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This week, FoodBev had the privilege of attending the opening of BioBetter’s first food-grade pilot facility located near the city of Qiryat Shemona in northern Israel. This marked our first time in Israel – a nation distinguished for its dynamic start-up ecosystem. Renowned as an epicentre for food-tech innovation, many Israeli companies are at the forefront of creating innovative solutions across every facet of the food-tech industry. Fuelled by its strong technological expertise, well-established research institutions, proactive regulatory environment and substantial investments, the country is home to a plethora of pioneering companies in the food-tech space, including Aleph Farms, Steakholder Foods and Believer Meats. But nothing could have prepared us for the groundbreaking technology and processes unveiled by BioBetter. Started in 2015, BioBetter has pioneered a unique protein manufacturing platform for producing growth factors (GFs) that uses tobacco plants as self-sustained, animal-free bioreactors. By turning tobacco plants into “natural bioreactors,” the start-up says it could bring the cost of GFs for cell-based meat down from the normal range of $50,000-$1 million per gram to just $1 per gram. The company was founded by Oded Shoseyov, entrepreneur, researcher and professor of protein engineering and nano-biotechnology at Hebrew University, Jerusalem; Dana Yarden, a bio-tech business expert; and Avi Tzur, an industrialist with an avid vision to put the tobacco plant to positive use. Shoseyov's entrepreneurial spirit has led him to start more than 20 companies, from Collplant – a regenerative medicine company focused on the 3D bioprinting of tissues and organs, to SavorEat – a start-up harnessing 3D printing technology to create realistic plant-based meat alternatives, to nanotechnology company SP Nano, which commercialises the use of nanoparticles in products made from composite materials. On the drive home from the facility back to Tel Aviv, Shoseyov's passion and confidence in BioBetter and northern Israel's innovation culture shone through, he said: "What you have seen here today is one of the most remarkable things in Israel. Science may start in the middle of the country, in one or two of the universities, but at the end of the day, it is my experience that the best place to perform, and the best place to execute, is here in the Upper Galilee." Why growth factors? As all cell-based meat requires GFs to stimulate cell development and differentiation and supplement cell culture media, GFs take up anywhere between 55-95% of the marginal cost of manufacturing cell-based foods, according to The Good Food Institute (GFI). GFs are usually gathered from livestock or made through fermentation – both of which are costly and complex. Fetal bovine serum (FBS) – which provides a mix of the most important factors required for cell attachment, growth and proliferation – has conventionally been used in cell-based meat production due to its richness in nutrients and GFs. However, FBS has been flagged as unsustainable, unethical and not scalable, due to its process of being harvested from the blood of fetuses taken from pregnant cows. BioBetter’s process that turns tobacco plants into bioreactors – using only water, CO2 and sunlight – for the expression of proteins, can produce various bovine GFs, including FGF2, transferrin and insulin. The company’s newly established plant has the capacity to process 100kg of tobacco plant-derived GFs daily with several thousand square metres of bovine-insulin and FGF2-expressing tobacco plants already thriving in northern Israel. Speaking to those who attended the opening of the new facility, BioBetter’s CEO Amit Yaari detailed just how disruptive this new technology could be: “To illustrate, if cultivated meat were to take just 10% of the global meat market, this would require 17,000 tons of insulin. Today, the entire global capacity of insulin is only 30 tons...Just a year ago, we made the commitment to complete a food-grade pilot facility, we are now setting a goal to build a factory capable of producing up to five tons of growth factors per day by the end of 2025”. BioBetter’s chief research and development officer, Yonatan Eran, gave us a tour of the facility while explaining how the plants are modified to express the proteins. “We take tobacco seeds, sterilise them and grow them in sterile conditions to create plantlets. Once we have the plantlets, we cut them and use small discs of leaf as our starting material. Then, we introduce DNA – for example, DNA that encodes an insulin gene from a cow, or green fluorescent protein from a jellyfish, whatever DNA you can imagine –into the genome of cells inside these leaf discs.” Together with the target gene, BioBetter introduces an antibiotic resistance gene, so transformed cells in the leaf discs have the foreign DNA and also resistance to an antibiotic drug. Then, the scientists incubate the leaf discs in a sterile plate that contains nutrients and also an antibiotic agent, meaning that only transformed leaf cells that contain the new DNA will survive and grow in the plate. And this is when the magic happens: The transformed leaf tissue begins regenerating itself into a new plantlet: it develops new roots and leaves. The young plantlet develops within few weeks into a mature and fertile plant containing DNA from a foreign source within its genome. Fluorescent jellyfish Back in the 1970s, scientists have isolated a specific gene encoding a green fluorescent protein (GFP) from a jellyfish in the Pacific Ocean. Since then, GFP has become a versatile biological marker for visualizing protein and detecting transgenic expression in vivo. “To demonstrate the power of our technology, we introduced this GFP gene into tobacco leaf discs and regenerated a transgenic plant, So, if you emit UV light, you will see the plant glowing, and it will show the abundance of protein expressed in the leaf.” Eran said that the plants contain somewhere between milligrams to grams of protein per kilogram of fresh leaves. “The proteins that are being produced right now for the cultivated meat industry, are super, super expensive. For example, FGF2 can cost up to $1 million per gram. And here we’re talking about one plant that produces one kilo of leaves and could potentially produce one gram of FGF2.” Side streams and sustainability Throughout our time at the facility, BioBetter’s ingenuity shined through every facet of its operations. For starters, the plants can be irrigated with recycled, low-quality or even salt water. “Tobacco grows on every continent besides Antarctica,” said Eran “Furthermore, tobacco plants can reach 2.5 metres tall in less than three months.” Co-founder Dana Yarden, who drove us on the two-hour journey from Tel Aviv to Qiryat Shemona, added: “We can grow tobacco four times per year, with a high yield, and when you cultivate the crop, it grows back”. “Nothing goes to waste,” she added. “We remove the nicotine, which can be used as a natural pesticide, and the remaining material can be used as animal feed or even used within construction”. Yarden said that while tobacco plants are grown on most continents, they do require warm weather to thrive. She mentioned that in areas with colder climates, the plants could be grown in quantity in vertical farming facilities, and that the plants can flourish even in extreme weather, having withstood temperatures of 50°C this spring. Furthermore, Yarden pointed out that as the world begins to understand the detrimental impact that smoking tobacco has on our health, the new technology has the potential to repurpose the tobacco crop, securing tobacco farmers’ jobs that could potentially be at risk. Current tobacco agriculture methods are very advanced due to the lucrative smoking market, which means that farmers have sophisticated machinery to optimise tobacco growth. Eran says that this is another advantage of using tobacco plants as all of the infrastructure already exists. For BioBetter, the new facility is the latest in a string of developments. In the last year, the start-up has achieved commercial-scale cultivation of its insulin- and FGF-expressing tobacco plants, reached GF expression levels that enable a significant reduction of production costs, enabled significant regulatory progress and advances with the Israel Ministry of Health, collaborated with leading cell-based meat companies and has secured a $10 million Series A investment led by Jerusalem Venture Partners. Following an exclusive tour of the company's facilities, BioBetter's founders and key leaders gave heartfelt speeches – showcasing their pride in the team's accomplishments and their enthusiasm for the future. BioBetter truly knows how to celebrate; the food was incredible and the wine was flowing, with smiles all round. A huge thank you to the BioBetter team for inviting us to the opening of the new pilot plant in Israel, and for the insight into how the start-up is shaking up the cell-based meat industry.