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Pesticide Resistance: Strategies and Tactics for Management.
1986. National Academy Press, Washington, D.C.
Biotechnology in
Pesticide Resistance Development
RALPH W. F. HARDY
The role and potential of biotechnology in pesticide resistance
development is projected to be quite large but has been minimally
used. Relevant biotechnology techniques are numerous, including
cell and tissue culture and genetic and biochemical techniques.
The classic case of the role of biotechnology in resistance is an-
tibiotic resistance. Biotechnology identified the basis of resistance
and is guiding synthesis of novel antibiotics to circumvent resistance;
antibiotic resistance provided a critical process for genetic engi-
neering. In the area of pesticide resistance, the only well-developed
application of biotechnology is for three different classes of herbi-
cides. The sulfonylurea herbicides are presented as an example of
the role and potential of biotechnology in any pesticide resistance
case. Biotechnology has not been applied to fungicide, insecticide,
or rodenticide resistances.
The opportunity for biotechnology is large, but will require a
multiplicity of skills beyond those used by scientists who are working
at the organismallphysiological and biochemical levels of pesticide
resistance. This opportunity should be pursued aggressively, since
it can provide new directions to alleviate or minimize pesticide re-
sistance where the benefits from additional organismal, physiolog-
ical, and biochemical studies may be limited.
INTRODUCTION
The new biotechnology is providing biology with a powerful array of
techniques that are advancing molecular understanding of biological pro-
cesses and phenomena at an unprecedented rate. Outstanding examples are
130
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BIOTECHNOLOGY IN PESTICIDE RESISTANCE DEVELOPMENT
131
antibody formation and oncogenes and cancer. From this understanding and
these techniques, useful new products, processes, and services are being and
will be generated. The generation will be direct in terms of biological prod-
ucts, processes, and services and indirect in terms of chemical products,
processes, and services. Agrichemical and pharmaceutical discoveries will
become increasingly driven by biotechnology or biotechnology-chemistry
rather than by the current dominant process of empirical chemical synthesis
coupled with biological screening. Tagamet@, an antiulcer drug that has
produced the highest sales for any single pharmaceutical, is an early example
of a biotechnology-chemistry-based innovation. Since the health care field
has been quicker in using the new biotechnology than the field of agriculture,
such a product has yet to be produced for agriculture. For example, the
application of the new biotechnology has only recently begun and is limited
in the area of pesticide resistance (Brown, 1971; Dekker and Georgopoulos,
1982; Georghiou and Saito, 1983; Hardy and Giaquinta, 1984~.
BIOTECHNOLOGY TECHNIQUES
Biotechnology comprises cell and tissue culture techniques and genetic
and biochemical-chemical techniques. Cell and tissue culture techniques range
from microbial culture through higher organism cell and tissue culture to
somatic cell fusion and regeneration. Somatic cell fusion has become es-
pecially useful for antibody production, where an antibody-producing cell
with a limited life is fused with a transformed cell with an infinite life to
produce a hybrid cell (hybridoma) that produces over an almost infinite period
of time a single type of antibody called a monoclonal antibody (MAB). These
MABs could become very useful in both qualitative and quantitative diagnosis
of pesticide resistance, as they are becoming useful as in vitro health care
diagnostics. Several start-up companies have been established for health care
MAB diagnostics.
Cell culture techniques will also be useful in developing and/or selecting
resistance in model systems. Resistance development may use microorgan-
isms or cells or tissues of higher organisms. In the latter, regeneration of
plants from culture often increases phenotypic variability, such as possible
herbicide resistance, over that shown in the parental cells. This phenomenon
is called somaclonal or gametoclonal variation, depending on the cell source.
Genetic techniques, especially molecular genetic techniques, have ex-
panded greatly during the last decade and are propelling our understanding
at the molecular level. Several of these techniques are the basis of a major
biotechnology called genetic engineering, in which defined genes are intro-
duced into foreign host cells. In theory any gene can be moved from a
microbe to a plant, a plant to an animal or human, a human to a microbe,
eliminating the barriers of sexual plant and animal breeding.
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MECHANISMS OF RESISTANCE TO PESTICIDES
Production of gene fragments is the initial technique used to generate
understanding and to perform genetic engineering. Restriction enzymes, of
which there are about 100, cleave DNA at specific sites dictated by the DNA
base sequence. The restriction enzymes cut the DNA of organisms such as
fungi, insects, plants, and animals into useful fragments called gene libraries.
