Woodrow Wilson Center - Sloan - Hastings - Venter - Nano_synbio2_electronic_final

8/14/2019 Woodrow Wilson Center - Sloan - Hastings - Venter - Nano_synbio2_electronic_final

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SYNBIO 2 / March 2009

Regulating FiRst-geneRation PRoducts oF synthetic B iology

new life,

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new life,

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AcronymsPresent in: New Lie/Old Bottles

APHIS Animal and Plant Health Inspection Service

DNA Deoxyribonucleic acid

EPA Environmental Protection Agency

EU European Union

FDA Food and Drug Administration

FDCA Federal Food, Drug, and Cosmetic Act

FIFRA Federal Insecticide, Fungicide and Rodenticide Act

IBC Institutional Biosaety Committee

MCAN Microbial Commercial Activity Notice

MIT Massachusetts Institute o Technology

NEPA National Environmental Policy Act

NIH National Institutes o Health

OSTP White House Ofce o Science and Technology Policy

RAC Recombinant DNA Advisory Committee

RDNA Recombinant DNA

RGs Risk Groups

TERA TSCA Experimental Release Application

TSCA Toxic Substances Control Act

USDA US Department o Agriculture


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Thisreportwasmadepossiblewithagrantfro

mtheEuropeanCommissiontosupp

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ethodsforhandling

globalchallenges.Itisbasedonindependentresearchanddoesnotrepresentthe

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ortheWoodrowWilson

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table of conens

About the Author 1

Foreword 3

Acknowledgements 5

Executive Summary 7

I Introduction: Biotechnology Past and Synthetic Biology Future 11

A Introduction 11

B Biotechnology Past: The Development o Regulatory Policies or Products o rDNA Biotechnology 12

C Synthetic Biology Future: The Relevance o Biotechnology Regulation to Synthetic Biology 15

II Synthetic Biology: Defnitions, Applications, and Risks 16

A What is Synthetic Biology? 16

B Potential Applications 181 Biouels 19

2 Pharmaceuticals 20

III Policies and Options: Managing the Risks o New Technologies 21

A Policy Goals and Framing New Technologies 21

B Synthetic Biology: Framing and Risk Characterization 23

1 Accidental release risk assessment 24

2 Intentional non-contained use 25

C Comparing Risks o Biotechnology and Synthetic Biology 27

IV Applying the Biotechnology Regulatory Framework to Synthetic Biology 29

A Developing the policy ramework or the regulation o Biotechnology 29

B Applying Biotechnology Policy and Regulation to Synthetic Biology 31

1 Research and Development Activities in Contained Facilities 31

2 Commercial or Industrial Production using Synthetic Microorganisms in a Contained Facility 38

3 Intended Environmental Releases o Synthetic Microorganisms 41

V Conclusions 46

Endnotes 47

Bibliography 49


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SYNBIO 2 / March 2009

Michael Rodemeyer

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new life,

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From 2000 unti l 2005, Mr. Rodemeyer was the Executive Director o the Pew Initiative on Food

and Biotechnology, a nonprot research and education project on genetically modied oods

unded by a grant rom The Pew Charitable Trusts. Beore that, Mr. Rodemeyer held a variety

o posts in the ederal government, including Assi stant Director or Environment in the Oce o

Science and Technology Policy in the Clinton administr ation and Chie Democratic Counsel or

the U.S. Congress House Committee on Science and Technology. From 1976 through 1984, Mr.

Rodemeyer was an attorney with the Federal Trade Commission, working on consumer protec-

tion and antitrust issues.

Currently, Mr. Rodemeyer is an independent consultant and writer on science, technology and

environmental policy. He is also an adjunct instructor in the Science, Technology and Society

Department in the School o Engineering and Applied Sciences at the University o Virgin ia and

has previously taught congressional and environmental policymaking at the Johns Hopkins Uni-

versitys Zanvyl Krieger School o Arts and Sciences. He has lectured widely on technology and

environmental policy issues.

Mr. Rodemeyer graduated with honors rom Harvard Law School in 1975 and received his under-

graduate degree rom Princeton University in 1972. He lives in Charlottesville, Virginia.

About te Autor


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3

By their very nature, emerging technologies challenge our approaches to oversight and regulation.

The novel properties exhibited by these technologies can underpin innovation in areas ranging

rom medicine to energy production, but can also present new risks and challenges to exist ing

regulatory rameworks.

Along with nanotechnology, synthetic biology is a cr itical emerging technology that has gained the

attention o both governments and the pr ivate sector. It builds upon the advances o biotechnology,

applying the principles o engineering to the world o biology to nely tune existi ng organisms and

even develop new ones rom scratch. How this emerging science and its applications are developed

and utilized by society wil l ultimately shape how it is regulated. Some scientists argue that synthetic

biology is just a more powerul version o genetic engineering and thus does not need much in the

way o new regulations. Though the rst generation o synthetic biology-derived microorganisms

is unli kely to be much dierent rom those we have already seen, subsequent generations are li kely

to be much more complex displaying novel characterist ics with little precedence in natu re.

It would be easy to relegate discussions about oversight to the backburner. Procrast ination bears a

risk, however, since a productive dialogue may become more dicult as the technology matures

and stakeholders become divided in their opinions about risks and benets. One can start a dis-

cussion now with the basic question o whether existing regu lationsor instance, the long-usedCoordinated Framework or Biotechnologywil l work with synthetic biology.

In this paper, Michael Rodemeyer o the University o Virginia provides an analysis o U.S. regula-

tory options or rst-generation synthetic biology products. He examines the benets and drawbacks

o using the existi ng U.S. regulatory r amework or biotechnology to cover products and processes

enabled by synthetic biology. He nds that the similarities between biotechnology and synthetic

biology are abundant enough to provide a good starting point, though how this emerging technol-

ogy is ra med or policymakersas novel and potentially dangerous, or amiliar and saewi ll

infuence the makeup o any uture regulatory policies.

Foreword

David Rejeski

Director, Synthetic Biology Project

Director, Project on Emerging Nanotechnologies

Woodrow Wilson International Center for Scholars


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Acknowledgments

Throughout my career, Ive had the good or-

tune to work with outstanding scientists and en-

gineers who have understood the importance o

engaging policymakers on technical issues. Less

requently, Ive had the opportunity to work

with policymakers who likewise understand the

need to engage with scientists and engineers.

None o these ormer colleagues is likely to win

the accolades o peers or trying to bridge the di-

vide between physicis t and novelist C.P. Snows

two cultures. But their will ingness to do so may

mark the dierence between societies that can

harness scientic knowledge and technologi-

cal change or the benet o all and those that

perceive themselves to be resentul victi ms o

technologys whims. To these envoys rom both

cultures we owe a great debt o appreciation.

Synthetic biology is the latest example o anemerging technology with remarkable promise

to apply biology to societal needs, rom renew-

able energy and environmental restoration to

new drugs and diagnostic tools. Synthetic biol-

ogy, like other powerul technologies, has also

raised concerns, many o which have been raised

by scientists themselves. The question now ac-

ing policymakers is how to ensure th at the tech-

nology is developed in a way that maximizes

benets and minimizes risks , while allowing or

change as new scientic knowledge is gained.

This report is an eort to look orward by look-

ing back: applying some o the lessons learned

about the regulation o biotechnology over the

past 30 years to the emerging area o synthetic

biology. It is by no means intended to be a com-

prehensive set o recommendations or the gov-

ernance o synthetic biology, but rather a way to

begin engaging the technical and policymaking

communities in asking some o those questions.

I want to express my appreciation to the Syn-

thetic Biology Project at the Woodrow Wilson

International Center or Scholars or this oppor-

tunity to explore some o the governance ques-

tions associated with synthetic biology. I also

beneted rom the assistance o a number o legalscholars, regulatory experts and scientists to help

me navigate some o the more complex shoals.

