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Biotechnology and the Army

This chapter provides a brief history of biotechnology, describes the characteristics of the biotechnology industry, and introduces relevant biological concepts. This background information lays the groundwork for the discussions of developments and applications in subsequent chapters.

HISTORY OF BIOTECHNOLOGY

Although the term biotechnology was not used until 1919, ancient civilizations used biological processes to leaven bread, brew beer, and ferment wine. The language of biotechnology used by scientists, pundits, and reporters that has become widespread in the last 30 years began when enzymes were recognized in, and isolated from, naturally occurring bacteria (also referred to as wild-type organisms). Once enzymes could be isolated, scientists could begin to direct the recombination of deoxyribonucleic acid (DNA) and perform genetic engineering, which is the basis of the biotechnology industry.

Typically, only a very small sample of DNA molecules is available naturally. The amplification of DNA in a test tube using DNA derived from wild-type organisms was first performed in 1985 by a method called the polymerase chain reaction (PCR) (see Box 2-1). Using PCR, DNA could be “amplified” to generate a large number of DNA molecules that are exact replicates of the originating material. With large amounts of DNA (measured in milligrams), scientists were able to carry out many studies that would not have been possible otherwise.

The first DNA polymerase isolated and identified was a protein from the thermophilic bacterium Thermus aquaticus (abbreviated Taq). The interval between the discovery of Taq and its use in PCR to identify the Hantavirus in 1993 was less than seven years (see Box 2-2). PCR, which can now be carried out in almost any laboratory using an instrument about the size of a shoebox, is no longer the exclusive purview of a few large research centers. In fact, these days experiments with DNA are often projects at high school science fairs. Because PCR has enabled a broad range of investigators to work at the level of DNA, it has democratized accessibility to DNA (Appenzeller, 1990).

PCR can be used in scientifically diverse applications and disciplines. For example, PCR is used to study DNA from long-dead species for tracking evolution, so called molecular archeology. DNA that has survived in ancient tissue for 45,000 years or more can now be amplified to provide large enough quantities for the DNA to be sequenced. Thus, PCR can provide a time machine enabling students of molecular evolution “to retrieve and study ancient DNA molecules and thus to catch evolution red-handed” (Pääbo et al., 1989).

Prior to 1970, gene-directed recombination of DNA was limited to plants and animals and carried out through selective breeding. Today, many plants, animals, and microorganisms have been genetically engineered, and genetic information from one species can even be introduced into a different species. New and beneficial properties can be introduced in a directed and predetermined way, starting with test-tube manipulations of DNA. For example, DNA derived from a human being has been introduced into E. coli to create a modified bacterium from which human insulin can be derived.

Some bacteria in nature produce a protein that is toxic to insects. When information that enables the bacteria to make this protein is introduced into a plant, the plant can generate this compound and become disease resistant. The creation of transgenics (i.e., plants or animals that carry genes from a different species and incorporate them into their own genetic information) is a major achievement of biotechnology.

The rapid development of laboratory tools and reagents has resulted in an expanding base of knowledge about the molecular basis of biology. Future commercial applications may include the following:

