Regulations, funding, and knowledge gaps: Challenges and opportunities in bringing agricultural biotechnology to market

Innovations in agriculture will play an increasingly important role in America’s quest to ensure resilient and sustainable production of food, medicine, and bioenergy products. Biotechnology, spurred by advances such as cheap sequencing, offers a realm of possibilities for novel agricultural inputs, such as more targeted pesticides that are less toxic and less likely to cause tolerance, less carbon-intensive alternatives to fertilizers, and more climate-resilient crop varieties. 

However, research and development of new agricultural biotech products can be expensive and time-consuming, due to the large physical scale and long timelines of field trials. At the same time, federal funding for agriculture research has historically paled in comparison to funding for defense, energy, and human health. For example, in 2022, the NIH’s R&D budget was more than 16 times that of the USDA’s. 

The Biden administration has demonstrated its recognition of the need to accelerate research and development in agricultural biotechnology, featuring it prominently in 2022’s Executive Order on Advancing Biotechnology and Biomanufacturing Innovation for a Sustainable, Safe, and Secure American Bioeconomy. Additionally, a bill to expand authorization of funding for a moonshot USDA research grant program, AgARDA (Agriculture Advanced Research and Development Authority), has broad bipartisan support. At the same time, there has been a commensurate increase in private funding

While this multi-front surge in enthusiasm and investment is welcome, many challenges remain in translating money, ideas, and laboratory results to the field and the market, including communication between the various stakeholders in agricultural biotechnology R&D. To better understand industry priorities and potential barriers to progress, we spoke to members of the executive team of Fall Line Capital (FLC), a venture capital (VC) and private equity firm that invests in food/agriculture startups. Fall Line’s investments include new biopesticides (Greenlight, Micropep), functional microbes (Pluton, Wild Microbes), and new equipment (Guardian Agriculture, Rantizo, LUMO), in addition to managing a farmland portfolio. As lifelong farmers as well as agriculture technology (agtech) investors, Clay Mitchell and Scott Day offer a multifaceted perspective on the current landscape.

We then outline actions for government actors that can address the challenges identified in our interview, in three key areas: regulatory oversight, federal R&D funding, and bioliteracy.

Q: What can the U.S. government do to provide a supportive landscape for new agricultural biotechnology?

Fall Line Capital: I think the biggest hurdles are regulatory. If the government wants to be truly supportive and innovative, it should be working to revamp the convoluted regulatory environment. The current system wasn’t designed to handle all the new technology being developed with novel mechanisms of action, so hurdles to creating and commercializing stifle innovation even more than they did in the past. 

Looking at new technology like RNA– and micropeptide-based pesticides, it’s been a difficult process to get those products registered, even though they should be embraced: compared to conventional pesticides, they have the potential to be highly specific to the target organism and minimally toxic to non-target organisms. During GreenLight’s discussions with the EPA to register their RNAi biopesticide for tackling invasive potato beetles, the EPA seemed to understand that this sort of technology is the future, but movement through the registration approval process was slow nevertheless; the application sat there for five 5 years. There were dozens of other biological pesticide product applications, and the EPA had to give every application the same level of scrutiny, even if many were obviously ineffective. There’s pressure to register more biological products as a prominent alternative to traditional chemical products, despite generally low efficacy. This clutters up the process, and the EPA was already short-staffed after extensive attrition during COVID. 

A substantial amount of the innovation is coming from small companies like Greenlight that don’t have the resources (which many of the large incumbent ag companies have) to navigate the current registration programs and protocols, which are spread across multiple agencies involved in regulating biotechnology: the USDA, EPA, and FDA. There needs to be a new concierge resource beyond what the Unified Website for Biotechnology Regulation currently provides, that could direct you to the right office, the right registration process, as well as appropriate funding opportunities and legal resources.

Q: What do you think are currently the most pressing challenges in agriculture?

FLC: Pest resistance continues to be a very serious concern in agriculture, so new and effective control measures need to be continually developed for all pests: weeds, insects, disease. There are two major pests of concern for my own farm in Western Canada. First, herbicide-resistant kochia weed, which has become a huge problem in the last five years all across the world. No one’s sure how exactly it spread so quickly. Second, flea beetles are decimating cruciferous crops. RNAi-based insecticides could be very effective here, if we can achieve sufficient persistence of the insecticide and avoid impacting non-target species.

In terms of challenges to agriculture-based businesses, there’s a lack of funding right now for getting tech to market. Funding for agtech from VC firms fell last year, as it did for most forms of tech. This was  following a very strong period of agtech funding for the previous two years, during which we saw over-investment in several sectors, such as alternative meat and indoor farming. At the same time, agtech companies typically have long timelines to product launch and need more funding than just one VC can provide. Right now, many companies who come to Fall Line for money are just looking for short-term “bridge funding” so they can make payroll and buy time until they can demonstrate enough progress to raise a successful “series” round with good valuation and favorable investment terms. And no one is going public right now.

Q: What are common knowledge gaps for agtech startups regarding farmers’ needs?

FLC: Agtech startups are often centered around a great idea or technology that’s looking for a problem to solve — but it’s hard for a specific technology to meet the needs of a variable problem. Farmers’ needs and priorities (e.g. pests, nutrients, etc.) are incredibly diverse, varying dramatically by crop and location, even from one field to the next on the same farm, or even within the same field. Today, it is very hard to get an accurate understanding of what is needed or desired at the farm level because there is no easy way to connect with growers on a broad scale. Farm papers have diminished in popularity just like mainstream papers, radio has diminished as well. Unless you have the email address or cell phone number of a farmer, it is hard to connect directly with them now, and most farmers don’t like doing surveys of any type anyway — and those that do aren’t that representative of the industry. I think this is why most types of polls are becoming less accurate as it is increasingly more difficult to get a representative sample of opinions. 

Farmers can be hesitant to adopt new technologies, since the risk can be high. And once they’ve been burned once by a product that failed to work as advertised, they’re unlikely to be willing to trust that company, or even that type of product, in the future. For example, last year, North Dakota State University scientists coordinated a large-scale field trial where it showed in a large field trial that most new biological products aimed at improving nitrogen-fixation in non-legume crops were ineffective at increasing yield. In general, the efficacy of biologicals can vary greatly depending on the exact field conditions, making it hard to reliably achieve the advertised result. There’s a huge jump from greenhouse results to field trials, another huge jump from field trials to commercial fields. But when a product’s value is obvious, farmers actually embrace new technology very quickly: both GMO crops and GPS achieved widespread adoption in a very short period of time.

