Several technological waves of genetic modification of crops have ensued over the last several decades. Genetic engineering has generally referred to the insertion of genetic material into an existing organism (often described as transgenic). Genetic editing is a later wave of genetic intervention, involving the direct alteration of a gene’s sequence on site (this CRISPR-fueled technology taking off since about 2012). A conceptual question of recent origin is whether both transgenic and genetically edited crops are classified as genetically modified organisms (GMOs). In the U.S., regulators have decided that genetically edited crops will not require any specific regulation, unlike transgenic organisms. In
March, the U.S. government announced that it would not impose any
particular regulation on genetically edited crops, regarding such crops as closer to those derived from traditional mutagenenesis. The U.S. Department of Agriculture (USDA) stated:
Under its biotechnology regulations, USDA
does not regulate or have any plans to regulate plants that could
otherwise have been developed through traditional breeding techniques as
long as they are not plant pests or developed using plant pests. This
includes a set of new techniques that are increasingly being used by
plant breeders to produce new plant varieties that are indistinguishable
from those developed through traditional breeding methods. The newest
of these methods, such as genome editing, expand traditional plant
breeding tools because they can introduce new plant traits more quickly
and precisely, potentially saving years or even decades in bringing
needed new varieties to farmers.
A new ruling from the European Court of Justice addresses whether genetically edited crops fall within the 2001 E.U. Directive on the Deliberate Release of Genetically Modified Organisms:
In today’s judgment, The European Court of Justice takes the view, first of all, that organisms obtained by mutagenesis are GMOs within the meaning of the GMO Directive, in so far as the techniques and methods of mutagenesis alter the genetic material of an organism in a way that does not occur naturally. It follows that those organisms come,in principle, within the scope of the GMO Directive and are subject to the obligations laid down by that directive.
In keeping with its more stringent regulation of genetically engineered (transgenic) crops, the E.U. has decided to maintain a cohesive scheme for modern genetic technologies, classifying genetically edited crops as GMOs. In contrast, the U.S. has bifurcated its oversight of genetically altered crops, with recent decision-making that allows genetically edited crops to advance quickly in field testing.
The National Academies of Sciences, Engineering, and Medicine (NAS) has issued a report on gene drive technology, Gene Drive Research in Non-Human Organisms: Recommendations for Responsible Conduct. A gene drive is a method by which specific genetic mutations (or alleles) are preferentially inherited, and over time, the effect is to eliminate other competing alleles. This has population-wide consequences for an organism, and can permanently alter (or reduce) the genetic diversity of a species. The phenomenon of a gene drive occurs in nature, and has been observed in many organisms:
In nature, certain genes ‘drive’ themselves through populations by increasing the odds that they will be inherited.
Now, however, advances in gene-editing technology have facilitated the development of deliberately engineered gene drives. From the report summary:
A wide variety of gene drives occur in nature. Researchers have been studying these natural mechanisms throughout the 20th century but, until the advent of CRISPR/Casfor gene editing, have not been able to develop a gene drive. Since early 2015, laboratory scientists have published four proofs-of-concept showing that a CRISPR/Cas9-based gene drive could spread a targeted gene through nearly 100% of a population of yeast, fruit flies, or mosquitos.
In other words, use of gene drive technology can impose a specific genetic allele (variant) on a population and eliminate all other forms of the gene. Effectively, the population is now homozygous for the preferred variant. That is both the attraction and the concern regarding the use of this technique. Genetic traits could be eliminated, and at its most extreme, whole populations could be "driven" out of existence. It is simple to imagine particular uses of the technology that would eliminate undesirable traits in a target population, such as the ability of mosquitos to spread malaria, or very currently, the ability of the Aedes aegypti mosquito to transmit the Zika virus. The report summarizes possible applications and the requirement for a deliberative approach to use of the technique:
Gene-drive modified organisms hold promise for addressing difficult-to-solve challenges, such as the eradication of insect-borne infectious diseases and the conservation of threatened and endangered species. However, proof-of-concept in a few laboratory studies to date is not sufficient to support a decision to release gene-drive modified organisms into the environment. The potential for gene drives to cause irreversible effects on organisms and ecosystems calls for a robust method to assess risks. A phased approach to testing, engagement of stakeholders and publics, and clarified regulatory over-sight can facilitate a precautionary, step-by-step approach to research on gene drives without hindering the development of new knowledge.
