Biotechnology

It has now been more than fifteen years since Robert Swanson, a young man who understood both finance and science, invited Herbert Boyer, a shy molecular biologist at the University of California, San Francisco, out for a beer. Swanson described his vision to Boyer: that the techniques and ideas that Boyer had devised for manipulating DNA could be translated into products at a private company yet to be established. As a result of that meeting, Genentech, the first well-known biotechnology corporation, was founded; Swanson and Boyer made their fortunes; and profound changes ensued in academic biomedical research.

–Robert Bazell. From The New Republic (April 1991).

As we move through the next millennium, biotechnology will be as important as the computer.

–John Naisbitt and Patricia Aburdene, Megatrends 2000.

Biotechnology is the term used to denote the use of genetic selection and/or engineering to produce commercially useful and/or scientifically interesting products by living cells. The US Congress Office of Technology Assessment (1991) proposed two definitions in 1984, one broad and one narrow. The broad definition states that biotechnology is “any technique that uses living organisms (or parts of organisms) to make or modify products, to improve plants or animals, or to develop microorganisms for specific uses.” The more narrow definition refers to “the industrial use of rDNA, cell fusion, and novel bioprocessing techniques.” A reference to synthetic peptides is also included in some definitions.

Table 12.1 Selected products of biotechnology

Product	Produced in/by (among other sources)
Vaccines (e.g., polio, rabies, or measles). Many vaccines are antigens.	Animal cells
Antibodies (e.g., immunoglobulins or antitetanus serum)	Animals
Lymphokines (e.g., interferons or interleukins)	White blood cells
Blood products (e.g., factor VIII or factor IX)	Human blood and endothelial tissues
Monoclonal antibodies	Lymphocytes, myelomas, and hybridoma cell lines
Enzymes	Fermentation
Antibiotics (e.g., penicillin)	Fermentation
Synthetic peptides (e.g., enkephalins)	Synthetic chemistry

In practice, biotechnology is an evolving set of novel molecular biological techniques applied to both basic research and to developing products. Through the techniques of biotechnology, it is possible to produce large quantities of specific products (usually proteins) that are almost totally pure, that do not deplete natural sources, and that are not limited to those molecular entities that already occur naturally. Their ultimate purity depends on the bioseparation methods used subsequent to their synthesis. While some methods of biotechnology have been known for millennia (e.g., fermentation to make beer and wine), the start of the modern biotechnology industry can be dated to the discovery of restriction enzymes that allowed the specific manipulation of pieces of DNA, as well as other genetic engineering methods and hybridoma production (which entails cell line fusion and cloning) in 1973 (Weatherall 1991), although some use the time decades earlier when the structure of DNA was identified (1953). During the 35 years since 1973, approximately 2,000 companies have been founded worldwide (approximately half in the United States) to utilize biotechnology techniques and methods to make a variety of products ranging from drugs to those with agricultural and industrial applications. Some of the types of products made are shown in Table 12.1.

Table 12.2 Three general categories of biotechnology-derived biologics^a

Type	Mechanism of action	Molecular size	Diseases where active	Examples
Drug type I	Well known	Large, usually a protein	Generally well established	Human insulin, tPA, and human growth hormone
Drug type II	Not well known	Large, usually a protein	Must be found by trial and error	Interleukin-2 and tumor necrosis factor
Drug type III	Variable	Relatively small size	Variable	Penicillins and most antibiotics
^a This table includes pharmaceuticals made using biotechnology methods in at least one step of the synthesis. tPA, tissue plasminogen activator.

In the early 1980s, many biotechnology companies in the pharmaceutical area appeared unaware of regulatory requirements for developing new drugs and believed that the Food and Drug Administration (FDA), for example, would “just have to approve our new drug within a few months, after they see how important our data are.” This naiveté evaporated during the 1980s following some notable product rejections and delays by the FDA. Most biotechnology companies in operation today have obtained or are seeking investment capital to sustain the many years of development needed to obtain sufficient high quality data to meet modern regulatory requirements, and, further, to capitalize the very significant investments that must be made to enable manufacturing scale production of these complex and often fragile products.

