This technology was designed to grow human cells. Now it’s transforming the cultured meat industry. – Massive Science

In 2009, Time magazine declared cultured meat one of their top 50 inventions of the year for its potential to curb the carbon footprint of industrial farming. This promising idea has since become a booming industry. Ever since Dutch researcher Mark Post debuted the first lab-grown hamburger in 2013 a $325,000 patty with an intense flavor that took two years to dish up nearly 60 companies have sprung up around the globe in pursuit of growing the perfect cut of cultured meat. In the first quarter of 2020 alone, $189 million was poured into these companies. Now that its gone from pipe dream to industry, what is stopping lab-grown meat from being available in a supermarket near you?

The chief hurdle is cost, which is related to what is known in the biz as the scalability problem." Every single slab of meat is an intricate mosaic of billions of cells of different types nerve cells, muscle fibers, fat cells, and more that lend a cut its specific flavor and texture. Researchers have spent years working out how to grow and sustain cultures of cells large enough to make meals at scale. Unfortunately, the mature cells that make up meat are only able to divide a certain number of times before they lose steam, a phenomenon known as senescence. Even if current methods could be expanded, the bulk wouldnt be considered truly clean; the nutritional soup used to grow most meat cultures relies on fetal bovine serum extracted from the blood of unborn cows.

A new ray of hope and innovation has come from a group of researchers taking a very different tack, coupling the raw potential of a special kind of stem cells, known as pluripotent stem cells, with a trick of genetic engineering. Pluripotent stem cells are often called the master cells of the body because they can differentiate into any cell type. Even niftier, these cells can divide endlessly and dont rely on fetal bovine serum to sustain their growth, providing a theoretically limitless supply of cells to serve as precursors to those that make up your favorite cut of meat. Differentiation from a pluripotent stem cell into a mature cell type can take months when left to nature, but neuroscientist Mark Kotter discovered a genetic workaround that cuts the process down to just a matter of days. Kotters technology, dubbed opti-ox, has opened the doors to streamlining the production of billions of cells of your choosing. While opti-ox was first developed to create an unlimited and consistent supply of human neural cells for research, its potential for the clean meat industry caught the eye of Daan Luining, the founder of Dutch-based food tech startup Meatable. The great challenge for them was transforming these animal stem cells into something consumers could eat.

They started a collaboration with a research team led by bit.bio biologist Anne-Claire Guenantin. Guenantin, a pluripotent stem cell expert, had never worked on cultured meat before and was now at the forefront of a massive breakthrough. Right as the project picked up steam, the coronavirus pandemic shut down the world. But Guenantin and her team werent about to let that stop them.

Guenantins entrance into the field was, in her words, by a bit of serendipity. Her roots are in biomedicine, investigating how pluripotent stem cells could be used to treat certain laminopathies, a group of rare genetic disorders resulting from mutations in genes that support the structural integrity of the cells nucleus. During graduate school, she became an expert in cardiac differentiation of pluripotent stem cells, transitioning in her postdoctoral career to a new system: adipocytes, or cells specialized for storing fat. Together with adipocyte expert Nolwenn Briand, she developed and patented one of the first procedures of its kind to derive these fat-storing cells from pluripotent stem cells.

Pluripotent pork cells differentiated into fat (red) and muscle (green) in 7 days.

Meatable

As Guenantin was emerging as a leader in adipocyte differentiation, she became increasingly curious about making the transition from academia to industry. I wanted to do more concrete science, she explains. While a postdoctoral fellow at the University of Cambridge in Prof. Antonio Vidal-Puig's laboratory, she met Thomas Moreau, Head of Research at bit.bio, who introduced her to the opti-ox system. He showed her research group a video of muscle cells differentiating from pluripotent stem cells in just ten days. I knew this is one of the most difficult cell types to [differentiate] from stem cells. I was blown away. The breakthrough made her next career step clear. I knew I wanted work there. That was it.

