With the recent bankruptcy announcement from Amyris, which marks the end of an era for the synthetic biology company specifically and perhaps the field more broadly, I thought some reflections and foresight might be worth sharing to stimulate healthy discussion and refocus our priorities to build more resilient next-generation synthetic biology companies and fully deliver on the bioeconomy.
In fact, over the past 20 years, I clearly remember the excitement, hope, and vision from when Amyris was founded in July 2003 through its IPO in September 2010 and beyond. Early on, there were significantly fewer companies in this newer space of synthetic biology (synbio), but the excitement was all around. In fact, this excitement had poured over into all of us, including John Cumbers, so much so that it led him to found this very platform of SynBioBeta in 2012—creating a synbio ecosystem that would unite and encourage collaboration between the many diverse stakeholders (industry, investors, academics, non-profits, government, & more). Since then, from 2010 to 2020, there has been an explosive growth of second and third-generation synbio companies formed/founded from the original Amyris generation. Many of these companies were trying to improve on their predecessors with new products and technologies but have been plagued by some of the same challenges.
Thus, rather than “armchair quarterback” the specific decisions that led to Amyris’—and other’s—eventual downfall, I thought it would be more helpful to rally the community around addressing the broader challenges affecting the entire synbio space, highlight the enormous opportunities that still exist, and more importantly, unpack the bright future and higher-level stakes of the bioeconomy that will positively impact our lives, in the US and worldwide.
Despite the hype, promises, and ‘plug-n-play’ description of bringing synbio products to market, the entire commercialization process has been an arduous endeavor. In fact, Roberta Kwok’s 2010 Nature article entitled “Five hard truths for synthetic biology” listed out scientific challenges, hype, progress, and the need to deliver that still exists to this day. Hence, it’s good to reflect and refocus our efforts on three main broad challenges of business, R&D, and scale-up.
Business Challenges: Of the many considerations, one of the more important challenges is to select a good product with a solid business case to balance the rewards and risks. Since the choice of possibilities is a bit dizzying and fragmented, this choice breaks down into two general approaches: 1. replacing an existing product (i.e., drop-in replacement) or 2. creating a new product and likely new market. In all cases, it’s critical to conduct a proper Techno-Economic Analysis (TEA) of your product to understand production targets (rate, titer, & yield), cost of goods, sales price, market size, and scale.
This information is more available when trying to replace an existing product, which reduces the market risks, as it’s already present and largely quantified. For these cases, it can be mutually beneficial to partner with an existing producer who may have issues with their current process. For example, some producers may extract their products from nature by brute force, which makes them subject to the variations of nature itself, such as droughts, floods, pests, and more, which could reduce their yields and add unpredictability to their business plan. Thus, a precision fermentation-based approach could be a great drop-in replacement option that could improve the predictability, scale, economics, and potentially reduce the carbon footprint of the process.
On the other hand, creating new products may offer higher rewards but likely come with greater risks. Again, for early-stage synbio companies, it may be mutually beneficial to share the rewards and risks with a larger partner that can help create the market and derisk the commercialization process, especially since creating a new market may take time, something an early-stage company usually does not possess. This time delay may also be caused by governmental regulations, alternative products, and other factors that affect the rate of adoption, if at all.
R&D Challenges: Once a great target product has been selected, it’s important to have a solid R&D team to execute, deliver, and achieve the technical commercialization targets. Interestingly, many of these companies have technically delivered, with solid revenues, but this may have come at the expense of increasing R&D costs due to various delays, inefficiencies, and lack of technologies to reduce headcount per project and time to market. Thus, while there are trade-offs, it’s important to promote a fast, efficient, lean, and cost-effective R&D structure and philosophy. Specifically, small tight teams of 4-6 people per project, 2-week Design-Build-Test-Learn (DBTL) cycle times & related technologies, and a healthy culture to encourage strong collaboration between the many scientific and business team members and maximize overall efficiency that leads to reduced time and cost.
Another factor affecting R&D efficiency and commercialization time relates to possessing solid chassis/host strains to produce/secrete small molecules, natural products, proteins/enzymes, and more. The more standard hosts of E. coli, S. cerevisiae, and Bacillus have been prevalent within the commercial scale-up landscape. However, other possibly more advantageous hosts have been gaining attention despite their tendency toward slower growth with fewer molecular biology tools, such as Pichia, Streptomyces, and various filamentous fungi. Thus, projects that use these later strains may provide a better starting point but may also carry greater risk to reach their commercial targets due to longer cycle times and lack of molecular biology tools.
Scale-Up Challenges: Lastly, of the many main challenges, there has been a lot of recent attention on the lack of scale-up fermentation capacity, especially in the US. Not only has this caused early-stage companies to look abroad, but this lack may have encouraged some to take a riskier path of funding their own scale-up facilities. Fortunately, on September 12, 2022, The White House issued Executive Order 14081, “Advancing Biotechnology and Biomanufacturing Innovation for a Sustainable, Safe, and Secure American Bioeconomy,” which will fund more than $2 billion into growing domestic biomanufacturing capacity, among many other related activities. Hopefully, this increased domestic capacity will lower the risk for many startup companies and set the stage for successful commercialization.
