Hazards of synthetic biology
The hazards of synthetic biology include biosafety hazards to workers and the public, biosecurity hazards stemming from deliberate engineering of organisms to cause harm, and hazards to the environment. The biosafety hazards are similar to those for existing fields of biotechnology, mainly exposure to pathogens and toxic chemicals, although novel synthetic organisms may have novel risks. For biosecurity, there is concern that synthetic or redesigned organisms could theoretically be used for bioterrorism. Potential biosecurity risks include recreating known pathogens from scratch, engineering existing pathogens to be more dangerous, and engineering microbes to produce harmful biochemicals. Lastly, environmental hazards include adverse effects on biodiversity and ecosystem services, including potential changes to land use resulting from agricultural use of synthetic organisms.
In general, existing hazard controls, risk assessment methodologies, and regulations developed for traditional genetically modified organisms (GMOs) are considered to be sufficient for synthetic organisms. "Extrinsic" biocontainment methods in a laboratory context include physical containment through biosafety cabinets and gloveboxes, as well as personal protective equipment. In an agricultural context they include isolation distances and pollen barriers, similar to methods for biocontainment of GMOs. Synthetic organisms might potentially offer increased hazard control because they can be engineered with "intrinsic" biocontainment methods that limit their growth in an uncontained environment, or prevent horizontal gene transfer to natural organisms. Examples of intrinsic biocontainment include auxotrophy, biological kill switches, inability of the organism to replicate or to pass synthetic genes to offspring, and the use of xenobiological organisms using alternative biochemistry, for example using artificial xeno nucleic acids (XNA) instead of DNA.
Existing risk analysis systems for GMOs are generally considered sufficient for synthetic organisms, although there may be difficulties for an organism built "bottom-up" from individual genetic sequences. Synthetic biology generally falls under existing regulations for GMOs and biotechnology in general, and any regulations that exist for downstream commercial products, although there are generally no regulations in any jurisdiction that are specific to synthetic biology.
Synthetic biology is an outgrowth of existing biotechnology methods. It is distinguished by the use of new biological pathways or organisms not found in nature. This contrasts with "traditional" genetically modified organisms created by transferring already existing genes from one cell to another. Synthetic biology also encompasses the re-design of existing genes, cells, or organisms for gene therapy. Novel aspects of synthetic biology include standardized libraries of synthetic biological circuits; the development of minimal cells, artificial protocells, and organisms or pathways based on alternative biochemistry; genome synthesis and editing; and do-it-yourself biology.:5
Industrial synthetic biology has potential commercial applications in energy, chemical and pharmaceuticals production, materials, food, and agriculture, as well as in medical diagnostics and therapeutics. There is a distinction between "contained use" within laboratories and manufacturing facilities, and "intentional release" in the context of medical, veterinary, cosmetic, and agricultural applications.:24 As research procedures scale up to industrial processes, the number and variety of workers exposed to commercial synthetic biology risk is expected to increase.
Biosafety hazards from synthetic biology are similar to those found in existing fields of biotechnology, mainly exposure to pathogens and toxic chemicals used in a laboratory or industrial setting. Hazardous chemicals typically found in laboratory settings include carcinogens, toxins, irritants, corrosives, and sensitizers. Biological hazards include viruses, bacteria, fungi, prions, and biologically-derived toxins, which may be present in body fluids and tissue, cell culture specimens, and laboratory animals. Routes of exposure for chemical and biological hazards include inhalation, ingestion, skin contact, and eye contact. Physical hazards include ergonomic hazards, ionizing and non-ionizing radiation, and noise hazards. Additional safety hazards include burns and cuts from autoclaves, injuries from centrifuges, compressed gas leaks, cold burns from cryogens, electrical hazards, fires, injuries from machinery, and falls.
Novel protocells or xenobiological organisms, as well as gene editing of higher animals, may have novel biosafety hazards, affecting their risk assessment. As of 2018, most laboratory biosafety guidance is based on preventing exposure to existing rather than new pathogens. Exposure to lentiviral vectors derived from the HIV-1 virus is of special interest; they are useful in gene therapy due to their unique ability to infect both dividing and non-dividing cells, but unintentional exposure of workers could lead to cancer and other diseases. In the case of an unintentional exposure, antiretroviral drugs can be used as post-exposure prophylaxis.
