In the preceding entry of the blog, I discussed how the regulatory programs of the U.S. Environmental Protection Agency and U.S Department of Agriculture might affect the use of genetically modified algae for biofuel uses. It would appear that the EPA Biotechnology Rule under the Toxic Substances Control Act (TSCA) was more likely to be applicable than the USDA’s biotechnology rules under the Plant Protection Act. But I’ll briefly comment on how algal programs might be handled under each of these programs, and discuss the need to develop a common understanding between regulators and the industry about how these regulations would affect companies developing modified algae for biofuel production and other uses.
Possible Requirements under EPA Regulations
As is described in more detail elsewhere in this blog, under the TSCA Biotech Rule, EPA regulates certain industrial uses of “new microorganisms”, which are defined as those that contain coding nucleic acids from more than one taxonomic genus. Although most R&D uses are exempt from reporting under TSCA provided the microorganism is used in a “contained facility”, the use of a new microorganism for a commercial purpose (in an industrial field subject to TSCA) would require the filing of a Microbial Commercial Activity Notification (MCAN) 90 days before the intended commencement of commercial use. (Please refer to that earlier blog entry for a great deal more detail on this regulatory program).
It is likely that any regulatory review of engineered algae would be subject to the same data and procedural requirements as has been the case for modified bacteria that have so far been subject to TSCA regulation. Specifically, this would include the need to submit a detailed description of the construction of the modified organism, a description of the manufacturing process in which it is intended to be used, description of the controls that would be put into place to minimize possible dissemination of the microbe outside the facility, and whatever data is in the applicant’s possession regarding the possible health or environmental effects of the organism. EPA’s review would focus on balancing the potential risks of the project against the potential benefits, and although one wouldn’t expect most algal strains to pose unusual environmental risks, the issues EPA addresses may be different for algae than they have been for the modified bacteria and fungi that have been the subject of all prior MCANs submitted to date.
For any algae projects subject to EPA authority under these rules, one potential area of concern would be the design of the bioreactors to be used with the algae. In current practice, algae are often grown in open-air reactors, or in other reactor designs that may differ considerably from traditional bacterial fermentation set-ups. If a reactor was judged by EPA not to be sufficiently “contained” as defined in the regulations, EPA would consider any use of such reactor with live algae to be an outdoor use, triggering the need for regulatory oversight (e.g. requiring submission of a TSCA Environmental Release Application) at the research level and possibly a greater level of scrutiny at commercial scale. Aside from such possible heightened concerns about issues like containment, controlled access to the facility, handling and inactivation of spent biomass and other wastes, one could expect that EPA review and handling of an MCAN for an engineered algae under the TSCA regulations would proceed in much the same way as prior reviews of MCANs for engineered bacteria. With proper planning, advance consultation with the Agency, and given sufficient time to develop the needed data package, algae projects that might fall subject to TSCA should not encounter too much difficulty in being cleared for commercialization.
Possible Requirements under USDA Regulations
USDA’s regulation of genetically engineered plants and agricultural microorganisms has been described in detail elsewhere in this blog. Although the great majority of engineered organisms regulated under this rule have been transgenic plants, the current version of the rule is broad enough to cover microorganisms (particularly agricultural microorganisms) that might be plant pests, depending on their genetic make-up and other characteristics. As discussed in the entry preceding this one, it is possible (although somewhat remotely) that certain biofuel algae strains may fall under these regulations, particularly if they contained nucleic acid sequences from a plant pest, or even from the commonly-used Agrobacterium tumefaciens transformation system.
There does not appear to ever have been any formal submissions to USDA for permits for interstate movement or field testing of any genetically modified algae strain. It would therefore be hard to speculate what approach USDA might take to define a class of algae that it would consider to be subject to the biotech regulations, although for any projects that might fall under these regulations, one would expect USDA to consider the same sorts of issues and require the same sorts of data as has been the case for those few modified microorganisms that have historically been subject to these regulations. Specifically, that would likely include the requirement to submit information describing the construction of the organism, and assessing the possibility that the engineered organism might have plant pest characteristics or other potential environmental impacts. However, it may turn out that USDA may determine that biofuel applications of genetically engineered algae are outside their core agricultural mission and so the agency may well decline to assert its regulations over such applications.
Impact of Biotechnology Regulations on the Use of Modified Algae for Biofuel Production
It is quite important for any uncertainty about the regulatory path for modified algae to be cleared up, so that companies developing such organisms can understand the path to regulatory approval and clearance for commercialization, and so that the general public can be assured that such uses are subject to proper, scientifically-sound, regulation. In fact, this is an issue that has recently been targeted by the Technical Standards Committee of the Algal Biomass Organization (ABO), in the draft of one of its Technical Standards Descriptions. The Committee notes the divisiveness that has often arisen over proposals for uses of GMOs, and hopes that standardization of regulatory requirements can go a long way towards preventing that from occurring in the future. The Committee hopes to develop standards for regulatory review of different categories of modified algae based on the genetic engineering method used in their creation (e.g. differentiating strains in which a single or a small number of exogenous genes are expressed from strains created by directed evolution or synthetic biology), and to develop a predictable, standardized “roadmap” for permitting and regulatory approval of projects involving modified algae. For example, the Technical Standards Descriptions talks of developing “the set of rules for operating each class of engineered organism in lab settings, outdoor pilot plants, and scaled up farm facilities” and “developing a permitting roadmap to encourage uniform, reasonable and affordable permitting processes to be developed in every national and international permitting jurisdiction that is pertinent to algal farming”.
