Biotechnology executive order opens door for regulatory reform and social acceptance of genetically engineered microbes in agriculture.

In the United States, regulatory review of genetically engineered microbes for agriculture falls under the Coordinated Framework for the Regulation of Biotechnology (CFRB). However, the lack of a centralized regulatory pathway and multiple oversight authorities can lead to uncertainty in regulatory review. Using three microbial-based technologies for agriculture as illustrative examples, this commentary identifies the weaknesses and challenges associated with the CFRB by assessing the current system and proposed changes to the system under a multi criteria decision analysis framework. In addition, it discusses opportunities for regulatory reform to improve clarity, efficiency, and public acceptance of genetically engineered microbes in agriculture under the CHIPS and Science Act and the 2022 Executive Order on the Bioeconomy.

Perspectives on Genetically Engineered Microorganisms and Their Regulation in the United States.

Genetically engineered microorganisms (GEMs) represent a new paradigm in our ability to address the needs of a growing, changing world. GEMs are being used in agriculture, food production and additives, manufacturing, commodity and noncommodity products, environmental remediation, etc., with even more applications in the pipeline. Along with modern advances in genome-manipulating technologies, new manufacturing processes, markets, and attitudes are driving a boom in more products that contain or are derived from GEMs. Consequentially, researchers and developers are poised to interact with biotechnology regulatory policies that have been in effect for decades, but which are out of pace with rapidly changing scientific advances and knowledge. In the United States, biotechnology is regulated by multiple agencies with overlapping responsibilities. This poses a challenge for both developers and regulators to simultaneously allow new innovation and products into the market while also ensuring their safety and efficacy for the public and environment. This article attempts to highlight the various factors that interact between regulatory policy and development of GEMs in the United States, with perspectives from both regulators and developers. We present insights from a 2022 workshop hosted at the University of California, Berkeley that convened regulators from U.S. regulatory agencies and industry developers of various GEMs and GEM-derived products. We highlight several new biotechnologies and applications that are driving innovation in this space, and how regulatory agencies evaluate and assess these products according to current policies. Additionally, we describe recent updates to regulations that incorporate new technology and knowledge and how they can adapt further to effectively continue regulating for the future.

Revisions to USDA biotechnology regulations: The SECURE rule.

In keeping with the directive in Executive Order 13874 (Modernizing the Regulatory Framework for Agricultural Biotechnology Products) to adopt regulatory approaches that are proportionate to risk and avoid arbitrary distinctions across like products, the US Department of Agriculture (USDA) revised its biotechnology regulations by promulgating the Sustainable, Ecological, Consistent, Uniform, Responsible, and Efficient (SECURE) rule. Specifically, the SECURE rule 1) establishes exemptions for plants modified by genetic engineering where the modification could otherwise have been made through conventional breeding, 2) uses risk posed by the introduced trait to determine whether an organism is regulated, rather than relying on whether the organism was developed using a plant pest, and 3) provides a mechanism for a rapid initial review to efficiently distinguish plants developed using genetic engineering that do not pose plausible pathways to increased plant pest risk from those that do. As a result of the focused oversight on potentially riskier crops developed using genetic engineering, USDA is expected to improve the efficiency and effectiveness of its oversight program. The reduced regulatory burden is expected to promote innovation by expanding the number and diversity of developers to include smaller businesses and academics and to increase the number and variety of traits being developed through biotechnology.

Genetic Engineering of Livestock: The Opportunity Cost of Regulatory Delay.

Genetically engineered (GE) livestock were first reported in 1985, and yet only a single GE food animal, the fast-growing AquAdvantage salmon, has been commercialized. There are myriad interconnected reasons for the slow progress in this once-promising field, including technical issues, the structure of livestock industries, lack of public research funding and investment, regulatory obstacles, and concern about public opinion. This review focuses on GE livestock that have been produced and documents the difficulties that researchers and developers have encountered en route. Additionally, the costs associated with delayed commercialization of GE livestock were modeled using three case studies: GE mastitis-resistant dairy cattle, genome-edited porcine reproductive and respiratory syndrome virus-resistant pigs, and the AquAdvantage salmon. Delays of 5 or 10 years in the commercialization of GE livestock beyond the normative 10-year GE product evaluation period were associated with billions of dollars in opportunity costs and reduced global food security.

Controlling CRISPR Through Law: Legal Regimes as Precautionary Principles.

Since its advent in 2012, CRISPR has spawned a cottage industry of bioethics literature. One principal criticism of the technology is its virtually instant widespread adoption prior to deliberative bodies conducting a meaningful ethical review of its harms and benefits-a violation, to some, of bioethics' "precautionary principle." This view poorly considers, however, the role that the law can play-and does, in fact, play-in policing the introduction of ethically problematic uses of the technology. This Perspective recounts these legal regimes, including regulatory agencies and premarket approval, tort law and deterrence, patents and ethical licenses, funding agencies and review boards, as well as local politics. Identifying these legal regimes and connecting them to the precautionary principle should be instructive for bioethicists and policy makers who wish to conduct ethical reviews of new applications of CRISPR prior to their introduction.