I would particularly like to acknowledge the

help o Jacqueline Corrigan-Curay, Mark Segal,

Brent Erickson, Julia Moore, Robert Friedman,

Michele Garnkel, Fran Sharples, Anne-Marie

Mazza, David Rejeski, Patrick Polischuk, Ele-

onore Pauwels and Andrew Maynard. I would

also li ke to acknowledge those who reviewed

earlier versions o thi s report and oered valuable

comments, including J. Clarence (Terry) Davies,

L. Val Giddings and Wendell Lim. Wh ile I owe

my thanks to them or improving the report,

the contents and opinions in the report are en-

tirely my own and should not in any way be at-

tributed to them or viewed as an endorsement.

Similarly, any errors let remain ing despite their

assistance must be laid solely at my doorstep.

Like the opinions expressed herein, any errors

are entirely my own.

Michael Rodemeyer

Charlottesville, Virginia

March 2009


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Executive Summary

Regulatng Ne Tecnlg:

Te Gldlcks Dlea

The contribution o innovation and new tech-

nology to economic well-being has by now

become so well established as to require little

elaboration. Technology can create valuable and

benecial new products, increase eciency and

productivity and lower costs, all contributing

to improved consumer welare and economic

growth. In recent years, new technologies in

medicine, computers, communication and ag-

riculture have revolutionized many industries

and reshaped societies.

But in addition to benets, new technologies can

present new health or environmental risks that

can pose dicult chal lenges or public policy.

Regulators ace t he Goldilocks dilemma: the

need to get regulation just right. I they aretoo precautionary, they will err by keeping sae,

valuable new products o the market. I they are

not precautionary enough, a product could come

to market that could cause unacceptable harm.

The regulatory challenge is made all the more

dicult because the inormation needed to assess

risks o a new technology is oten imperect and

uncertain, a not-surprising situation given its

very novelty. In such cases, policymakers oten

look to previous experience in trying to deter-

mine how to address the risks and regulation o

new technologies.

The discovery o gene-splicing biotechnology

techniques in the mid-1970s is an exa mple o

a new technology that led to questions about

appropriate regulation. Shortly ater that break-

through discovery, scientists raised concerns

about the potential or harm that could result

i microbes engineered through this new re-

combinant DNA (rDNA) splicing process were

accidentally released rom a laboratory. They

eared that some harmul microorganisms could

reproduce and spread, and the probability o such

an outcome was at that point largely unknown.

Scientists called or oversight by the National

Institutes o Health to set standards to ensurethat laboratory research was carried out in a

manner that protected laboratory workers, the

community and the environment. In the mid-

1980s, as products began to be developed or use

outside the laboratory, the Reagan administra-

tion developed a Coordinated Framework

or the regulation o biotechnology products.

The Coordinated Framework established the

policy that biotechnology production processes

posed no novel risks compared to conventional

production processes and that risks should be

thereore regulated under existing laws based on

the risk characteristics o the nal product, not

the method by which it was made. As a result,

in the United States, biotechnology products

are regul ated under the same laws that apply to

comparable conventional products.

Sntetc Blg

Today, the next biotechnology revolution is

brewing: synthetic biology. No longer limited

to laborious gene-splicing rom one organism to

another, scientists are learning how to construct

genetic code in the laboratory, with the hope o

using synthetic genetic elements to build novel

organisms that could be used or multiple pur-

poses, such as manuacturing drugs or invading

cancer cells in the body. While most commercialapplications are likely to be years away, research-

ers today are working on synthetic microorgan-

isms to produce the next generat ion o clean,

renewable biouels and o certain rare drugs.

Scientists have once again ta ken the lead in

raising concerns about the risks o sy nthetic

biology research. The issue that has garnered

the most serious attention is the concern over


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biosecuritywhether synthetic biology technol-

ogy could assist bioterrorists in creating more

dangerous pathogens. But todays scientists also

ace the same kind o biosaety concerns that were

initially rai sed and subsequently addressed about

the rst genetically engineered microbes 35 years

agothe risk s o harm to laboratory workers, the

community and the environment should a harm-

ul synthetic microbe be accidentally released and

spread through the environment.

The initial raming o a new technology can have

a strong impact on regulatory decis ions. A new

technology that is ramed as being similar to an

existing, amiliar product reassures the public

about its saety, allows policymakers to apply ex-

isting regulatory approaches and provides indus-

try with a clear and predictable path to market.

On the other hand, raming a new technology as

being truly novel can raise public ears about its

saety, pose a challenge or regulators and present

an uncertain commercial ization path or industry.

Many scientists argue that synthetic biology is just

a more poweru l version o the genetic engineer-ing that has been around or nearly 30 years and

should thereore be treated in the same way.

This report examines that assumption as it applies

to the likely rst generation o synthetic biology

products: synthetic microbes engineered to produce

biouels and drugs. The potential environmental

and public health risks o a synthetic microorganism

arise rom two scenarios: an accidental release rom

a contained acility and an intentional release into a

non-contained environment. These risks are simi-

lar in kind to the potential risks o microbes engi-

neered through rDNA technology.

The rst generation o synthetic biology mi-

croorganisms is unlikely to be remarkably di-

erent rom or more complex than those created

through other genetic engineering techniques,

and will probably not pose diculties in risk a s-

sessment. As the technology matures, however,

it has the capability to produce complex organ-

isms whose genomes have been assembled rom a

variety o sources, including articial sequences

designed and built in the laboratory. Whi le the

risk issues and risk assessment questions are simi-

lar to those raised by any genetically engineered

organism, providing adequate answers to those

questions may be signicantly more dicult or

such complex synthetic microorganisms.

Te Callenge f Uncertant

In rDNA biotechnology, regulators have typical-ly evaluated the risks o genetically engineered

microorganisms by comparing them to their

well-known unmodied counterparts and un-

derstanding the unct ion o the inserted genetic

material. Regulators can compare the naturally

occurring and genetically engineered varieties

to ensure that the new organism is as sae as

its known, conventional counterpart.

In complex organisms engineered through syn-

thetic biology, however, it may be dicult to

determine an organisms genetic pedigree i

it has been assembled rom multiple sources or

contains articial DNA. In addition, there is a

question o whether the genetic sequences will

continue to unction as they did in their original

sources, or whether there could be a synergistic

reaction among the new components that leads

to dierent unctions or behavior. Scientists

may be able to predict the unctions o specic

new genetic alterations based on growing u n-

derstanding o comparable genetic components,

but an organism assembled rom genetic parts

derived rom synthetic or natural sources could

display emergent behavior not seen in the

original sources. The complexity o advanced

synthetic microorganisms creates additional

uncertainty in the ability to predict unction

rom sequences and structures. Existing risk

assessment methods may not prove adequate

or predicting outcomes in complex adaptive

systems. In addition, while many scientists be-

lieve that engineered organisms are unl ikely tosurvive or reproduce in a natural environment,

the capability o synthetic organisms to mutate

and evolve raises questions about the poten-

tial o synthetic organisms to spread and to ex-

change genetic materials with other organisms

i released into the environment. While these

risks are aga in similar to those raised by any ge-

netically engineered organism, it may be more


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dicult to asse ss in advance the risk o complex

synthetic organisms developed in the uture.

Under such conditions o uncertainty, the chal-

lenge or regulators will be how to make de-

cisions that neither over-regulate nor under-

regulate. Risk research is an urgent requirement

parallel to product development. While generic

research will be useul, in many cases risk re-

search must also be carried out in the context

o speciic organisms, products and intended

applications.

Sntetc Blg Prducts Regulated

Under Current Btecnlg Fraerk

Most o the regulatory policies and gu idelines

original ly adopted to address these risks or bio-

technology appear to cover synthetic microor-

ganisms in stages rom research through com-

mercialization, although there are some gaps and

questions that agencies will need to address.

The National Institutes o Health (NIH) Guide-

lines or rDNA Research are the principal lineo deense against the accidental release o a

harmul genetically engineered organism rom

contained research laboratories. Assessing the

potential risk o a proposed research activity and

determining the appropriate level o conne-

ment and biosaety procedures is at the heart

o the NIH guideline-development process. In

2008, the NIH Recombinant DNA Advisory

Committee (RAC) recommended revisions to

the Guidelines to cover synthetic biology re-

search and to provide clearer guidance to the re-

search community on how to manage synthetic

biology research, given the greater uncertainty

involved with assessing its potential risks.

