Institute for Food Laws and Regulations

Scott Haskell teaches the online course “Animal Health, World Trade, and Food Safety” each fall semester, and "The Law of the Preventive Controls for Human Food Rule" each spring semester.

The latest adventure in food enhancement is CRISPR (e.g., clustered regularly interspaced short palindromic repeats/Cas9) gene-editing technology. It potentially has many major implications for enhanced global agriculture and much needed improvements in food security. CRISPR and gene editing tools simultaneously represents an extensive legal and regulatory challenge and additionally, a monumental scientific opportunity for the global food industry. With the development of genome editing technologies, the possibility of directly targeting and subsequently modifying genomic sequences in plants is intriguing. Genome editing can extend our ability to develop an extraordinary potential in applied biotechnology and its effects on increased world food production.

An important concept to the understanding of CRISPR/Cas came from scientific observations that the prokaryote repeat cluster (a family of DNA sequences found in the genomes of prokaryotic organisms such as bacteria and archaea) was incorporated into a set of homologous genes (having the same relation/structure or relative position) that make up CRISPR-associated systems or Cas genes. The Cas proteins show nuclease and helicase motifs (a linkage that is found in a great many other DNA processing enzymes) which suggests an important role of the CRISPR loci. The development of programmable nucleases (e.g., clustered regularly interspaced short palindromic repeat (CRISPR)–Cas-associated nucleases, zinc-finger nucleases (ZFNs), and transcription activator-like effector nucleases (TALENs)) has expedited the ability to improve the field of gene editing and subsequently potentially improve food production. CRISPR/Cas gene editing technology can potentially increase plant/crop yields and quality, plant drought resistance, herbicide and insecticide resistance, improved food safety and security, enhance the removal of antibiotic resistance (AMR), improve product shelf life and it can potentially accelerate the process of plant domestication. 

The field of biotechnology, in combination with a more supportive governmental regulatory environment, could mean that CRISPR/Cas could radically change global agriculture as well as food law and international regulations. So how about CRISPR vs. GMO (genetically modified organisms)? The process involved in the production of GMO crops/plants generally involves the insertion of DNA from another cell, especially bacterium into the plant to be modified. However, to produce CRISPR/Cas crops, scientists can insert or edit single nucleotides (nucleotides form the basic structural unit of nucleic acids such as DNA) from the crop’s own genome. Scientifically, CRISPR/Cas nucleotide changes are hard to detect due to this self-insertion without the incorporation of outside materials. CRISPR/Cas gene editing technology additionally allows important plant genetic manipulation of crop species, which then can potentially produce more sustainable species and higher yield crops.  

So how do we create a legal/regulatory environment that is more supportive of CRISPR/Cas development?  The U.S. Secretary of Agriculture Sonny Perdue issued a statement in 2018 clarifying the U.S. Department of Agriculture’s (USDA) oversight of plants produced through ‘innovative new breeding techniques’ which include genome editing. 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.” (USDA/APHIS)

“Plant breeding innovation holds enormous promise for helping protect crops against drought and diseases while increasing nutritional value and eliminating allergens,” Perdue said. “Using this science, farmers can continue to meet consumer expectations for healthful, affordable food produced in a manner that consumes fewer natural resources. This new innovation will help farmers do what we aspire to do at USDA: do right and feed everyone.”

