Let's talk about GMOs, part two: What are we using them for?



Introduction

In my first post, I discussed what DNA is and how it relates to phenotypical (outward) change through the central dogma of molecular biology. In the second post I discussed the techniques of genetic engineering, including the novel and prodigal technique called Crispr/Cas9.


We will now look at the current uses of the technology. I  do notwant to include research purposes in this overview, but in the next post because they are very relevant. We'll start with the most important current application, and move down from there towards areas that are not fully developed yet.

Medicine

I think this is our most important current application. We've already covered Insulin when discussing the technique, but there are others. The general name they use for this application is biologics made by recombinant DNA technology. A more common name is bio-pharmaceutical, also known as biologic(al) medical product. In principle, bio-pharmaceutical refers to any pharmaceutical whose manufacturing involves biological sources [wiki]. Wikipedia gives a list of the major kinds of such bio-pharmaceuticals:
An example of a book written on the principles and
applications of biotechnology. [ISBN-13: 978-1555814984]

  • Blood factors
  • Thrombolytic agents
  • Hormones 
  • Interferons
  • Interleukin-based products
  • Vaccines
  • Monoclonal antibodies
  • Additional (e.g. tumour necrosis factor, therapeutic enzymes)

This seems to bode well for the amount of examples we can find. This is not surprising; universities offer both undergraduate and graduate programs that focus on this topic alone. For illustration, I found a book (right) that is purely on the principles and applications of recombinant DNA technology, first written in 1994 and now in its 4th edition (2009). I'll try to give an example of each item in the list.

Hemophilia is caused by the failure to produce certain proteins required for blood clotting. A patient has a reduced or no ability to form blood clots and continues to bleed, even from minor injuries. In the late 1950s, the technique used for treatment of Hemophlia was 'Fresh Frozen Plasma'. In essence, donor blood was centrifuged so that only the plasma (containing trace amounts of clotting factors) was left. This was then administred, in large quantities, to Hemophilia patients. The technique was later refined; the trace amounts were separated. Even so, the amount of donor blood used to make a small amount of clotting factor was tremendous.  An additional issue is that viruses, such as hepatitis viruses and HIV, were transmitted with the plasma-derived clotting factors. Steps were taken to prevent this, but it was still of great concern. In 1984, the factor VIII gene was cloned. Three years later, recombinant human factor VIII entered clinical trials in humans. Factor IX was cloned as well, and both (recombinant) factors entered the market in the 90s [Hematology.org].

Thrombolysis is the breaking down of blood clots using medication. It is almost the opposite of blood clotting factors. It is often used as emergency treatment to dissolve blood clots that form in arteries feeding the heart and brain. These are the main cause of heart attacks and strokes. Another good application is clots in the legs, pelvic area or upper extremities. While these seem innocent, the clots or pieces of it can break off and travel to an artery in the lungs, causing acute pulmonary embolism [webMD]. I found a rather nice resource detailing the modifications made for the production of Tenecteplase, one of the approved medicines for Thrombolysis. It also notes the 'Pharmocodynamics', which explains how they work. In this case, it binds to clots rich in  'fibrin' and cleaves another protein. That protein's two parts degrade the fibrin, which eliminates the blood clot (Thrombus). Chinese hamster ovary cells are the cell line of choice. No, that doesn't mean hamsters are slaughtered for this purpose; they are cells first derived from a chinese hamster, but have mutated to reproduce under laboratory conditions. This is called an Immortalised Cell Line. The chinese hamster line is a common one, often used for this sort of research or application. A plasmid induces the gene for human Tenecteplase and a antiobiotic resistant gene. The cell line is allowed to reproduce and is then purged to find the succesful cells. There is no antibiotic present in the final product [FDA].

