Sloan Group Re-worked Synthetic Biology Chapter

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cHAPtEr 35

Synthetic Biology

Mi hele S. Ga f kel, d ew E y, Ge al L. Eps ei , a robe M.F ie ma , Sy he i Biology, i From Birth to Death and Bench to Clinic: The Hastings Center Bioethics Briefng Book or Journalists, Policymakers,and Campaigns , e . Ma y c owley (Ga iso , nY: the Has i gs ce e ,2008), 163-168.

2008, the Has i gs ce e

All igh s ese ve . no pa o his book may be ep o u e , s o e i a e ieval sys em, o a smi ei a y om o by a y mea s (ele o i , me ha i al, pho o opyi g, e o i g, o o he wise), wi hou

he p io w i e pe missio om he publishe , ex ep o he i lusio o b ie quo a io s i a eview.

We have a emp e o p ovi e omple e a a u a e i o ma io ega i g he i ivi uals, o ga iza io s,a age ies es ibe i his book. Howeve , we assume o liabili y o e o s, omissio s, o amagesa isi g om he use o his B ief g Book.

tHE HAStInGS cEntEr

o Jou alis s, Poli ymake s, a campaig s

B ioethics B riefing B ook

from Birth to death and Bench to clinic


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SyNTHETIc bIOLOGy 16

synthetic biology

n S ntheti iolog helps solve iologi alengineering pro lems adapting engi-neering on epts to design and re onstru tnew iologi al parts, or redesign existing,natural iologi al s stems.

n S ntheti iolog also allows s ientists toqui l onstru t new geneti designs thatdire tl test their h potheses.

n S ntheti iolog revisits safet and se uri-t on erns first identified with the inventionof re om inant DNA te hnolog . Similarl ,s ntheti iolog raises oth familiar andnew so ial and ethi al questions.

n Some enefi ial appli ations of s nthetiiolog ould also e used in harmful or

unintentionall dangerous wa s.

n The onstru tion of minimal organismsraises distin t ethi al questions, su h ashow or whether su h wor hanges the

on ept of what life is.

n Resear h suggests that s ntheti iologma soon e a te hnolog of hoi e for anation or ioterrorist hoping to develop or

a quire a pathogen for use as a weapon.n Other issues in lude the potential impa t of

organisms reated s ntheti iolog onthe environment, the ownership of te h-nologies, and distri ution of the enefits of su h resear h and its produ ts.

Framing the Issue

Using a number of technologies and intellectual approaches,synthetic biology solves biological engineering problems bydesigning and reconstructing new biological parts, or systemati-cally redesigning existing, natural biological systems. Implicit inthis process are some as-yet unresolved issues for policymakers.For example, some applications of synthetic biology that benefitsociety could also be applied in ways that can harm it, or thatcould be unintentionally dangerous; the use of such technologiesin the development of a biological weapon, such as a virus, is anobvious concern. But also of concern is that scientists who arecarrying out legitimate experiments could without malice con-struct an organism with disease-causing potential.

The issue of safety is further complicated because applicationsof synthetic biology that are considered beneficial by some may

be perceived as harmful or dangerous by others. Perhaps the best-studied example of this sort of disagreement is that of theintroduction of genetically engineered (often referred to asgenetically modified) food crops. Use of these crops may bring

benefits, such as the possibility of using less pesticide, yet manyconsider any such modification to be inherently harmful in theabsence of compelling evidence to the contrary.

Discussion and debate regarding these issues need to engagepractitioners (including students), policymakers, research admin-istrators, and commercial providers of raw materials for theresearch, both among themselves and in conjunction with adiverse range of interested citizens and civil organizations.

Background and ScienceThe concept of synthetic biology as an approach to biological

engineering dates to the mid-1970s when the advent of readilyavailable enzymes and other materials allowed pieces of DNA to

be easily swapped between organisms. The last 10 years have been a time of tremendous improvement in the ease of specific

techniques associated with synthetic biology, and this, along withrapidly falling costs and the dispersion of experimental approach-es once thought to be the domain of elite biologists, has resultedin the dissemination of synthetic biology widely (among sectorsand academic approaches) and deeply (from Nobel Prize winners

Mi hele S. Garfin el, Drew End , Gerald L. Epstein, and Ro ert M. Friedman

Michele S. Garfinkel, PhD, is a policy analyst for the J. Craig Venter Institute,Drew Endy, PhD, is assistant professor of synthetic biology at Stanford University, Gerald L. Epstein, PhD, is a senior fellow for science and security for the Center for Strategic and International Studies, and Robert M. Friedman,PhD, is deputy director for California at the J. Craig Venter Institute.