Finally, technology developers should keep in mind that problems can be solved by old or simple technology. When people think about controlled-environment farming, their minds jump to fancy things like vertical farming — but with irrigation and mulch films, you’re 90% of the way there. Simply by adding a mulch film to heat the soil, farmers can greatly extend the growing season in northern climates by a month. This approach allowed us us to substantially increase the yield from our corn fields in Wisconsin.

This conversation illustrates a clear need for change in three key areas:

Federal funding for agricultural R&D

Given the unreliability of private market funding for agricultural biotechnology R&D, which often entails long turnaround times and low margins relative to traditional tech companies, substantial federal funding through research programs such as AgARDA is vital for accelerating R&D. AgARDA, based on the ARPA Advanced Research Projects Agency model, would allow the USDA to support the development of transformative technologies for focus areas of its choosing. However, despite its popularity, AgARDA, which was first authorized in the 2018 Farm Bill for $50 million annually for FY2019-2023, only received $2m in that timeframe. The USDA requested $5m for AgARDA in FY2022 and again in FY2023; it only received $1m each year. By contrast, ARPA-H, the human health equivalent, was authorized in FY2022 and immediately received its full $1 billion authorization, followed by $1.5b in FY2023. 

The USDA has published an implementation framework for AgARDA. Unfortunately, misalignment between USDA and Congress appears to be preventing AgARDA from being fully funded to its authorized levels. Members of the Congressional agriculture committees want the USDA to show that it has made progress with the $2m it has received before they allocate additional funding, namely the appointment of a dedicated director and initiation of a pilot program with calls for grant proposals. However, the USDA has deemed the $2m insufficient to support long-term staff or a formal grant program, especially since the appropriations require annual renewal. The current impasse means that no AgARDA projects have been rolled out, despite the pressing nature of the research priorities identified by the USDA.  

The following steps should be taken for AgARDA to achieve its full potential:

Regulatory oversight

The U.S. regulatory system for biotechnology needs to be a) expanded, with funding for a larger agency staff to process applications quickly; b) updated, to be flexible such that it can accommodate new-to-market technologies; and c) coordinated, to streamline approval processes. 

The National Security Commission on Emerging Biotechnology (NSCEB) addresses these unmet needs in its interim report. First, NSCEB is “considering options to facilitate higher staffing levels”; this should be made a priority. 

Second, concerning regulatory oversight, NSCEB identified three potential paths for improvement:

Of these, the hybrid approach would likely provide the greatest flexibility. In contrast, discrete changes to individual statutes will likely involve slow, piecemeal changes that can easily become outdated again. While a unified regulatory process may be more streamlined, the report’s phrasing creates a sharp binary delineation between biotech and conventional that does not reflect reality. Such a delineation could engender a lot of wasted time debating biotech versus conventional classification for a given product. 

Finally, to address intra- and interagency coordination, the NSCEB presented two Farm Bill amendments that deserve Congressional support: the Biotechnology Oversight Coordination Act and the Agriculture Biotechnology Coordination Act.

Bioliteracy and agricultural education

Market demand and regulations are informed by consumer perceptions, which then impact R&D decisions. For example, fear of consumer and regulatory backlash can dissuade companies from investing in new genetic engineering technology for developing new plant varieties, despite their potential to improve agricultural sustainability. Increased bioliteracy across the American public would help consumers, businesses, and policymakers alike better understand new biotechnologies and engage with the burgeoning bioeconomy. This is a need that the NSCEB has also highlighted. At the K-12 level, improvements could comprise updating science curriculums to include contemporary topics like gene editing, as well as amending civics curriculums to better explain the modern functions of regulatory agencies. In addition, agricultural education can be embedded into biology and earth science curriculums to reconnect the public at large with the realities faced by producers. Similar to computer science literacy improvements through standard setting and funding, bioliteracy can be improved through state-level education initiatives.

The Federation of American Scientists values diversity of thought and believes that a range of perspectives — informed by evidence — is essential for discourse on scientific and societal issues. Contributors allow us to foster a broader and more inclusive conversation. We encourage constructive discussion around the topics we care about.

BioNETWORK: The Internet of Distributed Biomanufacturing


The future of United States industrial growth resides in the establishment of biotechnology as a new pillar of industrial domestic manufacturing, thus enabling delivery of robust supply chains and revolutionary products such as materials, pharmaceuticals, food, energy. Traditional centralized manufacturing of the past is brittle, prone to disruption, and unable to deliver new products that leverage unique attributes of biology. Today, there exists the opportunity to develop the science, infrastructure, and workforce to establish the BioNETWORK to advance domestic distributed biomanufacturing, strengthen U.S.-based supply chain intermediaries, provide workforce development for underserved communities, and achieve our own global independence and viability in biomanufacturing. Implementing the BioNETWORK to create an end-to-end distributed biomanufacturing platform will fulfill the Executive Order on Advancing Biotechnology and Biomanufacturing Innovation and White House Office of Science and Technology Policy (OSTP) Bold Goals for U.S. Biotechnology and Biomanufacturing.

Challenge and Opportunity

Biotechnology harnesses the power of biology to create new services and products, and the economic activity derived from biotechnology and biomanufacturing is referred to as the bioeconomy. Today, biomanufacturing and most other traditional non-biomanufacturing is centralized. Traditional manufacturing is brittle, does not enhance national economic impact or best use national raw materials/resources, and does not maximize innovation enabled by the unique workforce distributed across the United States. Moreover, in this era of supply chain disruptions due to international competition, climate change, and pandemic-sized threats (both known and unknown), centralized approaches that constitute a single point of attack/failure and necessarily restricted, localized economic impact are themselves a huge risk. While federal government support for biotechnology has increased with recent executive orders and policy papers, the overarching concepts are broad, do not provide actionable steps for the private sector to respond to, and do not provide the proper organization and goals that would drive outcomes of real manufacturing, resulting in processes or products that directly impact consumers. A new program must be developed with clear milestones and deliverables to address the main challenges of biomanufacturing. Centralized biomanufacturing is less secure and does not deliver on the full potential of biotechnology because it is: 

Single point failures in centralized manufacturing are a root cause of product disruptions and are highlighted by current events. The COVID-19 pandemic revealed that point failures in the workforce or raw materials created disruptions in the centralized manufacturing, and availability of hand sanitizers, rubber gloves, masks, basic medicines, and active pharmaceutical ingredients impacted every American. International conflict with China and other adversarial countries has also created vulnerabilities in the sole source access to rare earth metals used in electronics, batteries, and displays, driving the need for alternate options for manufacturing that do not rely on single points of supply. To offset this situation, the United States has access to workforce, raw materials, and waste streams geographically distributed across the country that can be harnessed by biomanufacturing to produce both health and industrial products needed by U.S. consumers. However, currently there are only limited distributed manufacturing infrastructure development efforts to locally process those raw materials, leaving societal, economic, and unrealized national security risks on the table. Nation-scale parallel production in multiple facilities is needed to robustly create products to meet consumer demand in health, industrial, energy, and food markets. 

