Forty two years ago, in February 1975, the Asilomar Conference on Recombinant DNA [1] established guiding principles for safe conduct of experiments utilizing recombinant DNA technology, which facilitated the creation of a biotechnology industry in the 1980s.

Since then, biotechnology advanced to its second-generation, also called “synthetic biology.” Synthetic biology involves applying the principles of engineering and chemical design to biological systems and includes two closely-related capabilities both of which may have wide utility in commerce and medicine.  1. Parts for Design and Assembly. While the transfer of already existing genes from one cell to another characterized an earlier phase of the field of biotechnology, synthetic biology involves the design, assembly, synthesis, or manufacture of new genomes, biological pathways, devices or organisms not found in nature. These operations are made possible by recent advances in DNA synthesis and DNA sequencing, providing standardized DNA “parts,” modular protein assemblies, and engineering models.  2. Re-Design Existing Genes. A second capability of synthetic biology involves the re-design of existing genes, cells or organisms for the purpose of gene therapy. Modification of existing genes in living animal and human cells is enabled by engineered nucleases such as meganucleases, zinc finger nucleases, transcription activator-like effector-based nucleases, and the CRISPR-Cas system. Progress in this branch of synthetic biology has yielded remarkable therapeutic advances in gene therapy well beyond the achievements of conventional drugs and biologic agents.

Synthetic biology promises tremendous societal benefits in treating human genetic disease. At the same time, synthetic biology has raised concerns about potential biosafety risks to workers and to society in general. The scope of industrial synthetic biology is expected to expand and create  huge commercial market potential for technology investors. For example, the biotechnology (including synthetic biology) sector of the U.S. economy has grown on average greater than 10% each year over the past ten years. Synthetic biology is playing an increasing role in the commercial bioeconomy as providers of biological designs, optimized biological molecules, laboratory suppliers of customer-specified DNA, RNA, enzymes and cell-cloning services, and in drug development. It is an enabling technology which found its uses across a broad range of applications including agricultural biologics, pollution remediation, renewable energy, industrial and specialty chemicals and health care.

Health and Safety Concerns

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 mid-1970s. The Asilomar Conference on Recombinant DNA concluded that (1) containment should be made an essential consideration in the experimental design and (2) the effectiveness of the containment should match the estimated risk as closely as possible [1]. The conference also suggested the use of both extrinsic (e.g. physical containment, good laboratory practices, education and training of laboratory workers) and intrinsic (e.g. nontransmissible and fastidious vectors) safety barriers as risk mitigation tools. These principles of biosafety laid the foundation for the NIH Guidelines for Research involving Recombinant or Synthetic Nucleic Acid Molecules, the primary biosafety guidelines in use today [2]. These quasi-regulatory guidelines were updated in 2013 to address the creation and use of organisms and viruses containing synthetic nucleic acid molecules.

Regulation

On the regulatory side, since the emergence of the biotechnology industry in mid-1980s, the Occupational Safety and Health Administration (OSHA) maintained that the general duty clause, together with a set of existing regulatory occupational safety and health standards, provided an adequate and enforceable basis for protecting biotechnology workers and that no new regulatory standards were necessary [3]. Examples of existing regulatory standards applicable to biotechnology laboratory workers include standards for bloodborne pathogens; toxic and hazardous substances; access to employee exposure and medical records; hazard communication; exposure to toxic chemicals in laboratories; respiratory protection; and safety standards of a general nature.

A recently published paper describes additional steps that could be taken to ensure the safety of workers in the synthetic biology workplace [4]. It calls for (1) enhanced risk governance strategies including health surveillance, (2) proactive risk assessment involving the larger occupational safety and health practice community beyond biosafety research professionals, (3) the application of prevention-through-design principles to new methods of intrinsic and extrinsic biocontainment and a formal study of their effectiveness, (4) specific safety guidance for synthetic biology processes used in advanced manufacturing in the new bioeconomy, (5) attention by occupational medicine professionals to viral vector post-exposure, and (6) greater involvement by U.S. national occupational safety and health research and regulatory agencies in ensuring safe approaches to the development of synthetic biotechnology. The use of synthetic biology in advanced manufacturing requires that occupational safety and health practitioners not currently involved in biosafety research must be educated about risks to workers associated with synthetic biology.

Real-world Example

An illustrative example of risks to workers in the synthetic biology workplace is application of viral vectors for gene therapy in research laboratories and health care settings. Some of the most widely used viral vectors for gene therapy are lentiviral vectors (LVVs). Unintentional exposure of workers to LVVs can result in the transduction of “off-target” cell types, generation of replication-competent lentivirus, and for insertional mutagenesis and the transactivation of neighboring genome sequences which could lead to cancer and other diseases in workers [4]. In order to reduce occupational risks of LVVs, Schlimgen et al. proposed a three-pronged approach last year [5]. First, Institutional Biosafety Committees should provide the support, guidance and training to principal investigators about potential risks and benefits of treating clinically relevant exposure incidents. Second, occupational health providers and laboratory personnel should weigh risks to determine individual’s preference for post- exposure prophylaxis. Third, information about LVV-exposed individuals should be collected to evaluate the long-term risks associated with lentiviruses [5].

The Asilomar conference on the safety of the first generation biotechnology laid the foundation for the proactive approach to risk mitigation of emerging technologies. NIOSH adopted this approach to workplace safety. It refined and applied this approach to other emerging technologies including nanotechnology [6] and collaborative robotics [7]. Now with the arrival of synthetic biology, NIOSH, as the sole U.S. government agency dedicated to conducting research on occupational safety and health, is well poised to lead efforts aimed at ensuring the safety of synthetic biology in the workplace. We would like to invite readers’ comments on the sorts of issues that they want NIOSH to examine in the area of synthetic biology and occupational health and safety.

John Howard, MD, Director, National Institute for Occupational Safety and Health

Vladimir Murashov, PhD, Senior Scientist, NIOSH Office of the Director

Paul Schulte, PhD, Director, Education and Information Division

References:

1. Berg, P., D. Baltimore, S. Brenner, R.O. Roblin III, and M.F. Singer: Summary statement of the Asilomar Conference on Recombinant DNA Molecules. PNAS 72(6):1981-1984 (1975).
2. National Institutes of Health (NIH): “NIH Guidelines for Research involving Recombinant or Synthetic Nucleic Acid Molecules.” U.S. Department of Health and Human Services, NIH Office of Science Policy, November, 2016. Available at http://osp.od.nih.gov/sites/default/files/NIH_Guidelines.html.
3. Office of Science Technology and Policy (OSTP): Coordinated Framework for Regulation of Biotechnology. Executive Office of the President, June 26, 1986. Available at http://www.aphis.usda.gov/brs/fedregister/coordinated_framework.pdf.
4. Howard, J., V. Murashov, and P. Schulte: Synthetic Biology and Occupational Risk. J. Occ. Env. Hyg. 14(3):224-236 (2017). DOI: 10.1080/15459624.2016.1237031.
5. Schlimgen, R., et al.: Risks Associated with Lentiviral Vector Exposure and Prevention Strategies. J. Occ. Env. Med. 58(12): 1159-1166 (2016).
6. Murashov, V., J. Howard: Essential features for proactive risk management. Nature Nanotech. 4:467-470 (2009).
7. Murashov, V., F. Hearl., J. Howard: Working Safely with Robot Workers: Recommendations for the New Workplace. J. Occ. Env. Hyg. 13(3):D61-D71, DOI: 10.1080/15459624.2015.1116700 (2016).