H I G H L I G H T S

Michele S. Garfinkel, PhD, Policy Analyst,J. Craig Venter Institute mgarfin el@

j vi.org, 301-795-7413

Drew Endy, PhD, Assistant Professor,Synthetic Biology, Stanford end @stan-ford.edu, 650-498-6135

Gerald L. Epstein, PhD, Senior Fellow for Science and Security, Center for Strategic and International Studies gepstein@

sis.org, 202-775-3125

Robert M. Friedman, PhD, Deputy Director for California, J. Craig Venter Institute rfriedman@j vi.org, 301-795-7390

Gregory E. Kaebnick, PhD, ResearchScholar, The Hastings Center

ae ni g@thehastings enter.org, 845-424-4040, x227

E X P E R T S T O

C O N

T A C T


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to high school students). Recent results of suchexperiments include:

n The construction of an infectious poliovirusgenome from oligonucleotides (short frag-ments of DNA that are strung together in the

laboratory)n The reconstruction of bacteriophage T7 to

simplify its genome (demonstrating that natu-rally occurring genomes can be systematicallyredesigned and rebuilt for further research orfor specific applications)

n The synthesis of a 582,970-base-pair genomeof Mycoplasma genitalium (showing that thefull genome of a replicating organism can beconstructed in the laboratory)

n Practical applications, including an attempt toproduce artemisinin, the precursor to themalarial drug artemisin, that are very close tosucceeding.

Although other biotechnologies could in manycases be applied to essentially the same purposes,the combination of easy access to synthesizedDNA, powerful computers to aid design, and thedistribution of these technologies to users beyondthe traditional biologist have raised unique safetyand security concerns about synthetic biology.Further, the idea of using these technologies to con-struct living organisms has sparked discussionsabout whether the use of these technologies is ethi-cal and, beyond that, what creating life means.

Ensuring that this field develops in a responsiblemanner, respectful of societys desires and beliefs,will require some combination of training, over-sight, and community external or self-regulation,constructed to allow the science and engineering toadvance without compromising safety, security, orsocietys values.

Ethics, Society, and Synthetic BiologyWe discuss here five major areas of concern

with respect to the societal impacts of research inand applications of synthetic biology. Theseinclude biosafety and biosecurity; the environ-ment; ownership; philosophical and theologicalissues; and the professional conduct of researchers.Some of these issues have been very well analyzed;for others analysis is just beginning. Each is out-

lined below.Biosafety and biosecurity. A key set of tech-

nologies for synthetic biology is the construction of

DNA in the laboratory from its constituent chemi-cals. Often referred to as DNA synthesis, genesynthesis, and synthetic genomics, this set of technologies makes it possible to build DNA of anyspecified sequence and length, up to the size of awhole genome. The biosafety and biosecurityimplications have been explored by the authorsand others in some detail (in Resources box, seeGarfinkel et al., National Science Advisory Boardfor Biosecurity, and Tucker and Zilinskas).

For our 2007 study, a working group of expertsin the technologies of DNA synthesis, researchapplications of DNA synthesis, engineering, policy,

law, ethics, and sociology conducted a technologyassessment of synthetic genomics. Over 20 months,we systematically explored the potential risks and

benefits of synthetic genomics; the technologiesthat currently exist for carrying out the research;and the technologies that may be available in fiveto ten years. The analyses aimed to identify the

benefits and risks that were specific to syntheticgenomics as opposed to biotechnology generally.

We found that, with very few exceptions, syn-thetic genomics would not now be the technologyof choice for a bioterrorist or nation-state hoping todevelop a virus for use as a weapon. Within five toten years, however, it may very well be the casethat synthesis will be easier than other means of obtaining a virus.

Based on these qualitative analyses, we con-structed a list of 17 possible options for gover-nance, focusing on the commercial suppliers of DNA; the machines and reagents that can be usedto synthesize DNA in laboratories; and the legiti-mate users of these technologies, including theirassociated organizations, such as universities.These options range from requiring that firmsscreen every order for potential malicious intent toextending the mandate of institutional biosafetycommittees to consider the potential securityimplications of experiments.

Commercial firms that make and sell synthetic

DNA have in fact already recognized that they havea role in assuring the safety of researchers andcommunities nearby and the security of all. Severalfirms have together formed the InternationalConsortium for Polynucleotide Synthetics (ICPS).ICPS members and others have published a poten-tial oversight framework for the development andimplementation of sequence screening tools andmechanisms for reporting and resolving concernsabout orders of potentially dangerous sequences.


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The U.S. government is also examining the risksfrom synthetic biology, particularly from the biose-curity perspective. The National Science AdvisoryBoard for Biosecurity (NSABB) recently releasedrecommendations for dealing with the synthesis of select agents. Various agencies are participating inthe U.S. government review of these recommenda-tions, and the NSABB and others are continuingwork on assessing whether the mechanisms of prior review of experiments by local institutional

biosafety committees will need to be modified toaccommodate security and safety concerns associ-ated with synthetic genomics.

