In their 2022 Executive Order, the Biden-Harris administration proclaims that:

For biotechnology and biomanufacturing to help us achieve our societal goals, the United States needs to invest in foundational scientific capabilities.  We need to develop genetic engineering technologies and techniques to be able to write circuitry for cells and predictably program biology in the same way in which we write software and program computers; unlock the power of biological data, including through computing tools and artificial intelligence; and advance the science of scale‑up production while reducing the obstacles for commercialization so that innovative technologies and products can reach markets faster.

Since the Executive Order in September 2022, there has been a significant focus in governmental activities regarding the future of biotechnology and synthetic biology products. The aim is to harness these technologies in a manner that is safe, sustainable, and beneficial for advancing the American bioeconomy. For instance, the White House Office of Science and Technology Policy’s (OSTP) 2023 report specifies a series of recommendations and ongoing initiatives designed to revamp the bioeconomy infrastructure in the United States. These “bold goals” include launching a comprehensive data initiative specific to the bioeconomy; enhancing domestic biotechnological manufacturing capabilities; cultivating a skilled workforce tailored to these emerging fields; and engaging in international collaboration in research and development. Notably, the OSTP also emphasizes the importance of (1) refining the regulatory framework to streamline the safe and efficient market introduction of biotechnological products; and (2) establishing a Biosafety and Biosecurity Innovation Initiative to mitigate potential risks posed by novel biotechnological advancements.

The National Security Commission on Emerging Biotechnology (NSCEB) is another important actor, in charge of contemplating the future trajectory of biotechnology and the requisite legislative frameworks to ensure national security, particularly in areas critical to the provision of safe food supplies and medical products. Here, genetically modified micro-organisms (GMM) hold transformative potential across diverse sectors including sustainability and climate change mitigation, manufacturing, healthcare, energy, and agriculture.

Acknowledging the renewed governmental interest and the profound potential benefits (and risks) associated with the deployment of GMMs into the environment, Caltech organized a workshop, Pathways Towards the Safe and Effective Deployment of Engineered Microbial Technologies, on February 27 & 28, 2024. The event brought together actors from various fields—including regulatory bodies, the biotech industry, and academia (spanning the natural sciences, social sciences, ethics, and history)—to explore the optimal frameworks for the safe utilization and regulatory oversight of engineered microbial technologies.

Christopher Voigt, Daniel I.C. Wang Professor of Bioengineering from MIT, highlighted a range of fascinating and innovative applications for GMMs, such as anti-corrosion mechanisms; self-repairing or protective materials for infrastructure like concrete and ship hulls; recovery of inaccessible oils; environmental pollution treatment; agricultural yield enhancement; and the decomposition of plastics. The list of potential applications, as detailed by McKinsey Global Institute, extends even further, reflecting the vast scope of GMMs’ potential impact.

The presentations at the first day of the workshop raised important questions, marking the beginning of an in-depth dialogue into the challenges and opportunities presented by the potential release of GMMs into the environment. This multidisciplinary, collaborative approach aims to synthesize the complex ethical, environmental, and regulatory dimensions of these technologies, ensuring their responsible integration into society.

Risk areas

The workshop highlighted that the inherent property of micro-organisms as self-replicating, and their intricate interconnections within ecosystems calls for a careful assessment of potential cascading effects that may ensue. Unlike plants, the miniscule size of micro-organisms and their capacity for horizontal gene transfer introduce unique challenges. These include the persistence of GMMs in the environment, as well as their potential for energy-efficient dispersal across vast areas.

Amid these concerns, the regulatory system for engineered micro-organisms and their release into open environments remains underdeveloped, prompting eager anticipation for opportunities to shape recommendations. It is already well established that good policies require a solid factual foundation – and that this requires cooperation between the scientists and policymakers. Marc Saner, an expert at the science/policy interface, explains how this partnership is vital to bridging the gap between scientific insights and policy formulation, enabling scientists to contribute meaningfully to societal advancements and policymakers to draw upon reliable data and predictions that only scientific research can provide.

In the critical interface of science and policy regarding GMMs, the workshop’s initial day asked the following question:

What scientific hurdles must be overcome to support policy discussions and inform existing decision-making frameworks?

Key among these scientific challenges were risk assessment considerations including dispersal, persistence, and the concept of equivalence, each necessitating rigorous scientific inquiry for the development of regulations.

