Animals are the major money producers in the U.S. agricultural system. Over 30 of the 50 United States (including North Carolina) list animals and animal products as their top agricultural income producer, and some $60 billion of cattle and dairy products are produced each year. Broiler chickens and eggs add another $12.3 billion to the total (North Carolina alone accounts for $1.6 billion). In such circumstances, a 5-10 percent increase in feed efficiency, fertility or product quality can mean hundreds of millions of dollars of increased profits. Although Israel's much smaller cattle and chicken production totals less than $1 billion annually, it accounts for 40 percent of the total value of Israeli agricultural production. Short on land, Israel's intensive high-tech approach to animal production has boosted efficiency to meet growing consumer demands.
Breeding leaner chickens is an important goal for an American public concerned about lowering its fat intake. It is difficult, however, to assess fat content without slaughtering the chicken, which makes further breeding impossible. Traditional breeding schemes must, therefore, assess breeding potential from the analysis of slaughtered relatives, an inefficient procedure. YISSUM is now offering a DNA-fingerprint method (DFP) to permit the selection of day-old chicks as high-potential lean-meat breeders and broilers based on their DNA profile. This new nondestructive assay is based on a DNA electrophoresis band (S6.6) researchers discovered linked to the abdominal fat content (AFP) of broilers.
The band S6.6 was missing in an experimental group of high-AFP chicks and increasingly intense in groups of chicks with lower AFP levels. Regression analyses showed the presence of the band (compared to its absence) was correlated with an AFP reduction of about 4 grams of fat per 1,000 grams/body weight, about 1/3 of the total average abdominal fat. The DNA in band S6.6 is now being isolated and cloned for use as a locus-specific probe. Already, however, by selecting for band S6.6, abdominal fat can be reduced in broilers without the need to measure it or to correct for sex, age, growth conditions and other factors. Such birds should produce marketable meat more efficiently from feed, as well as being healthier for consumption. North Carolina is America's second largest producer of poultry and poultry products, producing some $1.6 billion worth each year. In fact, it accounts for over 10 percent of the entire U.S. output.
Although transgenic cows are still a thing of the future, artificial insemination, embryo transfer and computer-guided breeding are widely used to extend the usefulness and efficiency of classical (sexual) breeding. Traditionally, American farmers have bred dairy cattle to produce more milk. Now, given the large milk surpluses in the United States, many industry leaders are modifying their breeding goals to include other important traits: butterfat and protein concentration, disease resistance, fertility, calving ease, calf mortality and growth rate. Researchers at Israel's Volcani Center, and their U.S. colleagues, have been using voluminous national dairy cattle records, insemination reports and sophisticated computing methods to evaluate the genetic component of (and the genetic relationship among) different traits. They have shown that breeding for disease resistance is possible (especially against mastitis), and that previous U.S. selection for milk production may have inadvertently reduced cow fertility. The team's results have reached dairy farmers through over 100 published papers. Besides boosting the profitability of local dairy industries, they have also boosted the reputation and demand for U.S. and Israeli dairy cattle, semen and embryos abroad. North Carolina has a $215 million a year dairy industry.
Although the Israel ARO, Kimron Veterinary Institute, and Israeli agribusiness consistently develop prize-winning new breeds using advanced genetics and reproduction-related techniques, no R&D-oriented companies are developing new commercializable biotechnology (by our definition) products or transgenic species. The same seems true, despite a variety of advanced experimental hatcheries and fish farms, in aquaculture/mariculture.
The sole exception is Serumtech's attempt to produce a transgenic goat that will secrete useful, recoverable human proteins in its milk. The basic research was done at the Israel ARO by a team that already has filed the world's first patent application for this technology, which is also being pursued in the U.S. (Genzyme) and elsewhere. Rorer Pharmaceuticals, now Rhone-Poulenc-Rorer (whose Rhone-Poulenc Agriculture has a laboratory in North Carolina's Research Triangle Park), provided $1 million of initial R&D capital. Serumtech was founded in 1994 with another $1 million from Teuza Venture Capital and Israel's Ministry of Industry and Trade.
