The application of biological processes to develop useful products is as old as Mendel's pea experiment, which he con ducted in 1866 (Figure 1.1). As a result of his avocation, Mendel developed the principles of heredity, and thereby laid the basis of modern genetics. While the listing of biotechnology in the dictionary did not occur until 1979, the fermentation technology we use today to produce recombinant proteins was first used in World War I to ferment corn starch (with the help of Clostridium acetobutylicum) and produce acetone for manufacturing explosives. Fermentation technology took on even greater importance with the development after World War II to produce antibiotics.
An enhanced understanding of protein structure, a detailed elucidation of cell replication and protein synthesis, and the isolation of DNA replication enzymes, including restriction enzymes and polymerases, led to the rapid development of recombinant DNA technology, permitting cloning and expression of proteins and peptides that had eluded efforts at isolation and harvest only a few years earlier. At about the same time, in 1975, scientists developed monoclonal antibody technology, which allowed large-scale preparation of purified, highly specific antibodies with mono-specific binding sites (spanning 6-10 amino acids in length) in a reproducible manner. This technology also allowed the generation and use of monoclonal antibodies as a tool to characterize and purify proteins that would selectively bind to respective antibodies with high specificity. These tools for preparation and characterization of recombinant products are essential for developing macromolecules into therapeutic products.
The biotechnology milestones are graphically presented in Figure 1.1. While each event listed in Figure 1.1 may not by itself have permitted the rapid application of biotechnology to drug development, in the aggregate they have led to the development of dozens of pharmaceutical products that could not have been realized without the availability of these technologies. The advances in technologies make the process possible or accelerate it, or just simply make the product cost-effective and much safer than the same material extracted from tissue sources. For example, the development of a yeast plasmid vector permitted mass production of hepatitis B surface antigen for vaccine development and the economical manufacture of recombinant human insulin.
Almost all of the biopharmaceuticals available today, other than vaccines, are proteins or peptides. Of considerable importance among this array of products are monoclonal antibodies. These "magic bullets" became a reality with the introduction of Orthoclone (muro-monab) in 1986. At present, monoclonal antibodies are the fastest growing category of biopharmaceuticals approved for therapeutic use. Our ability to identify novel, potentially therapeutic proteins and pep-tides, like monoclonal antibodies, has advanced at such a rate that we are now limited by the human effort and resources needed to develop and demonstrate the clinical efficacy and safety of these candidates.
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