  • detection of pollutants in the environment

  • diagnosis and treatment of diseases

  • development of new materials to replace materials



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Page 11 2 Biotechnology and the Army This chapter provides a brief history of biotechnology, describes the characteristics of the biotechnology industry, and introduces relevant biological concepts. This background information lays the groundwork for the discussions of developments and applications in subsequent chapters. HISTORY OF BIOTECHNOLOGY Although the term biotechnology was not used until 1919, ancient civilizations used biological processes to leaven bread, brew beer, and ferment wine. The language of biotechnology used by scientists, pundits, and reporters that has become widespread in the last 30 years began when enzymes were recognized in, and isolated from, naturally occurring bacteria (also referred to as wild-type organisms). Once enzymes could be isolated, scientists could begin to direct the recombination of deoxyribonucleic acid (DNA) and perform genetic engineering, which is the basis of the biotechnology industry. Typically, only a very small sample of DNA molecules is available naturally. The amplification of DNA in a test tube using DNA derived from wild-type organisms was first performed in 1985 by a method called the polymerase chain reaction (PCR) (see Box 2-1). Using PCR, DNA could be “amplified” to generate a large number of DNA molecules that are exact replicates of the originating material. With large amounts of DNA (measured in milligrams), scientists were able to carry out many studies that would not have been possible otherwise. The first DNA polymerase isolated and identified was a protein from the thermophilic bacterium Thermus aquaticus (abbreviated Taq). The interval between the discovery of Taq and its use in PCR to identify the Hantavirus in 1993 was less than seven years (see Box 2-2). PCR, which can now be carried out in almost any laboratory using an instrument about the size of a shoebox, is no longer the exclusive purview of a few large research centers. In fact, these days experiments with DNA are often projects at high school science fairs. Because PCR has enabled a broad range of investigators to work at the level of DNA, it has democratized accessibility to DNA (Appenzeller, 1990). PCR can be used in scientifically diverse applications and disciplines. For example, PCR is used to study DNA from long-dead species for tracking evolution, so called molecular archeology. DNA that has survived in ancient tissue for 45,000 years or more can now be amplified to provide large enough quantities for the DNA to be sequenced. Thus, PCR can provide a time machine enabling students of molecular evolution “to retrieve and study ancient DNA molecules and thus to catch evolution red-handed” (Pääbo et al., 1989). Prior to 1970, gene-directed recombination of DNA was limited to plants and animals and carried out through selective breeding. Today, many plants, animals, and microorganisms have been genetically engineered, and genetic information from one species can even be introduced into a different species. New and beneficial properties can be introduced in a directed and predetermined way, starting with test-tube manipulations of DNA. For example, DNA derived from a human being has been introduced into E. coli to create a modified bacterium from which human insulin can be derived. Some bacteria in nature produce a protein that is toxic to insects. When information that enables the bacteria to make this protein is introduced into a plant, the plant can generate this compound and become disease resistant. The creation of transgenics (i.e., plants or animals that carry genes from a different species and incorporate them into their own genetic information) is a major achievement of biotechnology. The rapid development of laboratory tools and reagents has resulted in an expanding base of knowledge about the molecular basis of biology. Future commercial applications may include the following: detection of pollutants in the environment diagnosis and treatment of diseases development of new materials to replace materials

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Page 12 BOX 2-1 The Polymerase Chain Reaction The polymerase chain reaction (PCR) is an enzyme-mediated, in vitro amplification of DNA for purposes of analysis. Since about 1985, this method has significantly increased the ease and speed of isolating DNA sequences in vitro. Developed by scientists of Cetus Corporation in 1984 and 1985, PCR is an enzyme-catalyzed reaction that facilitates gene isolation and eliminates the need for the complex process of cloning, which requires the in vivo replication of a target DNA sequence integrated into a cloning vector in a host organism. PCR is initiated by DNA denaturation, followed by primer annealing; a DNA polymerase and deoxynucleoside triphosphates are then added to form a new DNA strand across the target sequence. When this cycle is repeated n times, it produces 2n times as much target sequence as was initially present. Thus 20 cycles of the PCR yields a one million-fold increase or amplification of the DNA. Applications of PCR include comparisons of altered, uncloned genes to cloned genes, diagnoses of genetic diseases, and retrospective analyses of human tissue. Source: Arnheim and Levenson, 1990. derived from petrochemical sources or to mimic biological processes creation of new processes and products for improving foods, fibers, and agricultural processes The technologies necessary to implement these methods and products are changing monthly. The time line of significant events in biotechnology in Figure 2-1 is a graphical illustration of the accelerating rate of change. The biotechnology industry, which once consisted of a handful of agricultural and pharmaceutical manufacturing giants, now includes more that 2,000 new businesses and is exploiting products of increasingly sophisticated genetic research. Since the 1970s, when the first commercial company was founded to develop genetically engineered products, the biotechnology industry has grown rapidly in market capitalization and has significantly influenced the quality of the environment and the quality of life. In 1985, approximately 1,500 biotechnology patents were granted; by 1998 the number had increased to more than 9,000. Between 1994 and 1999, market capitalization more than doubled, from $45 billion to almost $97 billion, which is more than the estimated $75 billion market capitalization for the entire defense industry. The summary statistics in Table 2-1 illustrate this astounding growth. The demand for new drugs is a major incentive for the explosive growth in the biotechnology industry. Several hundred drugs and vaccines are currently in human clinical trials, and hundreds more are in the early development stage. Drug research will be used not only for medical therapeutics, but also to improve sensing and diagnostic capabilities for air and water safety, increase crop yields and improve food quality, provide new techniques for bioremediation of pollutants, enable DNA fingerprinting and forensic analyses, and for many other applications. These civilian applications overlap with Army needs. Advances in medical therapeutics have obvious applications in mitigating battlefield trauma, healing wounds, and developing vaccines. Sensing and diagnostic capabilities are important not only for detecting the presence of chemical and biological warfare agents, but also for collecting battlefield intelligence on other activities that could affect changes in the environment. Biological sensing and analysis capabilities may also extend to monitoring the health, safety, and performance of soldiers in the field. In general, new knowledge of biology will translate into new devices and new ways of analyzing and solving problems. Biotechnology is rapidly changing and growing. In 1975, visionaries would not have predicted that a draft of the human genome sequence would be completed by 2000. The developments described in this report may well occur much sooner than predicted. By the same token, midterm and long-term developments may never occur at all. Nevertheless, one trend is clear: Biology will be as important to consumer economics (and the Army) in the next century as physics and chemistry were in the last century. BOX 2-2 The Hantavirus: A Detective Story The polymerase chain reaction (PCR) and polymerase from the thermophilic bacterium Thermus aquaticus (Taq) have had immediate, beneficial impacts on tracking disease processes by characterizing genetic fingerprints of pathogenic organisms. Hantavirus, which was first isolated from striped field mice near the Hantaan River in South Korea in 1976, is associated with hemorrhagic fevers and renal disease. When a mysterious illness with these symptoms appeared in New Mexico in 1993, the Centers for Disease Control and Prevention (CDC) quickly began to search for the cause. Within 30 days of the first death, viral genes from the victim’s tissues had been propagated in large enough amounts so that the DNA could be studied, identified, and sequenced using PCR (Gomes, 1997). The CDC found the virus to be a previously unknown strain of Hantavirus that destroys the lungs instead of the kidneys (Nichol et al., 1993).

