The gene makers

C&I Issue 20, 2007

Life is cheap these days. Or at least it is in the currency of DNA. The cost of synthesising a gene has fallen from about US$ 30 per base pair to around a dollar, as productivity in DNA synthesis has vaulted 700-fold in just a decade.

Specialist gene foundries now allow researchers and industries to order online any gene they wish for delivery in just two weeks. Current estimates put the size of the gene synthesis market at between $50 and 75m globally, but this figure is growing rapidly.

GeneArt in Germany, the world’s largest manufacturer of genes, has seen its production capacity double each year since it entered the market in 2000. ‘The gene synthesis business is growing very fast; our revenues over the last few years grew by 70% per annum,’ says business development manager Bernd Merkl.  Net sales in 2006 were E7.8m and were estimated at E12.5 to 14m for this year.

The services of GeneArt and other gene makers are making researchers question the wisdom of adhering to traditional cloning as standard practice.  Over 90% of genes are acquired using these labour-intensive convention techniques, but outsourcing to GeneArt and others would save time and money.

Traditional cloning methods involve cutting a segment of DNA, say, from a mammalian cell and pasting it into the genome of a host suited to production or research, usually bacteria or yeast. But the message can get lost in translation, as the micro-organism struggles to comprehend the mammalian code. Gene manufacturers instead ‘type out’ sequences of DNA via chemical synthesis, allowing them to revise the code for easy reading by the target organism, while leaving the message untouched: the identical protein is produced, but in far greater quantities.  Of course, any sequence of DNA text can be typed and therefore any protein can be produced.

The ability to type DNA sequences also means that every amino acid in a given protein can be changed, giving a company or researcher access to a huge number of protein variants. this ‘directed evolution’ service has been used, for example, by companies seeking to improve enzymes in detergents, Merkl says.  It could potentially benefit
drug makers and the food processing industry by altering the functions of important proteins.

GeneArt has already used its ‘gene optimization’ skills in the development of a DNA vaccine for HIV; the vaccine successfully completed two phase I trials after being licensed to the European Eurovacc Consortium.  The tailor-made gene sequences developed by scientists at the company in collaboration with the University of Regensburg form the basis of this DNA vaccine, which is injected directly into patients.  In another example, PowderMed, a customer of GeneArt, is working to produce a synthetic vaccine for influenza. Such vaccines could be produced within two to three months of the target strain being identified.  This acceleration of production offers huge benefits in the event of a flu pandemic since current vaccines typically take at least six to nine months to develop, and availability is limited by production capacity as incubation occurs in chicken eggs.  Indeed, a report from the US research and advisory group Bio Economic Research Associates (Bio-era) in February estimates that synthetic DNA vaccines could account for more than half of the global vaccine market by 2015.

At US firm Codon Devices, cofounder Brian Baynes says that a broad range of customers are taking up its gene-making services, sometimes without initially having a specific gene sequence in mind. ‘A partner may require an enzyme that digests cellulose better or a drug that has greater stability. Codon will engineer those properties in,’ he says. He lists pharmaceutical companies, bio-industrial companies, and companies working on industrial enzymes or producing chemicals via biological or de novo routes. ‘Agricultural companies are pretty big customers,’ he says, being adept at leveraging genomic information to improve their crops.

By 2010, Bio-era estimates that bio-based chemical processes could account for more than $70bn in revenues, accounting for more than 10% of global chemistry industry sales. Chemical and energy companies may be able to harness gene synthesis to create new paths for yielding the same products in a way that is less capitally intensive and far cleaner, says Stephen Aldrich, president of Bio-era. In the energy sector, for example, Bio-era predicts that genome engineering will accelerate the growth of liquid biofuel revenues from $22bn in 2006 to up to $150bn by 2020.

Aldrich sees bioengineered bacteria feeding on sugar and producing a designer hydrocarbon, such as jet fuel, as a future possibility, together with cells that remove greenhouse gases from the atmosphere, or which remove and concentrate toxins from the environment for remediation.

Producing such organisms from chemically synthesised genes has several advantages over traditional cloning methods. Not least of these is the fact that they free researchers from requiring actual specimens, points out Claes Gustafsson, who cofounded the firm DNA 2.0. in 2003. With traditional cloning, a scientist needs tissue to grind up and manipulate, he notes. ‘That works if you have access to the starting point. But say you are interested in a gene that Craig Venter identified in the Sargasso Sea, you are not going to be able to do down into his freezer and get his clone. But because all these sequences are available, you can now take the sequence and modify it to fit your needs.’

Synthetic DNA products should allow people to skip the steps of traditional molecular biology. ‘Much like a software programmer doesn’t have to know how to write in ones or zeros, synthetic biology means people don’t have to speak in terms of cloning strategies.  People can now say they need a sequence and we can make it,’ Baynes explains.

Thus far, however, outsourcing gene synthesis is still a relatively new field and its full impact  remains to be felt. ‘People are just now thinking about how access to large engineered DNA fragments can impact on their research,’ says John Mulligan chairman and chief scientific officer of Blue Heron, one of the largest US gene makers. ‘We think that even existing customers haven’t internalised in thinking about how to design experiments where you can have any DNA sequence.’ The majority of Blue Heron’s customers request sequences close to what occurs in nature, but ‘a growing segment of the business, small now but we think it will be big, is completely novel sequences, engineered for specific purposes,’ he adds.

One claim under the belt for synthetic biology is atemisinin, a compound used to treat malaria.  Chemical engineer Jay Keasling of the University of California at Berkeley last year combined yeast, bacteria and wormwood genes in a yeast cell so that the cell churned out the artemisinin precursor.  Artemisinin is usually obtained in small quantities from the wormwood plant, making manufacture expensive.  The new method could dramatically reduce costs.

‘The chemical industry has been slow to recognise the potential of biology to support traditional chemical industrial processes,’ says Aldrich.  He warns that disruptive technologies like genome synthesis tend to leave incumbents stranded, since changes happen rapidly once begun.  His group’s report, Genome Synthesis and Design Futures, noted that there are ‘strong reasons to believe the revolution in biological engineering that is now emerging will advance much faster than previous technological revolutions, including the high tech revolution.’

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