These fragments are useful, since they are of a small size in which specific
genes can be identified. A gene library is the starting point. There are few
if any gene libraries available for agricultural pests, although the techniques
needed are available. Separating the fragments produced by the restriction
enzymes enables characterization of the genotype for polymorphisms. This
technique, called restriction enzyme mapping, could be used to diagnose and
characterize resistance at the genetic level so as to establish the similarities
or differences of observed resistances.
Study of a gene of interest, such as a resistance gene, requires its iden-
tification, isolation, biosynthesis or chemical synthesis, and cloning, usually
in a genetically well-characterized microorganism such as E. coli, to produce
adequate quantities for characterization or further use. The gene can be
isolated from the gene library, biosynthesized as a complementary DNA
(cDNA) from its messenger RNA (mRNA), or chemically synthesized di-
rectly if the DNA sequence is known. If the sequence is not known, powerful
DNA sequencing techniques exist for rapid sequencing. DNA sequencing
will identify the similarity or difference of resistant versus susceptible genes.
Genetic engineering of organisms requires these steps so as to obtain a
source of the desired gene and to generate genetic constructions with appro-
priate replication sites and control elements so that they can be introduced
into the desired host, retained, and replicated to produce the gene product
at an appropriate rate. Techniques have been developed to introduce func-
tional foreign genes into microorganisms, embryos of mammals, and cells
of at least dicotyledonous plants. Human insulin produced by microorgan-
isms, antibiotic-resistant model plants, and super rodents with additional
copies of the growth hormone gene are examples.
We are beginning to understand the molecular basis of how gene expression
is regulated. Recent studies on Drosophila are a major example in a model
sytem. As this knowledge becomes known, it should be very useful in ex-
ploring resistance on the basis of regulatory-based changes.
Overall, genetic techniques will be useful to understand, manage, circum
vent, and exploit pesticide resistance. These genetic techniques, however
will need to be coupled with chemical and biochemical techniques.
The biochemical and chemical techniques of biotechnology include syn-
thetic and analytical methods. Synthetic oligonucleotides for use as DNA
probes to identify genes can be made readily with automated commercial
instruments. These DNA probes will succeed MABs as even more useful
diagnostic agents for pesticide resistance. Micro quantities of proteins can
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BIOTECHNOLOGY IN PESTICIDE RESISTANCE DEVELOPMENT
133
be sequenced with commercial instruments, and synthetic peptides up to
about 20 + amino acid residues can be synthesized routinely. Biophysical
techniques utilizing X ray, nuclear magnetic resonance (NMR), and other
methods will provide three-dimensional structures of biological macromo-
lecules such as proteins; thus, we will be able to correlate structure with
pesticide activity or resistance.
Gene sequences and resultant protein sequences will be changed by design,
using site-specific mutagenesis to change the DNA sequence. For example,
p-lactamase, the antibiotic-resistant gene in bacteria, was altered to place a
cysteine at the active site in place of the naturally occurring serine. The
designed gene produced a novel active ,8-thiollactamase (Sigal et al., 19821.
By combining this wealth of information (generated from chemical, bio-
chemical, and genetic techniques) with computer graphics, we will be able
to design novel pesticides and genes.
BIOTECHNOLOGY AND XENOBIOTICS
Biotechnology has been intimately involved in antibiotic resistance re-
search and development. The techniques of biotechnology identified the basis
of resistance, which provided a critical resource for genetic engineering. For
example, penicillin and cephalosporins are widely used antibiotics. The ,8-
lactam ring of these molecules is essential for their antibiotic activity. Bac-
teria, however, have developed resistance to these molecules. The resistance
is located on small extrachromosomal circular pieces of DNA called plasmids,
and the resistance is specifically due to a gene that makes an enzyme called
,B-lactamase, which cleaves the ,8-lactam ring of these antibiotics and in-
activates them.
Antibiotic resistance has provided essential selectable markers for follow-
ing genetic constructions introduced into cells. Cells containing the new
functional genetic material are selected for their antibiotic resistance. The
markers have enabled genetic engineering of microorganisms to develop
rapidly. Understanding these antibiotics and antibiotic resistances facilitated
the knowledge of microbial cell-wall synthesis.