Given the overlap between synthetic biology and the do-it-yourself biology movement, concerns have been raised that its practitioners may not abide by risk assessment and biosafety practices required of professionals,:39 although it has been suggested that an informal code of ethics exists that recognizes health risks and other adverse outcomes.:15
Synthetic biology also has biosecurity concerns, as synthetic or redesigned organisms could theoretically be engineered to be used for bioterrorism, which is considered possible but unlikely given the resources needed to perform this kind of research. Synthetic biology could possibly expand the group of people with relevant capabilities, and reduce the amount of time needed to develop them.:2–7
One capability of concern is the recreation of known pathogens from scratch, including use of genome synthesis to recreate historical viruses such as the Spanish Flu or polio virus.:12, 14:2–7 Current technology allows genome synthesis for almost any mammalian virus, the sequences of known human viruses are publicly available, and the procedure has relatively low cost and requires access to basic laboratory equipment. However, the pathogens would have known properties and could be mitigated by standard public health measures, and could be partially prevented by screening of commercially produced DNA molecules. Creating existing bacteria or completely novel pathogens from scratch are not yet possible as of 2018, and are considered a low risk.:39–43, 54–56
Another capability of concern is engineering existing pathogens to be more dangerous. This includes altering the targeted host or tissue, as well as enhancing their replication, virulence, transmissibility, stability, or ability to produce toxins, reactivate from a dormant state, evade natural or vaccine-induced immunity, or evade detection. Bacteria are considered to be a higher risk than viruses because they are easier to manipulate and their genomes are more stable over time.:44–53
A final capability of concern is engineering microbes to produce harmful biochemicals. Metabolic engineering of microorganisms is a well established field that has targeted production of fuels, chemicals, food ingredients, and pharmaceuticals, but it could be used to produce toxins, antimetabolites, controlled substances, explosives, or chemical weapons. This is considered to be a higher risk for naturally occurring substances than for artificial ones.:59–65
There is also the possibility of novel threats that are considered lower risks due to their technical challenges. Delivery of an engineered organism into the human microbiome is also considered a possibility; delivery and persistence in the microbiome are challenges, though an attack would be difficult to detect and mitigate. Pathogens engineered to alter the human immune system by causing immunodeficiency, hyperreactivity, or autoimmunity, or to directly alter the human genome, are also considered lower-risk due to extreme technical challenges.:65–83
Environmental hazards include toxicity to animals and plants, as well as adverse effects on biodiversity and ecosystem services. For example, a toxin engineered into a plant to resist specific insect pests may also affect other invertebrates.:18 Some highly speculative hazards include engineered organisms becoming invasive and outcompeting natural ones, and horizontal gene transfer from engineered to natural organisms. Gene drives to suppress disease vectors may inadvertently affect the target species' fitness and alter ecosystem balance. In addition, synthetic biology could lead to land-use changes, such as non-food synthetic organisms displacing other agricultural uses or wild land. It could also cause products to be produced by non-agricultural means or through large-scale commercial farming, which could economically outcompete small-scale farmers. Finally, there is a risk that conservation methods based on synthetic biology, such as de-extinction, may reduce support for traditional conservation efforts.
Extrinsic biocontainment encompasses physical containment through engineering controls such as biosafety cabinets and gloveboxes, as well as personal protective equipment including gloves, coats, gowns, shoe covers, boots, respirators, face shields, safety glasses, and goggles. In addition, the design of the facility itself may include separation of the laboratory work area from public access, decontamination areas, and specialized ventilation and air treatment systems. These procedures are common to all microbiological laboratories.
In an agricultural context, extrinsic biocontainment methods include maintaining isolation distances and pollen barriers to prevent modified or synthetic organisms from fertilizing wild-type plants, as well as sowing modified and wild-type seed at different times so that their flowering periods do not overlap.
Intrinsic biocontainment is the proactive design of functionalities into organisms and systems to reduce their hazards. It is unique to engineered organisms such as GMOs and synthetic organisms, and is an example of hazard substitution and of prevention through design. Intrinsic biocontainment may have many goals, including controlling growth in the laboratory or after an unintentional release; preventing horizontal gene transfer to natural cells; preventing diversion to use for bioterrorism; or protecting the intellectual property of the organism's designers. There has been concern that existing genetic safeguards are not reliable enough due to the organisms ability to mutate them out. However, they may be useful in combination with other hazard controls, and may provide enhanced protections relative to GMOs.:6, 40–43
There are many approaches that fall under the umbrella of intrinsic biocontainment. Auxotrophy is the inability of an organism to synthesize a particular compound required for its growth, meaning that the organism cannot survive unless the compound is provided to it. A kill switch is a pathway that initiates cell death that is triggered by a signal from humans.:40–43 Inability of the organisms to replicate is another such method.:50
For plants, methods include cytoplasmic male sterility, where viable pollen cannot be produced; and transplastomic plants where modifications are made only to the chloroplast DNA, which is not incorporated into pollen.