For commercial products, the existing regulatory

ramework or biotechnology is likely to cover

most anticipated microbial products o synthetic

biology, although agencies may need to modiy

some rules to clariy their intended application.

The initial synthetic biology products are likely

to be relatively simple modications; however,

as the technology matures, regulatory agencies

will ace challenges in assessing the potential

risks o more complex synthetic organisms in

order to determine appropriate biosaety con-

trols. The greater uncertainty associated with

the risk asses sment o complex synthetic organ-

isms will lead to dierent regulatory outcomes

because o the regulatory patchwork that results

rom applying existing product laws. Depend-

ing on their nature, some products will requireextensive testing and a pre-market regulatory

saety approval, while others may go to market

with considerably less test ing and oversight. To

use existing laws, a number o agencies have

creatively stretched their authorities to cover

biotechnology products, in ways that have gen-

erated criticism o both over- and under-regu-

lation. In particular, some critics have argued

that the Toxic Substances Control Act, which

the Environmental Protection Agency would

likely use to regulate synthetic microbes, is an

inadequate regulatory approach or managing

the risk o products o new technologies.

At the same time, while the process has not been

without problems, the regulatory ramework

or biotechnology has general ly been success-

ul, particularly in comparison to the process-

oriented regulatory approaches o Europe and

other nations. Numerous valuable biotechnol-

ogy products, both in biomedicine and in ag-

riculture, have been successully developed and

commercialized throughout the United States

and around the world, without any public health

or environmental problems. U.S. consumers,

particularly compared to their European coun-

terpart s, appear to have condence in the regu-

latory system.

While the biotechnology regulatory model may

well be the likely direction or the regulation

o synthetic biology products, it is not a per ectmatch and carries with it some inherent prob-

lems. New legislation specically or synthetic

biology is an unlikely option, but some have

urged Congress to rationalize and modernize

the regulation o new converging technologies,

instead o attempting to shoehorn each new area

o technological development into laws previ-

ously written or a dierent set o issues.


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I. Introduction: Biotecnology Pastand Syntetic Biology Future

A. Intrductin

Thirty-ve years ago, Herb Boyer and Stanley Co-

hen discovered the principles o recombinant DNA

(rDNA), or gene splicing, technology, ushering in

the era o modern biotechnology. Even as early re-

searchers eagerly began to anticipate the potential ap-

plications o rDNA technology or medicine, agricul-

ture and industry, some o them raised concerns about

potential harm to public health and the environment

should these newly created genetically engineered

organisms be accidentally released rom the laboratory

and reproduce and spread in the environment.

The act that a new technology was raising questions

about risksand appropriate policies to manage

themis hardly surprising. New technology oten

brings with it both promises and perils, and nding

the right policies to maximize benets while mini-

mizing risks is not an easy task. New science and

technology can challenge old paradigms and pose

questions or which there are no clear answers. What

was unique about the introduction o biotechnology,

however, was that it was the scientists themselves

who were raising the questions at the very early stag-

es o their own research. From that beginning, poli-

cies to manage biotechnologys risks developed and

evolved much as the science and technology itsel.

While biotechnology and its regulation have not

always kept pace with each other or proceeded very

smoothly, the system has , despite its faws, largely

worked: the past ew decades have witnessed the

introduction o numerous biotechnology-derived

drugs, diagnostics and crops without apparent harm

to the public health or the environment.

Today, advances in genetics, inormation technolo-

gy and DNA synthesis are leading to the emergence

o a new set o potentially ar-reaching tools under

the name o synthetic biology. To some extent,

synthetic biology is a logical extension o rDNA

biotechnology. Instead o cutting and pasting dis-

crete genetic materials rom existing organisms, as

with rDNA biotechnology techniques, researchers

are increasingly able to design and build their own

genetic materials rom scratch in the laboratory and

then to synthesize those articial genetic constructs

into novel organisms with engineered unctions.

While synthetic biology mostly remains at the basic re-

search stage, many believe that it will be at least as revo-

lutionary as rDNA technologyand probably more so.

Synthetic biology may be able to deliver on some o the

as-yet unrealized hopes o biotechnology in terms o

developing new drugs, diagnostics and environmentally

riendly biouels and other industrial chemicals.

As the process o turning science into technology

begins in earnest, the issue o balancing benets and

risks is being raised again. As with the debate about

early rDNA biotechnology, concerns have been

raised about the potential risks to public health and

the environment rom accidental releases and rom

intentional non-contained uses. In addition, synthetic

biology has raised serious concerns about biosecurity:

the potential o the technology to enhance the ability

o bioterrorists to develop more virulent pathogens.

Some in the scientic community have once again

taken the lead in calling or sel-governance (Church,

2005). In addition, some non-governmental orga-

nizations have urged caution and pushed or ormal

oversight o synthetic biology (ETC Group, 2007).

Are the U.S. regulatory policies or rDNA biotechnol-

ogy products developed over the past 25 years an ap-

propriate template or rst-generation synthetic biology

products? To what extent does the existing regulatory

ramework developed or biotechnology products ad-

equately address concerns about potential risks rom ac-

cidental or intentional releases o synthetic organisms?


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B. Bitechny Past: The Devepment Reuatry Picies rPrducts rDNA Bitechny

The history o the development o a regulatory

ramework or rDNA biotechnology has strong

relevance or issues concerning the governance o

synthetic biology. In 1974, only a short time a ter

Cohen and Boyers discovery, several leading mo-

lecular biologists raised concerns about the saety

o rDNA research and called or a moratorium

on certain research until saety guidelines could

be developed and more experience gained to as-

sess risk (Berg, et al., 1974). Meeting in Asilomar,

Caliornia, in 1975, the molecular biologists cal led

or the development o saety guidelines and a

process or reviewing the saety o proposed rDNA

experiments (Berg, Ba ltimore, Brenner, Roblin

III, & Singer, 1975). These recommendations led

to the establishment o the Recombinant DNA

Advisory Committee (RAC) at the National In-

stitutes o Health (NIH) to oversee the saety o

rDNA research and to dene appropriate standards

or containment o potentially risky research.

As the ir st commercial products intended or

non-contained use in the environment began

to emerge rom laboratories in the mid-1980s,

ederal regulators charged with responsibility or

protecting public health and the environment

grappled with applying existing laws to new

biotechnology products. In 1986, the White

House Oce o Science and Technology Policy

published a Coordinated Framework or the

regulation o biotechnology (51 Fed. Reg. 23302

[1986]). That policy statement, which remains the

basic guidance document or U.S. biotechnology

policy, established a number o key principles.The Coordinated Framework, refecting scientic

consensus, stated that recombinant DNA technol-

ogy did not present any unique risks or pose any

specic problems that were dierent than those o

conventionally produced organisms. As a result,

the ocus o government regulation should be

the risk characteristics o the nal product, not

the process by which it was made. Looking at the

existing regulatory authority, the policy statement

urther concluded that then-existing laws were

adequate to deal with the potential risks associ-

ated with a ny biotechnology-derived product

likely to be developed in the oreseeable uture.

