Frequently Asked Questions
Synthetic nucleic acids are chemically or enzymatically manufactured polymers of nucleotides, which encode genetic information. These are distinct from naturally occurring nucleic acids, which can be isolated directly from an organism. The ability to make nucleic acids, based on a genetic sequence, allows a researcher to request custom nucleic acid sequences from a provider who will synthesize the order and ship it to the researcher, or to directly synthesize these genetic elements in their own laboratory using benchtop nucleic acid synthesis equipment.
The chemical synthesis of nucleic acids potentially allows for the generation or modification of pathogens or toxins. More specifically, nucleic acid synthesis could allow the de novo production of dangerous biological materials without the need to obtain them from natural sources or through networks of legitimate researchers and could also allow those with malintent to introduce new pathogenic or toxic traits to otherwise benign microorganisms.
Also, the latest technological advancements have made the conversion of different types of nucleic acids increasingly easy, which necessitated expansion of this new guidance to include both single and double-stranded form of both RNA and DNA. In addition, assembling long synthetic genes from shorter nucleic acids has become easier, prompting a recommendation to screen nucleic acids shorter than 50 nucleotides in length to identify orders whose components have appropriate sequences and overlaps that would allow them to be assembled into larger sequences of concern.
Many synthetic nucleic acid providers and manufacturers of benchtop nucleic acid synthesis equipment are eager for the U.S. government to provide them with guidance regarding best practices in mitigating emerging biosecurity risks.
The U.S. government, the synthetic biology industry, and the scientific community recognize that there are concerns that synthetic nucleic acid sequences not unique to Biological Select Agents or Toxins or Commerce Control List items also pose a biosecurity concern. The open availability of genetic sequence data poses concerns, that individuals with ill intent could exploit biotechnology for harmful purposes. The U.S. government has acted to reduce dangers to human, animal, and plant health due to biological pathogens and toxins on the select agents and toxins list and Commerce Control List. However, these regulated pathogens and toxins do not represent the entirety of the potential risks to public health, agriculture, plants, animals, or the environment that could arise from the misuse of synthetic nucleic acids. Non-regulated pathogens and toxins as well as other novel types of sequences may also pose significant risks if they are misused. The guidance seeks to more fully encompass the risks associated with synthetic nucleic acids by including all sequences that contribute to pathogenicity or toxicity in the definition of sequences of concern.
Benchtop nucleic acid synthesis equipment is sold by manufacturers and is intended to be used to synthesize nucleic acids for use within a research laboratory or within an institution. While this nucleic acid synthesis equipment may not be small enough to be placed on a benchtop (e.g., it sits on the laboratory floor), it is still considered benchtop equipment if it is sold with the intent that it will be used by researchers individually or in a core facility in an institution.
No, this document does not establish new regulations. Adherence is voluntary. The document recommends baseline standards for the gene and genome synthesis industry, other providers of synthetic nucleic acid products, the manufacturers of benchtop nucleic acid synthesis equipment, and individuals and institutions who receive, use, and transfer these materials regarding the screening of orders for certain sequences of concern and verifying the legitimacy of recipients. Some specific recommendations serve to remind providers of their obligations under existing regulations, but no new regulations are imposed.
The U.S. government does not currently have the authority to regulate the sale, use, or transfer of most synthetic nucleic acids or benchtop nucleic acid synthesis equipment. We support taking a voluntary approach to screening for sequences of concern in these orders, and both the commercial nucleic acid synthesis and benchtop synthesizer industries have acted responsibly in voluntarily taking many of the steps recommended in the guidance as well as in providing the U.S. government valuable feedback during the review and revision of this guidance.
Regulations already cover some types of orders of synthetic nucleic acids. The U.S. Department of Health and Human Services and the U.S. Department of Agriculture, under the Federal Select Agent Program, regulate nucleic acids that can produce infectious forms of select agent viruses or the active forms of select agent toxins. Orders of synthetic nucleic acids that fall into either of those categories must be stored, used, and transferred in compliance with existing regulations.