Biotechnology and genetic engineering techniques are generally applied to developing natural or modified human proteins as drugs (e.g., interferons, tissue plasminogen activator, growth hormone, erythropoietin). This has stimulated a search for potential drugs among the many natural human proteins that some estimate to be about 50,000. Many proteins are currently being investigated in a wide variety of diseases (e.g., colony-stimulating factors, superoxide dismutase, interleukins, tumor necrosis factor, and epidermal growth factor). There are also many proteins “looking for a disease” and vice versa. The types of drugs created by biotechnology may be classified into three groups (Table 12.2). It is possible, however, that the most important future discoveries will be in non-naturally occurring products which could be considered as “improvements on nature.” These products would be designed to have specific functions. One example is Humalog versus Humulin, where the stability of the complex was carefully
engineered to give a shorter half-life. Another example is the moncoclonal antibodies where binding affinities and associated constant region functions are increasingly being co-engineered.

TYPES OF BIOTECHNOLOGY COMPANIES

There is no single accepted classification of biotechnology companies, and the distinctions between biotechnology and pharmaceutical companies have become so blurred in recent years that it is often impossible to differentiate between the two. The same techniques are frequently being used in both types of companies in discovery and development, and the large pharmaceutical companies have either purchased biotechnology companies as subsidiaries and/or have multiple alliances with them. In the most common usage, the biotechnology industry is based on the new technologies described in this chapter, although many companies have a unique orientation and approach. In the particular classification shown below, any company could fit into one, two, or even more categories (i.e., the categories are not mutually exclusive and as the industry matures some of these will
have lost real meaning). The term biopharmaceutical is often used to describe companies, as the developers and producers of many biotechnology-based products are pharmaceutical companies who have the financial ability to see the development of these complex products through to licensure and marketing.

Table 12.3A Mean United States biotechnology company statistics, 2006

	All companies	Therapeutics	Diagnostics	Agriculture	Equipment, reagents, and services	Platform technology
Number of companies	1,664	760	164	91	223	137
Year founded	1990	1993	1987	1981	1985	1996
Employees	242	307	147	146	345	129
Revenues ($ millions)	360.8	416.8	88.8	466.0	608.2	60.4
R and D budget ($ millions)	46.5	57.9	13.8	10.1	54.4	58.7
R and D, research and development.

Table 12.3B Median United States biotechnology company statistics, 2006

	All companies	Therapeutics	Diagnostics	Agriculture	Equipment, reagents, and services	Platform technology
Number of companies	1,664	760	164	91	223	137
Year founded	1993	1995	1988	1987	1987	1999
Employees	33	40	35	22	36	25
Revenues ($ millions)	7.9	5.6	23.1	12.9	82.4	3.3
R and D budget ($ millions)	13.6	18.7	3.9	2.2	10.8	9.1
R and D, research and development.
Source: BioAbility, LLC (www.bioability.com) US Biotechnology Companies database, September 2006. This database is updated weekly based on public and fee-based data. Note that not all records for all companies were updated in 2006. Note also that there is a large disparity between the mean data (which includes data from some very large companies like Amgen or Centocor) and the median data which BioAbility feels more closely represents the “typical” biotechnology firm. Printed with permission of BioAbility, LLC. A brief explanation of the categories used is as follows:
• All companies—All companies in the US companies database with company type as biotechnology (i.e., not large, established corporations). The groups below are subsets this category.
• Therapeutics—Includes all biotechnology companies with primary focus of Drug Discovery, Cell/Tissue Therapy, Drug Delivery Systems, Gene Therapy, Therapeutics, or Vaccines.
• Diagnostics—Includes all biotechnology companies with primary focus of Human Diagnostics or Non-Human Diagnostics.
• Agriculture—Includes all biotechnology companies with primary focus of Animal Agriculture, Aquaculture, Bioremediation, Plant Agriculture, or Veterinary.
• Equipment, reagents, and services—Includes all biotechnology companies with primary focus of Contract R and D/Manufacturing, Cell Culture, Environmental Testing/Treatment, Equipment, Reagents, or Testing/Analytical Services.
• Platform technology—Includes all biotechnology companies with primary focus of Proteomics, Combinatorial Chemistry, Platform Technology, Nanotechnology, Genomics, or Transgenics.

Research companies. Companies without a specific product in development. These companies may focus on a niche technology, such as a delivery system, or on a broad therapeutic area.
Single-product companies. Companies that have a single product they are developing. Their product may be either in preclinical or clinical stage.
Multiple-product companies. Companies that have multiple products either in development or on the market.
Enabling (platform) technology companies. Companies with patents on a scientifically important technology that they hope can be applied to create multiple products. These research tools/approaches may play a major role in drug discovery.

A summary of the size, age, budget, and revenues of various types of biotechnology companies is given in Table 12.3. Both mean and median data are shown because of the difference in the way the industry appears based on whether the mean or median characteristics are viewed. It shows that therapeutic oriented companies are generally more research oriented, prevalent, and some are highly successful.

