Cell cultured meat startups keep the composition of their media tightly under wraps, but it typically contains water, amino acids (lysine, arginine etc), sugars (glucose), salts, vitamins, buffering agents, culture aids and/or essential co-factors, proteins (albumin, transferrin etc) and growth factors (FGF, IGF, TGF etc), which send signals to encourage cells to do certain things such as proliferate or differentiate.
As UPSIDE Foods’ VP Dr Eric Schulze recently observed, the costs of the most expensive components of cell media - growth factors - has come down “significantly” over the past 12-18 months as firms specializing in industrial fermentation have moved to food-, rather than pharma-grade protocols, and driven greater efficiency from the organisms (yeast, bacteria etc).
But if cell cultured meat is really going to take off, says Matt Anderson-Baron at Edmonton-based Future Fields, we need to think beyond microbes to bio-factories that he claims are far lower maintenance than microbes, and inherently better suited to producing the proteins in question: fruit flies.
‘We started this company because we knew that the cost of growth factors and recombinant proteins was wildly too expensive’
“We started this company because we knew that the cost of growth factors and recombinant proteins was wildly too expensive,” said Anderson-Baron, who originally set out to launch a cell-cultured poultry business, but quickly realized that the economics didn’t add up unless he could find a way to reduce the cost of growth factors and other proteins in the cell media.
The company then pivoted to focus on a protein expression system he felt was better equipped than yeast and bacteria for producing said growth factors: Drosophila melanogaster (the fruit fly).
In a nutshell, Future Fields takes the gene for the growth factor it wants fruit flies to express, and inserts it into the genome at the embryo stage. When the fly grows up, it secretes the growth factor from its cells (the insect line is then bred to build up stocks so this process doesn’t have to be constantly repeated). Near the end of their lifespan, the flies are humanely harvested and the resulting growth factors are purified.
‘The sheer magnitude of recombinant proteins we need to make cell ag financially viable, it’s staggering’
“We knew scale was going to be a big challenge and the more we more we dug into it, the more we realized that existing systems just weren't going to cut it,” Anderson-Baron told FoodNavigator-USA.
“The sheer magnitude of recombinant proteins we need to make cell ag financially viable, it’s staggering. And existing systems, the infrastructure required, just make it just a monstrous challenge.”
Yeast and E coli have been the workhorses of recombinant protein expression for decades, he said, “And they require bioreactors to grow in, and they have crazy upfront capex, they are very energy intensive, and they are very costly to operate.” Fruit flies by comparison are very low maintenance, requiring far less water and food (mostly yeast), and pretty low budget accommodation, he pointed out.
“The majority of our cost of production comes from the downstream processing steps, which are fairly analogous to other platforms although we can extract the proteins with gentler buffers than some other platforms. But our upstream production is so incredibly cost effective by comparison [with microbial recombinant protein expression systems].”
“Our in-house calculations show a nine-and-a-half-fold reduction in CO2 emissions with production of any recombinant protein [using fruit flies] compared to any microbial system, because insects are one of the most efficient bio-conversion systems in the world.
“They can convert 1.6 kilos of dry feed to one kilo of biomass; these are the ratios that we've achieved. They're just incredibly efficient at turning feedstock into biomass.” Insect material left after the harvesting and purification process can also be refined into useful material, such as chitosan, he said, while insect waste (‘frass’) can be used as fertilizer.
‘You can’t just dump 20,000 L of E.coli culture down the drain’
Compare that to a big steel fermentation tank full of bacteria engineered to produce proteins, he said: “You can’t just dump 20,000 L of E.coli culture down the drain. Cell culture waste needs to be sterilized with chemicals before it can be disposed of.
“So you know, there's a number of different ways these existing systems just aren't going to cut it. And so we believe that insects are the key to this challenge.”
Aside from their reduced production costs and lower environmental footprint, said Anderson-Baron, fruit flies have superior machinery vs bacteria or yeast cells to facilitate complex protein production, and enable firms to develop more species-specific growth factors (rather than using, say, bovine F2F for seafood cells).
“Our goal long term is to offer species specific solutions to any and all cell ag products out there, and that includes people working with more exotic cell lines in aquaculture and seafood production. In those cases, there's a greater need for species specific solutions. On the evolutionary tree, cows are really far away from certain types of fish.”