As a consequence, since the mid-1980s, bio-

technology products developed in the United

States have been reviewed under the same sets

o laws and regu lations that apply to conven-

tionally produced products (Tables 1-3). This

technology-neutral approach means that the type

o regulatory review depends on the specic cat-

egory o the product . For example, the Food and

Drug Administration (FDA) regulates ood, eed

Ttle f Act Abbreatn Agenc Cte

The Federa Insecticide, Funicide, and Rdenticide Act FIFRA EPA 7 USC 136

The Txic Substances Cntr Act TSCA EPA 15 USC 2601

The Fd, Dru, and Csmetic Act FDCA FDA; EPA 21 USC 301

The Pant Prtectin Act PPA USDA 7 USC 7701

The Virus Serum Txin Act VSTA USDA 21 USC 151

The Anima Heath Prtectin Act AHPA USDA 7 USC 8031

The Federa Meat Inspectin Act FMIA USDA 21 USC 601

The Putry Prducts Inspectin Act PPIA USDA 21 USC 451

The E Prducts Inspectin Act EPIA USDA 21 USC 1031The Anima Damae Cntr Act ADCA USDA 7 USC 426

The Anima Weare Act AWA USDA 7 USC 2131

The Natina Envirnmenta Prtectin Act NEPA (AII) 42 USC 4321

TABLE 1. FEDERAL LAwS PoTENTiALLy APPLiCABLE To GE oRGANiSmS AND PRoDUCTS

DERivED FRom ThEm

Surce: Pew Initiative n Fd and Bitechny (2004).


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and ood additives, as well as human and anima l

drugs, biologics and medical devices. The Envi-

ronmental Protection Agency (EPA) regulates

pesticides, pesticide residues in ood and certain

new chemical substances. The U.S. Depart-

ment o Agriculture (USDA) regulates potential

animal and plant pests under various laws. Since

each agency operates under di erent laws and

regulations, the type o regulatory review that a

product will receive diers dramatical ly. For ex-

ample, drugs and pesticides cannot be marketed

until the regulatory agency has ound that the

products are sae, and the burden o proo is

on the developer. (The denit ion o saety also

changes rom law to law.) On the other hand,

new, conventionally bred whole-ood varieties

may be introduced to the market without any

prior regulatory review; the ood manuacturer is

responsible or ensuring the saety o ood. While

biotechnology products are regulated under these

general authorities, each agency has had to in-

terpret and apply these laws to biotechnology

products through regulations and guidance.

Even ater more than 20 years, the regu latory

ramework or rDNA biotechnology products

continues to evolve1 and generate controversy.

Some critics have argued that t he biotechnol-

ogy regulatory system is i nadequate to address

the range o potential risks posed by various

biotechnology products (see, e.g., McGarity,

2002; Bratspies, 2004), while others argue that

biotechnology is heavily overregulated (see,

e.g., Miller & Conko, 2005; McHughen, 2007;

Strauss, 2003).

Despite these continuing debates, the regulatory

system or biotechnology has generally worked

as intended. Useul and valuable new products

developed through rDNA biotechnology have

come to the market. Recombinant DNA bio-

technology has revolutionized the development

o new drugs, therapies and medical diagnostics.

An estimated 200 new therapies and vaccines

have been developed through biotechnology,

with hundreds more in clinical testing (Biotech-

nology Industry Organization, 2008). In agricul-

ture, companies have developed new varieties o

pest-resistant and herbicide-tolerant corn, soy-

beans, cotton and canola that have been rapidly

adopted by U.S. and Canadian armers (U.S.

Department o Agriculture, National Agricul-

tural Statistics Service, 2008). In 2006, publicly

traded U.S. biotech companies were estimated

to have generated nearly $59 billion in revenues

(Biotechnology Industry Organization, 2008).

During this period, the biosaety record o new

biotechnology products has been reassuring. Cer-

tainly, the major ears that were expressed in the

early stages o the technology have not come to

pass.2 Whether that result is because scientists and

industry have been cautious, because regulators

have done a good job in keeping risky products

Genetcall Engneeredorgans

Agen La

PlANTS

A Pants USDA-APHIS PPA

ANIMAlS

Animals (including fsh) FDA FDCA

Livestock USDA AHPA; ADCA

MICRooRgANISMS EPA; USDA TSCA; PPA

Genetcall Engneeredorgans

Agen La

HUMAN FooDS

wle Fds

Pants (i.e., veetabes, ruits) FDA-CFSAN FDCA

Meat, Putry, and esUSDA-FSIS FMIA; PPIA; EPIA

FDA-CVM FDCA

Fish FDA-CVM FDCA

Fd Artcles

Fd additives FDA-CFSAN FDCA

Dietary suppements FDA-CFSAN FDCA

HUMAN FooDS FDA-CVM FDCA

DRUgS AND BIologICS

Human drus FDA-CDER FDCA

Human biics FDA-CBER FDCA

Anima drus FDA-CVM FDCA

Anima biics USDA-APHIS VSTA

HIgH-VAlUE PRoDUCTS

Csmetics FDA-CFSAN FDCA

TABLE 2. FEDERAL LAwS PoTENTiALLy APPLiCABLE To GE

oRGANiSmS AND PRoDUCTS DERivED FRom ThEm

(uncertain areas in italics)

TABLE 3. ThE REGULATioN oF PRoDUCTS DERivED FRom

GENETiCALLy ENGiNEERED oRGANiSmS

(uncertain areas in italics)

Surce: Pew Initiative n Fd and Bitechny (2004).


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o the market or because o simple good ortune,

remains a debatable question. In the absence o

perceived ood- or drug-saety problems, many

U.S. consumers remain unaware o the ubiquity

o biotechnology products (PIFB, 2006). What-

ever the reasons, the U.S. public has acquiesced in

the introduction o biotechnology products and

appears to trust the regulatory system to ensure

saety. A more dicult question i s whether the

regulatory system has had the eect o keeping

sae and useul products o the market by rais-

ing regulatory and economic barriers to entry, as

some have argued (Miller & Conko, 2005).

That is not to say that the regulation o biotechnol-

ogy, particularly in the area o agriculture and ood,

has been without problems in the United States.3

But U.S. regulation has been straightorward by

comparison with that in other parts o the world,

especially Europe, where popular opposition to ge-netically engineered ood and crops remains strong.

The reasons or European rejection o genetically

engineered oods are complex (Jasano, 2005), but

one major actor unquestionably is the mad cow

ood crisis in the mid-1990s, which shook consum-

er condence in the saety o the ood supply and

created distrust o the governments that had been

consistently assuring the public that bee was sae

to eat. For a number o reasons, politicians in the

European Union (E.U.), refecting European public

opinion, have been reluctant to approve genetically

engineered oods and crops, despite general scien-

tic agreement that they are likely to be substan-

tially equivalent to their conventionally produced

counterparts. E.U. policy, in direct contrast with

U.S. policy, more stringently regulates genetically

engineered crops and oods under specic new laws

and requires mandatory labeling. As a consequence

o regulation and consumer opinion, ew genetical-

ly engineered crops and oods have been approved

and even ewer are oered or sale in the market.

This policy confict has led to trade disputes and

unquestionably slowed the global introduction o

agricultura l biotechnology.

Could the same divergence pattern emerge with

synthetic biology? Early analyses o press cover-age o synthetic biology in the United States and

the European Union have shown a more pre-

cautionary raming in Europe with a ocus on

a much wider range o potential risks (Pauwels

& Irim, 2008). For example, U.S. news stories

were more likely than European news stories to

ocus on potential benets o synthetic biology.

Federa reuatrs chared

with respnsibiity r

prtectin pubic heath and

the envirnment rapped with

appyin existin aws t new

bitechny prducts.


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C. Synthetic Biy Future: The Reevance BitechnyReuatin t Synthetic Biy

In many ways, the current status o synthetic bi-

ology can be roughly compared to the situation

acing molecular biologists in the mid-1970s. Syn-

thetic biology remains a loosely conederated set o

technologies and disciplines, although its potential

power has been amply demonstrated. Much o the

ongoing work is at the undamental research level,

as scientists continue to try to understand how to

design synthetic genetic constructs and to synthe-

size larger sequences o DNA. How quickly this sci-

ence will advance is dicult to predict. Designingsynthetic microorganisms may turn out to be much

more dicult than anticipated (Aldr ich, Newcomb,

& Carlson, 2008). On the other hand, given the

recent history o unexpected developments in the

biological sciences, it is possible that progress could

be quite rapid and that products could be heading to

the marketplace in the not-too-distant uture.

Given the status o synthetic biology, are the poli-cies and approaches developed over the past two

decades to address similar concerns about rDNA

technology appropriate to apply to synthetic bi-

ology research and commercialization? To what

degree, i any, do the guidelines and regulations

developed or rDNA technology apply to syn-

thetic biology research and commercialization?

