Breakthrough Dividend:
Chapter 2 - What Is Biotechnology?

"When I use a word," Humpty Dumpty said,
in a rather scornful tone,
"it means just what I choose it to mean --
neither more nor less!"

"The question is," said Alice,
"whether you can make words
mean so many different things."

Through the Looking Glass, Lewis Caroll

Making Semantics Pay

Perhaps an argument over definitions seems a strange way to begin a serious report on biotechnology. Usually such arguments are pedantic exercises but, in the case of biotechnology, it is central to any reasonable investigation. Does Israel have 80, 71, 64 biotechnology companies, (all official figures), or only about 50 (this report's working estimate)? Does she export over $180 million of biotech products or less than $90 million? It depends. Is growth rapid or slow? Should we be excited or concerned? Conclusions can vary widely with your definition of what to put in the box with a "biotechnology" label.

Since biotechnology is a recent "buzz-word," and a key to greater attention and research grants (if not always business investment), everyone is anxious to relabel their existing R&D and climb aboard. Similarly, national officials are naturally concerned that nothing with a plausible claim to such prestigious modernity be thoughtlessly excluded. This has often led to exceptionally wide definitions (see Table 1). Thus, a list of biotechnology companies in the Israel National Committee for Biotechnology's (NCB's) Case for Israel Biotechnology includes "hatcheries of ornamental fish," a company making "radioisotopes for research" and a cosmetics company using Dead Sea salts and herbal extracts as biotechnology firms, along with companies doing R&D in "cell and gene therapy for AIDS, cancer and bone marrow transplantation." The NCB's excellent, deliberately comprehensive, Directory of Israeli Biotechnologists implicitly uses a more narrow definition, but still includes animal behavior, herbal medicine and new marine species.

The broadest, if least meaningful definition, "the use of living organisms to meet human needs," would include such age-old "biotechnologies" as beer brewing, yeast-bread baking, cattle ranching and sausage-making (not to mention prostitution and slavery!). Recognizing the impossibility of such breadth, broad-definition enthusiasts usually qualify their definitions with such words as "recent," "new" or "modern" biotechnology, which just further muddies the water. An exception is the NCB's definition (Table 1), which deliberately includes "traditional uses of organisms." Nevertheless, NCB's lists of biotech companies are more restrictive.

Examining the other extreme, the narrowest definitions -- largely confined to recombinant DNA, RNA and monoclonal antibody technologies -- exclude many important areas (cytokines, plant tissue culture, in vitro fertilization) that the average scientist, reader and investor would expect to be included. The U.S. Congress' Office of Technology Assessment (OTA) made a considerable contribution by producing both a well-worded, broad definition of "biotechnology" and a narrow definition of "new biotechnology" (Table 1), although the latter does not seem to explicitly include monoclonal antibody technology. In any case, we cannot, in one report, proceed in two different directions at once. Without taking sides, we need to both heed Alice's caution and to emulate Humpty Dumpty's initiative in deciding what to "choose" biotechnology to mean.

A Pragmatic Choice

In this report, biotechnology, without further qualification, refers to the applications of those recent breakthroughs in molecular biology and immunochemistry that began 25 years ago, and have begun yielding a rapidly increasing number of actual or potential marketable products over the last decade. Specifically, the study includes (representative examples in parentheses):

• DNA/RNA technologies (sequencing, cloning, RFLP, PCR, DNA probes);

• Gene transfer technologies (shuttle vectors, promotion/expression, transgenic organisms);

• Monoclonal antibody techniques (monoclonal vaccines, ELISA diagnostic tests);

• Other immunochemicals (interferons, interleukins, other cytokines);their applications, associated technologies (e.g., plant and animal cell and tissue culture), extensions and synergystic combinations.

We will particularly concentrate on applications involving:

• Human health and medicine and

• Plant and animal genetic improvement and health.

In deference to public opinion, recent developments involving hormones, neurochemicals, protein and enzyme engineering, and biological pest control are considered "closely related technologies." Biomedical engineering, radiation and nuclear medicine, biomass conversion, and herbal extracts, however, are excluded from this report.

Mariculture and aquaculture deserve special mention. Though raising fish and algae is no more "biotechnological" than raising chickens or dairy cows, several recent U.S. and Israeli biotechnological initiatives give aquaculture and marine resources particular emphasis. This partly follows from the relative neglect (until recently) of these species, ignorance of their biology and genetics, inexperience in breeding and improving their production in captivity, and their great underexploited economic potential. A few "biotechnological" aspects of aquaculture are included as part of a more general discussion of animal biotechnology.