The report did not recommend a moratorium on research, despite noting the potential for adverse consequences. Instead, it endorsed continued research on the technology with some limited field evaluations:
Although there is insufficient evidence available at this time to support the release of gene-drive modified organisms into the environment, the likely benefits of gene drives for basic and applied research are significant and justify proceeding with laboratory research and highly-controlled field trials.
The current regulatory landscape for gene drive applications is summarized:
In the United States, regulation of gene-drive modified organisms will most likely fall under the Coordinated Framework for the Regulation of Biotechnology, which includes the U.S. Food and Drug Administration, the U.S. Department of Agriculture, and the U.S. Environmental Protection Agency. However, the diversity of potential gene-drive modified organisms and contexts in which they might be used reveals a number of regulatory overlaps and gaps. The U.S. government will need to clarify the assignment of regulatory responsibilities for field releases of gene-drive modified organisms, including the roles of relevant agencies.
At the present time, the patchwork structure for biotechnology regulation is currently under formal review by the Obama administration (see earlier post for more background). In general, as the new products of genetic engineering have been developed over the years, they encounter oversight from any one (or more) of three agencies: the FDA, EPA, or USDA. As the regulatory framework is redesigned, we could expect that various applications of gene drive technology will face an approval process customized to the particular goal and purpose of the technology. The report states:
It is important to note that a one-size-fits-all approach to governance is not likely to be appropriate. Each phase of research activity—from developing a research plan to post-release surveillance—raises different levels of concern depending on the organism being modified and the type of gene drive being developed.
The NAS report has received criticism from opponents of field testing, who noted that precise control of such experiments is not possible, and wider, possiblly uncontrolled spread of altered organisms could occur. Other criticisms suggest that the scope of the report is too limited, and does not adequately address possible dual-use concerns (malevolent uses of the technology). The report has some conceptual overlap with efforts of the World Health Organization (WHO) has previously released a guidance framework for how to introduce genetically engineered mosquitoes that are reproductively disabled, thus reducing the population of a malaria vector. In summary, the NAS panel has cautiously endorsed further gene drive research in the U.S., and contemplates eventual field trials of engineered organisms.
Genetic alteration since the beginning of the biotechnology age has largely relied on the introduction of new genetic material into an organism to create a genetically engineered (GE) bacterium, plant or animal (also known as a genetically modified organism, GMO). Regulatory schemes reflected that dominant paradigm. Now, however, the use of gene-editing technology for genetic manipulation in plants can result in genetically altered plants that bypass the regulatory requirements for the introduction of standard GE plants into the marketplace. The traditional genetic engineering of crops employed the introduction of foreign genetic material into the crop; such gene transfer generally triggered formal review of the altered product because of the phenotype conveyed by the introduced gene(s), or because of the use of a vector that had plant pest characteristics. A GE plant product would trigger review if the newly introduced trait posed environmental or other safety-related risks. The review was conducted by the Animal and Plant Health Inspection Service (APHIS) of the USDA, pursuant to its statutory authority under the Plant Protection Act of 2000. (Depending on the product, additional oversight by the FDA or EPA could be required). Today, genetic alteration has moved beyond simple gene transfer into more precise techniques for changing the genome of an organism. Now, in a regulatory first, APHIS has made a determination that a white button mushroom altered by CRISPR/Cas9 gene editing technology to exhibit reduced browning is an “unregulated article” that will not require the kind of formal review usually applied to traditionally genetically engineered products containing foreign DNA:
APHIS does not consider CRISPR/Cas9-edited white button mushrooms as described in your October 30, 2015 letter to be regulated.
Here, CRISPR/Cas9 gene editing technology was used to introduce a small deletion in a polyphenol oxidase gene in the mushroom, with the result that the altered enzyme cannot produce the browning that shortens shelf life. The final product has no foreign DNA and no plant pest characteristics. This decision by APHIS follows earlier determinations that have resulted in at least 10 genetically altered products being approved without requiring a formal review. These products have been produced with, e.g., techniques that did not rely on the introduction of new genetic material using any plant pest vector, or non-CRISPR gene editing technologies. This shift in regulation highlights how modern genetic alteration writ large encompasses multiple technologies, some of which fall into an existing regulatory mandate, and some of which do not. The central theme of biotechnology regulation to date has been to focus on the product, not the process. As far back as the introduction of the federal Coordinated Framework for Regulation of Biotechnology in 1986, the prevailing scheme ensured that genetically engineered products would not be singled out for heightened review simply because of the way they were produced. The product was the focus; more precisely, the actual phenotypes of the GE plants or insects were evaluated to identify traits that required additional oversight. The traditional dichotomy between product-based or process-based paradigms for regulation biotechnology products has been criticized as a poor fit for the realities of the biotech marketplace. Evidence for an evolution of the regulatory scheme has been provided by the Obama administration’s announcement of a deliberative process to overhaul and modernize the regulation of biotech products, with the recruitment of the FDA, EPA, and USDA in the process (see earlier post). This regulatory renewal will no doubt eliminate a strict focus on gene transfer as the only genetic technology producing altered organisms, and strive to broaden the definition of the field of genetic alteration to reflect new realities, such as CRISPR and other gene-editing technologies. Then the calculus of risk/benefit analysis will need to be applied, in the context of emerging genetic technologies where risk profiles are not yet established.
