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Home , Biological engineering, Craig Venter, DNA synthesis, Drew Endy, Eckard Wimmer, ETC Group (eco-justice)

Extreme Genetic An Introduction to Synthetic

January 2007 This page intentionally left blank. Extreme An Introduction to

January 2007

ETC Group gratefully acknowledges financial support of the International Development Research Centre, Canada for our research on the implications of synthetic biology. We are grateful for additional support from SwedBio (Sweden), the Canadian International Development Agency (CIDA), Marin Foundation (USA), CS Fund (USA), and HKH Foundation (USA). The views expressed in this document, however, are solely those of the ETC Group.

Original artwork by Reymond Pagé. ETC Group is an international civil society organization based in Canada. We are dedicated to the conservation and sustainable advancement of cultural and ecological diversity and rights. ETC Group supports socially responsible development of useful to the poor and mar- ginalized and we address international governance issues affecting the international community. We also monitor the ownership and control of technologies and the consolidation of corporate power.

ETC Group’s series of reports on the social and economic impacts of technologies converging at the nanoscale include: Extreme Genetic Engineering: An Introduction to Synthetic Biology January 2007

Nanotech Rx – Medical Applications of Nanoscale Technologies: What Impact on Marginalized Communities? September 2006

NanoGeoPolitics: ETC Group Surveys the Political Landscape July/August 2005

Nanotech’s Second Patents: Implications for the Global South June 2005

Down on the Farm: The Impacts of Nanoscale Technologies on Food and November 2004 These and other publications are available free-of-charge on our website. www.etcgroup.org

ii Table of Contents Extreme Genetic Engineering: An Introduction to Synthetic Biology...... 1 Introduction: Original Syn?...... 3 Synbio Basics...... 6 Read/Write DNA: Synthesis...... 6 Cleaning up the Code – Codons, and Pathways...... 9 Five Alive – An Introduction to Five Major Areas of Research in Synthetic Biology...... 13 1: Making Minimal Microbes – Post-modern ...... 13 2: Assembly Line DNA – “Lego” -Forms to Order...... 15 3: Building Artificial Cells from the Bottom Up – Ersatz ...... 17 4: Pathway Engineering – Bug Sweatshops...... 19 5: Expanding Earth’s Genetic System – Alien ...... 21 Implications of Synthetic Biology:...... 23 I. Building a Better Bio-Weapon – What does synthetic biology mean for bioweapons?...... 23 II. The New Synthetic Agenda – Rebooting ...... 27 III. Synthesizing New Monopolies from Scratch – Synthetic Biology and Intellectual Monopoly...... 32 IV. Synthetic Conservation – What are the implications of gene synthesis and digital DNA for conservation of genetic resources and the politics of ?...... 36 V. Synthetic Commodities – Implications for Trade...... 40 VI. Synbiosafety...... 42 Synthetic Governance (Trust us. We’re experts.)...... 46 Recommendations...... 49 Case Study: Synthetic Biology’s Poster Child – Microbial Production of to Treat ...... 52 Glossary...... 56 Endnotes...... 57

Boxes, Tables and Map Box 1: BANG Goes Scientific Disciplines: Converging Nanoscale Technologies...... 5 Map: Commercial DNA Synthesis Companies...... 8 Box 2: Life is cheap – and fast...... 10 Box 3: DNA Computing: Nature’s PowerBook...... 18 Box 4: NSABB: Scientific Advice on How to Throw Out the Baby with the Bath Water...... 26 Table 1: A Sample of Recent Synthetic Biology Patents...... 35 Table 2: Companies with Synthetic Biology Activities...... 45

Words that are underlined in this document are defined in the glossary.

iii

Extreme Genetic Engineering: An Introduction to Synthetic Biology

Issue: Genetic engineering is passé. Today, scien- patents on the products and processes of synthetic tists aren’t just mapping and manipulat- genetics. Like biotech, the power to make synthetic ing , they’re building life from scratch – and life could be concentrated in the hands of major they’re doing it in the absence of societal debate and multinational firms. As gene synthesis becomes regulatory oversight. Dubbed “genetic engineering cheaper and faster, it will become easier to synthe- on steroids,” the social, environmental and bio-weap- sise a microbe than to find it in nature or retrieve ons threats of synthetic biology surpass the possible it from a gene bank. Biological samples, sequenced dangers and abuses of biotech. Synbio is inspired by and stored in digital form, will move instantaneously the convergence of nanoscale biology, computing across the globe and be resurrected in corporate labs and engineering. Using a laptop computer, published thousands of miles away – a practice that could erode gene sequence information and mail-order synthetic future support for genetic conservation and create DNA, just about anyone has the potential to con- new challenges for international negotiations on bio- struct genes or entire genomes from scratch (includ- diversity. ing those of lethal ). Scientists predict that Policy: In 2006 civil society organizations rejected within 2-5 years it will be possible to synthesise any proposals for self-regulation of synthetic biology put ; the firstde novo bacterium will make its debut forth by a small group of synthetic . Wide- in 2007; in 5-10 years simple bacterial genomes will spread debate on the social, economic and ethical be synthesised routinely and it will become no big implications of synbio must come first. Debate must deal to cobble together a designer , insert it not be limited to (bioweapons/bioterror- into an empty bacterial and – voilà – give birth to ism) and (worker safety and environment). a living, self-replicating . Other synthetic bi- The tools for synthesizing genes and genomes are ologists hope to reconfigure the genetic pathways of widely accessible and advancing at break-neck pace. existing to perform new functions – such It is not adequate to regulate synthetic biology on as manufacturing high-value drugs or chemicals. the national level. Decisions must be considered in a Impact: A clutch of entrepreneurial scientists, includ- global context, with broad participation from civil so- ing the gene maverick J. , is setting up ciety and social movements. In keeping with the Pre- synthetic biology companies backed by government cautionary Principle, ETC Group believes that – at funding and venture capital. They aim to commer- a minimum – there must be an immediate ban on cialise new biological parts, devices and systems that environmental release of de novo synthetic organisms don’t exist in the natural world – some of which are until wide societal debate and strong governance are designed for environmental release. Advocates insist in place. that synthetic biology is the key to cheap biofuels, a cure for malaria and remediation Definition:Synthetic Biology – media-friendly goals that aim to mollify public con- (also known as Synbio, , Construc- about a dangerous and controversial technol- tive Biology or ) – the and ogy. Ultimately synthetic biology means cheaper and construction of new biological parts, devices and widely accessible tools to build bioweapons, virulent systems that do not exist in the natural world and pathogens and artificial organisms that could pose also the redesign of existing biological systems grave threats to people and the planet. The danger is to perform specific tasks. Advances in nanoscale not just bio-terror, but “bio-error.” technologies – manipulation of matter at the level of and – are contributing to ad- Despite calls for open source biology, corporate and vances in synthetic biology. academic scientists are winning exclusive monopoly

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“Genetic engineering techniques are abysmally primitive, akin to swapping random parts between random cars to produce a better car. Yet our ignorance will fade; biolog- ical engineering will become a reality relatively soon.” – Letter to New York Times, 12 December 2000, by Rob Carlson, synthetic and senior scientist in , University of Washington1

Transgenics, the kind of - order to identify and understand ing you find in genetically modified the role of genes found in nature. tomatoes and corn, is old news. As As a result of the to read and recombinant DNA splicing-tech- map genomes, it is now possible niques turn 30 years old, a new gen- to sequence tens of thousands of eration of extreme biotech enthusi- base pairs per minute, and to do asts have moved to the frontier it relatively cheaply.4 As attention in the manipulation of life: building switches from reading to writing it from scratch. They call it synthetic genetic information (and indeed biology. whole organisms), synthetic biolo- “…if ever there were a Under the old paradigm of trans- gists can now snub their noses at guaranteed to cause nature’s in favor of made-to- genics, genetic engineering was public alarm and outrage, this order life-forms. Using engineering a cut and paste affair, in which is it. Compared with con- biotechnologists shuffled pieces of concepts borrowed from electronics DNA – the self-assembling and computing, synthetic biologists ventional and that instructs living organisms how are building simplified versions of genetic engineering, the risks , re-programming DNA as a to carry out every biological process involved in synthetic biology – between already existing . computing medium and assembling are far scarier.” By contrast, today’s synthetic biolo- new genetic systems that are human- gists are armed with the biologi- directed. As they do so, a real world – Philip Ball, consultant editor for Nature2 cal equivalent of word processors. with vast applications They are “beginning the and implications is fast emerging. from being able to…read genetic Millions of dollars of government code…to the early stages of being and corporate funding are already able to write code.”3 Using gene syn- flowing into synthetic biology labs. thesisers, they write the “sentences” Venture capital and government of DNA code one “letter” at a time. funding have nurtured the field and They can add new letters that have the first pure-play synbio companies never existed in nature, rearrange are now open for business. They them into new “genetic networks” hold growing patent portfolios and and bundle all that into an artificial foresee industrial products for uses “chassis” to go forth and multiply. as diverse as energy production, Synthetic Biology represents an climate change remediation, toxic important change in the direc- cleanup, textiles and pharmaceuti- tion of genetic technology, which, cal production. Indeed synthetic over much of the past 20 years, has biology’s first commercial products focused on deciphering genetic may be only a few years from mar- information (gene ) in ket. Meanwhile the “  industry” is growing up in a “Wild joined together in an open letter to West” free-for-all environment with the synthetic biology community, virtually no regulatory oversight. expressing concern that “this poten- In fact, “the synthetic biology com- tially powerful technology is being The “artificial life industry” is munity” – as the scientists refer to developed without proper societal growing up in a “Wild West” themselves – is making a concerted debate concerning socio-economic, free-for-all environment with effort to stave off government scruti- security, , environmental and ny by making proposals that amount human rights implications.”5 As virtually no regulatory over- to self-regulation. synthetic biology becomes the latest sight. Civil society and social movements, techno-fix for energy, agriculture particularly those that have cam- and in the global South, paigned against genetic engineering social movements may soon find and the patenting of life, recognise that the battle cry of “no to trans- that “extreme biotech” is a danger- genics” needs to be updated: “no to ous technology that must not be transgenics and synthetics.” developed in the absence of wide- This report outlines the new spread societal debate and legally- landscape of synthetic biology by Synthetic biologists are mak- binding regulation. For some, the describing its tools, some of the quest to build new, living organisms leading protagonists and the various ing a concerted effort to in the laboratory crosses unaccept- approaches they are pioneering. It stave off government scrutiny able ethical boundaries – a reduc- will examine some of the emerging by making proposals that tionist science that raises profound applications of synthetic biology and amount to self-regulation. implications for society. the implications for security, safety, In May 2006, 38 civil society orga- monopoly, and livelihoods. nizations from around the world

 Box 1: BANG Goes Scientific Disciplines: Converging Nanoscale Technologies Is it biotech? Is it nanotech? Or is it an information technology? The field of synthetic biology is in fact all three – an example of “converg- ing technologies,” the latest industrial strategy favored by OECD policy­ makers. The boundaries between technologies are “really getting sketchy,” says Mark Bunger, a market analyst with Lux Reseach.6 Technologists from disciplines such as biotechnology and physics have begun changing places with their colleagues in departments of and mate- The boundaries between rials science. All of them manipulate matter on the scale of atoms and technologies are “really molecules (the scale of the nanometer [nm], or one-billionth of a me- getting sketchy,” says Mark tre): A DNA molecule is 2.5 nm wide and an of iron is about .25 nm Bunger, a market analyst with in diameter. DNA synthesis, for example, involves the manufacture of a biological molecule that encodes information – that’s nanotech, biotech Lux Reseach. and infotech all in one. DNA computing (described on p. 18) manipu- lates matter at the nanoscale using the tools of biotechnology to carry out information processing tasks. Governments and industry around the world enthusiastically embrace (and heavily finance) technological convergence at the nanoscale. The US government, the loudest cheerleader for the convergence strategy, re- fers to it as NBIC – an acronym derived from the technologies involved: , biotechnology, information technology and cognitive ).7 In Europe, the vision of convergence is called CTEKS (con- verging technologies for the European knowledge society) and in Cana- Governments and industry da, convergence is known as BioSystemics Synthesis.8 Others may refer to around the world are enthu- acronyms such as GRAIN (Genetics, , Artificial Intelligence and siastically embracing tech- Nanotechnology),9 COMBINE (Cogno, Meets Bio, Info, Nanotech)10 or nological convergence at the GRIN (Genetics, Robotics, Informatics and Nanotechology).11 Without necessarily sharing the enthusiasm of governments for technological nanoscale. convergence, civil society has come up with its own name: BANG – from Bits, Atoms, Neurons and Genes, which are the operable units of the “NBIC” technologies.12 Nanotechnology – controlling matter through manipulation of Atoms – can converge with Biotechnology – controlling life through manipulation of Genes – can converge with Information Technology – controlling data through manipulation of Bits – can converge with Cognitive – controlling minds through manipulation of Neurons. Synthetic biology may be the converging technology, par excellence. Delve into the biographies of synbio’s luminaries and you’ll find Ph.D.s in chemical, electrical and , physics and pharma- cology (and surprisingly few biologists).

 Synbio Basics At the core of synthetic biology is a and represented by the let- belief that all the parts of life can be ters A, C, G and T) into the spiral- made synthetically (that is, by chem- ing ladder of the DNA molecule via istry), engineered and assembled to some fairly slow and complicated produce working organisms. Born . In 1970 the Nobel laure- in the dot-com communities of ate and an army of helpers succeed- Boston and , much of the ed in constructing the DNA of an Back in 1973 it would take vision of synthetic biology is articu- entirely artificial gene 207 base pairs one scientist a whole year to lated using computing metaphors. long (although it wasn’t until 1976 DNA code is regarded as the soft- that he and a team of 24 others make a length of DNA eleven ware that instructs life, while the cell managed to get their synthetic gene base pairs long. Today it membrane and all the biological to work). Back in 1973 it would take would take minutes and cost machinery inside the cell are re- one scientist a whole year to make around $200. garded as the hardware (or wetware a length of DNA eleven base pairs as it is sometimes known) that need long.14 Today Khorana’s monumen- to be snapped together to make a tal feat would take minutes and living organism. This section ex- would cost around $200. In the amines how far synthetic biologists same year that Khorana announced have gone in remaking this soft and his functional artificial gene (1976), wet ware in the lab. California-based start-up Read/Write DNA: Gene – the world’s first commercial bio- Synthesis tech company – invented a faster, automated method of synthesising It’s not quite the Biblical feat de- genes, and so the gene synthesis in- scribed in Genesis but if you give dustry was born. Epoch Biolabs of Houston, Texas a thousand dollars they can make For the last 30 years the primary a little bit of life (an entire gene) use of custom gene synthesis tech- out of chemical dust and post their nology has been the production of creation to you within seven days.13 (also known as “oli- From Moscow to Montreal, Norway gos” or “primers”) – short strands Thymine to Nashville a young industry of of DNA that genetic use gene synthesis companies builds as ‘hooks’ to copy natural DNA in artificial life one chemical at a time, order to decipher the sequence it as small sections of DNA to and amplify it. Oligos usually have labs that are pushing the limits of fewer than 200 bases and are single- stranded (DNA is double-stranded.) what is possible in the biotech field. Building artificial DNA is itself noth- Although do-it-yourself desktop ing new. In the 1960s an Indian- DNA synthesisers are used in labo- American Nobel prize winner, Har ratories to make short stretches of Gobind Khorana, first developed a DNA, most grateful biotechnologists chemical protocol for building DNA send an order over the Internet for DNA chains to order – arranging its four the desired DNA sequence to one Backbone compounds known as the of the dozens of commercial “Oligo bases (adenine, cytosine, guanine, Houses” worldwide. Korea-based

 Bioneer Corporation, for example, 40kbp (40,000 base pairs) of DNA has the capacity to produce 20,000 at one go. Some companies boast oligos per day.15 that there are no technical limits to the length of DNA they can pro- “We’re going to build you exactly what duce20 (although most sequences you are looking for: Whole , are not error-free). GeneArt claims whole genes, gene fragments . . . and that it can produce a half-million in one to two years, possibly a whole ge- base pairs of DNA per month21 nome.” – John Mulligan CEO of Blue – an amount of synthetic DNA that Heron Biotechnology, Washington “There is no technical barrier would have kept Khorana busy for (USA)16 to synthesizing and over 45,000 years. In July 2006 Co- “Gene foundries” – gene synthesis don Devices manufactured and sold , it will happen as companies that produce longer a strand of DNA exceeding 35,000 soon as anyone pays for it.” pieces of double-stranded DNA (in- base pairs – what they claim is the — , MIT cluding whole genes or genomes) largest commercially produced – sell made-to-order sequences over fragment to date.22 It’s a record the Internet. ETC has identified at that is sure to be broken soon. least 66 commercial gene synthesis Synthetic biologists predict that a companies (see world map of gene million base-pair synthesis companies, p. 8.). The will be constructed within the next gene synthesis business is grow- two years,23 that a genome of ing rapidly and is geographically about 12 million base pairs could be dispersed. Market estimates are synthesised in about 18-24 months preliminary. According to one in- and a would not dustry estimate, the current market take much longer. According to (late 2006) for gene synthesis is only engineering professor Drew Endy of $30-$40 million per year – a tiny Massachusetts Institute of Technol- fraction of the $1-$2 billion spent ogy (MIT), “There is no technical 17 on acquiring and modifying DNA. barrier to synthesizing plants and Although the United States is cur- animals, it will happen as soon as rently home to more gene foundries anyone pays for it.”2 than any other country, the industry In order to build whole genes, com- is rapidly moving offshore. Within panies employ dedicated DNA syn- a few years, notes John Mulligan of thesis – using either their Blue Heron Biotechnology, nearly own proprietary technology (such all commercial gene synthesis will “Within a decade a single as Blue Heron’s GeneMaker tech- be conducted in highly-automated nology25) or commercially available person could sequence . . . manufacturing facilities.18 Accord- gene-synthesis equipment (from a his or her own DNA within ing to Hans Buegl of GeneArt (Re- manufacturer such as ABI26). While gensberg, ), the market seconds.” a good DNA synthesiser can now be for gene synthesis has doubled in — Rob Carlson, purchased for less than $10,000, old- the past year.19 Most gene synthe- University of Washington er synthesisers can be bought sec- sis companies produce lengths of ondhand for under $1000. Professor DNA smaller than 3kbp at a time Endy speculates that do-it-yourself (3000 base pairs – a makes one ‘rung’ of the DNA ‘ladder’), synthesisers could be built using 27 however some companies, such as parts found in a hardware store. Blue Heron, can synthesise up to The DNA itself is constructed from  66 61 65 62 63 64 60 59 58 56-57 55 53 41-45 50-51 52 54 40 49 39 48 46-47 20-21 24 22-23 35 5-8 ommercial D N A Synthesis C ompanies C ommercial M ap: 27 1-4 32 33 36-37 38 18 25-26 17 34 19 9 28-31 10-16

 cheaply-produced sugar isolated computer processors would double from sugar cane. According to their speed and half their size every synthetic biologist Rob Carlson at two years).28 According to Carlson, Efficiency improvements in University of Washington (USA), ef- “Within a decade a single person gene synthesis machines are ficiency improvements in gene syn- could sequence or synthesise all the thesis machines are now speeding DNA describing all the people on now speeding up as fast, if not up as fast, if not faster, than Moore’s the planet many times over in an faster, than Moore’s Law. Law (the famous prediction by Gor- eight-hour day or sequence his or don Moore, founder of Intel, that her own DNA within seconds.”29

Key to Map 1. Cortec DNA Service Laboratories, Inc. - Kingston, ON, Canada 35. Commonwealth - Richmond, VA, USA 2. Fermentas International Inc. - Burlington, ON, Canada 36. Epoch Biolabs - Houston, TX, USA 3. Norclone - , ON, Canada 37. Picoscript - Houston, TX, USA 4. Biobasic - Markham, ON, Canada 38. Integrated DNA Technologies - Coralville, IA, USA 5. Alpha DNA - Montreal, QC, Canada 39. Yorkshire Bioscience Ltd. - York, UK 6. BioCorp - Montreal, QC, Canada 40. DNA Technology A/S - Aarhus, Denmark 7. Bio S&T - Montreal, QC, Canada 41. Geneart - Regensburg, Germany 8. Top Gene Technologies - Montreal, QC, Canada 42. Entelechon - Regensburg, Germany 9. Blue Heron Biotechnology - Bothell, WA, USA 43. MWG–Biotech AG - Ebersberg, Germany 10. DNA2.0 - Menlo Park, CA, USA 44. Eurofins Medigenomix - Martinsried, Germany 11. mclab - San Francisco, CA, USA 45. Metabion International AG - Munich, Germany 12. Genemed Synthesis - San Francisco, CA, USA 46. Biolegio bv - Nijmegen, The Netherlands 13. FastaDNA - San Francisco, CA, USA 47. BaseClear - Leiden, The Netherlands 14. BioNexus /ABP - Oakland, CA , USA 48. Eurogentec s.a. - Seraing, Belgium 15. Invitrogen - Carlsbad, CA, USA 49. Genosphere Biotechnologies - Paris, France 16. Biosearch Technologies Inc. - Novato, CA, USA 50. BioSpring - Frankfurt, Germany 17. Ambion Inc. - Austin, TX, USA 51. IBA - Gottingen, Germany 18. Bio–Synthesis Inc. - Lewisville, TX, USA 52. Microsynth - Balgach, Switzerland 19. Dharmacon Inc. - Lafayette, CO, USA 53. CyberGene AB - Huddinge, Sweden 20. ChemGenes Corporation - Wilmington, MA, USA 54. Medprobe - Oslo, Norway 21. Codon Devices - Cambridge, MA, USA 55. Inqaba Biotechnical Industries Ltd - Pretoria, South Africa 22. Gene Link Inc. - Hawthorne NY, USA 56. Zelinsky Institute of Organic Chemistry of the Russian 23. GenScript - Piscataway, NJ, USA Academy of Sciences - Moscow, Russia 24. BioServe Biotechnologies Ltd - Laurel, MD, USA 57. Evrogen - Moscow, Russia 25. Sigma Aldrich–Genosys - St. Louis, MO, USA 58. CinnaGen Inc. - Tehran, Iran 26. IBA - St. Louis, MO, USA 59. Imperial Bio-Medic (P) Ltd. - Chandigarh, India 27. AnaGen Technologies - Atlanta, GA, USA 60. BioServe Biotechnologies Pvt Ltd. - Hyderabad, AP, India 28. Bio Applied Technologies Joint - , CA, USA 61. GeneWorks Pty Ltd. - Thebarton SA, Australia 29. Retrogen - San Diego, CA, USA 62. ScinoPharm Taiwan Ltd. - Shan-Hua, Taiwan 30. Eton Bioscience - San Diego, CA, USA 63. Takara Biotechnology (Dalian) Co., Ltd. - Dalian, China 31. Illumina Inc. - San Diego, CA, USA 64. Tech Dragon - Hong Kong, China 32. Celtek - Nashville, TN, USA 65. Bioneer Corporation - Daedeok-gu, Korea 33. Biotechnologies - Huntsville, AL, USA 66. JBioS, Japan Bio Services Co. Ltd. - Asaka City, Japan 34. Certigen - Lubbock, TX, USA

 Box 2: Life is cheap – and fast. “In 2000, the cost of assembling sequences to order was roughly $10 to $12 per base pair… Some scientists foresee DNA synthesis dropping to 1 cent per base pair within a couple of years. That’s a gene for 10 bucks, a bacterial genome for the price of a car.” – Oliver Morton, “Life Reinvented,” Wired30 Back in the summer of 2000, John Mulligan, CEO of gene synthesis com- pany Blue Heron Biotechnology, boasted that the price of gene synthesis was dropping so quickly that, “If you look at the curve, it’s headed to about zero in 2006.”31 Blue Heron isn’t giving away synthetic DNA yet, but their product has dramatically dropped in price, or, as Andrew Hes- “DNA is getting pretty sel, a bioinformaticist in Toronto puts it: “DNA is getting pretty freaking freaking cheap to make.” cheap to make.”32 In mid-2006 ETC Group surveyed advertised costs and — Andrew Hessel, bioinformaticist found that most gene synthesis companies currently charge between US$1-$2 dollars per base pair (around “a buck a base” as they like to say).33 The cheapest advertised rate was Epoch Biolabs, at $.85 per base pair.34 In October 2006, Codon Devices advertised $.79 per base pair.35 At a May 2006 synthetic biology conference gene synthesis companies were confidently predicting that the price would drop to $.50 per base pair by the end of 2007.36 Gene synthesis for oligos (shorter, single strands) is al- ready at $.10 per base and a new method pioneered by George Church of Harvard University may reduce the cost ten-fold, to $.01 per base.37 Our informal survey suggests that most of the synthesis companies can turn around a synthetic gene (around 1,000 base pairs known as 1 kilo- base pair – Kbp) in under two weeks. At present Craig Venter holds the world’s gene-speed record for synthetically producing a 5,386 bp genome (of the virus phiX 174) in under 14 days (although there were errors in his copy).38 If you want to order that same synthetic virus from Epoch Biolabs they would charge you less than $6000 to synthesise the organism, DNA synthesis reduces the but it might take a few weeks longer. Ordering something more complex, time it takes genetic engineers such as a synthetic copy of the smallest bacterial genome, Carsonella rudii to isolate and transfer DNA (159,622 base pairs) would likely set you back about $126,000 at today’s in order to build genetically rates. Today’s DNA synthesis techniques allow us to put a theoretical price on human life: building the entire genome of a human being – around 3 modified organisms. billion base pairs – could be done today by a bargain basement synthesis company for just over $2.5 billion dollars – well within the reach of several individuals on the planet. Drew Endy of MIT speculates that within 20 years human genomes will be synthesised from scratch.39 Meanwhile, the growth of the DNA synthesis industry is making exist- ing technologies quicker, cheaper and easier. DNA synthesis reduces the amount of time it takes genetic engineers to isolate and transfer DNA in order to build genetically modified organisms – tedious activities that consume as much as 50% of GMO research.40 With DNA synthesis tech- nology, lab scientists can now order the complete genes they require in a matter of weeks, a huge short-cut in production.

