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(Note: This article is the 2nd in a 3 part series on Genetic Engineering. To read the 1st part, please click here. )
Written by Paul Melamud - Validation Manager, QPharma
Introduction
When we refer to organisms that are “transgenic”, this means that DNA from one species has been inserted into another species for expression. Gene transfer between organisms of the same species is often called “intragenic”, and that between species that are sexually compatible is called “cisgenic”. These latter types are widely known; for example, Gregor Mendel selectively mated pea plants to study genetics in the 1800s, and for another, dog breeders continually attempt to create dogs that perfectly match the personality and stature conformation standards set forth by the Americal Kennel Club. These also comprise the basics behind the theory of evolution.
The first transgenic products were plants, made primarily to create disease-resistant and higher-nutrition foodstuffs (refer, for example, to Hope, a traditionally-produced (non-recombinant) hybrid that saved American wheat crops in the 1930s). In the 1980s, the first true Genetically Engineered or "GE" plants (tobacco) were made with inherent insecticidal and herbicide-resistant properties. These days, there are many bright prospects for products being dubbed “plantigens” and “plantibodies” that will contribute to public health at large, if introduced into standard crops. What may be surprising to learn, then, is that there are not yet any FDA-approved, plant-biopharmed pharmaceutical products.
Processes
There are two main processes that are used to genetically engineer plants for traits such as herbicide resistance. Similar techniques would be employed to cause the plant to express phenotypes with human therapeutic use. The first process, bacteria-mediated transformation, is accomplished with a bacterial vector, most commonly Agrobacterium tumefaciens, a plant parasite that can cause tumors by injecting DNA into host cells. It is this unique mechanism that scientists have harnessed to deliver DNA of their choosing for expression in plants. The second process, biolistic transformation, involves coating pellets of metal, such as tungsten or gold, with DNA and literally firing them into plant cells so that they lodge in the nuclei. Once there, the DNA separates from the metal and becomes integrated with the host DNA for expression.
These two processes are illustrated below, one diagram from McGraw-Hill Higher Education and the other from BBC News (see links below image for references).
Introduction
When we refer to organisms that are “transgenic”, this means that DNA from one species has been inserted into another species for expression. Gene transfer between organisms of the same species is often called “intragenic”, and that between species that are sexually compatible is called “cisgenic”. These latter types are widely known; for example, Gregor Mendel selectively mated pea plants to study genetics in the 1800s, and for another, dog breeders continually attempt to create dogs that perfectly match the personality and stature conformation standards set forth by the Americal Kennel Club. These also comprise the basics behind the theory of evolution.
The first transgenic products were plants, made primarily to create disease-resistant and higher-nutrition foodstuffs (refer, for example, to Hope, a traditionally-produced (non-recombinant) hybrid that saved American wheat crops in the 1930s). In the 1980s, the first true Genetically Engineered or "GE" plants (tobacco) were made with inherent insecticidal and herbicide-resistant properties. These days, there are many bright prospects for products being dubbed “plantigens” and “plantibodies” that will contribute to public health at large, if introduced into standard crops. What may be surprising to learn, then, is that there are not yet any FDA-approved, plant-biopharmed pharmaceutical products.
Processes
There are two main processes that are used to genetically engineer plants for traits such as herbicide resistance. Similar techniques would be employed to cause the plant to express phenotypes with human therapeutic use. The first process, bacteria-mediated transformation, is accomplished with a bacterial vector, most commonly Agrobacterium tumefaciens, a plant parasite that can cause tumors by injecting DNA into host cells. It is this unique mechanism that scientists have harnessed to deliver DNA of their choosing for expression in plants. The second process, biolistic transformation, involves coating pellets of metal, such as tungsten or gold, with DNA and literally firing them into plant cells so that they lodge in the nuclei. Once there, the DNA separates from the metal and becomes integrated with the host DNA for expression.
These two processes are illustrated below, one diagram from McGraw-Hill Higher Education and the other from BBC News (see links below image for references).
 |
| http://www.mhhe.com/biosci/pae/botany/botany_map/articles/article_03.html |
 |
| http://news.bbc.co.uk/2/shared/spl/hi/pop_ups/03/sci_nat_how_a_plant_is_genetically_modified/html/3.stm |
There are a few other, less common methods that are used, including electroporation (electrically inducing transient holes through cell walls and membranes through which DNA can be introduced) and viral transduction (analogous to the bacterial vector transformation method). Electroporation is illustrated below.
 |
| http://www.inovio.com/images/IMG_how_ep_delivers.gif |
Any of these methods can be used to attempt to transform millions or billions of cells – and that’s a good thing, because successes may occur as rarely as one in a billion. Scientists can’t look at every cell, so they have developed techniques (as illustrated above) that can easily distinguish the successes and allow for their isolation. The above method illustrates the use of a “selective agent” or “selectable marker,” which means that only the successfully transformed cells will survive exposure to the negative stimulus (i.e. the herbicide against which the genetic change would protect). Another method is coupling the desired gene with a second one that will provide a “screening marker”, which can be observed by a scientist; an example would be a gene that causes a cell to fluoresce under UV light, which would indicate successful integration of the DNA that was introduced.
