This week, the National Science Advisory Board for Biosecurity (NSABB) returned to its ongoing deliberation over the scope and form of oversight of gain of function (GOF) research on viruses and other pathogens. Since a moratorium on federal funding was declared in 2014, the NSABB has been working on establishing guidelines both for funding and oversight of this specific research area. The concerns over GOF research are that experiments could produce particularly dangerous pathogens which pose public health risks (see earlier post for background). In this review, the NSABB actually focused its attention on a subset of GOF research, defined as Gain of Function Research of Concern (GOFROC):
[T]he working group identified the attributes of GOFROC, which is research that could generate a pathogen that is: 1) highly transmissible and likely capable of wide and uncontrollable spread in human populations; and 2) highly virulent and likely to cause significant morbidity and/or mortality in humans.
In its public meeting this week, the NSABB adopted recommendations from a report by its own internal working group; they are as follows (underlined for emphasis):
1: Research proposals involving GOF research of concern entail significant potential risks and should receive an additional, multidisciplinary review, prior to determining whether they are acceptable for funding. If funded, such projects should be subject to ongoing oversight at the Federal and institutional level.
2: An external advisory body that is designed for transparency and public engagement should be utilized as part of the U.S. government’s ongoing evaluation of oversight policies for GOF research of concern.
3: The U.S. government should pursue an adaptive policy approach to help ensure that oversight remains commensurate with the risks associated with the GOF research of concern.
4: In general, oversight mechanisms for GOF research of concern should be incorporated into existing policy frameworks when possible.
5: The U.S. government should consider ways to ensure that all GOF research of concern conducted within the U.S. or by U.S. companies be subject to oversight, regardless of funding source.
6: The U.S. government should undertake broad efforts to strengthen laboratory biosafety and biosecurity and, as part of these efforts, seek to raise awareness about the specific issues associated with GOF research of concern.
7: The U.S. government should engage the international community in a dialogue about the oversight and responsible conduct of GOF research of concern.
This completes the current NSABB review of federal policies pertaining to GOF/GOFROC research. However, the report does recommend an ongoing institutional apparatus to review policies, not individual experiments. It also recommends that privately-funded experiments involving GOFROC receive additional oversight, although that could require Congressional action. Finally, against a backdrop of reported safety lapses at federal laboratories (see here and here), the NSABB locates improved biosafety and biosecurity measures as an equally important concern in establishing how GOFROC can be managed.
The National Academies of Sciences, Engineering and Medicine (NAS) have released a report on the safety and impact of genetically engineered (GE) crops: Genetically Engineered Crops: Experiences and Prospects. This was an extensive evaluation by a committee comprised of academic experts to consider health and/or environmental effects of GE crops (note that the term "genetically modified organism/GMO" is used widely as well). As the authors described the scope of the report:
The committee examined almost 900 research and other publications on the development, use, and effects of genetically engineered characteristics in maize (corn), soybean, and cotton, which account for almost all commercial GE crops to date.
Here is a summary conclusion from the report:
[T]he study committee found no substantiated evidence of a difference in risks to human health between current commercially available genetically engineered (GE) crops and conventionally bred crops, nor did it find conclusive cause-and-effect evidence of environmental problems from the GE crops.
The committee noted that the majority of GE crops in commercial use are engineered to carry just a few additional genetic traits:
The committee used evidence accumulated over the past two decades to assess purported negative effects and purported benefits of current commercial GE crops. Since the 1980s, biologists have used genetic engineering to produce particular characteristics in plants such as longer shelf life for fruit, higher vitamin content, and resistance to diseases. However, the only genetically engineered characteristics that have been put into widespread commercial use are those that allow a crop to withstand the application of a herbicide or to be toxic to insect pests.
The fact that only two characteristics have been widely used is one of the reasons the committee avoided sweeping, generalized statements about the benefits and risks of GE crops. Claims about the effects of existing GE crops often assume that those effects would apply to the genetic engineering process generally, but different characteristics are likely to have different effects. A genetically engineered characteristic that alters the nutritional content of a crop, for example, is unlikely to have the same environmental or economic effects as a characteristic for herbicide resistance.