10 Cleaning Up the Code – works better in bacteria and another Codons, Proteins and Pathways in plants even though both produce 42 Cranking out DNA is pointless un- the same . less scientists know how to arrange Some synthetic biologists take the it into meaningful code. In the approach of combing through the popular understanding of genetics, of existing organisms a gene, a length of DNA composed and removing or reducing unneces- of base pairs, is regarded as the sary codons to get a sleeker version smallest functional unit of genetic of the genetic code. Others, by code, instructing cellular machinery combining codons into stand-alone via RNA (ribonucleic acid) which programming instructions, are de- proteins to manufacture. Those pro- veloping “standard parts” analogous teins in turn carry out the tasks and to the standard parts of electronic processes within organisms that we circuitry or the standard commands understand to be “life.” As Francis of a computer . They keep Crick, a co-discoverer of the DNA an inventory of these standard parts, double-helix, put it: “DNA makes and are making them available for Cranking out DNA is pointless RNA, RNA makes proteins, and others to assemble into more com- unless scientists know how proteins make us.”41 The building plex genetic systems. Others are de- blocks of those all-important pro- signing entirely new artificial amino to arrange it into meaningful teins are amino acids – 20 unique acids that result from codon com- code. amino acids have been identified binations not found in nature. In – and it is the codon that deter- the US and Europe some synthetic mines which amino acid will be pro- biologists hope to build an artificial duced within the cell. Codons are “” that will contain and ex- trinucleotides – that is, a series of press synthetic DNA as flexibly as a three (out of four) chemical bases computer stores document files and – linked together in a specific or- runs computer programmes. der. It is that order that determines Unfortunately for would be life- which amino acid will be added to builders, genetic code is not as the under construction. linear as computer code. While the Each codon carries the code for a popular view of genetics links units specific amino acid. of DNA (genes) to specific traits, Synthetic biologists want to work the reality is messier. In real life, below the level of the gene, at the genes and parts of genes co-operate level of the codon – to identify co- in subtle and complex networks, dons and rearrange them to build each producing proteins that pro- new sets of biological instructions. mote or suppress the behaviour of Because there are 64 possible co- other genes. The result is a system dons (four bases linked together of cellular regulation that controls in sets of three, or 43) but only 20 the amount or timing by which different amino acids they translate a substance or trait is produced into, synthetic biologists can choose – a bit like electronic circuits that among different options for codons regulate electrical current. Ge- when they want to express a specific neticists interested in manipulating amino acid (known as codon opti- genomes have begun mapping the mization). It may be that one codon interactions between genes to try 11 to determine the full set of interac- genome. This involves designing tions necessary to produce a desired not just one of DNA, protein. They can represent these but several different areas of code, Unfortunately for would be networks with circuit diagrams simi- and then putting them together as life-builders, genetic code is lar to those used in electronics. The a synthetic chromosome. By alter- not as linear as computer set of interactions that involve a net- ing these networks and pathways, code. work of DNA molecules acting to- synthetic biologists can increase the gether to produce a protein can be production of a protein or stimulate referred to as a “genetic pathway” the production of an entirely differ- and synthetic biologists are now try- ent substance, such as a or a ing to rebuild or alter these genetic drug.43 pathways as discreet sections of the

12 Five Alive – An Introduction to Five Major Areas of Research in Synthetic Biology

“We want to demonstrate what the heck life is by constructing it. If we do that, we’re going to have a very big party. The first team that does it is going to get the Nobel Prize.”44 – Steen Rasmussen, Synthetic Biologist at Los Alamos National Laboratory in New Mexico

The world’s first synthetic biology 1: Making Minimal Microbes – conference convened in June 2004. Post-modern Genomics Two months later, the University of In the race to synthesise life, genom- California at Berkeley announced ics mogul J. Craig Venter often over- the establishment of the world’s “We want to demonstrate shadows the rest of the pack. Venter, first synthetic biology department. dubbed “Biology’s Bad Boy,” led what the heck life is by In 2005, three synthetic biology the private company Celera, which, constructing it.” start-ups attracted over $43 mil- in the 1990s, sold lion in venture capital, and in late — Steen Rasmussen, Synthetic Biolo- data to pharmaceutical companies gist, Los Alamos National Laboratory 2006 there’s talk of establishing faster than the National Institutes (USA) an industry trade group for gene of Health – Celera’s competitor in synthesisers. The nascent field of the race to map the human genome synthetic biology is closely identi- – were able to decode it.45 In 1995 fied with a handful of high-profile Venter announced that he was first scientists (mostly men) who articu- to sequence the entire genome of late grand visions, and are striking a living organism (the bacterium different paths toward the common known as Hemophilus influenzae).46 In goal of creating artificial life. Some 2003 Venter made headlines when researchers are trying to build his team created the first synthetic synthetic biology’s basic enabling virus from scratch – and it took technologies. Others are focusing them only 14 days to do it. Venter is on real-world applications. In the notorious for pushing the bound- following pages, ETC Group profiles aries on the commercial exploita- some of synthetic biology’s leading Venter is notorious for pushing tion of life. His newest commercial practitioners and reviews five major the boundaries on the com- venture, Synthetic Genomics, Inc., areas that are being developed to founded in 2005 with $30 million mercial exploitation of life. His build and use artificial life. These in venture capital, aims to commer- newest commercial venture is include: cialise a range of synthetic biology Synthetic Genomics, Inc. 1. Making Minimal Microbes – applications, starting with energy Post-modern Genomics production.47 2. Assembly-Line DNA – “Lego” In the mid 1990s Venter’s non-profit Life-forms to Order outfit, The Institute for Genomic 3. Building Artificial Cells from the Research (TIGR), pursued a Mini- Bottom Up – Ersatz Evolution mal to discover the 4. Pathway Engineering – Bug fewest number of genes necessary Sweatshops for a bacterium to survive. The bac- 5. Expanding Earth’s Genetic terium they chose was System – Alien Genetics genitalium, a bug that causes urinary 13 tract . It has one of the considered living organisms). Ven- smallest known genomes of any liv- ter calls a ing organism (517 genes made up “synthetic chromosome” and his in- of about 580,000 DNA base pairs). tention is to use it as a flexible bio- Clyde Hutchison of TIGR began factory into which custom-designed modifying the genome of Myco- synthetic “gene-cassettes” of four to plasma genitalium, observing which seven genes can be inserted, geneti- genes could be disrupted without cally programming the organism to killing the organism and then dis- carry out specific functions.52 As a abling those genes one at a time. He first application, Venter hopes to de- guessed that the bacterium might velop a microbe that would help in be able to survive with almost half the production of either ethanol or its genes removed.48 In a 2005 work- for fuel production (see shop at the US Department of En- The New Synthetic Energy Agenda ergy, Hutchison’s team announced p. 27). He is also looking to harness Exotic microbes are the raw that they had reduced the genome the mechanisms of materials for creating new life- to about 386 essential genes. In to more effectively sequester carbon forms and new energy sources. another bacterium, , dioxide, ostensibly as a means of they found that all but 271 of 4100 slowing climate change. 49 genes could be knocked out. Oth- Venter’s team should have plenty of ers are now trying to minimise the genetic booty to exploit following 50 genome of organisms such as E. coli. its US government-funded For Venter’s team, the ultimate goal expedition on Venter’s yacht to col- of creating a minimal microbe is lect and sequence microbial genetic to use it as a platform for building diversity from around the globe. Ex- new, synthetic organisms whose ge- otic microbes are the raw materials netic pathways are programmed to for creating new life-forms and new perform commercially useful tasks energy sources. Venter claims that – such as generating alternative his expedition has discovered 3,995 fuels. Hutchison, Venter and Nobel new gene families not previously laureate Hamilton Smith are now known, and 6-10 million new genes attempting to artificially synthesise – which he describes as “design Venter claims his will be the their reduced version of the Myco- components of the future.”53 To har- first fully synthetic life-form, plasma genitalium genome so it could ness synthetic microbes for energy but the birthdate of his new be used as a stripped-down ‘chas- production, Venter’s non-profit in- organism is shrouded in sis’ for future synthetic organisms. stitutes have received over $12 mil- They will remove the DNA from an lion from the US Department of En- secrecy. existing bacterium and insert their ergy’s Genomes to Life project.54 In synthesised genome in its place.51 If February 2006 the former head of it successfully ‘boots up,’ their syn- that government programme, Aris- thetic organism, dubbed Mycoplasma tides Patrinos, became the president laboratorium, would amount to an of Venter’s Synthetic Genomics.55 entirely new species of bacterium Venter talks big. In 2004 he predict- – the first fully synthetic living spe- ed that “engineered cells and life- cies ever created ( must use forms [will be] relatively common a cell’s machinery in order within a decade.” And he claims his to replicate and are therefore not will be the first fully synthetic life- 14 form.56 The birthdate of Venter’s a study on the of synthetic new organism is shrouded in secre- biology, which will no doubt serve as cy. In August 2004 Venter boasted a pre-emptive strike against critics.63 to Wired magazine that there would When asked by interviewers if they be an announcement by the end of are , Venter’s colleague the year.57 It never came. In June Hamilton Smith gives a characteris- 2005 Venter told the Wall Street Jour- tically hubristic response: “We don’t nal that he was two years away from play.”64 completing the synthetic microbe 2: Assembly Line DNA – and that the number of people “Lego” Life-forms to Order working on the project was about Craig Venter and Hamilton Smith to jump from 30 to 100.58 In Febru- may not want to play, but Drew Endy ary 2006 Venter told a Hollywood certainly does. Endy is a thirty-some- “We don’t play.” gathering that his team was just a thing MIT professor who helped few months away from creating an — Hamilton Smith, responding to coin the term synthetic biology.65 “I an interviewer asking if he and artificial organism and, once that like to build stuff,” he told Wired. colleagues are playing God happened, the biotech field would “I’m a kid in that regard.”66 He and be blown wide open.59 Venter took a his grad school followers project more somber tone at this year’s syn- themselves as the hip, young antith- thetic biology conference in Berke- esis to Venter’s grown-up corporate ley (SynBio 2.0), predicting that biology. Instinctively populist, they his organism would be ready within publish comics about synthetic biol- two years, admitting that it has been ogy, edit light-hearted videos about “a rolling two years” for some time life in the lab and carry out their now.60 discussions over Internet blogs and Venter’s attempt to build an artifi- wikis (editable webpages). Endy, cial chromosome is among synbio’s an engineer by training, is also a most high-profile projects. It also computer programmer and he and has the most visible commercial those around him use computer backing, including corporate agri- and electronics metaphors to de- culture and energy interests. Syn- scribe synthetic biology: A living thetic Genomics received half its organism is a ‘computer’ or ‘ma- “Biological engineers of the start-up capital from Alfonso Romo chine’ made up of genetic ‘circuits’ future will start with their lap- Garza, the Mexican billionaire who in which DNA is the ‘software’ that 61 tops, not in the laboratory.” owns giant Savia. can be ‘hacked.’ He points out that, — Drew Endy, MIT Bloggers at the University of Cali- “Biological engineers of the future fornia-Berkeley conference known will start with their laptops, not in as SynBio 2.0 noted that Venter the laboratory.”67 Endy’s engineer- was conspicuously conversing with ing approach dismisses genetic code Silicon Valley’s top venture capital that evolved in nature because it’s investor, Vinod Khosla – the co- too messy and too redundant. He founder of Sun Microsystems and a would rather invent his own code. “I big proponent of ethanol-based fu- thought, Screw it,” Endy told Wired. 62 els. Accustomed to pushing ethical “Let’s build new biological systems envelopes, Venter expects his artifi- – systems that are easier to under- cial life-form to raise eyebrows, and stand because we made them that his institute is one of three heading way.”68

15 Endy longs for a logical and pre- convene an International Geneti- dictable biotechnology, what he cally Engineered Competi- and others refer to as “intentional tion (known as iGEM). Last year, biology.” “We would like to be able almost forty teams of synthetic biol- to routinely assemble systems from ogy students from around the world pieces that are well described and competed to create the “coolest” well behaved,” Endy explains. “That artificial life-form out of .72 Last year, almost forty teams way, if in the future someone asks According to the event’s organisers, of synthetic biology students me to make an organism that, say, “Jaw-dropping creativity, originality, from around the world com- counts to 3,000 and then turns left, and functionality will certainly be peted to create the “coolest” I can grab the parts I need off the factors in the Judge’s [sic] decisions shelf, hook them together and pre- of relative coolness.”73 artificial life-form. 69 dict how they will perform.” In line with the criterion of cool, To do this he and his colleague at iGEM, now in its fifth year, mostly MIT, artificial intelligence pioneer produces eye-catching gimmicks – Tom Knight, have invented several bacteria that blink different colours hundred discrete DNA modules that and biological films that can be behave a little like electronic com- programmed to take simple photo- ponents. They include sequences graphs and display images. In 2006 that turn genes off and on, transmit the iGEM team from MIT designed signals between cells or change E. coli bacteria that smell of colours between red, green, yellow and wintergreen.74 Behind these and blue. Knight and Endy then trivial applications are ones that encourage others to combine those could someday prove practical (and modules into more complex genetic lucrative). Biological films that take circuits. They call these modules photographs could be the basis of Biobricks or “standard parts” and new forms of lithography for assem- their non-profit BioBricks Founda- bling computer circuits, while sweet “If you can take even the tion maintains over 1500 BioBricks smelling bacteria could interest the most rudimentary concepts in its registry of standard parts that fragrance and flavouring industries. of electrical engineering and can be freely used by other syn- Endy talks about building circuits 70 can pull them off in a cell, the thetic biology researchers. Each of into cells that count these BioBricks is a strand of DNA how many times they divide in order control that could give you designed to reliably perform one to prevent run-away . “I and the applications are mind- and to be easily compatible could hook it up to a - boggling.” with other BioBricks in making lon- nism,” he speculates, “and any cell ger circuits. The completed circuits that divides more than 200 times, Emanuel Nazareth, quoted in The Globe and Mail are then dropped into E. coli, yeast it would say, ‘Kill it, it’s forming a or another microbial host to see if tumour’…”75 One of Endy’s long they function. The inspiration for term ambitions is to re-design the BioBricks are the brightly coloured seeds of a tree such that the tree is plastic bricks from the children’s programmed to grow into a house.76 toy known as Legos, of which Tom One iGEM participant, Emanuel Knight is a lifelong fan.71 Nazareth of the University of To- Every year Endy, Knight and their ronto, imagines using BioBricks to fellow synthetic biologists at MIT build programmable cells that scour

16 the body crunching through choles- 3: Building Artificial Cells from terol: “If you can take even the most the Bottom Up – Ersatz Evolu- rudimentary concepts of electrical tion engineering and can pull them off From A-Bomb to A-Life: The Latest in a cell,” Nazareth explains, “the Project in New Mexico’s Desert: control that could give you and the One synbio research team is at- 77 applications are mind-boggling.” tempting to create artificial life- Mind-boggling applications that are forms without using DNA at all. In already attracting big money: iGEM October 2004, theoretical physicist organiser Randy Rettberg reminds Steen Rasmussen won a $5 million competitors, “The goal is not just to grant from Los Alamos National One synbio research team is do science and something cool. It Laboratory (New Mexico, USA) attempting to create artificial is to make an industry.”78 The US- – the atomic bomb’s birthplace life-forms without using DNA based synthetic biology community, – to build a living cell entirely from at all. centred close to the dot.com hot- scratch. While most synbio projects spots of Silicon Valley and Boston, are top-down – re-arranging exist- attracts young graduates planning ing life or reverse-engineering it synthetic biology start-ups in the to arrive at life’s barest essentials hope of becoming the next Google – Rasmussen’s project is truly bot- or Yahoo. They call this “garage tom-up: He is trying to design life bio-hacking,” consciously emulating by creating its essential ingredients the small, informal and homegrown and mixing them together in a test software companies of Silicon Valley. tube.88 His research team believes At a recent gathering of synthetic their “protocell” will require three biologists, bloggers commented how elements to sustain life – a metabo- the field “has an interesting new lism that harvests and generates flavor, namely that of money,” with energy, an information-storing mol- venture capitalists and established ecule (like DNA) and a membrane companies sniffing around for in- to hold it all together.89 79 vestment prizes. In 2005, Endy and Rasmussen is tweaking nature’s cell Steen Rasmussen’s research Knight, along with several other syn- design for his “Los Alamos Bug.” thetic biology illuminati, raised $13 Rather than an oily membrane team is trying to design life by million to found their own synthetic keeping water inside, his cell is creating its essential ingredi- biology start-up. Known as Codon basically a droplet of oil, which ents and mixing them together Devices, the company is described keeps water on the outside.90 Fur- in a test tube. as a ‘biofab.’ The aim of Codon De- thermore, it uses a different double vices is to “eliminate construction as helix molecule to carry instructions: 80 a barrier to synthetic biology.” This Rather than DNA, the Los Alamos means that Codon Devices builds Bug uses human-made PNA – pep- DNA to order, inserts it in bacteria tide . PNA has the same and sends it back to the customer and is made from the as a living – providing a same chemical bases as DNA – G, C, shortcut for genetic engineers. A and T – but the molecule’s back- bone is made of , the build-

17 Box 3: DNA Computing: Nature’s PowerBook While Endy and his cadre use computer code to build life, others are using life to build computers. The fledgling science of DNA computing is founded on the insight that, like a computer, DNA both stores and processes coded information. DNA computing was born in 1994 when Leonard Adleman, professor of computer science at the University of Southern California, demonstrated how to solve a complex computation- al problem (whose solution he already knew) using DNA to sort through possible answers and find the correct one. While computers store and process information in binary strings – coded as the numbers 0 and 1 – DNA operates in (mathematical) base four. Its information is coded by the sequence of the four nucleotide bases, A, C, T and G. The bases are spaced every 0.35 nm along the DNA mol- It would take more than a ecule, giving DNA a data density of over one-half million gigabits per trillion music CDs to hold square centimeter, many thousands of times more dense than a typi- the amount of information cal hard drive.81 For example, it would take more than a trillion music that DNA can hold in a cubic CDs to hold the amount of information that DNA can hold in a cubic centimeter.82 Moreover, different strands of DNA can all be working on centimeter. computational problems at the same time – and are a lot cheaper than buying multiple PowerBooks. Adleman’s rudimentary DNA computer performed 1014 operations per second.83 DNA computers are still in the proof-of-principle stage – they look noth- ing like computers – just DNA strands suspended in liquid, and practical applications are in very early stages. But it is the potential to exploit DNA’s storage and processing capacity that excites researchers. In 2000, Adle- man asked, “…if you can build a computer, then what other useful devices could you build on that very small scale? The possibilities are endless.”84 One hope is that DNA computers can function as . With funding from the US National Aeronautics and Space Agency (NASA), Columbia University researcher Milan Strojanovic is developing a DNA computer that will act as a to monitor the health of astronauts.85 Mean- while, scientists at Israel’s Weizmann Institute, led by , are developing a DNA computer to recognise and treat disease. In an experiment, a DNA computer was able to detect abnormal activity in four targeted genes that are associated with prostate and lung . Not only that, after recognizing the malignancy, the computer released a drug suppressing the genes responsible for the abnormal activity.86 The researchers hope to develop an injectable version that could work inside the body – an accomplishment that could take decades. Ned Seeman, working with DNA computers at New York University, is try- ing to apply DNA’s self-assembly process to the manufacture of nanoscale . While hoping to make the most of DNA’s computing potential, he remains cautious: “DNA computation is sort of like aviation in about 1905. There was such a thing as an airplane, but who knew if it was actually going to become a major mode of transportation or just sort of a toy?”87