The USDA is one of three federal agencies (along with the Environmental Protection Agency (EPA) and the Food and Drug Administration (FDA)) which regulate products of food and agricultural technology. They have developed a Coordinated Framework for the Regulation of Biotechnology that will ensure CRISPR/Cas products are safe for human consumption and the environment. The USDA/APHIS (Animal Plant Health Inspection Service) have evaluated gene technology transfer and agrees that deletions, small insertions, and combinations of deletions and insertions are all possible outcomes resulting from the cellular mechanisms used to repair DNA breaks that occur naturally or that are induced during conventional plant breeding and all have been used in conventional plant breeding. The regulatory exemption in § 340.1(b)(1) has been revised to reflect the possible outcomes of natural DNA repair mechanisms that occur in the absence of a deliberately provided repair template. Published in the Federal Register (84 FR 26514-26541, Docket No. APHIS-2018-0034) as a proposal to amend these regulations. The June 2019 proposed rule and the final rule are consistent with the President's “Executive Order on Modernizing the Regulatory Framework for Agricultural Biotechnology Products” (June 11, 2019, Executive Order 13874). Executive order 13874 directs the Federal Government “to adopt regulatory approaches for the products of agricultural biotechnology that are proportionate to the risks such products pose, and that avoid arbitrary or unjustifiable distinctions across like products developed through different technologies.” Among other things, Executive Order 13874 states that “regulatory decisions should be science- and evidence-based, taking economic factors into account as appropriate and consistent with applicable law; that regulatory reviews should be conducted in a timely and efficient manner; and that biotechnology regulations should be transparent, predictable, and consistent.” The U.S. Animal Plant Health Inspection Service (APHIS) of the United States Department of Agriculture (USDA) administers the regulations in 7 CFR part 340, “Introduction of Organisms and Products Altered or Produced Through Genetic Engineering Which are Plant Pests or Which There is Reason to Believe are Plant Pests”. These regulations govern the introduction (importation, interstate movement, or release into the environment) of certain genetically engineered (GE) organisms.” (USDA)

The exemptions in § 340.1(b)(1) through (3) are based on three principles:

1. Plants created through conventional breeding have a history of safe use related to plant pest risk;
2. The types of plants that qualify for these exemptions can also be created through conventional breeding; and
3. There is no evidence that use of recombinant deoxyribonucleic acid (DNA) or genome editing techniques necessarily and in and of itself introduces plant pest risk, irrespective of the technique employed. (USDA)

The legal and procedural differences regarding genome edited organisms and CRISPR within the EU are specified in additional European GMO policies. In a recent legal judgment by the European Court of Justice (ECJ) of 25 July 2018, C-528/16: https://curia.europa.eu/jcms/upload/docs/application/pdf/2018-07/cp180111en.pdf), “organisms obtained by techniques of genome editing are GMOs and subject to the same obligations as transgenic organisms. Uncertainties emerge if genome edited organisms cannot be distinguished from organisms bred by conventional techniques, such as crossing or random mutagenesis. In this case, identical organisms can be subject to either GMO law or exempt from regulation because of the use of a technique that cannot be identified. Only an amendment to the regulations that govern the process of authorization for GMO release can substantially lower the burden for innovators. In a second step, any way forward has to aim at amending, supplementing or replacing the European GMO Directive (2001/18/EC).” (Wasmer 2019) Many members of the European plant breeding establishment have voiced their opposition to C-528/16. Their argument maintains “crops obtained by mutagenesis are GMOs and are, in principle, subject to the obligations laid down by the GMO Directive.” http://curia.europa.eu/juris/document/document.jsf?text=&docid=204387&pageIndex=0&doclang=EN&mode=req&dir=&occ=first&part=1&cid=765750

As a global community we struggle to provide food security to the current world population of seven billion people. Challenges are many but include increased demand for agricultural productivity, nutritional diversity, environmental factors and degradation, yield gaps, market access and pre- and post-harvest losses. Agricultural scientists must overcome these challenges to feed the global future. Lassoued et al determined: “A key finding is that genome edited crops pose marginal risk to the economy, human health and the environment. Yet, regulations governing biotechnology and some advocacy groups tend to discourage the use of new gene technologies in agriculture. In effect, discussions concerning the risks associated with genome editing, and targeted breeding techniques generally, are driven more by socio-political factors than by scientific principles.” (Lassoued et al. 2019)

Comprehensive CRISPR/Cas ‘off-target analysis on a genome-wide scale’ has been evaluated for human consumption safety in maize, tomatoes and rice. Scientists have measured the frequency of ‘off-target mutations’ in CRISPR/Cas expressing lines and their progeny. Studies have determined that the rate of ‘off-target mutation’ was well below the level of background mutation induced during normal seed amplification or tissue culture. (Lassoued et al. 2019) But what about product acceptance? Shew et al “conducted a multi-country assessment of consumers’ willingness-to-consume (WTC) and willingness-to-pay (WTP) for CRISPR-produced food in relation to conventional and genetically modified (GM) foods, respectively. In the USA, Canada, Belgium, France, and Australia, 56, 47, 46, 30, and 51% of respondents, respectively, indicated they would consume both GM and CRISPR food.” They also found “that biotechnology familiarity and perceptions of safety were the primary drivers for WTC CRISPR and GM food. Moreover, respondents valued CRISPR and GM food similarly – substantially less than conventional food – which could be detrimental for meeting future food demand.” (Shew et al. 2018)