There is a reiteration of the basic U.S. regulatory paradigm, which focuses on the nature of a GE product, rather than a process-based approach:
All technologies for improving plant genetics – whether GE or conventional -- can change foods in ways that could raise safety issues, the committee’s report notes. It is the product and not the process that should be regulated, the new report says, a point that has also been made in previous Academies reports.
In determining whether a new plant variety should be subject to safety testing, regulators should focus on the extent to which the novel characteristics of the plant variety (both intended and unintended) are likely to pose a risk to human health or the environment, the extent of uncertainty about the severity of potential harm, and the potential for human exposure – regardless of whether the plant was developed using genetic-engineering or conventional-breeding processes. ” –omics” technologies will be critical in enabling these regulatory approaches.
The United States’ current policy on new plant varieties is in theory a “product” based policy, but USDA and EPA determine which plants to regulate at least partially based on the process by which they are developed. But a process-based approach is becoming less and less technically defensible as the old approaches to genetic engineering become less novel and as emerging processes — such as genome editing and synthetic biology — fail to fit current regulatory categories of genetic engineering.
On the contentious issue of labeling food derived from GE crops (see here), the committee did not find a compelling scientific basis to require labeling, but noted that there are other considerations:
[T]he issue involves social and economic choices that go beyond technical assessments of health or environmental safety; ultimately, it involves value choices that technical assessments alone cannot answer.
The report therefore endorses the existing product-based framework, but coupled with a nuanced determination of what products should receive enhanced oversight. Critically, the report notes a fact which is not widely appreciated, which is that GE crops largely contain only two added traits: insect or herbicide resistance. Both of these characteristics serve agronomic ends, in contrast to alteration of product attributes, such as nutritional enhancement. As a result, the NAS committee notes that other GE traits could be introduced and require specific regulatory focus. This could be especially true when the goal of a GE alteration is a deliberate change in food composition. Finally, and not insignificantly, the committee finds that GE crops, on balance, have not led to increased yields, and notes the development of resistance in both insects and weeds. These latter conclusions will feature prominently as the cost/benefit calculus for the use of GE crops continues to be debated.
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.
In the ongoing outbreak of Zika virus infection across parts of North and South America, there are several developments which signal increasing concern over the exact impact and geographic reach of the virus (the first death in the U.S. linked to the virus has been reported). At least 55 countries report Zika outbreaks, according to the World Health Organization. The virus is spread by mosquitos, specifically the Aedes aegypti. In the U.S., 426 cases of Zika-infected individuals have been reported. Although a course of infection may be mild and easily resolved in most individuals, Zika has become a high-profile infectious disease because viral infection in pregnant women has been linked to an increased risk of microcephaly in offspring. There are suspicions that more developmental risks to the child of an infected mother may exist, possibly unknown and only seen as development unfolds. In general, the mosquito thrives in warm and tropical climates, but seasonal weather patterns can shift the field of exposure. NASA scientists and other colleagues have published an Aedes aegypti risk map of the U.S., showing that a wide swath of the eastern U.S. is potentially susceptible to mosquito (and thus virus) spread, especially in the upcoming summer of 2016; the potential spread goes north as far as New York City. A commercially available test for detection of the Zika virus received an Emergency Use Authorization (EUA) from the FDA (the Quest Diagnostics Zika RT-PCR test). A current legislative battle over possible increased funding for public health responses to Zika reached a stalemate before Congress adjourned. One bill calls for $1.6 billion in supplemental funding for dedicated Zika virus research and public health capabilities, but is encountering Republican opposition. Some of the political infighting over a federal response to the Zika outbreak recalls earlier conflicts during the Ebola virus crisis. However, the Zika virus is already in the U.S., cases are officially documented, and the upcoming summer portends more infections, not less. The 2016 Summer Olympics in Brazil this summer have already caused concern among attending athletes; the current understanding of transmission suggests that Zika virus cases in the U.S. are largely explained by travel to countries with high risk of infection; that fact will also impact the Olympics participation. No effective treatment or vaccine for the Zika virus is yet developed; increased NIH funding would certainly allow research to expand. Another target for intervention is to reduce the Aedes aegypti mosquito population; already, a British biotechnology has produced a genetically engineered (GE) mosquito that is reproductively crippled and is hoping to conduct trials in the U.S. An upcoming post will examine that option in more detail.
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.