18 ing blocks of proteins – instead of 4: Pathway Engineering – Bug DNA’s sugar-phosphate backbone. Sweatshops Howard Packer, Rasmussen’s collab- “Really, we are designing the cell to be orator as well as a pioneer of chaos a chemical factory. We’re building the , says that using PNA rather modern chemical factories of the future.” than DNA is a good idea for bio- – Jay Keasling, Professor of Chemi- safety reasons. Because PNA doesn’t cal Engineering, University of Cali- exist in nature, he says, the Bug may fornia at Berkeley95 be easier to control so it doesn’t “es- cape and cause problems.”91 At the University of California at Berkeley, the synthetic biology Rasmussen and Packard have estab- department led by Jay Keasling is lished a synthetic biology start-up engineering the genetic pathways of based in Venice, Italy, ProtoLife, cells to produce valuable drugs and “We’re building the modern to commercialise the Bug and/or industrial chemicals – a goal that is chemical factories of the its components. While Packard ac- fast becoming the cause célèbre of syn- future.” knowledges that their bottom-up bio. “Chemical engineers are good approach appears to lag behind life- — Professor Jay Keasling, University at integrating lots of pieces together of California, Berkeley creating teams led by Venter, Endy to make a large scale chemical and Jay Keasling (see below), he plant, and that is what we’re doing argues that the protocell approach in modern will lead to a better understanding – we’re taking lots of little genetic of living and non-living systems. pieces and putting them together “Right now,” he contends, “the state to make a whole system,” explains of the art for synthetic biology is a Keasling.96 hodgepodge of techniques which is, from an engineering and scientific Keasling’s team has synthesised perspective, groping.”92 Rasmus- about a dozen genes that work sen said, in February 2005, that he together to make the chemical pro- couldn’t promise a functioning cell cesses (or ‘pathways’) behind a class in three years – about the time it of compounds known as isoprenoids took to build the atomic bomb – but – high-value compounds important he “can guarantee that we’ll have in drugs and industrial chemicals. good progress.”93 Isoprenoids are natural substances produced primarily by plants. Be- There’s a good chance that the first cause of their structural complexity, lab to produce a working, evolving chemical synthesis of most isopren- protocell will be, like ProtoLife, a oids has not been commercially member of the PACE consortium. feasible, and isolation from natural PACE – Programmable Artificial sources yields only very small quan- Cell Evolution – is a project involv- tities. Synthetic biologists at Berke- ing 14 European and US universities ley hope to overcome these limita- and companies and is funded by the tions by designing new metabolic European Commission. PACE has pathways in microbes, turning them received over €6.5 million through into “living chemical factories” that th the Commission’s 6 Framework produce novel or rare isoprenoids.97 94 Programme. Most notably, they are focusing on a powerful anti-malarial compound

19 known as artemisinin. Backed by that produce natural rubber (also a $42.5 million grant from the Bill an isoprenoid).101 These pathways and Melinda Gates Foundation, the will then be incorporated into bac- Berkeley team believes that synthet- teria, or in sunflowers or desert ic biology is the tool that will allow plants, to boost rubber production unlimited and cheap production (see Synthetic Commodities, p. 40). of a previously scarce drug to treat Backed by a $42.5 mil- Other researchers exploring com- malaria in the developing world. In mercial uses for pathway engineer- lion grant from the Bill and 2003 Keasling and colleagues found- ing, include: Melinda Gates Foundation, ed a synbio start-up called Amyris Chris Voigt, a synthetic biologist at the Berkeley team believes Biotechnologies to bring the project to fruition. (See Case Study, p. 52.) the University of California at San that synthetic biology is the Francisco announced in May 2006 Amyris hopes to use the same tech- tool that will allow unlimited that he had re-engineered a nology platform to produce far and cheap production of a of salmonella to produce the pre- more lucrative drugs. “A number cursor to – a substance previously scarce drug to treat of drugs can be produced this way, as strong as Kevlar with 10 times the 98 malaria in the developing not just one,” Keasling explains. elasticity.102 “We’ve essentially created a platform world. that will allow you to produce many California-based Genencor has drugs cheaper. Down the road, we been working with chemical giant will be able to modify to DuPont to add synthetic genetic produce a number of different mol- networks to the cellular machinery ecules, even some that don’t exist in of E. coli. When mixed with corn nature.”99 syrup in tanks, their modified bacterium produces a key According to the company’s website, component in Sorona, a spandex- Amyris “is now poised to commer- like fibre. DuPont and sugar giant cialize pharmaceuticals and other Tate & Lyle are building a $100-mil- high value, fine chemicals taken lion biological factory in Tennessee, from the world’s forests and Amyris “is now poised to which they plan to complete in late by making these compounds in syn- 2006, to produce this new biomate- 100 commercialize pharmaceu- thetic microbes.” There are thou- rial.103 DuPont hopes that its new ticals and other high value, sands of isoprenoid compounds and bio-based textile will cause as much many of them have industrial uses. fine chemicals taken from the fuss as the introduction of nylon Amyris plans to use synthetic biol- world’s forests and oceans by back in the 1930s. DuPont plans to ogy to produce commercial drugs, build additional Sorona production making these compounds in , colourants, fragrances and factories, probably in the global synthetic microbes.” biofuels. The company claims that South. According to John Ranieri, its microbially-derived chemicals —Amyris Biotechnologies website Dupont’s vice-president of bio-based could be used for remediation of ra- materials, “one thing is for sure: we dioactive materials and to neutralise need to be close to the agricultural dangerous toxins such as sarin. producing centers, in Brasil, India Keasling’s lab is also attempting to or the USA.”104 re-engineer the metabolic pathways

20 5: Expanding Earth’s Genetic increase the number of System – Alien Genetics to 12. Benner calls his expanded “We’re not trying to imitate nature; we’re system of bases AEGIS (An Expand- trying to supplement nature. We’re try- ed Genetic Information System) ing to expand the genetic code.” – Dr. and has commercially licensed it Floyd E. Romesburg, Scripps Re- to privately-held EraGen Biosci- 106 search Institute, New York Times, July ences of Madison, WI (USA). 24, 2001 EraGen produces and sells DNA oligos built from the four natural While astronomers look to the stars DNA bases and the additional two “We’re trying to expand the for signs of alien life, a group of artificial ones. The company calls its genetic code.” synthetic biologists are creating it expanded genetic alphabet “a truly — Dr. Floyd E. Romesburg, Scripps in a Petri dish. Steven Benner, a revolutionary molecular diagnostics Research Institute and founder of the West- technology platform” that it uses heimer Institute for Science and for the development of new genetic Technology (Benner was formerly tests such as an assay for Cystic Fi- based at the University of Florida) brosis, or the detection of infectious is a pioneer of synthetic biology. biowarfare agents.107 He builds models of how life might function using unnatural genetic In 2004 Benner further showed that systems. His argument is simple: his six-letter DNA-like molecule There is no reason the limited set (including letters ‘K’ and ‘X’) could of molecules in DNA should be the support the molecular “photocopy- only form of life that has arisen in ing” operation known as polymerase the universe and we need models of chain reaction, in which the mol- what other kind of life could be out ecule copies itself and then directs there. “We can’t think of any trans- the synthesis of copies of copies. parent reason that these four bases Since natural polymerase enzymes [A, G, C and T] are used on earth,” rejected his artificial base pairs, “I suspect that, in five years Benner was forced to design a new, explains Benner.105 or so, the artificial genetic sys- compatible version of the Benner has demonstrated that a polymerase.108 tems that we have developed number of novel biological mol- will be supporting an artificial ecules can be chemically synthesised “Considering how hard we had to so that they reproduce and pass work to get Earth polymerases to life-form that can reproduce, on their genetic inheritance in the accept our artificial DNA, we doubt evolve, learn and respond to that our artificial DNA would sur- same way that DNA does. He sees environmental change.” artificial genetics as a way to explore vive for an instant outside of the — Steven Benner, Westheimer Insti- basic questions, such as how life got laboratory on this planet,” explains 109 tute for Science and Technology started on earth, how it evolves and Benner. “But a six-letter DNA even what forms it may take else- might support life on other planets, where in the universe. where life started with six letters and is familiar with them. Or even DNA Almost two decades ago, Benner led that contains up to 12 letters, which a team that created DNA contain- we have shown is possible.”110 ing two artificial nucleotide bases in addition to the four that appear in Building on Benner’s pioneering life as we know it. Later Benner was work, a number of other synthetic able to show that it was possible to biologists are developing practical

21 applications for artificial genetic one day it could be the genetic ma- systems. In 2005 Floyd Romesburg, terial for a new form of life, maybe a biochemist at the Scripps Institute here or on another planet.”112 in , California, added an ex- Benner and Kool haven’t built their tra letter F (made from flouroben- artificial genetic systems into full zene) to the existing four bases that organisms yet. “I suspect that, in occur naturally in DNA, and suc- five years or so, the artificial genetic cessfully created an enzyme that can systems that we have developed make the modified will be supporting an artificial life- self-replicate. form that can reproduce, evolve, chemist Eric T. learn and respond to environmen- Kool has re-designed the existing tal change,” Benner predicted in base pair A and T to be larger – cre- 2004.113 “We’ve designed a genetic ating an expanded Although Benner and others are system that’s completely new that glows in the dark and is unusu- confident that artificial genetic ally stable at higher temperatures. and unlike any living system systems will not survive outside the Kool dubbed his new molecule on Earth.” lab, research in this field raises pro- xDNA (for expanded DNA): “We’ve found biosafety questions. Dr. Jona- — Eric T. Kool, Stanford University designed a genetic system that’s than King, a professor of molecular completely new and unlike any liv- biology at MIT told the New York ing system on Earth,” announced Times: “It’s a powerful technology, 111 Kool. and like all powerful technologies Like Benner, Kool emphasises that it needs appropriate oversight and expanded DNA will not pose new regulation.” 114 One possible scenar- biosafety risks. “This new DNA io he suggested is that proteins with couldn’t function in the natural sys- artificial amino acids could elicit tem on Earth,” he asserts. “It’s too allergic reactions if used in drugs or big. However, we like to think that in food.115

22 Implications of Synthetic Biology: I. Building a Better Bio-Weapon – What does synthetic biology mean for bioweapons? II. The New Synthetic Energy Agenda – Rebooting Biofuels III. Synthesizing New Monopolies from Scratch – Synthetic Biology and Intellectual Monopoly IV. Synthetic Conservation – What are the implications of gene synthesis and digital DNA for conserving genetic resources and the politics of biodiversity? V. Synthetic Commodities – Implications For Trade VI. SynBioSafety

I. Building a Better Bio-Weapon “This is a wake up call,” he told – What does synthetic biology in July 2006.119 mean for bioweapons? In the same interview Wimmer “I expect that this technology will be revealed that he has repeated his misapplied, actively misapplied and it reconstruction a further would be irresponsible to have a con- six times and each time the work is 120 versation about the technology without easier and faster. acknowledging that fact.” – Drew Endy, Then there was the flu. The strain Synthetic Biologist, MIT116 of avian influenza that jumped to “I expect that this technology First there was . In 2002 a team early in the last century will be misapplied, actively of researchers at the State Univer- (H1N1), sometimes known as “The misapplied...” sity of New York at Stony Brook, led Spanish Flu,” killed somewhere — Drew Endy, MIT by molecular geneticist Dr. Eckard between 20 and 50 million people Wimmer, mail-ordered short se- worldwide in 1918-1919 – a higher 121 quences of synthetic DNA strands toll than all of World War I. (oligonucleotides) and pasted them Despite the lethal nature of the together into a functional version highly communicable virus, efforts of poliovirus. (The researchers in- to reconstruct it began in the 1950s. jected their de novo virus into some (By that time the H1N1 strain was unlucky mice for confirmation that eradicated from the earth – having the “worked.”)117 When disappeared with its last victims.) In this extreme genetic engineering 1997, Dr. Jeffrey Taubenberger of feat was announced to the world, the US Armed Forces Institute of Wimmer and his team were attacked in Washington, DC suc- as irresponsible and told that their ceeded in recovering and sequenc- published work could potentially ing fragments of the viral RNA from show terrorists how to make a bio- preserved tissues of 1918 flu victims 122 weapon. According to Wimmer, the buried in the Alaskan permafrost. point of undertaking the experi- Eight years later, Taubenberger’s ment was to illustrate that it was pos- team and collaborating researchers sible to construct such a dangerous at Mount Sinai School of Medicine pathogen using mail-order parts.118 in New York and the US Centers of Disease Control (CDC) in Atlanta 23 announced that they had resurrect- the synbio route in the past, even ed the lethal virus. They published when the road was much rougher details of the completed genome and longer than it is today. In a sequencing in Nature and details 2006 interview with Technology Re- of the virus recreation in Science.123 view, Serguei Popov, who genetically About ten vials of the flu virus were engineered bioweapons for the produced with the possibility that Soviet Union’s secret biowarfare “This is extremely foolish.” more could be made to accommo- programme, explained that over 25 date research needs, according to years ago, he “had fifty people do- and , comment- ing in on the pub- the CDC scientist who inserted the ing DNA synthesis manually, step lication of the 1918 flu virus genome virus into a living cell, the last step by step” to create biologically active in a public database in its reconstruction.124 Craig Venter viruses.129 “We had no DNA synthe- later described the resurrection of sisers then,” he says. “One step was the 1918 flu virus as “the first true about three hours, where today, Jurassic Park scenario.”125 with the synthesizer, it could be a Scientists responsible for recon- few minutes – it could be less than structing the 1918 flu virus may a minute. Nevertheless, already the have benefited from publications idea was that we would produce one 130 in high profile, peer-reviewed jour- virus a month.” nals and increased funding, but Today’s synbio industry has made enthusiasm for their work is not the work of bioweaponeers a whole universal. “Genetic characterization lot easier. Richard H. Ebright, a of influenza strains has important biochemist at Rutgers University, biomedical applications. But it is clarified forThe Washington Post not justifiable to recreate this par- that it would now be possible and ticularly dangerous eradicated strain “fully legal for a person to produce Today’s synbio industry has that could wreak havoc if released, full-length 1918 influenza virus or made the work of bioweapon- deliberately or accidentally,” admon- Ebola virus genomes, along with kits eers a whole lot easier. ished biologist Jan van Aken of the containing detailed procedures and bioweapons watchdog group, the all other materials for reconstitu- Sunshine Project, back in 2003.126 tion…it is also possible to advertise In a ‘post-reconstruction’ opinion and to sell the product…”131 Eckard piece in the New York Times, two Wimmer is even more blunt about leading technology thinkers, Bill Joy the potentially deadly combination and Ray Kurzweil, took the CDC to of accessible genomic data and task for publishing the full genome DNA-synthesizing capabilities: “If of the 1918 flu virus in the GenBank some jerk then takes the sequence database: “This is extremely foolish,” of [a dangerous pathogen] and they wrote.127 “The genome is essen- synthesizes it, we could be in deep, tially the design of a weapon of mass deep trouble.”132 destruction. No responsible scientist In June 2006, (UK) would advocate publishing precise announced that one of its journal- designs for an atomic bomb…reveal- ists ordered a fragment of synthetic ing the sequence for the flu virus is DNA of Variola major (the virus that even more dangerous.”128 causes ) from a commercial State-sponsored biowarfare pro- gene synthesis company and had grammes are known to have gone it delivered to his residential ad- 24 dress.133 The genome map of Variola works can then be inserted into mi- major is available on the Internet in crobial hosts such as E. coli or yeast. several public databases. Smallpox (See Pathway Engineering, p. 19.) is a highly infectious disease that Microbes could function as “biofac- hasn’t been around for almost 30 tories” to produce natural protein years, with the most recent natural poisons such as snake, and case occurring in Somalia in 1977, spider venoms, plant toxins and bac- according to the CDC. With ap- terial toxins such as those that cause proximately 186,000 base pairs, a anthrax, botulism, cholera, diphthe- “If some jerk then takes the commercial outfit could theoreti- ria, staphylococcal food poisoning sequence of [a dangerous 137 cally crank out the entire DNA for a and tetanus. In addition, biowar- pathogen] and synthesizes synthetic version of Variola major in fare experts are concerned that pro- it, we could be in deep, deep less than two weeks, for about the tein engineering could be used to price of a high-end sports car.134 The create hybrids of protein toxins.138 trouble.” company involved in The Guardian’s A 2003 declassified CIA document — Dr. , molecular investigation, VH Bio Ltd., based from the US, entitled “The Darker biologist who led the team that in Gateshead, UK, did not screen Bioweapons Future,” acknowledges synthesized poliovirus the requested sequence against that, “Growing understanding of the known genome sequences of the complex biochemical pathways dangerous , a pre- that underlie life processes has the cautionary (though voluntary) mea- potential to enable a class of new, sure to hinder malicious use.135 An more virulent biological agents earlier investigation by New Scientist engineered to attack distinct bio- found that only five of twelve DNA chemical pathways and elicit specific synthesis companies systematically effects...The same science that may checked their orders to ensure that cure some of our worst diseases they were not synthesizing and de- could be used to create the world’s livering DNA fragments that could most frightening weapons.”139 be used to assemble the genome The proliferation of synbio tech- 136 of a dangerous pathogen or the niques means that the threat of bio- genome of a new “chimera” virus terror (or bioerror, as Martin Rees, (that is, a combo-organism made the UK’s Astronomer Royal, has from two different pathogens), with called an unintentional but none- increased lethality and/or resistance theless deadly biotech mishap)140 is Synbio will also affect the way to known treatments. It is even pos- constantly evolving, challenging the that nations conduct war. sible that a chimera organism made abilities of the international Biologi- from benign sources of DNA could cal and Toxin Weapons Convention turn out to be pathogenic. (BWC) and civil society weapons- But concerns about synbio’s bio- watchdogs to monitor and prevent weaponry potential are not limited biowarfare. Synbio’s rapidly chang- to the construction or reconstruc- ing nature will also affect the way tion of virulent microorganisms. that nations conduct war. Drew Endy, Work in the area of pathway en- one of the leaders in the field of gineering is allowing synthetic synthetic biology, has warned about biologists to construct the genetic what he calls “the remilitarization of networks that code for particular biology”141 that could follow from de- proteins and these synthetic net- velopments in synbio-technologies.

25 Box 4: NSABB: Scientific Advice on How to Throw Out the Baby with the Bath Water The US CDC maintains a list of about eighty “select agents” (SAs) and tox- ins that pose a severe threat to public health and safety and whose posses- sion, use and distribution are controlled by law, known as the Select Agent Rules.142 The SA list includes, for example, bovine spongiform encepha- The same science that may lopathy (BSE) agent, Ebola, Lassa fever, Marburg, Foot-and-mouth disease, cure some of our worst reconstructed 1918 influenza andVariola major viruses as well as botulinum diseases could be used to neurotoxins. However, these restrictions appear to apply to possession, use and distribution of physical agents only, not related genomic data. In light create the world’s most of the challenges posed by emerging synbio-technologies, the US’s Nation- frightening weapons.” al Science Advisory Board for Biosecurity (NSABB) established a “Synthetic — CIA report, “The Darker Genomics Working Group” in November 2005 to deal with research that is Bioweapons Future” unclassified. The WG articulated some real-world concerns ushered in by the era of synthetic biology, such as the ease with which “individuals versed in, and equipped for routine methods in can use regularly avail- able starting material and procedures to derive some SAs de novo” and that synthetic biology now “allows expression of agents that resemble and have the attributes of specific Select Agent(s), without being clearly identifiable as SA based on the sequence.” In other words, syn-biologists can whip up virtually any toxin they want from scratch, and the DNA sequences in their potentially lethal products may or may not look identical to the sequences we know to occur naturally. To put it another way, the reality of the synbio age is that conventional taxonomies of dangerous substances cannot be comprehensive. Based on this observation, the WG draws a reasonable conclusion – that regulators should “re-evaluate reliance upon a finite list of agents as the foundation for the oversight framework.” Unfortunately, even shockingly, Syn-biologists can whip up the observation led the WG to weaken current regulation by recommending repeal of the law that makes it illegal to produce, engineer, synthesise or virtually any toxin they want acquire a virus containing 85% or more of the genetic sequence of Variola from scratch, and the DNA major (the smallpox agent).143 The Working Group’s recommendation to sequences in their potentially repeal US law 18 U.S.C. 175(c) was unanimously approved by the Board. lethal products may or may not The Sunshine Project describes the Board’s dangerous decision in this way: look identical to the sequences “Synthetic biology may be new; but challenges to taxonomic conventional wisdom are not. Evolution happens…The novel possibilities of synthetic we know to occur naturally. biology are thus not without precedent in nature, in the sense that taxono- my is always encountering the difficult-to-classify and is currently incapable of fully describing naturally occurring diversity. No matter what is cooked up in a synthetic biology lab, that doesn’t change the fact that there are diseases out there that can kill you. Scientists know what most of them are, and can reasonably define them. Hence the need for the Select Agent Rule is unaltered by the powers to manipulate, even create, dangerous forms of life (and nucleic acids) that is possibly offered by synthetic biology.”144