Other countries have noted concerns about thistechnology, as well. In Europe the concerns aregenerally more directed toward biosafety, particu-

larly as related to accidental releases of synthesizedorganisms.

Environment. Synthesized microbes might be

intentionally or unintentionally released to theenvironment. Concerns about the potential envi-ronmental impacts of the accidental release of engi-neered synthetic microorganisms are closely relat-ed to concerns about biosafety and the impact of an accidental release on communities immediatelysurrounding laboratories. The accidental release of a truly novel organism is worrisome, as therewould be, by definition, no prior experience withhow it would act in a specific environment.However, highly modified microorganisms areunlikely to survive in a natural environment.

With respect to planned releases, synthesizedorganisms would be subject to the same regulationsas any other genetically modified organism. Forexample, in the United States, the EnvironmentalProtection Agency, Food and Drug Administration,and the Department of Agriculture all regulate theintroduction of various foods, drugs, pesticides, her-

bicides, etc., including those that are geneticallymodified. The question is whether organismsshould be subject to a greater degree of scrutinysimply by virtue of having genomes that had been

modified using synthetic DNA, rather than DNAextracted from another organism.Ownership: access, sharing, intellectual

property, and innovation. Synthetic biology maypose special problems for those seeking ownershipof, or access to, what might become vast arrays of new technologies. Both patent thickets (the need toreceive licenses from multiple patent-holders) andthe anticommons (many patent owners blockingeach other) are potential roadblocks to the use and

distribution of these technologies. This is an areathat will need significant attention as the fielddevelops. It is being studied by several groups with-in the academic legal community, such as theCenter for the Public Domain at Duke Law Schooland the Samuelson Clinic at the University of California Berkeley School of Law (see Chapter 20:Intellectual Property and Biomedicine).

Philosophical and theological issues. Oneapplication of synthetic genomics is to build amicroorganism containing a minimal genome,defined as the smallest set of genes that would per-mit an organism to live and reproduce in a specificenvironment. The idea is to construct the minimalgenome of a particular bacterium, insert thatgenome into a cell, and show that the resultingorganism can replicate. Such a microorganism

would help scientists to better understand the basicfunctioning of cells, or perhaps be a platform for biotechnology applications.

This potential application led to one of the firstrobust ethics analyses of the field, which was pub-

lished in 1999 by Cho and colleagues (see bo x :Resources) and preceded any actual work on con-structing an organism with a minimal genome. Theanalysis took into account issues of religion, com-mercialization, and the potential benefits of the

G O V E R N I N G G E N E T I CE N G I N E E R I N G : T H E A S I L O M A RM O D E L

The power of manipulating DNA was re ognized earl on.The most famous onsideration of the potential dangers of geneti engineeringprimaril in terms of la orator andenvironmental safet was at the 1975 Asilomar conferen e, attended s ientists, along with somelaw ers, ph si ians, and journalists. The on lusions fromthat meeting were that although geneti engineeringresear h and appli ations posed ris s, those ris s ould emanaged largel through a self-governan e pro ess involv-ing funders and pra titioners, and that formal oversight andregulator pro edures ould e minimal (although not nil).However, Asilomar (and, until re entl , most other su h dis-

ussions) did not spe ifi all onsider the possi ilit of pur-poseful mali ious appli ations of geneti engineering.Although s ntheti iolog is not unique in its dual-usenature, leaders of the field have een aware of the dual-usepro lem and have een open in spea ing a out it and wa sto potentiall mitigate mali ious uses, starting as earl asthe first international meeting of its pra titioners atSynthetic Biology 1.0, whi h was held in cam ridge,Massa husetts, in 2004.


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research. It also looked at concerns about reduc-tionismthat is, the view that a cell or an organismis only the sum of its partsin this case, genes.This view is particularly problematic for those indi-vidualsbe they scientists, philosophers, or theolo-gianswho think about the interaction of cells ororganisms with the surrounding environment.Construction of a minimal genome thus can raisedistinct questions as to whether and how suchwork can contribute to or change the definition of

life, and whether policies are needed to assure anequitable distribution of benefits from suchresearch. At the time, those researchers concludedthat constructing a minimal (or even new) genomedoes not violate any moral principles. Others havedisagreed with this assessment, and little additionalrigorous analysis has been done in the last nineyears.