Regulation
We can all appreciate how relatively new such products are, and that the process of development, testing, and eventually clinical trials and/or field studies to bring these products to the market would still be underway. There are a few other reasons, though, that I think explains why we don’t see such products on the market yet.
One reason behind this is that...
a large number of agencies are involved with new and evolving regulations governing transgenic plant products, including:Regulation
We can all appreciate how relatively new such products are, and that the process of development, testing, and eventually clinical trials and/or field studies to bring these products to the market would still be underway. There are a few other reasons, though, that I think explains why we don’t see such products on the market yet.
One reason behind this is that...
- USDA – its Animal and Plant Health Inspection Service (APHIS) branch has jurisdiction over the planting of GE crops, and focuses on the risks of such crops escaping a farm and becoming agricultural pests. Authority is granted to them by the Plant Protection Act (PPA, 2000).
- USEPA – has responsibility for plant-incorporated protectants (PIPs), focusing on the environmental health and safety related to their pesticide qualities. Authority is granted to them by the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA, 1947 et seq.), the Toxic Substances Control Act (TSCA, 1976), and the Food Quality Act (FQPA, 1996).
- FDA – has jurisdiction over most food and feed uses of plants by humans (and other animals). Authority is granted to them by the Federal Food, Drug, & Cosmetic Act (FFDCA, 1938 et seq.).
- FDA again – has jurisdiction over the derived drug intended to be administered to humans or animals (for veterinary products).
Publications by regulatory bodies regarding transgenic plant products include (note: not intended to be an exhaustive list):
- USDA (APHIS): Guidance for APHIS Permits for Field Testing or Movement of Organisms Intended for Pharmaceutical or Industrial Use, July, 1998.
- USFDA (CBER): Points to Consider in the Production and Testing of New Drugs and Biologicals Produced by Recombinant DNA Technology, April, 1985 (DRAFT).
- USFDA (CBER): Draft Guidance for Industry: Drugs, Biologics, and Medical Devices Derived from Bioengineered Plants for Use in Humans and Animals, April, 2003.
- EMEA: 2001/18/EC, Directive on the Deliberate Release into the Environment of Genetically Modified Organisms (2001).
- Also see http://www.biotethics.org/downloads/articles/EU%20Legislation%20GMOs.pdf, which covers many other EU regulations, recommendations, and guidances on this subject.
Additionally, the reader is directed to 40 CFR Parts 700-725 for the US Environmental Protection Agency's (EPA) regulations on microbial products of biotechnology, which are enforced under the auspices of the Toxic Substances Control Act (TSCA) of 1976. EPA defines “new” microbial products as those “formed by deliberate combinations of genetic material from organisms classified in different taxonomic genera,” and therefore they have some overlap with this discussion of transgenic organisms.
Controversy
As stated in the introduction to my previous blog, there are already a few transgenic animal products (e.g. ATryn) on the market – so numerous and potentially confusing regulatory pathways cannot be the barrier here. Why then are there no transgenic plant pharmaceutical products on the market?
I haven't found the difference explicitly spelled out in the literature anywhere, but the biggest distinction is in the isolation and intended administration of the product. Generally speaking: GE plants would be ingested to impart their inherent therapeutic properties to the host, while animals tend to be engineered to produce a therapeutic agent (e.g. in blood or milk) that is treated more traditionally like a pharmaceutical chemical; namely: separated, purified, and administered as would most types of drugs (e.g. oral tablets, patches, injections). Given our history, risks are better understood in the latter “chemical production” processes.
So, what are the biggest risks considered inherent to GE plant products?
According to numerous articles, a primary concern is that the introduction of genes for antibiotic or viral resistance may be transferred to bacteria within the body of an animal or human that ingests the GE plants. The concern, then, is that the bacteria themselves could be transformed to be resistant, which would render even the conventional treatments ineffectual.
But to me, the main obstacle to extensive promotion and market acceptance of such products certainly lies in the ecological risks, as continually emphasized by public advocate and lobbying groups under the buzzword “biosafety.” Of particular concern is the fact that control of containment is difficult to manage (especially when compared to controlling animal breeding), as pollens can float through the air and off of the farm to hybridize with non-GE plant crops. Will escape of the gene cause massive changes in the wild-type flora, and ultimately affect the ecosystem? What if these changes render plants inedible to animals that rely on them for sustenance? Not only does this send ripples up the animal food chain, but it might create “superweeds” that could become invasive since they are no longer naturally kept in check. It is for increasing public awareness and concern for these risks that many governments (e.g. Japan, and even local governments in California) have been instituting bans on new GE food crops, with extensive testing against these kinds of risks to be presented before consideration shall be granted to allow a company to grow such a crop in one of those countries or states.
There are numerous other concerns that I feel are far lesser hurdles for public acceptance of such products. For example, ethically speaking, should corporations be allowed to own a food source (could this lead to a monopoly)? Would superior food be withheld from impoverished areas because there is little to no money to be made on such investment?