26 II. The New Synthetic Energy At the DOE, Patrinos had overseen Agenda – Rebooting Biofuels both the “Something I’m really excited about are and more recently the Genomes the synthetic biology projects they’re work- to Life (GTL) programme – which ing on to create new kinds of fuels so we supports research to focus synthetic can reduce our dependence on oil and biology on the production of biofu- protect our environment.” – Arnold els such as ethanol and hydrogen. Schwarzenegger, Governor of Cali- The GTL programme also promotes fornia146 research on technological fixes such as to mitigate When genetically modified - climate change.149 isms were first commercialised in the mid 1990s the controversy was Two months after Bush’s speech, Pa- largely focused on agriculture and trinos left the Department of Energy “We think this area [Synthetic food. A decade later, as fledgling to take up a new post as president Genomics] has tremendous of Craig Venter’s new company, companies seek to move synthetic potential, possibly within a Synthetic Genomics, Inc. The com- organisms from lab to marketplace, decade, to replace the petro- agriculture is once again on center pany aims to use microbial diversity stage – only this time the spotlight collected from seawater samples chemical industry.” isn’t shining on agri-food, but on as the raw material to create a new — Craig Venter speaking at Synthetic 145 agri-energy. synthetic microbe – one that is engi- Biology 2.0 neered to accelerate the conversion Synthetic biology’s promoters are of agricultural waste to ethanol. hoping that the promise of a very “green” techno-fix – synthetic mi- Patrinos is one of many high-profile crobes that manufacture biofuels industrialists and senior scientists cheaply or put a chill on climate who are climbing aboard the bio- change – will prove so seductive fuels bandwagon. Bill Gates, for ex- that the technology will win public ample, the soon-to-be retired chair- acceptance despite its risks and dan- man of Microsoft, recently bought Synthetic biology’s promoters gers. 25% of Pacific Ethanol, while his Microsoft co-founder Paul Allen has are hoping that the promise In his 2006 State of the Union ad- invested in Imperium Renewables, a of a very “green” techno-fix dress, US President George W. Bush Seattle-based company that will pro- will prove so seductive that announced that his government duce ethanol mainly from soybeans the technology will win public would devote “additional research and . Richard Branson, funds for cutting-edge methods of chairman of the Virgin Group of acceptance despite its risks producing ethanol, not just from companies, is devoting $400 mil- and dangers. corn, but from wood chips and lion to ethanol investment while 147 stalks or switchgrass.” Vinod Khosla, co-founder of Sun Synthetic biology is one of the “cut- Microsystems and partner at Kleiner ting-edge” methods for Perkins, a venture capital firm that production alluded to by Presi- famously backed AOL, Google and dent Bush. That part of his speech Amazon,150 now has a string of in- was written a few days earlier by vestments in ethanol companies. Aristides Patrinos, then-associate (See below.) director of the US Department of The growing enthusiasm for biofu- Energy’s (DOE) Office of Biologi- els in the US stems in part from a cal and Environmental Research.148 27 belated recognition that lerChrysler and General Motors supplies in “volatile” parts of the together aim to sell over 2 million world may not be so easily acquired ethanol-burning cars in the next through trade deals or wars. It also decade and the world’s largest re- deflects attention from tougher tailer, Wal-Mart, is mulling plans tasks like cutting energy consump- to sell an at its 380 US tion and promoting conservation. superstores.156 The ethanol boom The current buzz phrase for ethanol is especially good news for giant The surging demand for is “energy independence.” A typical agro-industrial corporations such articulation comes from a Depart- as Archer Daniels Midland (ADM), home-grown biofuels won’t ment of Energy report called From which controls about 30 percent of be easily met by current Biomass to Biofuels: “A robust fusion the US-based ethanol market.157 technologies. of the agricultural, industrial bio- But the surging demand for home- technology, and energy industries grown biofuels won’t be easily met can create a new strategic energy by current technologies. Fuel etha- independence and climate protec- nol can be produced in two ways: 151 tion.” The first is by breaking down agri- In addition to the energy independ- cultural starches into sugar, which ence mantra, environmental groups is then fermented into ethanol. In such as Natural Resources Defense Brazil ethanol is processed from Council (NRDC) are championing sugar cane; in the US the primary the development of certain types feedstock is corn. Growing corn and of ethanol as a climate-friendly fuel other food/feed crops for ethanol that could reduce global emissions will divert huge amounts of land, 152 of (CO2). water and energy-intensive inputs The US government’s Energy Policy away from food production to fuel Act of 2005 requires that 4 billion production. But even then, produc- gallons of ethanol per annum be tion levels would fall short of US mixed with gasoline at the pumps targets. The US Department of En- – that requirement will rise to 7.5 ergy calculates that if all corn now In fact, every bushel of corn billion gallons by 2012.153 (A gallon grown in the US were converted to grown in the US consumes equals 3.79 litres.) Spurred by lavish ethanol, it would satisfy only about between a third and a half- government subsidies and growing 15 percent of the country’s current enthusiasm for “energy indepen- transportation needs. Others put gallon of gasoline – making it 158 dence,” over 100 ethanol refineries that figure as low as 6 percent. But a costly and inefficient feed- were operating in the USA as of US corn production is energy in- stock for alternative energy. mid-2006, producing nearly 5 bil- tensive, requiring massive inputs of lion gallons of ethanol.154 fossil fuels for fertilisers, , tractors, post-harvest processing The biofuel buzz is about to become and transport (and corn must be a boom because the US government replanted every year unlike sugar mandates that at least 30 percent of cane, which is a perennial crop that fuel for transport be derived from produces for 3-6 years before being biofuels (mostly ethanol) by 2030 replanted). In fact, every bushel – a goal that would require roughly of corn grown in the US consumes 60 billion gallons of ethanol to be between a third and a half-gallon of 155 produced per year. Ford, Daim- gasoline159 – making it a costly and

28 inefficient feedstock for alternative GMOs haven’t solved the energy energy. equation either. An Ottawa-based A second approach is to produce company, Iogen, has genetically ethanol from cellulose, the fibrous modified a tropical to pro- material found in all plants. Cellu- duce enzymes that break down losic ethanol can be made from any cellulose, but it will cost five times leftover plant materials, including more to build its planned biofuel The hunt is on for a better woodchips, hulls, grasses (such refinery than to build a convention- 164 as switchgrass and miscanthus) and al corn ethanol processing plant. microbe that will cheaply and The hunt is on for a better microbe straw. There are abundant sources efficiently break down cel- that will cheaply and efficiently available for , lulose. That’s where synthetic as leaves and stalks – normally break down cellulose to sugars and considered waste – could become then ferment those sugars into etha- biology comes in. feedstocks.160 Processing ethanol nol – without costing energy. That’s from cellulose has the potential to where synthetic biology comes in. squeeze at least twice as much fuel The synthetic biology approach is from the same area of land as corn to custom design a ethanol, because much more bio- that can perform multiple tasks, mass is available per acre. Miscan- incorporating built-in cellulose-de- thus for example, a perennial grass grading machinery, enzymes that native to China yields approximately break down glucose, and metabolic 3,000 gallons of cellulosic ethanol pathways that optimise the efficient per acre.161 (One acre is approxi- conversion of cellulosic biomass mately 0.4 hectares.) into biofuel.165 Aristides Patrinos of If it sounds too good to be true Synthetic Genomics describes the – that’s because it is. It takes a lot all-in-one approach: “The ideal situ- of energy to break down cellulose ation would essentially just be one – much more energy, in the form big vat, where in one place you just of heat or steam or pressure, than is stick the raw material – it could be gained – especially once transport switch grass – and out the other end 166 and other lifecycle considerations comes fuel….” are factored in. A 2005 study by Da- Scientists haven’t managed to vid Pimentel (Cornell University) come up with a designer organism and Tad Patzek (University of Cali- that can do it all, but they are tak- Scientists haven’t managed fornia Berkeley) examines energy ing steps in that direction. A team to come up with a designer output of biofuels compared with from the University of Stellenbosch energy input for ethanol produc- (South Africa), collaborating with organism that can do it all, tion.162 They found that switchgrass engineering professor Lee Lynd at but they are taking steps in requires 45 percent more fossil Dartmouth University (USA), has that direction. energy than the fuel produced, and engineered a yeast that can survive wood biomass requires 57 percent on cellulose alone, breaking down more fossil energy than the fuel the plant’s cell walls and fermenting produced. According to Pimentel, the derived sugars into ethanol.167 “There is just no energy benefit to Meanwhile, Lynd’s group at Dart- using plant biomass for liquid fuel. mouth is working with a modified These strategies are not sustain- bacterium that thrives in high-tem- able.”163 perature environments and pro- 29 duces only ethanol in the process roughly equals the amount of CO2 of fermentation.168 Lynd hopes to produced in burning the fuel. But commercialise his technology at a these “carbon offset” calculations start-up company called Mascoma in are controversial because they are Cambridge, Massachusetts (USA).169 difficult, if not impossible, to sub- Chairing Mascoma’s board of direc- stantiate).174 Deeming cellulosic tors is venture capitalist and etha- ethanol carbon neutral, however, nol evangelist, Vinod Khosla, who will likely mean that it will qualify as recently snapped up Cargill’s head a Clean Development Mechanism of biotechnology, Doug Cameron, (CDM) activity under the Kyoto If any of these synbio as his chief scientific advisor. Khosla Protocol – a scheme established to approaches to biofuels is also funds another synthetic biol- reward polluting companies with successful, the agricultural ogy energy company known as LS9, emissions credits if they invest in based in the San Francisco Bay area “clean energy” projects in the global landscape could quickly (CA, USA).170 South.175 Civil society critics regard be transformed. At Purdue University’s Energy CDM as industry “greenwashing,” Center, Senior Research Scientist, a publicly subsidised scheme that Dr. Nancy Ho, has developed a will not combat climate change or 176 modified yeast that can produce 40 diminish its causes. Under the percent more ethanol from biomass CDM, Northern industries that grow than naturally occurring yeast, and large plantations of energy crops in she is now working with petroleum the South can be allowed to offset companies to convert straw into these projects against their emis- fuel.171 The Nobel Prize-winning sions. Of the 408 registered CDM head of the prestigious Lawrence activities as of mid-November 2006, Berkeley Lab, Dr. Steven Chu, 55 are described as biomass energy grabbed headlines last year when projects. India serves as “host coun- 177 he suggested that synthetic biology try” for 32 of the 55 projects. could be used to rewire the genetic The rush to plant energy crops in networks in a cellulose-crunching the global South threatens to shift bug found in the gut of termites.172 marginal land away from food pro- As a first step, the Berkeley Lab is se- duction, a trend that could intro- The rush to plant energy quencing microorganisms living in duce new and com- crops in the global South the termite’s gut, to identify genes promise food sovereignty. At SynBio threatens to shift marginal responsible for degrading cellulose. 2.0, the May 2006 conference held at Berkeley, Dr. Steven Chu noted land away from food produc- If any of these synbio approaches that there is “quite a bit” of arable tion, a trend that could intro- is successful, the agricultural land- scape could quickly be transformed land suitable for rain-fed energy duce new monocultures and as farmers plant more switchgrass crops, and that Latin America and compromise food sovereignty. or miscanthus – not only in North Sub-Saharan Africa are areas best 178 America, but also across the global suited for biomass generation. South. The US DOE considers cel- The 2005 US Energy Act mandates lulosic ethanol a “carbon neutral” the US State Department to trans- fuel source173 (meaning that the fer climate-friendly technologies (“ intensity reducing amount of CO2 absorbed in growing the plants that produce the biomass technologies”) to developing coun- tries,179 a move that could increase

30 pressure on already scarce or de- world, ADM is in a category of one pleted soil and water resources if it to capitalize on the exceptional op- involves large-scale production of portunity ahead.”183 energy crops. A 2006 report by the But converting plant biomass to fuel Sri Lanka-based International Wa- isn’t the only way that synbio could ter Management Institute (IWMI) upend the energy sector. Craig Ven- warns that growing crops for biofuel ter’s 2-year microbe-collecting expe- could worsen water shortages: “If dition netted previously unknown As presently envisioned, large- people are growing biofuels and species of bacteria that capture scale, export-oriented biofuel food it will put another new stress. sunlight with photoreceptors and This leads us to a picture of a lot convert it into chemical energy.184 production in the global South more water use,” explained David Since photosynthesis is capable of will have negative impacts on Molden of IWMI.180 By removing producing minute levels of hydro- soil, water, biodiversity, land biomass that might previously have gen, Venter’s team is exploring the tenure and the livelihoods of been returned to the soil, fertility idea of altering photosynthesis in and soil structure would also be cells to produce hydrogen. peasant farmers and indig- 181 compromised. As presently envi- enous peoples. sioned, large-scale, export-oriented University of California professor biofuel production in the global Jay Keasling, founder of Amyris South will have negative impacts on Biotechnologies, wants to design an soil, water, biodiversity, land tenure organism that produces a fuel simi- and the livelihoods of peasant farm- lar to gasoline. “Ethanol has a place, ers and indigenous peoples. but it’s probably not the best fuel in the long term,” Keasling told Tech- Growing demand for energy, and nology Review. “People have been us- the shift from food to fuel produc- ing it for a long time to make wine tion, could increase the energy and beer. But there’s no reason we sector’s influence in agricultural have to settle for a 5,000-year-old policies. It could also mean a new fuel.”185 Amyris recently hired John wave of consolidation in the form Melo, former president of US Fuels of mergers and strategic alliances Operations for BP, as its new chief “Basically, we are taking the between agribusiness and energy executive. “It even sounds amazing corporations. The Department of to us what we are trying to do,” said modern principles of synthetic Energy’s roadmap for developing Jack Newman, a co-founder of Amy- biology and trying to replace synthetic biology technologies for ris and vice president of research. crude oil.” ethanol production notes: “This “Basically, we are taking the modern research approach will encourage — Jack Newman, Amyris Biotech- principles of synthetic biology and nologies the critical fusion of the agriculture, trying to replace crude oil.”186 industrial biotechnology, and en- ergy sectors.”182 In a recent press re- The US military also wants to use lease on its biofuels strategy, ADM’s synthetic biology for energy produc- CEO Patricia Woertz claims that her tion. The US government’s Defense company is “uniquely positioned Advanced Research Projects Agency at the intersection of the world’s (DARPA) is funding a collaboration increasing demands for both food between Richard Gross of Polytech- and fuel. As one of the largest agri- nic University (New York) and gene cultural processors in the world and synthesis company DNA 2.0 (Silicon the largest biofuels producer in the Valley, California) to develop a new

31 kind of energy-rich plastic that can computing. And that means intel- be used first for packaging and lectual property claims related to then reused as fuel. DNA 2.0 aims synthetic biology involve not just to synthetically design the enzymes nanoscale DNA synthetically pro- to produce the polymer. The com- duced – but computers and software pany claims that soldiers in the field as well. Duke University (North will be able to burn the plastic that Carolina, USA) law professors Arti wraps their supplies, recovering Rai and James Boyle point out that 90% of the energy as electricity.187 biotech and software have proven III. Synthesizing New Monopo- ambiguous and problematic areas Over the past quarter century, from Scratch – Synthetic for law – a situ- vigorous and unbridled patent Biology and Intellectual Mo- ation that could create the “perfect 189 activity in the field of biotech nopoly storm” for synthetic biology. has paved the way for a Over the past quarter century, vig- Patents have already been granted on many of the products and pro- me-too approach in synthetic orous and unbridled patent activity in the field of biotech has paved cesses involved in synthetic biology biology. the way for a me-too approach (see Table 1, p. 35). Examples in- in synthetic biology. Diamond vs. clude: Chakrabarty, the 1980 US Supreme • Patents on methods of building Court case that opened the door to synthetic DNA strands190 the patenting of all biological prod- • Patents on synthetic cell ucts and processes, easily extends machinery such as modified to synthetic biology. In language ribosomes191 that perfectly describes today’s syn- • Patents on genes or parts of genes thetic organisms, the 1980 Court represented by their sequencing determined that, “…the patentee information192 has produced a new bacterium with markedly different characteristics • Patents for the engineering of 193 from any found in nature and one biosynthetic pathways having the potential for significant • Patents on new and existing utility. His discovery is not nature’s proteins and amino acids194 Patents have already been handiwork, but his own: according- • Patents on novel nucleotides that granted on many of the prod- ly it is patentable subject matter.”188 augment and replace the letters of ucts and processes involved in Unaltered genetic material in its DNA195 synthetic biology. natural environment is not patent- Some of these patents cast an ex- able, but once isolated, modified, tremely wide net. For example, US purified, altered or recombined, Patent 6,521,427, issued to Glen genetic material – including syn- Evans of Egea Biosciences (a Cali- thetic DNA – becomes fair game for fornia-based subsidiary of pharma monopoly patent claims (provided giant Johnson & Johnson) includes patent examiners deem that it broad claims on a method for syn- meets the criteria of novelty, utility thesizing entire genes and networks and non-obviousness). of genes comprising a genome, as Synthetic biology is inspired by the ‘operating system’ of living or- the convergence of nanoscale bi- ganisms – potentially a description ology/biotech, engineering and of the entire synthetic biology en-

32 deavour.196 Other patents awarded the wetware of life, synthetic biolo- to Jay Keasling and his colleagues gists have also expressed concern at Berkeley’s synthetic biology lab that broad concept-level patents cover methods for inserting artificial have been secured on the com- metabolic pathways into bacteria puter systems and software they and testing them for expression of use routinely.200 Such systems are new compounds.197 used to design genetic circuits in Patents can be granted on the ge- silico before synthesizing DNA in netic networks or ‘circuitry’ that syn- vivo. US Patent 5,914,891 owned thetic biologists have isolated from by Stanford University describes nature and on the distinct function- genes as ‘circuits’ and claims: “A al parts or units that make up those system and method for simulating circuits – whether they function the operation of biochemical net- as genetic switches, oscillators or works [that] includes a computer molecular ‘gates.’ MIT’s non-profit having a computer memory used Registry of Standard Biological Parts to store a set of objects, each object was created as a communal reposi- representing a biochemical mecha- tory for sharing, using, and improv- nism in the biochemical network to be simulated.”201 If enforced, such ing on the interchangeable modules Synthetic biologists have also broad claims could create a gate- – the BioBricks – that can be as- expressed concern that broad sembled to create biological systems keeper-like monopoly on the field in living cells. However, MIT’s Drew of synthetic biology, which requires concept-level patents have Endy estimates that about one-fifth massive computation and computer been secured on the com- memory to carry out the synthesis of the biological functions encoded puter systems and software by parts of BioBricks are already and design of DNA networks. they use routinely. covered by patent claims (held by In their article on synthetic biology individuals and organizations not and intellectual property, Duke Uni- associated with MIT’s BioBricks versity law professors Rai and Boyle project).198 cite the example of broad founda- There are also patents on classes of tional patents such as US Patent naturally occurring biomolecules 6,774,222, entitled “Molecular Com- commonly used as tools in synthetic puting Elements, Gates and Flip- biology. One example is ‘zinc fin- flops,” issued to the US Department gers,’ a family of proteins found in of Health and Human Services in 202 nature that are used by synthetic 2004. The patent involves DNA biologists because they bind to tar- logic devices that operate in a man- geted sequences of DNA. An article ner analogous to their electronic counterparts – for both computa- in Nature describes multiple pat- ents held by Sangamo Biosciences tion and control of . as a “stranglehold” on Rai and Boyle explain the far-reach- technologies, their uses in drug dis- ing scope of the patent: covery and the regulation of gene “The patent covers the combination 199 expression. MIT and Scripps Re- of nucleic-acid binding proteins and search Institute also hold patents on nucleic acids to set up data storage, zinc fingers. as well as logic gates that perform In addition to property claims on basic Boolean algebra. The patent

33 notes that the invention could be make a shambles of synthetic biol- used not only for computation but ogy.”205 Many practitioners in the also for complex (‘digital’) control fledgling field agree, and there is of gene expression. The broadest ongoing discussion about the pros claim, claim 1, does not limit itself and cons of a “conceal or reveal” ap- to any particular set of nuclei-acid proach to synbio.206 Some advocate binding proteins or nucleic acids. for an “open source” strategy, mim- Many types of molecular comput- icking the free software movement ing and control of gene expression in computing. Drew Endy and his “Overly restrictive licensing are likely to be covered by such a former colleague Rob Carlson first patent. Moreover, the claim uses coined the term “open source biol- and smotheringly broad language that would cover not ogy” while at Berkeley’s Molecular patent interpretations could only the ‘parts’ that performed the Sciences Institute in the late 1990s207 make a shambles of synthetic Boolean algebra but also any device and both continue to promote the and system that contained these idea as an integral part of their vi- biology.” parts. Such a patent would seem sion for synthetic biology. Their — Editorial, Scientific American effectively to patent algebra, or the model is Linux – the non-proprie- basic functions of computing, when tary computer operating system that implemented by the most likely hundreds of thousands of program- genetic means. It is difficult even mers developed voluntarily, building to imagine the consequences of an on each other’s work and releasing equivalent patent on the software their improved source code back to industry.” 203 common ownership. Endy ensures While some gene synthesis compa- that all his lab work is made public nies screen their product orders for on a wiki (publicly editable web potentially dangerous sequences, it pages) and makes the sharing of seems that no company screens se- genetic sequences a cornerstone of quences for possible patent infringe- MIT’s Registry of Standard Biologi- ment. Jeremy Minshull, of DNA2.0, cal Parts. told the attendees at the SynBio2.0 Endy and some of his colleagues dis- conference in Berkeley that his com- like the practice of patenting things pany specifically disclaims respon- found in nature (“It makes me phys- 208 It remains to be seen if open sibility for patent infringement in ically angry,” claims Endy). By de- the event that an ordered sequence signing genetic code into abstracted source proponents can coun- includes patented material. Mins- ‘BioBricks’ that easily snap together, ter a corporate-dominated hull explained that screening for Endy believes it will someday be science and techology that patented sequences would require a possible for anyone to participate in thrives on aggressive patenting company to keep a team of 50 law- the design of synthetic organisms. yers on the payroll, an expense that He imagines a new class of profes- activity. would be reflected in the market sionals similar to today’s graphic price of DNA: the price would be designers that will design new bio- closer to $100 per base rather than logical devices on laptops and then “a buck a base.”204 send those designs by email to gene foundries.209 In May 2006 the editors of Scientific American warned that “overly restric- Nevertheless, synthetic biologists tive licensing and smotheringly like Endy are also entrepreneurs. broad patent interpretations could Codon Devices, Inc., the synbio 34 Table 1: A Sample of Recent Synthetic Biology Patents

Inventor Patent / Application Publication Date Description Number Steven Benner US 6,617,106 9 September Methods for preparing oligonucleotides 2003 containing non-standard nucleotides Steven Benner US20050038609A1 17 Feb. 2005 Evolution-based functional genomics Steven Benner US 5,432,272 11 July 1995 Method for incorporating into a DNA or RNA using nucleotides bearing heterocyclic bases Harry Rappaport (Assignee: US 5,126,439 30 June 1992 Artificial DNA base pair analogues Temple University) George Church, Brian Baynes WO06076679A1 20 July 2006 Compositions and methods for protein (Assignee: Codon Devices, design Inc.) George Church, Jingdong US20060127920A1 15 June 2006 synthesis Tian (Assignee: Harvard) Noubar Afeyan, et al. (Assign- WO06044956A1 27 April 2006 Methods for assembly of high fidelity syn- ee: Codon Devices, Inc.) thetic Jay Keasling, et al. US20040005678A1 8 Jan 2004 of amorpha-4,11-diene (in a host cell, useful as pharmaceuticals) Jay Keasling, et al. US20030148479A1 7 August 2003 Biosynthesis of isopentenyl pyrophosphate (in a host microorganism, useful for phar- maceutical purposes) Keith K. Reiling, et al. (As- WO05033287A3 14 April 2005 Methods for identifying a biosynthetic path- signee: University of Califor- way nia) Ho Cho, et al. WO06091231A2 31 August 2006 Biosynthetic polypeptides utilizing non- naturally encoded amino acids (Assignee: Ambrx, Inc.) Robert D. Fleischmann, J. US20050131222A1 16 June 2005 Nucleotide sequence of the haemophilus Craig Venter, et al. (Assignee: influenzae Rd genome, fragments thereof, Human Genomes Sciences, and uses thereof (genome recorded on Johns Hopkins Univ.) computer readable medium - useful for identifying commercially important nucleic acid fragments by searching) Frederick Blattner, et al. (As- US 6,989,265 24 January 2006 New bacterium with a genome genetically signee: Univ. of Wisconsin) engineered to be at least 5% smaller than the genome of its native parent strain, use- ful for producing a wide range of commer- cial products Glen Evans (Assignee: Egea US 6,521,427 18 Feb. 2003 Method for the complete chemical synthe- Biosciences; subsidiary of sis and assembly of genes and genomes Johnson & Johnson) Jay Keasling, et al. US20060079476A1 13 April 2006 Method for enhancing production of iso- prenoid compounds James Kirby, et al. (Assignee: WO06014837A1 9 Feb. 2006 Genetically modified host cells and use of Univ. of California) same for producing isoprenoid compounds Nigel Dunn-Coleman, et al. US 7,074,608 11 July 2006 Method for the production of 1,3-propane- (Assignee: Dupont; Genen- diol by recombinant strain cor) comprising genes for coenzyme B12 syn- thesis Eric T. Kool US 7,033,753 25 April 2006 Compositions and methods for nonenzy- matic ligation of oligonucleotides and de- (Assignee: University of tection of genetic polymorphisms Rochester) Source: ETC Group