The most important human Hormone has already been discussed: Insulin. Another example is the Human Growth Hormone, first extracted from the pituitary glands of cadavers. Recombinant biotechnology made it possible to produce these hormones in bacteria. The recombinant form is called somatropin [Wiki]. Human growth hormone stimulated growth, cell reproduction and regeneration in humans and other animals. Somatropin is used as a prescription drugs to treat children's growth disorders and adult deficiencies. It is also banned from use by competitors in sports as a performance enhancing drug.

Interferons are a group of signalling proteins made and released in response to the presence of several pathogens such as viruses, bacteria, parasites and tumour cells. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defences. An example is Intron® A ([Merck]. This is another example of plasmid-induced medicine production in E. coli (like Insulin). It is used as a prescription medicine for various types of cancer, sometimes along with chemotherapy. Additionally for chronic hepatitis B and C with stable liver problems. Note that it has serious side effects [FDA], but that these are not related to the technique but to the substance.

Interleukins are another group of signalling proteins, first observed by white blood cells (leukocytes). A number of rare deficiencies of interleukin have been described, featuring autoimmune diseases and immune deficiencies. For example, Interleukin 2 greatly promotes the cell division, and thus amount, of certain T cells. T cells are an elementary part of the immune system. Aldesleukin is an example of recombinant interleukin (2), and is used against cancer, in particular metastatic liver and skin cancer [chemocare].

Recombinant vaccines are a subject so important that Nature, the giant of scientific publishing was my top result on Google. Nature features a dedicated 'subject' on recombinant vaccines. They summarise:
A recombinant vaccine is a vaccine produced through recombinant DNA technology. This involves inserting the DNA encoding an antigen (such as a bacterial surface protein) that stimulates an immune response into bacterial or mammalian cells, expressing the antigen in these cells and then purifying it from them.

A new and exciting form is just entering the research area, which we'll talk about in the next post. For now, I want to explain about 'DNA vaccines' and 'protein subunit vaccines' [genScript], both of which have just left the research area. Before we do that, we need to get a confusing term out of the way. An antigen is a molecule capable of inducing an immune response on the infected/host organism. It is any substance that causes the immune system to produce antibodies against it. Often, antigen and antibody confused.

DNA vaccines insert a purified plasmid, often cultured in E. coli, into the vaccinated individual. These plasmid only produce the antigen, leading the body to recognise and response as if the entire pathogen was there. However, only a antigen is made; it does nothing to you. But as they say, we need to use and boost our immune system. While that is a rather flawed statement, vaccines do exactly that; we use our immune system by giving it a harmless antigen that will teach it what to attack [WHO]. I do want to point out only a few are available for veterinary use and but a singular one for human use [Wiki]

Protein subunit vaccines are another example of the power of recombinant DNA technology. Antigens are produced in E. coli or other cells (e.g. yeast) and purified from there. Injection of these antigens triggers the immune response and memory, so that the recipient becomes immune. The two techniques listed here, and the new one I'll return to, are all techniques that synthesise part of a virus so that the host can be immunised in a carefree manner [Journal of Pharmacy and Pharmacology]. For instance, the protein subunit vaccine for Hepatitis B is composed of synthesised surface proteins only [GELifeSciences].

Monoclonal antibodies bind to specific antigens and induce an immune response. They are a part of possible cancer treatment, with several approved by the FDA for this purpose. They are also used for autoimmune disease because they can target the triggers of these diseases. Of course, you need to make a specific antibody; in the case of cancer, it can even be that you need to tailor the antibody to this specific cancer [Wiki]. It is clear where genetic engineering plays its role, typically by the plasmid method on E. coli [Methods in Molecular Biology]

I think the above gives a fair indication of genetic engineering in medicine. A lot of different applications have been found, and this increases ever more. And you can imagine what the impact of Crispr/Cas9 will be, as it makes the entire process significantly simpler.

Genetically Modified Crops

Ordinary rice (left) versus Golden Rice (right) [[Business Insider].