The federal regulation of biotechnology products is grounded in a design that was first announced in 1986 as the Coordinated Framework (CF) for the Regulation of Biotechnology, later updated in 1992. Those documents have largely shaped the the federal regulatory regime for biotechnology. A key concept in this original framework was that products produced through genetic engineering (or recombinant DNA) techniques would not receive special oversight because of the processes used to produce them. Instead, a risk-based approach was instituted that focused on the characteristics of actual products, not underlying production techniques. In 2015, the White House, through its Office of Science and Technology (OSTP), announced that it would launch an overhaul of the 1992 policy. In the memorandum, the OSTP provided a definition of “biotechnology products” to be included in the review:
For the purpose of this memo, “biotechnology products” refers to products developed through genetic engineering or the targeted or in vitro manipulation of genetic information of organisms, including plants, animals, and microbes. It also covers some of the products produced by such plants, animals, and microbes or their derived products as determined by existing statutes and regulations. Products such as human drugs and medical devices are not the focus of the activities described in this memorandum.
Since the 1980’s, the existing coordinated framework has divided the primary regulation of biotechnology products among three agencies: the U.S. Environmental Protection Agency (EPA), the U.S. Department of Agriculture (USDA), and the U.S. Food and Drug Administration (FDA). The OSTP is involved in a more general role as overseer of the regulatory design, rather than as a formal regulatory body. In the memorandum sent to the heads of the EPA, FDA and USDA, the OSTP alludes to the regulatory overlap, redundancy and confusion that has arisen with the multi-agency design:
Each of the Federal regulatory agencies with jurisdiction over the products of biotechnology has developed regulations and guidance documents to implement its authority under existing laws, resulting in a complex system for assessing and managing health and environmental risks of the products of biotechnology. While the current regulatory system for the products of biotechnology effectively protects health and the environment, in some cases unnecessary costs and burdens associated with uncertainty about agency jurisdiction, lack of predictability of time frames for review, and other processes have arisen.
As part of the modernization initiative, the Administration held 3 meetings organized by the relevant agencies to receive feedback on the proposed overhaul. Two documents were issued that are helpful to understanding the current climate that is precipitating calls for redesign: a table of current agency responsibilities, and a series of case studies illustrating how a singular GE product can be subject to multi-agency review. Pursuant to the OSTP charge, a committee formed by the National Academy of Sciences, Medicine and Engineering was commissioned to conduct a formal study, “Future Biotechnology Products and Opportunities to Enhance Capabilities of the Biotechnology Regulatory System.” This committee has set the following objectives:
Describe the major advances and the potential new types of biotechnology products likely to emerge over the next 5-10 years.
Describe the existing risk analysis system for biotechnology products including, but perhaps not limited to, risk analyses developed and used by EPA, USDA, and FDA, and describe each agency’s authorities as they pertain to the products of biotechnology.
Determine whether potential future products could pose different types of risks relative to existing products and organisms. Where appropriate, identify areas in which the risks or lack of risks relating to the products of biotechnology are well understood.
Indicate what scientific capabilities, tools, and expertise may be useful to the regulatory agencies to support oversight of potential future products of biotechnology.
The first public meeting of the NAS committee will be held on April 18, 2016. The agenda for the meeting is posted here.
