In 2016, a white button mushroom caused quite a stir. Designed to resist browning, it was the first CRISPR-Cas9 gene-edited product to skirt the U.S. Department of Agriculture’s regulation. The creators of the mushroom did not purposely try to evade the system, though. At the time, the USDA was only required to regulate genetically engineered products that contained foreign DNA. Since this instance of gene editing only involved mutations in the mushroom’s own genome, it was outside the USDA’s authority and was granted permission to proceed without further oversight.
In fact, since 2010, more than 35 gene-edited products have been submitted to the USDA inquiry process and deemed exempt from regulation. For each product and new technical advancement, like the CRISPR-Cas9 technique, an inquiry was necessary because there were no clear rules in the legal text guiding the treatment of gene-edited products. (Despite all the fanfare, the mushroom is currently not available for purchase, but the first gene-edited food product, a soybean oil, did enter the U.S. market in 2019.)
The case of the white button mushroom exemplifies the importance of definitions in regulating cutting-edge technologies. If the scope of a legal definition is not simultaneously specific enough to be meaningful and broad enough to recognize the potential for innovation, confusion will arise when new technologies are ready to enter the market. A Scientific American article about the mushroom explained, “With that regulatory door even slightly ajar, companies are racing to get gene-edited crops into the fields and, ultimately, into the food supply. … To companies, this suggests that U.S. authorities view the new techniques as fundamentally distinct from transgenic methods; to critics, it suggests a regulatory loophole that companies are exploiting.”
Policymakers had known for years that the U.S. regulation of crop biotechnology was out of date, and by 2016, discussions were already underway to revamp the legal texts. But changes weren’t made early enough to avoid the mushroom situation. The USDA has since updated its regulation in great detail to effectively handle gene editing. But unfortunately, the United States remains ill-equipped to make decisions about certain classes of emerging crop biotechnologies before they hit the market. If legal definitions of agricultural biotechnology don’t keep up with these advances, we will repeatedly encounter regulatory ambiguity that delays assessment of valuable technology and degrades public trust.
Historically, most crop improvement has relied upon changes to plant DNA sequences in order to confer desirable traits. In conventional breeding, this process involves crossing different plants together, combining their genetic diversity to discover a new variety that may have characteristics like sweeter fruit or higher yields. Other techniques integrate a gene from an unrelated organism into the DNA of a crop plant. Even the gene-edited mushroom was produced by researchers inducing precise DNA mutations—at heart, still a pretty traditional approach, despite the high-tech method. However, new technologies may be able to generate novel crop characteristics without altering the DNA code at all.
Genes are considered the building blocks of life, storing all the information necessary to make an organism. But DNA alone isn’t the whole story. The DNA code is managed by multiple mechanisms that ensure that the right genes are turned on at the right time, in the right tissue, and at the right magnitude. These mechanisms are essential to the proper functioning of the plant. For example, it makes sense that genes controlling proper root formation would need to be turned on in the root, but not in the leaves or flowers.
In nature, plants display vast variation in gene expression, even among individuals growing in the same field or forest with the exact same DNA. Sometimes, gene expression adaptations are driven by environmental stresses like lack of water or nutrients. As a result, identical plants exposed to contrasting climatic conditions are likely to display several differences in gene expression. The altered expression can be transient, but it can also be heritable and contribute to evolutionary change. Since it is not only what is directly encoded in the sequence of the gene but also the level to which it is expressed that causes specific characteristics, targeting gene expression is a growing part of plant biotechnology development. These new methods unlock more variation in a plant than targeting the genome alone and may hold some of the answers to developing complex and valuable crop traits such as tolerance of drought or extreme heat.
For example, consider spray-induced gene silencing, or SIGS. Gene silencing is a phenomenon that already exists naturally in plants as a way of maintaining proper gene expression levels and fighting off disease. When DNA is read, an intermediate messenger molecule is created that transports a copy of the genetic code to the protein factories of the cell. The gene silencing process operates via an RNA-guided protein complex that destroys the messenger before it has fulfilled its function. The prevention of protein assembly means the target gene’s product has been disrupted without mutating the DNA code.
The SIGS method uses carefully designed RNA that is literally sprayed onto plants. It diffuses into the plant’s cells, where the plant’s silencing mechanisms use the sprayed RNA as the guide to destroy the messenger derived from the target gene. No external DNA is ever incorporated. None of the plant’s gene sequences is touched. The induced changes would likely not be inherited by future generations.
So far, most SIGS development has focused on using the technology as a biopesticide by targeting genes of pests or pathogens. But there is also ongoing work applying SIGS to control gene expression in crop plants, and a U.S. patent has already been filed to do so. A benefit of SIGS is the temporal aspect of the treatment, meaning that the target gene could be silenced at a selected time in a plant’s life cycle. For example, it might be desirable to keep a certain gene “on” during early development to ensure healthy growth, and then SIGS could turn the gene “off” as the plant matures. This would not be possible if the DNA of the gene had been changed. Potential targets could include genes involved in traits like disease resistance or flowering time.