35 company co-founded by Endy in IV. Synthetic Conservation – 2005, holds an extensive patent What are the implications portfolio (63 patent applications of gene synthesis and digital and 22 issued patents as of late DNA for conservation of 2006). The company’s policy is to genetic resources and the “aggressively pursue patent protec- ­politics of biodiversity? tion for most of our proprietary “In the old days, all biology was ‘in vivo’ technology, and protect other – in life. Then scientists learned how aspects of our proprietary technol- to grow organisms ‘in vitro’ – in glass. “Pretty soon, we won’t have to 210 ogy as trade secrets.” Proponents Now biology is ‘.’” – Nathanael store DNA in large refrigera- of open source biology seek to Johnson, “Steal This Genome,” East tors. We’ll just write it when facilitate access and collaborative Bay Express,”212 innovation – worthy goals that, we need it.” unfortunately, do not address the Storing Diversity Digitally (or — Tom Knight, Synthetic Biologist, more fundamental controversies Goodbye CGIAR… Hello Google): MIT211 surrounding synbio’s development. When a team of synthetic biologists It also remains to be seen if open announced in 2005 that they had source proponents can counter a successfully resurrected and rebuilt corporate-dominated science and a fully working version of the 1918 technology that thrives on aggres- flu virus, it foreshadowed the era of sive patenting activity. electronic biodiversity – digital stor- age of DNA. Scientists predict that

36 within a few years it will be easier to formation. As of October 2006, Gen- synthesise a virus than to request it Bank, operated by the US National from a culture collection or find it Institutes of Health, has digitally in nature. Within a decade it may stored over 66 billion nucleotide be possible to synthesise bacterial bases214 from more than 205,000 genomes. Existing ex situ collections named organisms.215 The number Scientists predict that within of microbial strains (as well as seeds of nucleotide bases recorded in a few years it will be easier and animals) rely on the mainte- GenBank is doubling approximately to synthesise a virus than to nance of biological samples. If DNA every 18 months. As of September can be rapidly sequenced and the 2005 the database included 250 request it from a culture col- code stored digitally in silico the whole microbial genomes, seventy lection or find it in nature. potential exists for an organism’s of which had been deposited in the genome to be resurrected in vivo previous 12 months.216 These are via synthetic biology. As the price the raw data sources [libraries] from of gene sequencing continues to which synthetic biologists can gather fall, will cost-cutting bureaucrats DNA sequences to construct new be tempted to neglect repositories life-forms – just as of the world’s collected biodiver- rely on the culture collections of the sity in favor of computer servers, WFCC and plant breeders rely on hard drives and a network of gene a network of gene banks supported synthesisers? Will financial support by the Consultative Group on In- for gene banks and other genetic ternational Agricultural Research conservation strategies erode as a (CGIAR) such as IRRI (Interna- result? tional Rice Research Institute) and Today, members of the World CIMMYT (International and Federation of Culture Collections Improvement Center). (WFCC) in 66 countries store over DNA databases like GenBank could 1.3 million different samples of become as user-friendly as Google. bacteria, viruses, fungi and other In fact, the titanic search engine microbes.213 Given sufficient time has signaled interest in storing all and money, virtually any of these of the world’s genomic data in their DNA databases could become samples can be sequenced. If those google-farms (large complexes of as user-friendly as Google. same samples were stored digitally, servers and hard drives). According DNA molecules of any desired se- to an excerpt from The Google Story quence could be downloaded at the by Washington Post journalist David click of a mouse anywhere in the Vise, this plan was hatched in con- world. versation with synthetic biology pio- The cornerstone of today’s digital neer Craig Venter: “We need to use DNA system is the International the largest computers in the world,” Nucleotide Sequence Databases, Venter said. “Larry and Sergey which includes the European Mo- [founders of Google] have been ex- lecular Biology Laboratory (EMBL) cited about our work and about giv- Data (UK), the DNA Data- ing us access to their computers and bank of Japan and GenBank (US). their algorithm guys and scientists The three databases exchange data to improve the process of analyzing to maintain a uniform and compre- data… Genetic information is going hensive collection of sequence in- to be the leading edge of informa- 37 tion that is going to change the servation organizations, including world. Working with Google, we are the International Union for the trying to generate a gene catalogue Conservation of Nature (IUCN), to characterise all the genes on the plans to collect, preserve and store planet and understand their evolu- DNA and viable cells from animals tionary development. in danger of extinction.222 In the have wanted to do this for genera- next five years the project aims to tions…Over time Google will build ‘back up’ the DNA of the 36 species up a genetic database, analyze it, classified as “Extinct in the Wild” by and find meaningful correlations IUCN, and then collect the DNA of “If you wanted to resurrect for individuals and .”217 7,000 species that are listed as criti- an extinct bacteria – I could The use of DNA samples to recover cally endangered, endangered and imagine being able to do the genomes of rare or extinct spe- vulnerable. While the Frozen Ark that in the next decade, but cies is also gaining currency. In admits that it isn’t yet possible to reconstruct an extinct species from if you wanted to resurrect an December 2005 a team led by Hen- drik Poinar at McMaster University DNA specimens, the consortium is extinct – that’s still sequenced 1% of the genome of the putting lots of faith in future tech- very much in the realm of iconic woolly mammoth by working nologies: “We cannot predict what fantasy.” with a well-preserved 27,000-year-old may be possible even within the next few decades. It may become — Drew Endy, MIT 218 specimen from Siberia. His team is now working on the rest of the ge- possible to use samples to create nome.219 “While we can now retrieve clones of extinct animals when new the entire genome of the woolly methods have been developed. We 223 mammoth, that does not mean we are well on the way already.” can put together the genome into “The ability to synthesize functional organised in a nucle- genes and groups of genes should in- ar membrane with all the functional crease access to genetic materials for all apparatus needed for life,” explains scientists because exchange of actual Ross MacPhee, a researcher at the genetic material will not be necessary. American Museum of Natural His- Scientists will be able to synthesize genes tory who worked on the project.220 from published DNA sequences alone. In November 2006 researchers from A positive consequence of this is that a Germany’s Max Planck Institute greater number of scientists can have for Evolutionary in access to genes once their sequences are Leipzig announced that they have published. This will impact the use of sequenced one million base pairs material transfer agreements and con- of DNA taken from the bone of a tracts.” – DOE report on Synthetic 224 Neanderthal.221 An archaic human Genomics species, the Neanderthal has been Star-Trek Biopiracy: New Pathways extinct for some 30,000 years, but for Bio-Burglars? It sounds like researchers estimate they will have a something from the TV series Star complete genome, 3.2 billion base Trek, but today’s botanists (and pairs in length, in about two years. biopirates) who collect biological “The Frozen Ark,” an international specimens in diversity-rich areas of consortium sponsored by 11 mo- the South may soon have the option lecular biology, and con- of instantaneously “beaming back” samples to far-away labs without 38 relying on their checked baggage the CBD has merely facilitated le- or overnight courier. The combina- gal access to the genetic resources tion of rapid ‘lab on a chip’ gene and knowledge of indigenous and sequencing devices with ever faster other traditional peoples, mainly in DNA synthesisers means that it will the South. Although the CBD is a someday be possible to turn DNA multilateral agreement, it strongly samples into information at one encourages bilateral deal-making “Rather than send samples location, beam them digitally to an- and commercial exploitation of bio- through the mail, sequences other location and then reconstruct diversity.228) Today, with hundreds of them as physical samples anywhere thousands of DNA sequences being will be transferred electroni- else on the planet. This opens new downloaded daily from genomic cally between researchers pathways for biopiracy. databases such as GenBank or and directly into DNA EMBL, the CBD’s existing rules may Paul Oldham of Lancaster Univer- ­synthesizers.” sity’s ESRC Centre for Economic become even less relevant for gov- – Rob Carlson225 and Social Aspects of Genomics ob- erning access to and exchange of serves: “…the extraction of genetic biodiversity: The CBD does not take data has classically depended upon into account digital transmission of the collection, taxonomic identifica- biological materials. tion and storage of field samples, Researchers who access genebanks, i.e. within herbaria. However, it is such as those held in the CGIAR conceivable that technological in- system, are currently required to novation may one-day permit the in sign a legally binding Material situ extraction of genetic material Transfer Agreement, but the same and transfer of data to electronic researcher can obtain digital DNA form without the necessity of the sequences from GenBank practically collection, taxonomic identification anonymously with no legal strings and storage of field samples.”227 attached, unless the accession is Over the past 20+ years a piecemeal claimed separately by a patent. With a shift from biological array of international legal mecha- (A Material Transfer Agreement samples to digital DNA [MTA] is a contract that governs nisms and conventions have negoti- samples, will the legal concept ated controversial rules governing the transfer of research materials of national sovereignty over access to biodiversity (including from one party to another when the seeds, plants, tissues and microor- recipient intends to use them for genetic resources be turned ganisms) and exchange of genetic his or her own research purposes. on its head? resources around the globe, built on The MTA defines the rights of the the legal principle that nations have provider and the recipient with sovereignty over the genetic resourc- respect to the materials and any de- es within their borders. The UN rivatives.) Convention on Biological Diversity With a shift from biological samples (CBD), for example, has devoted to digital samples, will the legal thousands of negotiating hours to concept of national sovereignty over formulate rules on access to and genetic resources be turned on its exchange of genetic materials. (In head? Will synbio facilitate a new previous critiques of CBD negotia- wave of exclusive monopoly claims tions, ETC Group has pointed out based on digital DNA sequences? that, rather than support equitable If the genetic pathways for produc- exchange of genetic resources, 39 ing valuable natural substances the patent and the application was that are traditionally derived from eventually abandoned, but the mo- plants, animals and microorganisms nopoly claim illustrates the threat of can be identified by computers and far-reaching claims on digital DNA. fabricated by synthetic microbes V. Synthetic Commodities – in the laboratory, it could, among Implications for Trade other things, usher in a new and Will synbio facilitate a new “We’re making it easier for people to more complex era of biopiracy. make anything. They can make good wave of exclusive monopoly Companies such as Amyris Biotech- things, they can make bad things, and if claims based on digital DNA nologies foresee future profits from we’re going there, we’re going there very identifying new genetic pathways sequences? fast, at alarming exponential rates.” whether in silico or in vivo, re-creat- – Professor George Church, Har- ing them from scratch in microbes vard University geneticist and co- and then churning out products founder of Codon Devices231 such as artemisinin, taxol or other plant-derived substances that were Synthetic biologists are quick to formerly sourced from indigenous identify the potential benefits of and farming communities, or tradi- synthetic biology for the global tional healers. In theory, naturally- South – particularly in the form of occurring chemical substances such life-saving and cheap bio- as artemisinin are ineligible for fuels. However, the most far-reach- patenting because they are regarded ing impacts on poor economies, as “products of nature.” However, livelihoods and cultures are likely to a 2004 report for the Department come if synthetic organisms start to of Energy’s Biological and Envi- displace existing commodities: ronmental Research division notes Once More with Feeling: More than that “the ability to synthesize genes 15 years ago, ETC Group (then as will potentially lower barriers to RAFI) reported on US efforts to ge- patenting DNA sequences and the netically engineer guayule – a desert products that result by facilitating shrub native to the southwestern demonstration of utility and rais- US and Mexico – to increase yields The ability to synthesize genes ing questions about the barrier of of natural rubber.232 In the same re- 229 will potentially lower barriers ‘product of nature’ doctrine.” port, we highlighted USDA research to patenting DNA sequences In 2002, (the world’s larg- on a fermentation system of micro- est agrochemical corporation) filed organisms for large-scale production and the products that result. a 323-page patent application relat- of high-quality rubber in a bioreac- ed to its rice genome research that tor. Just last year, we reported on claimed monopoly control of key academic and industry researchers’ gene sequences that are vital for rice attempts to replace rubber (or breeding and dozens of other plant dramatically alter its properties) species. The scope of the patent was through nanoscale technologies. In unprecedented. Not only did the both cases, we focused on the poten- claims extend to at least 23 major tial impacts on rubber growers and food crops – they even extended to workers in the rubber-producing the use of gene sequences within countries in the South, particularly computer readable sequencing in- Southeast Asia. While scientists have formation.230 Civil society opposed yet to master rubber production in

40 the lab, they haven’t given up and cations.”234 Initially they are transfer- now the project has bounced over to ring genetic networks for rubber the field of synthetic biology. production into three microbes ( , Pathway engineers in Jay Keasling’s Escherichia coli Saccharomyces cere- and ), and lab are collaborating with the Cali- visiae fornia-based Yulex Corporation and will ultimately focus on whichever organism works best as a productive with researchers at the Colorado host for their rubber biofactory. If State Agricultural Experiment Sta- rubber-producing synthetic organ- tion to engineer metabolic pathways isms and enhanced rubber crops are The most far-reaching impacts in sunflowers and guayule that commercially successful, the USDA produce small quantities of natural on poor economies, livelihoods hopes to meet all domestic rubber rubber.233 They are also attempting and cultures are likely to come requirements this way. At present, to engineer a rubber-producing to- if synthetic organisms start to the US accounts for one-fifth of bacco. Alongside their engineering global rubber consumption (around displace existing commodities. work on rubber crops, Keasling’s 1.2 million tonnes a year).235 If suc- colleagues intend to create a strain cessful, US-based rubber production of bacteria that will produce high would supplant over $2 billion in quality natural rubber straight from export earnings from the South, the microbe. They explain, “The likely depressing rubber prices and goal of this proposed work is to pro- the livelihoods of small-scale rubber duce, in microorganisms, rubber producers and plantation workers. with the same qualities as natural rubber, and functionalized rubbers If the ability to cheaply produce with novel properties that might be other compounds from microbial used for biomedical or other appli- factories – including drugs, tropi-

If the ability to cheaply ­produce other compounds from microbial factories – including drugs, tropical oils, nutrients and flavourings – is ultimately achieved through synthetic biology, there will be a dramatic impact on the global trade in traditional commodities.

41 cal oils, nutrients and flavourings often made-to-order and extensively – is ultimately achieved through manipulated, it’s not simply trans- synthetic biology, there will be a dra- ferred from elsewhere in nature. As matic impact on the global trade in synbio products move from laptop traditional commodities.236 to lab and out into the real world, VI. Synbiosafety the question on everyone’s mind will be, “Is it safe?” “Around the globe, people continue to worry that unnatural organisms con- Synbio practitioners don’t hesitate taining recombinant DNA will become to offer up quotable quotes that environmental headaches, if not patho- acknowledge the possible pitfalls The question on everyone’s genic blights. For them, the news that and unanswered questions related to creating synthetic organisms. mind will be “Is it safe?” scientists could soon genetically tinker more easily and more extensively is any- In a recent Scientific American issue thing but good.” – Editorial in Scien- devoted to synthetic biology (June tific American, May 2006237 2006), for example, the editors pointed out that one way to “kill this “An engineer’s approach to looking at young science…is to underestimate a is refreshing but it the safety concerns.”240 But the ques- doesn’t make it more predictable. The tion, ultimately, is how to address engineers can come and rewire this and these concerns. that. But biological systems are not simple…And the engineers will find out Synthetic biologists claim that be- that the bacteria are just laughing at cause they are building whole sys- them.” – Eckard Wimmer, molecular tems rather than simply transferring geneticist at the State University of genes, they can engineer safety into New York at Stony Brook, who syn- their technology (e.g., by program- thesised poliovirus238 ming cells to self-destruct if they begin reproducing too quickly). Synbio’s suite of extreme genetic That assumes, of course, that the engineering techniques comes in life builders have complete mas- the wake of more basic genetically tery over their art – an impossible modified organisms that are not ful- standard since synthetic biologists, ly understood and have raised their for all their talk of circuits, software own global biosafety concerns.239 and engineering, are dealing with While genetically engineered or- the living wetware of evolution and Like GMOs before them, ganisms are often evaluated under all its unpredictability. Like GMOs organisms created through the principle of “substantial equiva- before them, organisms created lence” – where the altered organ- synthetic biology are far from through synthetic biology are far ism is equated with the organism’s being well understood. from being well understood. conventional, natural version based on genetic similarity – synthetic or- It’s well worth reiterating a few les- ganisms cannot lay claim to substan- sons learned from the experience of tial equivalence. The whole point genetic engineering: of synthetic biology, after all, is to Living organisms evolve and mu- create novel organisms that are sub- tate. It’s an oft-heard complaint stantially different from those that from synthetic biologists that their exist in nature: synthetic DNA is creations don’t like the status quo.

42 While the advantage of working with can produce uncertainty about the living cells is that they reproduce gene’s function as well as the func- on their own, the downside is that tion of the DNA into which it is in- they also evolve and mutate – chang- serted.244 They have also discovered ing the carefully crafted code that that the vast “non-coding” sequenc- their makers have programmed into es of DNA (so-called “junk” DNA), them. “From the perspective of an long considered irrelevant because engineer, we have not yet learned they yield no proteins, may actually Almost 55 years after the how to design evolving machines play indispensable roles in affect- that we can also understand,” ad- ing an organism’s function, health discovery of the double helix, mits Drew Endy, explaining, “No and .245 Recent scholarship molecular biologists are still engineer has faced the puzzle of on gene regulation and expression uncovering new information designing understandable evolv- emphasises the non-coding regions about how genes work and ing systems before.”241 Ron Weiss, a of DNA that transmit information synthetic biologist at Princeton Uni- in the form of RNA and on the im- what role they play in life versity puts it more practically: “Rep- portance of factors outside the DNA functions. lication is far from perfect… We’ve sequence.246 For all the talk about built circuits and seen them mutate synthetic bio’s genetic circuits and in half the cells within five hours. off-the-shelf parts, a living organism The larger the circuit is, the faster it is not a logical and predictable “ma- tends to mutate.”242 Before asserting chine.” that synthetically engineered organ- Living organisms can escape and in- isms are safe, synthetic biologists teract with their environment. In the would need to show that they know future, de novo synthetic organisms how their creations will behave from may be built from multiple genetic generation to generation or indeed elements that lack a clear genetic over hundreds of thousand of gen- pedigree. According to Jonathan erations since microbial organisms Tucker and Raymond Zilinskas, reproduce quickly. “the risks attending the accidental There’s a lot we don’t know about release of such as organism from living organisms. Almost 55 years the laboratory would be extremely after the discovery of the double difficult to assess in advance, includ- helix, molecular biologists are still ing its possible spread into new uncovering new information about ecological niches and the evolution For all the talk about syn- how genes work and what role they of novel and potentially harmful thetic bio’s genetic circuits play in life functions. Only recently characteristics.”247 and off-the-shelf parts, a have scientists rejected conventional Furthermore, several commercial living organism is not a logical wisdom about genetic inheritance: projects are looking to manufacture no single gene exclusively governs and distribute compounds pro- and predictable “machine.” the molecular processes that give duced by synthetic organisms. Will 243 rise to a particular inherited trait. substances produced by synthetic Scientists have moved away from the microbes behave identically to their “one gene = one trait” assumptions known counterparts? In addition, of earlier days. Scientists are still proposals to use synthetic organ- learning that when they introduce isms for or carbon a foreign gene into an organism it sequestration imply the intentional

43 environmental release of microor- thetic sections of DNA, under some ganisms with synthetic DNA. circumstances, could be transferred Will substances produced by Microbes, the main target of syn- to naturally occurring bacteria via synthetic microbes behave thetic biologists, are promiscuous the process of ‘horizontal gene identically to their known and can exchange genetic mate- transfer.’ Once incorporated into counterparts? rial with soil and gut bacteria. natural bacteria they could alter the The fashioning of short discrete functioning and behavior of natural synthetic pieces of code whether as microbial – affecting the ‘BioBricks’ or other active genetic environment in unforeseen and un- elements raises concerns that syn- predictable ways.