Table 1. What Is Biotechnology?

BROAD

Any technique using organisms and their components to make products, modify plants and animals to carry desired traits, or develop micro-organisms for specific uses.

U.S. Office of Technology Assessment (1984-I)

The manipulation and management of biological processes and principles to create various product-bearing technologies.

Cyrus McKell, Biotechnology and Development (U.N. 1992)

BROADER

Any technique that uses living organisms (or parts of organisms) to make or modify products and provide services to improve plants or animals, to cure diseases or improve health, or develop micro-organisms for specific uses. This definition [explicitly] encompasses new biological tools as well as traditional uses of selecting organisms for improving agriculture, animal husbandry, environment, health or brewing.

Israel National Committee for Biotechnology (1994)

BROADEST

The use of living organisms for human needs.

Common (if thoughtless) parlance

NARROWER

The [direct] manipulation of nature for the benefit of mankind at the subcellular and molecular levels.

Biotechnology at the Hebrew University (1992)

NARROWEST

"New" biotechnology is the industrial use of recombinant DNA, cell diffusion and novel bioprocessing techniques.

U.S. Office of Technology Assessment (1984-II)

How Many Biotechnology Companies in Israel?

Taking a recent National Committee for Biotechnology (NCB) list of 71 companies, and setting aside 23 specializing in food additives/vitamins, herbal medicines, chemicals, electro-optics, radioisotopes, drug delivery formulations, ornamental fish farming, sea cages/fish culture and cosmetics, leaves 48 companies actively using biotechnology for:

Israeli seed companies are also included. Incorporating total (mostly conventional) hybrid seed sales in some computations of Israeli biotechnology sales leads to inconsistencies with similar U.S. sales figures, which are more restrictive, and in comparisons of Israeli and American health/agricultural applications ratios.

Biotechnology is still an extremely fluid field, and new startups are being formed, merged and disbanded at varying rates every year, though the trend is definitely upward. Still, it is fair to say that Israel has approximately 50 biotechnology companies by our definition (a more comprehensive listing, using the NCB's very broad definition, is found at the end of Chapter 10), about the same as the State of North Carolina. This report will focus on the impressive research infrastructure and product development of these 50-odd companies.

Slicing the Pie

A related issue involves dividing up the various sub-areas of biotechnology and assigning projects, for easier retrieval and analysis, to each. The NCB's directory uses a comprehensive system based on 51 major categories and 251 sub-categories. Despite the system's strengths, a much simpler system will suffice for our purposes.

First, we divide projects by whether they directly benefit: humans (H), plants (P) or animals (A). Then we further divide projects by whether they involve: genetic manipulation (G), diagnostics (D), therapeutics/vaccines (T), or other applications (O) such as pest control or bioremediation. Combining both systems yields the simple 12-category classification scheme in Table 2. The first row corresponds to human health; the second two rows, to agriculture. Adding a few more divisions and subdivisions to cover special cases, leads to the reasonably complete 30-element classification scheme in Table 3. This system was used in organizing this report, especially Chapters 11-19.

Table 2. Biotechnology: Simplified Conceptualization

Table 3. Biotechnology: A Pragmatic Classification

H. HUMAN HEALTH

H.1 Genetic Manipulation (Gene Therapy)

H.2 Diagnostics

(a) Antibody-based

(b) DNA/RNA-based

H.3 Therapeutics and Vaccines

(a) Pharmaceuticals

(b) Vaccines

(c) Other

H.4 Immunoactive Agents (IL, IFN, etc.) and Immunotherapy

H.5 Hormones and Enzymes

H.6 Other

P. PLANTS

P.1 Genetic Manipulation

(a) Guided Classical Breeding

(b) Transgenic Plants (Genetic Eng.)

P.2 Diagnostics

P.3 Therapeutics and Vaccines

P.4 Propagation/Plant Tissue Culture

P.5 Biological Pest Control

A. ANIMALS

A.1 Genetic Manipulation

(a) Guided Classical Breeding

(b) Transgenic Animals (Genetic Eng.)

A.2 Diagnostics

A.3 Therapeutics and Vaccines

A.4 Propagation/AI and Embryo Transfer

A.5 Biological Pest Control

O. OTHER

O.1 Microbes and Fungi

O.2 Environmental Monitoring

O.3 Research and Development Methodology

O.4 Scaleup and Production Methodology