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Toting Up the Early Harvest Of Transgenic Plants



BIOTECHNOLOGY:
Toting Up the Early Harvest Of Transgenic Plants
Anne Simon Moffat

Many plants sporting foreign genes are winning big and others show promise,
but some efforts to develop new plants are lagging

In the early 1980s, after centuries of improving their crop plants and
domestic animals the old-fashioned way--by breeding in desirable
traits--agricultural scientists took a big step. They decided to circumvent
the uncertain, and often lengthy, standard breeding process by using the
tools of modern molecular biology to introduce genes into plants and
animals for the traits they wanted. Some 15 years after the first such gene
transfers, 700 researchers and policy-makers from 30 countries attended the
Second Agricultural Biotechnology International Conference, held last
summer in Saskatoon, Canada, to assess the fruits of their past labors and
look ahead.

Although researchers have had some success in genetically modifying
animals, especially in producing sheep or cows that make medically valuable
human proteins, most progress so far has been with plants. For example,
several major crop plants, including corn, oilseed canola, soybean, and
cotton, have been engineered with genes that make them resistant to insect
pests or to the herbicide glyphosate, so that the weedkiller doesn't
threaten the crop.

Such transgenic plants have met opposition in many European countries
because of fears that they may be unsafe for the consumer, damage the
environment, or lead to further, costly surpluses. But they are winning
acceptance in other countries, including the United States, Argentina,
China, and Canada. During this past growing season, at least 30 million
hectares worldwide were planted with the modified crops. As a result, more
than one-half of the world soybean harvest and about one-third of the corn
harvest now comes from plants engineered with genes for herbicide or
disease resistance. These commodities find their way into hundreds of
foods, such as breakfast cereals, cooking oils, corn syrup, soft drinks,
and candies.

"The speed of commercialization of agribiotech applications has taken many
by surprise," says Anatole Krattiger, executive director of the
International Service for the Acquisition of Agribiotech Applications in
Ithaca, New York. He adds that for industrialized nations, agbiotech can
increase the efficiency of producing existing crops by reducing the need
for pesticide applications and other costly treatments; in developing,
food-short nations, it can increase yields, essentially without the cost of
additional inputs, such as pesticides. And a few genetically modified
plants that promise entirely new products--including some that make
ingestible vaccines for human diseases and at least one, sweet potato, with
an improved protein content--are moving through the pipeline.

But not all efforts to genetically engineer plants are going smoothly.
Researchers are running into trouble in their efforts to transform
conventional crops into factories for high-value novel products, such as a
"natural" cotton/polyester blend grown by cotton plants, or for substances
traditionally supplied by synthetic chemistry, such as plastics. And
sometimes even successful genetic transformations can be stymied by
practical concerns.

Take the Flavr-Savr tomato, genetically engineered by the biotech firm
Calgene Inc. of Davis, California, with a so-called antisense gene that
slows down the activity of polygalacturonase, an enzyme that degrades cell
walls. By inhibiting rotting, this change allows the fruit to ripen on the
vine instead of being picked green and hard. But the Flavr-Savr tomato had
to be pulled from the market, mainly because conventional tomato-picking
and packing equipment damages the soft, naturally ripened vine fruit.

Keep it simple.

The modifications that have worked best are the simplest: those that can be
accomplished by introducing just one or a few foreign genes into a plant,
with minimal effects on its physiology. For example, researchers made
plants resistant to the herbicide glyphosate by transforming them with a
natural bacterial enzyme that is highly resistant to the herbicide, while
insect- resistant plants are created by adding the gene for one of the
toxins produced by Bacillus thuringiensis, a type of bacterium that infects
and kills insects. This can pay off economically. In 1997, in U.S. corn
belt states, corn transformed to express a BT protein had a 7% increase in
yield per acre, bringing the farmer, on average, an increased net return
per acre of $16.88.

