An HTML version of this document is available at
http://vm.cfsan.fda.gov/~lrd/bioeme.html
-------------------------------------------------------------------------
FDA Education/Compliance Program: 1995
 
 
         Emerging Technologies -- Biotechnology
 
GENETIC ENGINEERING
 
Biotechnological methods of genetic engineering are relatively
new techniques that plant breeders have to make direct
modifications of DNA, a living thing's genetic materials.
Scientists make copies to genes for desired traits and introduce
the gene copy into an organism such as a food crop.  The new gene
is usually a single gene whose function is well understood.
These new techniques avoid one of the major problems encountered
by plant breeders who use cross hybridization - no unwanted or
undesirable genes are introduced with the desired gene.  In
addition, scientists can make copies of genes from any organism -
plant, animal, or microbe - that may yield a desired trait and
introduce that gene into a food crop.  This greatly expands the
pool of potentially useful traits available to plant breeders to
improve food crops.
 
One a desired gene has been introduced into a crop via genetic
engineering, the gene is usually crossed into other crop lines
that have desired commercial traits.  Such crossing also permits
the breeder to evaluate the genetic stability of the new gene.
Overall, genetic engineering allows breeders to develop new
varieties more rapidly, but at this stage of the technology, the
new methods are used in conjunction with other methods of plant
breeding, such as cross-hybridization.
 
The time required to evaluate new varieties and the number of
field trials will vary depending on the need to confirm
performance, to evaluate characteristics of the food, to evaluate
environmental effects, and to produce the required amount of seed
before the new plant variety can be grown commercially by
farmers.
 
Genetic engineering is used to achieve the same goals of
agronomic and quality characteristics as traditional techniques
and allows the breeder to make some modifications that would not
be possible through other methods of plant breeding.  Genetically
engineered food crops have been developed to:
 
- resist pests and disease and to tolerate chemical herbicides;
- exhibit improved food processing traits;
- exhibit improved nutritional content;
- resist adverse soil and weather conditions; and to
- exhibit improved fruit ripening or softening, texture, or flavor.
 
FOODS PRODUCED BY GENETIC ENGINEERING
 
FDA evaluated the safety data and information developed by
Calgene, Inc. regarding the FLAVR SAVR  tomato, the first food
derived from a plant modified via recombinant DNA techniques to
be evaluated by the agency.  In May, 1994, FDA and the FDA Food
Advisory Committee agreed with Calgene that the FLAVR SAVR
tomato was as safe as other commercial varieties of tomato.
 
In response to a petition by Calgene, FDA also issued a food
additive regulation for the use of the selectable marker gene,
kanamycin resistance, to develop via recombinant DNA techniques
new varieties of tomato, including the FLAVR SAVR  tomato,
cotton, and oilseed rape (canola) plants.
 
In November, 1994, FDA reviewed the process for the FDA Food
Advisory Committee (FAC) by which firms are informing the agency
that they have completed their safety and nutritional assessment
of foods derived from new plant varieties developed through
recombinant DNA techniques.  The agency also presented to the FAC
the summary of the safety and nutritional assessment provided to
FDA on seven new products.  These included the following:
 
Delayed ripening tomatoes (DNA Plant Technology, Monsanto, Co.,
and Zeneca Plant Sciences).
 
Pest resistant crops:  Virus-resistant squash (Asgrow); and
Colorado potato beetle-resistant potato (Monsanto, Co.).
 
Herbicide-tolerant crops:  Bromoxynil-tolerant cotton (Calgene,
Inc.); and Glyphosate-tolerant soybean (Monsanto Co.).
 
The FAC agreed with FDA that there are no outstanding food safety
issues associated with these products.
 
These examples of foods derived from new plant varieties modified
via recombinant DNA techniques, including the FLAVR SAVR
tomato, were evaluated by the developers using safety and
nutritional assessments consistent with the standard to care
contained in FDA's 1992 policy.
 
FDA'S 1992 POLICY
 
In 1992, FDA published a policy statement that explains how foods
- fruits, vegetables, grains, and their by products such as
vegetable oils - are regulated under the FD&C Act.  This policy
applies to foods and food ingredients, including animal feeds,
derived from plants modified through all methods of plant
breeding, including genetic engineering.
 
