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Breakthrough Dividend: Chapter 17 - Agriculture/Plants (I)


Joint U.S.-Israel agricultural research is a major success story, dating to 1909, when Aaron Aaronsohn, the discoverer of the wild ancestor of domestic wheat, established an extensive cooperative program between the new Israeli pioneers and the U.S. Department of Agriculture (USDA). It thus pre-dates the State of Israel by over 40 years. In the 1950's and 1960's, informal research ties blossomed into hundreds of joint U.S.-Israel agricultural research projects, supported by blocked foreign currency accounts made available for that purpose under U.S. Public Law 480. This evolved into the current U.S.-Israel Binational Agricultural Research and Development Fund (BARD, Chapter 9), founded in 1977. Since then, agricultural and scientific developments in both countries have produced increasingly sophisticated and efficient agricultural systems, with considerable economic impacts.

Israel began with an agriculture-dominated economy, largely based on citrus exports. Although over half of all Israeli exports (excluding diamonds) are now high-tech products, agriculture still accounts for over $2 billion a year in sales. Although Israel's citrus exports continue to decline, exports of some higher value-added crops -- such as early-season melons and flowers for the European market -- continue to increase. Non-citrus fruits, vegetables and flower sales are now around $500 million, and Israel is second only to Holland in European flower sales. Israeli agriculturists are known for their innovative use of agricultural biotechnology, trickle-drip irrigation and industrial waste water. Agricultural technology and agricultural chemicals, especially Dead Sea fertilizers, are other major exports.

Given the agricultural emphasis of the original pioneers and the struggling young state, the Israeli Government has long been supportive of agriculture and agricultural R&D. Today, the Ministry of Agriculture's Agricultural Research Organization (ARO) has extensive programs in all fields of modern agricultural research. Its 1,200 employees work in seven major research institutes at the Volcani Center in Bet Dagan (near Tel Aviv) and in eight smaller ARO experimental stations throughout the country. Center staff maintain close contact with both academia and farmers. Although Israel's health-related biotechnology is generally regarded as competitive, her agricultural biotechnology has often been praised as unique. Unfortunately, as in most countries, private funding for commercializing agricultural biotechnology has been particularly hard to come by (Chapter 3).

Despite the lack of large industrial startups (although there are several hybrid seed companies), Israel's R&D in agricultural biotechnology continues unabated. Of the 26 new commercial opportunities in "Agrotechnology" listed in MATIMOP's most recent catalog, half are from university commercialization units, and about 10 seem Plant-Biotechnology in the sense of this report's definition. Using our simplified classification in Chapter 2, these further subdivide into:

Genetic Manipulation 5
Plant Protection 2
Propagation/Plant Tissue Culture 3

Similarly, YISSUM's most recent offering of 150 or so projects lists twelve in agricultural biotechnology, further divided into:

Genetic Manipulation 5
Plant Protection 5
Propagation/Plant Tissue Culture 2

Although they fit both classifications, plant protection strategies based on gene-transfer (transgenic plants) have been listed under Genetic Manipulation rather than Plant Protection. The remaining plant protection projects mostly involve classical biological control (predators, parasites, fungi, etc.) and are not technically biotechnology by the narrowest definitions. Finally, we note that neither list currently includes examples of plant diagnostics (e.g., ELISA tests for viruses), although this was an early area of Israeli emphasis and success.

Genetic Manipulation

Genetics is big business. For example, just a 10 percent increase in wheat yields would mean $100 million in additional profits for Kansas or Montana, each of which produces over $1 billion of wheat a year. Even North Carolina, largely a tobacco and poultry state, produces $83 million worth. Such statistics are not lost on researchers and seed companies in Israel, which lies within wheat's (and oat's and barley's) center-of-origin and center-of-genetic-diversity. Not surprisingly, Israel has exceptionally large collections of wild wheats, barleys, oats and legumes. Many contain genes that can boost protein content, disease resistance, insect resistance, salinity tolerance and other traits. Weighing in at far less than a trillionth of an ounce, genes may become Israel's most precious export.

