Scientific American Content
Emily Waltz, Nature Biotechnology
2021 11 23
In recent weeks, companies developing cell-based fish and shellfish have been drawing attention as they tout their offerings and expand their businesses globally. San Diego-based BlueNalu will introduce lab-made finfish to Europe through a collaboration announced in September with British frozen food distributor Nomad Foods. The same month, Hong Kong-based Avant Meats inked a deal with Singapore’s Bioprocessing Technology Institute to improve the economics of its cultivated fish production. In June, Wildtype opened a tasting room adjacent to its San Francisco pilot plant, where it has been offering bites of lab-grown, sushi-grade salmon.
These moves reflect a growing interest in alternative, biotech-derived fish. The need for sustainability has brought them to the fore: Of all the seafood consumed in the world, about half is raised in aquaculture and the other half is wild caught. Some species of wild-caught fish may contain mercury, microplastics and pollutants from environmental contamination; stocks are being depleted by the impact of climate change on ecosystems and overfishing. The harvest of wild-caught seafood cannot be increased sustainably, and yet the global population and its demand for protein continue to grow. “So we’ve got to come up with a lot of different ways to address these challenges,” says Kevan Main, associate vice president for research at Mote Marine Laboratory and Aquarium in Sarasota, Florida. “I believe that cell-based seafood is going to be one of those opportunities.”
Of the companies exhibiting various prototypes or scaling up production, BlueNalu is among the closest to market. In addition to its partnership with Nomad Foods, BlueNalu has partnered with Mitsubishi in Japan, seafood producer Thai Union in Thailand, and wellness food company Pulmuone in South Korea to develop market strategies in Asia for BlueNalu’s products.
Cell-based seafood—derived from commonly consumed fish (for example, salmon and tuna) or shellfish (for example, crustaceans such as shrimp and crab)—is also known as cultured, cellular or in vitro seafood. It is derived from the tissue of an aquatic species, but has never been part of a live, swimming animal. The flesh is made in the laboratory by harvesting cells from a small number of donor fish or shellfish and culturing them in a bioreactor. For three-dimensional tissues like fillets, an edible, biocompatible scaffold is needed to provide structure for cell growth and maturation. The resulting lab-made meat, a mix of mostly muscle and fat cells, tastes similar to the live-caught version, but has none of the animal ‘waste’: no bones, no scales, no eyeballs.
The strategy has already been applied to and commercialized in the in vitro culture of other kinds of meat, including beef, chicken and pork. Indeed, dozens of companies are developing cell-based terrestrial meat, and a few of them have racked up over a hundred million dollars each in venture capital. Chicken developed by Eat Just became the first cultured meat to reach the market when Singapore’s regulators in December 2020 approved its sale.
Singapore and other global regulators will likely supervise the in vitro cultivation of fish using the same criteria and pathways they use for chicken and beef. The United States, however, makes a distinction. Both the US Department of Agriculture (USDA) and the Food and Drug Administration (FDA) oversee cultivated terrestrial meat, but for cultivated fish, the FDA will have sole jurisdiction. That rule applies to all seafood except catfish, as a result of some political history.
So far, cultured seafood has lagged its terrestrial counterparts. According to the Good Food Institute, which tracks and advocates for the cultured meat industry, there are only about 14 companies in the world developing this kind of seafood.
The gap is, some biologists contend, due to a research bias towards terrestrial species. “It’s amazing to me how far advanced the science is with land-based animals,” says Main at Mote. “I think it’s because it’s easier: they’re right beside you, you can access those resources, and you can see what’s going on really easily. Whereas with seafood, everything’s happening in the water, so you have to first understand how to make things work in that aquatic environment,” she says.
Research on terrestrial meat also benefits from a relatively narrow selection of species. “When we’re talking about chicken, we are talking about one type of product with a specific flavor,” says Reza Ovissipour, an assistant professor at Virginia Tech specializing in food safety and cellular agriculture. Each seafood species, however, has its own flavor, texture, and cell line that requires a unique set of parameters in which to grow.
And developing cell lines from these species can prove elusive. Scientists start by harvesting adult or embryonic stem cells from the species of interest. They then look for cell lines that are self renewing, stable from generation to generation, and can differentiate into muscle, fat and connective tissue. The goal is to establish an immortalized cell line that continually regenerates on its own, eliminating the need to go back to the donor species.