Luckily for Guenantin, bit.bio was in search of a researcher to work out how to differentiate pluripotent porcine stem cells into the characteristic muscle and fat cells needed to make tasty pork. Guenantin is one of only a few experts in adipocyte differentiation, in part because there is less interest in research around fat stem cell therapies compared to treatments centered on cardiac or neuronal cells. Her expertise in this niche field uniquely positioned her for this monumental task. When she was hired at bit.bio Kotters company holding the opti-ox technology she was tasked with programming the fate of Meatables cells.

Guenantins first challenge was to figure out how to sustain and grow a culture of pluripotent stem cells derived from pork. Its a really different thing to cultivate animal cells than to cultivate human cells, she says. The promise of human stem cell therapies has flooded the research field with standardized protocols and tried-and-true chemical reagents needed to reliably grow a healthy culture of human cells. The same isnt true for culturing stem cells from animals like pigs and cows. Guenantin estimates that the field is 15 years or so behind human cells.

After months of mining the literature, testing various recipes for growth media, and piloting different environmental conditions, Guenantin was able to find the right formula for growing a seemingly endless pool of happy and healthy pluripotent porcine stem cells. It was crazy interesting and really took teamwork, she stresses. Nothing would have happened without all the input from people working in the lab.

The next piece of the puzzle was led by stem cell biologist Sara Gomes, who worked to genetically engineer the opti-ox system into the expectant stem cells. Gomes and Guenantin worked together to figure out how to drive differentiation of the stem cells into the desired muscle and fatty cell fates. While the researchers at bit.bio had a protocol in place for differentiating human muscle from stem cells, it had to be adapted to suit the subtleties of pork muscle. Guenantin recalls, Differentiating the muscle cells was relatively straightforward, but for differentiating adipocytes thats where my expertise came in.

Guenantin and Gomess work at the lab bench was aided by the addition of two new research assistants to the team: Madeleine Garrett and Patrick Thomas. But right as their team expanded, the coronavirus pandemic hit. Guenantin, who was pregnant at the time, had to pull back from her work in the laboratory. As she notes, At this point, we didnt know if it was okay for pregnant women to go to work.

Gomes was left to supervise the work in the lab, which adjusted to staggered shifts to comply with public health guidelines, with Guenantin overseeing and advising on the project from home. The first shifts were stressful and bumpy, Gomes admits, But we quickly reached an efficient way of dividing the workload. The team had daily meetings over Zoom, both to discuss progress on the project and to check in with each other. I wanted to make sure everyone was okay, Guenantin notes. In the beginning, it was okay, but then back in May, [the pandemic] began feeling long and difficult.

The team, from left to right: Anne-Claire Guenantin, Madeleine Garrett, Patrick Thomas, and Sara Gomes.

But COVID-19 did not deter their progress. They worked through the spring and summer of 2020, alternating shifts in and out of the lab, to fine-tune a protocol that would reliably re-program the opti-ox-expressing stem cells into the cells of their choosing. Its a sum of small victories, Guenantin says. We celebrated every step because you have to do that as a scientist. If you dont, you become depressed because basically its never working until its working. To ensure the final cells were up to snuff, the team ran a series of tests to characterize the newly differentiated cells, tapping into Guenantins expertise in fat cell form and function until they were satisfied with the end result. They passed the pork cells over to their colleagues at Meatable who then got to work growing the cultures in bioreactors that provide a three dimensional scaffold for the cells to grow and take shape.

Meatable has continued to raise money to support bringing in $60 million through a combination of Series A funding and support from the Eurostars Programme. In the meantime, Guenantins team and their counterparts at Meatable continue to refine their methods to deliver pork muscle and fat at scale and have begun to turn their attention to stem cells derived from cows.

In the meantime, regulators recognize the demand for a future of clean meat, with Singapore becoming the first country to approve a lab-grown meat product in December 2020. The appeal of cultured meat cuts across a wide swath of consumers, including those passionate about cutting carbon emissions, those seeking to spare animals from the cruel conditions of factory farming, or ones looking for innovative ways to feed the worlds ever-growing population.

This project has raised a lot of questions for me, Guenantin says. It mades me think about the future generations and how this problem of global warming will end up. We need to think about innovative solution to feed the growing planet with tasty and sustainable products.

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This technology was designed to grow human cells. Now it's transforming the cultured meat industry. - Massive Science