Changes down on the pharm

The age of molecular farming may be the salvation of many Australian farms.

Tobacco farmers at Mareeba, in far north Queensland, are planting their last commercial crop this year. Rising costs and falling prices have seen average farm debt rise to around $200,000, causing serious economic and social problems in the once prosperous region.

Mareeba's tobacco farmers are looking for a new, high value crop for their salvation. The most promising prospect is a familiar crop: tobacco.

Australia's sugar cane farmers are in similarly dire straits due to collapsing world prices - they're also looking for an alternative, high-value crop. It's likely to be sugar cane.

At Melbourne University, veterinary science PhD student Simone Poznanski has introduced a gene from the tapeworm Taenia solum, into the plant geneticist's green rat, Arabidopsis thaliana and confirmed with an antibody test that it is expressed in its native form.

The gene encodes a peptide derived from a surface antigen on the tapeworm's eggs, identified by Poznanski's supervisor, parasitologist Dr Marshall Lightowlers.

Taenia is a major intestinal parasite of humans in Asia, Mexico and South America. Lightowlers and his colleagues have shown the peptide is strongly immunogenic - and thus, is a potential candidate for a vaccine that would disrupt the parasite's life cycle.

Poznanski is aiming to produce the Taenia 'plantigen' in tobacco, but says clinical trials are a long way off.

New age dawning

The age of molecular farming is coming. Within the decade, some Australian farmers may be growing grow transgenic crops engineered to synthesise high-value molecules such as monomers for plastics manufacture, modified edible oils and 'smart' sugars.

Others may go 'biopharming' -- growing crops engineered to produce monoclonal antibodies, vaccines or other therapeutic molecules for human and veterinary use.

Queensland University of Technology (QUT) molecular geneticist Prof James Dale says the question for Australia's ailing tobacco and sugar industries is whether the age of molecular farming will dawn fast enough to revive their economic fortunes.

Dale is CEO and scientific officer of Brisbane-based Farmacule Bioindustries, which is commercialising his QUT research group's patented INPACT (In-Plant ACTivation) gene modification technologies.

Farmacule is working on both tobacco and sugar cane. Dale says tobacco is an ideal subject for growing high-value proteins in plants. "It's easy to engineer, and highly productive in terms of biomass," he says.

"Most importantly, it's not a food crop. A lot is known about its genetics -- it's diploid, and is highly self-fertile and doesn't outcross because of its tight flowers."

Tobacco is highly adaptable -- it grows in Mareeba's tropical climate, but also flourishes at Myrtleford, in the frosty foothills of the Victorian Alps, where farmers are also looking to exit the industry.

"These farmers are used to growing to growing under strict conditions, under contract, which is just what we want for high-protein products," Dale adds.

"That's the direction we're heading, and it's getting very close to decision time. Do we go down the therapeutic protein track? It's a big issue, and there are certainly opportunities there."

Time is short, and farmers can't afford mistakes. And 'biopharming' is particularly problematic because the route from laboratory to farm gate goes via the US Food and Drug Administration's regulatory maze.

"There are issues of product development and clinical trials, the Food and Drug Administration process, and processing and purification techniques -- they wouldn't be [Farmacule's] proteins," says Dale.

Farmacule has already grown high-protein transgenic tobacco at glasshouse scale. Unfortunately, says Dale, a single glasshouse could probably meet the global demand for some high-value therapeutic proteins: "We need to identify products that would be required in sufficiently large amounts to justify broad-acre farming."

The greater potential, Dale believes, lies in producing industrial proteins or products in plants -- such proteases, lipases and clarifiers, widely used by the food, beer and winemaking industries, and enzymes used by the tanning industry.

Australia imports large quantities of these enzymes, so there is a potential import-replacement benefit.

"The economics are very different, because they're already required in bulk quantities, and it becomes a matter of whether we can produce them at that scale," Dale says.

"But growing tobacco isn't cheap, so it's going to be very dependent on protein yield and value, and the cost of processing. Most of these things are now produced by microbial fermentation, so we couldn't compete, but from the calculations I've done, tobacco is going to be very competitive for medium-value proteins. Producing bioplastics in tobacco is another possibility, but here the options are circumscribed by patents. "Nobody has turned bioplastics into a market yet," Dale says.

