Earlier blog entries have discussed the regulatory schemes of the U.S. EPA and U.S Department of Agriculture that might affect the use of genetically modified microorganisms and plants for biofuel uses. I’ll now turn my attention to how genetically engineered algae might be regulated under these or other regulatory programs. From a technological standpoint, programs for genetic modification of biofuel algae strains have lagged behind similar efforts for microbes and plants (but see the excellent recent review by Radakovits et al. of progress in engineering algae for biofuel use), and so there have been few, if any, companies that have reached or approached the point where they might have to worry about how commercial use of modified algae might be regulated. And for the same reason, it seems that the agencies themselves have not given this question much thought, or at least that the agencies have made few if any public statements about the applicability of their programs to engineered algae. However, uncertainty about the regulatory path that might await modified biofuel algae could become a factor holding back the industry’s development, as evidenced by the concern over this issue expressed by the Algal Biomass Organization’s Technical Standards Committee (which I’ll discuss in more detail in the next entry of the blog). In this entry, I’ll discuss whether engineered algae might fall under EPA’s TSCA Biotech Rule or USDA’s biotechnology regulatory program, and in the entry to follow, I’ll discuss some of the issues raised by the ABO committee, including the possible impact of these regulations on algal biofuel programs, along with some thoughts about how companies can successfully navigate the applicable regulatory requirements.
Applicability of EPA Biotech Regulations on Use of Modified Algae in Biofuels Projects
My earlier blog entries have described EPA’s program of regulating certain genetically modified microorganisms under the Toxic Substances Control Act (TSCA), when used for certain industrial purposes not regulated by other federal agencies. All the new microorganisms that have been subject to EPA oversight under this rule have been modified versions of host organisms that were either bacteria, yeast or fungi. So the question would be whether algae strains genetically modified to contain coding nucleic acid sequences from another taxonomic genus (i.e., “intergeneric”, or “new” under the Biotech Rule) would fall under EPA jurisdiction under the TSCA Rule.
There appears to be a basis in the TSCA regulations for certain algal strains to be subject to EPA oversight. Section 725.3 of the TSCA regulations define the term “microorganism” as encompassing “those organisms classified in the kingdoms Monera (or Procaryotae), Protista, and Fungi, the Chlorophyta and the Rhodophyta of the Plantae, and viruses and virus-like particles” . This definition is further explained in the preamble to the 1997 Federal Register notice (emphasis added):
In the proposed rule (59 FR 45550-51), EPA defined “microorganisms” in Sec. 725.3 as those organisms classified under the 5-kingdom system of Whittacker … in the kingdoms Monera (or Procaryotae), Protista, and Fungi, the Chlorophyta and the Rhodophyta of the Plantae, and viruses and virus-like particles. Therefore, this definition includes, but is not limited to, bacteria, protozoa, fungi, mycoplasmas, mycoplasma-like organisms, spiroplasmas, microphytoplanktons, green and red algae, viruses, and virus-like particles (e.g., viroids, satellites, and virusoids). …
Commenters thought the proposed definition of “microorganism” was reasonable and included the appropriate organisms. Thus, EPA will retain the definition of “microorganism” as discussed in the proposed rule and found in the regulatory text in Sec. 725.3.
In addition, in its Regulatory Impact Analysis accompanying the 1997 rule, EPA stated the following (emphasis added):
The microorganisms potentially affected by the rule are those for which the corresponding chemical use would be subject to TSCA jurisdiction. By statute, the Toxic Substances Control Act (TSCA) regulates all chemical applications not specifically exempted in the Act. Language in the Act has been interpreted to include living microorganisms (i.e., microscopic living cells such as bacteria, fungi, protozoa, microscopic algae, and viruses).
Neither the preamble language nor the Regulatory Impact Analysis language carries the force of law, but this language makes it clear that the Agency considers that it has the authority to claim oversight responsibility over certain uses of genetically modified algal species.
Applicability of USDA Biotech Regulations on Use of Modified Algae in Biofuels Projects
As described in earlier blog entries, the U.S. Department of Agriculture regulates most transgenic plants used for agricultural or other research and commercial purposes using its biotechnology regulations under the Plant Protection Act. Although many algal species are photosynthetic, it is not clear whether any algal species would be considered to be potentially subject to USDA’s existing biotechnology regulations. In the current regulations, the term “Plant” is defined as: “Any living stage or form of any member of the plant kingdom including, but not limited to, eukaryotic algae, mosses, club mosses, ferns, angiosperms, gymnosperms, and lichens (which contain algae) including any parts (e.g. pollen, seeds, cells, tubers, stems) thereof, and any cellular components (e.g. plasmids, ribosomes, etc.) thereof”. But under the biotechnology rule, APHIS does not regulate “plants”, but instead “plant pests”, and so the fact that “eukaryotic algae” are included in the definition of “plant” may have little bearing on the question. “Regulated articles” under the biotech regulations include only “organisms that are or contain plant pests”, and in practice this has largely resulted in the regulation of those genetically engineered plants and some agricultural microorganisms which contained sequences from specific microbial, plant and animal genera that contain species that are potential plant pests. The list of known or potential plant pest species is contained in 7 CFR Part 340.2. This list does not appear to include the names of any of the genera of algae that have been suggested for biofuel use.
