David Glass BIO World Congress Algae Regulation July 2015

The Emerging Roadmap to Gain Regulatory Approvals for Uses of

Genetically Modified Algae in Biofuel or Bio-Based Chemical

Production David J. Glass, Ph.D.

D. Glass Associates, Inc.BIO World Congress on Industrial Biotechnology

July 20, 2015

Advanced Biotechnology can Improve Usefulness of AlgaeEnhance algal growth rate.Enhance or alter lipid biosynthesis.Enhance photosynthesis.Enable use of alternate food sources.Create new biosynthetic pathways;

enable production of new products.Enable secretion of lipids

to aid oil/water separation.Rosenberg et al. 2008, Radakovits et al 2010, Jones et al. 2012, Larkum et al. 2012, Work et al. 2013 (and others).

D. Glass Associates, Inc.

Overview of U.S. Biotechnology Regulation Environmental Protection AgencyMicrobial pesticides, plant pesticides.Engineered microorganisms used for other industrial

purposes.

U.S. Department of AgricultureTransgenic plants, potential plant pests.Plant-produced industrial products.

Food and Drug AdministrationFoods, food additives, pharmaceuticals.

TSCA biotech rule

USDA biotech rule

Product –specific regulation

Possible applicability to algae


Regulatory Jurisdiction for Engineered AlgaeProposed use of engineered algae by Mera

Pharmaceuticals in pharmaceutical production in Hawaii in 2005: no federal agency claimed jurisdiction, state law and state courts ultimately determined outcome.

2008 USDA opinion letter to Coastal BioMarine stated no USDA oversight over engineered algal strain if no “plant pest” sequences, and no oversight for smaller-scale use in contained reactors.

Can USDA, EPA work together on GM algae regulation, with one agency designated as the lead?


EPA TSCA Biotechnology Regulations (1)Regulations adopted in 1997 under the Toxic Substances

Control Act (TSCA) cover commercial uses of “new microorganisms”.

Regulations cover only those industrial uses not regulated by other agencies as foods, drugs, cosmetics, pesticides.

Among covered activities: industrial enzyme production, bioremediation, biotreatment, manufacture of fuels, chemicals.

New microorganisms are defined as “intergeneric”: containing deliberate combinations of coding nucleic acids from more than one taxonomic genus.


EPA TSCA Biotechnology Regulations (2)EPA considers scope of coverage to include algae.From the biotechnology rule:

“Microorganism” means an organism classified, using the 5-kingdom classification system of Whittacker, in the kingdoms Monera (or Procaryotae), Protista, Fungi, and the Chlorophyta and the Rhodophyta of the Plantae, and a virus or virus-like particle.

From the rule’s preamble:

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).


EPA TSCA Biotechnology Regulations (3)Commercial use or importation of intergeneric organism

requires 90 day advance notification to EPA, through submission of a Microbial Commercial Activity Notice (MCAN).

Most research and pilot projects would not require EPA review if conducted in suitably “contained” facilities, with procedures for controlled access, inactivation of wastes, emission controls, worker notification.

R&D with intergeneric organisms under non-contained conditions, such as open-pond algae reactors, would require EPA review through submission of a TSCA Experimental Release Application (TERA) 60 days in advance of proposed activity.


EPA TSCA Biotechnology Rule:TSCA Experimental Release ApplicationsTERAs submitted to EPA 60 days in advance, describing

the organism, the proposed research, and the proposed controls and monitoring procedures.

EPA can approve or deny TERAs, or approve testing with limitations or required monitoring.

To date, 30 TERAs submitted, most for agricultural or bioremediation microorganisms. All but three of these have been approved.

The 5 TERAs most recently filed and approved were from Sapphire Energy, Inc., for open-pond research with modified algae.


EPA TSCA Biotechnology Rule:TSCA Experimental Release ApplicationsSapphire TERAs covered open-pond research at UCSD using

different modified strains of the photosynthetic green algae Scenedesmus dimorphus.

Goals: assess ecological impact; test field efficacy of strains shown effective in laboratory.

Among findings (J. Shurin, personal communication):Modified algae can disperse and spread up to 50 meters away from

the test site, but rate of dispersal declines with distance. Both modified and wild-type algae grew in water from nearby lakes. GM algae had no apparent effects on biomass, diversity, or native

algae species. GM Scenedesmus is ecologically indistinguishable from the wild-type

strains.