44 Table 2: Companies with Synthetic Biology Activities

Company Location SynBio business area Synthetic Biologists Ambrx La Jolla, CA Develops utilizing Associated with Dr. Peter Schultz, www.ambrx.com USA artificial amino acids Scripps Research Institute, San Diego, USA Amyris Biotechnologies Emeryville, CA Developing synthetic microbes to pro- Founded by Prof. Jay Keasling of www.amyrisbiotech.com USA duce pharmaceuticals, fine chemicals, University of California, Berkeley; nutraceuticals, vitamins, flavors and CEO John G. Melo was previously biofuels president of U.S. Fuels Operations for British Petroleum; Vice Presi- dent of Research is Dr. Jack D. Newman Egea Biosciences San Diego, CA Now wholly owned by Johnson & John- Founded by Dr. Glen Evans, for- www.egeabiosciences.com USA son. Develops innovative genes, pro- merly a leading investigator in the www.centocor.com teins and biomaterials for J&J medical Human Genome Project subsidiary Centocor; Egea holds broad patent on genome synthesis Codon Devices Cambridge, Describes itself as a ‘Bio Fab’ able to Founders include: Prof. Drew www.codondevices.com MA, USA design and construct engineered ge- Endy (MIT), Prof. George Church netic devices for partners in medicine, (Harvard), Prof. Jay Keasling (Ber- biofuels, agriculture, materials and other keley), Prof. Ron Weiss (Princeton) application areas and others Diversa San Diego, CA Diversa adds new codons to ‘optimise’ Eric Mather, Vice-President of Sci- www.diversa.com USA enzymes taken from natural bacteria to entific Affairs apply to industrial processes DuPont Wilmington, DuPont is partnering with Genencor, BP, John Pierce is Vice President, Du- www.dupont.com Delaware Diversa and others to develop microbes Pont Bio-Based Technology USA that will produce fibers (Sorona) and biofuels EngeneOS Waltham, MA Designs and builds programmable bio- Founders include Prof. George www.engeneOS.com USA molecular devices from both natural and Church (Harvard); Joseph Jacob- artificial building blocks son (MIT) EraGen Biosciences Madison, WI Develops genetic diagnostic tech-nolo- Founded by Dr. Steven A. Benner www.eragen.com USA gies based on expanded genetic alpha- bet Firebird Biomolecular Gainesville, FL Supplies nucleic acid components, li- Founded by Dr. Steven A. Benner Sciences USA braries, polymerases, and software to www.firebirdbio.com support synthetic biology Genencor Palo Alto, CA Develops and sells biocatalysts and Owned by Danisco www.genencor.com USA other biochemicals. Undertakes pathway engineering Genomatica San Diego, CA Designs software that models genetic www.genomatica.com USA network for synthetic biology applica- tions LS9 San Francisco, Designs microbial factories that produce Founders include Prof. George www.LS9.com CA, USA biofuels and other energy related com- Church (Harvard) pounds Mascoma Cambridge, Developing microbes to convert agricul- Founded by Dr. Lee R. Lynd (Dart- www.mascoma.com MA, USA tural feedstock into cellulosic ethanol mouth College) Protolife Venice, Italy Developing artificial cells and synthetic Founded by Dr. Norman Packard www.protolife.net living systems Sangamo Biosciences Richmond, CA, Produce engineered ‘zinc finger’ pro- www.sangamo.com USA teins for controling gene regulation Synthetic Genomics Rockville, MD Developing as chassis Founded by Dr. Craig Venter and www.syntheticgenomics. USA for energy applications Dr. Hamilton Smith; President is Dr. com Ari Patrinos (formerly US Depart- ment of Energy)

45 Synthetic Governance (Trust us. We’re experts.) “There are two ways of dealing with dangerous technologies…One is to keep the tech- nology secret. The other one is do it faster and better than everyone else. My view is that we have absolutely no choice but to do the latter.” – Tom Knight, New Scientist, 18 May 2006 If a small circle of synthetic biolo- Berkeley in May 2006 (SynBio 2.0), gists get their way, governance of would serve as pre-emptive action extreme genetic engineering will be to avoid potentially more stringent left entirely in their hands. Stephen government regulations. If the Maurer is an attorney and direc- synthetic biologists could agree on tor of the Information Technology these few proposals, the message to and Homeland Security Project at the rest of the world would be that Berkeley’s Goldman School of Pub- the field is in responsible hands: Ev- lic Policy. In early 2006 he and two erything is under control. Trust us, colleagues received funding from we’re experts. two foundations to investigate what The proposals carried echoes of level of oversight those working on an earlier episode in the history of synthetic biology deemed appropri- “If we choose to regulate gene technology. In 1975 scientists ate and palatable. Recognising that working with new recombinant the industry, we have to be the field was already beginning to DNA techniques (what we today call willing to pay the price for attract concern and criticism, par- genetic engineering) met at Asilo- ticularly because of the potential to that, which means there won’t mar in Northern California amid build new bioweapons, Maurer and be cheap antimalarial drugs growing calls for strong regulation his colleagues undertook 25 hour- of DNA technologies. The scien- developed and there won’t be long interviews and then prepared tists agreed to impose a short-lived potential biofuels developed a paper proposing a short list moratorium on some of their work, of soft, self-governance guidelines. and other drugs for other pending new biosafety frameworks. The white paper’s proposals were diseases and cleaning up the The Asilomar Declaration of 1975 almost entirely focused on issues is often portrayed as a shining ex- environment and all the things related to bioweapons. One pro- ample of responsibility and restraint posal was for scientists working in that come from this area.” by the scientific community, acting the field of synthetic biology to boy- — Jay Keasling, Discover, December for the greater good of humanity. cott gene synthesis companies that 2006 In reality, the Asilomar Declaration did not screen orders for dangerous was a move by a handpicked group pathogens, and the development of of elite scientists to preempt govern- software that could check genetic ment oversight by promoting an code for sequences that could be agenda of self-regulation. Asilomar used maliciously. He also proposed participants focused narrowly on a confidential hotline for synthetic biosafety issues – excluding broader biologists to check if their work, social and ethical concerns. By ap- or the work of others, was ethically pearing to voluntarily relinquish acceptable. These measures, put some recombinant DNA experi- forward for formal adoption at the ments (if only for a brief period of Synthetic Biology conference in time), the Asilomar scientists took 46 the heat out of a rising storm of de- ence media. “Scientists creating bate, and avoided public participa- new life-forms cannot be allowed tion on the issues.248 to act as judge and jury,” explained As early as October 2004, an edito- Sue Mayer, director of GeneWatch. “The implications are too serious rial in Nature suggested there might be a need for an “Asilomar-” to be left to well-meaning but self- conference on synthetic biology interested scientists. Public debate and policing is needed.” Those sign- and reference to Asilomar has sur- In response to the synthetic ing the open letter included social faced several times since within the biologists’ scheme for self- community of synthetic biologists. justice advocates (e.g., Third World Maurer’s consultation with synthetic Network), environmental groups ­governance, a coalition of 38 biologists included two “town hall (such as International civil society organizations, and ), farm meetings,” one in Berkeley, CA and including ETC Group, drafted one in Boston, MA – home to the groups (such as the Canadian Na- an open letter to conference two largest academic communities tional Farmers Union), bioweapons of synthetic biologists in the US. watchdogs (such as The Sunshine attendees. Only a handful of people attended Project), trade unions (e.g., the In- the Berkeley meeting while the MIT ternational Union of Food Workers) (Boston) meeting was slightly more and science organisations, includ- energised, but still inconclusive. The ing the International Network of chair of the Boston meeting, Drew Engineers and Scientists for Global Endy, noted candidly, “I don’t think Responsibility. [these proposals] will have a signifi- In the end, Asilomar 2.0 never quite cant impact on the misuse of this took off. Inside the conference, too, technology.” In May 2006, all the self-governance proposals were com- leading science press were primed ing under fire – though for different for “Asilomar 2.0” to take place in reasons. New Scientist noted that the Berkeley at SynBio 2.0. Nature sent a proposal to boycott non-compliant reporter to blog live from the event gene synthesis companies was weak- while Scientific American put synthetic ened because delegates didn’t want “Scientists creating new life- biology as their cover story and one to hobble the gene synthesis indus- of the original organisers of Asi- try. A final declaration emerged sev- forms cannot be allowed to lomar, Professor , eral weeks later, which didn’t rule act as judge and jury. The gave the keynote speech. out self-governance but placed it as implications are too serious one among a suite of possible gover- No civil society representatives were to be left to well-meaning but in attendance – those who tried nance approaches to synthetic biolo- self-interested scientists.” to register were turned away due gy: “We support ongoing and future to “limited space.” In response to discussions with all stakeholders for —Sue Mayer, GeneWatch the synthetic biologists’ scheme for the purpose of developing and ana- self-governance, a coalition of 38 lyzing inclusive governance options, civil society organizations, includ- including self governance, that can ing ETC Group, drafted an open be considered by policymakers and letter to conference attendees.249 others such that the development The letter dismissed the self-gover- and application of biological tech- nance proposals as inadequate and nology remains overwhelmingly 250 sounded the alarm on synthetic constructive.” biology to the international sci- Proposals for self-governance of 47 synthetic biology also feature promi- As yet, synthetic biology is not on nently in a December 2006 draft the radar of any international trea- report “Synthetic Genomics: Op- ties, agreements or conventions, tions for Governance,” prepared by although there are moves afoot to individuals from the J. Craig Venter bring the matter for discussion at Institute, Center for Strategic and the Biological and Toxin Weapons International Studies (Washington, Convention (BWC), which already DC) and MIT. The 18-month study, bans the development, production, funded by a $570,000 grant from stockpiling and transfer of “mi- the Alfred P. Sloan Foundation, crobial or other biological agents, If a small circle of synthetic is limited in scope to the issues of or toxins whatever their origin or biologists get their way, biosecurity (i.e., bioweapons and method of production, of types and ­governance of extreme genetic ) and biosafety (i.e., in quantities that have no justifica- worker safety and the environment), tion for prophylactic, protective engineering will be left entirely fails to include consultation with or other peaceful purposes.”252 ­in their hands. civil society and focuses primarily on Thus, the BWC already prohibits the US context for governance. One the synthesis of known or novel mi- of the study’s primary criteria for croorganisms for hostile purposes. effective governance is minimizing Moreover, if synthetic organisms costs and burdens to industry and were designed to produce toxins, government. Rather than call for their development and production legally-binding regulations, the draft would theoretically be prohibited by report emphasises a softer path both the BWC and the 1993 Chemi- such as options for monitoring and cal Weapons Convention. In 2005, controlling gene synthesis firms and the US National Institutes of Health DNA synthesisers, educating practi- established a Synthetic Biology tioners and beefing-up Institutional Working Group affiliated with the Biosafety Committees (IBCs). IBCs National Science Advisory Board in academic and commercial institu- for Biosecurity to make proposals tions, established by the US govern- related to bioweapons. (See Box 4). ment’s National Institutes of Health Although it was reported in mid- guidelines, assess the biosafety and 2006 that the Office of the Director environmental risks of proposed of National Intelligence in the US rDNA experiments, and decide on would form an advisory group to the appropriate level of contain- examine classified research in the ment. Critics charge that IBCs are area of synthetic biology, there is no ineffective and unenforced.251 further information available on the formation of this advisory body.253

48 Recommendations “The discoverer of an art is not the best judge of the good or harm which will accrue to those who practice it.” – Plato, Phaedrus Synbio without Borders: The tools Berkeley, California, “Novel DNA se- for DNA synthesis technologies are quences are now designed and built not only advancing at break-neck de novo for introduction into living pace, they are becoming cheaper, cells or incorporation into new or- geographically disperse and widely ganisms by undergraduate students accessible. The economic and tech- in technical universities.”256 nical barriers to synthetic genomics Not “business as usual:” ETC Group research are collapsing: notes that some synthetic biologists • In 2000 the price of synthetic are beginning to shun the spotlight The economic and technical DNA was about $10 per DNA and may seek to avoid public scru- barriers to synthetic genomics tiny by asserting that it is impossible base-pair; today it’s less than $1 research are collapsing. per base-pair and by the end of to clearly distinguish their work 2007 the price could fall to 50 from earlier advances in recombi- cents. nant DNA technology (genetic engi- neering). Because synbio is all part • The costs of equipping a lab for of the same toolbox, they argue, it synthetic biology research are “low simply isn’t possible to compartmen- and dropping” and the skill-level talise their research for purposes of required can be mastered by first- regulatory oversight. This refrain year university students with no (“synthetic biology is really noth- training in biological sciences.254 ing new”) is likely to be heard often • Within 2-5 years it may be possible in the coming months and years. to synthesise any virus; in 5-10 In reality, the ability to design and years it will become fairly routine construct synthetic organisms from The ability to design and to synthesise simple bacterial off-the-shelf DNA has the potential construct synthetic organisms genomes. to revolutionise biology and amplify from off-the-shelf DNA has • Around 66 commercial firms the power of technologies converg- (with locations on five continents) ing at the nanoscale. Synthetic biol- the potential to revolutionise specialise in synthesizing gene-and ogy is a nanoscale technology, and it biology and amplify the power genome-length pieces of double- must be considered in the broader of technologies converging at stranded DNA. context of converging technologies. the nanoscale. • Over 10,000 labs worldwide have Ongoing international dialogues on the technical capacity to conduct nanotechnology should incorporate synthetic biology research.255 synthetic biology in their discus- 257 Using desk-top DNA synthesisers or sions. mail-order DNA from commercial Beyond Regulation? Given the gene foundries on the Internet, the widespread availability of synthetic do-it-yourself assembly of synthetic biology tools, some argue that it genes and genomes is possible will be impossible to regulate, and almost anywhere in the world. Ac- that efforts to control it will force cording to Roger Brent, Director of research offshore or drive it under- the Molecular Sciences Institute in ground. Governments cannot abdi- 49 cate oversight of synbio because of organizations and social movements the regulatory challenges it poses. such as farmers’ organizations, Governments must determine what trade unions, human rights advo- is safe and acceptable for society, en- cates, peace, disarmament and envi- courage public dialogue and greater ronmental organizations. awareness of potential risks. As a Whether by deliberate misuse or as starting place, ETC Group offers the a result of unintended consequenc- Debate must go beyond following recommendations: es, synthetic biology will introduce biosecurity and biosafety to There must be a broad societal new and potentially catastrophic incorporate discussions about debate on synthetic biology’s wider societal risks. ETC Group yields to socio-economic and ethical implica- the expertise of groups such as the control and ownership of tions, including potential impacts on Sunshine Project and the Center for the technology and whether health, environment, human rights Non-Proliferation Studies in making it is socially acceptable or and security. Debate must go be- detailed recommendations on the yond biosecurity and biosafety to in- biosecurity aspects of synthetic biol- ­desirable. corporate discussions about control ogy. However, in keeping with the and ownership of the technology , synthetic and whether it is socially acceptable microbes should be treated as dan- or desirable. Because synthetic biol- gerous until proven harmless. At a ogy is highly de-centralised and its minimum, environmental release of impacts will be global, governance de novo synthetic organisms should options must be debated in an inter- be prohibited until wide societal national framework. debate and strong governance are It is not for scientists to either con- in place, and until health, environ- trol public discourse or determine mental and socio-economic implica- regulatory frameworks. In May 2006 tions are thoroughly considered. civil society organizations rejected Governments should maintain zero proposals put forth by a small group tolerance for biowarfare agents, of synthetic biologists for voluntary, synthesised or otherwise, and adopt self-regulation of their work. In an strong legal measures and enforce- ment to prevent the synthesis of It is not for scientists to either open letter, 38 civil society organiza- tions called on synthetic biologists biowarfare agents. Civil society must control public discourse or to participate in a process of open challenge the notion of ‘defensive’ determine regulatory frame- and democratic oversight of the bioweapons research because the line between ‘defensive’ and ‘offen- works. technology. Although some scien- tists and companies appear to be in sive’ research is indistinguishable. favor of dialogue, that process has International bodies must urgently not begun. review the implications of DNA Civil society should meet at na- synthesis and synthetic biology for tional, regional and international their mandates. In the future, the levels to evaluate and plan a coor- construction of synthetic genes dinated response to the emergence or microbial genomes using com- of synthetic biology in the context mercially-available gene sequences will become faster and easier than of wider, converging technologies. These meetings should be informed obtaining biological samples from by, but not limited to, civil society source countries, or from gene

50 banks. The Food commodities) has proven elusive in and Agriculture Organization’s years past. Will synthetic biology suc- Commission on Genetic Resources ceed in engineering synthetic mi- for Food and Agriculture should crobes to produce natural substanc- examine the potential implications es? If “genes now have the potential of synthetic biology for in situ and ex to be the design components of the situ genetic conservation future world economy,”258 the UN and for Farmers’ Rights. The UN Conference on Trade and Develop- Broad patents on synbio Convention on Biological Diversity ment should monitor the potential could be used to consolidate and its Subsidiary Body on Science, impacts on commodities, trade and Technology and Technological Ad- people whose livelihood depends on ­corporate power over a vice (SBSTTA) must also examine the production and processing of new generation of biological the potential implications of synbio raw materials. ­engineering and the parts, for the protection of biodiversity To facilitate coordinated global ac- ­devices and systems for and for existing rules on access to tion, an international body should ­synthetic life. and exchange of genetic materials. be established to monitor and as- The building blocks of life must sess societal impacts of emerging not be privatised: Despite earnest technologies, including synthetic calls for “open source biology,” ex- biology. Rather than approach tech- clusive monopoly patents are now nology assessment in a piece-meal being won on the smallest parts of fashion, governments and civil soci- life – on gene fragments, codons ety should consider longer-term and and even the molecules that make ongoing strategies to address the living organisms (i.e., novel amino introduction of significant new tech- acids and novel base pairs). Broad nologies. To break free from the The building blocks of life patents on synbio could be used to cycles of crisis that accompany each must not be privatised. consolidate corporate power over a new technology introduction, the new generation of biological engi- international community needs an neering and the parts, devices and independent body that is dedicated systems for synthetic life. to assessing major new technologies Biosynthesis of high-value products and providing an early warning/ (such as rubber and other South early listening system.

51 Case Study: Synthetic Biology’s Poster Child – Microbial Production of Artemisinin to Treat Malaria

Over 90% of malaria occur and managed to insert and express in sub-Saharan Africa. Global health them in a modified yeast strain. The initiatives have failed to deliver on microbe thus behaves like a minia- simple prevention measures such as ture factory to produce artemisinic mosquito netting, and the worsen- acid. According to Keasling, what’s The promise of unlimited ing crisis has led the World Health left to do is to increase the yields ­supplies of a drug to treat Organization (WHO) to reverse of artemisinic acid, and then use a 30-year policy – it now backs the “high-yielding chemistry” to convert ­malaria has become the use of a 20th-century silver bullet, artemisinic acid to artemisinin. raison d’être for synthetic the controversial DDT, The promise of unlimited supplies as a malaria prevention strategy. biology. of a drug that can roll back a global WHO regards artemisinin-based killer has become the raison d’être drugs as the best hope for treating for synthetic biology and given the over one million people – most of field a philanthropic sheen – remi- them African children – who would niscent of biotech’s much-heralded otherwise die of malaria each year. genetically engineered, Vitamin-A However, a global shortfall in the rich “” to feed the poor. supply of natural artemisinin, which (Since 2000, the biotech industry is extracted from sweet wormwood has used the promise of Golden plants (Artemisia annua), has kept Rice in public relations campaigns the price of this much-prized com- designed to win moral legitimacy pound out of reach for poor people. for its genetically engineered crops Using synthetic biology to combat – but the controversial product is malaria is compelling: a technologi- Keasling’s bacterial factories not yet available.) Though they’ve cal fix comes to the rescue when are already churning out produced only tiny quantities of investments in malaria prevention artemisinic acid so far, Jay Keasling’s copious amounts of priceless and control in Africa are declining, bacterial factories are already churn- PR for the fledgling synbio and failing. ing out copious amounts of priceless industry. In April 2006, Professor Jay Keas- PR for the fledgling synbio industry. ling of the University of Califor- The December 2006 issue of Discover nia-Berkeley and 14 collaborators names the Berkeley professor its announced in Nature they had suc- first-ever Scientist of the Year and ceeded in engineering a yeast strain the magazine’s editors ooze with ad- to produce artemisinic acid, which miration: “Through his significant is a necessary step in the produc- synthetic biology advancements, tion of artemisinin itself.259 Using ­Keasling is changing the world, mak- sophisticated and ing it a better place with every new screening techniques, the team discovery he makes.”260 But will bet- claims to have discovered the genes ting on synthetic biology’s medicinal involved in Artemisia annua’s natu- microbes to tackle malaria (backed ral production of artemisinic acid, by $42.5 million from the Bill and

52 Melinda Gates Foundation) divert Kenya, Tanzania, India, Uganda, attention and resources from other Gambia, Ghana, Senegal and Brazil. approaches that are less front page- In East Africa, an estimated 1,000 friendly, but nonetheless sustainable small-scale farmers (average 0.3 and de-centralised? Will promising hectares) and 100 larger scale farm- options for addressing malaria be ers (average 3 hectares) currently A report from the Royal 263 cast aside in single-minded pursuit grow artemisia. In light of global ­Tropical Institute of the of synbio’s silver bullet? demand and recent campaigns to Netherlands concludes that The current situation: WHO re- reinvigorate the fight against ma- the current artemisia shortfall quires that artemisinin be mixed laria, that figure is expected to grow with other malaria drugs (a drug to approximately 5000 smallholders could be met solely by in- and 500 larger-scale farmers.264 combination known as Artemisinin creasing cultivation of worm- Combination Therapies or ACTs) The report by the Royal Tropical wood, especially in Africa. to prevent the malaria parasite from Institute of the Netherlands con- developing resistance. ’s cludes that the current artemisia proprietary ACT drug (known as shortfall could be met solely by in- Coartem) is the only one that has creasing cultivation of wormwood, received pre- from WHO especially in Africa. Increasing local (meaning that it is approved for production is attractive as a sustain- procurement by UN agencies), giv- able and decentralised approach. ing Novartis a virtual monopoly on “From a technical point of view, ACT drugs. According to a 2006 it is possible to cultivate sufficient study on artemisia conducted by artemisia and to extract sufficient the Royal Tropical Institute of the artemisinin from it to cure all the Netherlands: “This monopoly-like malaria patients in the world. An situation has created an imperfect ACT could be made available at market defined by scarcity of raw an affordable price within just 2-3 materials, speculation and extreme- years.”265 The report estimates that ly high retail prices.261 between 17,000-27,000 hectares of Under contract to WHO, Novartis Artemisia annua would be required provides Coartem at cost (US$ 0.90 to satisfy global demand for ACT, to treat infants; US$ 2.40 to treat which could be grown by farmers in 266 adults) to the public sector in malar- suitable areas of the South. ia-endemic countries in the South. The Institute’s report warns, how- A two-tier pricing system allows No- ever, that the prospect of synthetic vartis to sell their ACT compound artemisinin production could de- The prospect of synthetic for ten times the cost to Northern stabilise a very young market for artemisinin production could markets and international travelers. natural artemisia, undermining the destabilise a very young Other drug companies are develop- security of farmers just beginning to ing ACT drugs, with Sanofi-Aventis plant it for the first time: “Growing market for natural artemisia. closest to having a marketable prod- Artemisia plants is risky and will not uct.262 be profitable for long because of the Novartis currently buys almost all synthetic production that is expect- 267 of the world’s wormwood crop, ed to begin in the near future.” sourcing from thousands of small Sold on synbio’s synthetic vision: farmers across China, , Keasling’s team believes that using

53 synthetic microbes to manufacture tion, extraction and (possibly) man- artemisinin could increase supplies ufacturing of ACT in regions where more quickly and reliably than malaria is prevalent will shift to the planting new crops. “You would main production sites of Western need to plant the state of Rhode pharmaceutical companies.”274 Island to meet demand,” quips Jack Could artemisia be a viable crop for Newman, co-founder – along with small farmers in sub-Saharan Afri- Keasling – of Amyris Biotechnolo- ca? Are local production, extraction gies, the company that will bring and even manufacturing of ACTs Will promising options for 268 synthetic artemisinin to market. possible in regions where malaria is ­addressing malaria be cast Amyris predicts that microbial prevalent? The Dutch researchers aside in single-minded pursuit production will lower the cost of who studied this possibility conclude 269 of synbio’s silver bullet? artemisinin to 25 cents per dose. that it won’t be easy – requiring not The company’s non-profit partner, only a hefty capital investment, but OneWorld Health, will steer the also “a total redesign of the supply product through the regulatory pro- and distribution chain.” 275 They sug- cess and conduct preclinical studies gest a number of policies that could to determine the safest artemisinin be implemented to promote cultiva- derivatives.270 tion of Artemisia annua while at the However, large-scale production same time protecting farmers from of synthetic artemisinin still faces un-due risk. For example, a procure- significant technical difficulties. ment fund could be established in OneWorld Health explains that “the Africa to stabilise the market for ar- yield of artemisinic acid would need temisia; quality seed could be made to be improved several hundred fold available to African farmers; other to be economically acceptable for medicinal crops could be promoted large-scale manufacturing.”271 Mean- to reduce the economic risk to farm- while, WHO notes that “clinical tri- ers; a task force could be established als have not yet begun, and filing for to enhance transparency, coherent regulatory approval will probably policy making and knowledge shar- not occur before 2009 to 2010.”272 ing.276 Keasling, too, sees late 2009 or early Where ACT drugs are not accessible 2010 as the earliest realistic target Are local production, extrac- or affordable, community-based for mass distribution.273 tion and even manufacturing efforts are focusing on local produc- If microbial production of synthetic tion of artemisia plants for use in of ACTs possible in regions artemisinin is commercially suc- herbal tea to treat malaria. Conven- where malaria is prevalent? cessful, pharma giants like Novartis tional health systems such as WHO would benefit because it will al- do not sanction the use of artemisia low them to replace a diverse set tea because of the difficulty of es- of small suppliers with one or two tablishing a standard dosage and conveniently located production quality control. However, Anamed factories. The Royal Tropical Insti- (Action for Natural Medicine), tute notes that, “pharmaceutical a Christian-based group of scien- companies will accumulate control tists and health workers, believes and power over the production pro- that the tea is effective in treating cess; artemisia producers will lose a upwards of 80 percent of malaria source of income; and local produc- cases.277 Anamed’s ‘grow your own’ 54 approach to fighting malaria pro- annua anamed (A-3) and the group vides artemisia seeds, community has introduced over 715 artemisia workshops and agronomic support growing projects in 75 countries.279 for small-scale plots based on mixed Their partners include the World farming methods across Asia and Af- Agroforestry Center (ICRAF) in rica. Anamed promotes a method of Mozambique, which has taught combining the tea with other com- thousands of southern African farm- pounds (either cheap medicines ers in their network how to grow or locally adapted herbs) to mimic artemisia from stem cuttings.280 No one knows if synthetic the combination effect of pharma- Anamed’s seeds are sold for $.01 per ceutical ACTs, but without using seed and each plant can treat up to biology will ultimately deliver proprietary drugs. Anamed believes eight malaria sufferers. Those plants safe and sufficient quantities that compounds found in artemisia can then be further propagated by of low-cost artemisinin for leaves, including 36 different fla- taking stem cuttings.281 controlling malaria in the vonoids, enhance the anti-malarial No one knows if synthetic biology developing world. properties of the tea (which they say will ultimately deliver safe and suf- are lost when the compound is puri- ficient quantities of low-cost artemis- 278 fied for drug use). inin for controlling malaria in the While the use of artemisia tea developing world. The Gates Foun- may be controversial, the need to dation should insure that its focus increase the world’s supply of arte- on a synbio anti-malarial drug does misia is not. Anamed has developed not foreclose options for commu- a variety of artemisia adapted to Af- nity-based, farmer-led approaches. rican conditions known as Artemisia