Despite the existence of both live and inactivated poultry vaccines, Newcastle disease outbreaks still occur, often causing many millions of dollars of poultry losses. The current vaccination of day-old chicks provides only a brief period (about three weeks) of protection. Subsequent vaccination means extra expenses and, often, deleterious side-effects. Combined live/aerosol and inactivated/injected immunizations routinely require several repeated doses, and can be costly. Israel has been a leader in developing Newcastle disease (ND) vaccines. For example, Hebrew University scientists were the first to develop a successful inactivated oil-adjuvant ND vaccine. They have now devised a new live vaccine that establishes long-term immunity in the respiratory tract, through which the ND enters. One dose provides lifelong local immunity for broiler chicks (layers require additional doses). Patents for the new vaccine have already been filed and granted in the United States. This advance could also be significant for North Carolina's large poultry industry.
A particularly innovative Israeli approach to a new vaccine involves ticks, a major human and livestock pest. During their blood meals, ticks can transmit such diseases as babesiosis, encephalitis, Rocky Mountain spotted fever and Lyme disease (the most important vector-borne disease in the U.S.). Tick-related cattle losses amount to billions of dollars a year worldwide. Ticks rapidly develop resistance to chemical acaricides, and a new, environmentally-sound approach is needed. A team of U.S.-Israel Cooperative Development Research Program (CDR, Chapter 9) grantees at the Hebrew University, and their colleagues at the International Centre of Insect Physiology and Ecology (ICIPE) in Kenya, have developed a highly novel defensive vaccine. Lengthy tick blood meals -- they can last hours or even days -- are maintained by special receptors near the tick's mouth. These bind corresponding chemicals in the victim's blood and signal "keep feeding!" The CDR grantees have developed a vaccine that stimulates the host to produce antibodies that block these receptors, short-circuiting the feedback required to sustain feeding.
Encouraged by their success with ticks, CDR grantees are now developing a vaccine against lice. Millions of Americans and Israelis, especially children, are afflicted with these pests. U.S. livestock production losses due to lice exceed $100 million a year. Other CDR researchers have helped Peruvian scientists develop a vaccine that protects goats from caprine arthritis-encephalitis virus.
Fish and other aquatic products represent an important, underutilized resource for a protein-hungry world. Natural catches are dropping even as demand continues to increase, making aquaculture increasingly attractive. In Israel, pond-raised tilapia and trout are the main species. Intensive, crowded pond aquaculture is highly vulnerable to the spread of disease and, in 1985, disaster struck in the form a previously unknown disease that wiped out about one-third of the fish population, reaching 50-60 percent in some ponds. Losses in 1989 reached $3 million, which is considerable considering Israel's small size.
By examining bacteria taken from the brains of diseased tilapia, the Israeli investigators discovered Israeli fish were infected with two distinct species of Streptococcus, which have since been named S. shiloi and S. difficile. These caused the fish-equivalent of bacterial meningitis, a human disease that can be caused by such bacteria as Streptococcus pneumoniae. An injected dose of 10-100 million cfu (colony-forming units) of either fish bacterium sufficed to kill half of the fish in the investigators' experiments (i.e., their LD50 was 107-108 cfu). By extracting bacteria from the brains of the fish that contracted meningitis, and reinjecting them into new fish, and doing this twice more, the investigators isolated strains of both bacteria that were thousands of times more virulent (LD50 was 102-103 cfu). A whole-cell S. difficile vaccine was then made by killing the bacteria with formalin. This was injected twice (3 weeks apart) and followed by an ordinarily lethal dose of bacteria (100-500 times LD50) three weeks later. An acellular vaccine was made by sonicating the bacteria and binding the soluble bacterial proteins to aluminum hydroxide to make an "alum" vaccine.
Vaccination with whole cells dramatically reduced the death of tilapia, compared to controls. Vaccinated fish displayed high levels of anti-streptococcal antibodies, the control fish almost none. The acellular vaccine provided almost complete protection. A large field trial is now underway involving 150,000 vaccinated fish in a naturally-infected pond. After three months, mortality among the vaccinated fish is 7 percent, compared to 45 percent among the unvaccinated fish. North Carolina is America's second largest producer of trout, producing over four million pounds a year.