Highlights of some of the important factors included in FDA's
guidance to industry are the following:
 
1.  GENETIC MODIFICATION
 
The introduced genetic materials should be well-characterized to
ensure that any introduced genes do not encode harmful substances
and should be stably inserted in the plant genome to minimize the
chance for subsequent undesired genetic rearrangements.
 
2.  TOXICANTS
 
Plants are known to produce toxicants and antinutritional
factors, such as protease inhibitors, hemolytic agents, and
alkaloids which often protect the plant against pests and
disease.  Many of these toxicants are present in today's crops at
levels that do not cause acute toxicity or do not affect humans
or animals when the food is properly prepared.  New plant
varieties should not contain levels of such toxicants that are
above the range that exists in today's crops.
 
3.  NUTRIENTS
 
Another unintended consequence of genetic modification of the
plant may be an alteration (relative to the total diet) in levels
of important nutrients and bioavailability of a nutrient due to
changes in the form of the nutrient or of other constituents that
effect absorption or metabolism of nutrients.
 
4.  NEW SUBSTANCE
 
In some cases using genetic engineering, plant breeders may
introduce genes into food crops that encode substances that
differ substantially in structure and function from substances
currently found in food.  Based on current developments, such
substances would be expected to be proteins or protein enzymes
that modify carbohydrates and fatty acids in the food.  In some
cases, such substances will require premarket approval as food
additives; in other cases, the food may require new labeling to
properly inform consumers of the new attributes of the food.
However, in most cases to date, the substances that occur in food
as a result of gene transfer have been safely consumed as food
previously or are substantially similar to food substances and
would not require premarket review by FDA.
 
5.  ALLERGENICITY
 
There are thousands of different proteins in our food supply, and
only a few cause food allergy reactions.  However, because
genetic engineering can result in the introduction of genetic
material from essentially any source (plant, animal, or microbe)
into food, there is a possibility that a protein encoded by the
newly introduced genetic material will be an allergen and produce
an allergic response in some members of the population.  FDA has
raised this issue in its guidance to industry, especially in
cases where the transferred genetic material is derived from a
source that is known to be commonly allergenic.  Examples of such
foods that affect the U.S. population include milk, eggs, fish
crustacea, mollusks, tree nuts, wheat, and legumes (particularly
peanuts and soybeans).  FDA believes that proteins derived from
commonly allergenic sources should be presumed to be allergens
and special labeling would be required, unless scientific
evidence demonstrates otherwise.
 
In cases where a protein is derived from a source that is not
known to be allergenic, it is not possible to definitively
predict allergenic potential.  While it is unlikely that a new
protein that occurs in very low concentrations in food will be an
allergen (as is the case for most proteins introduced via genetic
engineering at this time), developers have taken steps to
minimize the likelihood that a new protein will be an allergen by
evaluating whether the new proteins exhibit characteristics
typical of allergenic proteins (such as stability to heat, acid,
and enzyme degradation).
 
FDA encourages developers to discuss questions regarding
allergenicity with agency scientists.
 
6.  ANTIBIOTIC RESISTANCE MARKERS
 
In experiments involving genetic engineering, only a few plants
cells take up the desired new gene.  Developers use selectable
marker genes during gene transfer experiments to improve their
chances of selecting plants that have successfully incorporated
the desired gene.  The most widely used marker is kanamycin
resistance gene that produces the enzyme, aminoglycoside
3'-phosphotransferase II (also referred to as APH(3')II and neomycin
phosphotransferase II).  Plant cells are normally killed by
antibiotics.  APH3'II inactivates the antibiotics kanamycin and
neomycin and permits plant cells to grow in culture that have
incorporated gene and express the APH(3')II enzyme.
 
Once the desired plant variety has been selected, the marker gene
serves no useful purpose in the new plant, but it does continue
to produce the gene product, APH(3')II in the case of kanamycin
resistance.  This enzyme is present at very low concentrations in
food.
 
The use of marker genes that encode resistance to clinically
important antibiotics raises questions regarding whether the
enzyme in the food could inactivate oral doses of the antibiotic
or whether the gene present in the plant DNA could be transferred
to pathogenic microbes in the GI tract or in soil rendering them
resistant to treatment with the antibiotic.  FDA evaluated these
questions for the use of kanamycin resistance in tomato, cotton,
canola.
 
