Land of the rising microbe

Japan, famously, lacks natural resources. Although it has coal reserves, it has no oil, no gas. It's even short of flat land. However, this hasn't held it back from industrial development; it's just had to find different ways of achieving its goals.

A recent mission organised by the UK Department of Trade and Industry's GlobalWatch organisation found that the Japanese willingness to find alternatives and maximise their particular advantages may hold lessons for British industry.

Although Japan is poor in fossil fuels, it is rich in other resources. In particular, it has one of the highest diversities of micro-organisms of any region. This is because of its huge range of different climatic and environmental conditions. The Japanese archipelago is over 1000 miles long, stretching over 20 degrees of latitude - temperate in the North, near-tropical in the South. It has mountains up to 3776m high, and marine trenches plunging over 8km deep.

And as industrial chemists in the US and Europe are finding, micro-organisms are increasingly valuable tools in the process industries. Need to carry out a tricky reaction? There's likely to be a microbe which does something similar. Toxic waste requiring treatment? There's probably a bacteria which treats it as a tasty snack.

And in Japan, where every gramme of soil contains between 10 million and 100 million microbes, there's a fair chance that the bacterium you need lives in the soil outside your laboratory window, or halfway up the mountain overlooking your university.Biological processes are nothing new to Japan.

In fact, they're ingrained in the culture. The national drink, sake, is produced by a complex double fermentation process, with both reactions occuring simultaneously. Similar techniques are used to make soy sauce and miso, or soy bean paste.

'We've lived with microbes since ancient times,' explains Professor Sakayu Shimuza of the Hakko Laboratory at Kyoto University. 'They've always been essential for us. We extend our thanks to them.'

Shimuza is one of the leading figures in Japanese biotechnology. Between 1984 and 2000, his laboratory developed 29 enzyme-mediated industrial processes, working with companies from Japan, Korea and Singapore.

These produced compounds ranging from amino acids, sweeteners, edible oils and vitamins, to pharmaceutical intermediates, through to bulk chemicals. The processes also span the range of bioprocesses: some used membrane bioreactors, where colonies of whole, live microorganisms carry out the conversions, while others were purely enzymatic processes, where the enzyme is isolated from its original host organism and used in the same way as a conventional catalyst.

Much of the work of the Hakko Laboratory involves screening micro-organisms for industrially-useful activity. This is tedious, repetitive work, which Shimuza acknowledges would not be economical for a commercial company. However, the university has an important advantage - students.

'Young students enjoy tedious and time-consuming screening,' he says. 'Their fresh, careful and patient observation sometimes brings serendipitous results - and their will is more important than their skill.'

The laboratory uses two kinds of screening process. The conventional low-tech screening - the preserve of Shimuza's enthusiastic students - involves looking at a large number of naturally-occurring organisms and enzymes. The other depends on genetic modification techniques. Researchers subject only one, or a few, enzymes or genes to methods such as random mutagenesis, DNA shuffling or site-directed mutagenesis, tailoring the biological processes to produce the required products.

The results can be striking. For example, Hakko Laboratory collaborated with Mitsubishi Rayon for a process to make acrylamide, an intermediate in acrylic resin production, from acrylonitrile, using cells derived from R. rhodochorus bacteria as a catalyst .

Using conventional chemistry, this reaction poses problems, says Andy Wells, a principal scientist at AstraZeneca and one of the GlobalWatch team.

'If you ask an industrial chemist, he'd say that you need a concentrated sulphuric acid and copper ion catalyst, and you'd need to do it at 90°C. You'll get pretty poor selectivity and incomplete conversion, so you'd have to put in some recovery steps. And you'd end up with a huge amount of sodium sulphate and copper salts in the waste. But do it with a biocatalyst, and you're using supported cells as the catalytic material, you need temperatures of 5° to 10°C, you get 99.9% selectivity for acrylamide, 100% conversion, and your only waste is water. It's got to be the best way to make bulk acrylamide.'

Indeed, the efficiency of the process can be seen from the size of Mitsubishi Rayon's facility in Yokohama: producing 30 000tpa of acrylamide, it's a low-rise building looking more like a light industrial unit than a chemical plant.

So why don't European and American companies use more biotransformations? Part of the answer is in the rigid working methods in the West, says Andy Wells.

'In Japan, it's not unusual for fermentation specialists to work with microbiologists, synthetic chemists and engineers, all in one team, from the start of the project,' he says.

'In the UK, it's still quite rare for the organic chemists to talk to the engineers.' The conservatism of the engineers themselves is also a factor. 'They know about continuous stirred tank reactors, they know inorganic catalysts, it's all fully costed.' Changing to a biological paradigm is a big step, he says - and it's one which alarmingly few engineers seem willing to take.

For the past five years, Japan's government has been sponsoring research to increase the use of microbes. The main goal of the programmes is energy reduction - Japan is almost completely reliant on imported fuel for energy generation, and biologically-mediated processes tend to need milder conditions (and therefore less energy) than classic inorganic-catalysed industrial chemistry.

A study from Kyoto University estimated that the chemical industry consumed 13% of all energy in Japan, but if 30% of chemical production were achieved by enzyme-mediated processes, total energy consumption would fall by one percentage point. Japan is one of the world's highest energy consumers, using 50% more energy than the UK - a 1% cut would present a considerable saving.

The study also recommended that microbial conversion of biomass into gas could meet a fifth of energy needs. The initial project set a target of 2007 for the enzymatic processes goal, and 2010 for the biogas target. Japan's industrial ministry, METI, estimates that 10% of chemical production through enzymes by 2007 is probable, and 15% is achievable.