For viral vectors, methods include splitting components into multiple plasmids, omitting accessory proteins that are important for a natural virus as a pathogen but not as a vector, and the use of self-inactivating vectors.
It has been speculated that xenobiology, the use of alternative biochemistry that differs from natural DNA and proteins, may enable novel intrinsic biocontainment methods that are not possible with traditional GMOs. This would involve engineering organisms that use artificial xeno nucleic acids (XNA) instead of DNA and RNA, or that have an altered or expanded genetic code.:33–36, 43, 49 These would be theoretically incapable of horizontal gene transfer to natural cells. There is speculation that these methods may have lower failure rates than traditional methods.:33–36, 43, 49
While the hazards of synthetic biology are similar to those of existing biotechnology, there are potential differences in risk assessment procedures given the rapidity with which new components and organisms are generated.:5 Existing risk analysis systems for GMOs are generally considered sufficient for synthetic organisms. However, there may be difficulties in risk assessment for an organism built "bottom-up" from individual genetic sequences whose characteristics are less obvious than traditional GMOs, where genetic sequences from a donor organism with known traits are inserted into a recipient organism.:v, vii Synthetic organisms also may not be included in existing risk groups.:20 An additional challenge is that synthetic biology engages a wide range of disciplines outside of biology who may be less familiar with microbiological risk assessment.:v Workplace health surveillance can be used to enhance risk assessment.
For biosecurity, assessment about the level of concern of a capability includes the ease of use by potential actors; its efficacy as a weapon; practical requirements such as access to expertise and resources; and the capability to prevent, anticipate, and respond to an attack.:2–7 For environmental hazards, risk assessments and field trials of synthetic biology applications are most effective when they include metrics on non-target organisms and ecosystem functions.:18 Some researchers have suggested that traditional life-cycle assessment methods may be insufficient because the industry–environment boundary is blurred, and there is informational content rather than only chemical substances being transferred across it, allowing it to change its amount and properties.
Several treaties contain provisions which apply to synthetic biology. These include the Convention on Biological Diversity, Cartagena Protocol on Biosafety, Nagoya–Kuala Lumpar Supplementary Protocol on Liability, Biological Weapons Convention, and Australia Group Guidelines.
In general, the United States relies on the regulatory frameworks established for chemicals and for pharmaceuticals to regulate synthetic biology, mainly the Toxic Substances Control Act of 1976 as updated by the Frank R. Lautenberg Chemical Safety for the 21st Century Act, and the Federal Food, Drug, and Cosmetic Act.
The biosafety concerns about synthetic biology and its gene-editing tools are similar to the concerns lodged about recombinant DNA technology when it emerged in the mid 1970s. The recommendations of the 1975 Asilomar Conference on Recombinant DNA formed the basis for the U.S. National Institutes of Health (NIH) guidelines, which were updated in 2013 to address organisms and viruses containing synthetic nucleic acid molecules. The NIH Guidelines for Research Involving Recombinant and Synthetic Nucleic Molecules are the most comprehensive resource for synthetic biology safety. Although they are only binding on recipients of NIH funding, other government and private funders sometimes require their use, and they are often voluntarily implemented by others who are not obligated to do so. In addition, the 2010 NIH Screening Framework Guidance for Providers of Synthetic Double-Stranded DNA provides voluntary guidelines for vendors of synthetic DNA to verify the identity and affiliation of buyers, and screen for sequences of concern.
The Occupational Safety and Health Administration (OSHA) regulates the health and safety of workers, including those involved in synthetic biology. In the mid 1980s, OSHA maintained that the general duty clause and existing regulatory standards were sufficient to protect biotechnology workers.
The Environmental Protection Agency, Department of Agriculture Animal and Plant Health Inspection Service, and Food and Drug Administration regulate the commercial production and use of genetically modified organisms. The Department of Commerce Bureau of Industry and Security has authority over dual-use technology, and synthetic biology falls under select agent rules.
