Molecular Biotechnology. Bernard R. Glick

responsible for the establishment of official guidelines and governmental agencies for conducting and regulating recombinant DNA research, respectively; and contributed to the formation of the molecular biotechnology industry.

      The nature of biotechnology was changed forever by the development of recombinant DNA technology. Genetic engineering provided the means to create, rather than merely isolate, highly productive microbial strains. Not long after the production of the first commercial preparation of recombinant human insulin in 1982, bacteria and then eukaryotic cells were used for the production of insulin, interferon, growth hormone, viral antigens, and a variety of other therapeutic proteins. Recombinant DNA technology also facilitated the biological production of large amounts of useful low-molecular-weight compounds and macromolecules that occur naturally in minuscule quantities. Plants and animals became targets as natural bioreactors for producing new or altered gene products that could never have been created either by mutagenesis and selection or by crossbreeding. Molecular biotechnology has become the standard method for developing living systems with novel functions and capabilities for the synthesis of important commercial products.

      Most new scientific disciplines do not arise solely on their own. They are often formed by the synthesis of knowledge from different areas of research. For molecular biotechnology, the biotechnology component was perfected by industrial microbiologists and chemical engineers, whereas the recombinant DNA technology portion owes much to discoveries in molecular biology, bacterial genetics, and nucleic acid enzymology (Table 1.1). In a broad sense, molecular biotechnology draws on knowledge from a diverse set of fundamental scientific disciplines to create products that are useful in a wide range of applications (Fig. 1.1).

Table 1.1 Selected developments in the history of molecular biotechnology

      Figure 1.1 Many scientific disciplines contribute to molecular biotechnology, which generates a wide range of commercial products.

      The Cohen and Boyer strategy for gene cloning was an experiment “heard round the world.” Once their concept was made public, many other researchers immediately appreciated its potential. Consequently, scientists created a large variety of experimental protocols that made identifying, isolating, characterizing, and utilizing genes more efficient and relatively easy. These technological developments have had an enormous impact on generating new knowledge in practically all biological disciplines, including animal behavior, developmental biology, molecular evolution, cell biology, and human genetics. Indeed, the emergence of the field of genomics was dependent on the ability to clone large fragments of DNA into plasmids in preparation for sequence determination.

Commercialization of Molecular Biotechnology

      The potential of recombinant DNA technology reached the public with a frenzy of excitement and many people became rich on its promise. Indeed, within 20 minutes of the start of trading on the New York Stock Exchange on 14 October 1980, the price of shares in Genentech, the company founded by Boyer with chemist and entrepreneur Robert Swanson that produced recombinant human insulin, went from $35 to $89. This was the fastest increase in the value of any initial public offering in the history of the market up to that time. It was predicted that some genetically engineered microorganisms would replace chemical fertilizers and others would eat up oil spills; plants with inherited resistance to a variety of pests and exceptional nutritional content would be created; and livestock would have faster growing times, more efficient feed utilization, and meat with low fat content. Many were convinced that as long as a biological characteristic was genetically determined by one or a few genes, organisms with novel genetic constitutions could be readily created. Today, in many cases, the promise of recombinant DNA technology has become a reality.

      In the 35 years since the commercial production of recombinant human insulin, more than 300 new drugs produced by recombinant DNA technology have been used to treat over 300 million people for diseases such as cancer, multiple sclerosis, rheumatoid arthritis, cystic fibrosis and strokes, and to provide protection against numerous infectious diseases. The majority of these are therapeutic monoclonal antibodies, hormones, and growth factors, many of which are more effective and have fewer side effects than other therapies. Moreover, hundreds of new biological drugs are in the process of being tested in human clinical trials to treat various cancers, autoimmune diseases, and infectious diseases. Similarly, many new molecular biotechnology products for enhancing crop and livestock yields, decreasing pesticide use, and improving industrial processes such as the manufacture of pulp and paper, food, energy, and textiles have been created and are being marketed.

      The impact on agriculture has been tremendous. While the global population is expanding rapidly, yield increases of all major crops have decreased due to poor agricultural management practices, decreased acreage of arable land, and increased reliance on fertilizers and pesticides that diminish soil quality. To produce more food on less land, 18 million farmers in 28 countries are now planting genetically engineered crops on 450 million acres of land. These crops are predominantly soybeans, corn, cotton, and canola that are resistant to herbicides and insects. The global market value of genetically modified crops is currently $15.3 billion. Small resource-poor farmers are among the beneficiaries of agricultural biotechnology. In a comparative study of small cotton farms in South Africa, it was found, over three seasons, that the yield of cotton from plants that were genetically engineered to produce a bacterial insecticide was on average about 70% greater than those from nongenetically modified plants. Higher yields and reduced pesticide and labor costs translated into doubled revenues despite the slightly higher costs of the transgenic seeds. In India, which is the largest cotton producer in the world, revenues from insect-resistant cotton increased by $1.6 billion in 2014 compared to the previous year.

      The ultimate objective of all biotechnology research is the development of commercial products. Consequently, molecular biotechnology is driven to a great extent by the prospect of financial gain. By nightfall on 14 October 1980, the principal shareholders of Genentech stock were worth millions of dollars. The unprecedented enthusiastic public response to Genentech encouraged others to follow. Between 1980 and 1983, about 200 small biotechnology companies were founded in the United States with the help of tax incentives and funding from both stock market speculation and private investment. Like Herbert Boyer, who was first a research scientist at the University of California at San Francisco and then a vice president of Genentech, university professors started many of the early companies.

      Today, there are about 2,500 biotechnology companies in the United States and 2,100 in Europe, with annual earnings of $132 billion in 2015. The biotechnology industry in these regions employs more than 200,000 people. Large multinational chemical and pharmaceutical companies, such as Monsanto, Bayer, Du Pont, Pfizer, GlaxoSmithKline, Merck, Novartis, Hoffmann-LaRoche, Gilead Sciences, and Amgen, to name but a few, have made significant research commitments to molecular biotechnology. During the rapid proliferation of the biotechnology business in the 1980s, small companies that tended to specialize in one particular type of recombinant DNA product were often absorbed by larger ones, strategic mergers took place, and joint ventures were undertaken. For example, in 1991, 60% of Genentech was sold to Hoffmann-LaRoche for $2.1 billion. Inevitably, and for various reasons, there were a number of bankruptcies of biotechnology companies. This state of flux is a characteristic feature of the biotechnology industry. Currently, the roster of biotechnology companies is extensive and includes those focused on vaccines, protein and nucleic acid therapeutics, drug delivery, molecular diagnostics, genomics, industrial processing, and agricultural biotechnology.

Concerns and Consequences

      While many people appreciate the potential of molecular biotechnology to solve important problems in agriculture, medicine, and industry, they recognize the need to be cautious about its widespread application. Indeed, one of the first scientific responses to this new technology was a voluntary moratorium on certain experiments that were thought to be potentially hazardous.