Four major challenges on commercialization of cell culture meat

Four major challenges on commercialization of cell culture meat. Nature Outlook: Four major challenges facing the commercialization of cell culture meat! 

Nowadays we are all concerned about cell culture meat. This article can bring some enlightenment and help to related industry professionals and readers.

① Cell culture meat

In 2015, when Laura Domigan established her own research group at the University of Auckland, New Zealand, she hoped to continue working on cell culture meat in the laboratory. However, since there was almost no funding to support the research of cultivating meat in academia at that time, Domigan could only transform to research the application of biomedical materials in tissue engineering.

As a well-trained protein biochemist, she is committed to making artificial corneas for eye surgery-a far cry from growing steaks in the laboratory.

Despite this, she never gave up her dream of cultivating meat for consumption in vitro. Domigan said: “I have to maintain super patience and keep working hard.” Although it took many years, Domigan’s strategy paid off in the end.

In the beginning, she won a fund for a doctoral student to develop a nutrient medium formula for growing cell culture meat.

Then, in October 2020, the research team led by Domigan received millions of dollars in funding from the governments of New Zealand and Singapore to explore which cells are the best starting materials for culturing meat, and in the laboratory The question of whether the nutrient content of the meat cultivated in the medium is equivalent to the real meat.

Domigan said: “There is still a lot of research to be done in this area.” Most of the research has just begun, and it started in some visible ways.

In the past few years, investors have poured hundreds of millions of dollars into research on cultivating meat, accompanied by hype and exaggerated news reports that an agricultural revolution may bypass the environment and animal welfare of traditional meat production. problem.

An estimate by Kearney, a consulting firm in Chicago, Illinois, said that by 2040, 35% of the meat consumed worldwide will be cultivated. This change is expected to reduce greenhouse gas emissions and the use of antibiotics. . As the COVID-19 pandemic has revealed key weaknesses in the global food supply chain, some people currently expect this transition to cultivated meat to happen more quickly.

At the beginning of December 2020, a US start-up called Eat just announced that its chicken nuggets (70% are cultured chicken cells and added with vegetable protein) have been approved by the regulatory authorities to be available to consumers in Singapore For sale, this is the world’s first commercialized product to cultivate the meat industry.

What scientists worry about is that getting the product to market so quickly may mean that basic research has not yet been conducted or that it is kept secret because of trade secrets.

Abhi Kumar, venture partner of Lever VC, a New York-based venture capital fund focusing on alternative protein start-ups, said that start-ups have displayed laboratory-grown chicken nuggets, pork sausages, steak strips and seafood dumplings. . But these only show that these companies “can produce on a small scale.” He said the challenge now is to scale it up.

It is indispensable to improve the cell raw materials, the nutrient matrix required for the growth of fluid cells, and the scaffold that supports the 3D tissue structure. The next-generation bioreactor platform must be able to grow large numbers of cells at high density. The research work is so expensive that many people in the field doubt whether there is private funding that can support these research and produce affordable products.

This is why leading thinkers in the field of cellular agriculture, such as Erin Rees Clayton of the Good Food Institute (GFI), advocate more open science and public funding.

Rees Clayton, deputy director of science and technology at GFI, a non-profit think tank in Washington, said: “These fields need public research. This field is still far from competition, and everyone can do more work in a more open way. We Both can benefit from it and make faster progress.”

In order to fill the funding gap, GFI has developed a research funding program. In the past two years, the program has provided nearly US$3 million in funding to 16 research teams engaged in the research of meat cultivation projects.

At the same time, academic institutions are also considering the recruitment of talents related to this new subject. For example, the Technical University of Munich began accepting applications from professors of cellular agriculture. Moreover, as evidenced by Domigan’s financing success, governments are also paying attention to calls for financial support.

The field of cellular agriculture is beginning to face some huge scientific and engineering challenges, and scientists from various disciplines have also joined this field.

Glenn Gaudette, a biomedical engineer at Worcester Polytechnic Institute in Massachusetts, said: “This cellular agriculture research is my motivation for getting up early every day.”