The BioNETWORK inverts the problem of a traditional centralized biomanufacturing facility and expertise paradigm by delivering a decentralized, resilient network enabling members to rapidly access manufacturing facilities, expertise, and data repositories, as needed and wherever they reside within the system, by integrating the substantial existing U.S. bioindustrial capabilities and resources to maximize nationwide outcomes. The BioNETWORK should be constructed as an aggregate of industrial, academic, financial, and nonprofit entities, organized in six regionally-aligned nodes (see figure below for notional regional distribution) of biomanufacturing infrastructure that together form a hub network that cultivates collaboration, rapid technology advances, and workforce development in underserved communities. The BioNETWORK’s fundamental design and construction aligns with the need for new regional technology development initiatives that expand the geographical distribution of innovative activity in the U.S., as stated in the CHIPS and Science Act. The BioNETWORK acts as the physical and information layer of manufacturing innovation, generating market forces, and leveraging ubiquitous data capture and feedback loops to accelerate innovation and scale-up necessary for full-scale production of novel biomaterials, polymers, small molecules, or microbes themselves. As a secure network, BioNETWORK serves as the physical and virtual backbone of the constituent biomanufacturing entities and their customers, providing unified, distributed manufacturing facilities, digital infrastructure to securely and efficiently exchange information/datasets, and enabling automated process development. Together the nodes function in an integrated way to adaptively solve biotechnology infrastructure challenges as well as load balancing supply chain constraints in real-time depending on the need. This includes automated infrastructure provisioning of small, medium, or large biomanufacturing facilities, supply of regional raw materials, customization of process flow across the network, allocation of labor, and optimization of the economic effectiveness. The BioNETWORK also supports the implementation of a national, multi-tenant cloud lab and enables a systematic assessment of supply chain capabilities/vulnerabilities for biomanufacturing.

s a secure network, BioNETWORK serves as the physical and virtual backbone of the constituent biomanufacturing entities and their customers, providing unified, distributed manufacturing facilities, digital infrastructure to securely and efficiently exchange information/datasets, and enabling automated process development.

As a secure network, BioNETWORK serves as the physical and virtual backbone of the constituent biomanufacturing entities and their customers, providing unified, distributed manufacturing facilities, digital infrastructure to securely and efficiently exchange information/datasets, and enabling automated process development.

Plan of Action

Congress should appropriate funding for an interagency coordination office co-chaired by the OSTP and the Department of Commerce (DOC) and provide $500 million to the DOC, Department of Energy (DOE), and Department of Defense (DOD) to initiate the BioNETWORK and use its structure to fulfill economic goals and create industrial growth opportunities within its three themes

  1. Provide alternative supply chain pathways via biotechnologies and biomanufacturing to promote economic security. Leverage BioNETWORK R&D opportunities to develop innovative biomanufacturing pathways that could address supply chain bottlenecks for critical drugs, chemicals, and other materials. 
  2. Explore distributed biomanufacturing innovation to enhance supply chain resilience. Leverage BioNETWORK R&D efforts to advance flexible and adaptive biomanufacturing platforms to mitigate the effects of supply chain disruptions. 
  3. Address standards and data infrastructure to support biotechnology and biomanufacturing commercialization and trade. Leverage BioNETWORK R&D needed to enable data interoperability across the network to enable scale-up and increase global competitiveness. 

To achieve these goals, the policy Plan of Action includes the following steps: 

1. Congress should appropriate $10 million to establish an interagency coordination office within OSTP that is co-chaired by the DOC. This fulfills the White House Executive Order and CHIPs and Science mandates for better interagency coordination among the DOE, DOC, DOD, National Institute of Standards and Technology (NIST), and the National Science Foundation (NSF). 

2. Congress should then appropriate $500 million to DOC and DOE to fund a biomanufacturing moonshot that includes creating the pilot network of three nodes to form the BioNETWORK in regions of the U.S. within six months of receiving funding. This funding should be managed by the interagency coordination office in collaboration with a not-for-profit organization whose mission is to build, deploy, and manage the BioNETWORK together with the federal entities. The role of the not-for-profit is to ensure that a trusted, unbiased partner (not influenced by outside entities) is involved, such that the interests of the taxpayer, U.S. government, and commercial sectors are all represented in the most beneficial way possible. The mission should include education, workforce development, safety/security, and sustainment as core principles, such that the BioNETWORK can stand alone once established. The new work to build the network should also synergize with the foundational science of the NSF and the national security focus of DOD biotechnology programs.

3. Continued investment of an additional $500 million should be appropriated by Congress to create economic incentives to sustain and transition the BioNETWORK from public funding to full commercial operation. This step requires evaluation of concrete go/no-go milestones and deliverables to ensure on-time, on-budget operations have been met. The interagency coordination office should work with DOC, DOE, DOD, and other agencies to leverage these incentives and create other opportunities to promote the BioNETWORK so that it does not require public funding to keep itself sustainable and can obtain private funding.   

