
- Number of harvests in
semi-continuous mode
Detailed white paper
forthcoming later this
quarter!

gfi.org
Economic viability depends on scale, cost, and product
67
Cost
Production volume
Pilotscale
Large
scale
Bench
scale
Bluefin
tuna
Chicken
nuggets

gfi.org
How saturated is the clean meat field?
What is the opportunity for exploratory research
to translate into a revolutionary commercial reality?
68

gfi.org
$1.275 Billion Invested
in Plant-based and Clean Meat, Egg, and Dairy Companies
Source: Crunchbase; YTD as of 8/18

gfi.org 71
SOLAR
Spheres represent global R&D investment into
renewable energy in a single year (2011).
Total combined R&D into clean meat (across
ALL years): about $50M
WIND BIOMASS BIOFUELS HYDRO MARINE GEOTHERMAL
Data: Global Trends in Renewable Energy 2012
$147.4bn $83.8bn $10.6bn $6.8bn $5.8bn
$2.9bn
$0.2bn
71
Clean meat development is highly tractable and first-
movers can easily differentiate themselves

gfi.org
Recap: Opportunities abound
72
Market trends indicate that alternative proteins – and especially meat alternatives – will
experience tremendous growth, and that there is a sizeable market that will continue to
demand animal meat rather than plant-based alternatives.
Expertise in meat science, synthetic biology, genomics, biochemistry, mechanical
engineering, and data analytics will accelerate development of novel and improved
products.
While the clean meat competitive landscape has become increasingly crowded in the last
two years, there remains very large opportunity to develop products, services, or
technologies that supply the clean meat industry itself.

Impact tech: Opportunities in Clean Meat and Cellular Agriculture by Liz Specht

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Impact tech: Opportunities in Clean Meat and Cellular Agriculture by Liz Specht