FDA found that kanamycin and neomycin are very toxic antibiotics
and as such have very limited oral clinical use and are used only
in situations where patients are not consuming food.  There is
also too little of the essential cofactor, ATP, present in food
for the enzyme to degrade a significant amount of antibiotic.
 
There is no known mechanism by which a gene can be transferred
from a plant chromosome to a microbe.  Thus, the possibility of
that such transfer would generate new resistant organisms is very
small, especially when compared to the high rate of spread of
resistance through known mechanisms of microbe to microbe
transfer to antibiotic resistance.  FDA believes that the use of
marker genes that encode resistance to other clinically useful
antibiotics can be evaluated by similar criteria that were used
for kanamycin resistance.
 
7.  ANIMAL FEEDS
 
Feeds developed for animals raised as food sources must be meet
the same safety standards as human food under the FD&C Act.  In
contrast to the human diet, an animal feed derived from a single
plant may make up over half of the animal's diet.  Further,
animals consume plants and plant parts that are not part of the
human diet.  Nutrient composition and availability of nutrients
are important considerations for animal health.
 
8.  LABELING
 
The FD&C Act defines the information that must be disclosed in
labeling (including the food label).  The Act requires that all
labeling be truthful and not misleading.  The Act does not
require disclosure in labeling of information solely on the basis
of consumer desire to know.  The Act does require that a food be
given a common or usual name, and that the label disclose
information that is material to representations made or suggested
about the product and consequences that may arise from the use of
the product.
 
FDA will require special labeling if the composition of a food
developed through genetic engineering differs significantly from
its conventional counterpart.  For example, if a food contained a
major new sweetener as a result of genetic modification, new
common or usual name or other labeling may be required.
Similarly, if a new food contains an allergen that consumers
would not expect in that food, labeling would be necessary to
alert sensitive consumer.  However, if a protein commonly
produces very serious allergic reactions (e.g. peanut protein)
and is transferred to another food, FDA would need to evaluate
whether labeling would provide sufficient consumer protection.
 
To date, FDA is not aware of information that would distinguish
genetically engineered foods as a class from foods developed
through other methods of plant breeding and, thus, require such
foods to be specially labeled to disclose the method of
development.  The agency has not required labeling for other
methods of plant breeding such as chemical - or radiation-induced
not required to be labeled "hybrid sweet corn"  because it was
developed through cross-hybridization.
 
FDA is reviewing public comments on labeling issues.  One issue
that is particularly difficult is the question of whether special
labeling should be required for a food derived from a plant that
has been modified to express a gene derived from an animal and
whether the presence of such a gene or its product affects
certain ethical or religious beliefs.  Currently, no foods are
approaching the market that raise this issue.  However, the issue
is very complex, and FDA believes that further discussion is
warranted.
 
SUMMARY
 
FDA has provided guidance for developers that establishes a
standard to care to ensure that foods derived from new plant
varieties are safe and wholesome.  Irrespective of the method by
which a food is produced, all foods must meet the same stringent
safety standards and be properly labeled in accordance with the
FD&C Act.
 
 
 
REFERENCES
 
1.  Statement of Policy:  Foods Derived from new Plant Varieties,
Federal Register, May 29, 1992, Vol. 57, pages 22984-23005.
 
2.  Food Labeling; Foods Derived from New Varieties, Federal
Register, April 28, 1993, Vol. 58 pages 25837-25841.
 
3.  Memorandum, Summary of Consultation with Calgene, Inc.
Concerning FLAVR SAVR  Tomatoes, May 17, 1994, HFS-206 to HFS-200.
 
4.  Secondary Direct Food Additives Permitted in Food for Human
Consumption; Food Additives Permitted in Feed and Drinking Water
of Animals; Aminoglycoside 3'-Phosphotransferase II, Federal
Register, May 23, 1994, Vol. 59, pages 26700-26711.
 
5.  Procedures of Industry-FDA Interaction Prior to Commercial
Distribution of Foods Derived from New Plant Varieties Developed
Using Recombinant DNA Techniques and Memoranda of Conference on
Seven Genetically Engineered Crops.