biotechnology

biotechnology is unique amongst the three principal technologies for the twenty-first century — information technology, materials science, and biotechnology — in being a sustainable technology based on renewable biological resources. Such natural resources include animals, plants, yeasts, and microorganisms and have formed mankind's nascent food and beverage industry for several millennia. However, the modern era of scientific biotechnology commenced with the elucidation of the structure of DNA by Watson and Crick in 1953 and the subsequent development of the tools to cleave and resplice genetic material in the early 1970s. Not surprisingly, therefore, the term ‘biotechnology’ is generally considered synonymous with gene splicing and other forms of genetic engineering. In practice, however, biotechnology refers to a library of advanced scientific tools for the manipulation of biological organisms, systems, or components for the production of goods or services in all sectors of human activity.

The early years of the ‘new’ biotechnology focused on the technologies required to clone, overexpress, purify, and administer biopharmaceuticals such as insulin, growth hormone, factor VIII (deficient in haemophilia), and erythropoietin, with some 200 other proteins currently in the pipeline. However, in the future, the most significant breakthroughs in human medicine will result from mapping and understanding the human genome — in elucidating the exact sequence of the billions of nucleotides that constitute the estimated 30 000–40 000 genes that are the collective blueprint for human beings and are responsible for some 10 000 genetic disorders. The Human Genome Project was launched in 1990 as a 15-year, $3 billion international effort to map and sequence all human genes. Innovations in sequencing technology have ensured that the project moved ahead of schedule. With less than 5% of all human genes identified at the start of the project, it has become increasingly clear that each new gene discovery proffers new drugs for the diagnosis, treatment, and prevention of human disease. These drugs include therapeutic proteins, diagnostics, gene therapy reagents, and small molecules. A significant proportion of the human genome has been sequenced and many new human disease genes are being characterized. These advances will enable biotechnologists not only to measure disease potential and expand the applications for genomic diagnostics but also to devise fundamental new therapeutic approaches.

Genomics and genetic engineering are also playing a substantial role in the development of agricultural biotechnology. This sector is finally moving out from under the shadow of the biopharmaceutical community and is now competing in terms of publicity and investor attention. This is because $1 billion is considered an attractive market in the biopharmaceutical industry, whilst global agricultural markets can readily top $10 billion and the total end-use value of food, fibre, and biomass is estimated to be over $1500 billion. The addressable market on which value can be added and costs cut is at least 6–7 times that of its pharmaceutical counterpart. Two of the factors that have encouraged biotechnologists to enter the genetically engineered food and plant arena are the desire of consumers for better tasting foods and a preference for products grown using fewer pesticides. Calgene was the first company to market a genetically improved tomato which could be ripened on the vine without softening and thereby result in improved taste and texture. Antisense technology was used to inhibit the enzyme polygalacturonase which degrades pectin in the cell wall. Similarly, laurate Canola is the world's first oilseed crop that has been genetically engineered to modify oil composition. Laurate is the key raw material used in the manufacture of soap, detergent, food, oleochemical, and personal care products. Other examples of transgenic agricultural crops include high stearate and myristate oils, low saturate oils, high solids tomatoes and potatoes, sweet minipeppers, modified lignin in paper pulp trees, pesticide-resistant plants, and biodegradeable plastics.

The early goals in the development of transgenic livestock were the increase of the meat and of the production characteristics of food animals. However, long research and development timelines and low projected profit margins, especially in developed nations where food is relatively inexpensive, have shifted priorities to the production of protein pharmaceuticals and nutraceuticals in the milk of transgenic animals. Milk has a high natural protein content and is sequestered in a gland where its proteins exert little direct systemic effect. It provides a renewable production system that is capable of complex and specific ‘post-translational processing’: that is, modifications to the protein that occur after it has been synthesized as a polypeptide (such as conjugation with carbohydrate moieties), which can alter the biological or therapeutic properties of the protein. Such changes cannot easily be accomplished in conventional cell culture systems. As a result, the ‘biopharming’ focus has shifted to the production of human blood plasma proteins and other therapeutic proteins, in ruminants such as cows, sheep, and goats which are easy to milk.

Marine organisms are also capable of producing a variety of polymers, adhesives, and compounds for cosmetics and food preparation. Bioactive natural products are found in organisms that reside in areas which stretch from easily accessible intertidal zones to depths in excess of 1000 m. Collaborations between marine chemists, molecular pharmacologists, and cell biologists have yielded an impressive library of potentially useful cancer, viral, antibiotic, anti-inflammatory, cardiovascular, and CNS drugs.

The pharmaceutical, agrichemical, and speciality chemical industries are increasingly requiring molecules which have distinct left- or right-handed forms, so-called chiral compounds. Whilst chemical and biological techniques for producing single left- or right-handed forms are developing apace, it is apparent that no single approach is likely to dominate. Suppliers and customers alike must continue to draw upon the entire range of chemical, enzymatic, and whole-organism tools that are available to produce chiral compounds. Unfortunately, only 10% of the 25 000 or so enzymes found in nature have been identified and characterized, and, of these, only 25 are produced in large quantities. Despite some duplication in activity among enzymes, there is a need to characterize more in order to exploit their unique specificity and activity. However, barriers to enzyme scale-up include product inhibition and a general reluctance on the part of chemists to use water-based reagents in systems which are traditionally non-aqueous. Consequently, enzymes should be made more user-friendly both for bench chemists exploring novel synthetic strategies and for all stages in pharmaceutical scale-up. However, the biologists' toolbox for catalysis is expanding. For decades, there were only two types of catalyst — metals and enzymes — but since 1986 two new classes of biocatalyst have emerged along with the enzymes, ribozymes, and catalytic antibodies. These novel biocatalysts are prepared both by classical biochemical and immunological methods and by recombinant and phage display technologies. Whilst there are still many catalysts still to be discovered, such biocatalysts will have to exhibit improved performance, stability, turnover numbers, specificity, and product yields.

Biotechnology is also playing a role in ‘clean’ manufacturing. Nevertheless, various types of chemical manufacturing, metal plating, wood preserving, and petroleum refining industries currently generate hazardous wastes, comprising volatile organics, chlorinated and petroleum hydrocarbons, solvents, and heavy metals. Bioremediation with microbial consortia is being investigated as a means of cleaning up hazardous sites. Methods include in situ and ex situ treatment of contaminated soil, groundwater, industrial wastewater, sludges, soil slurries, marine oil spills, and vapour-phase effluvia.

Biotechnology is expected to contribute massively to the global economy, largely through the introduction of recombinant DNA technology to the production of biopharmaceuticals. In the future, biotechnology will concentrate on the complexity and interrelatedness of biology, with such targets as the human genome project; genetic medicine; gene and cell therapy; tissue engineering; vaccines; factors for transcribing DNA into RNA; signal transduction and the control of gene expression; managing ageing at the level of programmed cell death, and genes that control cell division; neurobiotechnology; agri-industrial biotechnology; drug delivery; cell adhesion and communication; and novel diagnostics. Needless to say, and subject to clarification of certain ethical and public acceptance issues, biotechnology is set to make an indelible contribution to human health and welfare well into the foreseeable future.

C. R. Lowe