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Playing God

Hope Shand, Jim Thomas and Kathy Jo Wetter

1st May, 2007

Scientists are on the brink of creating the world’s first artificial life form – a living organism never before found in nature. They promise solutions to everything from malaria to climate change. Salvation? Or a step too far?

Transgenics, the kind of engineering you find in genetically modified crops, is suddenly so last-century. As recombinant DNAsplicing techniques pass the 30 year mark, researchers are moving at breakneck pace to the next frontier in the manipulation of life: building it from scratch. It's called synthetic biology, and it's poised to revolutionise our life sciences.

Under the paradigm of transgenics, genetic engineering was a cut-and-paste affair. Biotechnologists manually shuffled pieces of DNA - the self-assembling molecule that instructs living organisms how to carry out every biological process - between existing species. Over much of the past 20 years, genetic technology has focused on deciphering DNA code - the sequence of base pairs that make up DNA's double helix - in order to identify genes and understand their role in plant and animal life. As a result of this race to read and map genomes, it is now possible to decode, or "sequence" tens of thousands of base pairs per minute, and do it relatively cheaply.

Synthetic biology represents a seismic shift in this landscape. Attention is being switched from reading to writing genetic code, with synthetic biologists beginning to scorn nature's designs in favour of made-to-order life forms. At the core of synthetic biology is a belief that life's components can be made synthetically (that is, by chemistry), engineered and assembled to produce working organisms.

Born in the dot-com communities of Boston and northern California, much of the vision of synthetic biology is articulated via computing metaphors. Using concepts borrowed from electronics and computing, synthetic biologists are building simplified versions of bacteria, re-programming DNA and assembling new genetic systems. DNA code is now regarded as the software that instructs life, while the cell membrane and all the biological functions within the cell are seen as the hardware that must be snapped together to make a living organism. Using gene synthesisers, they write the "text" of DNA code one "letter" at a time, sometimes inventing their own "alphabet" - to come up with new "genetic networks" bundled together in an artificial "chassis" - a living, self-replicating organism made from scratch.

The world's first synthetic biology conference, Synthetic Biology 1.0, convened in June 2004 at the University of California at Berkeley. Two months later, Berkeley announced it was establishing the world's first synthetic biology department. In 2005, three synthetic biology start-ups attracted more than US$43 million in venture capital, and in late 2006 there was talk of establishing an industry trade group for gene synthesisers. While most of the formal activity, self-identified as synthetic biology, has taken place on US soil, such extreme genetic engineering is happening all around the world. 2007's conference (SynBio3.0) will be held in Zrich, hosted by the Swiss Federal Institute of Technology (ETH).

Millions of dollars of government and corporate funding are already flowing into synthetic biology labs. Venture capital and government funding have nurtured the field and the first pure-play synbio companies are now open for business. They hold growing patent portfolios and foresee industrial products in fields as diverse as energy production, climate change remediation, toxic cleanup, textiles and pharmaceuticals. Indeed, synthetic biology's first commercial products may be only a few years from market.

In the beginning…

It's not quite the biblical feat described in Genesis; but if you give $1,000 to Epoch Biolabs of Houston, Texas they can make an entire gene and post this little bit of life to you within seven days. From Moscow to Montreal, Norway to Nashville, a young industry of gene synthesis companies crank out the main ingredient for artificial life, one chemical at a time and ship it to research labs that are pushing the limits of what is possible in the biotech field.

Building synthetic DNA isn't new. In the 1960s an Indian-American Nobel Prize winner, Har Gobind Khorana, first developed a chemical protocol for building chains of DNA to order, arranging its four compounds, known as the nucleotide bases (adenine, cytosine, guanine and thymine, represented by the letters A, C, G and T) into the spiralling ladder of the DNA molecule via some fairly slow, complicated chemistry. Back in 1973, it would take one scientist a whole year to make a length of DNA of 11 base pairs long. Today it would take minutes and cost around $200.

For the past 30 years the primary use of custom gene synthesis technology has been the production of oligonucleotides ("oligos") -short strands of DNA that genetic engineers use as hooks to copy the natural DNA of interest, in order to decipher a sequence and amplify it. Oligos usually have fewer than 200 bases and are single-stranded (DNA is doublestranded). The DNA itself is constructed from cheaply-produced sugar isolated from sugar cane. Although do-it-yourself desktop DNA synthesisers are used in laboratories to make short stretches of DNA, it is more common for researchers to go on the internet and order a desired DNA sequence from one of dozens of commercial oligo houses worldwide.