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Page 13 ~ enlarge ~ FIGURE 2-1 Timeline of significant events in biotechnology. More than half of the significant events in the past century occurred in the last 20 years. Source: BIO, 2000a

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Page 14 TABLE 2-1 Biotechnology Industry Statistics, 1993–1999 (in $ billions) Year 1993 1994 1995 1996 1997 1998 1999 Sales 5.9 7.0 7.7 9.3 10.8 13.0 13.4 Revenues 8.1 10.0 11.2 12.7 14.6 17.4 18.6 R&D 4.9 5.7 7.0 7.7 7.9 9.0 9.9 Market capitalization N/A 45 41 52 83 93 97 Number of companies 1,231 1,272 1,311 1,308 1,287 1,274 1,283 Number of public companies 225 235 265 260 294 317 327 Number of employees 79,000 97,000 103,000 108,000 118,000 141,000 153,000 Source: BIO, 2000b. SCOPE OF BIOTECHNOLOGY Biotechnology covers all aspects of living organisms, from medicine to agriculture. In the broadest sense, biotechnology is a tool that addresses life itself. Biological principles, through bioprocess engineering, can be used to control the functions of cells or the molecular components of cells, including their genetic material. Through bioprocess engineering, the activities of plants, animals, insects, and microorganisms can be directed to produce bioactive compounds (e.g., compounds that elicit biological activity), therapeutic molecules (e.g., recombinant proteins for treating heart disease and cancer), and other useful materials. The knowledge derived from the study of the genetic characteristics, molecular biology, metabolism, and biology of organisms promises to facilitate the design of devices, software, and genetically altered organisms capable of detecting and diagnosing the effects of pathogens and genetic conditions on human activity. Biotechnology includes the manufacture of products ranging from food-grade sweeteners to fuel alcohol, as well as the use of chemicals to modify the behavior of biological systems, the genetic modification of organisms to produce new traits, and the treatment of genetically based diseases by the manipulation of DNA. Bioprocess engineering translates biotechnologies into unit operations, biochemical processes, equipment, and facilities for manufacturing bioproducts (Ladisch, in press). Translating the discoveries of biology into tangible commercial products, thereby putting biology to work, requires engineering. Bioprocess engineering is expected to lead to many advances in the future: identification of genes, and the protein products that result from them, to prevent or remediate diseases and develop new medicines understanding of what proteins do and how they interact to reveal how structure determines function production of microorganisms, cells, or animals with new or enhanced capabilities to generate bioproducts, such as new proteins and plants with special characteristics development of biological sensors that can be coupled with computers to control bioprocesses and monitor biological systems (including humans) Central Role of Biology Assessing the possibilities and probabilities of changing outcomes through biological means or biologically inspired methods requires a comprehensive understanding of biological principles and processes, especially evolution: All organisms, and all cells that constitute them, are believed to have descended from a common ancestor cell by evolution. Evolution involves two essential processes: (1) the occurrence of random variation in the genetic information passed from one individual to its descendants and (2) selection in favor of genetic information that helps its possessors to survive and propagate. Evolution is the central principle of biology, helping us make sense of the bewildering variety in the living world (Alberts et al., 1989). Watson et al. (1992) explained the importance of DNA: There is no substance as important as DNA. Because it carries the hereditary information that determines the structures of proteins, it is the primary molecule of life. The instructions that direct cells to grow and divide are encoded by it; so are the messages that bring about the differentiation of fertilized eggs into the multitude of specialized cells that are necessary for the successful functioning of higher plants and animals.. . . [Cells themselves are] tiny expendable factories that simultaneously synthesize several thousand different molecules. Biomimetics In a briefing before the committee, the Army program manager responsible for soldier systems (e.g., clothing, electronics, and sensors) expressed the Army’s concern over the heavy 92.6-pound load that soldiers must carry into combat (Jette, 2000). Examples from nature suggest that soldier load-carrying capacity and efficiency can be increased. An ant, for example, can bear tremendous loads relative to its weight for relatively long periods of time. In fact, an ant can lift 50 times its weight and pull 30 times its own weight. If this phenomenon were understood, perhaps mimicking the