For nearly 20 years, he has been committed to the development of stent technology for cardiac regeneration therapy. Now, he applies his expertise to the question of how to train meat. “Can it be commercialized? No, not yet, hopefully one day. But this technology is really exciting.”

② Challenge 1 Competition for funds

At the beginning of the 21st century, the National Aeronautics and Space Administration (NASA) briefly supported the cultivation of goldfish muscles in the laboratory as a potential source of protein for astronauts in long-term missions.

A few years later, the Dutch government sponsored a €2 million (US$2.3 million) research project to grow pork using stem cells. The project also received a 250,000 euros funding from Google co-founder Sergey Brin, and triggered the most remarkable moment in the field so far-at the time Mark Post, a vascular biologist at Maastricht University in the Netherlands, in 2013 Launched the world’s first training burger in 1988.

However, apart from the funding provided from time to time to explore the social impact of using cell cultured meat, few other public funds are used for research on cultured meat.

Kate Krueger, former head of research at the non-profit organization New Harvest, said that government agencies have largely avoided this field because this type of science is unproven and involves interdisciplinarity and runs counter to the traditional boundaries of official funding sources. .

Krueger said: “Cell agriculture is a no-man’s land between biomedical research and agricultural research.” He also currently runs a consulting company in Cambridge, whose business focuses on cell agriculture.

The funds of GFI and New Harvest have filled the funding gap to a certain extent. However, the situation is changing.

As the scientific community’s interest in this subject has increased day by day, the government has also begun to inject more funds into this field. Several large grants have been issued in the past few months alone.

For example, in November 2020, the government agency Flanders Innovation and Entrepreneurship (Flanders Innovation and Entrepreneurship) began funding a four-year project called CUSTOMEAT with an amount of 2.1 million euros. Co-operated by scientists from Wen University.

In the United States, the National Science Foundation (NSF) allocated US$3.5 million in September 2020 to continue funding a meat training federation at the University of California, Davis in the next five years.

David Block, a chemical engineer in charge of Davis’ research, said: “We hope that we can provide basic knowledge and cultivate a well-trained workforce. These are all things needed to develop an industry.”

Johannes le Coutre, former head of the research team at Nestlé, the Swiss food giant, said that experts say that many companies that cultivate meat may have over-commitment and under-delivery, but academic science can help them “maintain their credibility.” Johannes le Coutre joined the University of New South Wales in Sydney, Australia in 2019 to run a laboratory specializing in cellular agriculture.

Amy Rowat, a biophysicist at the University of California, Los Angeles, pointed out that academia also provides researchers with intellectual freedom to engage in research projects. They can use their expertise in basic sciences to come up with innovative ways of thinking, or to solve problems that have nothing to do with product development. Directly related but important to the entire field.

According to David Kaplan, a bioengineer at Tufts University in Medford, Massachusetts, the next generation of scientists entering the field is “fully motivated to make change.”

He said: “In my decades of work in this field, I have never seen such a positive and enthusiastic student.” Andrew Stout is an example. Stout is a PhD student in the Kaplan laboratory. He is rethinking the whole of cell agriculture. The process starts with the most basic ingredient: the muscle cell itself.

Most companies that cultivate meat in the laboratory either use cells from animal tissue biopsies directly, or use cell lines that spontaneously become immortal through natural mutations that allow them to proliferate indefinitely in the laboratory.

However, due to concerns about strong consumer opposition, few companies will consider genetic manipulation to obtain the best performance. However, Stout realized that genetic engineering provided a way to realize the nutritional prospects of cultivated meat.

Picture. Ka Yi Ling and Sandhya Sriram are co-founders of Shiok Meats in Singapore.

③ Challenge 2 Selection of original materials

He inserted three genes into the muscle cells of cattle [1]. The enzymes encoded by each gene are involved in the synthesis of antioxidants, which can alleviate diseases related to the consumption of red meat and processed meat, such as colon cancer. These enzymes may also contribute to the production of cultured meat, because unstable molecules attacked by antioxidants can prevent the proliferation of cells grown in certain laboratories.