This is where the public debate rages. I will remind readers that this post is not about the safety of things, but about the current applications of the technology. We will discuss the safety, regulations and ethics behind it in another part of the series. In this section, I want to discuss the currently available technologies. I won't go into the companies or their practises. I also won't discuss the future uses, which is a different post in the series.

A lot of the currently available crops are herbicide resistant. The first technology we want to look at are GM soybeans, whose patent has expired and which are now in the public domain.

The soybean are engineered to be resistant to the herbicide glyphosate. You might have heard of that pesticide; it has accumulated interest when one branch of the World Health Organisation (WHO) classified it as 'probably carcinogenic to humans', much like grapefruit juice or working a night shift [IARC]. That branch was then found to be wrong by other branches of the WHO, but also by other agencies such as the European Food Safety Authority [EFSA]. As one of the most used pesticides [Nature] it understandably receives a lot of criticism from anti-pesticide groups and the organic lobby. While this might seem about safety, it is too recent and relevant not to mention it. We'll discuss this in depth in the safety post.
Acreage in Yield of soybean in the US [USDA].

Why would you want a glyphosate-resistant soybean? Is it so you can spray more? Not really, because glyphosate is expensive. While it is true that a farmer can spray more herbicide in a single application, the amount of applications over a growing season is less. A rather nice report featuring a metric (number representing fairly) of the toxicity of a pesticide and the amount of active ingredient shows that the amount of active ingredient has been reduced since 1996 and the environmental impact has fallen by 20.4% [ BioFortified ]. A more recent version of that report, covering the period of 1996-2013, concludes:

Across all of the countries that have adopted GM Herbicide Tolerant soybeans since 1996, the net impact on herbicide use and the associationed environmental impact has been: 

  • In 2013, a 3.1% increase in the total volume of herbicide active ingredient applied (6.8 million kg) but a 9.3% reduction in the environmental imapct 9measured in terms of the field EIQ/ha load);
  • Since 1996, 0.1% less herbicide active ingredient has been used (2.3 million kg) and the environmental impact applied to the soybean crop has fallen by 14.5%.
However, these seem to be absolute numbers. The chart on the left shows us that since 1996, a 15% increase in the acreage of soybeans in the US is also present. That would indicate a 13% decrease in herbicide active ingredient per acre, which I consider to be a good result. The environmental impact would have lessened by more than 25% per acre. (If we assume the increase in the US is typical.) The report also details the increases in yield for soybeans and many other GM crops.

Most of us feel uncomfortable with the idea of spraying pesticides on our crop. However, we have no such issue with plants that deal with their pests by themselves. Why not make them? These plants would be extremely specific, only dealing with the pests that feed on them. This could reduce insecticide use, pest suppression and conservation of beneficial natural enemies. More than 66 million hectares of Bt crops were planted in 2011 alone, accounting for 67% of corn in the US in 2012 and 79-95% of cotton planted in Australia, China, India and the United states during 2012-2012. In India, for instance, the average Bt cotton farmer realises a pesticide reduction of roughly 40% and a yield increase of 30-40%. Farmers their satisfaction is reflected in a high willingness to pay for Bt seeds [Journal of Agrobiotechnology Management & Economics].

Of course, such uses have drawbacks, particularly insects evolving resistance. Numerous strategies are being implemented and concern to deal with that problem. The primary one is called the refuge strategy, which is that most of the rare resistant pests (mutants) surviving on Bt crops will mate with the relatively abundant susceptible pests from nearby refuges of host plants without Bt toxins. If inheritance of resistance is recessive, the progeny from such mating will die on Bt crops, delaying the evolution of resistance [Nature Biotechnology].
Timeline of the Golden Rice project [IRRI].