These goals are laudable, and arguably critical for the ultimate success of the algal biofuel industry. In fact, such roadmaps have emerged for applications such as agricultural biotechnology that have used more traditional microbial or plant hosts, and the experience that industry and governments have gained with those prior biotechnology efforts should go a long way towards seeing a favorable outcome for algae as well. For example, it would be very useful to develop and articulate the universal principles that could define safe, commercially appropriate procedures for the large-scale growth of industrial algal strains, with the goal of having these principles implemented and adopted across regulatory programs in the U.S. and internationally. Although such principles could reach across various aspects of the R&D and production process, they might be most valuable in specifying what hardware, procedures, and other safeguards could be put in place to ensure that novel algal strains could be grown under conditions to minimize or prevent both contamination from outside algal species as well as release of the production strain from the facility, in a manner that would satisfy existing regulatory requirements for “containment”. As noted above, I expect this will be a major point of discussion companies will face with regulatory agencies for commercial use of GMO algae strains.
However, it may be somewhat unreasonable to hope that one could separately define different categories of organism based on the technology used to create the genetic modification, as ABO’s Technical Committee hopes, so that the different categories might be regulated differently. This would certainly be difficult in the U.S., where the definitions specifying which organisms fall under the regulations and which are not covered have been fixed in regulation or legislation for many years. In fact, a cornerstone of the early years of policy development of biotech regulations in the U.S. (approx. 1983 to 1991) was that regulations should not be “process based” (i.e. based on the method used for the genetic modification), but that the level of regulatory oversight be determined by the inherent potential risks of the organism regardless of the method by which it was constructed. So, for example, under the TSCA rule, a microorganism is covered if it is “intergeneric”, regardless of how it got that way; and under the USDA rule, an organism is regulated solely on its potential to exhibit plant pest characteristics, regardless of the method of construction. Under the current regulatory scheme it would be up to the applicable regulatory agency to determine if, for example, a strain created by the precise engineering of synthetic biology posed any greater or lesser risk than a strain created by mutation or by older methods of recombinant DNA genetic engineering. The same is likely to be true overseas – I hope to summarize some of the applicable European Union standards in a future blog entry, but for now I’ll say that my understanding of these standards is that levels of regulatory oversight in the EU are determined by the inherent risk of the organism without undue regard for the method by which it was constructed, and that manufacturers using engineered organisms in commercial production are allowed to determine on their own what procedures and safeguards are appropriate to ensure “containment” of the production strain.
In the meantime, under the current U.S. regulatory regime, I can offer the following comments and recommendations for companies contemplating the use of modified algae in biofuel projects.
- Well in advance of the projected commercial start date, seek guidance from a regulatory attorney or consultant about the regulatory status of the production strain(s), and possibly plan an early presubmission meeting with agency staff.
- Although use of a genetically modified organism in research or in a pilot plant would ordinarily be exempt from oversight by either EPA or USDA, in the case of algae this would be dependent upon the nature of the reactor in which the organisms would be used, and if an open-air algal reactor is not be judged to be sufficiently “contained”, this could cause even research use to be subject to agency oversight.
- Because there may be uncertainty over federal agency jurisdiction, companies should be alert to the possibility of state or local government involvement in projects involving modified algae. In certain situations it might be desirable to involve such local agencies in early discussions, so that there are no surprises if they are brought into the process later on.
I expect that many of these issues will be discussed in the near future, as more companies begin to approach commercial stage with modified biofuel algae strains. As is often the case, it will likely be the “early adopters” who are first to propose such projects to the regulatory agencies that will not only blaze the trail but also bear the brunt of resolving any regulatory uncertainty there may be over how modified algae would be regulated.
D. Glass Associates, Inc. is a consulting company specializing in several fields of biotechnology. David Glass, Ph.D. is a veteran of nearly thirty years in the biotech industry, with expertise in industrial biotechnology regulatory affairs, patents, technology licensing, and market and technology assessments. This blog provides back-up and expanded content to complement a presentation Dr. Glass made at the EUEC 2010 conference on February 2, 2010 entitled “Prospects for the Use of Genetic Engineering in Biofuel Production.” The slides from that presentation, along with more information on D. Glass Associates’ regulatory affairs consulting capabilities, are available at www.slideshare.net/djglass99 or at www.dglassassociates.com.