The problem of antibiotic resistance has led to several ways to circumvent
it. An empirical approach such as the use of clavulinic acid (a naturally
occurring suicide inhibitor of ,8-lactamase) in combination with an antibiotic,
amoxacillin, is one way to circumvent the resistance problem. Another ap-
proach is to develop commercial semisynthetic ,B-lactam antibiotics, which
have incorporated within them the ability to also inhibit ,B-lactamase. Of
possible greater significance, based on the understanding generated by bio-
technology, are current efforts to design drugs to which resistant bacteria are
susceptible.
In pesticide resistance management, biotechnology can play a key role,
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MECHANISMS OF RESISTANCE TO PESTICIDES
but much more research is necessary before we can fully exploit these ben-
efits. For example, herbicide research and development offers opportunities
and limitations. We little understand the mechanisms of action of herbicides;
therefore, informed decisions on research and development, safety, and use
are limited. The empirical synthesis-screening approach through which al-
most all herbicides are discovered is becoming increasingly inefficient; re-
searchers must synthesize some tens of thousands of new chemical structures
to find a commercial product.
Crops usually have inadequate tolerance to herbicides; thus, herbicides are
selected for tolerance to specific crops. The lack of broad crop tolerance
limits broad crop use of most herbicides, as do soil residues. More herbicide-
resistant crops are desirable for broad use of low-cost herbicides and crop
rotation. Finally, a few weeds have developed resistance to herbicides such
as atrazine, and it may be desirable to manage or circumvent this resistance.
The earliest products of crop biotechnology will probably be crops with
specific herbicide resistance, followed by designed herbicides. The sulfo-
nylurea herbicides illustrate the major role that biotechnology can play in
generating understanding of pesticides and, in this case, resistance. The
sulfonylurea herbicides demonstrate the integrated role of a number of tech-
niques and disciplines.
Using empirical synthesis and screening, the du Pont Company developed
a novel class of herbicides, some examples of which are Allying, Classics,
Gleans, Londax~, and Oust@. These herbicides are very potent, with un-
usually low application rates.
Plant physiological investigations on the active sulfonylurea compounds
in Gleans and Ousts showed that these sulfonylureas rapidly inhibited cell
division. Tobacco cell cultures grown on media containing the sulfonylureas
yielded cell lines and regenerated plants with a chromosomally localized
single resistant gene and a greater than 100-fold increase in resistance to
sulfonylureas (Chaleff and Ray, 19841. Further mechanistic studies utilized
less complex, more defined microorganismal systems. The sulfonylureas also
inhibited the growth of several, but not all, bacteria. The biocidal target of
these herbicides was an enzyme, acetolactate synthase (ALS II and III), that
is involved in the synthesis of the branched-chain essential amino acids valine,
isoleucine, and leucine (LaRossa and Schloss, 19844. Physiological, bio-
chemical, and genetic analyses confirmed the target site.
Along these same lines a molecular biological characterization showed
that a major form of resistance in yeast arises from an altered structural gene
for ALS, in which a praline amino acid residue in the sensitive ALS is
replaced by a serine in the resistant ALS. Other forms of resistance were
also found. The structural ALS resistance gene may be useful as a selectable
marker for genetic engineering in higher organisms, as antibiotic resistance
has been in bacteria.
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BIOTECHNOLOGY IN PESTICIDE RESISTANCE DEVELOPMENT
135
This rapidly generated base of information in model microorganismal sys-
tems led to the identification of ALS as the site of herbicidal activity in plants
(Ray, 19841. A less-sensitive ALS was shown to be the basis of herbicidal
resistance in resistant tobacco. Other plant studies showed that herbicide
selectivity in crop plants arose from metabolism of the sulfonylureas to a
nonherbicidal form in the tolerant crops, not to a less-sensitive ALS. Her-
bicidal activity can be evaluated directly on the ALS target, thus providing
more rigorous structure/activity information than whole plant screens, where
activity is the result of ALS activity and penetration, translocation, and
detoxification of the sulfonylureas.
Biophysical studies on sulfonylureas and ALS at the kinetic and structural
levels can provide information on the specific mechanism of inhibition.