55 Glossary Amino Acid – Small molecules that link together Isoprenoid – a diverse class of chemical molecules to form proteins; often referred to as “the building produced primarily by plants. Although over 50,000 blocks” of proteins. 20 unique amino acids have been isoprenoids are known, only a small fraction have identified. been exploited for pharmaceutical and industrial Biopiracy – The appropriation of the knowledge purposes. Taxol (derived from the yew tree) and and genetic resources of farming and indigenous artemisinin (derived from the wormwood tree) are communities by individuals or institutions who seek examples of isoprenoids. exclusive monopoly control (patents or intellectual Nucleotide – One of the structural components of property) over these resources and knowledge. ETC DNA and RNA. A nucleotide consists of a base (one group believes that intellectual property is predatory of four chemicals: adenine [A], thymine [T], gua- on the rights and knowledge of farming communities nine [G], and cytosine [C]) plus a molecule of sugar and indigenous peoples. and one of phosphoric acid. Chromosome – A long, continuous piece of DNA Oligonucleotide – Short, single-stranded sequences that contains many genes, regulatory elements and of DNA, typically made up of twenty or fewer bases other intervening nucleotide sequences. (though automated gene synthesizers produce oligo- Codon – A series of three chemical bases linked to- nucleotides that may be 200 bases long). gether in a specific order. During protein synthesis, Synthetic Biology (also known as Synbio, Synthetic it is the order of the codon that determines which Genomics, Constructive Biology or Systems Biology) amino acid will be added to the protein under con- – The design and construction of new biological struction within the cell. Each codon carries the code parts, devices and systems that do not exist in the for a specific amino acid. natural world and also the redesign of existing bio- DNA – A self-assembling, cellular molecule that con- logical systems to perform specific tasks. Advances in tains the genetic instructions for the development nanoscale technologies – manipulation of matter at and function of living things. DNA is made up of sim- the level of atoms and molecules – are contributing ple units called nucleotides that are held together by to advances in synthetic biology. a “backbone” made of sugar and phosphate groups. Sources: ETC Group, Genetics Home Reference DNA’s structure is a double helix. Glossary (http://ghr.nlm.nih.gov/ghr/glossary/ami- noacid), Wikipedia (www.wikipedia.org), Amyris Bio- technologies, Inc.

56 Endnotes On December 13, 2006, all of the ULs provided in the endnotes 17 John Mulligan, Blue Heron Biotechnology, “An Intro- were active. duction to Gene Synthesis,” presentation made on Decem- 1 Rob Carlson, letter to New York Times: http://www. ber 4, 2006 at meeting on Synthetic Genomics: Options for synthesis.cc/NYT_Letters_Dec_12_2000.pdf Governance, Washington, DC. Mulligan emphasises that these estimates are very rough and no one knows the defini- 2 Philip Ball, “What Is Life? Can We Make It?” Prospect tive market value at this time. Magazine, Issue # 101, August 2004. 18 John Mulligan, Blue Heron Biotechnology, “An Intro- 3 David Whitehouse, “Venter revives synthetic bug talk,” duction to Gene Synthesis,” presentation made on Decem- BBC News Online, 4 July 2005: http://news.bbc.co.uk/2/hi/ ber 4, 2006 at meeting on Synthetic Genomics: Options for science/nature/4636121.stm Governance, Washington, DC. 4 Erica Check, “Fast sequencing comes to light,” Nature 19 Presentation by Hans Buegl of GeneArt at Synthetic News, 31 July 2005, on the Internet: http://www.nature. Biology 2.0 Conference, Berkeley, CA: webcast on the com/news/2005/050725/full/050725-14.html Internet: http://webcast.berkeley.edu/events/details. 5 The text of the Open Letter is available on the Inter- php?webcastid=15766 net: http://www.etcgroup.org/en/materials/publications. 20 http://www.blueheronbio.com/genemaker/genemaker. html?id=8 html 6 Anon., “The next big bang: Man meets machine,” 21 http://www.geneart.com/english/products-services/ TheDeal.com, May 29, 2006. gene-synthesis/index.html 7 Roco, M., Bainbridge, W. (eds.), Converging Technologies 22 “Synthetic gene firms evolve toward sustainable busi- for Improving Human Performance. Nanotechnology, Biotechnol- ness?” Nature Biotechnology, November 2006, p. 1304. ogy, Information Technology, and , National Science Foundation/Department of Commerce Report, 23 From the Introduction to “Synthetic Genomics Study” at 2002. http://openwetware.org/wiki/Synthetic_Genomics_Study 8 Raymond Bouchard, “Bio-Systemics Synthesis,” Science 24 Interview conducted with Drew Endy, Boston, 6 October and Technology Foresight Pilot Project (STFPP) Research 2006. Report # 4, June 2003. 25 http://www.blueheronbio.com/genemaker/genemaker. 9 Douglas Mulhall, Our Molecular Future, Prometheus html Books, 2002. 26 For ABI Gene Synthesisers, see https://products.ap- 10 See Jeffrey Harrow, “Quote of the Week”, Harrow Tech- pliedbiosystems.com:443/ab/en/US/adirect/ab?cmd=catN nology Report, 31 Jan. 2005; on the Internet: http://www. avigate2&catID=600588. theharrowgroup.com/articles/20050131/20050131.htm 27 Interview conducted with Drew Endy, Boston, 6 October 11 Joel Garreau, Radical Evolution: The Promise and Peril of 2006. Enhancing Our Minds, Our Bodies – and What It Means to Be 28 “Synthetic biology: Life 2.0,” , August 31, Human, Doubleday, 2005. 2006, available on the Internet: http://www.economist. 12 See ETC Group Communiqué, “The Little BANG Theo- com/business/displaystory.cfm?story_id=7854314 ry,” Issue # 78, March/April 2003, http://www.etcgroup.org 29 Carlson quoted in Paul Boutin, “Biowar for Dummies,” 13 See Epoch Biolabs’ web site for estimated costs and de- Paul Boutin blog, 22 Feb. 2006; on the Internet: http:// livery times: http://www.epochbiolabs.com/genesynthesis. paulboutin.weblogger.com/stories/storyReader$1439 asp?pageName=products. 30 Oliver Morton, “Life Reinvented,” Wired, Jan. 2005. 14 Dr. Michael J. Gait, “50 Years of Nucleic Acids Synthesis: 31 Antonio Regalado, “Biologist Venter aims to create life a Central Role in the Partnership of Chemistry and Biol- from scratch,” The Wall Street Journal, 29 June 2005. ogy,” p. 2; on the Internet: www.fco.gov.uk/Files/kfile/ 32 Carolyn Abraham, “Playing God in Running Shoes,” drMichaeljay.pdf The Globe and Mail (Toronto, Canada), 17 December 2005, 15 John Mulligan, Blue Heron Biotechnology, “An Intro- page F1. duction to Gene Synthesis,” presentation made on Decem- 33 Jeremy Minshull, President of DNA2.0, characterised ber 4, 2006 at meeting on Synthetic Genomics: Options for DNA synthesis pricing as “a buck a base” at SynBio2.0, Governance, Washington, DC. Berkeley, CA; webcast on the Internet: http://webcast. 16 Carolyn Abraham, “Playing God in Running Shoes,” The berkeley.edu/events/details.php?webcastid=15766 Globe and Mail (Toronto, Canada), December 17, 2005, page F1. 57 34 http://www.epochbiolabs.com/genesynthesis. 52 See Synthetic Genomics web site: asp?pageName=products http://www.syntheticgenomics.com/about.htm 35 Matthew Herper, “Architect of Life, ” Forbes.com, 2 Oc- 53 Presentation made by J. Craig Venter, “Synthetic Ge- tober 2006, on the Internet: http://www.forbes.com/free_ nomics: Risks and Benefits for Science and Society,” Wash- forbes/2006/1002/063.html ington, DC, December 4, 2006. 36 Prediction by John Danner of Codon Devices, Synthetic 54 US Department of Energy, News Release, “Researchers Biology 2.0 DNA Synthesis panel, 20 May 2006; webcast on Funded by the DOE ‘Genomes to Life’ Program Achieve the Internet: http://webcast.berkeley.edu/events/details. Important Advance in Developing Biological Strategies to php?webcastid=15766 Produce Hydrogen, Sequester Carbon Dioxide and Clean 37 David Rotman, “Rewriting the Genome,” Technology up the Environment,” November 13, 2003. ­Review, May/June 2006. 55 Synthetic Genomics Press Release, “Dr. Aristides Patri- 38 Sylvia Pagán Westphal, “Virus synthesised in a fort- nos Named President Of Synthetic Genomics, Inc.,” on the night,” 14 November 2003, NewScientist.com; on the Inter- Internet: http://www.syntheticgenomics.com/press/2006- net: http://www.newscientist.com/article.ns?id=dn4383 02-02.htm 39 Interview conducted with Drew Endy, Boston, 6 Octo- 56 Dan Ferber, “Microbes Made to Order,” Science, 9 Janu- ber 2006. ary 2004: Vol. 303. No. 5655, pp. 158-161. 40 MIT Museum Soap Box Public Discussion (21 March 57 James Shreeve, “Craig Venter’s Epic Voyage to Redefine 2006), Drew Endy: “The Implications of Synthetic Biology;” the Origin of the Species,” Wired, August 2004. On the In- on the Internet: http://mitworld.mit.edu/video/363/ ternet: http://www.wired.com/wired/archive/12.08/ 41 As quoted on the National Center for Biotechnol- 58 Antonio Regalado, “Next Dream for Venter: Create En- ogy Information webpage, “What is a Genome?” On the tire Set of Genes From Scratch,” Wall Street Journal, June 29, Internet: http://www.ncbi.nlm.nih.gov/About/primer/ 2005, p. A1. genetics_genome.html 59 John Borland, “Mixing genius, art and goofy gadgets,” 42 An RNA codon table is available at http://en.wikipedia. CNET News.com, February 5, 2006; on the Internet: http:// org/wiki/Genetic_code news.com.com/Mixing+genius%2C+art+and+goofy+ gadgets+-+page+2/2100-1026_3-6035313-2.html?tag=st.next 43 For more information about gene regulatory networks, see the web site of US Department of Energy’s Genomes to 60 Craig Venter speaking at Synthetic Biology 2.0 Life project: http://www.doegenomestolife.org/science/ Conference, Berkeley, CA; webcast available on the In- generegulatorynetwork.shtml ternet: http://webcast.berkeley.edu/events/details. php?webcastid=15766 44 Bob Holmes, “Alive! The race to create life from scratch,” New Scientist, 12 February 2005. 61 Michael S. Rosenwald, “J. Craig Venter’s Next Little Thing,” Washington Post, February 27, 2006. 45 Meredith Wadman, “Biology’s Bad Boy Is Back,” Fortune, March 8, 2004. 62 Rob Carlson’s Synthesis Blog, 21 May 2006; on the In- ternet: http://synthesis.typepad.com/synthesis/2006/05/ 46 Nicholas Wade, “Bacterium’s Full Gene Makeup Is De- live_from_synth_1.html coded,” New York Times, May 26, 1995. 63 MIT Press Release, “Study to explore risks, benefits 47 See Synthetic Genomics web site: of synthetic genomics,” June 28, 2005; on the Internet: www.syntheticgenomics.com http://web.mit.edu/newsoffice/2005/syntheticbio.html 48 Alexandra M. Goho, “Life Made to Order,” Technology 64 , “Ripped Genes,” The Daily Telegraph, Review, April 2003, pp. 50-57; on the Internet: http://www. May 27, 2006; on the Internet: http://www.edge.org/3rd_ technologyreview.com/articles/goho20403.asp?p=1 culture/highfield06/highfield06_index.html 49 John I. Glass et al., “Estimation of the Minimal Myco- 65 Rob Carlson’s Synthesis Blog, “Synthetic Biology 2.0, Part plasma Gene Set Using Global Transposon IV: What’s in a name?” On the Internet: http://synthesis. and Comparative Genomics,” Genomes to Life Contrac- typepad.com/synthesis/2006/05/synthetic_biolo_1.html tor-Grantee Workshop III, February 6-9, 2005, Washington, DC; on the Internet: http://www.doegenomestolife.org/ 66 Oliver Morton, “Life, Reinvented,” Wired, Jan. 2005. pubs/2005abstracts/venter.pdf 67 Drew Endy, Comments made during meeting on Syn- 50 See, for example, the PEC (Profiling of E. coli Chromo- thetic Genomics: Risks and Benefits for Science and Soci- some) database on the Internet: http://www.shigen.nig. ety, Washington, DC, December 4, 2006. ac.jp/ecoli/pec/index.jsp 68 Quoted in Oliver Morton, “Life, Reinvented,” Wired, 51 , “Tinker, Tailor: Can Venter Stitch Togeth- Jan. 2005. er A Genome From Scratch?” Science, February 14, 2003. 58 69 W. Wayt Gibbs, “Synthetic Life,” Scientific American, May 90 Bob Holmes, “Alive! The race to create life from 2004. scratch,” New Scientist, 12 February 2005. 70 See www.BioBricks.org 91 Presentation by Norman Packard, “It’s Alive: Synthetic 71 Oliver Morton, “Life, Reinvented,” Wired, Jan. 2005. Biology” at Pop!Tech, October 2005, Camden, Maine USA; on the Internet: http://www.itconversations.com/shows/ 72 For information on iGEM, see http://parts.mit.edu/ detail761.html wiki/index.php/Main_Page 92 Ibid. 73 iGEM registration FAQ: http://parts2.mit.edu/wiki/ index.php/Registration_FAQ 93 Bob Holmes, “Alive! The race to create life from scratch,” New Scientist, 12 February 2005. 74 Interview conducted with Drew Endy, Boston, 6 Octo- ber 2006. 94 See PACE web site: http://134.147.93.66/bmcmyp/ Data/BIOMIP/Public/bmcmyp/Data/PACE/Public/ 75 Carolyn Abraham, “Playing God in Running Shoes,” paceprosheet.html and http://www.protolife.net/ The Globe and Mail (Toronto, Canada), December 17, 2005, company/partnerships.php page F1. 95 Robert Sanders. “Keasling and Cal: A perfect fit,”Berke - 76 Interview conducted with Drew Endy, Boston, 6 Octo- ley Media Releases, 13 December 2004. ber 2006. 96 Ibid. 77 Carolyn Abraham, “Playing God in Running Shoes,” The Globe and Mail (Toronto, Canada), December 17, 2005, 97 See Amyris Biotechnologies’ website: http://www. page F1. amyrisbiotech.com/biology.html 78 http://parts2.mit.edu/wiki/index.php/MIT_teach_ 98 Daniel S. Levine, “Breathing new life. Emerging field the_teachers_summary_2006 could offer scientists building blocks for new forms of life,” San Francisco Business Times, 19 August 2005. 79 Rob Carlson’s Synthesis Blog, 21 May 2006; on the In- ternet: http://synthesis.typepad.com/synthesis/2006/05/ 99 Ibid. live_from_synth_1.html 100 http://www.artemisininproject.org/Partners/amyris. 80 Talk by John Danner of Codon Devices at Synthetic htm Biology 2.0, 20 May 2006; webcast on the Internet: http:// 101 Keasling Lab research webpage on Biopolymers: webcast.berkeley.edu/events/details.php?webcastid=15766 http://www.cchem.berkeley.edu/jdkgrp/research_ 81 Will Ryu, “DNA Computing: A Primer,” Ars Technica, ­interests/biopolymers.html 2000; on the Internet: http://arstechnica.com/reviews/ 102 Presentation by Chris Voigt, “Secreting in 2q00//dna-1.html Salmonella,” Synthetic Biology 2.0, 21 May 2006; webcast 82 Stefan Lovgren, “Computer Made from DNA and En- on the Internet: http://webcast.berkeley.edu/events/ zymes,” National Geographic News, February 24 2003. details.php?webcastid=15766 83 Jack Parker, European Molecular Biology Organization, 103 Elizabeth K. Wilson, “Engineering Cell-Based Fac- “Computing with DNA,” EMBO reports, Vol. 4, No. 1, 2003, tories,” Chemical & Engineering News, Vol. 83, No. 12, 21 p. 7. March 2005. 84 R. Colin Johnson, “Time to Engineer DNA Computers.” 104 Lucia Kassai, “DuPont uses corn to produce bio-fiber,” EE Times, 28 December 2000; on the Internet: http://www. Gazeta Mercantil, June 2005. eetimes.com/story/OEG20001221S0032 105 Andrew Pollack, “Scientists Are Starting to Add Letters 85 Associated Press, “Scientists find logic machines in biol- to Life’s Alphabet,” New York Times, 24 July 2001. ogy” CNN.com, August 18, 2003. 106 See http://www.eragen.com/diagnostics/technology. 86 Alexandra Goho, “Injectable Medibots: Programmable html DNA could diagnose and treat cancer,” Science News, Vol. 107 See http://www.eragen.com/productsandservices.html 165, No. 18 p. 275, week of 1 May 2005; on the Internet: 108 University of Florida News Release, “UF scientists cre- http://www.sciencenews.org/articles/20040501/fob1.asp ate first artificial system capable of evolution,” 20 February 87 Aileen Constans, “Coding with Life’s Code: Applica- 2004. tions and developments in DNA-based computing,” The 109 Ibid. Scientist, November, 2002, 16(23):36; on the Internet: http://www.the-scientist.com/article/display/13400/ 110 Ibid. 88 Michael Stroh, “Life Built to Order,” Popular Science, 111 Stanford University News Release, “Researchers create February 2005. ‘supersized’ molecule of DNA.” 24 Oct. 2003. 89 Ibid. 112 Ibid. 59 113 Philip Ball, “Synthetic Biology: starting from scratch,” Na- 137 Jonathan B. Tucker and Craig Hooper, “Protein en- ture, 431, 7 Oct. 2004, pp. 624-626. gineering: security implications,” EMBO reports 7 (2006), 114 Andrew Pollack, “Scientists Are Starting to Add Letters Special Issue, pp. S14–S17. to Life’s Alphabet,” New York Times, 24 July 2001. 138 Ibid. 115 Ibid. 139 Central Intelligence Agency’s Office of Transnational 116 MIT Museum Soap Box Public Discussion (21 March Issues, “The Darker Bioweapons Future,” 3 November 2006), Drew Endy: “The Implications of Synthetic Biology;” 2003. on the Internet: http://mitworld.mit.edu/video/363/ 140 See, for example, http://www.longbets.org/9 117 Jeronimo Cello, Aniko V. Paul, Eckard Wimmer, 141 Interview conducted with Drew Endy, Boston, 6 Octo- “Chemical Synthesis of Poliovirus cDNA: Generation of ber 2006. Infectious Virus in the Absence of Natural Template,” Sci- 142 The full list of select agents is available at http://www. ence, 9 August 2002: Vol. 297. No. 5583, pp. 1016 – 1018. cdc.gov/od/sap/docs/salist.pdf 118 Joby Warrick, “Custom-Built Pathogens Raise Bioter- 143 For another view, see anon., “Legal kerfuffle over ror Fears,” Washington Post, July 31, 2006. smallpox,” New Scientist, 4 November 2006; on the In- 119 Ibid. ternet: http://www.newscientist.com/channel/health/ 120 Ibid. mg19225762.700-legal-kerfuffle-over-smallpox-research. html 121 For a brief overview of the influenza epidemic of 1918, see http://virus.stanford.edu/uda/ 144 The Sunshine Project news release, “Bedfellows at the Biosecurity Board,” 30 October 2006, on the Inter- 122 See http://www.gi.alaska.edu/ScienceForum/ net: http://www.sunshine-project.org/publications/pr/ ASF13/1386.html pr301006.html 123 Associated Press, “Using Old Flu Against New Flu,” 145 Craig Venter speaking at Synthetic Biology 2.0 Wired News, 5 Oct. 2005; on the Internet: http://www. Conference, Berkeley, CA; webcast available on the In- wired.com/news/medtech/0,1286,69101,00.html ternet: http://webcast.berkeley.edu/events/details. 124 Ibid. php?webcastid=15766 125 Craig Venter speaking at Synthetic Biology 2.0 146 Marie Felde, “Gov. Schwarzenegger gets of UC Conference, Berkeley, CA; webcast available on the In- ‘ power’ in visit to LBNL,” UC Berkeley News, 19 August ternet: http://webcast.berkeley.edu/events/details. 2005; on the Internet: http://www.berkeley.edu/news/ php?webcastid=15766 media/releases/2005/08/19_als.shtml 126 The Sunshine Project, News Release, “Lethal Virus 147 George W. Bush, “State Of The Union Address By The from 1918 Genetically Reconstructed,” 9 October 2003. President,” 31 Jan. 2006. 127 Ray Kurzweil and Bill Joy, “Recipe for destruction,” 148 Jamie Shreeve, “Redesigning Life to Make Ethanol,” New York Times, 17 October 2005. Technology Review, 21 Jul 2006. 128 Ibid. 149 Information on the Genomes to Life project can be 129 Mark Williams, “The Knowledge,” Technology Review, found at http://genomicsgtl.energy.gov/ March/April 2006. 150 Chris Taylor, “Ethanol War Brewing,” Business 2.0, 130 Ibid. June 27, 2006. 131 Joby Warrick, “Custom-Built Pathogens Raise Bioter- 151 US Department of Energy Office of Science, “Break- ror Fears,” Washington Post, July 31, 2006. ing the Biological Barriers to Cellulosic Ethanol: A Joint Research Agenda - A Research Roadmap Resulting from 132 Holger Breithaupt, “The engineer’s approach to biol- the Biomass to Biofuels Workshop, December 7–9, 2005, ogy,” EMBO reports, Vol. 7, No. 1 (2006), pp. 21-23. Rockville, Maryland,” June 2006. 133 James Randerson, “Lax laws, virus DNA and potential 152 NRDC Briefing “Move Over, Gasoline: Here Come for terror,” The Guardian, 14 June 2006. Biofuels,” 20 June 2005; on the Internet: http://www.nrdc. 134 At “a buck a base,” the cost would roughly equal the org/air/transportation/biofuels.asp cost of a new Mercedes convertible. 153 Committee on Energy and Commerce Democratic 135 James Randerson, “Lax laws, virus DNA and potential staff, “Summary of Policy Provisions of the Energy Policy for terror,” The Guardian, 14 June 2006. Act of 2005 Conference Report,” 27 July 2005. 136 Peter Aldous, “The bioweapon is in the post,” New Sci- 154 US Senate Committee on Energy and Natural Re- entist, 12 November 2005, p. 13. sources, Press Release, “Energy Bill Brings Prosperity to Ru-