How many countries have mandatory GMO labeling? Currently, 64 nations globally require labeling of genetically modified foods. Status of development, regulation and adoption of GM agriculture in Africa is important. The utilization of GM crop technology is helping to reduce food security issues and improve poverty levels in Africa but continues to generate consumer consumption issues over its benefits and safety. Only four countries, South Africa, Sudan, Burkina Faso and Egypt have commercialized GM crops in Africa. The status of development, regulation and adoption of GM agriculture in Asia is also under scrutiny and controversy. The use of GM crop technology in Asia continues to generate debates over its benefits and safety. India enforces its GM labeling laws on some products but not others. China requires labeling on nearly all GM products. As for GM agriculture in Latin America, continued scrutiny and doubt is common. Mixed messages are country specific: Brazil and Bolivia have mandatory labeling requirements on GM products. Mexico and Argentina have no current labeling requirements in place.

The need for government and public/private collaborations to invest in agricultural biotechnology-based companies is essential for continued CRISPR/Cas progress. Clear legal initiatives are required to support private industry. Research and development with governmental partnerships are important in order to enhance the gene revolution and its potential benefits globally.

Perception drivers of public acceptance are important factors even after governments potentially approve the science. Recent scientific and legal studies have elucidated CRISPRs potential benefits to global food security, but consumer preference is lacking. Public acceptance and subsequent valuation of the final product will determine if CRISPR/Cas technology can feed the masses of an ever-growing world. Transparency and an open forum are essential component drivers of success.

Disclaimer.

References

APHIS: Movement of Certain Genetically Engineered Organisms https://www.federalregister.gov/documents/2020/05/18/2020-10638/movement-of-certain-genetically-engineered-organisms

Wolt, J and Wolt, C (2018) Policy and Governance Perspectives for Regulation of Genome Edited Crops in the United States Front Plant Sci. 2018; 9: 1606. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236124/

Shew, A et al, (2018) CRISPR versus GMOs: Public acceptance and valuation. Global Food Security Volume 19. Pages 71-80 https://www.sciencedirect.com/science/article/pii/S2211912418300877

Wasmer, Martin (2019) Roads Forward for European GMO Policy-Uncertainties in Wake of ECJ Judgment Have to be Mitigated by Regulatory Reform. Front Bioeng Biotechnol 2019 Jun 5;7:132. https://pubmed.ncbi.nlm.nih.gov/31231643/  

Lassoued, R. et al (2019) Risk and safety considerations of genome edited crops: Expert opinion Current Research in Biotechnology, Volume 1, November 2019, Pages 11-21 https://www.sciencedirect.com/science/article/pii/S2590262819300024

Hickey, L. T. et al. Breeding crops to feed 10 billion. Nat. Biotechnol. 37, 744–754 (2019). https://pubmed.ncbi.nlm.nih.gov/31209375/

Yuan-Yuan, T. et al. (2020) Gene editing: an instrument for practical application of gene biology to plant breeding J Zhejiang Univ Sci B 2020 Jun;21(6):460-473. https://pubmed.ncbi.nlm.nih.gov/32478492/

Chengdao, L (2020) Breeding crops by design for future agriculture J Zhejiang Univ Sci B 2020 Jun;21(6):423-425. https://pubmed.ncbi.nlm.nih.gov/32478489/

Klerkx, L and Rose, D (2020) Dealing with the game-changing technologies of Agriculture 4.0: How do we manage diversity and responsibility in food system transition pathways? Global Food Security Volume 24, March 2020, 100347  https://www.sciencedirect.com/science/article/pii/S2211912419301804

Zhang, C., Wohlhueter, R., Zhang, H (2016) Genetically modified foods: A critical review of their promise and problems Food Science and Human Wellness Volume 5, Issue 3, September 2016, Pages 116-123 https://www.sciencedirect.com/science/article/pii/S2213453016300295

Florian Hahn, F and Nekrasov, V (2019) CRISPR/Cas precision: do we need to worry about off-targeting in plants? Plant Cell Reports (2019) 38:437–441 https://doi.org/10.1007/s00299-018-2355-9