This proposal was developed to foster discussion about the state of synthetic biology regulations in the United States. More specifically, this proposal discusses the regulation of biological containment devices that are exposed to ecological settings. This issue of biocontainment as a possible means to reduce barriers to implementation is under-discussed and relatively unknown: over one-third of the respondents in the iGEM team survey, which we administered, were not aware of biocontainment. This proposal represents an attempt to standardize the regulations of biocontainment methods and the measures of success across regulatory agencies in the United States.
Revisions to this document were informed by discussions with experts in the field. These experts include Dr. Jessica Tucker from the NIH, Deputy Commissioner Charles Green from Virginia’s Department of Agriculture and Consumer Services, and Branch Chief Alan Pearson from APHIS. Please see our Interviews page for more details on these conversations. We have submitted the document as a public comment on the FDA Notice: Clarifying Current Roles and Responsibilities Described in the Coordinated Framework for the Regulation of Biotechnology. This proposal represents the amalgam of several iterations after feedback from different stakeholders and advisors. However, it is by no means a final draft, and we welcome any and all feedback. Please contact us to respond to this proposal!
This proposal describes rules and regulations regarding the testing, application, monitoring, and termination of biological containment devices. As new applications emerge, it will become essential to have regulation regarding biological containment devices in place to facilitate the smooth and safe introduction of novel technologies. For the purpose of these guidelines, a biological containment device refers to a biological system that utilizes cellular frameworks to establish control over an organism and where it can survive in an environmental setting. Biological containment devices will henceforth be referred to as devices.
No current regulation exists for devices in synthetic biology systems in ecological settings. While devices are not yet regulated, synthetically modified organisms are incompletely regulated, largely by the US Environmental Protection Agency (EPA), the US Department of Agriculture’s Animal and Plant Health Inspection Service (USDA/APHIS) and the US Food and Drug Administration (FDA). Among these agencies, different authorities regulate the development and the deployment of synthetically modified organisms, which presents a challenge in selecting one agency to regulate biological containment devices.refReference:
Shlomiya Bar-Yam, Jennifer Byers-Corbin, Rocco Casagrande, Florentine Eichler, Allen Lin, Martin Oesterreicher, Pernilla Regardh, R. Donald Turlington, and Kenneth A. Oye (2012). The Regulation of Synthetic Biology (SynBERC). We suggest to expand the authority of one of these agencies to encompass the regulation of devices.
The NIH, in its 2016 Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, hereinafter referred to as the NIH Guidelines, describes the guidelines for laboratory research involving synthetic genetic material.refReference:
Department of Health and Human Services (2016). NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (National Institute of Health). In contrast, there are three primary regulatory agencies for synthetic biology products: the EPA, USDA/APHIS and the FDA. A 2014 report on Synthetic Biology and the US Biotechnology Regulatory System by the J. Craig Venter Institute cites that these agencies have an adequate level of authority to address most, but not all, environmental, health and safety concerns with regard to synthetic biology.refReference:
Sarah R. Carter, Ph.D., Michael Rodemeyer, J.D., Michele S. Garfinkel, Ph.D., and Robert M. Friedman, Ph.D. (2014). Synthetic Biology and the US Biotechnology Regulatory System: Challenges and Option (J. Craig Venter Institute). Because APHIS’ authority extends over engineered plants and the FDA’s authority extends over foods and drugs, the EPA is the most appropriate of these three agencies to make regulatory decisions based on risks posed by genetically modified microbes to health and safety of humans, animals and ecosystems. This proposal goes beyond the current scope of the EPA, but if adopted, could enhance the current regulatory model.
In this document, all references to the agency adopting these recommendations are marked in italics.
A developer must include the following items with every device submission:
Submission of devices is allowed at the beginning of each calendar year. After a device is submitted to the agency, it will undergo a series of confirmatory tests to determine its potential success and application.
Initial Testing of a Device
Initial testing will include an escapee propagation assay wherein the system using the device is grown within a standard laboratory environment. As prompted by the containment boundaries of the device, the rate of cell death will be recorded and used to demonstrate the viability of the device. If the device fails to prevent escapees, it will be terminated and the developer will be notified. If the device prevents escapees, it will continue to GPM testing.
A verification test will check the validity of the GPM. The agency will test the GPM by applying mutagenic stressors to the system to simulate mutagenic drift. For example, in bacteria, a fluctuation test in reference to the agent conferring containment will be conducted. Gene sequencing will be performed on multiple surviving units. Comparison between the sequences and the residues of interest in the GPM will confirm or refute the GPM documentation.
The GPM Threshold will be established by the agency and will serve as a comparative model for future tests. It will serve as an indicator of device failure prior to inactivation of the device. For example: if a device has three residues that, when all mutated, deactivate the biological containment mechanism, we recommend that the GPM Threshold is set at two out of three mutations. Devices that have two critical mutations will be terminated. This measure ensures that the device is still functioning when terminated and prevents escapees. A device’s GPM Threshold will be determined on an individual basis.
