Sea of dreams

Genetically modified microbes will lead to a revolution in industrial biotechnology

CRAIG VENTER, the man who led the privately funded project to sequence the human genome, is someone who likes to mix business with pleasure. And for a geneticist whose passion is sailing, there can be few more satisfying ways of doing so than sampling genes in the Sargasso sea, near Bermuda. The samples he took there last year yielded a surprise. The sea had looked as though it was the oceanic equivalent of a desert, bereft of nutrients, and with little life beyond the Sargassum weed that gives the sea its name. But when Dr Venter ran his samples through his newly developed method for sequencing the DNA of an entire environment, some 1.2m new genes turned up from an estimated 1,800 species of microbe previously unknown to science. An apparently empty sea was teaming with bacterial life.

Such newly discovered genes are the raw material for the infant, but rapidly developing field that makes useful chemicals via genetically modified organisms. It is part of what is known as industrial biotechnology, where cells from animals, plants and bacteria are used to generate industrially useful products. The Sargasso results, outlined last week to the World Congress on Industrial Biotechnology and Bioprocessing, in Orlando, Florida, by Dr Venter's colleague Karin Remington, suggest there are a lot of useful raw materials to be found.

Dr Venter's Institute for Biological Energy Alternatives, based in Rockville, Maryland, is now taking further samples from around the world. Although Dr Venter is turning such bioprospecting from a sport using a fishing line to one using a trawling net, looking for new bacteria is already a well-established activity. The business models of firms such as Diversa, a company based in San Diego, are centred on it.

Blowing hot and cold Diversa is prospecting in hot springs, ocean beds, soda lakes and on the Arctic tundra. The genes it, and others, are looking for are instructions for producing proteins—many of which are natural catalysts inside living cells. By searching in wild and wonderful environments, microbiologists hope to find new genes that might be of use to investors and customers.

Many people now hope that this year's Orlando congress will become an annual event. They see industrial biotechnology as the wave of the future—a phenomenon that will eventually rock entire economies. Whether this is the case or not, in the shorter term it does seem likely that industrial biotechnology will shake up the chemical industry. And it may provide a route to a future less dependent on fossil fuels, and one that puts less climate-changing carbon dioxide into the atmosphere.

Finding a gene, though, is only the first step towards a product of commercial interest. Philippe Soucaille, chief scientific officer of a company called Metabolic Explorer, based in Clermont-Ferrand, France, told the meeting that his firm is working with a database of all the biochemical pathways it can get its hands on and a computer model of the metabolism of a bacterium called Escherichia coli. This is the most popular organism for bacterial geneticists to experiment upon, their equivalent to a laboratory rat.

Given a starting material and an end-product, Metabolic Explorer's system will assemble the best set of pathways and then work out how to fit them into E. coli, and say which existing E. coli pathways should be deleted. It will also identify potential biochemical bottlenecks where enzymes might need modifying to speed things up. Thus the company can pick-and-mix biochemical pathways from different organisms and put them together in a single bacterium, as a computer programmer might assemble a piece of software from pre-written sub-routines.

Once the pathways have been selected, and the new enzymes designed, it is just a question of adding the relevant genes to E. coli, removing the genes for the undesired pathways, and seeing whether the result lives up to expectations. Metabolic Explorer has already done such work under contract for several other firms. Currently it is using the process for its own benefit, to produce methionine, an amino-acid animal-feed supplement with a market worth $1.4 billion a year. Bio-Technical Resources, of Manitowoc, Wisconsin, has used a similar technique to produce glucosamine, an amino-acid supplement favoured by many people with arthritis.

Such sums, of course, are peanuts compared with the money to be made outside the niche end of the chemicals market. But they represent a bonanza to small biotechnology firms. And industrial biotechnology looks set to make further inroads into the market for boutique chemicals. Many other products have fallen, or look ready to fall, to biotechnological processes that are cheaper than traditional chemistry, have higher yields or produce a cleaner product. These include other amino-acid supplements, vitamin supplements, antibiotics, anti-influenza drugs, foundation creams for cosmetics and even the solid rocket-fuel that is used in air-to-air missiles. According to Jens Riese, of McKinsey, a consultancy, about 5% by value of the world's chemical output is already biotech-based and this is expected to rise to 10% over the next six years.