If consumers are willing to accept this type of DNA enhancement, Stout said: “Genetic engineering and metabolic engineering can have a great impact on and benefit from cultivated meat, and even allow us to create novelty that we cannot obtain in another way. food.”

Other researchers are reconsidering whether the cells used to grow meat products need to come from species that are commonly eaten in Western culture.

For example, Natalie Rubio, another graduate student at Tufts University, has explored the use of insect cells to grow meat to create products that taste like crab, shrimp and other seafood.

Using the muscle cells of Drosophila melanogaster [2] and the juvenile caterpillar of tobacco hornworm, Rubio showed that insect cells can grow more easily and at a lower cost than cells of traditional livestock species, and may have nutritional advantages.

At the same time, other scientists hope that the idea of ​​cell-cultured zebrafish fillets will unite the research team, at least as a tool to accelerate progress in this field.

The zebrafish (Danio rerio) is a model organism for studying the genetic, neurological and behavioral basis of diseases.

Alain Rostain, executive director of Clean Research, a non-profit organization in New York, now also hopes to turn it into a target species for cellular agriculture basic research projects. He said: “There is not much basic understanding yet. We need a lot of people to participate and think about science freely together.”

And, as Rostain and his colleagues have stated [3], researchers can benefit from the molecular toolbox already established for zebrafish.

In addition, as a lean fish with very little fat content in its muscles, zebrafish fillets should be easier to produce than laboratory-grown fatty salmon, tuna, beef, pork and similar slices. Rostain said that the taste of cultivated zebrafish meat is likely to be similar to that of white fish such as cod or haddock, and the findings in zebrafish research can also be applied to any other edible species.

Regardless of the starting material, all cells need an optimized growth medium-a broth rich in chemicals and proteins to support cell proliferation and differentiation.

Many companies have designed culture methods that do not require nutrient-rich fetal bovine blood (fetal bovine blood is the cornerstone of most in vitro culture media) to create the slaughter-free products required by the industry. However, this serum-free medium increases the cost of cultivating meat, making it unaffordable for the public.

Ka Yi Ling, chief scientific officer of Shiok Meats, a cell culture seafood company in Singapore, said: “It is difficult to find a cost-effective option.”

④ Challenge 3 Construction of medium

According to an analysis by GFI [4], the current growth medium accounts for most of the total production cost of cultured meat, and the protein called growth factor is its most expensive component.

As start-ups dedicated to serving the cellular agriculture industry devise new ways to manufacture these products, costs are falling. But as Matt Anderson Baron, co-founder and chief scientific officer of Future Fields in Edmonton, Canada, admits, “There is still a lot of work to be done in optimization and discovery.”

Assuming that researchers find the right combination of cell line and growth medium, they must also grow these cells on the scaffold. The ideal scaffold should be edible so that it does not need to be removed from the final product.

For minced meat products such as burgers and sausages, small balls called microcarriers can provide most of the surface properties required for the growth of muscle cells and fat cells. But for any product with a more complex meat structure, such as steak or Iberian ham, they require more complex tissue engineering methods.

A team from Harvard University in Cambridge, Massachusetts offered an option. Biological engineer Kevin Kit Parker and his colleagues developed a spinning technology that is like a cotton candy machine, which can squeeze long and thin fibers from gelatin [5].

The researchers put gelatin (a protein product derived from collagen) into their machine and produced fine threads (narrower than the width of hair) that are highly similar to the fibrous structure in muscle tissue.

Last year, Parker and his colleagues discovered that the muscle cells of rabbits and cows grown on gelatin fibers are arranged correctly [6]. Although these cells are still not as dense as real muscles, Parker, together with his three postdoctoral fellows and students, founded a company called Boston Meats to further improve the technology.

He said: “Now, with our stand, your choice can change from a burger to a fish fillet.”

In other places, researchers have prepared scaffolds from foods, such as textured soy protein and various vegetables that have been stripped of cellular components and retain only the protein and sugars of the supporting structure.

