Biotechnology: an innovation driver in the French biobased industry

Olivier Rolland, Michael O'Donohue, INRAE France

In France, a range of public and private initiatives in industrial biotechnologies are contributing to the development of the circular bioeconomy.

Global biomass production and use are under pressure, with the planet’s natural resources facing numerous threats, from the negative effects of climate change to ever-intensifying industrialization, mixed with unsustainable consumer behavior and increasing food and energy needs. Considering today’s societal challenges, biomass has a critical role to play in the transition from an economy powered by fossil energy, to a bioeconomy and, more broadly, a circular bioeconomy. This transition is urgently needed to avoid the most severe consequences of climate change. However, to successfully transit to a circular bioeconomy, available biomass must be used efficiently, meeting both increasing food demand and non-food needs, while drastically reducing greenhouse gas emissions. Finally, the COVID-19 pandemic has underlined the importance of territorial autonomy within the wider global economy. This is important for territorial resilience and to ensure national sovereignty in strategic manufacturing areas. For these reasons, biomass production and usage must be improved, optimized and stabilized to guarantee future biomass availability.

In the context of a circular bioeconomy, industrial biotechnology has a major part to play. This

family of technology is incredibly well adapted for biomass-based processes and for building circular value chains.

EXPLOITING THE VERSATILITY OF INDUSTRIAL BIOTECHNOLOGY

Industrial biotechnology involves biological catalysts that derive from living systems and their natural components and offers the possibility to operate sober processes that alleviate environmental pressure exerted by current manufacturing methods. Exploiting the versatility of industrial biotechnology provides the means to optimize available biomass, making a range of products from single crops and thus reducing pressure on land use. Moreover, industrial biotechnology supports a variety of environmental services, such as bioactive molecules for biocontrol systems to improve crop management or carbon and mineral recycling processes to maintain soil fertility. In the field of polymers, industrial biotechnology has been harnessed to convert biomass into performance materials, such as the conversion of sugarcane or sugar beet into biodegradable polylactic acid (PLA). Moreover, industrial biotechnology offers the possibility to couple environmental services to manufacturing, converting waste into useful products. Using breakthrough technologies such as those developed by LanzaTech or Carbios, it is possible to use industrial or consumer waste streams, such as still mill exhaust gas and waste plastics, to build useful molecules, or recover monomeric building blocks, thus allowing a fresh manufacturing cycle and avoiding environmental pollution that would result from traditional waste treatment. Industrial biotechnology also provides solutions for growing food and energy demands because microbial fermentation processes deliver different types of energy dense molecules that can be used as fuels (e.g. aviation fuel) as well as highly nutritive ingredients, while cell culture technologies furnish meat substitutes.

So far, the large-scale deployment of industrial biotechnology is limited to several well-documented examples, such as the production of sugar-derived (mostly from sugarcane, corn and sugar beet) ethanol (>80 Mt/year) or the manufacture of specialty products (insulin, vitamins, amino-acids etc.). Its wider deployment is however hampered not only by the persistence of cheap fossil resources, but also by the relative immaturity of the sector. In its present 21st century form, industrial biotechnology is still a growing field displaying untapped potential. Efforts to develop this industry have so far been fragmented and insufficient to drive this technology family to a higher level of manufacturing maturity France’s unique innovation model dedicated to deeptech biotechnology start-ups.

THE FRENCH POTENTIAL IN BIO-BASED INDUSTRY

As a circular bioeconomy player, France possesses numerous advantages. It is well-endowed with biomass resources, with significant forest and a powerful agriculture sector, being a major producer of cereals and sugar beet. In 2010, 16% of all agricultural land in the European Union (EU) was located within French territory, and in 2014 France was the single biggest (18% of total EU production) producer of agricultural products in the EU.

More recently, the role of biomass has been publicly recognized as a key factor in the post-pandemic relaunch of the French economy. It is anticipated that biomass will play a central role in helping France to green its economy and achieve ambitious targets regarding reductions in greenhouse gas emissions and the improvement of overall sustainability. Prior to the pandemic, France was already mustering political support for the development of biomassbased value chains and the further maturation of biotechnology. This is being achieved using France’s Investments for the Future Program (PIA) operated by the French Agency for Ecological Transition (ADEME). Since the pandemic, France has been amplifying its efforts and promoting bioeconomyoriented policy as illustrated in the recent France Relance recovery plan.