In examining those questions, this report will o-

cus primarily on the potential risks to the public

health and the environment o an accidental release

o a harmul synthetic microorganism, and on the

health and environmental impacts o synthetic mi-

croorganisms intended or non-contained uses in

the environmentthe same concerns expressed

in the early development o rDNA biotechnology.

To be sure, synthetic biology raises other signi-

cant concerns. The issue o biosecurity has already

received signicant debate, particularly in the aca-demic and deense communities. It is not the intent

o this report to revisit those issues (National Science

Advisory Board or Biosecurity, 2006; National

Research Council, 2004; Garnkel, Endy, Epstein,

& Friedman, 2007). Synthetic biology also raises

signicant ethical, religious and social impact issues

(Balmer & Martin, 2008). When the rst reproduc-

ing synthetic organism is created at some point in

the uture, it will inevitably rekindle the controversyover the propriety o creating lie previously raised

by some rDNA biotechnology applications. Issues

relating to patents and intellectual property are also

likely to be controversial and complex. While all

these issues are clearly signicant and will have ma-

jor implications or the uture trajectory o synthetic

biology, they are beyond the scope o this study.

iven the recent histry

unexpected devepments in the

biica sciences, it is pssibe

that prress cud be quite

rapid and that prducts cud

be headin t the marketpace

in the nt-t-distant uture.


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synthetic biology that covers all the activities currently

being carried out under that title. The Royal Society

has dened it as an emerging area o research that

can broadly be described as the design and construc-

tion o novel articial biological pathways, organisms

or devices, or the redesign o existing natural biologi-

cal systems (The Royal Society, 2008). One writer

attempted to summarize it as the area o intersection

o biology and engineering that is ocused on the

design and abrication o biological components and

systems that do not already exist in the natural world,

and the redesign and abrication o existing biologi-

cal systems (Bhutkar, 2005). One group summed

up the variety o activities with the observation that

synthetic biology is the engineering o biology: the

synthesis o complex, biologically based (or inspired)

systems, which display unctions that do not exist in

nature. This engineering perspective may be applied

at all levels o the hierarchy o biological structures

rom individual molecules to whole cells, tissues and

organisms. In essence, synthetic biology will enable

the design o biological systems in a rational and

systematic way (European Commission, 2005).

Perhaps a better way to understand the emerging dis-

cipline o synthetic biology is to look at some examples

o current research. Craig Venter, the scientist who

raced the government-sponsored Human Genome

Project with a novel sequencing method, is leading

several research initiatives. At the Institute or Genomic

Research (now part o the J. Craig Venter Institute),

researchers have become interested in determining

the minimal set o genes required to support lie.

Working with the M. genitalium bacterium, an organ-

ism with one o the smallest genomes consisting o

only 517 genes, researchers were able to reduce the

number o genes to a core set o between 265 to 350

genes that still enabled the bacterium to sustain lie.

Beyond its purpose in helping understand the unctions

o genes, part o the motivation or this research is the

concept o creating a small, fexible and universal bac-

terial platorm that could be modied with dierent

gene packages to carry out dierent unctionssuch

as producing drugs or industrial chemicals.

Eorts to build whole-length genomes rom scratch,

using genomic-sequence inormation, have been go-

ing on or some time. In 2002, a team o researchers

made headlines or assembling an inectious poliovirus

directly rom nucleic acids in the laboratory (Cello,

Paul, & Wimmer, 2002). In the ollowing year, re-

searchers at the Venter Institute succeeded in con-

structing the genome o a similar-length virus in only

two weeksin contrast to the year it took to assemble

the poliovirus (Smith, Hutchinson III, Pannkoch, &

Venter, 2003). In 2005, scientists reconstructed the

genome o the 1918 strain o infuenza fu virus, usingsamples o DNA taken rom rozen cells o victims to

generate a genetic sequence to copy (Tumpey, et al.,

2005). These studies launched a signicant debate

about the biosecurity implications o sequencing and

synthesizing inectious and pathogenic agents.

More recently, in February 2008, researchers at

the Venter Institute announced the largest synthe-

sized whole genome to datethe nearly 600,000

base-pair-long genome oM. genitalium. Evidencing

the continuing acceleration o genetic sequencing

and synthesizing technologies, the M. genitalium ge-

nome was an order o magnitude larger than any pre-

viously synthesized DNA product (Casci, 2008).

An example o the construction category o synthetic

biology is provided by Drew Endy (now at Stanord)

and his ormer colleagues at the Massachusetts Institute

o Technology (MIT), who have established the Bio-

bricks Foundation (http://bb.openwetware.org/), a

non-prot organization that is attempting to create an

open catalog o standardized DNA parts that encode

basic biological unctions, such as a switch that turns

gene expression on or o. Based on the open-source

sotware philosophy, these BioBrick parts are made

reely available or researchers around the world. Each

year, the oundation supports the International Ge-

netically Engineered Machine competition in which

undergraduate student teams compete to construct

novel biological machines using BioBrick standard

parts (www.2008.igem.org). In 2007, entries included

bacteria that mimic the behavior and property o red

blood cells, inector detector organisms that detectedantibiotic resistant microbes and a bacterial-based pho-

tographic imaging system (Lichtenstein, 2007).

Other research that comes under the umbrella o

synthetic biology includes eorts to create synthetic

DNADNA that is not limited to the naturally

occurr ing base pair combinations o A-T, G-C. Ex-

panding the genetic alphabet by creating novel

chemical base pairs could be useul or any number


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B. Ptentia Appicatins

Despite these scientic breakthroughs, synthetic bi-

ology or the most part remains at the basic research

stage. Most o the unding or synthetic biology work

comes rom the public sector, although venture capi-

tal appears to be slowly increasing, particularly in

the area o biouels, discussed in more detail below

(International Risk Governance Council, 2008;

Aldrich, Newcomb, & Carlson, 2008). With some

o the exceptions noted below, most observers do

not expect commercial applications to arise rom

synthetic biology or another decade. However,

as is always the case with technology, unoreseen

breakthroughs could enable more rapid technology

development than currently expected. Given the

current state o the science, several observers have

suggested that it i s quite conceivable that in 10 years

we will be able to ully redesign or make new cells,

bacteria or viruses (Serrano, 2007). Craig Venter in

2004 predicted that engineered cells and lie orms

would be relatively common within a decade (Fer-

ber, 2004). Nevertheless, many signicant technical

hurdles remain (Holt, 2008).

While the time horizons may be uncertain, researchers

envision an astonishing array o potential synthetic biol-

ogy applications: more ecient production o vaccines

or human and animal health and related diagnostics,

new and improved drugs, bio-based manuacturing,

sustainable energy production rom renewable sources

and bioremediation o environmental contamination

(Pieper & Reineke, 2000) and biosensors capable o de-

tecting toxic chemicals (International Risk Governance

Council, 2008). While similar goals are being pursued

using conventional technologies, synthetic biology o-

ers several potential advantages. Synthetic microorgan-

isms might be capable o producing pharmaceutical or

industrial compounds that would be very dicult to

produce using existing chemical or biological tech-

niques. Further down the line, synthetic biology may

o purposes, including the potential to penetrate cell

wells and neutralize undesirable RNA molecules

(Pollack, 2001; Geddes, 2008). Scientists have al-

ready developed diagnostic tests that use a rticial

nucleotides to screen or HIV, cystic brosis and

other diseases (Benner, 2004). Other eorts are o-

cusing not just on genetic sequences but on whole

proto-cells that would create synthetic living cells

(Szostak, Bartel, & Luisi, 2001; OMalley, Powell,

Davies, & Calvert, 2007).

