Industrialisation of life

Synthetic Biology: Life reconstructed by engineers and multinationals

by Agnès Rousseaux

According to its proposents, synthetic biology would seem to be leading us into a brighter future, full of promises of better medicines, anti-pollution bacteria and synthetic fuels. But whilst it continues to attract investments from the largest global companies in the biotechnology, energy and agribusiness sectors, the use of lab-built DNA and of patented gene factories to produce life at industrial scale raises many questions. As the first fully computer-designed organisms are just beginning to come to life, engineers are already dreaming of pre-programming evolution and correcting nature’s ‘imperfections.’

This article was originally published in French. Translation: Jocelyn Timperley.

‘The construction of life.’ That is, in a nutshell, the purpose of synthetic biology. This branch of biotechnology wants to create, from scratch, living organisms unknown in nature. This goes much further than GMOs, in which the genetic code of the organism is modified to provide it with a new feature – such as growing faster or resisting to a pesticide. With synthetic biology, we are entering into a new dimension: moving past the alteration of genes and towards the large-scale production of artificial organisms modelled and simulated by computers.

‘A new world is opening,’ according to a promotional website created by the French Ministry of the Economy. Synthetic biology, the latest techno-scientific El Dorado, ‘could provide more effective therapies, cheaper drugs, new easily recyclable materials, biofuels, bacteria capable of degrading toxic substances from the environment…’, public authorities enthuse. Chemicals, energy, agro and pharmaceutical giants such as BP, Exxon Mobil, BASF or Cargill are all lining up to take part in this gold rush, and so are high-tech multinationals like Microsoft and Google [1]. However, for the moment, it is still replicated life: the recreation of the basic components of a genetic code in a laboratory.

How does it work? After computer modelling, DNA sequences are ‘custom-made’ and connected together via enzymes and bacteria. This DNA is then inserted into a biological body – a bacterium or yeast cell for example – so that it can ‘function.’ The synthetic DNA is like a piece of software, inserted into a computer framework. ‘Genes and proteins, among others, are to cells what transistors, capacitors and resistors are to computers,’ researchers from Princeton University explain [2], according to a recent survey by the French Ministry of Research, which aims to take things to the next level. ‘There is a large pool of expertise waiting to be mobilised in France, which means we can aim to be second or third globally.’ [3] In 2007, the Institut de biologie systémique et synthétique (“Institute of Systemic and Synthetic Biology”, or iSSB) was created, which includes the abSYNTH platform, whose equipment is made available both to companies and universities.

In 2009, Total created a biotech department with a focus on synthetic biology. The oil company has also become a major shareholder in the American biotechnology company Amyris, which owns an advanced synthetic biology platform. Amyris’ technology allows to build yeasts very rapidly, which become ‘living factories, optimized to ferment sugars, and to produce molecules of interest.’ and are then transformed into biofuels [4]. In the health sector, it’s the French company Sanofi which s running the show. In 2013, Sanofi announced the large-scale production of a semi-synthetic artemisinin, an active ingredient used against malaria. Following ten years of research financed by the Bill and Melinda Gates Foundation, the method has been patented by Amyris [5] and a license has been granted to Sanofi.

The end of ‘natural’ agriculture?

There’s just one problem: thousands of farmers make their livelihoods from the production of natural artemisinin. The artificial production of artemisinin therefore comes as a competition, which risks undermining their livelihoods. It’s a case study of the risks of synthetic biology, according to French science watchdog Fondation sciences citoyennes: a project which responds to a public health issue – and so is seemingly unassailable - but which features collusion between scientists and business interests, innovation developed in universities but patented by individual researchers through their own start-ups, and then sold on to big business. The result? Large profits for corporations from genetic resources which already available in nature [6].

There could soon be similar competition between agriculture and biosynthetic industrial production with regards to liquorice, vanilla and rubber: substitutes for these products based on synthetic biology are already being developed. The tire manufacturer Goodyear and the chemicals company DuPont have begun research on synthetic microorganisms to produce isoprene, used for the manufacture of tires. This could jeopardise the livelihoods of 20 million families who currently depend on the production of natural rubber. Michelin is working on similar projects, again with Amyris. Synthetic biology could allow for the low cost production of high cost products: essential oils, flavours and fragrances, medicinal compounds and cosmetic ingredients. ‘Cheap synthetic alternatives not dependent on specific growing areas, conditions or producers,’ says Canadian NGO ETC Group, which has published numerous reports on the subject. Does the emergence of synthetic biology mark the beginning of the end for agriculture? Patents are already multiplying: Amyris is working hard to patent the biosynthesis of isoprenoids, which include more than 55 000 natural compounds among which rubber, neem oil, palm oil, patchouli and pine oil.

