Regulatory Challenges for Microbiome Engineering

A major hurdle in microbiome engineering will be the regulatory barriers that prevent engineered organisms from being used outside the lab – as therapeutics and diagnostics, or in open environments like agricultural tracts. Many intersecting factors contribute to the difficulties that will need to be overcome if engineered microbiomes, or methods for engineering native microbiomes, are to see wider adoption. At a regulatory level in the U.S., multiple federal- and state-level agencies may have jurisdiction over a genetically modified organism, depending on how it is created and how it is used. At the moment, the United States Department of Agriculture (USDA), Food and Drug Administration (FDA), and Environmental Protection Agency (EPA) may all have regulatory authority over an engineered organism.¹Committee on Future Biotechnology Products and Opportunities to Enhance Capabilities of the Biotechnology Regulatory System, Board on Life Sciences, Board on Agriculture and Natural Resources, Board on Chemical Sciences and Technology, Division on Earth and Life Studies, & National Academies of Sciences, Engineering, and Medicine. (2017). Preparing for Future Products of Biotechnology (p. 24605). National Academies Press. View Publication If the same organism is to be used outside the U.S., then additional sets of guidelines need to be followed to become compliant with local regulations. Policymakers and regulators should take an active role to help scientists and biotechnology companies navigate these frameworks and streamline the processes used to vet and approve new technologies.

Microbiome engineering will also require significant collaboration between government, industry, and academia to share risks at multiple steps in the research and development process. Engineered microbiomes are a high-risk area for biotech companies due to additional regulatory hurdles and additional possible points of technical failure. Additionally, there are still many unknown aspects of microbial ecology that make it difficult to predict the impact of adding an engineered organism to a natural environment. Increased collaboration between government, industry, and academia can encourage communication throughout the research and development process so expectations of potential hurdles, such as regulatory requirements, are understood well before any technology comes to market. As microbiome engineering research advances it will be important that sufficient controls are put into place to ensure safety, without creating so many legal and regulatory hurdles that companies are discouraged from developing high-risk, high-reward technologies.

Policies to Support Microbiome Engineering

Even though costs associated with microbiome engineering will decrease on a per-replicate basis, it is important to recognize that the total costs of an experiment may actually increase over time. Comprehensive multi-omic studies will require a sufficient number of samples to assess microbiome dynamics, and a sufficient number of replicates to have practical statistical power. Additionally, a significant technical challenge is improving data reproducibility, and in particular, better translating data obtained in controlled environments with expected outcomes in natural microbiomes. While scientists have an interest in advancing reproducibility for the sake of their research, institutions like the National Institute of Standards and Technology have started getting involved with microbial measurements,²NIST Food Safety Working Group. (2020a). Harnessing measurement science to advance food safety (NIST SP 1251; p. NIST SP 1251). National Institute of Standards and Technology. View Publication^,3NIST Food Safety Working Group. (2020b). Opportunities for national metrology institutes and reference material producers to ensure global food safety: A companion report (NIST SP 1252; p. NIST SP 1252). National Institute of Standards and Technology. View Publication and should be encouraged to invest further for microbiome engineering technologies.

Addressing these challenges may require funding agencies to shift support towards centralized facilities that have specialized technical expertise and infrastructure for performing such experiments, but work with and serve all microbiome researchers. The Department of Energy’s Joint Genome Institute is one possible model for centralized research centers, but such centralized research infrastructure would broadly be a significant departure from current practices in biology; however, it is reminiscent of the national and international collaborations found in experimental physics, where the scale of facilities required to perform experiments necessitates coordination between many organizations.

Security Considerations of Microbial Misuse

Microbiome engineering will pose novel biosecurity risks for the environment, existing natural microbiomes, animals, plants, and humans. Used properly, engineered microbiomes can help address many societal problems identified in our Application Sectors. However, the same technologies that allow microbiomes to enhance agricultural soils or cure diseases as therapeutics, have the potential for abuse. Despite the ubiquitous synthesis and use of engineered DNA, government guidance on the risk assessment of manufactured DNA sequences has lagged behind technological advances, leaving the decision-making process to industry groups or individual labs and companies. Microbiome engineering will be even more challenging, as a microbiome that is deemed safe in one ecosystem under a given set of environmental conditions may function differently or pathologically in a different ecosystem or under different conditions. Therefore, it is of great interest to invest in tools and methods for estimating, anticipating, and monitoring potentially unintended consequences of microbiome engineering on ecosystems and organisms.

Government agencies, funders, researchers, and industry partners will need to work together to solve this challenge. Scientists will need to demonstrate that a microbiome will not cause harm if accidentally or intentionally released into the wrong environment, or that it does not produce harmful or illegal chemicals if fed a different set of chemical precursors. Additionally, even if released in the correct environment, engineered microbiomes must not detrimentally impact the broader ecosystem (e.g., microbiomes that improve a crop, but harm pollinator species). As a result, additional financial and administrative support for field trials (particularly for agricultural microbiomes) will be important to understand how microbiome engineering can go wrong. These studies will not only be important for gaining a better understanding of how engineered microbiomes function, but will also improve their safety and security.  Funding agencies should provide monetary support both to develop mitigating technologies and containment approaches as well as to train scientists to reduce the chances that their science could be misused.

Footnotes & Citations

1. Committee on Future Biotechnology Products and Opportunities to Enhance Capabilities of the Biotechnology Regulatory System, Board on Life Sciences, Board on Agriculture and Natural Resources, Board on Chemical Sciences and Technology, Division on Earth and Life Studies, & National Academies of Sciences, Engineering, and Medicine. (2017). Preparing for Future Products of Biotechnology (p. 24605). National Academies Press. https://doi.org/10.17226/24605
2. NIST Food Safety Working Group. (2020a). Harnessing measurement science to advance food safety (NIST SP 1251; p. NIST SP 1251). National Institute of Standards and Technology. https://doi.org/10.6028/NIST.SP.1251
3. NIST Food Safety Working Group. (2020b). Opportunities for national metrology institutes and reference material producers to ensure global food safety: A companion report (NIST SP 1252; p. NIST SP 1252). National Institute of Standards and Technology. https://doi.org/10.6028/NIST.SP.1252