How does synthetic biology dier rom rDNA bio-

technology? To some extent, synthetic biology is an

extension o biotechnology; there is a certain amount

o overlap, and no clear dening line between the

two areas.5 For example, molecular biology and

rDNA techniques can also be used to alter genetic

sequences. However, DNA synthesis technologies

provide a much more ecient way to achieve the

same ends, permitting scientists to ocus on novel

designs unlimited by natural constraints. As one study

explained, Whereas other recombinant DNA meth-

ods start with an organisms genome and modiy it

in various ways, with results that are constrained by

the original template, synthetic genomics permits

the construction o any specied DNA sequence,

enabling the synthesis o genes or entire genomes

(Garnkel, Endy, Epstein, & Friedman, 2007).

Because synthetic biology is not limited to us-

ing existing organi sms, synthetic biology allows

more complex and sophisticated engineering

than can be achieved through recombinant DNA

techniques. Current biotechnology techniques

generally ocus on modiying components o

living cells to achieve a desired unction, such as

splicing a gene rom one organism to another, or

orcing a mutation in a gene or a specic pur-

pose. In contrast, synthetic biology is concerned

with designing and building articial regulatory

elements into genomes or constructing a com-

plete genome rom scratch (Bhutkar, 2005). As

Jay Keasling o the University o Caliornia at

Berkeley, explains, Were talking about tak ing

biology and building it or a specic purpose,

rather than taking exist ing biology and adapting

it. We dont have to rely on what natures neces-

sarily created (Pollack, 2006).


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19

even be able to create molecular-sized tools or tissue

repair and cell regeneration (European Commission,

2005). Scientists at the Caliornia Institute o Technol-

ogy are working on synthetic biological switches that

would reside within a cell and detect and destroy cancer

(Pollack, 2006). Synthetic biology may enable public

health ocials to quickly design and produce synthetic

vaccines in order to respond to rapidly evolving viruses

(Garnkel, Endy, Epstein, & Friedman, 2007). Ari

Patrinos o Synthetic Genomics has talked about using

synthetic genomics to nd the holy grail: microbes

that would convert carbon dioxide into a eedstock or

biouels and biochemicals (Patrinos, 2008).

1. BfuelsWhile most o these applications remain in an indenite

uture, many believe that the rst potential application

(the killer app) o synthetic biology may well be in

the area o biouels (Wade, 2007). Biouels come rom

renewable resources that can be grown in the United

States and have the potential to be carbon-neutral, there-

by serving the twin policy goals o reducing dependence

on imported oil and reducing the carbon impact o ossil

uels. Given high energy prices, the environmental andeconomic limitations o producing ethanol rom corn

and signicantly increased public and private unding or

R&D o alternative uel sources, researchers are ramping

up eorts to use synthetic biology to create biouels.

One area o research interest is the development o

alternative and improved eedstockssuch as switch-

grass and other cellulosic biomassto produce biouel.

The major technical limitation with such eedstocks

is that they typically have dense cell structures that

must be broken down to yield the sugars rom which

biouels are madea process that is in itsel energy

intensive. To make the biouel process more energy

ecient, and thereore more economical and environ-

mentally sustainable, scientists are using biotechnology

and synthetic biology tools to look at several points

in the biouel process where biology could make a

signicant dierence. One area o interest is in devel-

oping a microbe with the ability to both extract the

sugars rom cellulosic biomass and to convert those

sugars to uel, consolidating the separate biological

processes and thereby reducing the costs o extraction

(Lynd, van Zyl, McBride, & Laser, 2005).

The most advanced use o synthetic biology to create

biouels, however, has been in the development o syn-

thetic microbes that can more eciently convert sugars

directly to uels that are directly compatible with the

range o uels currently used (i.e., gasoline, diesel, jet

uel). Several companies have small-scale pilot projects

that have demonstrated technical easibility, but scal-

ing up to produce industrial quantities o biouels at acompetitive price remains a signicant challenge.

While it is dicult to say how close any o these

products may be to being commercialized, at least a

hal-dozen companies are developing products in this

area, and several claim to have products or processes

that are close to testing on larger scales. Whether all o

these microorganisms can be considered products o

synthetic biology or simply advanced biotechnology

is not always clear; or the most part, the companies

listed below have claimed that they are using synthetic

biology techniques. A non-exhaustive illustrative list

o these companies activities are noted below.

LS9(www.ls9.com), a company located in South SanFrancisco and ounded by Harvard Medical School

proessor o genetics George Church, is developing a

proprietary microbe through synthetic biology to en-

able the development o a variety o products that will

be directly comparable to existing uels derived rom

oil, such as gasoline, diesel and jet uel. Starting with

eedstocks such as sugarcane and cellulosic biomass,

these synthetic organisms convert sugars directly intohydrocarbons more eciently than current methods.

In September, 2008, LS9 opened a pilot plant to test

this technology with the goal o a constructing a

50,000- to 100,000-gallon production acility by

2011 to produce a replacement or diesel uel.

Ars(www.amyris.com) is a Caliornia startupcompany using synthetic biology to develop engineered

microbes to produce high-value compounds, includ-ing renewable biouels. Like LS9, Amyris is looking

to use its proprietary microbes to produce diesel rom

sugarcane stock. According to Amyris, the new biouel

process should achieve lower costs and greater scale than

vegetable oil-based biodiesel. In 2008, Amyris signed

an agreement with Crystalsev, one o Brazils largest

ethanol distributors and marketers, to begin scaling

up or commercialization in 2010. The joint project


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predicts being able to produce 30 million gallons o

diesel as early as 2010, with gasoline and jet uel produc-

tion ollowing within one to two years.

oPX Btecnlges(www.opxbiotechnologies.com),located in Boulder Colorado, uses synthetic biol-ogy to design custom organisms in biouel production to

reduce production costs. In addition to its engineering ca-

pability, OPX is using a search technology platorm to scan

genomes and identiy potentially useul gene sequences,

enabling the testing and engineering o microbes 1,000

to 5,000 times aster than conventional methods, accord-

ing to the company. The company states, Our ability to

understand rapidly the workings o microbes at the indi-

vidual gene level and test a huge number o modicationssimultaneously enables us to engineer new microbes that

can provide major improvements in tolerance, productiv-

ity, and specicity or uel and chemical production.

Slae(www.solazyme.com), another South SanFrancisco rm, is using a patented process to make biod-

iesel rom genetically modied marine algae. The uel,

named Soladiesel, is being road-tested in Caliornia, and

the company expects to be producing commercial quan-tities in several years. Solazyme is also working on other

synthetic biology applications. The company promotes its

expertise in automated directed evolution (i.e., screening

mutated organisms or desirable unctions), optimizing

production strains and metabolic engineering.

Ge (www.gevo.com), located in Denver, has the

goal o developing new cellulase genes, testing them

in mixtures o enzymes and then engineering those

genes into bacteria that wil l eciently convert sugars

into butanol and isobutanol at costs comparable to

those o current ethanol production.

Sntetc Gencs(www.syntheticgenomics.com), ounded by Craig Venter, may have the most

ambitious R&D plans. The company is pursuing

paths similar to those o the companies above, search-

ing or and engineering microorganisms that directly

convert eedstocks (such as sugar and cellulose) into

biouels. The company recently predicted that a pilot-

scale project or liquid biouels would be operating

within two years, with large-scale production by

2013. In addition, Synthetic Genomics is lookingmore broadly at the renewable-uel process, includ-

ing the genetic modication o eedstocks to increase

yields in sugars and oils and potentially enhancing soil

microbes to improve eedstock perormance (Patri-

nos, 2008). In addition, the company has partnered

with BP to use synthetic genomics or enhancing the

biological conversion processes or subsurace ossil

uels, such as oil shale, natural gas, oil and coal.

2. Paraceutcals

Just as genetic engineers used the tools o recombinant

DNA to develop engineered bacteria to produce in-

sulin and other valuable drugs and chemicals, scientists

are using the more advanced tool set o synthetic biol-

ogy or the same purposes. The high value o biophar-

maceuticals makes this area attractive both to venture

capital investors and to philanthropic oundations like

the Bill & Melinda Gates Foundation. At this early

stage o research, most o the work is being done at

universities and university-based startup companies,

rather than at large pharmaceutical companies.