Although the regulations give APHIS leeway to determine that other organisms are “potentially” plant pests, generally speaking, if an engineered algae is not from one of the genera shown on the list in Part 340.2, it would not a priori be subject to regulation under the existing rules. However, many transgenic plants have been captured by the regulations because the most common vectors for plant transformation include sequences from the genus Agrobacterium, a genus found on the list of potential plant pests. So, some engineered algae may become subject to the regulations if the vectors used in the genetic engineering include “plant pest” sequences, and (as summarized in the recent review by Radakovits et al. 2010) it is true that Agrobacterium-mediated transformation is one method that has been used in genetic engineering of algae, although it is not likely to be the most common method used today.
At least one online reference has reported that, as part of its ongoing rulemaking process, APHIS has considered making its jurisdiction over algae more explicit, but I’ve reviewed the 2008 Proposed Regulations, and I could not find any evidence of such intent. The proposed rule defines the scope of organisms that would be potentially subject to regulation much differently than the current rule. Proposed Section 340.0 of the proposed regulations defines two categories of organisms as requiring permits:
(b) Genetically engineered organisms whose importation, interstate movement, or release into the environment is subject to the regulations in this part are:
(1) Genetically engineered plants if:
(i) The unmodified parent plant from which the GE plant was derived is a plant pest or noxious weed, or
(ii) The trait introduced by genetic engineering could increase the potential for the GE plant to be a plant pest or noxious weed, or
(iii) The risk that the GE plant poses as a plant pest or noxious weed is unknown, or
(iv) The Administrator determines that the GE plant poses a plant pest or noxious weed risk.
(2) Genetically engineered non-plant, non-vertebrate organisms if:
(i) The recipient organism can directly or indirectly injure, cause damage to, or cause disease in plants or plant products; or
(ii) The GE organism has been engineered in such a way that it may increase the potential for it to be a plant pest: or
(iii) The risk that the GE organism poses as a plant pest is unknown, or
(iv) The Administrator determines that the GE organism poses a plant pest risk.
The proposed rule’s definition of “plant” is far more general than that of the current rule, and it is not clear whether an algal strain could be considered a “genetically engineered plant” under subclause (a) of the above definition. However, the Agency could use the discretionary powers of subclauses (b)(2)(ii), (iii) or (iv) to determine that a genetically engineered algae might require regulation under these proposed rules, particularly if there are any vector sequences or other introduced genes that might have arisen from a “plant pest” organism or a noxious weed. However, it does not appear that any algal strain, either modified or naturally occurring, has been regulated by USDA under any of its regulations, including its longstanding plant pest regulations under 7 CFR Part 330.
In my view it is unlikely that USDA would assert regulatory authority over a proposed biofuel use of a modified algal strain unless it was a fairly large-scale commercial use of the strain, and only if there were some clear link, such as a possible plant pest risk, to agriculture or to a particular region or sector of U.S. agriculture. And further, it’s unlikely that the agency would claim jurisdiction over applications where the novel strain was used in a contained reactor, because their regulations cover only interstate movement or outdoor uses of engineered organisms (see discussion below). So, my sense is that USDA regulation of engineered algae is unlikely.
Possible precedents for regulation of engineered algae
There are two prior cases that illustrate how challenging it might be for genetically modified algae to fit neatly within the purview of one federal regulatory program. There is one publicly-known situation where a company requested a USDA ruling on whether a specific engineered algal species would be subject to the biotechnology regulations. The company is Coastal BioMarine of Bridgewater, Conn. (www.coastalbiomarine.com), an aquaculture company dedicated to growing shellfish and algae (algae being a food source for shellfish). Coastal contacted USDA in April 2008 to request clarification of the regulatory status of three marine algal species engineered with a gene encoding a glucose transporter protein. USDA responded in a letter dated May 19, 2008, and their response, although limited to this specific situation and not related to biofuel applications at all, provides useful insight into how the agency might regulate algae for a biofuel application.