In the European Union, synthetic biology is governed by Directives 2001/18/EC on the intentional release of GMOs, and 2009/41/EC on the contained use of genetically modified micro-organisms,:vi as well as Directive 2000/54/EC on biological agents in the workplace. As of 2012, neither the European Community nor any member state had specific legislation on synthetic biology.
In the United Kingdom, the Genetically Modified Organisms (Contained Use) Regulations 2000 and subsequent updates are the main law relevant to synthetic biology.:16 China had not developed synthetic biology specific regulations as of 2012, relying on regulations developed for GMOs. Singapore relies on its Biosafety Guidelines for GMOs, and the Workplace Safety and Health Act.
- Howard, John; Murashov, Vladimir; Schulte, Paul (2017-01-24). "Synthetic Biology and Occupational Risk". NIOSH Science Blog. Retrieved 2018-11-30.
- "Opinion on synthetic biology II: Risk assessment methodologies and safety aspects". EU Directorate-General for Health and Consumers. 2016-02-12. doi:10.2772/63529.
- Bailey, Claire; Metcalf, Heather; Crook, Brian (2012). "Synthetic biology: A review of the technology, and current and future needs from the regulatory framework in Great Britain" (PDF). UK Health and Safety Executive. Retrieved 2018-11-29.
- Howard, John; Murashov, Vladimir; Schulte, Paul (2016-10-18). "Synthetic biology and occupational risk". Journal of Occupational and Environmental Hygiene. 14 (3): 224–236. doi:10.1080/15459624.2016.1237031. ISSN 1545-9624. PMID 27754800.
- "Laboratory Safety Guidance" (PDF). U.S. Occupational Safety and Health Administration. 2011. pp. 9, 15, 21, 24–28. Retrieved 2019-01-17.
- Biodefense in the Age of Synthetic Biology. National Academies of Sciences, Engineering, and Medicine. 2018-06-19. doi:10.17226/24890. ISBN 9780309465182. PMID 30629396.
- Trump, Benjamin D. (2017-11-01). "Synthetic biology regulation and governance: Lessons from TAPIC for the United States, European Union, and Singapore". Health Policy. 121 (11): 1139–1146. doi:10.1016/j.healthpol.2017.07.010. ISSN 0168-8510. PMID 28807332.
- "Future Brief: Synthetic biology and biodiversity". European Commission. September 2016. pp. 14–16. Retrieved 2019-01-14.
- "Final opinion on synthetic biology III: Risks to the environment and biodiversity related to synthetic biology and research priorities in the field of synthetic biology". EU Directorate-General for Health and Food Safety. 2016-04-04. pp. 8, 27. Retrieved 2019-01-14.
- "Biosafety in Microbiological and Biomedical Laboratories, 5th Edition". U.S. Centers for Disease Control and Prevention. 2018-04-20. Section III – Principles of Biosafety. Retrieved 2019-01-07.
- Devos, Yann; Demont, Matty; Dillen, Koen; Reheul, Dirk; Kaiser, Matthias; Sanvido, Olivier (2009-11-11). "Coexistence of Genetically Modified and Non-GM Crops in the European Union: A Review". In Lichtfouse, Eric; Navarrete, Mireille; Debaeke, Philippe; Véronique, Souchere; Alberola, Caroline (eds.). Sustainable Agriculture. Springer Science & Business Media. pp. 210–214. ISBN 9789048126668.
- Seager, Thomas P.; Trump, Benjamin D.; Poinsatte-Jones, Kelsey; Linkov, Igor (2017-06-06). "Why Life Cycle Assessment Does Not Work for Synthetic Biology". Environmental Science & Technology. 51 (11): 5861–5862. doi:10.1021/acs.est.7b01604. ISSN 0013-936X.
- Pei, Lei; Bar‐Yam, Shlomiya; Byers‐Corbin, Jennifer; Casagrande, Rocco; Eichler, Florentine; Lin, Allen; Österreicher, Martin; Regardh, Pernilla C.; Turlington, Ralph D. (2012), "Regulatory Frameworks for Synthetic Biology", Synthetic Biology, John Wiley & Sons, Ltd, pp. 157–226, doi:10.1002/9783527659296.ch5, ISBN 9783527659296