Individuals with no legitimate, bona fide, and peaceful need should be prevented from accessing genetic materials that could contribute to pathogenicity or harm, even when they are not from Federal Select Agent Program (FSAP) or Commerce Control List pathogens or toxins. Information that would allow those transferring those materials to authenticate the recipient of materials or equipment as a legitimate member of the scientific community is critical to ensuring that sequences of concern are handled responsibly. Information such as proposed end-use of the order, institutional or corporate affiliation (if applicable), the name of a biosafety officer (if available), documentation of internal review and approval of the research, evidence provided by the recipient's Responsible Official that the recipient is registered with FSAP or Statement by Ultimate Consignee and Purchaser (i.e., a completed BIS-711 form) (if applicable), or other evidence of a legitimate research or training program (e.g., publication history, researcher persistent identifiers such as Open Researcher and Contributor Identifier [ORCID], business licenses, grant numbers, research plan) or other legitimate use (e.g., diagnostic test development or manufacture) may be helpful for such verification.
The guidance recommends recording transfers of nucleic acids containing sequences of concern from customers to any other individuals not listed in the original order, such as through a Material Transfer Agreement (MTA) or another sample tracking process. The guidance also recommends that records of SOCs and their transfers are retained for at least three years. Business practices already in place at institutions may be used to fulfill this recommendation.
The U.S. government has consulted with representatives of synthetic nucleic acid providers and manufacturers of benchtop nucleic acid synthesis equipment to understand their current practices and help ensure that these recommendations will not cause undue burden. The vast majority of synthetic these companies are already conducting similar sequence and customer screening.
Because major synthetic nucleic acid providers and manufacturers of benchtop nucleic acid synthesis equipment already conduct similar screening, the implementation of the recommendations in Screening Framework Guidance for Providers and Users of Synthetic Nucleic Acids is unlikely to add an additional burden to those companies.
Customers are best positioned to understand the nature of their synthetic nucleic acids and oversee and shepherd their responsible use. Customers are encouraged to streamline the screening of their synthetic nucleic acid orders by providing verification of their legitimacy to providers, if they know that their order contains SOCs. Since they may also transfer these synthetic nucleic acids to other end users – such as colleagues – certain recommendations are made for this case in the guidance.
Since scientists, or other customers, may also transfer these synthetic nucleic acids or benchtop nucleic acid synthesis equipment to other end users – such as colleagues – certain recommendations are made for these cases in the guidance.
In developing Screening Framework Guidance for Providers and Users of Synthetic Nucleic Acids, the U.S. government consulted with representatives of synthetic nucleic acid providers and of manufacturers of benchtop nucleic acid synthesis equipment to understand their current practices. While there may be some differences in screening details between the U.S. government approach and that of individual providers or manufacturers, the overarching recommendations and intent are fairly consistent among industry and the U.S. government.
The screening approach strikes a balance between mitigating biosecurity risks and minimizing any negative impacts on the conduct of research or business operations. A goal in developing the guidance was to ensure it would be feasible for small and large providers, as well as international providers. The guidance provides an acceptable baseline.
These recommendations were developed to align with existing protocols and business practices, to be implemented without unnecessary cost, and to minimize any negative impacts on the conduct of research and business operations. Where practical to do so, entities should use existing business practices to verify the legitimacy of customers and colleagues to track the transfer of materials containing SOCs.
Finally, the guidance acknowledges that the ongoing development of best practices by providers in this area is commendable and encouraged.
Manufacturers of benchtop synthesis equipment are encouraged to consider several areas for developing best practices in this context: customer screening to ensure that the user has a legitimate purpose for obtaining nucleic acid synthesis equipment; implementing mechanisms to track continuously the legitimacy of users of their equipment, including when it is potentially transferred to new users during the lifecycle of these equipment; and, providing the capability into their nucleic acid synthesizers to screen for sequences of concern and verify the legitimacy of users. Manufacturers are also encouraged to include a data logging function to maintain a record of the oligos synthesized on the equipment.
Institutions should aim to ensure, as soon as it is possible to do so, that benchtop nucleic acid synthesizers – including those that were acquired prior to this guidance – are only accessed by users with a legitimate need, such as through validated user accounts. If this equipment is housed in a core facility for an institution, or in other cases when the equipment is being operated by an authorized user on the behalf of another individual, then the institution should aim to ensure that the legitimacy of the individual receiving any synthetic nucleic acids containing SOCs from the authorized user or core facility is also verified.