As genetic engineering emerged from laboratories in the 1970’s into the biotechnology industry in the 1980’s, the possibility of government regulation arose, with a central question of whether a drug, for example, produced by genetic engineering rather than conventional chemical synthesis, required a distinct regulatory response. In another version of that same question: did a genetically modified plant require a distinct biotechnology regulatory treatment or could the plant fit into established oversight routes for plants produced through convention breeding techniques? In its most generic form, the debate that began in the 1980's wrestled with whether biotechnology processes produce inherently distinct products that demanded novel regulatory responses. According to the Coordinated Framework for the Regulation of Biotechnology announced by White House Office of Science and Technology Policy (OSTP) in 1986, the answer was generally no; a product or an engineered organism could be evaluated by the traditional agencies and laws that already existed to identify and manage risk. The
coordinated framework thus divided the primary regulation of
biotechnology products among three agencies – the Department of
Agriculture’s Animal and Plant Health Inspection Service (APHIS), the Environmental Protection Agency (EPA), and the Food and Drug
Administration (FDA). That scheme was updated in 1992, and that document continued to be the last word in regulatory design. Now the White House OSTP has announced that it will initiate a modernization of the 1992 policy. In a just-published memorandum to the three federal agencies, the OSTP first provides a definition of “biotechnology products” that will be the targets of the review:
For the purpose of this memo, “biotechnology products” refers to products developed through genetic engineering or the targeted or in vitro manipulation of genetic information of organisms, including plants, animals, and microbes. It also covers some of the products produced by such plants, animals, and microbes or their derived products as determined by existing statutes and regulations. Products such as human drugs and medical devices are not the focus of the activities described in this memo.
In a briefing document on its blog, the OSTP has described the process ahead:
The goal of the effort is to ensure public confidence in the regulatory system and improve the transparency, predictability, coordination, and, ultimately, efficiency of the biotechnology regulatory system. Here is a bit more detail about the effort’s three components:
First, the Administration will update the Coordinated Framework, after public input, by clarifying the current roles and responsibilities of the EPA, USDA, and FDA in the regulatory process. This update will help clarify which biotechnology product areas are within the authority and responsibility of each agency and outline how the agencies work together to regulate products that may fall under the authorities of multiple agencies.
Second, the Administration will develop a long-term strategy, after public input, to ensure that the Federal regulatory system is well-equipped to assess efficiently any risks associated with the future products of biotechnology. This will include performing periodic horizon-scanning of new biotech products, coordinating support for the science that informs regulatory activities, developing tools to assist small businesses as they navigate the regulatory system, and creating user-friendly digital tools for presenting the agencies’ authorities, practices, and basis for decision-making.
Third, the Administration will commission an outside, independent analysis of the future landscape of the products of biotechnology. The Administration has already asked the National Academies of Sciences, Engineering, and Medicine to conduct such an analysis.
A modernized jurisdictional design could address some overlap between the responsible agencies, while also considering newer technologies and their placement into the scheme. For example, new organisms or products from the more recent field of synthetic biology might not fit the traditional category of “genetically engineered” which contemplated a small number of discrete and planned changes into an existing organism. A recent study from the Venter Institute on the regulatory challenges raised by synthetic biology endorsed the basic earlier principle that a product should be evaluated for its own discrete risk profile even when produced through synthetic biology; however, the study notes that specific jurisdictional boundaries between the three federal agencies and specific legal authorities need to be updated to account for an expanding portfolio of genetic engineering modalities that will produce even more novel organisms than the first wave of genetic engineering.
The U.S. Department of Agriculture's Animal and Plant Health Inspection Service (APHIS) has announced this week that it will heighten its regulatory review for the possible introduction of the next wave of herbicide-resistant genetically engineered (GE) crops. Using its authority under the Plant Protection Act, APHIS regulates genetically engineered crops because it has determined that they may pose a risk as plant pests. Companies seeking to introduce a new crop to market file an application for deregulated status with APHIS. In this case, the applications seeking APHIS deregulation are for Dow Chemical’s corn and soybeans genetically engineered for resistance to the herbicide 2,4-D and Monsanto’s cotton and soybeans genetically engineered for resistance to dicamba. In addition to compliance with the Plant Protection Act, APHIS must also comply with the National Environmental Policy Act (NEPA).
Under the National Environmental Policy Act, APHIS is required to evaluate the potential environmental impacts from a "major Federal Action" - that can include the deregulation of new GE plants by the Agency. If APHIS finds that its potential regulatory decision may significantly affect the quality of the human environment, the Agency must prepare an EIS (environmental impact statement) before making a decision on the proposed Federal action.
APHIS had prepared a draft environmental assessment for the crops in the Dow petition. Petitions for deregulation of these crops (which would allow commercial release) had been submitted to APHIS and published for public comments; APHIS noted that significant numbers of comments had been received. APHIS has thus concluded:
With regard to these new herbicide-resistant plants, through its analysis of information submitted by the developers, as well as public comments, APHIS has determined that its regulatory decisions may significantly affect the quality of the human environment. APHIS therefore believes it necessary under NEPA to prepare these two EIS's to further assist the Agency in evaluating any potential environmental impacts before we make a final determination regarding the products' regulatory status.