Create a Pilot Network of Three Nodes

To accelerate beyond current biomanufacturing programs and efforts, the first three nodes of the BioNETWORK should be constructed in three new disparate geographic regions (i.e., East, Midwest, West, or other locations with relevant feedstocks, workforce, or component infrastructure) to show the networking capabilities for distributed manufacturing. The scale of funding required to design, construct, and deploy the first three nodes is $500 million. The initiation and construction of the BioNETWORK should commence within six months. The DOE should lead the initiation and deployment of the technical construction of the BioNETWORK through Theme 2 of their Biomanufacturing goals, which “seeks alternative processes to produce chemicals and materials from renewable biomass and intermediate feedstocks by developing low-carbon-intensity product pathways and promoting a circular economy for materials.” Each node should create regional partnerships that have four entities (a physical manufacturing facility, a cell programming entity, an academic research and development entity, and a workforce/resource entity). All four entities will contain both physical facilities such as industrial fermentation and wet lab space, as well as the workforce needed to run them. On top of the pilot nodes, a science and technology/engineering integrator of the system should be identified to coordinate the effort and lead security/safety efforts for the physical network. Construction of the initial BioNETWORK should be completed within two years. 

Achievement of the BioNETWORK goals requires the design plan to:

The BioNETWORK construction milestones should fulfill the White House OSTP bold goals through new capabilities delivered via distributed manufacturing infrastructure: 

Full Network: Plan for Sustainability 

Congress and executive branch agencies establish economic incentives for commercial entities, state/local governments, and consumers of bioindustrial manufacturing products to create commercialization pathways that enhance local economies while also supporting the national network. These include tax credits, tax breaks, low interest loans, and underwritten loans as a starting point. To facilitate tech transition, unique lab-to-market mechanisms and proven tools to address market failure and applied technologies gaps should be used in conjunction with those in the Inflation Reduction Act. This includes prize and challenge competitions, market shaping procurement or loan programs, and streamlined funding of open, cross-disciplinary research, and funding at the state and local levels. 

A new public-private partnership could coordinate across multiple efforts to ensure they drive toward rapid technology deployment and integration. This includes implementing a convertible debt plan that rewards BioNETWORK members with equity after reaching key milestones, providing an opportunity for discounted buyout by other investors during rounds of funding, and working with the federal government to design market-shaping mechanisms such as advance market commitments to guarantee purchase of a bioproduction company’s spec-meeting product. 

Additionally, the BioNETWORK should be required to expand the repertoire of domestic renewable raw materials into a suite of high-demand, industry-ready products as prescribed in the DOC’s goals in biomanufacturing. This will ensure all regions have support for commercial goods and can automatically assess domestic supply chain capabilities and vulnerabilities, and are provided compensatory remediation on demand. The full BioNETWORK consists of six nodes—aligned to each of the major geographic regions and/or EDA regions in the United States—which have unique raw materials, workforce, infrastructure, and consumption of products that contribute to supporting the overall network functionality. The full BioNETWORK should be active within five years of project initiation and be evaluated against phased milestones throughout. 


Networked solutions are resilient and enduring. A single factory is at risk of transfer to foreign ownership, closure, or obsolescence. The BioNETWORK creates connectivity among distributed biomanufacturing physical infrastructure to form a network with a robust domestic value chain. Today’s biomanufacturing investments suffer from the need to vertically integrate due to lack of flexible capacity across the value chain, which raises capital requirements and overall risk. The BioNETWORK drives horizontal integration through the network nodes via new infrastructure, connecting physical infrastructure of the nodes within the system. The result is a multi-sided marketplace for biotechnology innovation, products, and commercialization. 

The federal government should initiate a new program and select performers within the next six months to begin the research, development, and construction of the first three nodes of the BioNETWORK. Taking action to establish the BioNETWORK ensures that the United States has the necessary physical and virtual infrastructure to grow the bioeconomy and its international leadership in biotechnology. The BioNETWORK creates new job opportunities for people across the country where training in biotechnology expands the skill sets of people with broad-spectrum applicability from trades to advanced degrees. The BioNETWORK drives circular economies where raw materials from rural and urban centers enter the network and are transformed into high-value products such as advanced materials, pharmaceuticals, food, and energy. The BioNETWORK protects U.S. supply chain resiliency through distributed manufacturing and links regional development into a national capability to establish biomanufacturing as a pillar of economic and technological growth for today and into the 22nd century.

Frequently Asked Questions
How is this idea different from the regional technology and innovation hub program within the EDA and the Biofoundries program at the NSF or other recent government-funded hubs?

Establishment of the BioNETWORK scales, connects, and networks the impact of a hub and tailors it to the needs of bioindustrial manufacturing, which requires regional feedstocks and integration of small-, intermediate-, and large-scale industrial fermentation facilities scattered across the United States to form an end-to-end distributed biomanufacturing platform. Similar to the goals of the EDA hub program, the BioNETWORK will accelerate regional economic activity, workforce development, and re-establishment of domestic manufacturing. Leveraging activity of the EDA and NSF Biofoundries program is an opportunity for coordination across the interagency.

What infrastructure needs to be built to achieve this?

Retrofitting existing small-, intermediate-, and large-scale biomanufacturing facilities/plants is necessary to construct the connected BioNETWORK. This includes new/modified fermentation equipment, scale-up and purification hardware, software/communications for networking, transportation, load-balancing, and security infrastructure.

What is needed to ensure the BioNETWORK is enacted within five years?

Clear, measurable intermediate milestones and deliverables are required to ensure that the BioNETWORK is on track. Every three months, key performance metrics and indicators should be used to demonstrate technical functionality. Planned economic and workforce targets should be established every year and tracked for performance. Adjustments to the technical and business plans should be implemented if needed to ensure the overarching goals are achieved.

What does success look like if the BioNETWORK program is enacted? What does failure look like?

A major outcome of the BioNETWORK program is that biomanufacturing in the United States becomes on par with the other traditional pillars of manufacturing such as chemicals, food, and electronics. Workforce retraining to support this industry leads to new high-paying jobs as well as new consumer product sectors and markets with new avenues for economic growth. Failure to deploy the BioNETWORK leaves the United States vulnerable to supply chain disruption, little to no growth in manufacturing, and out competition by China and other peer nations that are investing in and growing biotechnology.

Secondary milestones include key performance indicators, including increased capacity, decrease in production time, robustness (more up time vs. down time), cheaper costs, better use of regional raw materials, etc.

“The US needs to lean into an old strength”: Maintaining Progress and Growing US Biomanufacturing

The U.S. bioeconomy has been surging forward, charged by the Presidential Executive Order 14081 and the CHIPS and Science Act. However, there are many difficult challenges that lay ahead for the U.S. bioeconomy, including for U.S. biomanufacturing capabilities. U.S. biomanufacturing has been grappling with issues in fermentation capacity including challenges related to scale-up, inconsistent supply chains, and downstream processing. While the U.S. government works on shoring up these roadblocks, it will be important to bring industry perspectives into the conversation to craft solutions that not only addresses the current set of issues but looks to mitigate challenges that may arise in the future.