One area o research involves engineering the meta-

bolic pathways o microorganisms to dramatical-

ly increase the production o terpenoids, a class o

molecules with wide-ranging pharmaceutical ap-

plications, including anti-cancer and anti-malarial

properties (Ajikumar, Tyo, Carlsen, Mucha, Phon,

& Stephanopoulos, 2008). Jay Keasling, at the Uni-

versity o Cal iornia, Berkeley, published work in

2006 demonstrating the modication o a yeast to

produce artemisinic acid, a precursor o artemisinin,a highly eective drug against malaria (Ro et al.,

2006). Artemisinin is currently derived rom the

sweet woodworm plant, but is expensive and in short

supply.6 Keaslings process is being ur ther developed

to optimize yield and increase scale o production by

Amyris, the Caliornia synthetic biology company

with which Keasling is associated. Amyris, which is

being supported in this eort by the Bill &Melinda

Gates Foundation, has indicated that it will take noprots rom this technology. (Keasling is using a simi-

lar platorm in his or-prot biouel work.) In March

2008, Amyris announced that it had partnered with

the Institute or OneWorld Health, a U.S.-based non-

prot pharmaceutical company, and the pharmaceu-

tical company Sano-Aventis, or the development

and commercialization o synthetic artemisinin, i

they can achieve certain technological benchmarks.


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be sold until the appropriate regulatory agency has

ound that they are sae, based on evidence submit-

ted by the developer.

Whether a new technology is ramed as presump-

tively risky or sae has signicant implications, not

only or the protection o public health and the

environment but also or its commercialization.

Laws and regulations that require a mandatory

pre-market saety-approval process may provide a

higher level o protection and precaution, but at the

cost o an expensive, lengthy and oten-uncertain

regulatory process. Typically, the developer needs

to provide the agency with the inormation it needs

to determine that the product is sae. That may in-volve years o testing to meet strict agency protocols

or addressing various concerns. As a consequence,

mandatory pre-market approval approaches create a

airly high barrier to entry to new products, thereby

conficting with the policy goal o encouraging

the introduction o valuable new products to the

marketplace. This confict is particularly apparent

in the cases where a new technology, though not

without some risk, appears to be signicantly saer

than a product already on the market. (At the same

time, having regulatory approval provides an eco-

nomic benet to the developer by helping ensure

market and consumer condence in the saety o

the new product.)

On the other hand, allowing a new technology to

come to market more quickly, without a pre-mar-

ket saety-approval process, increases the chance

that some harmul product will be missed by

regulators. Balancing the confict between these

two policy goalsprotecting public health and

the environment on the one hand and encour-

aging valuable and innovative new products on

the otheris a well-recognized challenge. The

history o FDA drug regulation provides ample

examples where the FDA has been roundly criti-

cized or dragging its heels in approving helpul

new drugs in some years, and then pilloried or

recklessly approving dangerous drugs in other

years. Policymakers need to balance the desire

to avoid over-regulation on one handthat is,

keeping truly beneicial sae products o the

marketwith a desire not to under-regulatethat is, allowing a tru ly harmul product onto

the market. This is the traditional Goldilocks

dilemma: determining how to impose only those

regulatory controls and costs that are necessary to

match the actual risks o a product.

When they have the legal fexibility to do so, regu-

lators oten turn to the process o risk assessment to

help them determine the potential risk o novel prod-

ucts and new technologies and to tailor appropriate

risk management controls. While risk assessment in

theory provides an approach with the potentia l or a

more nuanced and tailored approach to risk manage-

ment, it suers rom several limitations. As noted in

more detail below, risk assessment requires inorma-

tion, and in many cases inormation about risks o a

new technology is simply unavailable or uncertain.

In such cases, the regulatory decision depends upon

the deault policy assumptions about the inherent

saety o the technology. In turn, the deault policy

assumption is shaped by the raming o the new tech-

nology in relation to existing technologies.9

For example, in the 1980s, the FDA was aced with

the decision o whether to regulate oods derived

rom genetically engineered crops. I genetic engi-

neering was ramed as a signicant departure rom

conventional breeding techniques, the FDA could

have chosen to regulate the new proteins introduced

into genetically engineered oods as ood additives

under the Federal Food, Drug, and Cosmetic Act

(FDCA), thereby triggering a mandatory pre-market

approval o the ood additives saety. On the otherhand, i genetic engineering was ramed as being

substantially the same as conventional breeding

technologies, then the FDA could treat genetically

engineered oods without a mandatory pre-market

approvalthe same as any other new variety o po-

tato or whole ood. With the latter approach, the rel-

evant risk assessment question would not be whether

the genetically engineered variety was sae; the ques-

tion instead would be whether it was as sae as its

conventionally produced counterpart. The level o

inormation needed to support a nding o saety

would have been signicantly more demanding than

the inormation required to make the assessment that

a ood was simply as sae as another variety.10 Thus,

FDAs risk assessment or genetically engineered oods

depended to a signicant extent on the policy deci-

sion to treat such oods as being comparable to new

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B. Synthetic Biy: Framin and Risk Characterizatin

The initial raming question is whether the haz-

ards posed by synthetic biology are similar to

or qualitatively dierent rom those posed by

rDNA engineering or other genetic engineer-

ing techniques. Scientists h ave long argued that

genetic engineering poses no unique environ-

mental or public health risks, and that thereore

the relevant regulatory question is the risk o

the nal product, not o how it was produced.

Similarly, synthetic biology researchers argue

that synthetic biologyparticularly in its cur-

rent state o developmentis just an extension o

rDNA and other genetic engineering techniques.

Synthetic biology acil itates the manipulation o

the structure o genetic elements and provides

researchers with a more ecient means to en-

gineer organisms. Engineered genetic pathways

will still be based on naturally occurring com-

ponents, and the engineered construct must still

unction within the connes o the biological re-

quirements o a living organism. In the end, the

nal productsi.e., engineered organismsare

similar to t hose produced by other genetic engi-

neering techniques. As a result, some synthetic

biology researchers argue that there should be no

distinction drawn between synthetic biology and

other genetic engineering techniques.

As Benner states, Much o what is current-

ly called synthetic biology is congruent with

recombinant DNA technology discussed in Asi -

lomar 30 years ago. This includes bacteria that

express heterologous genes, proteins in which

amino acids have been replaced, and cells with

altered regulatory pathways. Placing a new name

on an old technology does not create a new haz-

ard (Benner & Sismour, 2005).

The emphasis on the continuity with past technol-

ogy is a ami liar pattern in the raming o a new

technology. Similar arguments were made both

with rDNA technology and nanotechnology.11

The not new raming then becomes an argu-

ment or maintaining that existing regulations are

sucient to deal with the new technology.

Future developments in synthetic biology, how-

ever, could alter that view. Synthetic biology

is likely to be not only a more ecient genetic

engineering technology but also a means to

engineer much more complex genetic modi-

ications than can be accomplished through

standard genetic engineering techniques. In

addition, synthetic biology may enable the

modications o organisms with genetic ele-

ments designed rom scratch that could have

properties that are quite dierent rom those

that can be created through todays genetic

engineering techniques. How ar natural

biologic limits can be stretched remains to be

seen and is indeed a major ocus o synthetic

biology research. It is, o course, the very di -

erence between synthetic biology and other

genetic engineering techniques that makes its

anticipated novel applications possible.

While synthetic biology provides more powerul

tools or genetic engineering, there is no basis to

assume that the novelty o the process itsel poses

new or enhanced risks. Instead, the kinds o ge-

netically engineered products that are likely to

be produced using synthetic biology are similar

to those produced through other direct genetic

engineering and conventional breeding tech-

niques. The more relevant regulatory question,

then, is whether the novel engineered organisms

created through synthetic biology are likely to

present new or enhanced risks compared to those

o other genetic engineering techniques.

Most scientists believe that the biosaety risks o

synthetic biology products are the same ki nds

o risks presented by products o other genetic

engineering. For example, Serrano states that

the risks associated with the accidental release

o synthetic biology products are in act simi-

lar to the current biosaety problems associated

with genetically modied crops, the use o en-

gineered microorganisms to enhance production

o desired targets etc. (Serrano, 2007).