Let's follow this up with a brief example. The simplest wheat varieties have 7 pairs of chromosomes, durum or pasta-wheats have 14 pairs and commercial hybrid bread wheats have 21 pairs. This makes classical wheat breeding -- sexual crosses between superior cultivars in which all the genes are shuffled pretty much at random -- rather uncontrollable. Israeli scientists have developed special wheat varieties that differ by only a single chromosome, or even just part of a chromosome. This allows more specific, controlled changes, even when sexually mating parent varieties.

Using such "chromosome engineering" techniques, researchers at the Weizmann Institute have successfully transferred genes that make some Israeli wild wheats produce extra high protein grain to commercial wheats. In some cases the new wheat strains also produced extra high protein grain, up to a hefty 18 percent higher than normal, but with lower overall yields. Other strains, with less spectacular protein increases, were remarkably high-yielding. Such "engineering" boosted the overall yields of some pasta wheat strains by up to 40 percent, and produced 15 percent increases in bread wheats. Several newer strains have both higher protein and higher overall yields. Israeli seed companies have already moved to exploit these particular advances, but they are just a minor indication of Israel's genetic treasures. One aspect of Israel's uniqueness is a fortunate combination of valuable genetic resources and the advanced biotechnological R&D infrastructure needed to help exploit them. American seed companies might do well to follow the mutually-beneficial example of the USDA-Aharonson cooperation.

To provide an orderly sampling of more recent advances and near-term future opportunities in Israeli plant genetic manipulation, we must first divide the field into two distinct parts:

a) The use of genetic techniques (e.g., DNA markers, chromosome engineering) to guide or improve sexual breeding programs, and

b) The direct insertion of useful foreign genes into host plants, to create transgenic plants.

The Weizmann Institute high-protein wheat, just described, provides an example of the first. Another is a recent YISSUM technique that can unambiguously genetically identify ("DNA fingerprint") commercial cultivars of roses, carnations and gerbera to protect breeders from unauthorized infringement. This is far from an idle exercise. According to the USDA, the American wholesale rose market is worth $160 million a year ($141 million hybrid tea roses, $20 million long stem roses). Isozyme analysis and pigment analysis lack the required accuracy, since few genetic loci are involved, and the observed results can be affected by growth conditions. Hebrew University researchers have developed procedures to use mini- and micro-satellite sequences to simultaneously detect a large number of tandem repeat loci in the plant genome. Their cultivar identification methods have already been shown to be highly accurate in carnations (less than 2 in a million chance of error) and have several advantages over DNA-marker techniques (RFLP, RAPD).

Turning to gene-transfers and genetic engineering, YISSUM offers a whole series of new (proven or presumed) virus-resistant transgenic plants, usually tobacco, which have been fortified by the addition of protective foreign genes from one of three distinct sources:

  • Viral genes, both those coding for protein components of the viral coat (structural genes) and nonstructural genes;

  • Plant defensive genes, for example, the antiviral gp22 and gp35 genes previously identified by Hebrew University scientists in tobacco (IVR, AVF, Chapter 18); and

  • Foreign defensive genes, such as human alpha and beta interferon, with virus-fighting properties.

All of these have been cloned, and Hebrew University investigators have already produced three genetically-stable transgenic tobacco cultivars, demonstrably resistant to viruses, namely tobacco carrying:

  • N1a, a non-structural viral gene which confers resistance to potato virus Y (PVY);

  • The first 3' three cistrons of PVY, which also confer resistance to PVY; and

  • The coat protein gene of CMV, which confers resistance to CMV virus.

A N1a-carrying tomato plant and a CMV-satellite-carrying tobacco plant are already under test. Beta-interferon-carrying plants have already been produced and show signs of being resistant to tobacco mosaic virus. Attempts to produce gp22 and gp35 transgenic plants are next in line. Several transgenic plants (and the N1a gene) have been patented. The next steps are transferring the genes to other crop plants and testing and marketing them.