To get a better understanding of industry perspectives on the U.S. bioeconomy and the U.S. biomanufacturing sector, the Federation of American Scientists interviewed Dr. Sarah Richardson, the CEO of MicroByre. MicroByre is a climate-focused biotech startup that specializes in providing specialized bacteria based on the specific fermentation needs of its clients. Dr. Richardson received her B.S. in biology from the University of Maryland in 2004 and a Ph.D. in human genetics and molecular biology from Johns Hopkins University School of Medicine in 2011. Her extensive training in computational and molecular biology has given her a unique perspective regarding emerging technologies enabled by synthetic biology.

FAS: The U.S. Government is focused on increasing fermentation capacity, including scale-up, and creating a resilient supply chain. In your opinion, are there specific areas in the supply chain and in scale-up that need more attention?

Dr. Sarah Richardson: The pandemic had such an impact on supply chains that everyone is reevaluating the centralization of critical manufacturing. The United States got the CHIPS and Science Act to invest in domestic semiconductor manufacturing. The voting public realized that almost every need they had required circuits. Shortages in pharmaceuticals are slowly raising awareness of chemical and biomedical manufacturing vulnerabilities as well. The public has even less insight into vulnerabilities in industrial biomanufacturing, so it is important that our elected officials are proactive with things like Executive Order 14081.

When we talk about supply chains we usually mean the sourcing and transfer of raw, intermediate, and finished materials — the flow of goods. We achieve robustness by having alternative suppliers, stockpiles, and exacting resource management. For biomanufacturing, an oft raised supply chain concern is feedstock. I can and will expound on this, but securing a supply of corn sugar is not the right long-term play here. Shoring up corn sugar supplies will not have a meaningful impact on industrial biomanufacturing and should be prioritized in that light.

Biomanufacturing efforts are different from the long standing production of consumer goods in that they are heavily tied to a scientific vendor market. As we scale to production, part of our supply chain is a lot of sterile plastic disposable consumables. We compete with biomedical sectors for those, for personal protective equipment, and for other appliances. This supply chain issue squeezed not just biomanufacturing, but scientific research in general.

We need something that isn’t always thought of as part of the supply chain: specialized infrastructural hardware. This  may not be manufactured domestically. Access to scale up fermentation vessels is already squeezed. The other problem is that no matter where you build them, these vessels are designed for the deployment of canonical feedstocks and yeasts. Addressing the manufacturing locale would offer us the chance to innovate in vessel and process design and support the kinds of novel fermentations on alternate feedstocks that are needed to advance industrial biomanufacturing. There are righteous calls for the construction of new pilot plants. We should make sure that we take the opportunity to build for the right future.

One of the indisputable strengths of biomanufacturing is the potential for decentralization! Look at microbrewing: fermentation can happen anywhere without country-spanning feedstock pipelines. As we onboard overlooked feedstocks, it may only be practical to leverage them if some fermentation happens locally. As we look at supply chains and scale up we should model what that might look like for manufacturing, feedstock supply chains, and downstream processing. Not just at a national level, but at regional and local scales as well.

There are a lot of immediate policy needs for the bioeconomy, many of which are outlined in Executive Order 14081. How should these immediate needs be balanced with long-term needs? Is there a trade-off?

Counterintuitively, the most immediate needs will have the most distant payoffs! The tradeoff is that we can’t have every single detail nailed down before work begins. We will have to build tactically for strategic flexibility. Climate change and manufacturing robustness are life or death problems. We need to be open to more creative solutions in funding methods, timeline expectations; in who comes to the table, in who around the table is given the power to affect change, and in messaging! The comfortable, familiar, traditional modes of action and funding have failed to accelerate our response to this crisis.

We have to get started on regulation yesterday, because the only thing that moves slower than technology is policy. We need to agree on meaningful, aggressive, and potentially unflattering metrics to measure progress and compliance. We need to define our terms clearly: what is “bio-based,” does it not have petroleum in it at all? What does “plant-based” mean? What percentage of a product has to be renewable to be labeled so? If it comes from renewable sources but its end-of-life is not circularizable, can we still call it “green”?

We need incentives for innovation and development that do not entrench a comfortable but unproductive status quo. We need to offer stability to innovators by looking ahead and proactively incubating the standards and regulations that will support safety, security, and intellectual property protection. We should evaluate existing standards and practices for inflexibility: if they only support the current technology and a tradition that has failed to deliver change, they will continue to deliver nothing new as a solution. 

We need to get on good footing with workforce development, as well. A truly multidisciplinary effort is critical and will take a while to pull off; it takes at least a decade to turn a high school student into a scientist. I only know of one national graduate fellowship that actually requires awardees to train seriously in more than one discipline. Siloing is a major problem in higher education and therefore in biomanufacturing. What passes for “multidisciplinary” is frequently “I am a computer scientist who is not rude to biologists” or “our company has both a chemical division and an AI division.” A cross-discipline “bilingual” workforce is absolutely critical to reuniting the skill sets needed to advance the bioeconomy. Organizations like BioMADE with serious commitments to developing a biomanufacturing workforce cannot effectively address the educational pipeline without significantly more support.

Hand holding petri dish with bacterial striations.

MicroByre is working to advance alternatives to substrates currently favored by the bioeconomy.

When we emphasize the collection of data — which data are we talking about? Is the data we have collected already a useful jumping off point for what comes next? Are the models relevant for foreseeable changes in technology, regulation, and deployment? For some of it, absolutely not. As every responsible machine learning expert can tell you, data is not something you want to skimp or cheap out on collecting or curating. We have to be deliberate about what we collect, and why. Biases cannot all be avoided, but we have to take a beat to evaluate whether extant models, architecture, and sources are relevant, useful, or adaptable. A data model is as subject to a sunk cost fallacy as anything else. There will be pressure to leverage familiar models and excuses made about the need for speed and the utility of transfer learning. We cannot let volume or nostalgia keep us from taking a sober look at the data and models we currently have, and which ones we actually need to get.

What are the major pain points the biomanufacturing industry is currently facing?