Opportunities for designed herbicides, designed resistance genes, and the
genetic engineering of herbicide-resistant crops come from this multidisci-
plinary and multitechnique generation of understanding. Without microor-
ganismal techniques and development of model resistance, the time required
to generate this level of understanding on the sulfonylureas would have taken
several additional years. Although sulfonylureas were used in the above
study, similar examples exist for the s-triazine (Arntzen and Duesing, 1983)
and glyphosate herbicides (Coma) et al., 19831. The time required to reach
an understanding of the s-triazines and glyphosate was much longer than for
the sulfonylureas, because the newer biotechnology techniques were not
available or not initially used for most of the former studies.
BIOTECHNOLOGY IN PESTICIDE RESISTANCE
Schematics of the role and potential of biotechnology in pesticide research
and development, understanding, management, circumvention, and exploi-
tation and in pesticide resistance and development are presented in Figures
1 and 2. The following sections will consider biotechnology in all phases of
pesticide resistance.
Resistance Development
Xenobiotics select or generate resistance broadly in organisms (Georghiou
and Mellon, 19831. Fungi, acarina, and insects have shown resistance to
fungicides. Bacteria, fungi, nematodes, acarina, insects, crustacea, fish, frogs,
rodents, and higher plants have shown resistance to insecticides. Bacteria,
yeast, and higher plants have shown resistance to herbicides. This broad
occurrence of resistance suggests that by using model systems, we can un-
derstand the molecular process of resistance. The model system should be
biochemically and genetically well-characterized and as simple as possible,
such as a microorganism, although some problems will require more complex
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MECHANISMS OF RESISTANCE TO PESTICIDES
Empirical Synthesis Pest Screening
· Biocide discovery
Model (Microbial) Systems
· Mechanism of biocide action
· Biocide target genes and gene products
· Surrogate screens
Pest-Host Systems
· Biocide target in pest
· Molecular biological characterization of target and biocide target interaction
· In vitro biocide structure target activity relationships
· Designed biocides
· Host tolerance/resistance
FIGURE 1 Biotechnology pesticide research and development.
systems. Development of model resistance in defined organisms will accel-
erate the understanding, management, circumvention, and exploitation of
resistance.
Resistance Understanding
Most if not all resistances result from one of three genetic changes. With
qualitative change a structural gene is altered so that its protein product is
less affected by the pesticide, such as the sulfonylurea resistance gene with
its altered ALS enzyme. The other genetic changes are quantitative: gene
Empirical Synthesis Resistant Pest Screening
· Biocide discovery
Model (Microbial) Systems
· Resistance development
· Resistance types
· Resistance genetic and gene products
· Surrogate screens
· MABs, DNA probes, restriction maps as diagnostics
Pest-Host Systems
· Pest resistance types
· PesVhost resistance genes and gene products
· MABs, DNA probes, restriction maps as diagnostics
· In vitro biocide structure resistance relationships
· Designed biocides
· Resistant hosts by somaclonal variation
· Genetically engineered resistant hosts
· Natural biocides
· Synergists
· Agriregulators
FIGURE 2 Biotechnology- pesticide resistance research and development.
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BIOTECHNOLOGY IN PESTICIDE RESISTANCE DEVELOPMENT
137
regulation and gene amplification, in which increased amounts of gene prod-
uct make the organism less sensitive to the pesticide. Structural gene changes
usually produce stable resistance, while gene amplification changes may be
less stable.
To understand resistance we need to address the number of types; identify
the general types such as target site, metabolism, penetration, reproduction,
excretion, storage, and feeding; and define the genetic change responsible.
Biotechnology has provided this level of understanding for at least three
herbicides-glyphosates, sulfonylureas, and s-triazines where altered
structural genes, gene amplification of target-site genes, and altered regu-
lation of target-site genes have been demonstrated. In some the product of
the altered structural gene is as active as the unaltered (sulfonylureas and
glyphosates) or highly fit; in others (s-triazines) the product is less active or
less fit. Biotechnology should provide similar definition for other pesticide
resistances where an adequate physiological, biochemical, and genetic base
exists in an appropriate experimental organism. Effective programs will be
highly interdisciplinary using a breadth of biotechnology techniques. Bio-
technology can expand our understanding in most if not all areas of pesticide
resistance. Unfortunately, biotechnology has been little used in this field.
