Microbes in industry. The revolution in biotechnology
Chemists, awed by how easily lowly microbes outperform test tube wizardry, express their envy in the ''Organic Chemist's Ode'': I fall upon my knees And pray that all my syntheses May no longer be inferior To those conducted by bacteria.m
Actually, chemists have been involved with microbes for a long time. US industrial microbiology turns out a mix of products worth some $10 billion a year. The pharmaceutical industry, in particular, has transformed itself over the past four decades to become highly dependent on organic processes to create medicinal products. However, following the economics of using cheap oil as a raw material, the chemical industry has stuck largely with synthetic, energy-intensive processes.
Now oil is no longer cheap and energy must be conserved. Economics is turning against the chemist's syntheses and in favor of doing things the microbe's way. New prospects for genetically redesigning microbes to be more efficient on the job enhance the trend. Industrial chemistry as a whole is ripe for transformation into a biologically based industry on a scale never before known.
The congressional Office of Technology Assessment (OTA), in a major study, concludes that biotechnology ''will cut across the entire spectrum of chemical groups: plastics and resin materials, flavors and perfumes materials, synthetic rubber, medicinal chemicals, pesticides, and the primary products from petroleum that serve as . . . raw materials. . . .'' It notes: ''estimates of the expected economic impacts are in the billions of dollars per year for dozens of chemicals within 20 years.''
Many of those billions won't represent new products or new markets for the industry so much as new ways of producing established materials. OTA looked at over 100 chemical compounds in 17 product categories with a present annual market value of over $27 billion. It found that ''within 20 years all these products could be manufactured using genetically engineered microbial strains on a more economical basis than using today's conventional technologies.''
There are also billions of dollars to be made with products that probably wouldn't be available at all without the help of microbes. These will include medicinals, such as human insulin, which a bacterium has now been designed to make, or alcohol for fuel. Genex Corporation estimates that markets for wholly new products and expansion of markets to absorb increased production of established products could total $26 billion by the end of the century.
All such estimates of future markets are uncertain. What is clear is that the modern chemical industry, which now satisfies over 90 percent of its raw material needs with oil, has valuable partners in microbes that can transform wood, organic wastes, and other ''biomass'' to meet certain needs.
The basic chemical process involved is fermentation - the transformation of organic compounds using enzymes, usually those made by microbes. Enzymes are proteins that ease otherwise difficult chemical reactions. Each reaction has its specific enzyme. The chemical facility of microbes - indeed of all living cells - lies in their ability to produce thousands of these enzymes as needed, and in the amounts needed, to smooth the processes of organic life as directed by the genetic instructions each species carries.
People have used fermentation for millenniums. Yeast was used to break down sugars to form carbon dioxide and leaven Egyptian bread over 6,000 years ago.
Out of more than 100,000 species of microbes on Earth, only a few hundred are likely to be directly useful to people. They include yeasts, molds, bacteria, and the actinomycetes (which make antibiotics). Nevertheless, while this may be a small part of Earth's microbiota, they produce some 200 commercially useful materials, only a few of which industry makes biologically today. This suggests the industrial growth potential of the ancient art - now the science - of using fermentation.
Sometimes the industrial chemist dispenses with the microbe and uses an enzyme or enzymes directly. The role of the microbe is reduced to supplying the enzyme initially. This is what has happened in one of those quiet little revolutions at the grocery store that sometimes slip by unnoticed.
A few years ago, bread and soft drinks were sweetened with cane sugar. There were outcries from consumers when the cost of sugar shot up. Now, a corn syrup sweetener is taking over. Large-scale production of fructose (a sugar) by fermentation from cornstarch threatens the dominance of sucrose (beet and cane sugar).
Production of fructose syrup is approaching 3 million tons a year. According to estimates by investment analysts at L. E. Rothschild, Unterberg, Towbin, the annual worldwide sweetener market is some $14 billion, including $5 billion in the United States alone. Thus the stakes are high to continue development of this technology, which is already producing a sweetener at costs competitive with cane sugar.
In terms of the number of patents held and current industrial applications, Japan leads the world in enzyme technology, according to Daniel Thomas and Gerard Gellf of the Technological University of Compiegne in France, who recently published a worldwide review of the field. But considerable work is also being done in the US and the European Economic Community. France has made biotechnology a national priority. Several other countries, including the Soviet Union, are showing interest too.
Industrial use of enzymes has been hampered by technical difficulties of working with these useful molecules in chemical solutions. They can be overcome somewhat by tying the enzymes down to a solid substrate while the substance they are to transform washes over them, as is done in making fructose syrup.