As an example of this approach, consider the tomato yellow leaf curl virus (TYLCV), a single-stranded DNA virus (geminivirus) carried by the whitefly vector Bemisia tabaci, which debilitates tomato plants throughout the tropics and subtropics (it recently reached Southern Europe). ARO and HU scientists have cloned the gene coding for the protein (V1) that forms the outer coat (capsid) of the TYLCV virus. By adding appropriate control elements from the cauliflower mosaic virus, and splicing the combo into an Agrobacterium tumorfaciens vector (a DNA-transporting plasmid created from the disabled agent of the crown gall disease) the V1 gene was transferred to the genomes of tomato leaf cells growing in plant tissue culture. When these were regenerated into whole plants, the investigators found that three (of nine) transgenic tomato varieties were indeed resistant to TYLCV. Symptoms appeared one month later, and disappeared four months later. Subsequent exposures produced increasingly mild transient symptoms. Other TYLCV-related genes, such as an anti-sense C1 gene (a gene complementary to the C1 gene of TYLCV and, therefore, can bind and inactivate it), have also been transferred to tomato plants. Anti-C1 transgenic plants are also TYLCV resistant. These developments have attracted considerable scientific and commercial interest.

Another recent Israeli advance, this time involving Tel Aviv University (TAU) scientists, boosts the efficiency with which transgenic grain varieties can be produced. Plasmid vectors have been widely used to successfully introduce foreign genes into such non-grain crops as tobacco, tomato and cotton; however, it is precisely the grain crops -- wheat, rice, barley, and oats -- that feed the bulk of humankind, and many domestic animals. Unfortunately, standard vector techniques do not work very well in monocots, which include all grass-derived grains. Furthermore, most current genetic transfer techniques involve growing the recipient cells in plant tissue culture (PTC). Whole plants regenerated from these PTC cells often display considerable unwanted somaclonal genetic variation. In the TAU method, plasmid DNA is applied directly into the pollinated flowers of normal mature plants. The foreign DNA ends up in the host cell's nucleus, and are replicated as part of the cell's own library of DNA messages (genome). This efficient new method yields transformation frequencies of up to 6 percent, compared to 0.1-0.5 percent by other techniques (a 10-fold increase), without using PTC.

As a test of their methods, the TAU investigators have successfully introduced three bacterial genes into twelve commercial, high-yielding bread wheat varieties with diverse genetic backgrounds. The transformation conferred resistance to two antibiotics and the nonselective herbicide BASTA. The latter resistance gene already has considerable agricultural value. For example, transgenic wheat carrying a BASTA-resistance gene would remain intact, while nearby noxious weeds were destroyed by the herbicide. The introduced genes were stabilized after just a few generations of self-crossing, without the prolonged breeding and selecting required by other methods, and the transgenic wheat and plants preserved the maturity, stature, fertility and yield of their untransformed parents, even after several generations of self-crossing. The U.S. market for transgenic grain varieties should be major, especially since grains for human consumption are usually marketed as an indistinguishable part of a composite processed product (thus avoiding the transgenic tomato's high-visibility problems). The U.S. produces an incredible $7.71 billion of wheat a year.

Corn (maize) is another important monocot food crop benefiting from Israeli biotechnology. Some wild corn smuts harbor "offensive" virus particles whose double-stranded RNA directs the production of toxins that kill many other strains of corn smut (Ustilago) and related pests. So far, three types of toxin have been found, and the gene for one of them has already been cloned in yeasts and bacteria. More recently, this gene has been sequenced and used to create transgenic plants, which may eventually be able to produce the protective toxins themselves. Similar techniques should protect other grains. The size of the potential market can be judged from the fact that the U.S. produces $14 billion of corn (maize) annually. Corn is also North Carolina's most important feed grain; $194 million worth is produced each year.