"Gene foundries" - around 66 commercial firms worldwide – produce longer pieces of double-stranded DNA (including whole genes or genomes). According to one industry estimate, the market for gene synthesis in late 2006 was only $30 to $40 million per year – a tiny fraction of the $1 to $2 billion spent on acquiring and modifying DNA. Although the USA is currently home to more gene foundries than any other country, the industry is rapidly spreading. According to Hans Buegl of GeneArt (Regensberg, Germany), the market for gene synthesis has doubled in the past year.

As the industry grows, its products become cheaper. In mid-2006 most gene synthesis companies were charging between $1 and $2 per basepair (around ‘a buck a base’, as they like to say). At a synthetic biology conference in May 2006, gene synthesis companies were confidently predicting that the price would drop to $.50 per base pair by the end of 2007.

Some companies boast that there are no technical limits to the length of DNA they can produce (although most synthesised sequences are not error-free). GeneArt claims that it can produce 500,000 base pairs of DNA per month. In July 2006, Codon Devices manufactured and sold a strand of DNA exceeding 35,000 base pairs – what they then claimed was the largest commercially produced fragment to date.

Synthetic biologists predict that a one million base pair bacterial genome will be constructed within the next two years, that a yeast genome of around 12 million base pairs could be synthesised in 18 to 24 months, and a plant chromosome would not take much longer. Rob Carlson, a synthetic biologist at the University of Washington (USA), says gene synthesis machines are improving in efficiency so fast that, ‘Within a decade, a single person could sequence or synthesise all the DNA describing all the people on the planet many times over in an eight-hour day, or sequence his or her own DNA within seconds.’

Future Perfect?

The grand vision of synthetic biology is to create a novel, living system. The work of two US-based research teams illustrates two different approaches to realise this goal.

At the University of California at Berkeley, the synthetic biology department led by Jay Keasling is engineering cellular genetic pathways to produce valuable drugs and industrial chemicals. 'Chemical engineers are good at integrating lots of pieces together to make a large-scale chemical plant, and that is what we’re doing in modern biological engineering – we’re taking lots of little genetic pieces and putting them together to make a whole system,’ explains Keasling.

Keasling’s team has synthesised around a dozen genes that work together to reproduce the chemical pathways behind a class of compounds called isoprenoids – high-value compounds important in drugs and industrial chemicals. Isoprenoids are natural substances produced primarily by plants. Because of their structural complexity, chemical synthesis of most isoprenoids has not been commercially feasible, and isolation from natural sources yields only very small quantities. Synthetic biologists at Berkeley hope to overcome these limitations by designing new metabolic pathways in microbes, turning them into ‘living chemical factories’ that produce novel or rare isoprenoids.

Most notably, they are focusing on a powerful anti-malarial compound known as artemisinin. Backed by a $42.5 million grant from the Bill and Melinda Gates Foundation, the Berkeley team believes that synthetic biology is the tool that will allow unlimited and cheap production of a currently scarce natural compound to treat malaria in the developing world. In 2003, Keasling and colleagues founded a synbio start-up called Amyris Biotechnologies, to bring the project to fruition. The promise of unlimited supplies of a drug that can roll back a global killer has become the raison d’être for synthetic biology and given the field a philanthropic sheen. Though they’ve produced only tiny quantities of artemisinic acid so far, Jay Keasling’s bacterial factories are already churning out copious amounts of priceless PR for the fledgling synbio industry. The December 2006 issue of Discover named the Berkeley professor its first-ever Scientist of the Year and the magazine’s editors oozed with admiration: ‘Through his significant synthetic biology advancements, Keasling is changing the world, making it a better place with every new discovery he makes.’

In reality, large-scale production of synthetic artemisinin still faces significant technical hurdles. What’s more, a 2006 report by the Royal Tropical Institute of the Netherlands points out that it is technically possible to cultivate sufficient amounts of wormwood to produce enough artemisinin to treat all the malaria patients in the world. An estimated 17,000-27,000 hectares of Artemisia annua would be required to satisfy global demand, which could be grown by farmers in suitable areas of the South. The Institute’s report warns, however, that the prospect of synthetic artemisinin production could destabilise a very young market for natural artemisia, undermining the security of farmers just beginning to plant it for the first time: ‘Growing Artemisia plants is risky and will not be profitable for long because of the synthetic production that is expected to begin in the near future.’