All this progress is largely invisible to the public. Indeed, given the consternation about public reactions to agricultural biotech, there were some misgivings among delegates as to what would happen when the public realised what was going on. If the next phase of industrial biotechnology works, the field's profile will grow considerably more visible. The really serious money is to be made in bulk chemicals and fuels.

Fantastic plastic Genetic engineering can already deliver many traditional chemical-feedstock molecules. Metabolic Explorer, for example, can turn glucose into acrylate, a feedstock for the plastics industry. Cargill, a large agricultural company that has been interested in biotechnology for some time, is turning its attention to a glucose-derived substance called 3-hydroxypropionic acid. This can be made with modified microbes. Further microbes can then produce a dozen chemicals that are precursors for plastics. John Frost of Michigan State University (and the inventor of biotech rocket-fuel) has even worked out how to use bacterial enzymes to make a form of Nylon. It all sounds promising. But what biotechnology mostly cannot do yet is produce either feedstock or finished product more cheaply than the petrochemical industry.

There are a few well-trumpeted exceptions. Cargill-Dow, a joint-venture between Cargill and Dow Chemicals, produces a cost-effective polymer made from lactic acid that has, in turn, been made from maize-derived glucose. Metabolix, a small firm based in Cambridge, Massachusetts, has a suite of plastics called polyhydroxyalkanoates, which are grown inside genetically engineered bacteria and that the firm seems confident will be cost-competitive with at least some existing specialist plastics. And DuPont, another big chemical company, has Sorona, a plastic that is half biotech and half traditional. But the breakthrough everybody is waiting for is a way of producing glucose really cheaply. For glucose is to industrial biotech what crude oil is to petrochemicals.

Once again, microbes are the key. The main source of industrial glucose in North America is maize starch, which is relatively costly. But most of the dry weight of a plant is composed of cellulose. Cellulose, like starch, is a polymer of glucose. Unlike starch, though, it is tough. But if it could be used to make glucose, much agricultural waste, such as straw and the leftovers from maize farming, could be turned to account. It can be broken down biologically, and the enzymes to do such a job are found in many bacteria and fungi. The search is now on for the best enzymes and ways of upgrading these into industrial products.

Some significant progress has already been made. Novozymes is a Danish company with a research laboratory in Davis, California that is devoted to the question. And as Sarah Teter, one of the people in charge of the project, explained, the firm is working on a mixture of fungal enzymes that collaborate by attacking different parts of the cellulose chain.

Novozyme's target chemical is actually ethanol. This is fermented from glucose, and can be used as a substitute for petrol. The firm has improved the process of fermenting cellulose into glucose, and then glucose into ethanol, in ways that have reduced the cost ten-fold.

This still means that the enzyme processing for an American gallon of cellulose-derived ethanol costs 50 cents. But Novozyme hopes to bring that cost down another ten-fold over the next few years, to a point where ethanol derived from cellulose might be cost-competitive with petrol. And if ethanol can be made cheaply from cellulose, then so can a lot of other bulk chemicals. One idea is to use special chips known as DNA microarrays, which show what genes are active at a given moment, to work out what other enzymes the fungi are making when they digest cellulose. Chucking those enzymes into the mixture should make a significant difference.

In an announcement whose timing was probably not coincidental, a Canadian company called Iogen proudly proclaimed at the meeting that its cellulose-ethanol plant in Ottawa—the first such commercial venture in the world—had just opened for business. That plant is, in part, the product of subsidies, so its true relevance remains to be seen. But it is, as it were, a straw in the wind.

Biotechnology is going to be the wave of the future with the earth's dwindling natural resources. However, the uptmost care (strict sterile laboratory procedures) must be adhered to when intermixing and splicing genes of a bacterium mostly indigenous to the sargasso sea and/or making new substances, so that they will not inadvertently be introduced into our ecosystem (such as washing it down a drain).

How can the producers of these new products be sure of their desired outcome when they are eventually let go into the environment? Or, of not reacting in adverse ways when natural biodegrading produces the reverse and might potentially harm the environnment with a new mutated specie altogether? The earth is a much different laboratory with a multitude of variables, much more so than a (closed structured) parametered laboratorial climate!

Which government body regulates and oversees the research and development of new biotechnological products? Or, is this only regulated after it is produced and set into motion in the environment? Taking care before unleashing is of paramount concern here.

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