Buoyed by these successes, researchers are now expanding their efforts. One
goal is to use genetic engineering to enhance food quality. Early
indications are that some of these attempts will work, particularly those
involving the manipulation of only one gene. At the meeting, for example,
C. S. Prakash of Tuskegee University in Alabama described progress in
improving the quality of the proteins made by sweet potato, an important,
easy-to-grow food crop in areas such as the poorer countries of the
tropics, where high-quality protein foods may be hard to come by. Prakash
inserted into sweet potato plants a synthetic gene coding for a storage
protein that has a high content of the so-called essential amino acids,
ones that the human body can't make for itself.

Early on, Prakash worried that the energy drain imposed by synthesis of the
foreign protein would reduce the harvests of the transgenic sweet potato
plants, but his fears proved unwarranted. Although the protein content of
two strains of the genetically engineered plants increased by 2.5- to
5-fold, the first field trials in Alabama during the summer of 1997 showed,
if anything, a slight increase in yields. The transgenic plants produced
between 64 and 68 bushels per hectare, compared to the control plants' 61
bushels per hectare. "We had a bountiful harvest," Prakash says.

These transgenic potatoes are not yet in commercial production, as
researchers are just beginning to assess their nutritional quality. A first
feeding trial on hamsters looks promising, though. Animals fed the
transgenic, high-protein potatoes weighed 56% more than controls after 28
days and showed no evidence of any toxic effects.

Other efforts are aimed at getting plants to make commercially useful
products. For example, at the Hebrew University in Jerusalem, Joseph
Hirschberg has induced tobacco plants to make a carotenoid pigment called
astaxanthin, which can be used to tint flowers, farm-raised shrimp, and
salmon and, when fed to chickens, can color egg yolks a vibrant orange.
Currently, astaxanthin is extracted from seashells or synthesized
chemically and carries a price tag of about $2600 per kilogram. But
Hirschberg's efforts may help bring that price down.

He has taken a gene from a green alga that codes for a ketolase enzyme and
introduced it into tobacco plants. There the enzyme converts betacarotene
to a compound called canthaxanthin, which the plants' own enzymes can use
to make astaxanthin. "We've shown that all you need is one enzyme to
redirect biosynthesis" to astaxanthin, says Hirschberg. High levels of the
chemical accumulate in the flower's nectary, from which it can be
extracted. Hirschberg says the transgenic system has been licensed to
European food and feed firms.

Still in development are plants that would produce edible vaccines. These
could be a big help in the Third World, where the cost of transportation,
the lack of refrigeration, and the hazard of using needles can make
conventional vaccine administration impractical. Edible vaccines might be
used, for example, to protect against diarrhea, a major cause of infant
mortality in developing countries.

At the conference, Hugh Mason and his Boyce-Thompson Institute (BTI)
colleagues reported on their efforts to protect against two
diarrhea-causing pathogens: the bacterium Escherichia coli and Norwalk
virus. In one set of experiments, the researchers introduced the gene for
an E. coli protein into potatoes, which made the protein. When eaten raw by
volunteers at the University of Maryland School of Medicine in Baltimore,
the modified potatoes induced production of antibodies to the protein. The
researchers now hope to do clinical trials in which the immunized
volunteers will be given the disease-causing form of E. coli to test
whether the antibodies can in fact protect against diarrhea. The work with
Norwalk virus isn't as far along, but the BTI group has introduced the gene
for a viral coat protein into potatoes.

And complementing this work, in the October issue of Nature Biotechnology,
William Langridge and his colleagues at Loma Linda University in California
report that it might even be possible to use transgenics plants to make an
edible form of the hormone insulin. They introduced into potatoes a hybrid
gene that produces human insulin fused to a cholera toxin subunit, which
directs the insulin to lymphoid tissue in the gut. This allows animals to
build tolerance to the insulin, suppressing the animals' inappropriate
immune response to the protein. Feeding the transgenic potatoes to mice
with a genetic form of diabetes delayed the onset of symptoms by 4 to 8
weeks.