Several points are worth noting about the APHIS decision and the larger debate over the use of genetically engineered crops (which are largely engineered for agronomic, not dietary purposes). In
contrast to several other proposed deregulations over the last several
years (alfalfa, sugar beets), where APHIS did not conduct an EIS, and
was sued for noncompliance with NEPA, here APHIS is triggering an EIS of
its own accord. The use of genetically engineered glyphosate-resistant crops (most famously, Monsanto Roundup Ready corn, soybeans) since the 1990’s led to extensive litigation over how APHIS managed its NEPA requirements; ultimately, judicial action compelled APHIS to prepare an EIS, and it then deregulated the crops. In the decade or more since the Roundup approach to weed management, glyphosate-resistant weeds have emerged, thus undermining the viability of this strategy for weed containment. Debate continues over whether successive waves of genetic engineering related to designated herbicides will adequately provide effective weed management (one research group describes an “accelerated transgene facilitated herbicide treadmill”). Criticism is also directed at the environmental consequences from the use of the herbicides; litigation against the Environmental Protection Agency attempted to rescind its approval of 2,4-D. However, it is notable that APHIS specifically cabins the focus of the EIS:
While the EIS’s will look more broadly at potential impacts to the environment as a whole, APHIS’ regulatory authority is based on The Plant Protection Act and the Agency’s oversight is specific to evaluating the potential for the GE plants to pose a plant pest risk to crops or other plants.
While technically true, APHIS is also charged by NEPA with an evaluation that considers how a “potential regulatory decision may significantly affect the quality of the human environment.” The decision by APHIS suggests that the agency might have anticipated immediate litigation if it had not prepared an EIS, and due to the delays that previous cases have imposed, may have decided that direct preparation of an EIS was more efficient. That, of course, does not predict the outcome of the EIS. However, it will take place against the backdrop of some of the limitations to genetically engineered weed management that have been revealed by earlier containment strategies.
An update on the litigation involving the genetic contamination of the commercial rice crop in the U.S. by genetically engineered (GE) rice, specifically LibertyLink, produced by Bayer CropSciences. LibertyLink was engineered with a gene that confers herbicide resistance, meaning that weed killers can be used on the field without injury to the crop. The initial complaint alleged the contamination of native rice crops by the GE rice. The harms to rice farmers were numerous, including an immediate export ban imposed by the EU. The multi-district litigation, In re Genetically Modified Rice Litigation, ended in a settlement in which Bayer must pay $750 million; the time frame for farmers to register a claim will end in November; a stipulation of the settlement is that 85% of an identified set of claimants must register for the settlement to take effect. This litigation took several years in federal court, under the jurisdiction of the Eastern District of Missouri. The contamination was discovered in 2006. The Bayer GE rice was classified as a nonregulated crop by the Animal and Plant Inspection Service (APHIS), an agency with the U.S. Department of Agriculture (USDA). APHIS refused to deregulate the crop in 2006, despite calls to do so. By 2007, APHIS confirmed the contamination of the native rice crop by the GE strains. Bayer's corporate predecessor, Aventis Crop Science, was the source of the Starlink contamination of the U.S. corn crop in 2000.
Genetic engineering (GE) in agricultural production has two possible goals: one is to produce a GE food with superior nutritional properties, while the other is to provide an agronomic benefit that improves crop development. The The strategy behind the development of the well-known Bt corn, produced by Monsanto, is agronomic:to create a genetically engineered corn stock which contains a bacterial protein that is toxic to the rootworm; the stock essentially producing an insecticide that avoids the need for topical application of a pesticide to the field. The current U.S. Department of Agriculture (USDA) estimate is that about 65% of the corn planted in the U.S. is Bt corn. A recent research report in PloS One provides the first account of rootworm resistance to the protein, with the consequence that the GE component of the corn is no longer effective. The results, while preliminary and not yet widespread, are a reminder that genetic alterations, whether through breeding or engineering, function against a dynamic backdrop of evolving organisms, which could out maneuver a strategy that relies on the performance of a single protein. Monsanto replies that the use of Bt corn should occur against a backdrop of complementary tactics, such as crop rotation, possible supplementary GE crops, and attention to refuge requirements. Since more GE crops are engineered for agronomic purposes than nutritional advantage, demonstrations of ineffectiveness are sure to draw attention, as the shelf life for the intervention is shortened, but the genetic modifications nonetheless persist in the food supply as biochemical artifacts.