The key points made by USDA in the letter are as follows:
- Based on the information provided, the engineered algal strains would not be covered by the USDA biotech regulations, because neither the recipient (“host”) species nor the source of the glucose transporter gene are listed on the “plant pest” list in Part 340.2 of the regulations. However, this determination would change if the vector sequences or selectable markers used in the genetic engineering arose from “plant pest” organisms.
- Even if the species were subject to the regulations, USDA oversight would not be needed to use the organisms in a contained reactor. This is important because USDA’s biotechnology regulations cover only outdoor use and interstate movement of potential plant pests.
- Large-scale use of these organisms, particularly for use in a biofuel application, might raise environmental issues that would trigger a need for USDA oversight. The letter suggested that in order to progress to large-scale commercial use of such species, an applicant might need to pursue a “delisting” petition to establish non-regulated status for the organisms.
- USDA suggests that other agencies, notably FDA and EPA, might be involved in regulating such species.
This decision by USDA is interesting, and it is consistent with some of the circumstances regarding the proposal by Mera Pharmaceuticals for algal pharmaceutical production that is discussed below. In particular, the decision that USDA lacks regulatory authority for small-scale tests if there is no “plant pest” risk, and the uncertainty about other agencies’ jurisdiction, are both features also seen in the Mera story.
Mera’s 2005 proposal to grow genetically modified algae in Hawaii for the purpose of pharmaceutical production is illustrative of how local concerns or opposition could lead to a state or local government assuming control over a project, especially in the absence of federal oversight. As is well documented on the Internet (e.g. http://archives.foodsafety.ksu.edu/agnet/2005/8-2005/agnet_aug_3.htm#story2 or http://www.ibiblio.org/ecolandtech/SoilWiki/message-archives/JoeCummins/msg00519.htm), Mera proposed moving as many as eight strains of Chlamydomonas reinhardtii from California into Hawaii, for the purpose of growing them to produce pharmaceuticals including antibodies and interleukins. According to these Web accounts, the three federal agencies that oversee almost all commercial biotech activities, FDA, USDA and EPA all waived oversight of these field trials, opening the door to state regulation. The Hawaii Department of Agriculture (DOA) eventually took responsibility for permitting the trials, because Chlamydomonas is listed on the state Department of Agriculture’s “list of restricted organisms” under its quarantine laws. Further, DOA staff determined that the biopharm algae posed an “above moderate risk,” which means that the BOA needed to approve the project. The DOA made this determination based on the lack of federal oversight, the DOA’s lack of experience with engineered algae, concerns regarding large-scale production outdoors, and the “unknown effects on the environment if accidentally released.” This project drew a great deal of public criticism and opposition, and although it appears that the Hawaii DOA eventually granted permits for to allow at least some portions of the trial, a local citizen’s group filed a lawsuit that resulted in a judicial ruling that an environmental assessment would be needed before the trials could proceed. This decision was ultimately affirmed by an appeals court, and it appears that Mera’s field tests of these engineered algae have never taken place.
Although this is a cautionary tale for algae biofuel projects, there are unique aspects of the Mera story that may not make it completely applicable to biofuels. Specifically, the fact that the algae were to be used in R&D to develop a pharmaceutical production process may have led to the lack of federal oversight. In a nutshell, both EPA and USDA may have decided that, because the project involved pharmaceutical manufacture, each agency would yield to FDA authority. In EPA’s case, not only would TSCA jurisdiction be ruled out due to FDA jurisdiction but perhaps also because it was a research project; in USDA’s case the Agency probably decided there was no plant pest risk for a small-scale project (as they did for Coastal BioMarine, discussed above). However, to my knowledge, the FDA does not regulate pharmaceutical manufacturing processes until the manufacturer is ready to have the final, commercially-ready process certified, and so FDA would not have the infrastructure or the regulatory authority to exercise any control over a small-scale project. So, this may be viewed as an isolated incident, but it should serve as a reminder that (as was often the case in the early days of agricultural biotechnology) state or local governments, not to mention concerned citizens, will often jump in where there is a perceived federal regulatory vacuum, so that developers of engineered biofuel algae need to pay attention not only to regulatory agencies at all governmental levels, but also to good community relations practices and principles.
So, it may prove that there might be conflicting agency oversight over projects involving modified algae, or more correctly that certain projects may fall through the cracks between differing agency authorities. And as the Mera story and other situations throughout the history of biotechnology have shown, when there is a vacuum in federal regulatory authority, the states or local governments may step in with stricter regulations than would have been faced under a federal program.
In the next entry of the blog, I’ll discuss how these regulations may impact plans to use modified algae for biofuel production and comment not only on how individual companies should plan for such regulation but also about the efforts by the algal biofuel industry to have a greater influence on the regulations that may affect commercialization efforts.
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.