Will betting on synthetic biology’s medicinal microbes to tackle malaria divert attention and resources from other approaches that are potentially sustainable and decentralised?

Amyris hopes to use the same technology platform to produce drugs far more lucrative than artemisinin. ‘We’ve essentially created a platform that will allow you to produce many drugs cheaper,’ explains Keasling. ‘Down the road, we will be able to modify enzymes to produce a number of different molecules, even some that don’t exist in nature.’

According to the company’s website, Amyris ‘is now poised to commercialise pharmaceuticals and other high-value, fine chemicals taken from the world’s forests and oceans by making these compounds in synthetic microbes.’ Amyris plans to use synthetic biology to produce commercial drugs, plastics, colorants, fragrances and biofuels. The Berkeley lab is also attempting to re-engineer the metabolic pathways that produce natural rubber. If commercially successful, rubber-producing microbes could dramatically impact the demand for natural rubber and the livelihoods of people and economies that depend on this commodity.

Pathway engineering is already being used for commercial applications. For example, California-based Genencor has been working with chemical giant DuPont to add synthetic genetic networks to the cellular machinery of E. coli. When mixed with corn syrup in fermentation tanks, their modified bacterium produces a key component in Sorona, a spandex-like fibre. DuPont hopes that its new bio-based textile will cause as much fuss as the introduction of nylon back in the 1930s. DuPont plans to build additional Sorona production factories, probably in the global South. According to John Ranieri, Dupont's vice-president of bio-based materials, one thing is for sure: we need to be close to the agricultural producing centres, in Brazil, India or the USA.

Dr frankenstein, I presume?

In the race to synthesise life, the genomics mogul J Craig Venter often overshadows the rest of the pack. Venter, dubbed Biology's Bad Boy, led the private company Celera in the race to map the human genome. Venter is notorious for pushing the boundaries on the commercial exploitation of life. His newest commercial venture, Synthetic Genomics Inc., founded in 2005 with $30 million of venture capital, aims to commercialise a range of synthetic biology applications, starting with energy production. The company received half its start-up capital from Alfonso Romo Garza, the Mexican billionaire who owns agribusiness giant Savia.

In the mid-1990s, Venter's non-profit outfit, The Institute for Genomic Research (TIGR), pursued a Minimal Genome Project to discover the fewest number of genes necessary for a bacterium to survive. The bacterium they chose was Mycoplasma genitalium, a bug that causes urinary tract infections. It has one of the smallest known genomes of any living organism (517 genes, made up of around 580,000 DNA base pairs). By contrast, the human genome is estimated to comprise around 22,000 genes, made up of some three billion base pairs. The yeast genome (Saccharomyces cerevisiae) has around 6,000 genes and 12 million base pairs. For Venter's team, the ultimate goal of creating aminimal microbe is to use it as a platform for building new, synthetic organisms whose genetic pathways are programmed to perform commercially useful tasks such as generating alternative fuels.

Venter and his research team, which includes Nobel Laureate Hamilton Smith, are now attempting to synthesise their streamlined version of the Mycoplasma genitalium genome so it could be used as a "chassis" for novel, synthetic organisms. If it can operate as a viable, self-replicating organism, their synthetic microbe, dubbed Mycoplasma laboratorium, would amount to an entirely new species of bacterium - the first fully synthetic living species ever created.

Venter calls Mycoplasma laboratorium a synthetic chromosome and his intention is to use it as a flexible bio-factory into which custom-designed synthetic gene-cassettes of four to seven genes can be inserted, genetically programming the organism to carry out specific functions. As a first application, Venter hopes to develop a microbe that would help in the production of either ethanol or hydrogen for fuel production. In the case of ethanol production, for example, the synthetic biology approach is to custom-design a microorganism that can perform multiple tasks, incorporating built-in cellulose-degrading machinery, enzymes that break down glucose, and metabolic pathways that optimise the efficient conversion of cellulosic biomass into biofuel. With more than $12 million in funding from the US Department of Energy, Venter expects to harness the mechanisms of photosynthesis for ways to more effectively sequester carbon dioxide, ostensibly as a means of slowing climate change.