Downstream processing is the work of separating target molecules from the background noise of production. In purely chemical and petrochemical fields, separation processes are well established, extensively characterized, and relatively standardized. This is not the case in industrial biomanufacturing, where upstream flows are arguably more variable and complex than in petrochemicals. Producers on the biomedical side of biomanufacturing who make antibiotics, biologics, and other pharmaceuticals have worked on this problem for a long time. Their products tend to be more expensive and worth specialized handling. The time the field has spent developing the techniques in the urgent pursuit of human health works in their favor for innovation. However, separating fermentation broth from arbitrary commodity molecules is still a major hurdle for a bioindustrial sector already facing so many other simultaneous challenges. Without a robust library of downstream processing methods and a workforce versant in their development and deployment, new industrial products are viewed as significant scaling risks and are funded accordingly.

There is fatigue as well. For the sake of argument, let us peg the onset of the modern era of industrial biomanufacturing to the turn of the latest century. There have been the requisite amount of promises any field must make to build itself into prominence, but there has not been the progress that engenders trust in those or future promises. We have touted synthetic biology as the answer for two and a half decades but our dependence on petroleum for chemicals is as intense as ever. The goodwill we need to shift an entire industry is not a renewable resource. It takes capital, it takes time, and it takes faith that those investments will pay off. But now the chemical companies we need to adopt new solutions have lost some confidence. The policy makers we need to lean into alternative paths and visionary funding are losing trust. If the public from whence government funding ultimately springs descends into skepticism, we may lose our chance to pivot and deliver.

The right investment right now will spell the difference between life and death on this planet for billions of people.

This dangerous dearth of confidence can be addressed by doing something difficult: owning up to it. No one has ever said “oh goody — a chance to do a postmortem!”. But such introspective exercises are critical to making effective changes. A lack of reflection is a tacit vote for the status quo, which is comfortable because we’re rarely punished for a lack of advocacy. We should commission an honest look at the last thirty years — without judgment, without anger, and without the need to reframe disappointing attempts as fractional successes for granting agencies, or position singular successes as broadly representative of progress for egos. 

Biomanufacturing is so promising! With proper care and attention it will be incredibly transformative. The right investment right now will spell the difference between life and death on this planet for billions of people. We owe it to ourselves and to science to do it right — which we can only do by acknowledging what we need to change and then truly committing to those changes.

Corn sugar tends to be the most utilized biomass in the bioeconomy. What are the issues the U.S. faces if it continues to rely solely on corn sugar as biomass?

History shows that low-volume, high-margin fine chemicals can be made profitable on corn sugar, but high-volume, low-margin commodity chemicals cannot. Projects that produce fine chemicals and pharmaceuticals see commercial success but suffer from feedstock availability and scaling capacity. Success in high-margin markets encourages people to use the exact same technology to attempt low-margin markets, but then they struggle to reduce costs and improve titers. When a commodity chemical endeavor starts to flag, it can pivot to high-margin markets. This is a pattern we see again and again. As long as corn sugar is the default biomass, it will not change; the United States will not be able to replace petrochemicals with biomanufacturing because the price of corn sugar is too high and cannot be technologically reduced. This pattern is also perpetuated because the yeast we usually ask to do biomanufacturing cannot be made to consume anything but corn sugar. We also struggle to produce arbitrary chemicals in scalable amounts from corn sugar. We are stuck in an unproductive reinforcing spiral. 

Even if commodity projects could profit using corn sugar, there is not enough to go around. How much corn sugar would we have to use to replace even a fifth of the volume of petroleum commodity chemicals we currently rely on? How much more land, nitrogen, water, and additional carbon emissions would be needed? Would chemical interests begin to overpower food, medical, and energy interests? What if a pathogen or natural disaster wiped out the corn crop for a year or two? Even if we could succeed at manufacturing commodities with corn sugar alone, locking out alternatives makes the United States supply chain brittle and vulnerable.

Gloved hands holding petri dish showing light green bacterial striations.

MicroByre is working to advance alternatives to substrates currently favored by the bioeconomy.

Continued reliance on corn sugar slows our technological development and stifles innovation. Specialists approaching manufacturing problems in their domain are necessarily forced to adopt the standards of neighboring domains. A chemical engineer is not going to work on separating a biomass into nutrition sources when no microbiologist is offering an organism to adopt it. A molecular biologist is not going to deploy a specialized metabolic pathway dependent on a nutrition source not found in corn sugar. Equipment vendors are not going to design tools at any scale that stray from a market demand overwhelmingly based on the use of corn sugar. Grantors direct funds with the guidance of universities and industry leaders, who are biased towards corn sugar because that’s what they use to generate quick prototypes and spin out new start up companies. 

The result of relying on corn sugar is an entrenched field and consequently we might lose our chance to make a difference. Without introducing low-cost, abundant feedstocks like wastes, we run the risk of disqualifying an entire field of innovation. 

What does the U.S. need to do in order for other biomass sources to be utilized beyond corn sugar? Are there ideas (or specific programs) that the U.S. government could supercharge?

Federal agencies must stop funding projects that propose to scale familiar yeasts on corn sugars to produce novel industrial chemicals. We must immediately stop funding biomass conversion projects meant to provide refined sugars to such endeavors. And we must stop any notion of dedicating arable land solely to corn sugar solely for the purposes of biomanufacturing new industrial products. The math does not and will not work out. The United States must stop throwing money and support at such things that seem like they ought to succeed any minute now, even though we have been waiting for that success for 50 years without any meaningful changes in the economic analysis or technology available.

Ironically, we need to take a page from the book that cemented petroleum and car supremacy in this country. We need to do the kind of inglorious, overlooked, and subsequently taken for granted survey of the kind that enabled the Eisenhower Interstate System to be built. 

We need to characterize all of the non-corn feedstocks and their economic and microbial ecosystems. We need to know how much of each biomass exists, what it is composed of, and who is compiling where. We need to know what organisms rot it and what they produce from it. We need to make all of that data as freely available as possible to lower the barriers of entry for cross-disciplinary teams of researchers and innovators to design and build the logistical, microbiological, chemical, and mechanical infrastructure necessary. We need to prioritize and leverage the complex biomasses that cannot just be ground into yeast food. 

We need to get the lay of the land so – to use the roadway analogy – we know where to pour the asphalt. An example of this sort of effort is the Materials Genome Initiative, which is a crosscutting multi-agency initiative for advancing materials and manufacturing technology. (And which has, to my chagrin, stolen the term “genome” for non-biological purposes.) An even more visible example to the public is a resource like the Plant Hardiness Zone Map that provides a basis for agricultural risk assessment to everyone in the country.