Researchers initially grow the cells in a single layer adhering to the surface of small flasks or other labware. The cells grow in nutrient-rich media typically consisting of a unique, species-specific combination of glucose, amino acids, peptides, fatty acids, vitamins, salts and growth factors such as hormones, recombinant proteins and cytokines. Many researchers in the industry initially used components from bovine serum in their growth media, but most are experimenting with alternatives.
The next step is to scale up to produce enough biomass to eat, and this can prove challenging. Scientists must coax the cells to grow in higher volume, three-dimensional bioreactors, in which cells are suspended in their growth environment.
Once this is accomplished, researchers gradually scale up the operation to larger and larger bioreactors. The cellular meat produced in these bioreactors comes out soft, like minced meat. If researchers want to give the meat the texture of a fillet, they must coax the cells to combine and grow on edible scaffolds.
Each step of the process presents its own set of challenges. Developing cell lines, for example, can consume years of a company’s early R&D budget, says Jennifer Lamy, who leads the Good Food Institute’s alternative seafood efforts. Berlin-based Bluu Biosciences benefits in this area from the foundational research of its co-founder, Sebastian Rakers. The marine biologist had previously established more than 80 different cell lines from more than 20 different marine species during his 12 years with the Fraunhofer Society.
In May 2020, Rakers helped launch Bluu, which is focusing on common carp, Atlantic salmon and rainbow trout. The first products will be unstructured, scaffold-free meat prepared in balls, which are common in Asian cuisines. Fish cells comprise half the product, while plant-based proteins and a small percentage of non-plant-based proteins make up the other half. The company has not yet held tastings of its products.
For Wildtype, a company developing sushi-grade salmon, it took three years to establish cell lines to the point where they could be grown in suspension in bioreactors, says co-founder Aryé Elfenbein. In moving from glass plates to a bioreactor, Wildtype scientists initially used microcarriers, which are beads that provide a place for cells to attach in suspended cell culture, to help increase their viability. From there the company transitioned to growing the cells in clusters, and finally to single-cell suspension.
Visitors to Wildtype’s tasting room can watch how their food is being made through a glass door—an idea unheard of in the conventional meat industry. “Can you imagine a tasting room next to a slaughterhouse?” Elfenbein asks.
Some people object to the idea of their meat being grown in a lab, but Wildtype’s founders say that more awareness about slaughter is changing that. “A lot of people have intentionally turned a blind eye to how our meat and seafood is made because we all know it’s not a great story,” says Justin Kolbeck, who co-founded the company with Elfenbein. “Slaughterhouse conditions are notoriously unpleasant for both workers and animals, and aquaculture operations are not much better,” he says. “However, I think there’s been a big shift in terms of people wanting to know more and having more visibility and transparency into what they’re eating.”
To make sushi-grade salmon, Wildtype must use scaffolds, which the company is developing in-house using plant-derived ingredients. Scaffolds are tricky because they must promote cell growth, ensure thermal stability and also provide the right texture to the human palate. “The process of cell–scaffold integration at a very large scale is something that just doesn’t exist today,” says Elfenbein. Wildtype’s scientists spent several years screening thousands of scaffold candidates with these attributes. When they found ones that were also low-cost, plant-based, widely available and currently in use in the US food supply, they developed a high-throughput method to produce them.
Like all companies in the cultured meat industry, Wildtype faces the formidable challenge of scaling up in an economically viable way. In fact, Wildtype has never made more than a few pounds of salmon sushi at a time.
That’s because scaling up isn’t a simple matter of multiplying each component by a factor. Operating on a larger scale requires different equipment and management of a different set of heat and gas transfer rates, pH control, nutrient and oxygen supply, and raw material impurities. “On a larger scale, controlling the environment isn’t as easy, and sometimes the cells don’t show the same properties as when they were at the smaller scale,” says Ovissipour. “So you are dealing with a completely different setup which requires more optimization and modeling,” he says.
No matter what the scale of the operation, the cost of producing cultured meat is astronomically high compared with that of conventional meat—over $20,000 per kilogram at the high end, by one estimate prepared by consulting firm CE Delft for the Good Food Institute. That won’t change without a tremendous amount of R&D and an approach to cell culture that differs radically from the way scientists have been growing cells for the past 70 years. “The entire biopharma industry has been built on harvesting the proteins that cells produce and discarding the cells,” says Kolbeck. The production of monoclonal antibodies is one example of that. “In our system the inverse is true: [We want to learn] how to concentrate large quantities of cells while keeping them viable for their onward journey to a scaffold.”
This article is reproduced with permission and was first published on November 15 2021.