It is a concept that was originally studied in Berlin in the 1950s. Twelve years ago, Tanabe Seiyaku Company in Japan made the first satisfactory industrial use of it to produce certain amino acids - the building blocks of proteins. More than 2,000 research papers have been published about the idea in the past few years.
Speculating about future uses, Thomas and Gellf note that rennin for making cheese is becoming expensive. If that enzyme could be immobilized, cheesemakers could reuse the expensive material several times. Looking further ahead to a time when more-complicated enzyme systems can be assembled, they foresee such things as removal of pesticides from water, nitrogen-fixation for fertilizer using immobilized living cells, and even production of hydrogen for fuel by splitting water molecules in a photosynthetic reaction.
Meanwhile, microbes themselves are finding wider applications. Their utility lies only partly in the kinds of products they can make. Equally valuable is the fact that they can use a variety of materials and perform chemical reactions at low temperatures and pressures. This contrasts to energy-intensive, nonbiological processes that typically need high temperatures and pressures.
Noting that the chemical industry had been seduced by cheap oil to abandon fermentation technology used early in this century, OTA observes that ''the chemical industry's constant search for cheap and plentiful raw materials is now about to come full circle.'' Coal will provide many substitutes. ''Nevertheless, '' OTA says, ''economic, environmental, and technical factors will increase the industry's interest in biomass as an alternative source of raw materials. . . . Biology will thereby take on the dual role of providing both raw materials and a process for production.
''This is clearly evident in the production of ethyl alcohol or ethanol. Quite apart from its prospects as a fuel, ethanol already has major industrial uses as a solvent, extractant, antifreeze, and basic material for other products. Only about a third of the current US annual production of around 300 million gallons is used for fuel. This proportion could change radically over the next two decades if alcohol becomes a substantial substitute for oil-derived gasoline.
About 70 percent of US ethanol is made synthetically from oil-derived raw materials. A number of microbes, however, including the same yeast species that leavens bread, can do the job. Rising oil costs are pushing industry toward alcohol biosynthesis even without the gasohol incentive.
In the US, surplus grain could provide something like 2 billion gallons a year or less. But there is no need to be restricted to grain as a raw material or to divert any food material to such use. Organic wastes, such as cornstalks, could be used if the more complicated biochemistry involved were developed. Charles Cooney of the Massachusetts Institute of Technology, one of a number of biochemists working on ethanol fermentation around the world, insists that the real value of the process is the opportunity it offers to use a variety of cheap , abundant biomass materials in place of oil.
However, while people have been fermenting grain for thousands of years, wood is more difficult to work with. Of its three main constituents - cellulose, hemicellulose, and lignin - only cellulose is readily fermentable today. In his laboratory, Professor Cooney and his colleagues have bred two strains of bacteria to perform a direct fermentation from ligno-cellulose biomass to alcohol. Cooney calls it ''a kind of cellulose yogurt.
''So far, he has used selective breeding rather than the more exotic techniques for rewriting genetic instructions directly. Nevertheless, as the research advances, he foresees not only alcohol production, but direct fermentation of wood to such other basic organic chemical materials as acetic or lactic acids. ''The possibilities are limited only by the imagination,'' he says.
Some other basic industrial chemicals, such as propylene oxide, widely used in the manufacture of plastics, also seem ripe for bioproduction. In fact, Cetus Corporation expects this to happen before 1990 and forecasts global sales worth basics, there are many end products which biotechnology can help manufacture. These will even include upgraded oil products such as lubricants made by biological processing of heavy oil and residuals.
Developing the ''bugs'' to do the job is only part of what will be needed. Elmer L. Gaden Jr. of the University of Virginia points out in reviewing industrial microbiology in the magazine Scientific American that ''a biological process can attain its full utility only when adapted to a context of production.'' He adds that ''both the environment and the technology (for fermentation) are generally provided by a system of vats, pipes, pumps, valves, and other devices. It follows that genetic engineering is only one factor in the success of a biological industry. . . .
''The microbe and the chemical engineer are both needed to make the new biotechnology work. Yet without modern techniques of intensive selective breeding and the ability to rewrite an organism's genetic programs, much of what is forecast here would be impractical. It is these new capacities that make possible what British geneticist David Hopwood calls ''the selection or construction of freak organisms, genetically programmed to make a normal metabolic product in amounts that would be a disastrous drain on a wild organism's resources.''
The genetic breeding methods enable industrial chemists to anticipate what microbiologist Douglas E. Eveleigh of Rutgers University describes as ''the rational design and synthesis of enzymes.
''Such are the fruits of genetic science. As OTA observes, ''several decades of support for some of the most esoteric basic research has unexpectedly provided the foundation for a highly useful technology.''