‘The existing systems just aren't going to cut it’
But if it’s such a no brainer, why isn’t everyone producing recombinant proteins for the nascent cell cultured meat industry from fruit flies?
“It’s a great question,” said Anderson-Baron, who insist he’s not in a field of one because he’s drunk his own Kool aid, but is more likely plowing a lonely furrow right now because the field is so new, in that there wasn’t really much incentive to find far cheaper ways to produce these proteins before the cell cultured meat industry started to develop.
“Until now, there just hasn't been a drastic need to drop production costs and increase scale… and, you know, necessity is the mother of innovation. So I think that's ultimately what's driven us to explore alternative approaches; we need to think outside the box and come up with some new platforms for production because the existing systems just aren't going to cut it.”
The vegan factor: ‘We cause quadrillions of deaths of insects every year just by growing plants’
So what about the fact that insects are animals, and the whole point of cell-cultured meat is to produce ‘real’ animal meat, without animals, hence all the emphasis on finding ‘animal component free’ cell media?
Does the fact that proteins produced from harvested fruit flies are clearly not vegan present a problem for cell cultured meat companies looking for more cost effective growth media?
Not so far, claimed Anderson-Baron, who said that insect agriculture is not regarded in the same way as factory farming of sentient beings such as cows, pigs or chickens. “In our experience, the majority of the industry is open to exploring this and the majority don't have an issue with it. We need to be pragmatic. Insects don’t have the same ethical baggage as you know FBS [fetal bovine serum].
“It’s an ethical solution. The big problem with factory farming is we're putting sentient creatures into conditions they should not be experiencing or would not normally experience in the wild. That's totally the opposite with insects. We are ultimately creating conditions these insects like: damp, dark, moist, crowded environments and we go the extra mile to ensure our fruit flies are happy. We've also consulted with entomologists to ensure our insects are being treated as ethically as possible.”
As for animal-free food systems, he said, “What exactly does that even mean?” If it means that the entire production system does not cause deaths of animals, you’ll struggle to find anything that fits that description, as mechanical tillage of crops kills countless forest animals every year (insects, deer, mice, squirrels) for example, and growing plants as crops typically involves pesticides of some description.
“We cause quadrillions of deaths of insects every year just by growing plants.”
‘We see this consistently with our products: they perform better than [products from] competing platforms’
As for the proteins themselves, right now, Future Fields’ ‘EntoEngine’ is churning out albumin, transferrin, and FGF2, with a suite of other products in the pipeline including prolactin, which helps mammalian cells produce milk, said Anderson-Baron, who noted that not all commercial products out there right now are the same.
“There's a common misconception that growth factors are going to be commoditized, that they are all the same, when the reality is there's a huge range in efficiencies and performance.
“It’s not a case of, 'it works or it doesn't,' there's a spectrum, which has to do with the binding efficiencies of the growth factors to their receptor and that ultimately comes down to how well is that growth factor produced in the expression system? And that's where we also see another big advantage as insect cells are just better equipped to produce more complex proteins, particularly mammalian proteins.
“If you look at the evolutionary tree,” he said, “yes, insects are pretty far away from cows, but they're a heck of a lot closer than plants or yeast cells. So because of that, the cellular machinery of an insect cell more closely matches a cow cell.
“The closer we can make that growth factor to its native form from the cow cell, the better it's going to function in culture. And so we see this consistently with our products: they perform better than [products from] competing platforms.”
‘Our goal is to be producing hundreds of kilos of recombinant protein per month by 2024’
So where do things stand currently at Future Fields, which is currently raising money, and expects its 20-strong team will likely double in size over the next 18 months?
“Our goal is to be producing hundreds of kilos of recombinant protein per month by 2024 in our pilot facility, which will be solely dedicated to GMP production of recombinant proteins,” said Anderson-Baron.
‘I believe cultured meat will be a reality, but people underestimate the scale needed’
Stepping back, he said, “I believe cultured meat will be a reality, but people underestimate the scale we're talking about. People are talking about the infrastructure needed for the consumer products, the bioreactors to grow the meat, but what about the supply chain for recombinant proteins for cell media if you just use traditional [microbial expression] systems?
“The number of bioreactors that would be needed is just astronomical, so that's what I mean when I say we really need to think about the outside the box if we want to make this work.”