In May 2006, Venter predicted that his team would deliver a living Mycoplasma laboratorium in two years, but he admitted that its ETA has been a rolling two years for some time now. When an interviewer asked Hamilton Smith if he and Venter were playing God, Smith gave a characteristically hubristic response: We don't play.

Synthetic Governance?

Advocates promote synthetic biology as the key to cheap biofuels, a cure for malaria, cheaper drugs and climate change remediation - a strategy that aims to preempt public concerns about a dangerous and controversial technology.

However, a growing number of civil society organisations and social movements, particularly those that have campaigned against genetic engineering and the patenting of life, recognise that such extreme biotech is a technology that could pose grave threats to people and the planet, despite its media friendly gloss. For some, the quest to build new, living organisms in the laboratory crosses unacceptable ethical boundaries - the ultimate reductionist science.

Concerns were heightened in May 2006 when proposals for self-governance were put forward by synthetic biologists meeting at Syn Bio 2.0 in Berkeley -measures that would serve as pre-emptive action to avoid potentially more stringent government regulations. In response, 38 civil society organisations from around the world signed an open letter to the synthetic biology community, expressing concern that this potentially powerful technology is being developed without proper societal debate concerning socio-economic, security, health, environmental and human rights implications. The letter dismissed the self-governance proposals as inadequate and noted that the implications are too serious to be left to wellmeaning but self-interested scientists.

Synthetic biologists counter that the field of synthetic biology is one of the most open, outgoing and self-critical fields of research that's ever existed, citing wiki discussions (editable web pages), lectures and town hall meetings (one held at MIT, the other at Berkeley) as examples. While these attempts at openness are important, the discussion of synbio's impacts has yet to extend much beyond a small circle of scientists, many of whom are invested in the unfettered development of the field, both professionally and often financially through their own or colleagues start-up companies.

Synbio's self-governance has focused primarily on biosecurity threats, especially the potential for a rogue scientist to cause harm. In fact, the mad scientist scenario is evoked as an argument for governments not to regulate the industry because, synthetic biologists argue, efforts to control the technology will drive it underground. The more likely scenario is that risks to society will come from unforeseen and unintended consequences.

Ultimately, it is not for scientists to control public discourse or determine regulatory frameworks. Whether by deliberate misuse or as a result of unintended consequences, synthetic biology will introduce new and potentially catastrophic societal risks. In keeping with the Precautionary Principle, synthetic microbes should be treated as dangerous until proven harmless. At a minimum, environmental release of de novo synthetic organisms should be prohibited until wide societal debate and strong governance are in place. Public debate must go beyond biosecurity (bioweapons/bioterrorism) and biosafety (worker safety and environment). There must be a broad societal debate on synthetic biology's wider socio-economic and ethical implications, on control and ownership of the technology and whether it is socially acceptable or even desirable.

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Building a better bio-weapon

"I expect that this technology will be misapplied, actively misapplied and it would be irresponsible to have a conversation about the technology without acknowledging that fact". Drew Endy, Synthetic Biologist, MIT.

Gene synthesis technology vastly enhances the potential to construct deadly, designer pathogens in the laboratory using mail-order DNA. In 2002, a team of researchers at the State University of New York at Stony Brook, led by molecular geneticist Dr Eckard Wimmer, mail-ordered synthetic DNA strands (oligonucleotides) and pasted them into a functional poliovirus. This is a wake-up call, Wimmer told the Washington Post in July 2006.

In 2005, another team of researchers announced that they had resurrected the lethal H1N1 flu virus that killed up to 50 million people worldwide in 1918-19 (the Spanish flu). Although the H1N1 strain had vanished from the earth with its last victims, researchers were able to recover and sequence fragments of the viral RNA from preserved tissues of 1918 flu victims buried in the Alaskan permafrost. Today, the full genome sequences of the H1N1 flu virus and the poliovirus are publicly available on the Internet-accessible database, GenBank.

Eckard Wimmer bluntly describes the potentially deadly combination of accessible genomic data and DNA synthesising capabilities: If some jerk then takes the sequence [of a dangerous pathogen] and synthesises it, we could be in deep, deep trouble.

This article first appeared in the Ecologist May 2007

 

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