THIRD WORLD NETWORK BIOSAFETY INFORMATION SERVICE
Dear Friends and Colleagues
Serious Lack of Regulatory Oversight Over Releases of Nucleic Acids and Proteins into the Environment
New technologies allow nucleic acids (DNA, RNA) and proteins to be delivered to cells, tissues and organisms in the open environment. These ‘penetration technologies’ allow nucleic acids such as double-stranded RNA (dsRNA) and proteins such as gene editing nucleases to be used at ecosystem levels as biocides. The technologies also allow ecosystem level trait modification that may be heritable.
Biological-molecule-based products are being developed for use in medicine, agriculture and food production or preservation, comprising topical chemical or physical agents. Topically applied products use nucleic acids and/or proteins wherein the active biological is transferred by contact, ingestion or inhalation. The first open environment use of penetration biotechnologies at scale is expected to be the use of dsRNA in agriculture, for the control of crop pests.
However, commercial and non-commercial formulations may cause intended, unintended, or malicious releases of biologically active nucleic acids and proteins. Biological actives may evade risk assessment and regulatory review because they are often excluded from the category of hazardous chemicals and are actively being excluded as agents of genetic modification. A recently published paper warns that this emerging gap in oversight could lead to either dual use appropriation or unintended harm to human health or the environment.
With best wishes,
Third World Network
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10400 Penang
Malaysia
Email: twn@twnetwork.org
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ENVIRONMENTALLY APPLIED NUCLEIC ACIDS AND PROTEINS FOR PURPOSES OF ENGINEERING CHANGES TO GENES AND OTHER GENETIC MATERIAL
by Heinemann, J. A., & Walker, S.
Biosafety andHealth
https://doi.org/10.1016/j.bsheal.2019.09.003
14 Oct 2019
https://www.sciencedirect.com/science/article/pii/S2590053619300266
[EXCERPTS BELOW]
Highlights
• New technologies allow DNA, RNA and proteins to be delivered to cells, tissues and organisms in the open environment.
• These penetration technologies allow nucleic acids such as double-stranded RNA and proteins such as gene editing nucleases to be used at ecosystem levels as biocides.
• The technologies also allow ecosystem level trait modification that may be heritable.
• Commercial and non-commercial formulations may be used to cause intended, unintended, or malicious releases of biologically active nucleic acids and proteins.
• Regulation of penetration technologies is ad hoc or absent.
Abstract
In this article we summarize the development of vehicles for penetrating living cells, tissue and organisms with nucleic acids (DNA and RNA) and proteins that damage or repair DNA. The purpose in doing so is to provide an assessment of the potential for these technologies to unintentionally cause harm to human health or the environment or to be re-tasked with an intention to cause harm. Two new types of biological-molecule-based products are being developed for use in medicine, agriculture and food production or preservation. The first type are genetically modified organisms, such as those that express bio-pesticides. They produce molecules and that are difficult to alter at scale after release. Products of this type are usually evaluated by both food and environmental regulators. The second type comprises topical chemical or physical agents. Most of these are in pre-commercial testing phase. Topically applied products use nucleic acids and/or proteins wherein the active biological is transferred by contact, ingestion or inhalation. From a survey of the research and patent literature we suggest that chemical formulations and physical manipulations that can be used to ferry nucleic acid and protein cargo into cells, tissues or organisms could be assembled de novo or repurposed from existing commercial products and loaded with proteins and/or nucleic acids designed using publicly available genome sequences. Biological actives may evade risk assessment and regulatory review because they are often excluded from the category of hazardous chemicals and are actively being excluded as agents of genetic modification. This emerging gap in oversight could lead to either dual use appropriation or unintended harm to human health or the environment.
Discussion
The use of biological active ingredients in the open environment has obvious potential to improve pest management in agriculture, reduce food wastage and decrease the toxicity of both urban and rural exposures to pesticides including those used on household pets. Their use in cosmetics and skin protection products is yet to be fully tested, but also could provide benefits to consumers. Benefits, however, are not the opposite of hazards and do not negate them. Therefore it is important to separate the discussion of promised benefits from a strict evaluation of potential hazards as part of a risk assessment.
We have gathered together reports of methods and apparati being developed to penetrate cells, tissues or organisms with nucleic acids and/or proteins. This effort was done because there is a general lack of familiarity with developments in biotechnology intended to introduce biological molecules into living organisms in situand at environmentally relevant scales. Some outcomes of the use of these methods and apparati will result in organisms containing altered genes or other genetic material which may sometimes be heritable and could lead to populations of modified organisms (Heinemann 2019).
These biotechnology techniques are beginning to be discussed at both the national and international levels by regulators (Heinemann 2019; Singh et al. 2019). For recent reviews of national and international discussions, see Singh et al. (2019), Heinemann (2019) and Eckerstorfer et al. (2019b). The techniques have the potential to cause harm to human health or the environment but may not be regulated in some countries because of disagreements over whether the molecules used create genetically modified organisms. While definitions are important for regulation, we think it is also important to recognize that the spectrum of risks created through the use of these techniques significantly overlaps with those created through the release of genetically modified organisms or highly potent chemical and radiation mutagens.
The plausability of using genetic modification as a platform for bioterrorism or biocrime was reviewed recently by Mueller (2019). She concentrated on novel biologicals that are produced by genetically modified plants, including novel dsRNA molecules. We expand the analysis to vehicles other than living genetically modified organisms.
The first open environment use of penetration biotechnologies at scale is expected to be the use of dsRNA in agriculture, for the control of crop pests. When used as a pesticide, the active ingredient must be able to adhere to or be ingested or inhaled into a target pest, remain stable in the environment, transfer into the cells of the pest, and be taken up at biologically relevant concentrations. These attributes are not demonstrated by pure nucleic acids and are therefore bestowed by the delivery agents, either viruses or chemical formulations, or chemical modifications of nucleotides. Pesticides are designed for both broad-area mechanized delivery from vehicles such as tractors and airplanes and by portable sprayers and syringes. In short, they have the characteristics necessary for dual use or biocrime.
A risk assessment would consider intended and unintended adverse effects to target and non-target organisms in the places of dissemination of commercial products. Another important consideration for the risk assessment is how the active ingredients were made or purified (Heinemann 2019) and how resistant the product is to contamination or tampering.
We predict that the greatest contribution to uncertainty in the risk assessment will come from an incomplete picture of the non-target animals (including insects), plants, bacteria and fungal organisms in the environment that may be exposed. Loss of beneficial species over time may have critical effects on treated ecosystems that are hard to detect in short time periods. Because the technologies are guided to target nucleic acid sequences, at least a reliable metagenomic mapping might be required. As discussed above, bioinformatics tools have not so far been validated as accurate predictors of off-target effects, so even metagenomic profiles may not be sufficient to address all biosafety concerns.
The lifecycle of active ingredients may also complicate risk assessment. There is debate about the stability of the active ingredients in various environments. New studies suggest that dsRNA persistance in some environments may be underestimated because of its ability to adsorb to soil particles (Parker et al. 2019). Regardless of historic measures of stability, chemical modifications of nucleic acids and proteins applied to these active ingredients in the future may significantly alter there stability in many different environments.
Based on the scalability and potential to re-task or create non-commerical vehicles and combine them with biological active ingredients, a risk assessment should also consider malicious, criminal and military uses of methods and apparati, particularly those that may be widely available as commercial products in the future. The chemical formulations and some of the mechanical methods for penetrating organisms with biological active ingredients are sufficiently simple and accessible that re-tasking products by substitution of different nucleic acids or proteins is prime facie plausible.