Maturity of Biotechnology Companies

One spectrum for viewing biotechnology companies is based on their stage of development and maturity. In that consideration, six stages may be defined. In addition, a pre-stage exists when scientists and venture capitalists are thinking about and discussing their starting a company, In some cases, it is possible for a company to be in multiple stages at the same time.

Stage I: New private company being formed or formed within the past year.
Stage II: Private company conducting discovery research but has no biologic in development.
Stage III: Private or public company that has a product in early stage development activities, but has not yet demonstrated proof of principle of their biologic in humans.
Stage IV: Mature private or public company that has one or more products in development past the go-no-go decision point in late Phase 2.
Stage V: Mature public or private company that has products in Phase 3 development nearing the market.
Stage VI: Public or private company with one or more products on the market.

METHODOLOGIES USED BY BIOTECHNOLOGY COMPANIES

Biotechnology can be viewed as a manufacturing process or as an array of research and development tools to produce certain products with biological activity. In this aspect of biotechnology, it is useful to have an overview of the basic principles employed used (Fig. 12.1). This figure illustrates that bacteria, yeast, or other cells are manipulated to enable them to produce a protein of interest in significant amounts. The production cycle should be as short as possible, usually in terms of days, as this will be a major determinant in the productivity that can ultimately be achieved. The yield of product at the time of harvest is expressed as the number of micrograms per milliliter of cell culture.

The major methodologies (i.e., genetic engineering) that are used to produce biotechnology derived products (e.g., recombinant products or monoclonal antibodies) are briefly described below.

Cells as Factories

The design and creation of specific deoxyribonucleic acid (DNA) sequences, as well as gene splicing with selected pieces of naturally-occurring DNA, are used along with established and productive cell lines to obtain a unique cell that manufactures the desired product. A portion of the genetic material (i.e., DNA) that includes a gene from one species (usually mammalian and often human) is removed from the chromosome or reverse transcribed from messenger ribonucleic acic (RNA) (complementary DNA) and spliced into the DNA of a second species. The DNA pieces are thus recombined (thus explaining the term recombinant DNA) and information in the DNA from the first species is transcribed and translated into protein using the production capability of the second. Thus, if the gene from the first species (e.g., human) coded for a specific protein that could be used as a drug (e.g., tissue plasminogen activator, insulin, or human growth hormone), then the bacteria, yeast or mammalian cell line that received this human gene is able to produce the desired human protein. As the cell with recombined DNA continues to divide and re-divide, all of its progeny contain the genetic ability to manufacture the same human protein, although the stability of the foreign-DNA insert can vary and must be meticulously monitored. In order to produce the protein needed, a company enables many cell divisions to occur from working cell banks, derived from the master cell bank, and using various scales of fermentation from a few hundred liters to many thousands as appropriate to the amounts and nature of the protein needed. After the original cell has divided into billions of cells (amplification) and production of the desired protein is induced, the protein product is harvested by separation from the cells. The product then undergoes a series of purification steps. Biologics produced in this way include alpha interferon, tissue plasminogen activator, erythropoietin, and human growth hormone. For the early biotech products the second species was usually a bacterium [e.g., Escherichia coli (E. coli)], and later yeast cell lines were develop to act as the factory to make the protein of interest. The choice of cell line is critical to the nature of the product. For example, bacterial cell lines such as E. coli cannot make glycosylated proteins (those with additional sugars attached) whereas yeasts can. The more recently developed mammalian cell lines, such as CHO (derived from Chinese hamster ovary cells), can be more difficult to culture and grow, but have further attributes critical to the post-translational aspects of the recombinant product that may be critical to its ultimate ability to function in the human body in the way needed for therapeutic effect.

A related methodology using an in vitro cultured hybridoma cell line enables one to prepare a monoclonal antibody that has a therapeutic (e.g., antirejection), preventive (e.g. vaccination), or diagnostic (e.g., assay kit) use. All copies of an antibody produced by these means are identical. Increasingly recombinant technology and hybridoma technology are converging and the ability to design very specific attributes into the ultimate antibodies is being realized.

Figure 12.1 Schematic illustration of the process of recombinant DNA engineering. In the situation where the messenger RNA is used from the cytoplasm outside the nucleus, it reassembles to form a new plasmid containing the DNA of interest. The host cell may be yeast. The recombination of the plasmid and gene is accomplished by splicing. The final step occurs as a result of amplification processes.

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