Furthermore, whether the scale-up facility is internal or external with a Contract Development Manufacturing Organization (CMO/CDMO), there’s a technical challenge of predictive microbial scale-up performance, also known as the “Valley of Death.” While there may be a minor debate as to which step in scale the “Valley of Death” actually refers to, each ten-fold jump in fermentor size presents an inherent financial risk. Thus, it’s critically important to not only have a good tech transfer process but also form a tight bond between individuals in the hand-off where subtle differences are captured and conveyed in a way that is best quoted by the famous French microbiologist and chemist Louis Pasteur, when he stated, “In the fields of observation, chance favors only the prepared mind.”
Despite these challenges, there are still boundless opportunities out there. This has been especially highlighted by a variety of reports from Bioeconomy Capital, Boston Consulting Group, McKinsey, and most recently by the Schmidt Futures venture firm. Specifically, the US bioeconomy is estimated to be near $1 trillion and projected to grow somewhere between $4 and $30 trillion globally in the next 10 to 20 years. These opportunities are broadly bucketed into the areas of agriculture, biopharma, and industrials.
The agricultural space has seen explosive growth across several sectors. For example, there has been considerable investment in the “food tech” space, where several companies are focusing on precision fermentation to produce bio-synthetic milk, eggs, collagen, fish, chicken, beef, and more. They boast faster turn-around times, reduced carbon footprint, cleaner operations, more flavorful meals, and eliminating livestock cruelty. Still, they’ll also need many large-scale fermentation facilities to achieve the price parity of their native competition. In addition, several companies have focused on optimal crop growth with engineered microbes to aid in sustainable nitrogen fixation to replace the less efficient and high greenhouse gas emissions from the traditional Haber-Bosch process. Lastly, in the area of crop protection, there has been considerable attention on microbially produced biopesticides and bioherbicides that are highly effective but far less toxic to humans and other important insects such as bees.
As for the industrial space, there’s been a lot of exciting activity across a range of opportunities, from bio-based plastics, urethane, nylon, car tires, cement, dyes (denim & food), and more. In addition to the compelling outputs, there has been a big push to decarbonize by employing more enzymatic approaches and the use of carbon dioxide and methane as feedstocks.
Lastly, synbio has made a big impact on the biopharma space in the areas of vaccine production, antibody & biologics discovery, CAR-T therapy development, cell & gene therapies, and new CRISPR technologies—not to mention a renewed interest in natural product drug discovery and biomanufacturing. Synbio continues to expand into all these areas and more for faster, more efficient, and cost-effective discovery and biomanufacturing workflows.
Clearly, the bioeconomy has a strong economic outlook for the near future, assuming we can overcome our challenges, which I believe we’re on a solid path forward. So far, I’ve highlighted the opportunities and challenges from a company “boots on the ground” perspective. However, the future of the bioeconomy poses an even higher-level impact on the US and World, specifically relating to global economic competitiveness, national security, and sustainability/environment.
In 2000, the US had a global economic competitiveness ranking of #1, but as of 2023, its ranking has dropped to #9. This drop is due to various factors, including economic performance, government efficiency, business efficiency, and infrastructure. Thus, it’s been critical to have the recent White House and federal support in biotechnology and biomanufacturing paving a path for us to lead and regain our strong economic position in the bioeconomy.
This also relates to our national security, which was recently tested by our entire COVID response and experience. Specifically, we must strengthen our supply chains through multisourcing, nearshoring, manufacturing network diversification, and more. In fact, the bioeconomy can help diversify our primarily petro-based products to bio-based alternatives that make us less susceptible to global oil fluctuations that could destabilize our economy. Furthermore, we need to prepare for the next pandemic and related through the investment into new diagnostics, medicines, and vaccines.
Finally, and maybe most importantly, it’s impossible to view any current news or social media without being confronted with devastating climate events, whether it’s life-threatening fires in Maui, California, or Canada to multi-week record temperature highs in Arizona, Texas, and Florida to hot tub comparable ocean temperatures to more frequent intense hurricanes and floods. Wherever you sit on the climate debate, the weather is undoubtedly affecting our lives more than ever. In fact, life-threatening weather aside, insurance providers are withdrawing from risky areas as climate threats increase from wildfires and droughts to hurricanes and floods, which has deep implications for our homes and overall livelihood. Moreover, with this link between our economy, national security and climate, there is a considerable momentum to reduce our greenhouse gas emissions, with 69% of US adults favor taking steps to become carbon neutral by 2050, and where synthetic biology and the bioeconomy can help yet again to decarbonize our old processes and products for a less volatile future.
Overall, despite the bankruptcy of Amyris and the struggle of others, they likely made bold moves during necessary times, and there still remain enormous opportunities within the bioeconomy, especially for those willing to tackle its challenges, create more resilient synthetic biology companies for a stronger economy, natural security, and a sustainable future for their families, local communities, US, and world. Furthermore, and on a personal note, many of you may know I was proudly born and raised in the legendary Flint, Michigan, birthplace of the automotive assembly line. Unfortunately, it’s now part of the historical Rust Belt of once-great cities that have had considerable difficulty transitioning to a better future, especially with the loss of manufacturing jobs in the US. Thus, my hope and mission going forward are to help grow the bioeconomy in all the great ways just mentioned, and especially encourage it to fill the void of manufacturing jobs once embraced by the middle-class across America and possibly heal some wounds of our divided country.
Michael Clay, PhD, has over 20 years in the synthetic biology space and has excelled at building the critical infrastructure and teams required to bring bio-based products to market across multiple synbio companies culminating in the co-founding of Infinome Biosciences that was acquired in early 2023. Since then, Mike has been focused on helping early-stage companies navigate the science, business, scale-up, and commercialization of their own bio-based products and ultimately grow the bioeconomy.