david glass plenary presentation at 4th algal biomass, biofuels and bioproducts confeence

David J. Glass, Ph.D.

D. Glass Associates, Inc.

June 18, 2014

Overview, Key Points

History and overview of U.S. biotechnology regulation affecting industrial uses of GM algae.

Although the U.S. biotechnology framework singles out modified organisms for additional scrutiny, approvals for commercial uses of GM algae can be obtained with proper planning.

Scientific issues relating to regulation and risk assessment of uses of GM algae.

Legitimate scientific issues should be addressed in a risk assessments for industrial uses of GM algae.

Industry, government and academia can collaborate to create research database to support risk assessments.


Advanced Biotechnology can Improve Usefulness of Algae Enhance 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, Li et al. 2008;

Angermayr et al. 2009, Radakovits et al 2010.


U.S. Biotechnology Regulation: Historical Perspective Biotechnology framework arose in the mid-1980s amid

considerable public interest and debate.

The Reagan Administration decided against a biotechnology-specific law, in favor of relying on existing laws and regulations.

Although meant to be “product-based” rather than “process-based”, inevitably some regulations single out uses of engineered organisms for greater scrutiny than uses of unmodified organisms.

Although broad enough to cover all commercial uses, the greatest focus was on “deliberate releases” to the environment.


Overview of U.S. Biotechnology Regulation Environmental Protection Agency

Microbial pesticides, plant pesticides.

Engineered microorganisms used for other industrial purposes.

U.S. Department of Agriculture

Transgenic plants, potential plant pests.

Plant-produced industrial products.

Food and Drug Administration

Foods, food additives, pharmaceuticals.

TSCA biotech rule

USDA biotech rule

Product –specific regulation

Possible applicability to algae


Regulatory Jurisdiction for Engineered Algae Proposed 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 Applications TERAs 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 at UCSD using different modified strains of the photosynthetic green algae Scenedesmus dimorphus.


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 properties

Potential 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. 65 MCANs filed since 1997. Number and

frequency have increased in last 3 years.

Most early MCANs covered GMOs for production of

industrial enzymes.

14 MCANs for S. cerevisiae, 3 for Zymomonas

mobilis, all for ethanol production.

Joule, Algenol have filed MCANs for cyanobacteria;

Solazyme has filed 2 MCANs for modified microalgae.

Complete list available at

www.epa.gov/biotech_rule/pubs/submiss.htm.


0

2

4

6

8

10

12

14

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014(to

date)

MCANs Submitted to EPA by Fiscal Year


©2013 Joule. Rights Reserved. Proprietary & Confidential. www.jouleunlimited.com

Joule SunSpringsTM Hobbs: Where the vision becomes reality

Production Unit

Central Plant

Commissioned in September 2012 to test and demonstrate the platform at increasingly larger scale

Core production unit and infrastructure in place to advance to full process demonstration

Achieving progress on numerous variables, e.g. productivity, process efficiency

Sustained Sunflow®-E ethanol production, with other products to follow

Facility and processes will become the blueprint for future commercial plants

Biocatalyst Prep

©2013 Joule. Rights Reserved.

Joule Unlimited: MCAN for Modified Synechococcus First MCAN for commercial ethanol production strain filed

July 2012. The MCAN included all available information

to enable a risk assessment for the strain.

EPA completed its review Fall 2012, concluded that the

use of the strain at Hobbs facility is unlikely to present

unreasonable risk.

Consent Order signed July 2013, allows use of the strain

at Hobbs under specified conditions, with certain

additional testing, monitoring and reporting required.

Additional MCANs will be needed for improvements to

the strain.

©2013 Joule. Rights Reserved.D. Glass Associates, Inc.

EPA TSCA Biotechnology Rule:Summary Algae 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&D R&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:Summary Tens 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 Regulation Most countries around the world have biotechnology

regulations, in most cases based on principles of the

Cartagena Protocol on Biosafety.

These countries differ from the U.S. in having unified

laws and regulations that cover all genetically

modified organisms.

However, principles of risk assessments for algae

and microorganisms should be similar throughout

the world.


Scientific Issues in the Regulation of GM Algae (1)Legitimate scientific issues need to be addressed

for many projects involving modified algal strains.

Stability of vector and introduced genes.

Possible deleterious functions encoded by

transgene(s) such as algal toxins.

Potential for horizontal gene transfer, crossing to wild

algae species.


Scientific Issues in the Regulation of GM Algae (2) Potential for engineered strain to be transported

outside facility, survive and compete in environment.

Potential persistence in the environment: soil or

water in vicinity of site of use.

Potential disruption of natural ecosystems or native

algae populations.

Creation or enhancement of harmful algal blooms or

ecologically disruptive algal blooms.


Research Needs for GM Algae Risk Assessment (contained research) Basic research into biology, ecology, natural history

of commercially-relevant wild type algae strains.

Basic research addressing key regulatory concerns:

gene transmissibility, survival, persistence in

environment, genetics of algal toxin production.

Laboratory, microcosm and macrocosm studies to

model behavior of modified species in the

environment.


Research Needs for GM Algae Risk Assessment (controlled field tests) Stepwise field studies with GM strains, carried out

under regulatory auspices, e.g. EPA TERA process.

Conduct and monitor small-scale field tests of

modified algae in open ponds: develop database

addressing dispersal, environmental persistence, etc.

Create a role for USDA and academic investigators in

EPA review of commercial uses of GM algae.

Government support for field research: utilize DOE

national labs, other government facilities as field test

sites?


Impact of Biotechnology Regulations Efforts to promote interagency cooperation and the

participation of the research community, are important

to ensure a science-based regulatory framework.

The existing biotech regulatory framework provides a

straightforward path to commercial approval, with

many prior successes in agricultural, industrial

biotechnology.

The regulatory process can

be successfully managed

with proper advance planning.


http://tech.c4ads.org/uploaded_images/algae5-726190.jpg

http://tech.c4ads.org/uploaded_images/algae5-726190.jpg

Thank you very much

David J. Glass, Ph.D.


124 Bird Street

Needham, MA 02492

Phone 617-653-9945

[email protected]

www.dglassassociates.com


david glass plenary presentation at 4th algal biomass, biofuels and bioproducts confeence

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