Dispersal

Our understanding of the dispersal rates and persistence times of micro-organisms in various types of natural environments are still limited. To learn more about how GMMs may disperse in the environment, Jennifer Martiny, Professor of Ecology and Evolutionary Biology at UC Irvine, discussed her group’s research. The mechanisms governing microbial dispersal—ranging from water percolation and plant root interactions to the presence of protozoa and airborne soil particles—present complex variables in assessing microbial behavior in natural settings. It was argued that advancements in quantifying dispersal rates, routes, and sources will be paramount for regulatory bodies to make informed decisions on GMM deployment. Collaborative efforts between researchers and regulatory agencies, through the establishment of testing facilities, may be critical for generating the necessary data under controlled conditions.

Persistence

The issue of persistence emphasizes the balance that must be struck between an engineered micro-organism’s functional longevity and the potential risks associated with its prolonged environmental presence that could lead to increased rates of horizontal gene transfer. Factors influencing persistence include soil type, native microbiota, root structures, plant types, and invertebrates. Regulatory perspectives on persistence are dated and varied, lacking standardized metrics for acceptable microbial population declines. This complicates the approval processes for engineered micro-organisms. Therefore, innovations in measuring and controlling persistence using modern high-throughput–omics; machine learning/AI; ecological modeling; and cellular metabolic modeling will be key areas of research that can further inform and adapt regulatory frameworks.

Equivalence

The concept of equivalence presents another challenge in determining how GMMs compare to well-understood biological counterparts. Ways of establishing equivalence will be vital for regulatory frameworks, as they can streamline the approval process for GMMs deemed similar to existing entities, thereby saving time and resources. Conversely, significant differences may necessitate a re-evaluation of risks versus benefits. Consider the research that has gone into understanding the use of gene drives in mosquitos to accomplish a genetic change through a population. Would gene drives in micro-organisms work in a similar way? How will the genetic change spread through the environment?

Narrowing in on regulation

The workshop further delved into the key barriers highlighted by the President’s Council of Advisors on Science and Technology (PCAST), pinpointing regulatory uncertainty and an outdated national bioeconomy strategy as significant impediments. PCAST emphasizes the need for an integrated bioeconomy strategy that is both cohesive and adaptable to the evolving nature of biotechnologies such as CRISPR-Cas9 gene editing (which can create modifications without introducing foreign DNA) and synthetic biology constructs.

Richard Murray, Thomas E. and Doris Everhart Professor of Control and Dynamical Systems and Bioengineering at Caltech; Steve Evans, Senior Technical Fellow at BioMADE, and Christopher Wozniak from Wozniak Biopesticide Consulting, LLC all further detailed the current regulatory landscape’s positives as well as limitations for GMMs. A primary concern was the Coordinated Framework’s fragmented approach, where multiple agencies and statutes could regulate microbial products based on various criteria such as origin, purpose, and distribution channels. The nature of the genetic modification—whether it involves addition, deletion, or editing of genetic material, or whether the product is transgenic or not—can influence the regulatory scrutiny applied. Moreover, it was noted that GMMs for open water, infrastructure, materials, and open air & extraterrestrial spaces do not even have a path to decision within the Coordinated Framework. These limitations create a complex environment for engineered micro-organisms for environmental release, leading to protracted product cycles that can inhibit innovation and commercial viability.

Pivot Bio was a case in point. Representatives Natalie Hubbard, Vice President of Regulatory and Government Affairs, and Kirsten Benjamin, Vice President of Product Innovation, discussed Pivot Bio’s innovations within context of current regulation. Pivot Bio builds micro-organisms that enable food crops to produce their own nitrogen, replacing nitrogen fertilizer. Their product ProveN, for example, is based on Klebsiella variicola whose genome is remodeled to knock out a repressor (nifL) and replaced with a promoter from elsewhere in its genome. Applied at planting, this engineered micro-organism naturally associates to the root, fixing atmospheric N₂ into NH₃ continuously, providing the plant with precise, steady NH₃ throughout the growing season, regardless of weather. Their manufacturing process requires dramatically less energy with almost no greenhouse gas emissions.

Pivot Bio’s approach is described as leveraging naturally occurring micro-organisms rather than introducing foreign genes, making their technology cisgenic rather than transgenic. Cisgenic engineering involves the modification of organisms using genes found within the same (or closely related) species, which regulation is more friendly towards. This contrasts with transgenic modifications, where genes from different species are inserted, raising several regulatory alarm bells.