Further back along YISSUM's R&D pipeline, Hebrew University researchers are focusing on a unique strain of Dunaliella, a single-cell green aquatic algae, which grows well over a wide range of salinities. The only difference between the algae grown in 0.1M (low molarity) and 3.0M (high molarity) salt solutions is the appearance of one extra polypeptide at high salt concentrations. Hebrew University investigators hope to clone the corresponding gene, and transfer it to non-salt-tolerant Dunaliella to see if it can improve their salt tolerance. If successful, tests in higher plants would follow. Although speculative at this stage, the potential impact seems worth the risk. Increased salinity is a major problem throughout modern irrigation-intensive agriculture.

Another recent YISSUM project at the beginning of the R&D pipeline involves the phytoene desaturase gene (pds), which controls the conversion of phytoene to beta-carotene, a yellow pigment converted to vitamin A when eaten. Transgenic plants bearing normal pds could produce fruits high in beta-carotene and with more marketable colors. Transgenic plants bearing specific pds mutants could be resistant to such "bleaching herbicides" as norflurazon and fluridone. This would not only provide a useful selectable genetic marker for research, but could also produce a variety of herbicide-resistant crops. So far, the researchers have located, cloned and sequenced the pds genes of Synechococcus PCC9742 and Synechocystis PCC6803, both cyanobacteria, Dunaliella and tomatoes. The corresponding amino acid sequences were highly conserved, even in the putative norflurazon-binding region, which bodes well for future progress.


Although Israel does not yet have companies specifically dedicated to the production of transgenic plants, it does have two established seed companies, and one smaller startup: Hazera, Zeraim Seed Growers, and A.B. Seed Co. (Appendix C). Israel, despite its small size, exports $40 million worth of seeds each year, and commands a significant share of the total world market for exported hybrid vegetable seeds.

Hazera, founded in 1939, nine years before the State, is easily Israel's largest seed company, with $35 million in annual sales. Hazera was founded by Israel's kibbutzim and moshavim to supply seeds of field and vegetable crops for local sale and planting. Now, over 80 percent of its vegetable seeds are exported, and considerable effort is expended on R&D and breeding to produce new hybrids and varieties. This includes the use of such biotechnologies as DNA-markers to guide sexual breeding programs and some research devoted to producing transgenic plants.

Zeraim ($8.8 million annual sales) was founded in 1952, A.B. Seed in 1991. Both also produce hybrid vegetable seeds. According to Ohad Zuckermann, Zeraim's Marketing Manager, Israeli companies are not producing transgenic seeds or other biotech products for market. Rather they use such biotech tools as RFLP (restriction fragment length polymorphism) and DNA repeats to identify or verify the presence of superior genetic traits, and to trace them in the course of complex conventional (sexual) breeding programs. Much of Zeraim's breeding work is done at the Hebrew University, Weizmann Institute or the ARO Volcani Center. They fund the breeding research in exchange for exclusive rights to market the new varieties, on which they also pay royalties.

Zeraim is still privately owned, somewhat a rarity, and would welcome appropriate joint ventures with U.S. firms. International interest in Israeli agricultural R&D, seeds and markets is high, according to Zuckermann, and the easiest and perhaps the only way to participate is through an Israeli company. Pioneer, one of the world's largest seed companies (particularly for corn), recognized this fact when it bought a small Israeli company, Holyland Seeds, to create an Israeli presence. R&D is critical for Israeli firms, because they depend on the profits reaped during the several-year lead time each new discovery yields. Then other, larger firms enter the same international market. One recent Israeli success was long shelf-life tomatoes.

North Carolina's Ciba Agricultural Biotechnology Company (RTP) was founded in 1983 by Ciba-Geigy, Ltd. (Switzerland) to develop improved crop plants through biotechnology research. PTC, cell culture, recombinant DNA techniques and other biotechnologies are widely used to produce transgenic plants with improved resistance, growth and productive capacity. In addition to its work on human and animal peptide therapeutics, Demeter Bio Technologies Ltd. (RTP) also does some R&D on transgenic plants. Maize Genetic Resources, founded in 1984, continues to develop and license hybrid stress-resistant corn varieties.