Democratic Governance of Human Germline Genome Editing.

An international regulatory commission convened by scientific academies is a premature and problematic approach to governing human germline genome editing. Given the complex, international landscape of genome editing and significant cross-national differences among regulatory cultures, deferring to a single commission to set the agenda for global governance raises troublesome questions of framing and representation. Rather, democratic governance on a global level demands a new mechanism for active, sustained reflection by scientists on their own practices, conducted in partnership with scholars from other disciplines, as well as public representatives from varied social, political, and religious backgrounds. To be legitimate, ideas of the right form of governance in this emerging and highly consequential area of research need to be opened up to a wider diversity of views and voices.

Heritable Genome Editing and the Downsides of a Global Moratorium.

In 2018, Dr. He Jiankui reported that he had edited human embryos and transferred them to a woman, causing her to give birth to twin girls with modified genomes. An international group of scientists and ethicists responded by proposing a global moratorium on heritable genome editing (HGE). In this article, I oppose this proposal on several grounds. A global moratorium might encourage participating nations to ban HGE or postpone access to it indefinitely. It might also deter or delay basic research that could lead to safe and effective HGE. Lastly, a global moratorium might induce participating nations to adopt or maintain laws and regulations that stigmatize children born with modified genomes. As an alternative, I argue that nations should regulate HGE for safety and efficacy only and without distinguishing between therapeutic and enhancing modifications.

Report on the SCRA Nuts and Bolts Workshop II: case studies of citrus greening, Ultra-low Gossypol Cotton, and blight tolerant, low-acrylamide potato.

To be commercialized and grown in the US, genetically engineered (GE) crops typically go through an extensive food, feed, and environmental safety assessment process which, in certain instances, requires complex consultations with three different US regulatory agencies. Many small market, niche, and specialty crops have been genetically engineered using the modern tools of recombinant DNA but few have been commercialized due to real or perceived regulatory constraints. This workshop discussed the practical aspects of developing dossiers on GE specialty, niche, or small-market crops/products for submission to US regulatory agencies. This workshop focused on actual case studies, and provided an opportunity for public or private sector scientists and crop developers to spend time with regulatory officials to learn the specifics of compiling a dossier for regulatory approval. The objective of the workshop was to explain and demystify data requirements and regulatory dossier compilation by small companies, academics, and other developers.

Canadian regulatory aspects of gene editing technologies.

The development of gene editing techniques, capable of producing plants and animals with new and improved traits, is revolutionizing the world of plant and animal breeding and rapidly advancing to commercial reality. However, from a regulatory standpoint the Government of Canada views gene editing as another tool that will join current methods used to develop desirable traits in plants and animals. This is because Canada focusses on the potential risk resulting from the novelty of the trait, or plant or animal product entering the Canadian environment or market place, rather than the process or method by which it was created. The Canadian Food Inspection Agency is responsible for the regulation of the environmental release of plants with novel traits, and novel livestock feeds, while Health Canada is responsible for the regulation of novel foods. Environment and Climate Change Canada, in partnership with Health Canada, regulates modified animals for entry into the environment. In all cases, these novel products may be the result of conventional breeding, mutagenesis, recombinant DNA techniques or other methods of plant or animal breeding such as gene editing. This novelty approach allows the Canadian regulatory system to efficiently adjust to any new developments in the science of plant and animal breeding and allows for risk-appropriate regulatory decisions. This approach encourages innovation while maintaining science-based regulatory expertise. Canadian regulators work cooperatively with proponents to determine if their gene editing-derived product meets the definition of a novel product, and whether it would be subject to a pre-market assessment. Therefore, Canada's existing regulatory system is well positioned to accommodate any new innovations or technologies in plant or animal breeding, including gene editing.

Are current EU policies on GMOs justified?

The European Court of Justice's recent ruling that the new techniques for crop development are to be considered as genetically modified organisms under the European Union's regulations exacerbates the need for a critical evaluation of those regulations. The paper analyzes the regulation from the perspective of moral and political philosophy. It considers whether influential arguments for restrictions of genetically modified organisms provide cogent justifications for the policies that are in place, in particular a pre-release authorization requirement, mandatory labelling, and de facto bans (in the form of withholding or opting out of authorizations). It is argued that arguments pertaining to risk can justify some form of pre-release authorization scheme, although not necessarily the current one, but that neither de facto bans nor mandatory labelling can be justified by reference to common arguments concerning naturalness, agricultural policy (in particular the promotion of organic farming), socio-economic effects, or consumers' right to choose.