60 ral America,” 14 June 2006; on the Internet: http://energy. 171 Presentation by Dr. Nancy Ho, “Ethanol Production,” senate.gov at Synthetic Biology 2.0 Conference Berkeley, May 2006; 155 US Department of Energy Office of Science, “Break- webcast on the Internet: http://webcast.berkeley.edu/ ing the Biological Barriers to Cellulosic Ethanol: A Joint events/details.php?webcastid=15766 Research Agenda - A Research Roadmap Resulting from 172 Lee Dye, “Bugs in Termite Guts May Offer Future the Biomass to Biofuels Workshop, December 7–9, 2005, Fuel Source,” ABC News, May 25, 2005; on the Inter- Rockville, Maryland,” June 2006. net: http://abcnews.go.com/Technology/DyeHard/ 156 Associated Press, “Wal-Mart mulls selling ethanol- story?id=786146&page=1 based fuel,” MSNBC.com, June 1, 2006. 173 See for example, US DOE Federal Energy Manage- 157 Michael Pollan, “The Great Yellow Hope,” New York ment Program news release, “DOE Releases Plan to Ad- Times Blog, May 24, 2006. vance Cellulosic Ethanol,” July 7, 2006; on the Internet: http://www.eere.energy.gov/femp/newsevents/release. 158 US Department of Energy Office of Science, “Break- cfm/news_id=10121 ing the Biological Barriers to Cellulosic Ethanol: A Joint Research Agenda - A Research Roadmap Resulting from 174 Larry Lohmann, of the UK research and campaign- the Biomass to Biofuels Workshop, December 7–9, 2005, ing group, The Corner House, has explained, “To be able Rockville, Maryland,” June 2006. to say you’ve ‘neutralized’ the emissions from your car by investing in efficient stoves or machinery, you have to be 159 Michael Pollan, “The Great Yellow Hope,” New York able to calculate exactly how much of an improvement Times Blog, May 24, 2006. over ‘business as usual’ you’re making. But there are huge 160 US Department of Energy Office of Science, “Break- disputes raging over these calculations…Experts are com- ing the Biological Barriers to Cellulosic Ethanol: A Joint ing up with estimates that differ by orders of magnitude.” Research Agenda - A Research Roadmap Resulting from From Corner House, SinksWatch, CDM Watch, et al. news the Biomass to Biofuels Workshop, December 7–9, 2005, release, “Environmentalists Cry Foul at Rock Stars’, Pollut- Rockville, Maryland,” June 2006. ing Companies’ ‘Carbon-Neutral’ Claims,” 6 May 2004. 161 Talk by Dr. Steven Chu, “The Role of Synthetic Biol- 175 For more background on the Clean Develop- ogy in Solving Energy Problem,” at Synthetic Biology 2.0 ment Mechanism of the Kyoto Protocol, see: http:// Conference; webcast on the Internet: see http://webcast. en.wikipedia.org/wiki/Clean_Development_Mechanism berkeley.edu/events/details.php?webcastid=15766 176 See, for example, World Rainforest Movement, www. 162 David Pimentel and Tad W. Patzek, “Ethanol Produc- wrm.org.uy tion Using Corn, Switchgrass, and Wood; Biodiesel Pro- 177 The registered CDM activities are listed at http://cdm. duction Using Soybean and Sunflower,”Natural Resources unfccc.int/Projects. A search was conducted on November Research, Vol. 14:1, March, 2005, pp. 65-76. 14, 2006 using the search term “biomass” in the title. 163 Susan S. Lang, “Cornell ecologist’s study finds that 178 Talk by Dr. Steven Chu, “The Role of Synthetic Biol- producing ethanol and biodiesel from corn and other ogy in Solving Energy Problem,” at Synthetic Biology 2.0 crops is not worth the energy,” Cornell University News Conference; webcast on the Internet: see http://webcast. Service, July 5, 2005; on the Internet: http://www.news. berkeley.edu/events/details.php?webcastid=15766 cornell.edu/stories/July05/ethanol.toocostly.ssl.html 179 Committee on Energy and Commerce Democratic 164 Jamie Shreeve, “Redesigning Life to Make Ethanol,” staff, “Summary of Policy Provisions of the Energy Policy Technology Review, 21 Jul 2006. Act of 2005 Conference Report,” 27 July 2005. 165 Anonymous, “Solar to Fuel: Catalyzing the Science,” 180 Alister Doyle, “Food, Biofuels Could Worsen Water science@berkeley lab, May 13, 2005. On the Internet: http:// Shortages,” Reuters, 21 August 2006. www.lbl.gov/Science-Articles/Archive/sabl/2005/May/01- solar-to-fuel.html 181 Ibid. 166 Michael S. Rosenwald, “J. Craig Venter’s Next Little 182 US Department of Energy Office of Science, “Break- Thing,” Washington Post, Feb. 27 2006. ing the Biological Barriers to Cellulosic Ethanol: A Joint Research Agenda - A Research Roadmap Resulting from 167 Jamie Shreeve, “Redesigning Life to Make Ethanol,” the Biomass to Biofuels Workshop, December 7–9, 2005, Technology Review, 21 Jul 2006. Rockville, Maryland,” June 2006. 168 Ibid. 183 ADM press release, “ADM Bioenergy Strategy,” Novem- 169 Ibid. ber 8, 2006; on the Internet: http://www.agobservatory. 170 Khosla Ventures News Release, “Khosla Ventures Adds org/agribusiness_records.cfm?nID=1063 General Partner, Chief Scientific Officer,” July 18, 2006.

61 184 Natural Resources Defense Council, “Voyage of the 2006; on the Internet: http://gspp.berkeley.edu/iths/ Sorcerer,” OnEarth, Summer, 2006; on the Internet: http:// SynBio%20Workshop%20Report.htm www.nrdc.org/OnEarth/06sum/frontlines2.asp 199 See Thomas Scott, “The zinc finger monop- 185 Jamie Shreeve, “Redesigning Life to Make Ethanol,” oly,” Nature Biotechnology, Vol. 23, No. 8. Aug. 2005 and also Technology Review, 21 Jul 2006. wiki discussion: http://openwetware.org/wiki/Synthetic_ 186 David Morrill, “New funding pumps up Amyris,” Oak- Society/Ownership,_sharing_and_innovation land Tribune, 15 October 2006. 200 http://openwetware.org/wiki/Synthetic_Society/ 187 DNA 2.0 News Release, “DNA 2.0 Awarded DARPA Ownership,_sharing_and_innovation Bioengineering Grant,” 27 September 2004; on the Inter- 201 US Patent 5,914,891: “System and method for simulat- net: https://www.dnatwopointo.com/corp/News092704.jsp ing operation of biochemical systems” issued to Stanford 188 US Department of Commerce/USPTO, “2105 Patent- University. able Subject Matter - Living Subject Matter [R-1] – 2100 202 Arti Rai and James Boyle, “Synthetic Biology: Caught Patentability,” Manual of Patent Examining Procedure, Oc- Between Property Rights, The Public , and the tober 2005; on the Internet: http://www.uspto.gov/web/ Commons,” PLOS, November 1, 2006. offices/pac/mpep/documents/2100_2105.htm 203 Ibid. 189 Arti Rai and James Boyle, “Synthetic Biology: Caught 204 Jeremy Minshull, President of DNA2.0, speaking on Between Property Rights, The Public Domain, and the Gene Synthesis Panel at SynBio 2.0, Berkeley, CA; Commons,” PLOS, November 1, 2006. 205 Editorial, “How to Kill Synthetic Biology,” Scientific 190 See for example US 6,521,427, “Method for the American, June 2006. complete chemical synthesis and assembly of genes and genomes,” assigned to Egea Biosciences, a subsidiary of 206 Reporter notes by Stephen Maurer, “Synthetic Biol- Johnson & Johnson. ogy/Economics Workshop: Choosing the Right IP Policy,” UC Berkeley Goldman School of Public Policy March 31, 191 See for example WIPO Patent WO05123766A2: “Meth- 2006; on the Internet: http://gspp.berkeley.edu/iths/ ods Of Making Nanotechnological And Macromolecular SynBio%20Workshop%20Report.htm Biomimetic Structures,” awarded to Alexander Sunguroff. 207 David Cohn, “Open Source Biology Evolves,” Wired 192 See Paula Campbell Evans, “DNA and Patent Law,” on News, January 17, 2005. On the Internet: http://www.wired. the Internet: http://www.thebiotechclub.org/industry/ com/news/medtech/0,66289-1.html?tw=wn_story_page_ articles/dnapatentlaw.php next1 193 See for example WIPO Patent WO05033287A3: “Meth- 208 Kristen Philipkoski, “Biology yearns to be free,” Wired ods For Identifying A Biosynthetic Pathway Gene Product” News, April 20, 2001; on the Internet: http://www.wired. claimed by The Regents of the University of California, or com/news/technology/1,1282,43151,00.html US20060079476A1, US patent application entitled, “Meth- od for enhancing production of isoprenoid compounds.” 209 Interview conducted with Drew Endy, Boston, 6 Octo- ber 2006. 194 See for example WIPO Patent WO06091231A2: “Bio- synthetic Polypeptides Utilizing Non-Naturally Encoded 210 Codon Devices, Inc. website: http://www.codondevices. Amino Acids” (2006) awarded to Ambrx, Inc. com/science.aspx?id=118 195 See for example US 5,126,439, “Artificial DNA base 211 Alexandra M. Goho, “Life Made to Order,” Technology pair analogues,” awarded to Harry P. Rappaport; and S. Review, April 2003, pp. 50-57; on the Internet: http://www. Benner, US Patent 6,617,106, “Methods for preparing oli- technologyreview.com/articles/goho20403.asp?p=1 gonucleotides containing non-standard nucleotides.” 212 Nathanael Johnson, “Steal This Genome,” East Bay 196 Glen A. Evans (Egea Biosciences, Inc., San Diego, express, 30 March 2005; on the Internet: http:// CA), “Method for the complete chemical synthesis and as- www.eastbayexpress.com/issues/2005-03-30/cityside2.html sembly of genes and genomes,” US 6,521,427, 18 February 213 World Data Centre for Microorganisms (WDCM) Sta- 2003 tistics, “The Culture Collection in this World,” 30 Septem- 197 See for example WIPO Patent WO05033287A3: “Meth- ber 2006; on the Internet: http://wdcm.nig.ac.jp/statistics. ods For Identifying A Biosynthetic Pathway Gene Product,” html claimed by The Regents of the University of California. 214 NCBI GenBank Flat File Release 155.0, “Distribution 198 Email with Drew Endy, November 16, Release Notes,”15 Aug. 2006; on the Internet: ftp://ftp. 2006. Reporter notes by Stephen Maurer, “Synthetic Biol- ncbi.nih.gov/genbank/gbrel.txt ogy/Economics Workshop: Choosing the Right IP Policy” 215 Dennis A. Benson et al., “GenBank,” Nucleic Acids Re- UC Berkeley Goldman School of Public Policy March 31, search, Vol. 34, Database Issue, 2006, pp. D16-D20; on the

62 Internet: http://nar.oxfordjournals.org/cgi/reprint/34/ 232 RAFI, “Biotechnology and Natural Rubber – A Report suppl_1/D16 on Work in Progress,” RAFI Communiqué, June 1991. 216 Ibid. 233 Information about the project, “Development of Do- 217 David Vise and Mark Malseed, The Google Story, New mestic Natural Rubber-Producing Industrial Crops through York: Delta Trade Paperbacks, September 2006, p. 285. Biotechnology,” is available on the USDA’s Agricultural Re- search Service web site: http://www.ars.usda.gov/research/ 218 MIT Museum Soap Box Public Discussion (21 March projects/projects.htm?ACCN_NO=408518&fy=2005 2006), Drew Endy: “The Implications of Synthetic Biology;” on the Internet: http://mitworld.mit.edu/video/363/ 234 Keasling Lab research webpage on Biopolymers: http://www.cchem.berkeley.edu/jdkgrp/research_ 219 Robert Roy Britt, “Decoding of Mammoth Genome ­interests/biopolymers.html Might Lead to Resurrection,” LiveScience.com, 19 December 2005; on the Internet: http://www.livescience.com/ 235 Ibid. animalworld/051219_mammoth_dna.html 236 See ETC Group, “The potential impacts of nanoscale 220 Ibid. technologies on commodity markets: The implications for commodity dependent developing countries,” South Cen- 221 Nicholas Wade, “New Machine Sheds Light on DNA of tre T.R.A.D.E. Research Papers, November 2005. Neanderthals,” New York Times, 15 November 2006. 237 Editorial, “How to Kill Synthetic Biology,” Scientific 222 Frozen Ark, “Most frequently asked questions about American, June 2006. the Frozen Ark;” on the Internet: http://www.frozenark. org/faqs.html 238 Holger Breithaupt, “The engineer’s approach to biol- ogy,” EMBO reports, Vol. 7, No. 1 (2006), pp. 21-23. 223 Ibid. 239 See, for example, the Cartagena Protocol on Biosafety, 224 Report prepared by the US Department of Energy’s http://www.biodiv.org/biosafety/default.aspx See also, Office of Biological and Environmental Research, “Syn- NAFTA Commission for Environmental Cooperation, thetic Genomes: Technologies and Impact,” Dec. 2004, pp. “Maize and Biodiversity: The Effects of Transgenic Maize in 8-9; on the Internet: http://www.er.doe.gov/OBER/berac/ Mexico: Key Findings and Recommendations,” August 11, Reports.html 2004; on the Internet: www.cec.org/maize 225 Rob Carlson, “On the parallels and contrasts (anti- 240 Editorial, “How to Kill Synthetic Biology,” Scientific parallels?) between the open-source software movement American, June 2006. and open-source biology,” 10 Dec. 2000; on the Internet: http://www.intentionalbiology.org/osb.html 241 Personal communication with Drew Endy, 19 October 2006. 226 Interview conducted with Drew Endy, Boston, 6 Octo- ber 2006. 242 W. Wayt Gibbs “Synthetic Life,” Scientific American, May 2004. 227 Paul Oldham, “Global Status and in Intel- lectual Property Claims: Genomics, and Bio- 243 W. Wayt Gibbs, “The Unseen Genome: Gems among technology,” Submission to the Executive Secretary of the the Junk,” Scientific American, November 2003. Convention on Biological Diversity by Dr. Paul Oldham 244 Rob Carlson, letter to New York Times: http://www. from the ESRC Centre for Economic and Social Aspects of synthesis.cc/NYT_Letters_Dec_12_2000.pdf Genomics (CESAGen), United , 2004. 245 W. Wayt Gibbs, “The Unseen Genome: Gems among 228 See, for example, ETC Communiqué, “From Global the Junk,” Scientific American, November 2003; see also, Enclosure to Self Enclosure: Ten Years After – A Critique of John Mattick, “The hidden genetic program of complex the CBD and the ‘Bonn Guidelines’ on Access and Benefit organisms,” Scientific American, October 2004. Sharing (ABS),” January/February, 2004. www.etcgroup. 246 John Mattick, “The hidden genetic program of com- org plex organisms,” Scientific American, October 2004. 229 Report prepared by the US Department of Energy’s 247 Jonathan Tucker and Raymond Zilinskas, “The Prom- Office of Biological and Environmental Research, “Synthet- ise and Peril of Synthetic Biology,” The New Atlantis, Spring, ic Genomes: Technologies and Impact,” Dec 2004; on the 2006. Internet: http://www.er.doe.gov/OBER/berac/Reports. html 248 For historic analysis of 1975 Asilomar Conference, see Susan Wright, Molecular Politics, University of Chicago Press, 230 ETC Group, “Syngenta – The Genome Giant?” ETC 1994, pp. 144-159. Communiqué, issue # 86, January/February 2005. 249 The text of the open letter is available on the Inter- 231 George Church, “Constructive Biology,” Edge – 187, net: http://www.etcgroup.org/en/materials/publications. June 29, 2006. On the Internet: http://www.edge.org html?id=8

63 250 Declaration of the Second International Meeting 266 WHO report, “Meeting on the production of artem- on Synthetic Biology, Berkeley, California, USA, 29 May isinin and artemisinin-based combination therapies,” 2006; on the Internet: http://syntheticbiology.org/ 6-7 June 2005, Arusha, United Republic of Tanzania, p. SB2Declaration.html 19; on the Internet: www.who.int/malaria/docs/arusha- 251 See www.sunshineproject.org ­artemisinin-meeting.pdf 252 The text of the Convention is available on the Inter- 267 Willem Heemskerk et al., “The World of Artemisia in net: http://www.opbw.org/convention/conv.html 44 Questions,” The Royal Tropical Institute of the Nether- lands, March 2006, from the Executive Summary, pp. i-ii. 253 The advisory group is mentioned by Gerald Epstein of the Center for Strategic and International Studies 268 Michael Kanellos,” Gates foundation to promote syn- (CSIS) in his talk at SynBio 2.0, Berkeley, CA; on the thetic biology,” CNET News, 13 Dec 2004. Internet: http://webcast.berkeley.edu/events/details. 269 Katherine Purcell, “Gates Foundation Invests $42.6 php?webcastid=15766 Million in Malaria Drug Research,” HerbalGram, Issue 69, 254 Roger Brent, “In the Valley of the Shadow of Death,” 22 2006, pp. 24-25. November 2006, p. 3; on the Internet: http://hdl.handle. 270 WHO report, “Meeting on the production of artem- net/1721.1/34914 Observation about skill-level made by isinin and artemisinin-based combination therapies,” Drew Endy during remarks at “Synthetic Genomics: Op- 6-7 June 2005, Arusha, United Republic of Tanzania, p. tions for Governance,” Washington, DC, December 4, 19; on the Internet: www.who.int/malaria/docs/arusha- 2006. ­artemisinin-meeting.pdf 255 Roger Brent, “In the Valley of the Shadow of Death,” 22 271 OneWorld Health Press Release, “On Nature Arti- November 2006, p. 3; on the Internet: http://hdl.handle. cle Regarding Antimalarial Drug Precursor Artemisinic net/1721.1/34914 Acid In Engineered Yeast,” 14 April 2006; on the Inter- 256 Ibid. net: http://www.oneworldhealth.org/media/details. php?prID=144 257 See, for example, Meridian Institute’s “Global Dia- logue on Nanotechnology and the Poor;” on the Internet: 272 WHO report, “Meeting on the production of artem- http://merid.org/showproject.php?ProjectID=9233.4 isinin and artemisinin-based combination therapies,” 6-7 June 2005, Arusha, United Republic of Tanzania, p. 258 http://www.syntheticgenomics.com/about.htm 19; on the Internet: www.who.int/malaria/docs/arusha- 259 Jay Keasling et al., “Production of the antimalarial ­artemisinin-meeting.pdf drug precursor artemisinic acid in engineered,” Nature 273 Discover Magazine News Release, “Discover Magazine 440, 13 April 2006, pp. 940-943, on the Internet: Names Jay Keasling Its First Annual Scientist of the Year,” http://www.nature.com/nature/journal/v440/n7086/ November 14, 2006. abs/nature04640.html 274 Willem Heemskerk et al., “The World of Artemisia in 260 Discover Magazine News Release, “Discover Magazine 44 Questions,” The Royal Tropical Institute of the Nether- Names Jay Keasling Its First Annual Scientist of the Year,” lands, March 2006, p. 51. November 14, 2006. 275 Ibid., p. 53. 261 Willem Heemskerk et al., “The World of Artemisia in 44 Questions,” The Royal Tropical Institute of the Neth- 276 Ibid. erlands, March 2006, p. 50; on the Internet: www.kit.nl/ 277 http://www.anamed.net smartsite.shtml?ch=FAB&id=7648 278 http://www.anamed.net 262 A good overview of Artemisia and artemisinin produc- 279 Telephone conversation with Dr. Hans-Martin Hirt of tion is Willem Heemskerk et al., “The World of Artemisia Anamed, 3 October 2006. in 44 Questions,” The Royal Tropical Institute of the Netherlands, March 2006, p. 50; on the Internet: www.kit. 280 Rachel Rumley, ICRAF, “African Malaria Day Special nl/smartsite.shtml?ch=FAB&id=7648 Report: Artemisia, a homegrown cure for malaria,” no date; on the Internet: http://www.worldagroforestrycentre. 263 Ibid., p. 39. org 264 Ibid. 281 Telephone conversation with Dr. Hans-Martin Hirt of 265 Ibid., from the Executive Summary, page i. Anamed, 3 October 2006.

64 This page intentionally left blank. ETC Group is an international civil society organization based in Canada. We are dedicated to the conservation and sustainable advancement of cultural and ecological diversity and human rights. ETC Group supports socially responsible development of technologies useful to the poor and mar- ginalized and we address international governance issues affecting the international community. We also monitor the ownership and control of technologies and the consolidation of corporate power.

ETC Group’s series of reports on the social and economic impacts of technologies converging at the nanoscale include: Extreme Genetic Engineering: An Introduction to Synthetic Biology January 2007

Nanotech Rx – Medical Applications of Nanoscale Technologies: What Impact on Marginalized Communities? September 2006

NanoGeoPolitics: ETC Group Surveys the Political Landscape July/August 2005

Nanotech’s Second Nature Patents: Implications for the Global South June 2005

Down on the Farm: The Impacts of Nanoscale Technologies on Food and Agriculture November 2004 These and other publications are available free-of-charge on our website. www.etcgroup.org