Plants may also be used to mass-produce expensive monoclonal antibodies
that, after appropriate modification, such as sugar addition, might be used
to treat various ills. For example, in the December Nature Biotechnology,
Kevin Whaley of Johns Hopkins University and his colleagues report that
antibodies made in soy plants prevent infection of mice by the genital
herpes virus, and Julian Ma of Guy's Hospital, London, has previously used
antibodies made in tobacco to deter the bacterial infections that often
result in tooth decay. Antibodies produced by plants should be less
expensive and perhaps safer than those made in mice and other animals.

Green factories?

Although these simple gene modifications are succeeding, more complex
manipulations are proving harder to pull off. One hope, for example, was
that plants could be used to produce plastics, such as polyesters, now
synthesized from nonrenewable sources such as petroleum products. Early
results looked promising.

AREA OF TRANSGENIC CROPS PLANTED (MILLIONS OF HECTARES)
Country           1997       1998
U.S.A.                  8.1         20.5
Argentina           1.4            4.3
Canada                1.3            2.8
Australia            0.1            0.1
Mexico                0.1            0.1
Spain                  0.0            0.1
France                0.0            0.1
South Africa       0.0            0.1
Total                 11.0         27.8

The work made use of the fact that many bacteria synthesize and store
natural, biodegradable polyesters, such as poly-3- hydroxybutyrate (PHB).
However, large-scale bacterial production of this class of natural
polyesters seemed impractical and costly, in part because fermentation
equipment the size of several breweries would be needed to produce
commercially significant amounts. But only three genes are required to make
PHB, and Chris Somerville of the Carnegie Institution of Washington at
Stanford was able to transfer all three into the plant Arabidopsis. The
plants transformed with the gene made some PHB, but they were sickly, for
reasons not clearly understood.

Somerville and his colleagues solved this problem about 4 years ago by
adding a targeting sequence to the genes that directs the expressed
biosynthetic enzymes to the chloroplasts of the plant cell. The result was
much higher PHB production and relatively healthy plants. Researchers
believe that this tinkering helped because the chloroplast is the major
biosynthetic factory for the plant cell and, thus, better designed for
polymer production. Unfortunately, PHB is too brittle to be commercially
useful.

More recently, Monsanto polymer biochemist Ken Gruys and his colleagues
induced both Arabidopsis and canola to produce a copolymer of PHB and
poly-3- hydroxyvalerate (PHBV) by transferring four genes into the plants.
This material, which is much more pliable than PHB, has been produced
commercially by fermentation. Biochemist William Page of the University of
Alberta says, however, that even if these efforts succeed, extracting the
plastic is likely to be difficult. As a result, he says, "the savings
of producing polyester in the field may be lost in extraction.

In a different effort to make bulk commodities in genetically engineered
plants, Maliyakal John and his colleagues at Agracetus (now part of
Monsanto) transformed cotton plants to synthesize polyester in the hopes of
producing a natural polyester/ cotton blend. But they too have hit an
impasse. The researchers have been unable to get the polyester genes
expressed in the boll, where the cotton is made, and the project has been
put on a back burner. To revive the idea, researchers will need a better
grasp of how cotton plants direct synthesis of proteins to specific
locations, such as the boll.

Indeed, how plants regulate gene expression is one of the big issues
researchers need to grapple with, especially if they try to develop
improved plant varieties by tinkering with large gene clusters, such as the
packets of genes that direct nitrogen fixation or photosynthesis. So far,
researchers have done little with these systems, because, says BTI
president Charles Arntzen, "they're too complicated." But that doesn't mean
researchers have given up--just that they will need to understand the
systems better to try to identify modifications that might improve their
efficiency. Says Kenneth Gruys, "What seems routine now, such as
transforming a plant with a single gene to yield a new commercial product,
was deemed extremely difficult not that long ago." Successful manipulations
of multiple genes will be realized, too, he predicts.

		Copyright 1998 by the American Association for the Advancement of Science.