Synthetic biology: a miracle technology?

Potential profits are huge. Synthetic biology ‘is seen as the miracle solution that will boost growth whilst preserving the environment,’ explain researcher Bernadette Bensaude-Vincent and journalist Dorothée Benoit-Browaeys [7]. Just like nanotechnology and geo-engineering, it relies on the hope of solving the problems caused by the technologies of yesterday with the technologies of tomorrow.’ Energy crisis, civilisational diseases, pollution… synthetic biology has all the answers. After the internet bubble, now comes the ‘synbio’ bubble: ‘The same investment mechanisms underpinned by a promise-based economy, the same forecasts of exponential growth.’

Applications in the areas of health and energy are already being disseminated. This is happening without any public debate on the underlying issues, without any control by public authorities and without any form of assessment of the health and environmental risks of releasing these synthetic molecules in nature. Living organisms, even artificial ones, reproduce, and therefore, they tend to proliferate. If synthetic biology allows a far quicker production of vaccines, these techniques could also be used to produce viruses, with all the associated risks of abuse and bioterrorism. Legislation, as usual, is either late-coming or non-existent. Scientists recommend that research into synthetic biology should be conducted only in highly secure laboratories of biosafety level P3 or P4 (for pathogen class 3 or 4), where viruses and bacteria are handled under high protection. In 2012, more than a hundred international organisations called for a moratorium on the commercial uses of synthetic biology.

Managing uncertainty through a suicide mechanism

What does the French government think? ‘The General Delegation for Armaments (DGA) has created a database of players in the field of synthetic biology and identified biosecurity options,’ a report from the Ministry of Research succinctly states in a report. A monitoring of synthetic biology developments has been set up, in addition to a ‘yearly inter-ministerial concertation meeting’. But, the report also says, ‘so as not to harm the progress of research in this area, we must consider the new risks with an attitude of positive uncertainty.’ Unfortunately, it’s difficult to know what this ‘positive attitude’ version of the precautionary principle means exactly.

Researchers are working on ways to limit unwanted dispersal of the organisms, such as incorporating a ‘suicide-mechanism’ which would lead the synthetic organisms to self-destruct once they have finished their work. Another possibility is making them unable to reproduce, as with the ‘terminator’ gene, which renders second-generation GMO seeds sterile. But synthetic organisms could evolve or adapt by crossing with other natural or modified organisms or through spontaneous mutations. ‘We can ensure that the organisms remain dependent on humans for food. But they could evolve. In 10-15 years, they will have found another way to eat, by symbiosis for example,’ researcher François Kepès, of iSSB, explains [8].

Xenobiology: Towards a new ‘alphabet of life’

Since the number of companies that manufacture synthetic genes remains limited, it would be possible to regulate the sector. Standardised DNA sequence banks such as BioBricks or GenBank could be subject to norms and rules. However, some researchers put forward another solution: ‘semantic containment.’ In order to avoid artificial DNA contamination, they say, we must use bases different to the existing bases – A (adenine), T (thymine), G (guanine) and C (cytosine) - which make up the ‘backbone’ of DNA. We would thus be changing the genetic language that underpins all life on the planet - the ‘alphabet of life.’ That’s what the Xenome project, led by biologist Philippe Marlière at the Évry Génopole in partnership with the French Commissariat à l’énergie atomique, proposes. This new branch of synthetic biology – xenobiology – aims to create a new code of life, different to the DNA which has existed for three billion years. The further artificial organisms are from existing terrestrial DNA (so goes the theory), the lesser the risks of interference.

