When most people look at fruit flies they see tiny specks that flock to our slightly overripe fruit and have a unique talent to stick themselves into the corners of our eyes. They don’t see a mini bioreactor capable of producing life-saving therapeutic proteins.
But Matt Anderson-Baron isn’t most people.
In his view, insects – specifically, Drosophila melanogaster (the common fruit fly) – are the solution to recombinant protein production’s biggest bottleneck: scale-up.
The high price of scaling recombinant protein production
Recombinant protein production – while the powerhouse of the biotherapeutics industry – is a complex process that for the past 30 to 40 years has relied largely on just three biological systems: Chinese ovarian hamster (CHO) cells, E. coli, and yeast. These cell types were chosen for their relatively rapid growth, easy-to-work-with nutrient requirements, and the genetic knowledge and tools available to tinker with their genomes and coax them to produce a variety of useful proteins.
But they all have one thing in common – in order for them to produce the massive amounts of protein necessary to meet market demand, they must be grown in bioreactors, large metal tanks that support the growth of billions of cells. Not only is it challenging to replicate optimal growth conditions defined in 1L-sized bench experiments in thousand-litre bioreactors, but it is also incredibly expensive – particularly because of the amount of growth media required.
Anderson-Baron first encountered the problem with bioreactors when, as a graduate student, he began working on cultivated chicken nuggets in his free time.
“I was really passionate about cultured meat – I felt it could really change our world and in my lifetime,” he says. “But when we started to crunch the numbers, we kept running into ceilings within the bioreactor-based systems. Our eyes were opened to the immense challenges around cost and scale faced by the industry.”
Thinking outside the tank
The cost and scale challenges Anderson-Baron talks about are the exact reason why it cost $330,000 to produce the world’s first cultivated meat hamburger in 2013. While costs have dropped significantly since then, they still preclude bringing cultivated meat to the market, and companies continue raising millions to develop a solution.
One of the reasons a viable solution hasn’t been found yet, says Anderson-Baron, is that companies just haven’t “thought outside the tank.”
He considered one organism that has been studied for decades, has an incredibly well-described genome, significant homology to human genes, and countless genetic tools: the fruit fly. Could fruit flies be used to produce recombinant proteins at scale? At the time, there was no precedent – no one had produced a commercially viable recombinant protein in the fruit fly.
So, Anderson-Baron gathered a team to figure it out, and his company Future Fields was born. And none too soon – as the synthetic biology revolution creates more demand for recombinant proteins, the industry desperately needs to close the supply chain gap caused by manufacturing bottlenecks.
Why flies are the perfect bioreactor
If you think about it, fruit flies are a no-brainer solution. Their potential to express a range of useful proteins is boundless because, in essence, fruit flies grown en masse are literally the large-scale expression of multiple tissue types. Targeting recombinant protein expression to specific tissues in the fruit fly can enable the production of proteins that other systems – such as bacteria and yeast – struggle with.
CHO cells, which partially solve the expression issues encountered when using prokaryotes, are used to produce about 70% of biologics globally. However, they are extremely prone to contamination, making them expensive and inefficient. An inane amount of time must be spent sterilising equipment and testing cells for contamination to ensure contaminated products aren’t delivered to the market. When contamination is found, the process of eliminating it is time-consuming and costly, requiring the destruction of entire stocks and starting over with new cells.
Fruit flies, on the other hand, carry a minimum risk for contamination. Because they have immune systems, they can handle some degree of contamination naturally. Turnover from egg to harvest of protein is also rapid—only 4 days—so diseases don’t really get a chance to propagate among Future Fields’ fruit flies.
Fruit flies are also inherently non-pathogenic and non-hazardous. The FDA isn’t too concerned about them: up to 10 dead fruit flies are permitted per 8-ounce container of raisins sold for public consumption. Of course, Anderson-Baron and his team uphold the same purity and cleanliness standards as any other recombinant protein producer, but starting out with fruit flies puts them one step ahead of the game when it comes to avoiding safety issues.
But one of the biggest advantages to using fruit flies to produce recombinant proteins – and the whole reason why Anderson-Baron wanted to use them in the first place – is the scale of production they permit.
“We probably have the only truly continuous system in the world because of the way our rearing system works,” explains Anderson-Baron. “We’re producing and harvesting biomass every single day, and that’s not going to change as we scale up.” This is in comparison to existing approaches, which can require days or even weeks to move from vial to bioreactor and viable product. The entire process in fruit flies yields recombinant protein 30 times faster than traditional bioreactor systems.
Flies are actually sustainable
Fruit flies are also kinder to budgets and the environment. To put it frankly, bioreactors plug into outlets and fruit flies don’t. It’s difficult to estimate the precise economic and environmental impact of this, but Anderson-Baron gives us an idea:
“I was reading a book about bioreactors, and the author was saying the first time he saw the energy requirements of a fermentation system, he thought it was a typo, just because it was such a big number.”
Future Fields’ approach to feeding their fruit flies is also ingenious: they developed their own feedstock consisting of only six ingredients that can be purchased at any grocery store. The feedstock is far cheaper than the millions of gallons of FBS (which requires cows, the food they eat, and the space they take up) used in bioreactors and isn’t susceptible to supply chain issues. Not only that, but the fruit flies aren’t picky—they’re happy to feed on food that would otherwise end up in the landfill because it’s not perfect enough to be sold to human consumers.
From cultivated meat to vaccine development
Future Fields’ platform, called EntoEngine™, has already served over 60 customers with serum-free, bioactive growth factors. Growth factors impact every aspect of the life sciences, says Anderson-Baron, not just cultured meat production. Virtually every lab working with cell culture uses it. It’s a staple consumable. The economic and environmental impact of replacing FBS with Future Fields’ serum-free growth factors is unfathomable.
But growth factors are only the beginning for Future Fields. Anderson envisions the impact of his company going far beyond cultured meat and into biotherapeutics and even vaccine development. To that end, the company just completed an $11.2 million USD funding round led by Bee Partners and Toyota Ventures that will enable the expansion of their production facilities. This expansion will enable Future Fields to make their production processes GMP-compliant and will help them expand their portfolio of recombinant proteins.
Fruit flies are more than just annoying pests. They just might be the solution the synthetic biology industry has been hoping for – the solution that will release the bottlenecks around innovation so we can create the cleaner, healthier, more sustainable world we all envision.
Originally posted by John Cumbers for Forbes at https://www.forbes.com/sites/johncumbers/2023/02/22/thinking-outside-the-tank-why-this-startup-thinks-fruit-flies-will-solve-synbios-scale-up-problem/?sh=1158f73f33f5
Caltag Medsystems is the distributor of Future Fields products in the UK and Ireland. If you have any questions about these products, please contact us.