Plant gene expression in nature can also be regulated by molecular factors that bind or interact with DNA, signaling to the cell’s machinery whether the gene should be read. Researchers have developed systems that allow precise direction of proteins known to be activators or repressors of gene expression to specific DNA sequences, changing the expression level of the gene target. Due to ongoing advancement of delivering these systems to plants via protein complexes, nanoparticles, and virus vectors, it is probable that these new technologies will soon not require any DNA sequence modification steps at any point in the process. The effects of some of these applications may be heritable.
It would be logical to assume that these technologies would be covered by the texts governing “biotechnology,” since they harness biological systems to create a product, even if they don’t change DNA code. However, current legal definitions fail to capture these methods, leaving innovators without sufficient clarity to guide decision-making and consumers without the transparency needed to maintain public trust.
In the most recent update to the U.S. Coordinated Framework for the Regulation of Biotechnology (2017), “biotechnology products” are defined as “products developed through genetic engineering or the targeted or in vitro manipulation of genetic information of organisms, including plants, animals, and microbes.” Throughout the 2017 update, the terms “biotechnology” and “genetic engineering,” or GE, seem to be used almost interchangeably. This conflation of terms creates the first point of confusion. The stated scope of “biotechnology” encompasses more than genetic engineering alone. Yet all of the “hypothetical cases” of future biotechnology applications included in the 2017 update are discussed as “GE” and are examples of DNA sequence modification.
In 2020, the USDA legally redefined “genetic engineering” as “techniques that use recombinant, synthesized, or amplified nucleic acids to modify or create a genome.” As regulators constructed the new definition, they specifically considered including changes to gene expression but firmly decided against it, confirming that the DNA sequence of an organism must be modified in order to be considered genetically engineered. That means SIGS and other targeted gene expression systems that alter a plant’s characteristics, but not the genome, do not fall under the legal definition of “genetic engineering.”
The second point of confusion concerns the latter half of the definition of biotechnology: “targeted or in vitro manipulation of genetic information.” What exactly constitutes “manipulation”? What if access to and expression of genes are altered, but the information encoded in the genes remains untouched? Even if “genetic information” is broadly interpreted as all material that is inherited by future generations and not limited to only DNA, what about expression changes that are not heritable and only exist in directly treated plants? Such uncertainty is troublesome.
While it is important for decision-makers to consider risks and trade-offs, we have no reason to be concerned about these new technologies. Rather, they hold much promise for helping to address the challenges facing agriculture, from adapting to the harsh effects of climate change to resisting crop-threatening diseases. But allowing these technologies to slip through the cracks leaves many questions and does not live up to the framework’s goal of ensuring “public confidence in the regulatory system.”
We need to stop conflating all biotechnology with genetic engineering. When policymakers, popular media, and sometimes even scientists use terms like “biotechnology,” “bioengineering,” “genetic engineering,” “gene editing,” and “GMO” interchangeably, it isn’t just frustrating. It is inaccurate. As we have seen, the way “biotechnology” and “genetic engineering” are basically used as synonyms in the U.S. Coordinated Framework overlooks emerging gene expression techniques that do not modify DNA sequence. Many agricultural biotechnologies have absolutely nothing to do with gene sequence or even gene expression, like targeted protein degradation methods that are already in commercial development.
Differentiating between biotechnology techniques in our policy definitions may seem tedious, but it is important for all stakeholders involved. For industry, definitions are necessary for clarity in what regulatory expectations and costs will be for a new product. And for the consumer, policies that are up to date with cutting-edge innovation can diminish fears that regulatory loopholes are being abused (as was suggested for gene editing before the regulation was updated). Therefore, precision in our terminology is important for structuring transparent policy, fostering successful innovation, and promoting meaningful public discourse.
We also must ensure that the scopes of definitions encompass the possibilities posed by emerging biotechnologies, regardless of the degree to which they will or will not be regulated. It is impossible to see infinitely into the future of scientific innovation. But when a technology has been clearly established in the development pipeline, it is necessary to swiftly examine existing definitions to ensure regulatory procedures remain relevant for the new advance. Multiple methods of gene editing had already been in use long before the white button mushroom hit the headlines, yet guidelines were still horribly outdated. Targeted gene expression technologies were on the radar and even described in detail by the National Academies years before they were omitted from the 2020 USDA updates.
It is indeed justifiable to separate gene expression–based technologies from the definition of “genetic engineering” because they do not change DNA sequence. But then, scientific government agencies like the USDA should create new terms that describe the types of advancements we are witnessing in the pipeline instead of simply ignoring them until market pressures inevitably force a regulatory decision. As we saw with the button mushroom, no matter how beneficial certain uses of a technology may be, legal ambiguity leads to worries about corporate opportunism, skepticism about new discoveries, and distrust in regulatory bodies. At a time when faith in government institutions and support for science are frequently questioned, we cannot accept lack of clarity and foresight in our legal documents that govern innovation.