Advantageously, France boasts a vibrant industrial ecosystem that covers the length and breadth of biomass-based value chains. Through a cooperative system, several large agro-industrial players, such as Limagrain or Vivescia, provide a solid basis for biomass production, while internationallyrenowned companies such as Lesaffre or Roquette support biomass-based manufacturing. In addition to these industrial giants, France also benefits from a well-organized R&D ecosystem, including national research institutes such as INRAE (see box), CNRS and CEA, technical universities (e.g. INSA), incubation structures (e.g. Genopole), investors (e.g. Sofinnova Partners, Truffle Capital), as well as from a whole host of innovative start-ups (e.g. Metabolic Explorer, Global Bioenergies etc.).

Within France’s biobased industry ecosystem, TWB is an organizational innovation based on a unique public-private partnership model. At the heart of TWB is a unique capability based on experimental hardware that forms a highly automated, cutting-edge bioprocess development infrastructure and a technology-driven team, designed

and dedicated to support bioprocess development (including biological catalysts) up to the preindustrial stage (from Manufacturing Readiness Levels - MRL 3 to 6). It is operated by three of France’s leading research operators: INRAE, CNRS and the technical university INSA Toulouse.

The genius of TWB resides in its flourishing public-private ecosystem that confers TWB with the knowledge continuum necessary to conduct R&D across the innovation divide. Public knowledge assets form the bedrock of innovations that are further nurtured and completed using the combined knowledge and knowhow of a variety of companies, on the one hand large industrial groups, SMEs and start-ups focusing on product and process development, and on the other investors and tech transfer funding specialists. All these stakeholders are bound by an innovative, overarching consortium agreement that fluidifies exchanges (notably regarding intellectual property rights and licenses) and accelerates project pipelines. Fostering synergies between all stakeholders requisite for the development of biobased products and services, TWB forms a hub where public and private researchers are able to translate ideas into innovation, receiving advice and support along the process, bringing innovation to preindustrial maturity.

INRAE: A MAJOR EUROPEAN CONTRIBUTOR TO BIOTECHNOLOGY RESEARCH

INRAE’s commitment to the circular bioeconomy transition is reflected by its strong investment in biotechnology-related research. As shown by its publication record (over 350 publications per year in WoS fields related to biotechnology for industry and the environment), INRAE is a significant contributor to the biotechnology field. Key laboratories are in several cities, but notably in Marseille, Narbonne, Paris region, and Rennes, with a strong biotechnology pole located in Toulouse, which is home to both the Toulouse Biotechnology Institute (TBI) and its close neighbour TWB. INRAE’s activities in the field cover the whole spectrum, from systems and synthetic biology to bioprocess development. INRAE’s laboratory in Narbonne is a world leader in the field of waste treatment and biogas production, while TWB and TBI are heading IBISBA (www.ibisba.eu), which is an ESFRI-recognized European distributed research infrastructure specialized in synthetic biology and industrial biotechnology. In Marseille, INRAE’s research is supported by a major collection of filamentous fungi that provides a rich source of novel biomass-active enzymes. INRAE’s activities in biotechnology are also supported by an impressive range of cutting edge experimental infrastructure, which in addition to TWB, include transcriptomics

and metabolomics core facilities for systems biology research, automated enzyme discovery platforms, and a range of pilot scale facilities supporting INRAE’s activities in the field of waste valorization research.

TWB is particularly supportive of start-ups, which have been a major activity of the TWB story since the outset. Using its unique collaborative framework, TWB has played a part in the growth of successful companies that are now at the industrial development stage such as Carbios (www.carbios.fr), with its enzyme-based process to recycle plastic and Amoeba (www. amoeba-nature.com), with its process to produce biocides and biocontrol systems. Since 2015, TWB has also hosted 7 start-ups in its premises, offering them access to cutting edge technologies and in-house expertise. In each case, TWB’s contribution has enabled start-ups to mature their technology and lower their development costs. During their stay with TWB, startups also benefit from a range of support services, including help with administration and business development, scientific mentoring and numerous networking opportunities. Examples of TWB-hosted start-ups include Micropep Technologies, Green Spot Technologies and iMean. Having discovered a novel family of plant-based molecules, Micropep is now building a unique discovery pipeline aimed at unleashing the ability of plants to defend themselves. Green Spot Technologies is developing a fermentation platform to convert fruit and vegetable byproducts into highly nutritious ingredients, while iMean is developing digital twins of various organisms that are used as predictive tools to help clients to get the best out of their biobased processes. All of these companies are contributing to the development of the circular bioeconomy developing sustainable solutions for a variety of biobased markets. The level of engagement with startups is ‘à la carte’ and can involve strategic partnership aimed at co-development and cocommercialization of technologies. TWB has also been active at the European level, organizing an annual competition (the TWB Start-Up Day) that rewards winning companies and entrepreneurs with access to its platforms and to

mentoring, leveraging its publicprivate ecosystems to deliver it.