For example, at the University of Ottawa in Canada, biophysicist Andrew Pelling and his students used decellularized celery stalks and proved that the grooves created by its natural structure help promote the formation and arrangement of muscle cells [7].

The Gaudette team at Worcester Polytechnic Institute cultivated fat and muscle cells on acellular spinach leaves. The delicate vein branch network of the plant provides an ideal channel for the nutrient medium to reach each cultured meat cell.

However, because muscle cells and fat cells require different growth substrates, researchers usually culture these two types of cells on separate scaffolds and place them in different nutrient pools. Some researchers, including Rowat, have devised a strategy that weaves muscle and fat together in order to obtain the flavour of a lean steak.

Rowat explained: “These cells actually fuse with another companion scaffold on a time scale of several hours to form these composite structures.” In an unpublished study, she used mouse and rabbit cells to create miniature Lean and fat steaks, and began to study pig and cattle cells.

But even with the latest scaffolding strategy, some muscle biologists worry that key aspects of tissue physiology are still being ignored.

James Ryall, chief scientific officer of Vow, a Sydney-based start-up company dedicated to the production of animal cell culture meat such as kangaroos and alpacas, said: “As an industry, we pay too much attention to cell division, but ignore fusion and maturity.”

In order to form muscle tissue, thousands of precursor cells must first fuse together to form long muscle tubes. These cells need physical stimulation to mature into muscle fibers.

Lieven Thorrez, a muscle tissue engineer at the KU Leuven Kortrijk campus, said that only then will the muscles grown in the laboratory have the texture and nutritional properties of real meat.

He said: “This process takes time. You can’t differentiate cells in just a few days and claim that this muscle fiber is the same as the muscle fiber of an adult animal. However, this issue is largely ignored.”

⑤ Challenge 4 Scale

Since there are many scientific problems to be solved, the research on cell culture meat is still in the experimental stage, whether in academic laboratories or private laboratories. In order to achieve commercial viability, the industry needs to find unprecedented ways to organize production on a large scale.

Che Connon, a tissue engineer at Newcastle University in the United Kingdom, estimates that using laboratory-grown meat to supply the world’s population requires the establishment of a system that grows 10 to 24 cells per year. The current ideal scale is based on mammals. The batch biological processing technology used in the production of cells cannot be achieved.

Global production capacity can meet about one billionth of this demand. Connon said: “This is a huge limiting factor.” He developed a continuous cell bioreactor platform, which he plans to commercialize through a spin-off company called CellulaREvolution.

At the same time, Simon Kahan, president of Seattle life science software company Biocellion SPC and computer scientist, led a team called the Cultivated Meat Modeling Consortium.

The team was established in 2019 to optimize bioprocessing technology through modeling technology. With funding from the German technology company Merck, the team developed a proof-of-concept model of a stirred tank bioreactor, which only involved rotating rotors and free-floating tiny beads for culturing muscle cells.

This bioreactor may be quite rudimentary, but the team’s computer model is completely different. Simulations of fluid mechanics and cell biomechanics reveal the core challenges of culturing muscle cells or fat cells on a large scale.

Kahan said: “You have two contradictory goals. In order to support the exchange of nutrients and gas, you are trying to keep the substances in a good state of mixing, and you need to try to subject the cells to very little mechanical fluid pressure.” Investment from industry partners Next, the team plans to add more complexity to its model to simulate a model of a bioreactor in the real world.

The Block team with NSF funding did not even have time to experiment with bioreactor design. His team has a lot of things to do. It is busy solving the problems of cell lines, media and scaffolds, and evaluating the feasibility of the cell culture meat industry.

Block said: “For me, it is unclear whether this will be a viable option”, whether from a technical, economic or sustainability perspective. However, with every new grant or every new research team entering the field, the goal of cultivating perfectly grilled half-ripe steaks from cells becomes closer and closer.

~~~ Four major challenges on commercialization of cell culture meat ~~~

(sourcesohu, reference only)

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