Upon GPM verification, the device proceeds to primary rating tests.
Rating a Device
A device’s rating is split into three categories: Revertant Susceptibility, Environmental Applicability, and Chassis Applicability. Once a device has been tested and rated, it will be listed on a centralized online catalog run by the agency. This catalog will include all necessary information about a device including the implementation and termination protocols, the GPM and GPM Threshold, and ratings. Each device’s information will be collected in a concise document, similar to the commonly used Materials Safety Data Sheet (MSDS).
Rating: Revertant Susceptibility
The Revertant Susceptibility rating measures the security of a GPM Threshold and designates the level of post-application monitoring a device will receive.
This rating is split into two classes:
- The Class A rating is granted to devices that are unlikely to develop revertants, and are less likely to require termination. Class A devices are best used in low turnover applications. One possible application that would suit this classification is a plot of genetically engineered crops. This Class receives low level post-application monitoring.
- The Class B rating is granted to devices that have a significant revertant likelihood and are therefore more likely to require termination. Class B devices are best used in high turnover applications where a population will be refreshed and recycled in quick succession. One possible application that would suit this classification is a microbial approach to oil spill remediation. This Class receives a high level of post-application monitoring.
For example, the device mentioned in the Initial Testing section that requires three mutations to deactivate would be a Class B device and require frequent monitoring. In contrast, a device requiring one hundred mutations would be a Class A device and require less monitoring. The agency will be responsible for quantifying the distinction between Class A and Class B designations.
Rating: Environmental Applicability
The Environmental Applicability rating is based on the developer’s environmental selection and subsequent verification testing. The verification testing is performed under specified environmental conditions which vary depending on the recommended class. Devices will be judged upon two criteria: cellular escapee propagation within specified environmental conditions; and genetic escapee propagation, which is measured by comparing genetic material from the chassis in testing to the GPM Threshold. The device fails if it does not prevent escapees or if mutation levels exceed the GPM Threshold. Passing these tests awards a specific class designation to a device. Devices can acquire multiple class designations, but each class must be individually tested for.
The possible classes are as follows:
- Tropical Rainforest
- Shallow ocean
- Deep ocean water
- Deep ocean surface
Note: If implemented, a similar policy would require details about the migratory capability, pH, humidity, temperature range, UV exposure, native species, and other properties of each environment.
Rating: Chassis Applicability
The Chassis Applicability rating serves to designate possible chassis in which the device can be used. Verification testing is performed on the device in the chassis recommended by the developer’s data. For each chassis, the device is subjected to verification testing. Measurements will be taken in terms of both escapee propagation and the GPM, as described for the Environmental Applicability rating.
All tested chassis will be clearly labeled in a device’s Chassis Applicability class designation.
Acquiring a Device
Organizations adhering to correct procedures can acquire any device from the catalog that matches their intended chassis and ecological setting. An organization must apply to receive the device. The application must address the need for a device: any system that has been approved to interact with an ecological setting by the appropriate agency will be acceptable. The application must also demonstrate that the intended use of the device matches the rating of the requested device.
Implementing a Device
Information regarding escapee propagation data as well as proper protocols for use in rated organisms will be made available in the catalog. Research organizations will have access to the pertinent information for their device, including the implementation and termination protocols, the GPM, and the ratings. In order for an organization to be authorized to release an organism, they must follow protocols for correct implementation of the device. A sample of the secured organism will be sent to the agency for verification tests consisting of escapee propagation and GPM tests. If the tests pass, the device is ready for use by that organization. If the device fails the tests, the organization cannot implement the device.
Prior to implementation, the agency will ensure that no two devices sharing a biological containment-conferring agent will be within a radius that risks cross-contamination. This radius will be determined based on the organisms used.
Monitoring a Device
The agency will monitor activity in the following ways:
- If the device falls under a Class A Revertant Susceptibility rating, it is subjected to a low level of monitoring. Samples of the organisms will be taken on an annual basis and subjected to GPM tests. If the organism fails the GPM tests, the product will be flagged for termination and will follow the same protocol as a Class B organism.
- If the device falls under a Class B Revertant Susceptibility rating, it is subjected to a high level of monitoring. Samples of the organism will be taken three times per year and subjected to GPM tests. Should the GPM test fail, the product will be flagged for termination. The organization using the contained organisms will be responsible for the termination of all contained organisms.