In vitro gametogenesis and reproductive cloning: Can we allow one while banning the other?

In vitro gametogenesis (IVG) is believed to be the next big breakthrough in reproductive medicine. The prima facie acceptance of this possible future technology is notable when compared to the general prohibition on human reproductive cloning. After all, if safety is the main reason for not allowing reproductive cloning, one might expect a similar conclusion for the reproductive application of IVG, since both technologies hold considerable and comparable risks. However, safety concerns may be overcome, and are presumably not the sole reason why cloning is being condemned. We therefore assess the non-safety arguments against reproductive cloning, yet most of these can also be held against IVG. The few arguments that cannot be used against IVG are defective. We conclude from this that it will be hard to defend a ban on reproductive cloning while accepting the reproductive use of IVG.

Will CRISPR Germline Engineering Close the Door to an Open Future?

The bioethical principle of autonomy is problematic regarding the future of the embryo who lacks the ability to self-advocate but will develop this defining human capacity in time. Recent experiments explore the use of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 for germline engineering in the embryo, which alters future generations. The embryo's inability to express an autonomous decision is an obvious bioethical challenge of germline engineering. The philosopher Joel Feinberg acknowledged that autonomy is developing in children. He advocated that to reserve this future autonomy, parents should be guided to make ethical decisions that provide children with open futures. Here, Feinberg's 1980 open future theory is extended to the human embryo in the context of CRISPR germline engineering. Although the embryo does not possess the autonomous decision-making capacity at the time of germline engineering, the parental decision to permanently change the unique genetic fabric of the embryo and subsequent generations disregards future autonomy. Therefore, germline engineering in many instances is objectionable considering Feinberg's open future theory.

Mexico and mitochondrial replacement techniques: what a mess.

Background: The first live birth following the use of a new reproductive technique, maternal spindle transfer (MST), which is a mitochondrial replacement technique (MRT), was accomplished by dividing the execution of the MST procedure between two countries, the USA and Mexico. This was done in order to avoid US legal restrictions on this technique. Sources of data: Academic articles, news articles, documents obtained through freedom of information requests, laws, regulations and national reports. Areas of agreement: MRTs are new reproductive techniques that present novel ethical and legal challenges, since genetic material from three people is employed to create a child. Areas of controversy: Could the first MST procedure that culminated in a live birth negatively impact reproductive medicine in Mexico? Growing points: The USA and Mexico need specific and clear legislation on MRTs, in order for such techniques not to be governed by prior existing legislation on assisted reproduction that is inadequate for dealing with the new challenges that these techniques present. Areas timely for developing research: There is a pressing need for work to be done on the international governance of new reproductive techniques.

Bottlenecks for genome-edited crops on the road from lab to farm.

Gene discovery and government regulation are bottlenecks for the widespread adoption of genome-edited crops. We propose a culture of sharing and integrating crop data to accelerate the discovery and prioritization of candidate genes, as well as a strong engagement with governments and the public to address environmental and health concerns and to achieve appropriate regulatory standards.

The contribution of transgenic and genome-edited animals to agricultural and industrial applications.

For centuries, animal breeders have intentionally selected the parents of the next generation based on their concept of the 'ideal' animal. The dramatic differences seen in the appearance and productivity of different breeds show the power of such selection on DNA sequence variations. Unfortunately, the global furore over the use of modern biotechnologies to introduce desired genetic variations into animal breeding programmes, and the regulatory uncertainty associated with these recombinant DNA techniques, has effectively precluded the use of these technologies in food animal breeding programmes. Ironically, many of these early transgenic animal applications targeted traits that favoured sustainability, such as disease resistance and decreased environmental impact. As a consequence, transgenic animals have had little opportunity to affect global agriculture, and only a handful of pharmaceutical applications have been successfully commercialised. New developments in genome editing hold considerable promise for targeting traits that improve both animal health and welfare, and frequently involve no introduction of DNA sequences from other species. Nonetheless, future global regulation and public acceptance of such methods remain uncertain. Proposals to regulate genome-edited animals based solely on the process used to influence DNA sequence variations (i.e. intentional genome editing) and any potential attendant risks, with no counterbalancing consideration of the ensuing benefits or risks associated with conventional selection programmes, will potentially forestall the use of genome editing in animal breeding programmes. No activity can survive a risk-only evaluation, and there are considerable opportunity costs associated with preventing breeders' access to safe technologies in order to achieve genetic improvements in livestock populations.