Xenobiology would therefore prevent DNA contamination. It would also allow the development of biodiversity, says Philippe Marlière [See here (in French).]: ‘Terrestrial biodiversity is limited and imperfect. It could be expanded and surpassed by inventing alternative living worlds. […] The biosphere constantly fixes its own mechanisms and works out ways to create new ones.’ This evolution by toying and tinkering ‘reveals how a multitude of other chemical assemblies that would have led to organisms radically different from those we know today have been overlooked. Xenobiology is nothing other than the project to generate this unique biodiversity in order to explore it scientifically and exploit it commercially.’ An artificial biodiversity, built in labs; engineers who plan life and evolution…

Biohackers and ‘open source’ genetic tinkering

Faced with the risk of a privatisation of life by synthetic biology, another strand has emerged in the field, inspired by the open source movement and the ideals of open access to knowledge. Its principle: no patents on genes. The ‘biobricks’ which form the basis of synthetic biology could not be privatised by companies or research labs but, instead, would be available to everyone. The supporters of this idea - ‘biohackers’ - experiment with genetic code from information available on the internet and cheap second-hand equipment. With the falling cost of DNA sequencing, it is now possible to play with genetics in your garage.

You can even order a segment of synthetic DNA designed on your computer from a laboratory, which will produce it according to your specifications. In France, this ‘DIY’ synthetic biology is particularly active around the biohacker-space ‘La Paillasse,’ a ‘community laboratory for citizen biotechnology,’ in Vitry-sur-Seine, in the suburbs of Paris. There is also a flourish of collectives in the United States, such as the DIYbio - Do-it-Yourself Biology – group in San Francisco, with whom you can learn to extract DNA from saliva with a pinch of salt, washing-up liquid, grapefruit juice and rum. Want to synthesise human DNA? No problem - the recipe is online: you can download human genome sequences from the internet (here), it’s as easy as downloading a movie!

What happens to the synthetic organisms?

‘The debates around open source in synthetic biology seem like a diversion, focussed on developments with no great industrial interest; the strategic DNA sequences, on the other hand, are indeed privatised,’ says Dorothée Benoit-Browaeys. But DIY DNA in the guest-room does not bode well in terms of unwanted contamination or dissemination. The testimony of Josh, a Californian computer technician and biohacker, speaks volumes: ‘When I modify my bacteria to be producing ethanol, I also introduce a second modification that makes them resistant to antibiotics. Then I inject antibiotics into their jar to separate them: only those on which the modification was successful survive.’ What does Josh do with these genetically-modified antibiotic-resistant bacteria, that ‘could transmit their resistance to other pathogenic bacteria dangerous to humans?’ That part of the story remains a mystery.

Large-scale publicising and popularization of synthetic biology is also encouraged through the IGEM (International Genetically Engineered Machine) competition. More than 200 student teams from around the world are invited each year to invent new constructions in synthetic biology from an inventory of approximately 12,000 standard, open source bio-bricks. The 2013 creations included: the first bacterial calculator by students from Toulouse[[See the details here (in French).], a biological version of the Minesweeper game from a Zurich team, and a bacterial cell that you can print yourself with a 3D printer. Each team is sponsored by corporations - for the above: EADS, Sanofi, Novartis, Syngenta and Sofiprotéol.

Yourself could become a host for artificial DNA

November 2012. In the amphitheatre of a Parisian chemistry school, a team of students present their project for the IGEM competition: DNA was injected into a tadpole, whose body became a ‘framework’ for synthetic biology. What are the limits to modification of life, ask the public? What status for synthesized organisms? ‘A tadpole isn’t really a living thing,’ says one of the students. Some of them wear a green plastic strap, delivered at an IGEM gathering: ‘It means we agree to become hosts ourselves,’ they explain. Experimentation on themselves. ‘I am amazed by the innocence of IGEM students. They are taught that ‘everything is possible’, in a joyful and friendly atmosphere,’ says Catherine Bourgain, researcher, president of the Fondation sciences citoyennes and a member of the French National Observatory of Synthetic Biology. ‘Many young people have no critical distance: they are astoundingly naive. The only rule is ‘free your creativity.’ It’s scary.’

In what direction will these future synthetic biology researchers steer their discipline? What controls will public authorities have on future developments? What guidance will citizens have in order to understand the issues? ‘The key challenge is to create the conditions in which advances in synthetic biology can be made decisively in a climate of civic trust and visibly responsible innovation,’ says the French Ministry of Research. Minister of Research Geneviève Fioraso advocated this ‘responsible debate on innovation’ in a report to the French Parliamentary Office for the assessment of scientific and technological options in 2012, in order, most especially, ‘to prevent the excesses that characterised the public debate on GMOs and nanotechnology’ (sic). For now, ‘public dialogue’ is at a standstill. The matter seems to be settled already.