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Page 15 ant might lead to solutions that would help soldiers carry even heavier loads. Biological systems might also serve as models for improving materials for uniforms, particularly by reducing their weight and increasing their functionality. A soldier’s clothing must protect against extremes of weather, chemical and biological agents, heat and humidity, and other factors. Many animals cope with similar drastic changes in their environments. For example, an ordinary horse can withstand winter cold and desert heat protected only by hair and its leathery skin. Passive heat transfer alone cannot account for the resistance and isolation necessary to cope with these extreme temperature differentials. Understanding how horses and other animals overcome drastic changes in their environment would be extremely useful. As a measure of the importance of biomimesis, the Army has declared biomimetics one of its Strategic Research Objectives (primary focus areas for basic research). The Defense Advanced Research Projects Agency (DARPA) has investigated the behavior of insects and other animals in research for the Department of Defense (DOD) (Rudolph, 2000). The principles of design, biosynthesis, and structure-property correlations in “living” materials and systems will be very important in determining new military applications of biotechnology. Thinking in terms of biological systems may not only provide solutions to specific problems, but may also provide clues to future opportunities. Genomics and Proteomics Classical approaches to the study of biology have involved biochemistry (the study of proteins in isolation) and genetics (the study of individual genes in isolation). But the examination of an entire genome and its products, a relatively new subdiscipline known as genomics (the study of the genetic material of life), may unlock the secrets of the communication, structure, organization, and interaction of cells and molecules and how they create function. The long-term implications of genomics will present the Army with opportunities and challenges even in the next decade. Genomics will provide tools for identifying the underlying basis of complex traits, shedding new light on human behavior and performance. It will also help scientists uncover the genetic bases of diseases, such as early-onset Alzheimer’s and Huntington’s chorea. The term proteome is often attributed to Marc Wilkens, an Australian researcher who proposed the study of all proteins in a genome about five years ago. The subdiscipline of proteomics now encompasses a range of technologies related to the characterization of protein expression, post-translational modifications, and interactions in complex biologic samples (Blackstock and Weir, 1999). Proteomics complements genomics by bridging the gap between genetic message and protein-expression levels (Anderson and Seilhamer, 1997). As discussed later in Chapter 7, genomics and proteomics have already been instrumental in the development of tools for DNA research, as well as for identifying new materials and applications for biotechnology. However, new applications and capabilities for the Army will require a methodical, systems approach that incorporates a range of scientific and engineering disciplines. Genomics will provide many, but not all, of the answers. The committee believes that no single entity or institution can change the influence of biology or the trends in biotechnology. The Army can, however, promote development of new products and processes that will be consistent with or specific to its missions and needs. This will require that the Army be fully aware of the synergistic effects of biological tools on the new developments in biotechnology.