Obvious opportunities are cytochrome P4so in cases of some insecticide re-
sistances and ,B-tubulin in the case of benomyl fungicide resistances.
Resistance Management
In the short term, biotechnology can provide the reagents and techniques
for qualitative and quantitative diagnosis of pesticide-resistant organisms.
MABs may be useful for measuring structurally altered gene products and
an altered quantity of gene products. Restriction maps and DNA probes
should be useful, but they will require an expanded base of information.
These techniques should enable researchers to define the similarities or dif-
ferences of observed pesticide resistances in the same or different labora-
tories. They would be used first as research diagnostics, but could become
field diagnostics to guide pesticide use practices.
Also in the short term, biotechnology would help researchers to establish
rigorous pesticide structure/resistance relationships that may differ from pes-
ticide structure/activity relationships, especially for altered target sites. Pes-
ticide use practice could be guided by this base of understanding.
In the midterm, increased understanding of multiplicity, type, and genetic
change will result in informed, early decisions on agronomic use practices
that will minimize the impact of resistance. For example, gene amplification-
based resistances are probably less stable than altered structural-gene resis-
tances, suggesting alternation of pesticide use as a desirable practice in the
first case. Further, an expanded use of biotechnology will provide significant
new opportunities for the more effective management of pesticide resistance.
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MECHANISMS OF RESISTANCE TO PESTICIDES
Resistance Circumvention
Circumvention of resistance may be sought through new pesticides, natural
pesticides, synergists, and agriregulants. New pesticides could be discovered
by empirical synthesis or design. Empirical synthesis could be coupled with
a screen using resistant organisms under continuous pesticide selection pres-
sure to discover chemical structures that inhibit critical, nonalterable enzyme
or protein sites. This approach realistically assumes the existence of critical
sites that cannot be changed and still maintain an adequately fit activity for
the pest. Designed synthesis would use target-site knowledge and computer
graphics to guide synthesis of novel pesticides to be tested. Target sites could
be selected that have low opportunity for change and retention of adequate
fitness for the pest. A highly conserved gene such as the quinone-binding
protein that is inhibited by the s-triazines is an example of a target site with
limited opportunity for change and retention of adequate fitness. Additional
critical catalytic sites unique to pests need to be identified.
Natural pesticides may circumvent synthetic pesticide resistance. For ex-
ample, biocontrol organisms could be genetically engineered to produce
natural pesticides. Beneficial organisms such as plants could be genetically
engineered for endogenous production of natural pesticides (Schneiderman,
19841. In both, methods for timed bioproduction of the pesticide would be
needed, since continuous production would facilitate the development of
pesticide resistance. Agriregulators, as described later in this subsection, may
be developed for temporal control of biopesticide biosynthesis.
Synergists may also circumvent pesticide resistance. These molecules are
inactive as pesticides, but they synergize the activity of pesticides. As such
they may decrease metabolic detoxification by inhibiting the detoxification
system. Genetic, biochemical, and chemical biotechniques may improve our
understanding, so that scientists can design synergists or produce quantities
of the cloned detoxification system for use as in vitro screens for potential
synergists. Genetic engineering may produce naturally occurring synergists,
and biotechniques may synthesize modified synergists. Biotechnology tech-
niques have been applied to several cytochrome P4so systems but not to any
involved in pesticide detoxification.
Synthetic compounds that regulate gene expression will be major oppor-
tunities for agrichemicals and pharmaceuticals. One or more model examples
already exist. The genes for biological nitrogen fixation are not expressed
when N2-fixing organisms are grown in an environment containing adequate
fixed nitrogen or ammonia. A synthetic molecule, methionine sulfoxamine
(MS), causes the expression of the biological N2-fixing genes in the presence
of adequate ammonia. Synthetic compounds such as MS will become im-
portant useful future agriregulator agrichemicals. They will be discovered
by empirical synthesis screening and by designed synthesis as our knowledge
. . .
O: gene expression increases.
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BIOTECHNOLOGY IN PESTICIDE RESISTANCE DEVELOPMENT
139
The opportunity for agriregulators is expected to be large. Plants may
already contain the genetic information for natural pesticides, or genetic
engineering will introduce the genetic information into crop plants. Agrire-
gulators will be used to turn on the expression at the time of need. The idea
that many of the detoxification systems for insecticides are regulated by a
common genetic system suggests a major opportunity for an agriregulator
that inhibits the genetic system regulating detoxification genes.