EPA TSCA Biotechnology Rule: Microbial Commercial Activity Notifications (MCANs)MCAN reporting required at least 90 days before

commencing commercialization or importing a “new microorganism” for a TSCA purpose.

MCAN requires submission of data to EPA.Microorganism identity, construction and its propertiesPotential health and environmental impacts.Information about the industrial process,

control/containment measures, worker exposure, possible environmental release.

EPA review, clearance of MCAN authorizes commercial use for any purpose.


EPA TSCA Biotechnology Rule:Biofuel, Bio-Based Chemical MCANs Approx. 85 MCANs filed since 1997. Number and

frequency have increased in last 4-5 years. Most early MCANs covered GMOs for production

of industrial enzymes. 18 MCANs for S. cerevisiae, 3 for Zymomonas

mobilis, all for ethanol production. Joule, Algenol have filed MCANs for

cyanobacteria; Solazyme has filed 4 MCANs for modified microalgae.

Complete list available at www.epa.gov/biotech_rule/pubs/submiss.htm.



1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 20140

5

10

15

20

25

MCANs Submitted to EPA by Fiscal Year

Fiscal Year

Numberof

MCANs

EPA TSCA Biotechnology Rule:SummaryAlgae and cyanobacteria covered under the rule;

EPA has recent experience with MCANs and TERAs for algae and cyanobacteria.

MCAN reviews for contained manufacturing have been straightforward; EPA has recent track record reviewing microorganisms for use in biofuels, bio-based chemical production.

The TERA process provides a stepwise approach to regulation and risk assessment of outdoor uses.


USDA Biotechnology Regulations (1)Regulations issued in 1987, administered by USDA

Animal and Plant Health Inspection Service (APHIS).Regulations cover environmental uses or interstate

movement of organisms considered to be “potential plant pests”.

Potential plant pest status is based on presence of DNA sequences from listed potential plant pests. Inclusion of Agrobacterium on the list has captured most transgenic plants.

Most submissions have been for transgenic plants, some for modified agricultural microorganisms.


USDA Biotechnology Regulations (2)Rules have generally not covered “contained” use of

organisms in manufacturing, but could cover open-pond uses.

Applicability to algae under current definitions not clear; most algae strains would not be covered unless engineered to contain DNA from potential plant pest.


USDA Biotechnology Regulation:Oversight over R&DR&D use covered only if in open environment.

Notifications: 30 day advance notice.Permits: submit application 120 days in advance.Permits generally required for industrial uses.

Submissions require:Description of host organism and genetic

modifications.Description of field test; proposed procedures and

controls.Assess environmental impact of field use.


USDA Biotechnology Regulation:Approvals for Commercial UseApproval for commercial use and sale

through “petitions for nonregulated status”. Since early 1990s, USDA has approved over

100 petitions to allow commercial sale of engineered crop plants.

Commercial approvals can take 1-4 years, and require USDA to prepare Environmental Impact Statements.


USDA Biotechnology Regulation:SummaryTens of thousands of transgenic plant field tests

approved under these regulations, over 100 modified crop varieties approved for commercial sale – no approvals for algae?

Limited experience with R&D permits for novel biofuel feedstocks, no commercial approvals.

USDA likely to have scientific expertise to review biology of photosynthetic algae, but applicability under existing definitions unclear.


International Biotechnology RegulationMost countries around the world have biotechnology

regulations, in most cases based on principles of the Cartagena Protocol on Biosafety.

Many countries differ from the U.S. in having unified laws and regulations that cover all genetically modified organisms: no jurisdictional issues for algae.

However, principles of risk assessments for algae and microorganisms should be similar throughout the world.


Pathway for approval:Contained Use of GM Algae


Pathway for approval:Open-Pond Use of GM Algae



Industrial Biotechnology,April 2015Volume 11, Number 2Pages 71-83

DOI: 10.1089/ind.2015.1503

Additional information available at our blog, Advanced Biotechnology for Biofuels (dglassassociates.wordpress.com)

Thank you very muchDavid J. Glass, Ph.D.


124 Bird Street

Needham, MA 02492

Phone 617-653-9945

[email protected]

www.dglassassociates.com


David Glass BIO World Congress Algae Regulation July 2015

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