The United States needs to lean into an old strength and fund infrastructure that gives all the relevant specialties the ability to collaborate on truly divergent and innovative biomass efforts. The field of industrial biomanufacturing must make a concerted effort to critically examine a history of failed technical investments, shake off the chains of the status quo, and guide us into true innovation. Infrastructure is not the kind of project that yields an immediate return. If venture capital or philanthropy could do it, they would have already. The United States must flex its unique ability to work on a generational investment timeline; to spend money in the very short term on the right things so as to set everyone up for decades of wildly profitable success — and a safer and more livable planet.

Extending Human Life with Senescent Cell Treatments

Research into senescent cells could result in extended human lifespans and significant policy implications

Improved housing, sanitation, and healthcare have significantly increased humans’ life expectancy, and biomedical advances have the potential to further extend people’s lives. The life expectancy of a person born in 1860 was only about 39 years; a person born today can expect to live about 79 years. Now some researchers are studying whether altering humans’ senescent cells could increase lifespans to an even greater extent.

Cellular senescence – a process by which cells stop replicating after a set amount of time – is vital to prevent devastating cancers, but also contributes to age-related diseases. Every time a cell replicates, its DNA accumulates a low number of errors. If cells replicate unchecked, these errors can snowball, forming masses of non-functioning cells that damage healthy tissues. For example, the cells responsible for malignant cancers, which can be deadly, do not show any sign of senescence. On the other hand, senescent cells, which are alive but no longer dividing, can build up in a person’s tissues, release harmful chemicals, and contribute to age-related health issues.

Reducing the numbers of senescent cells in peoples’ bodies could extend human lives. Studies in mice have shown that removing senescent cells can help mice live longer and maintain their physical abilities. Treated mice lived, on average, 36 percent longer than mice that retained senescent cells. Furthermore, old mice given a drug that reduces the number of senescent cells were able to survive COVID-19 in significantly higher numbers than old mice not given the drug. While these results are promising, whether the results can be reproduced in humans is an open question. Some early trials in humans testing drugs that reduce populations of senescent cells are targeting specific diseases, such as age-related macular degeneration, glaucoma, and chronic obstructive pulmonary disease.

If it becomes possible to further diminish the effects of aging over the next few decades, there would be substantial policy implications. For example, greater longevity could mean older Americans experience longer periods of dependency on their families or the government, increasing retirement and medical costs. People might also stay healthier for longer, which may necessitate an increase of the retirement age. As this research into human longevity matures, it is important that policymakers consider the fiscal, legal, and medical implications of extending human lives.

This CSPI Science and Technology Policy Snapshot expands upon a scientific exchange between Congressman Bill Foster (D, IL-11) and his new FAS-organized Science Council.

DNA for Data Storage and Retrieval

To reduce the burden on traditional data centers, improving on DNA data storage could be the key

The pace at which data – such as photos, videos, and social media posts – are being generated is ramping up drastically, exceeding the scaling limits of traditional silicon-based data storage technologies, and DNA could be deployed to help meet this challenge. As an indication of the massive amount of data storage that may be required, one model predicts that by the year 2030, electricity use by data centers could approach about eight percent of total global electricity demand. New paradigms for data storage, such as the use of DNA for preserving information, are necessary.

DNA is genetic material that contains plans for the design of living things, but DNA can also be used to store data created by living things. DNA is an attractive material for data storage – it is stable, writable, readable, and information dense. In theory, the entire world’s data could be stored in a coffee mug-sized portion of DNA.

So how does storing, for example, a video, in DNA work? (See Figure 1.) First, an algorithm is used to encode the video into the As, Ts, Cs, and Gs that make up DNA molecules. The DNA molecules are then synthesized, and stored. To access the data, the DNA molecules would be sequenced, and the DNA sequences translated using the same algorithm, reproducing the video.

Figure 1.

Data storage and retrieval in DNA. First, data – like those stored on a computer hard drive – are processed by an algorithm that translates 1s and 0s into DNA sequences made up of As, Ts, Cs, and Gs. DNA strands with those sequences are then synthesized – or written – and stored either in living cells (in vivo) or in the test tube (in vitro). Data can be retrieved from storage in part by using PCR – the same technology deployed to test for the coronavirus that causes COVID-19 – to selectively target specific data packages. The PCR products can be read with DNA sequencing instruments, providing the original DNA sequences, and reproducing the data. Figure adapted from Ceze, Nivala, and Strauss 2019, Nature Reviews Genetics.

DNA is a polymer – a substance consisting of a high number of similar building blocks that are linked together – and other polymers can be used to store information, too. For example, plastic polymers are being explored for information-storage applications; one group synthesized a plastic polymer that, when read out, reproduced a quote by Jane Austen. By expanding experimental development efforts into (i) increasing the rates at which DNA can be synthesized and sequenced and (ii) detecting and correcting for errors in DNA synthesis, and by pursuing fundamental research into data storage across a variety of polymers, it is possible the U.S. science and technology enterprise could devise a polymer-based method for rapid data storage and retrieval, and meet the data storage challenge.

This CSPI Science and Technology Policy Snapshot expands upon a scientific exchange between Congressman Bill Foster (D, IL-11) and his new FAS-organized Science Council.

Safeguarding Benchtop DNA Synthesis

Benchtop DNA synthesizers could become more ubiquitous, and it’s up to policymakers to chart the way forward

The genetic blueprints for humans, plants, disease-causing bacteria, and all other living things are written in DNA, and machines capable of synthesizing DNA are becoming more accessible to potential users. Benchtop DNA synthesizers promise to increase the speed and efficiency of research in academic and industrial laboratories; however, it will be critical to incorporate safeguards into benchtop machines to prevent the printing of DNA sequences that would be used for harmful purposes. Researchers should be permitted to operate a benchtop DNA synthesizer to, for instance, make genetic material that is then used by a microbe to build a biofuel. But, aside from research conducted by pre-approved specialists, printing DNA that codes for deadly agents like the ricin or diphtheria protein toxins, for example, should be prohibited. As instruments capable of small-scale, rapid-turnaround DNA synthesis are already starting to enter the market, policymakers may be faced with a new era of democratized DNA synthesis, and should grapple with how to maximize the benefits of this technology while minimizing potential harm.