Resistance Exploitation
Xenobiotic resistance genes are and will be useful selectable markers to
enable researchers to track and select organisms containing genetic construc-
tions. Antibiotic resistance is the most common example, but pesticide-
resistant genes will be increasingly used. Herbicide resistance may be used
to follow genetic introductions into higher plants.
Introducing herbicide-resistant genes into crop plants to increase tolerance
and enable crop rotation and the use of herbicides on a broader group of
crops is being pursued aggressively and may be the first major practical
example of genetic engineering in crop agriculture. Similar approaches may
be used to introduce rodenticide and insecticide resistance genes into pets
and food animals and insecticide resistance genes into beneficial insects such
as bees.
With a dynamically expanding base of understanding of basic biological
processes, researchers should be able to identify many exploitable targets,
not only in agriculture (such as pest control and yield and quality improve-
ment) but also in health care, food, energy, pollution control, and chemicals.
Application to Pesticides Other than Herbicides
Examples of the comprehensive application of biotechnology to fungicide,
insecticide, or rodenticide resistance do not exist. An outline for such a study
follows, using the rodenticide, warfarin, as the example.
Model studies would use microbes to develop warfarin resistance, with
emphasis on identifying resistance in a microbe for which the biochemical
and genetic information is greatest. The type of resistances and the resis-
tance genes and gene products would be identified as previously described
for the sulfonylurea resistance microbes. Such resistances for warfarin may
involve the biosynthetic pathway for vitamin K. The resistant microbes may
provide useful screens to evaluate members of this class of rodenticides for
ability to circumvent resistance. Diagnostic approaches such as MABs, DNA
probes, and restriction maps may be developed to identify each type of
resistance.
Information and diagnostics from these model studies should facilitate
studies of resistance in the more complex rodent pests. The rodent resistance
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MECHANISMS OF RESISTANCE TO PESTICIDES
genes and gene products would be identified. Diagnostics would be developed
to identify each type of resistance. The rodenticide structure/resistance re-
lationships could be measured in vitro, eliminating effects of the nontarget
components in the rodent. Rodenticides may be designed to circumvent or
minimize the resistance using in vitro tests. Resistant animals such as pets
could be developed by genetic engineering so as to decrease effects of ro-
denticides on nontarget animals. Natural rodenticides may be produced by
biotechnology. Synergists may be developed on the basis of the understanding
generated by biotechnology. Similar approaches could be used for fungicides
such as benomyl, where an altered p-tubulin is the site of resistance, or for
insecticides, where in many cases detoxification by cytochrome P4so systems
generates resistance.
CONCLUSION
Biotechnologies have been used very little in pesticide resistance research
and development. Biotechnology has tremendous potential in almost all phases
of pesticide resistance investigations and applications, as shown in the sul-
fonylurea herbicide example. Biotechnology research and development with
this and other herbicides has been useful in resistance development, under-
standing, and exploitation. If desirable, biotechnology would also be useful
in pesticide resistance management and circumvention. The most successful
biotechnology efforts in pesticide resistance, as in almost all other areas,
will integrate a multiplicity of biotechnologies by a group of multidiscipli-
narians.
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Chaleff, R. S., and T. B. Ray. 1984. Herbicide resistant mutants from tobacco cell cultures. Science
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Comai, L., L. D. Sen, and D. M. Stalken. 1983. An altered aroA gene product confers resistance
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Dekker, J., and S. G. Georgopoulos. 1982. Fungicide Resistance in Crop Protection. Wageningen,
Netherlands: Centre for Agricultural Publishing and Documentation.
Georghiou, G. P., and R. B. Mellon. 1983. Pesticide resistance in time and space. Pp. 1-46 in
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Hardy, R. W. F., and R. T. Giaquinta. 1984. Molecular biology of herbicides. BioEssays 1:152.
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Ray, T. B. 1984. Site of action of chlorsulfuron inhibition of valine and isoleucine biosynthesis in
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Schneiderman, H. A. 1984. What entomology has in store for biotechnology. Bull. Entomol. Soc.
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Sigal, I., B. G. Harwood, and R. Arentzen. 1982. Thiol p-lactamase: Replacementofthe active-
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141
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Representative terms from entire chapter:
resistance development