Yet, innovations like living infrastructure can also be beneficial, and introduce new dimensions to regulatory considerations, such as the potential environmental impact of shedding micro-organisms or the transmissibility of applied treatments across borders. Here, traditional ways of testing and regulation may not be applicable. Regarding this point, the workshop emphasized the importance of the cost of “inaction”, which can be underseen at times. Prohibiting the regulatory approval of GMMs, for example, can lead to the continued use of harmful products that different parties have become reliant on. PCAST also highlights the broader implications of inaction, including missed opportunities for job creation, reduced carbon footprint, and the acceleration of the U.S. economy through innovative biotechnologies. Workshop participants discussed possible standards to evaluate the “no-action alternative” comprehensively.

Historical context

The workshop would not be complete without incorporating historical context into the discourse on scientific advancements. This is crucial as it illuminates the idea that science is an endeavor conducted by individuals within specific cultural and temporal frameworks. This perspective allows for a more profound integration of scientific inquiry within the fabric of society. Luis Campos, Associate Professor of History at Rice University, emphasized these remarks, illustrating how historical milestones can significantly influence the development and perception of science within cultural contexts.

A prime example of this is the Asilomar Conference of 1975, a pivotal event that established foundational principles for the conduct of biotechnological research and its regulatory oversight, emphasizing the need for containment measures and risk assessment to protect both the environment and public health. Many viewed it as a successful, proactive approach to addressing the safety and related ethical concerns associated with recombinant DNA technology, whereas others criticized the strength and legitimacy of self-regulation, without input from broader society.

Adopting a historical lens facilitates critical examination of key issues, such as the reasons certain research questions gain prominence at specific times (and how they are framed), the potential challenges that may arise in what seems like a straightforward scientific trajectory, the extent of human intervention in nature one deems as acceptable, and the responsibilities borne by creators of genetically modified organisms for any long-term effects. Such inquiry is instrumental in addressing possible controversies akin to those that arose with the development of “ice-minus” bacteria, genetically engineered to lack the gene that causes frost formation on plants, and Monsanto’s genetically modified crops, which ignited extensive debates over environmental implications and intellectual property rights.

The workshop highlighted how the path to public acceptance and trust in biotechnological innovations are critically determined by the early and ongoing engagement with consumers and society at large. Hence, the success of GMMs hinges both on scientific and technical achievements but also on societal and regulatory endorsement. As McKinsey’s analysis suggests, more than two-thirds of the total impact of emerging biotechnology, including GMMs, could hinge on consumer, societal, and regulatory acceptance of these applications. Therefore, an informed dialogue that integrates historical context, addresses ethical considerations, and transparently communicates the benefits and risks associated with biotechnological applications will be important for securing a favorable reception and ensuring the sustainable advancement of the bioeconomy.

Conclusion

The workshop, Pathways Towards the Safe and Effective Deployment of Engineered Microbial Technologies, convened a diverse group of stakeholders—each with unique perspectives—ranging from regulatory authorities and academic researchers to humanists and social scientists, to deliberate on the contingency of introducing engineered micro-organisms into the environment. The discourse centered on two pivotal inquiries: firstly, identifying the scientific hurdles that must be surmounted to inform and refine existing policy frameworks and decision-making processes; and secondly, addressing the current regulatory constraints that impede the efficient market entry of products, alongside exploring how scientific advancements can facilitate regulatory processes through the development of novel tools and methodologies.

The overarching objective of this collaborative effort is to harness our innovative capacities to address global challenges—ranging from climate change mitigation and food security to healthcare—while simultaneously safeguarding human health and environmental integrity. The discussions underscored the vital role of clear and flexible regulation in enabling innovation and increasing public confidence in regulatory policies.

The identification of research gaps was a focal point of the workshop, highlighting areas such as the need for comprehensive metagenomic data on microbial persistence, dispersal, and ecological impacts; the application of pandemic sequencing infrastructure for tracking global microbial flow; and the utilization of artificial intelligence and machine learning for analyzing microbial sequences for potential toxicity, pathogenicity, and environmental impact. Furthermore, the development of pre-approved “safe chassis” micro-organisms, incorporating recoding, genetic stability, and safety switches, along with cost-effective data collection methods and environmental modeling, were introduced as critical needs for advancing GMM deployment.

The Center for Science, Society, and Public Policy is a platform for engaging scientists in policy discussions, offering Caltech researchers—from graduate students to faculty—an invaluable perspective on the policy implications of scientific research. It emphasizes the importance of considering regulatory frameworks from the outset of research projects, leading to a more integrative approach to scientific and regulatory science. The anticipated final workshop report will offer a comprehensive set of policy and scientific recommendations, addressing the essential questions that will necessitate new scientific endeavors. This document will guide researchers—at Caltech and beyond—in aligning their work with the needs of regulatory science, thus contributing to the broader scientific discourse and policy development.

 

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