There are of course many possible other traits that could be introduced in GM crops. For example, Golden Rice. Vitamin A deficiency is prevalent among the poor whose diets are based mainly on rice or other carbohydrate-rich, micro-nutrient-poor calorie sources. Rice does not contain any pro-vitamin A, which their body could convert to vitamin A. Vitamin A deficiency compromises the immune systems of approximately 40% of children under five in the developing world, being most severe in Southeast Asia and Africa [goldenrice]. What if we could make a simple change, introducing a variant of Rice that does have pro-vitamin A? This is the driver behind the International Rice Research Institute. The project is non-commercial; the idea is to develop the product and give it to those who need it. In June 2016, 123 Nobel Laureates wrote to Greenpeace, the UN and the governments around the world. They stated that organisations opposed to modern plant breeding, with Greenpeace in the lead, have repeatedly denied these facts and opposed biotechnological innovations in agriculture. That they misrepresented the risks, benefits and impacts, supporting the criminal destruction of approved field trials and research projects. They specifically called for these organisations to abandon their campaign against GMOs and Golden Rice in particular [SupportPrecisionAgriculture].

Again, I am not able to give you a complete overview of all the different technologies that are the result of modern plant breeding, as the laureates so beautifully put it. However, I do think this is a nice first look at it. Having covered medicine and crops, we move on to modified Animals.

Animals

I've alluded to genetic engineering as a vibrant and active area of research. For animals, this too is true. We will again skip this topic, because we discuss the use of genetic engineering in research in the next post. Given both the difficulty of genetically modifying image and the strong precautionary principle at work, the number of technologies that we can discuss in this section is limited.

First, we have an anticoagulant antithrombin that is gathered from a genetically modified goat. It is the first medicine produced using genetically engineered animals, producing the same amount of antithrombin in a year as ninety thousand blood donations. It has been approved by the FDA in 2009. A point of concern that is always stronger when we speak of animals is the well-being of the host animal. There are no ill-known effects; it's just a milk goat [Wiki].

A genetically altered zebrafish, called the GloFish for the US brand, is a patented brand of fluorescent zebrafish with bright red, green and orange fluorescent colour. It is only sold as a pet in the United States and Taiwan. Originally, the fish was a part of a research project. Zebrafish are model organisms, a species that is extensively studied to understand particular biological phenomena. Dr. Gong and his colleagues at the National University of Singapore were working on making a zebrafish that would signal pollution by selectively fluorescing in the presence of pollution [Wiki]. The concept of having fluorescent fish that respond to certain chemicals seems to be one that he is still interested in.

AquAdvantage salmon via Nature news.
AquAdvantage salmon is a genetically modified Atlantic salmon that is also triploid. Triploids means that the gametes of these animals have three sets of chromosomes [Wiki], a trait that is not characterised as genetic modification. The sterility arises when only one sex is released; having three sets of chromosomes, their gonad development is impaired. For female triploids, they do not develop at all. Male triploids undergo partial or altered puberty, but cannot reproduce [Sustainable Fish Farming]. Triploid fish have been used in the US state of Washington to stock waterways for angling. AquAdvantage salmon have the trait of directly producing a growth hormone protein, achieving accelerated growth rates. Inducing triploidy reduces the risk of interbreeding with wild-type fish and increases growth by removing the stress of reproduction [Wiki]. The AquAdvantage salmon has been approved for human consumption, and is the first genetically modified animal with that approval [Nature News].

Conclusion

We've now discussed a number of currently available technologies. Surprising to some, most of the current applications lie in medicine, not agriculture. Part of the reason that medicine is not discussed as much is because it is seen as a more complex topics, the details of which people do not want to know. Agriculture and farming in general is quite complex, but more accessible to people their imagination. Even so, people often think that their experience managing a few square metres of vegetables is sufficient data to make claims about agriculture.

Additionally, especially when discussing the genetically modified salmon, we have touched on some safety concerns. In the next post, we will continue speaking of genetic engineering applications, now with a focus on applications in research. That will be a difficult post, largely because research concerns are often quite complex and arcane. However, it will also be interesting because it opens up the Horizon of genetic engineering applications.




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