Agnès Rousseaux

Photos: DNA and Nano (source). P4 class laboratory (maximum security) of INSERM in Lyon (Inserm / P Latron).

[1A 2012 survey by the Canadian NGO ETC Group revealed that globally, ‘corporations investing in Synthetic Biology include 6 of the top 10 chemicals Companies, 6 of the top 10 energy companies, 6 of the top 10 grain traders and the top 7 pharma companies.’]. According to its supporters, synthetic biology even has the potential to eventually replace the whole chemicals industry, providing a silver bullet solution for dealing with issues such as pollution and resource depletion.

Living Lego built from DNA bricks

It is only recently, however, that the field has begun to be developed. In 2010, after 15 years of work, a team at the J. Craig Venter Institute in the United States created a new sort of bacteria whose unique chromosome is composed of DNA entirely synthesised by researchers. It was the first artificially created living organism. ‘This is the first self-replicating species that we’ve had on the planet whose parent is a computer,’ said its creator, Craig Venter[[The bacterium is composed of only one chromosome containing 1.155 million base pairs. A DNA molecule is formed from two helical strands which are placed on four types of complementary bases - adenine (A) and thymine (T), cytosine (C) and guanine (G) - linked in pairs.

[2Quoted by Frédéric Gaillard in Innovation scientifreak: la biologie de synthèse. L’échappée éditions, 2013. Also available to read (in French) on the website of the Pièces et main d’oeuvre website.] collective]. It becomes a sort of living Lego, based on standardised DNA ‘bio-bricks,’ which are either originals or copies of DNA bricks already existing in nature.

Gene Factories

The potential applications of synthetic biology are innumerable, and in recent years research funding in this area has been growing exponentially. Products are already arriving on the market: bioplastics made from corn, synthetic textiles made from sugar, biosynthetic grapefruit flavour, biodiesel... With the prospect of producing microorganisms or modified algae capable of converting biomass into fuel, investments are especially booming on the energy sector. Could the solutions to the post-petroleum age come from synthetic biology laboratories?

The oil giant Exxon, in partnership with Synthetics Genomics - a company led by Craig Venter - has already invested $100 million in the development of fuel from algae. BP has devoted $500 million to the development of synthetic biofuels within the Energy Biosciences Institute. As for the Bill and Melinda Gates Foundation, it is financing research into medical applications to the tune of $43 million… Two types of companies currently share the synthetic biology market. Firstly, there are those that manufacture the basic components: synthetic genes. These include ‘gene foundries’ like Tech Dragon in Hong Kong or Gene Art in Germany - their catalogues include genetic sequences of the human brain, liver and heart - and DNA 2.0 in the United States, which also offers free software to ‘design sequences de novo without being limited by what nature can provide.’ Biotechnology companies, such as Synthetic Genomics in the US, then create and market organisms built from these genes. In total, 3,000 researchers from 40 countries work in the field of synthetic biology.

Privatisation of natural resources

Several research teams at the “Genopole” in Évry and seven biotechnology companies are now bringing synthetic biology to France[[One in Clermont-Ferrand, one in Nîmes, and five in Île-de-France. Source (in French).

[3Ministry of Research, Stratégie nationale de recherche et d’innovation (National Strategy for Research and Innovation), 2011. Read here (in French).

[4Source: Total.

[5The company has designed a modified yeast strain that produces artemisinic acid from glucose. This compound then allows the production of artemisinin.

[6Sanofi’s objective is ‘to produce 35 tonnes of artemisinin in 2013 and around 50-60 tonnes in 2014. This will largely meet market demand.’ Source: Sanofi. See also the review on artemisinin by Fondation sciences citoyennes (in French).

[7Bernadette Bensaude-Vincent and Dorothy Benoit-Browaeys, Fabriquer la vie, Où va la biologie de synthèse ? (Making life: where is synthetic biology going?) Seuil, Paris, 2011.

[8Speech at the Life Conference, UNESCO, November 30, 2012.