Finally, TWB is also actively involved in public-private innovation contracts. These are large, multi-year, multi-partner programs aimed at developing implementable biotech processes. Current projects include BioImpulse (www.bioimpulse.fr), led by the Michelin Group. It aims to develop a process enabling the manufacture of a new biobased adhesive resin devoid of Substances of Very High Concern (SVHC). At the European level, TWB is also involved in an ambitious initiative, entitled Industrial Biotechnology Innovation and Synthetic Biology Accelerator (IBISBA), which ambitions to launch a pan-European research infrastructure to support industrial biotechnology.

THE EUROPEAN INDUSTRIAL BIOTECHNOLOGY LANDSCAPE

Europe is a powerhouse of industrial biotechnology, possessing all the ingredients for success, although its resources are inevitably fragmented because of Europe’s current political organization. Its key players are the United Kingdom (now no longer a member of the European Union), Germany and France. In terms of infrastructure, over the last decade all these countries and others have invested in industrial biotechnology, with UK public investment focusing on accelerating the development of synthetic biology. In terms of bioprocess development facilities, these are scattered across the European continent with examples being IBioIC and the National Industrial Biotechnology Facility (UK), the center for Chemical-Biotechnological Processes CBP (Germany) and TWB (France), although many others can be cited. Globally speaking, the coordination of industry biotechnology-related focused infrastructure at the European level is lacking and even national coordination is rarely a strong feature of the landscape. When coordination does exist, it is often at a local level in the form of clusters and business parks (e.g. DTU Biosustain, which is part of a dense biotech ecosystem that encompasses Copenhagen and Malmö). Overall, this leads to a rather fragmented innovation landscape.

Regarding financing, Europe is also lagging when compared to the USA, where capital investment is much more readily available for innovators. Nevertheless, within the EU some local initiatives are bolstering innovation. For example, since its creation in 2018 the BioInnovation Institute Foundation (BII), supported by Denmark’s Novo Nordisk Foundation, has funded 85 life science start-ups, awarding a total of 48M€. Similarly, Vlaams Instituut voor Biotechnologie (VIB), which receives finances from the Flemish (Belgium) government, provides a host of services in support of biotech innovators. Together, BII, VIB and TWB are good examples of successful publicprivate partnerships that leverage a range of financial resources to ensure that innovation is nurtured all along the maturation pathway. Additionally, at the pan-European level the Bio-Based Industries Joint Undertaking has so far mobilized €1 billion in funds to support 123 R&I projects. This successful scheme is set to be renewed in the form of the Circular Bio-based Europe Joint Undertaking. The European Innovation Council (EIC) Accelerator is also supporting high-risk, high-potential small and medium-sized enterprises, with support in the form of grants (up to €2.5M) and equity (up to €15M). To address the intrinsic fragmentation of the Europe’s R&D&I infrastructure landscape the IBISBA initiative is looking to create a simplified entry point for clients. This bold initiative requires considerable organizational innovation aimed at harmonizing business practices across a network of research infrastructure and developing the means to deliver seamless, bespoke R&D&I services. IBISBA’s aim is to provide end-toend bioprocess development using different access modes adapted to the needs of both academics and companies, with a special focus on SMEs.

As a European research infrastructure present on the ESFRI roadmap, IBISBA is currently under preparation. Ongoing work is focusing on the development of advanced digital tools, such as its IBISBAhub (a digital knowledge commons) and on the definition of IBISBA’s governance structure, the aim being to bring together different European members states as stakeholders of a single legal structure able to deliver efficient services to clients.

A final defining feature of the European landscape related to industrial biotechnology is regulation. Current European regulation supports the bioeconomy transition, incentivizing the use of biomass and promoting, for example, the production of renewable biobased energies (the European Renewable Energy Directive).

Nevertheless, more needs to be done to encourage the development of biobased markets and to promote breakthrough technologies, such as synthetic biology. This is vital to remain competitive in the world arena and to ensure that the European Union can continue to impose its rigorous standards on its trading partners.