Israel has two major companies that produce veterinary vaccines (Appendix C). ABIC, a domestic subsidiary of Teva Pharmaceuticals, was founded in 1939. Although it produces human and animal drugs as well, ABIC is well-known for its veterinary vaccines. Recent products include a live attenuated fowl cholera vaccine and a live turkey hemorrhaging enteritis vaccine. North Carolina leads America in turkey production, raising 62 million head ($475 million worth) a year. In fact, it accounts for over 21 percent of all U.S. production. ABIC's annual sales exceed $60 million. A comparative newcomer, Shafit Biological Laboratories, established in 1990, generates sales of $1.5 million in veterinary sales.
North Carolina's Centeral Biologics (Raleigh) produces a variety of poultry therapeutics and live and killed poultry vaccines. Embrex (RTP) also specializes in poultry vaccines (and growth-enhancing agents). One product already on the market is an in-ovo vaccine for Marek's disease. Developing a diagnostic test for Marek's disease was one poultry-related success of the BARD program (see below).
Israeli investigators at the Kimron Veterinary Institute, and their U.S. collaborators, have developed a highly-sensitive ELISA test for Rift Valley Fever (RFV), a debilitating, mosquito-borne virus that infects cattle, sheep and humans in many developing countries. The new diagnostic, a great improvement over conventional methods, successfully detected the virus in cattle and sheep blood samples from Greece and Mali, and in human blood samples from Egypt, Sudan, Senegal, Zambia and Greece. ELISA tests were also developed for Sicilian, Naples, Gordil, Salehabad, Saint-Floris, Karimabad and Gabek Forest phleboviruses, which cause related animal and human disease.
Other Israeli investigators, and their USDA colleagues, have developed a new diagnostic test to detect Mareks Disease Virus (MDV) in the feather tips of chickens. The investigators used their test to monitor a serious outbreak of MDV in Israeli flocks, isolated and molecularly characterized virulent MDV isolates, and evaluated the efficacy of new commercial vaccines. This research helped curb the epidemic and had a significant economic impact on the affected poultry farmers. Still other researchers at Washington State University and the Kimron Institute have developed highly sensitive ELISA diagnostics to detect anaplasmosis, tick-borne cattle disease.
Israel has two companies specializing in veterinary diagnostics. HY-Labs, founded in 1973, markets human (entereo-pathogenic bacteria), cattle (bovine mastitis) and poultry serum diagnostics. However, HY-Labs' Scientific Director, Dr. Ruth Cohen, says the company's main interests include marketing culture media and supplies locally and tests for the bacterial contamination of foods (salmonella, shigella, etc.) The latter are used mostly in statistical surveys of food quality. Almost all the company's R&D on new tests is done through Technology Incubators supported by the Ministry of Industry and Trade (Chapter 7). HY-Labs is now working on an ELISA-like test to detect antibiotic residues in milk, and on an all-organic livestock feed that promotes weight gain without steroids. HY-Labs would be very interested in locating an American strategic partner. Its only current U.S. relationship (with Upjohn) is an indirect one, through the Wisconsin-based distributor for their mastitis test.
Founded in 1987, Biogal is a kibbutz industry, which produces "ImmunoComb" (see Orgenics, Chapter 12) test kits for veterinary diagnostics. Its kits are sold in Israel and 16 foreign countries. A third company, Biodetectors, produces test kits for milk, beef and goose liver products, although not for the animals themselves.
North Carolina's EDITEK, Inc. (Burlington) has developed veterinary diagnostic tests for canine heartworm and feline leukemia, although most of its $3 million sales come from human diagnostics for drugs of abuse.
This area continues to excite particular interest in many U.S.-Israel fora. Since we know little about how to raise, protect and reproduce most species (except carp, tilapia and a few others), biotechnology techniques could help:
Clarify the biology and life cycle of new species;
Promote fertility, growth, meatiness and egg-laying through hormonal treatment;
Diagnose fish diseases (common in overcrowded ponds) and prevent them with vaccines; and
Promote the scientific raising of rotifers and other fingerling food.
One important commercial goal could be the economical production of disease-free embryos and fingerlings of salmon, trout, bass, bream and other valuable species, safe and uniform enough for export. There are several joint U.S.-Israeli studies in this area, such as the recent initiative between the U.S. Center for Marine Biotechnology (Maryland) and the Israel Oceanographic and Limnological Research (IOLR) laboratory in Eilat.