As for vaccines, Dale says, "Reality has hit the edible vaccine sector.

"Most groups have recognised it's not going to be a matter of plucking a banana off a hand and eating it -- dosage has to be carefully controlled for most vaccines, and there will have to be a high level of quality control over production.

"'Edible' is a misnomer. The vaccines will be edible, but in a different form. If you're using tomatoes, for example, they would be harvested, freeze-dried and the level of the antigen would be controlled.

"Once you go that level, there's no longer any need to produce those vaccines in an edible crop. Something like tobacco becomes an option -- you'd extract the antigen, and put it in a chewable product or some other formulation.

"But it's another question as to whether it would be a good business, because the edible vaccine concept was directed towards developing nations, and motivated by philanthropy. It's a great idea, but maybe not a commercial one."

'Plantibodies'

Dale says there has been good progress on 'plantibodies' -- monoclonal antibodies produced in mod-gene crops, for therapeutic applications.

"Plants are amazingly good at producing antibodies, both the heavy and light chains. The commercial opportunity is there, because with so many monoclonal antibody therapies coming on line, production has become a limiting factor."

Again, IP issues are a significant constraint. But Dale sees opportunities to produce some antibody derivatives in plants. "They will need to be produced in large amounts, and cost of production becomes important," he says.

"I've done some calculations for tobacco -- essentially, if you can obtain yield of between 0.1 and 1 per cent of total soluble protein as recombinant product, you're really starting to produce antibodies cheaply, at between $10 to $100 a gram.

"There are opportunities to produce proteins like albumens, which are used in large quantities in cell-culture media."

Dale says Farmacule has its INPACT technology working well in tobacco and sugar cane. "It's a platform technology for producing anything in plants -- our involvement is in technology transfer and implementation. We're not involved in any projects towards specific products."

Out-crossing crops like maize are probably unsuitable hosts because they could contaminate non-GM food varieties. Given such problems, Dale says, it is "not a silly idea" to consider transforming a weed into a crop.

When the world's largest sugarcane grower, Brazil, went into recession several years ago, demand for ethanol fermented from cane slumped. Cheap Brazilian sugar flooded the international market, and prices collapsed.

Dr Peter Twine, director of the new Cooperative Research Centre for Sugar Industry Innovation Through Biotechnology, says the long-term outlook for the industry, which has relied on a single commodity for 130 years, is bleak. It must rationalise, and diversify its product base.

Twine says the options are to modify the crop to lift sucrose yields even further, divert photosynthesate into other metabolic pathways, or "find other molecules we can mine".

"CSR and the University of Queensland are already doing some work on modifying cane to produce isomaltulose, instead of sucrose - CSR has a patent on isomaltulose as high-value, low-calorie sweetener," he says.

"Another possibility is to modify sugar cane to produce another sugar, trehalose, which is used as a good preservative. Sorbitol is another possibility - industry knows it can get hundreds of different molecules out of the plant, or use downstream processing to make them.

"Companies like Toyota are interested in using sugar cane as a host for producing sugars and starches for conversion into polymers that are currently made from petroleum, but the costs of implementing the technology are significant, and there's a question about whether such products can be expressed at a sufficiently high level in the plant to make the technology viable."

Averting community concerns

Biofarms would also have to be located away from conventional sugarcane farms to avoid consumer concerns about contamination -- even though sugar cane is not an outbreeding crop.

For this reason, Twine sees downstream processing as a first step. The transition to GM cane would be made as the community became "more relaxed" about GM crops. Mills would then extract the raw material for the polymers, and the remaining sugars would be fermented to produce liquid fuel - no sugar from GM cane would enter the food chain.

Sugar cane would not be used to grow neutraceuticals or therapeutics - it would be used to produce low- to medium-value industrial feedstocks.

But GM varieties engineered for low lignin content could allow the entire plant to be fermented, to improve the economics of ethanol production.

Dale's INPACT technologies, which include techniques for switching genes on or off with external cues, could be used to activate plant enzymes that would pre-digest cellulose before harvest.

"The Brazilian sugar industry was fermenting sugar to make biodegradable plastics years ago," Twine said. "The technology is not new, and with Australia talking about putting a levy on plastic bags, we could make biodegradable plastics here instead of importing them."