However, there is a clear need for ethicists, the-

ologians, scientists, engineers, policymakers, andthe public to understand each others views onthese issues, and such examinations are ongoing.The Venter Institute is continuing its efforts in thisarea. The Hastings Center has recently embarkedon such a project, called Ethical Issues in Synthetic

Biology: Toward Clearer Understanding and Better Policy, funded by the Alfred P. Sloan Foundation.

Professional conduct of researchers. Codes of conduct, ethics or practice have been consideredfor biological science in general, and synthetic biol-ogy in particular, but none have yet been adopted.Engineers have long worked under various codes of conduct. Training students on aspects of profes-sional responsibility and ethical conduct is a criti-cal feature of the process leading to adherence tothese codes and has long been a part of engineer-ing curricula. Devising standards of practice mighteventually be a task for any professional society

Web sites

http://pol s nth.info The International consortium for Pol nu leotide S nthesis. In ludes lin s to parti ipating inter-national s ntheti iolog ompanies and some resour es.

http://www.s n er .org The S ntheti biolog EngineeringResear h center. In ludes edu ational, training, and out-rea h materials.

http://s n iosafe.eu S n iosafe. This EuropeanUnionfunded proje t aims to proa tivel stimulate a de ateon issues in s ntheti iolog ; in ludes proje t produ ts andan online dis ussion forum.

http://s ntheti iolog .org S ntheti biolog . In ludes lin s,resour es, and event information.

http://p d.l l.gov/s onf S ntheti biolog 2.0. The onfer-en e site for the Se ond International Meeting on S nthetibiolog , held in ber ele in 2005, in ludes a we ast of the

onferen e and dis ussion forums.

http://www.s ntheti iolog 3.ethz. h S ntheti biolog 3.0.The onferen e site for the Third International Meeting onS ntheti biolog , held in Zuri h in 2007, in ludes videos of the tal s and pro eedings availa le for download.

Recent news

John Harris, Whos Afraid of a S ntheti Human? TheTimes , Ma 17, 2008.

colin Ni erson, A Quest to create Life Out of S ntheti s,Boston Globe , April 2, 2008.

Wend Orent, cr ing Wolf Over bioterror, Los AngelesTimes , Mar h 2, 2008.

Eri Parens, Ma ing cells Li e computers, Boston Globe ,

Fe ruar 18, 2008.

Natalie Angier, Pursuing S ntheti Life, Dazzled Realit ,New York Times , Fe ruar 5, 2008.

Further reading

Mildred k. cho, David Magnus, Arthur L. caplan, DanielM Gee, and the Ethi s of Genomi s Group, Ethi al

considerations in S nthesizing a Minimal Genome, Science ,De em er 10, 1999.

committee on Resear h Standards and Pra ti es to Preventthe Destru tive Appli ation of biote hnolog , Biotechnology Research in an Age of Bioterrorism, National A ademiesPress, 2004.

Hui de Vriend, constru ting Life: Earl So ial Refle tionson the Emerging Field of S ntheti biolog , wor ing do u-ment 97, Rathenau Institute, The Hague. Report availa le atwww.lis onsult.nl.

Drew End , Re onstru tion of the Genomes, Science ,Fe ruar 29, 2008.

Mi hele S. Garfin el, Drew End , Gerald L. Epstein, andRo ert M. Friedman, S ntheti Genomi s: Options for Governan e, J. craig Venter Institute, center for Strategiand International Studies, and Massa husetts Institute of Te hnolog , O to er 2007. Report availa le at www.j vi.org.

National S ien e Advisor board for biose urit , Addressingbiose urit con erns Related to the S nthesis of Sele tAgents, De em er 2006. Report availa le at www. iose uri-t oard.gov.

Jonathan b. Tu er and Ra mond A. Zilins as, The Promiseand Perils of S ntheti biolog , The New Atlantis, Spring2006.

R E S O U R C E S


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developed for synthetic biology (see Endy inResources box). But whether or not synthetic biol-ogy as a discipline articulates a full code of con-duct, such codes have been and likely will continueto be communicated to students and researchers inthe field at forums such as the InternationalGenetically Engineered Machine Competition,where the participants are mainly undergraduatesfrom various disciplines and national origins, andthe series of annual international synthetic biologymeetings, where a wide variety of students andresearchers gather.

In 1971, in describing the content of a talk in aconference he was organizing, Sidney Fox wrote,

As such processes [of synthetic biology] are brought under control in the laboratory, they haveincreasing implications for society and its philoso-phy. This is perhaps even truer today, as the fullimplications of the science and engineering areonly now being appreciated.

Acknowledgments

We are grateful to the Alfred P. Sloan Foundationof New York for the opportunity to contribute todiscussions of governance of synthetic biology byits funding of the synthetic genomics governanceproject discussed in this paper.

Sloan Group Re-worked Synthetic Biology Chapter

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