A National Academies of Sciences, Engineering, and Medicine report speculated that by 2027, individuals both with and without formal scientific training would be rapidly prototyping and developing biological designs and products. In both institutional and DIY contexts, there are protections that could be put in place to drastically reduce the likelihood of the misuse of benchtop DNA synthesizers. For instance, a January 2020 report from the World Economic Forum, crafted in collaboration with the Nuclear Threat Initiative, recommends that benchtop DNA synthesizers:

Before efficient benchtop DNA synthesizers become even more ubiquitous, decision-makers have an opportunity to craft forward-thinking policies that both (i) protect the technology from misuse and (ii) promote its potential to advance human health, a cleaner environment, and many other public goods.

This CSPI Science and Technology Policy Snapshot expands upon a scientific exchange between Congressman Bill Foster (D, IL-11) and his new FAS-organized Science Council.

Nominee for OSTP director – Dr. Eric Lander – sees key federal role for creating and sharing synthetic biology toolkits, best practices

The field of synthetic biology has enormous potential for constructively impacting society, already contributing products such as drugs, food ingredients, and living fertilizers. As the field continues to develop, standardization of synthetic biology tools, techniques, and processes could help realize that potential. The rapid growth of the semiconductor industry in the 20th century, and its push for standardization, serves as a potential model for the synthetic biology industry. This idea was explored during a late April hearing held by the Senate Commerce, Science, and Transportation Committee, convened to discuss the nomination of Dr. Eric Lander to be director of the Office of Science and Technology Policy.

The potential of synthetic biology

It is critical for the U.S. to continue to lead in synthetic biology. Synthetic biology has the potential to revolutionize many sectors, such as healthcare and agriculture. For example, researchers are working to engineer immune cells to treat cancer, correct defective genes, and optimize antibody and vaccine production. In agriculture, synthetic biology could be used to optimize plants’ ability to use nitrogen and phosphorus, decreasing the amount of chemical fertilizer necessary, or to increase the nutritional value of foodstuffs. Policymakers recognize the potential of synthetic biology; for instance, the discipline is listed as a key research priority in the Endless Frontier Act, and is the primary focus of a separate bipartisan bill that aims to support U.S. synthetic biology.

During the hearing, Dr. Lander suggested (1:06:05) that to make synthetic biology technologies accessible to even more innovators, the federal government should play a role in creating and disseminating synthetic biology “toolkits,” as well as sharing best practices for their use. Dr. Lander related this to the early stages of working with semiconductor toolkits and assembling integrated circuits. Standardization contributed to the advancement of the semiconductor industry, and to take full advantage of synthetic biology’s potential, standards, and standardization, could play a role. Setting standards allows for exact measurements and more precise communication between researchers. For synthetic biology specifically, standardization would support the ability to scale production and take on even more complex tasks. Some of the challenges surrounding standards are the possibility that standardization could reduce researchers’ flexibility and creativity, as well as identifying which systems or processes should be standardized, and successfully deciding on what those standards should be.

Many standardization attempts in synthetic biology have been focused on bacteria because they are generally more easily engineered than other types of cells, and they can produce valuable compounds for both research and industrial uses. Cell-free systems, where components of interest are produced artificially or extracted or enriched from other cells and then refined in vitro, have been successfully standardized, but unfortunately, these systems lack the ability to scale or produce important substances without human intervention. Some areas that researchers are looking to standardize further include the design of strands of DNA, and the production of data and biosystem models.

One federal agency, the National Institute for Standards and Technology (NIST), is already working on establishing standards in synthetic biology. NIST is currently working with researchers and manufacturers to develop measurement tools to help compare and reproduce scientific results. One accomplishment was to produce human genome reference materials to help compare the genes of people with different lineages, increase confidence in DNA sequencing, and improve genetic tests. NIST has also helped develop reference materials for monoclonal antibodies and RNA, as well as developed the first method to use DNA to authenticate mouse cell lines used in genetic research.

Standardization would help improve communication between researchers, and quality assurance across the field. The act of standardizing research processes and manufacturing has aided many other industries before, and, as Dr. Lander referenced, one of those is the semiconductor industry.

Semiconductors and standardization

The advent of semiconductors, which are now critical to electronic devices, began in the early 1800s, and research and development continued into the 1900s. A semiconductor is a material whose ability to conduct electricity falls between that of a conductor, such as most metals, and an insulator, such as rubber or glass. Unlike most metals, whose ability to conduct electricity decreases as they get hotter, semiconductors improve their electrical conductivity as they increase in temperature. A large number of semiconductors are made of silicon, though there are other materials, like germanium and gallium arsenide, used as well. Their unique properties make semiconductors extremely important in all modern electrical devices.

When first developed, semiconductors were not standardized. By 1972, there were more than 2,000 different specifications for silicon semiconductor wafers. One of the major industry organizations, the Semiconductor Equipment and Materials International (SEMI), decided to develop standards for semiconductors and published its first book of these standards in 1978.

These SEMI standards are developed through a network of small volunteer task forces. When a new standard needs to be devised, a task force is created with volunteers from SEMI’s industry member organizations. Any proposed standards are reviewed and voted on by the entire membership. If there are any negative votes, open forum meetings are convened to discuss why those organizations opposed the standards, additional evidence is presented, and if the opposition is considered persuasive, the proposed standards are sent back to the task force for revision. Only after all negative votes have been considered and addressed are the standards approved. All standards developed by SEMI are re-evaluated every five years to ensure they remain up to date.

There have been many benefits to standardization in the semiconductor industry. For example, standardizing the sizes of semiconductors allowed manufacturers to focus on ways to decrease production costs and increase performance without having to devote a substantial amount of time to the fabrication process. Furthermore, measurement standards have allowed scientists to efficiently build upon past research, obtain follow-on funding, and work toward commercialization of new semiconductor technologies.

Moving forward

Synthetic biology will contribute to important advances in medicine, agriculture, and numerous other sectors in the coming years. However, there are still questions as to how to develop standards that allow researchers to more effectively compare data, reproduce results, and create products. The semiconductor industry can be a useful example of how standardization aided the rapid growth of an industry that has revolutionized people’s lives. As different legislative initiatives make their way through the congressional policymaking process, the discussion around synthetic biology standards will only become more necessary. We encourage the CSPI community to serve as a resource to Congress and the federal government in this area as we monitor for future policy developments.