Only the device itself will be regulated by the agency. All other aspects of the organism and its use will be monitored by the appropriate agencies. Any product, including modified plants, animals, and microbes that will be used as a drug, that will produce a drug, that will be added to food and is not generally recognized as safe, that will be used as or will produce a dietary supplement, or that will be used as or will produce a cosmetic should be regulated by the FDA. Any gene inserted into an animal that will be used for any purpose or any modified organism that will be used as a food is also regulated by the FDA. Any product, including modified plants, animals, and microbes that is a plant pest, uses a plant pest in its creation, or incorporates a pest’s DNA should be regulated by USDA-APHIS. Any product, including modified plants, animals, and microbes that will be used as a pesticide or any intergeneric microorganism that will be used for any commercial purpose not listed should be regulated by the EPA.refReference:
Sarah R. Carter, Ph.D., Michael Rodemeyer, J.D., Michele S. Garfinkel, Ph.D., and Robert M. Friedman, Ph.D. (2014). Synthetic Biology and the US Biotechnology Regulatory System: Challenges and Option (J. Craig Venter Institute).
Terminating a Device
Devices that fail routine monitoring will be terminated. Methods of termination of a protected organism depend on the device used. Information regarding termination methods will be available in the device catalog. Organizations must begin termination immediately at the time of notification. Verification tests will be conducted on a time frame consistent with the expected rate of death of the device. The verification test will be an analysis of sampled terrain from the controlled area for the presence of escaped organisms. Should no undesired organisms be detected, the termination is considered complete. Should undesired organisms be detected, extreme termination measures such as chemical destruction of the affected region must be taken to eliminate escaped organisms. The extent and range of this process depends on the concentration of escaped organisms found in the sample.
Note that additional extermination methods are not expected to be necessary if the previously stated guidelines are adhered to. The GPM test is designed to fail before escape is possible, resulting in termination while the device is still functional.
Penalties of Misuse
This section deals with potential misuse of devices and the related penalties associated with misuse. This section does not cover misuse of organisms or any technology that is using the device. Misuse of this type falls under the jurisdiction of the agencies stated in the Monitoring a Device section. If another agency has standing regulations regarding the organism using the device, said regulation will take precedence over regulations stated here.
If an organization is found guilty of a Misuse below, the following Penalties will be incurred. See the next section for a description of each Penalty.
|Misrepresentation of Data or Test Results||Will receive a monetary fine and an external review. If this Misuse is found by reviewers to be intentional, the organization will be permanently banned from agency services. If the reviewers find that organism escape occurred because of this Misuse, the organization will be charged triple damages and the offending party will be reported to the FBI for criminal charges.|
|Infrastructural Oversights Resulting in Organism Escape||Will receive a monetary fine, an external review, and a warning. This Misuse will immediately result in a report to the FBI for criminal charges. Devices in use will be terminated and can only be re-implemented according to reviewers’ recommendations. Should the Misuse occur a second time the organization will be issued a ban on the specific organism.|
|Release of Protected Organism into an Untested or Uncertified Area||Will receive a monetary fine, external review, and devices in use will be terminated. A second instance of this Misuse will result in a permanent ban and triple damages. If the release is found to be intentional, the organization will be issued triple damages, banned from agency services, and the offending party will be reported to the FBI for criminal charges.|
|Integration of a Device into a Non-Certified Organism||Will receive a monetary fine. The organization must immediately terminate the organism. If the organism has been released into any area the organization will also receive a Release of protected organism into untested or uncertified area Misuse and if standard termination is unsuccessful the organization will pay triple damages and receive an external review.|
|Withholding Information from the Regulatory Agency Services||Will receive an external review.|
|Failure to Cooperate with Expected Deadlines of Termination||Will receive a monetary fine and external review. Should this Misuse result in organism escape, the organization will be subject to all appropriate penalties associated with the Infrastructural oversights resulting in organism escape Misuse and the organization will be permanently banned.|
|Tampering or Modification of existing Devices Without Agreement with Agency||Will receive a monetary fine and a warning. A second offense of this Misuse will result in an organism-specific ban.|
|External Review||The organization must expend costs for a representative from the regulatory agency to evaluate the misuse of the device and determine what penalties are required. The organization will be temporarily banned from agency services and must terminate all active devices for the duration of the external review.|
|Monetary Fine||As determined by the agency representative, the organization must pay a fine whose amount depends on the severity of misuse.|
|Triple Damages||An organization must pay for termination, extra extermination, and triple damages for costs related to ecological damage.|
|Ban of a Specific Organism||An organization is barred from acquiring any devices for use in a specific organism and must terminate any active instances of said organism.|
|Permanent Ban from Agency Services||An organization is barred from acquiring any devices in the future and must terminate any currently active devices. Any individual considered an active participant in the Misuse, including the head of the organization, will be blacklisted from services in all future work. Any organizations formed from blacklisted individuals will be immediately banned.|
|Report to the FBI||An official criminal report will be issued to the FBI’s Bioterrorism Risk Assessment Group in accordance with all established protocol.|