Pendant des siècles, les éleveurs ont exercé une sélection des reproducteurs au sein de leurs troupeaux afin de donner naissance à de nouvelles générations d'animaux correspondant à leur conception de l'animal d'élevage « idéal ¼. Les différences d'aspect et de productivité constatées entre les différentes races démontrent l'importance des effets de cette sélection sur les mutations des séquences d'ADN. Malheureusement, l'indignation planétaire suscitée par le recours aux biotechnologies modernes pour introduire des traits d'amélioration génétique chez les animaux d'élevage et les incertitudes sur la réglementation applicable aux techniques de l'ADN recombiné ont eu pour effet d'exclure l'utilisation de ces technologies dans les programmes d'élevage d'animaux destinés à la consommation humaine. L'ironie de la chose est que la plupart des premières applications recourant aux animaux transgéniques visaient à introduire des traits favorisant un élevage durable, par exemple des traits induisant une résistance contre certaines maladies ou permettant de diminuer l'impact environnemental des élevages. En conséquence, les conditions n'étaient guère réunies pour que les animaux transgéniques contribuent à transformer l'agriculture mondiale et seules quelques rares applications pharmaceutiques, ont pu être mises au point et commercialisées avec succès. Les récents développements de l'édition génomique ouvrent des voies extrêmement prometteuses pour cibler des traits permettant d'améliorer la santé et le bien-être des animaux, très souvent sans qu'il soit nécessaire d'introduire des séquences d'ADN provenant d'autres espèces. Néanmoins, des incertitudes subsistent sur l'évolution de la réglementation mondiale en la matière et sur l'acceptation sociale de ces méthodes à l'avenir. On peut donc s'attendre à ce que l'utilisation de l'édition génomique dans les programmes de sélection animale sera devancée par des propositions visant à la réglementer ; ces propositions ne prendront en compte que le processus induisant une modification ciblée de séquences d'ADN et les risques potentiels qui lui sont associés, sans les contrebalancer par un examen des bénéfices apportés ni des risques inhérents aux programmes de sélection classiques. Aucune activité ne peut survivre à une évaluation basée exclusivement sur les risques ; par ailleurs, les coûts d'opportunité induits par le fait d'empêcher les éleveurs d'accéder à des technologies sûres pour améliorer le patrimoine génétique des populations d'animaux d'élevage sont considérables.

Durante siglos, los criadores de animales han seleccionado intencionadamente a los progenitores de la siguiente generación en función de su concepción de animal «idóneo¼. Las espectaculares diferencias de aspecto externo y productividad que se observan entre las distintas razas ponen de manifiesto el poder de esta selección ejercida sobre las variaciones de secuencias de ADN. Lamentablemente, el clamor mundial contra el empleo de las modernas biotecnologías para introducir las variaciones genéticas deseadas en los programas de producción animal, sumado a las incertidumbres reglamentarias existentes en torno a esas técnicas de ADN recombinante, han obstaculizado el uso eficaz de estas tecnologías en programas de cría selectiva de animales destinados a la producción alimentaria. Irónicamente, muchas de esas primeras aplicaciones de animales transgénicos tenían que ver con rasgos que favorecían la sostenibilidad, como la resistencia a enfermedades o la reducción del impacto ambiental. Como consecuencia, apenas ha habido ocasión de que los animales transgénicos influyan en la agricultura mundial y solo se han comercializado con éxito un puñado de aplicaciones farmacéuticas. Las últimas novedades surgidas en la edición genómica parecen bastante prometedoras para actuar sobre rasgos que mejoren tanto la salud como el bienestar de los animales, a menudo sin que ello requiera la introducción de secuencias de ADN de otras especies. Sin embargo, sigue reinando la incertidumbre acerca del grado de aceptación pública y la futura reglamentación de tales métodos a escala mundial. Lo más probable es que las propuestas de reglamentar la cuestión de los animales obtenidos por edición genómica atendiendo únicamente al proceso empleado para obtener variantes de secuencias de ADN (esto es, la edición genómica deliberada) y a los eventuales riesgos conexos (sin tener en cuenta, en contrapartida, los consiguientes beneficios o riesgos asociados a los programas de selección convencionales) desemboquen en la imposibilidad de aplicar la edición genómica a programas de cría selectiva de animales. No hay actividad alguna que pueda superar el filtro de una evaluación basada únicamente en el riesgo, y el hecho de impedir que los criadores accedan a tecnologías seguras para lograr la mejora genética de sus poblaciones de ganado entraña importantes costos de oportunidad.

Crop Gene-Editing: Should We Bypass or Apply Existing GMO Policy?

Recent advances in crop gene-editing technologies allow for efficient site-specific mutagenesis without introducing exogenous DNA, potentially bypassing product-based genetically modified organism (GMO) regulations. Conversely, such plants can be subject to process-based GMO regulations. However, it is important to tailor existing GMO regulations with the aim to ensure social acceptance of gene-edited crops.