I recognize that public fears do erode over time, with the onset of scientific understanding and promises of wonderful things. For example, how many of us remember the introduction of the microwave oven? These devices took many years to gain wide public acceptance; in fact, we now use colloquially the expression “nuking one’s dinner” in a positive way, while it still echoes the main fears of ingesting irradiated food. These days, it is the rare modern household that does not own at least one of these handy appliances. So despite the major challenges presented here, I do predict a future for GE-plant-based biopharmaceuticals.
Further Reading
For more reading on this subject, I recommend the websites referenced within this article, and additionally the following articles, which are available for free on-line:
Controversy
As stated in the introduction to my previous blog, there are already a few transgenic animal products (e.g. ATryn) on the market – so numerous and potentially confusing regulatory pathways cannot be the barrier here. Why then are there no transgenic plant pharmaceutical products on the market?
I haven't found the difference explicitly spelled out in the literature anywhere, but the biggest distinction is in the isolation and intended administration of the product. Generally speaking: GE plants would be ingested to impart their inherent therapeutic properties to the host, while animals tend to be engineered to produce a therapeutic agent (e.g. in blood or milk) that is treated more traditionally like a pharmaceutical chemical; namely: separated, purified, and administered as would most types of drugs (e.g. oral tablets, patches, injections). Given our history, risks are better understood in the latter “chemical production” processes.
So, what are the biggest risks considered inherent to GE plant products?
According to numerous articles, a primary concern is that the introduction of genes for antibiotic or viral resistance may be transferred to bacteria within the body of an animal or human that ingests the GE plants. The concern, then, is that the bacteria themselves could be transformed to be resistant, which would render even the conventional treatments ineffectual.
But to me, the main obstacle to extensive promotion and market acceptance of such products certainly lies in the ecological risks, as continually emphasized by public advocate and lobbying groups under the buzzword “biosafety.” Of particular concern is the fact that control of containment is difficult to manage (especially when compared to controlling animal breeding), as pollens can float through the air and off of the farm to hybridize with non-GE plant crops. Will escape of the gene cause massive changes in the wild-type flora, and ultimately affect the ecosystem? What if these changes render plants inedible to animals that rely on them for sustenance? Not only does this send ripples up the animal food chain, but it might create “superweeds” that could become invasive since they are no longer naturally kept in check. It is for increasing public awareness and concern for these risks that many governments (e.g. Japan, and even local governments in California) have been instituting bans on new GE food crops, with extensive testing against these kinds of risks to be presented before consideration shall be granted to allow a company to grow such a crop in one of those countries or states.
There are numerous other concerns that I feel are far lesser hurdles for public acceptance of such products. For example, ethically speaking, should corporations be allowed to own a food source (could this lead to a monopoly)? Would superior food be withheld from impoverished areas because there is little to no money to be made on such investment?
I recognize that public fears do erode over time, with the onset of scientific understanding and promises of wonderful things. For example, how many of us remember the introduction of the microwave oven? These devices took many years to gain wide public acceptance; in fact, we now use colloquially the expression “nuking one’s dinner” in a positive way, while it still echoes the main fears of ingesting irradiated food. These days, it is the rare modern household that does not own at least one of these handy appliances. So despite the major challenges presented here, I do predict a future for GE-plant-based biopharmaceuticals.
Further Reading
For more reading on this subject, I recommend the websites referenced within this article, and additionally the following articles, which are available for free on-line:
- www2.biologie.uni-halle.de/genet/plant/staff/koebnik/teaching/biotech2004/Talks/8_Plantibodies/8_Literatur/Giddings_1151.pdf
- www2.biologie.uni-halle.de/genet/plant/staff/koebnik/teaching/biotech2004/Talks/8_Plantibodies/8_Literatur/Mason_324.pdf
- http://aob.oxfordjournals.org/cgi/reprint/84/3/269.pdf
Questions to Our Readers:
- What do you think of the author’s opinions about why we don’t have any transgenic plant-based drugs on the market yet? Is he missing something, or do you agree?
- Vaccination by way of eating potatoes was referenced last week – a pretty crazy and cool idea, huh? Does this technology give you any interesting or even fantastical concept for a new plant-based product?
- What do you see for the future of transgenic plant-based products?
- Can you provide hyperlinks any other articles on this subject that might be of interest to the readers?
In the next blog entry, I shall focus on transgenic animal products. Stay Tuned!
Concerns have arisen about the amount of medications and their residues (Triclosan and Prozac to name a few) being found in American municipal water systems. Should such ramifications be included when discussing the adoption of trans/intra/cis-genic substances in addition to the possiblity of altered organisms escaping into the wild?
ReplyDeleteThat is going to be highly dependent on the nature of those medications and the GE animals. For the most part, industry has tried to make GE animals that are in most respects similar to their natural counterparts except for one or two differences. In the case of the salmon, it is the rate of growth, not even the extent (size). So I don't see the introduction of human medication contamination being of particular concern any moreso than it would be for the natural population.
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