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What are the risks o genetically engineered

organisms? Are organisms created through syn-

thetic biology likely to pose dierent risks or a

dierent level o risk? What are the risks associ-

ated with the likely rst generation o synthetic

biology products, such as synthetic microorgan-

isms used to produce biouels, industria l chemi-

cals and pharmaceuticals?

1. Accdental Release Rsk Assessent

The rst ri sk scenario involves the accidental re-

lease o a synthetic microorganism12 rom a labo-

ratory or other contained environment, such as a

commercial bioreactor. Because such organisms

are potential ly capable o reproduction, evolutionand spread through the environment, the risks o

synthetic microorganisms, like other genetically

engineered microorganisms in general, are di-

erent rom those o conventional chemicals. I a

synthetic microorganism is inectious, pathogen-

ic, toxic or capable o reproduction, an accidenta l

release could pose a risk to laboratory workers,

the health o the adjacent communities, and the

environment (Tucker & Zilinskas, 2006).

This issue is especially important or synthetic

biology since the applications likely to emerge

in the near uture are microorganisms that are

intended or contained use, either in academic

or industrial research laboratories, or as part o

a closed-end industrial production process to

produce a nal, oten conventional, industrial

or pharmaceutical chemical. Since these micro-

organisms will not be intended or use outside

o a contained production acility, it will be im-

portant to assess the risks associated with an ac-

cidental release rom such contained acilities.

An initial consideration in assessing the risk i s the

probability o a synthetic microorganism being

able to reproduce and spread should it e scape the

contained environment. Some biological scientists

assume that accidentally released synthetic micro-

organisms will pose a minimal risk because they are

unlikely to surv ive in the natural environment.

The more dierent an articial living system isrom natural biological systems, the less likely

it is that the articial system wil l survive in the

natural world The 30 years o experience

with genetically altered organisms since Asilo-

mar have indicated that virtually any human-

engineered organism is less t than its natur al

counterpart in the natural environment. I they

survive at all in the environment, they do so

either under the nurturing o an attentive hu-

man, or by ejecting their engineered eatures(Benner & Sismour, 2005).

Other scientists are less condent about the abil-

ity to predict the survival and spread o synthetic

microorganisms, particul arly more complex or-

ganisms l ikely to be developed in the longer term.

Near-term products, derived rom well-under-

stood bacterial hosts and natural genetic sequences,

other scientists are ess

cnfdent abut the abiity t

predict the surviva and spread

synthetic micrranisms,

particuary mre cmpex

ranisms ikey t be

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are likely to be comparable in risk to currently pro-

duced genetically engineered organisms. However,

uture synthetic organisms created rom scratch

will lack a clear genetic pedigree and could have

emergent properties ar ising rom the complex

interactions o its constituent genes. Accordingly,

the risks attending the accidental release o such

an organism rom the laboratory would be ex-

tremely dicult to assess in advance, including

its possible spread into new ecological niches and

the evolution o novel and potentially harmul

characteristics(Tucker & Zilinska s, 2006).

The potential uture ability to construct organ-

isms containing articial DNA with non-con-ventional base pairs also ra ises questions about the

ability o such organisms to survive, reproduce

and spread i accidentally released. Some scien-

tists argue that such organisms would be highly

unlikely to surv ive. [I ] a completely synthetic

lie orm ... has eight nucleotides in its genetic

alphabet, [it] would nd survival very dicult

i it were to escape rom the laboratory. What

would it eat? Where would it get its unnatural

nucleosides? (Benner & Sismour, 2005).

A second element o a risk assessment is deter-

mining the hazard should an organism be acci-

dentally released, become established, reproduce

and spread. Not all engineered microorganisms

would pose a health or an environmental risk

i there was an accidental release. With rDNA

molecular research, as with microbiological

research in general, risk is assessed largely on

the underlying risk o the donor or host organ-

isms: or example, known pathogens obviously

pose greater risk i released than benign organ-

isms.13 As a consequence, the NIH Guidelines

or Research Involving Recombinant DNA

Molecules (discussed in more detail below) re-

quire containment measures to be proportionate

to the risk characterist ics o the host or donor

organisms. Organisms known to be extremely

dangerous must be handled in the highest-level

biosaety connement laboratories. Thus the

probability o a harmul accidental release is

reduced by biosaety management practices in-tended to ensure containment and prevent the

spread o dangerous inectious agents. While

there have been rare reported incidents o harm-

ul accidental releases o dangerous microbio-

logical agents rom laboratories,14 the long and

generally sae record o research laboratories

in handling k nown dangerous agents should

provide assurance that researchers have the ca-

pability to protect workers and the surrounding

community rom dangerous microorganisms,

engineered or naturally occurring.15

2. intentnal Nn-cntaned Use

The second risk scenario involves the poten-

tial health and environmental risks associated

with a synthetic organism that ha s been designed

or use in a non-contained setting. Examples

include the use o synthetic microorganisms in

ermentation ponds used or industrial chemical

production, or applications such as microbial

pesticides, bioprocessing agents to help seques-

ter or capture carbon or bioremediation agents

that would require use in the open environ-

ment. Unlike microorganisms intended solely

or contained use, synthetic organisms intended

or non-contained use will be specically engi-

neered to survive and unction in the environ-

ment into which they are being released. As a

result, they are more likely to be t or surviva l

and competition in the natural environment

than organisms intended solely or contained

use, making the r isk o reproduction, spread andevolution more probable.

The potential environmental concerns about

such synthetic microorganisms all into sever-

al categories. One concern is that a synthetic

microorganism designed or a particular task

could interact with naturally occurring organ-

isms and adversely aect the environment. This

could occur i the synthetic organism inects or

displaces existing organisms (including plants

and animals), or otherwise intereres with the

existing balance o the ecosystem into which

it was released. I the synthetic organism es-

tablishes itsel in an ecological niche, it might

become diicult to eradicate. There is also a

potential risk that some o the synthetic genetic

traits could be spread through gene fow to other


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natural microorganisms, resulting in the spread

o unwanted traits or the inclusion o articial

genetic sequences in related organisms, i the

trait provides a tness advantage (Bhutkar, 2005;

Tucker & Zilinskas , 2006).

In addition, the propensity o microorganisms

to evolve when placed in an environment with

multiple selective pressures creates problems.

For synthetic biology engineers, the challenge

is to nd ways to prevent the microorganisms

rom evolving and potentially losing their en-

gineered trait: ater all, engineers want their

inventions to remain stable and to continue to

unction as designed over many generations. Forrisk assessors, the potential or microorganisms

to evolve creates additional uncertainties, since

the pathway o evolution is dicult to predict.

It is one thing to assess the environmental risk

o the organism as designed, but quite another to

try to predict what the organism could become

many generations hence. Thus, developing ways

to prevent the unwanted evolution o synthetic

microorganisms is a challenge both or engineers

and or risk regulators.

As with saety practices or rDNA molecules in

laboratories, regulators have signicant experi-

ence with assessing the risks o genetically engi-

neered organisms intended or release into the

environment. Over the last 25 years, USDA and

EPA have reviewed and approved thousands o

applications or eld trials or experimental ge-

netically modied plants and microorganisms.

The type o review depends on the specic prod-

uct and its intended use, but typically agencies

assess such potential risks as toxicity, potential

invasiveness, impacts on other organisms (in-

sects, plants and animals) and the potential or

unwanted gene fow to wild relatives. The risk

assessment is based on a amiliar ity with the char-

acteristics o host and donor organisms and vec-

tors, consideration o the specic environment

into which the organism is intended to be used

and other actors. On the basis o the risk asse ss-

ment, agencies typically impose restrictions oneld trials o genetically engineered organisms to

prevent their unintended spread and to minimize

pot

Documents

Woodrow Wilson Center - Sloan - Hastings - Venter - Nano_synbio2_electronic_final