Stop bringing knives to the gun fight

It is a fact that agricultural biotechnology fails to live up to its expectations. Even if there are groundbreaking developments, the cost of meeting the regulatory conditions is enormous and it takes many years to reach the market (and the market will eventually respond with fear and rejection). Only a few traits have managed to reach the field. Agricultural biotechnology potential is not realized, although it can help hundreds of millions of farmers around the world and become a leading tool in the fight against food supply risks.

However, in recent years voices have been raised claiming that it will be the genetic editing methods, with CRISPR as the most prominent of them, which will pave the way for biotechnology in agriculture. This argument has two components:

  1. Genetic editing may have similar technological potential as other biotechnological methods (or maybe even greater).
  2. Genetic editing will not face the barriers of regulatory procedures and public opposition.

Without an answer to these two components of the argument, genetic editing will not lead to a real revolution in agricultural biotechnology, i.e. the method must have the technological capabilities and also be able to cross the barriers on the way to the field. Therefore, each of these claims must be checked separately and see if they are valid.

In this article we will examine the validity of the two components of the argument. And more importantly, we will analyze in depth the basis for the barriers placed in the path of agricultural biotechnology. Then we will try to see how the obstacles can be removed even without further technological developments.
Let’s begin with the first element in the argument for genetic editing, the technological capabilities:
Genetic editing has been a hot topic in agricultural biotechnology in recent years. Although the ability to perform genetic modification in plants has been around since 1988 , 5 years after the creation of the first transgenic plant , it was the CRISPR technology , developed over the last decade, that improved the ease of editing and made it more accessible to all developers. With CRISPR, a specific change in DNA can be made (deleting, replacing, or adding a small number of bases in a defined location within the genome), thus preventing the proper gene expression (Knockout), or altering its activity (Knockin). In addition, there is an option for CRISPR to insert a foreign DNA segment into a defined location in the genome, without using recombination (this option is in the early stages of research and has no industrial applications yet).Let’s analyze CRISPR’s abilities and advantages:

1. Targeting the modification within the genome
The main advantage of genetic editing is the ability to operate in a site specific manner. This way a control can be gained on both the genetic change and its location.
Targeting of the genetic modification can reduce the collateral damage caused by off target mutations in random mutagenesis, thus preventing the need for backcrossing.
But in relation to “traditional” genetic engineering the advantage is very weak. On the one hand, this ability can prevent problems related to position effect. On the other hand, a simple scan of several lines will result in finding a line with sufficient expression and without deleterious effects. In fact, there is an advantage in scanning lines with different insertion location when it comes to introduction of new genetic traits. Different genetic traits will need different locations within the genome (which would lead to different levels and patterns of expression) in order to maximize their benefits. There is no golden position (Perhaps except for the case of the use of plants as a vectors for protein expression).

2. Eliminating gene activity (Knockout).
The ability to target a specific gene is unique to genetic editing. Adding or removing of just one base in the beginning of a gene’s open reading frame (ORF) will cause a frame shift and thus a complete knockout of the Gene.
The knockout of genes is the basis for the domestication of all crops. For instance the loss of function of the MLO gene in barely during the process of domestication made it resistance to all varieties of the mildew fungus and so as with the mutation in the TGA1 gene in maize which made its kernels to have a smoother and digestible coat. There is a reason knocking out of genes was the primary basis for domestication. Without an informed scanning of plant populations and the ability to induce genetic variance, this is the more likely variance with the more obvious results. In genetic engineering there is the option of Knocking down the expression levels of a gene through RNAi methods, and traits developed using this techniques has been commercialized. There might be even cases were a partial decrease in expression is more preferable than a complete knock out. But overall, in relation to genetic engineering, there is a real advantage here. In random mutagenesis this possibility exists as well, but as mentioned, there is the need for scanning and backcrossing.

3. Changing of the genetic trait (Knockin).
This is an option with far greater potential than the previous one. While eliminating genes activity is limited to the number of genes in the genome, modification of genes opens a door for infinite possibilities. A point mutation within a gene can lead to advanced capabilities and even to a complete change in the activity of a gene. Making this change requires preliminary data. This data could be generated through a previous mutagenesis screen, as with the case of point mutating the ALS gene for imidazolinine resistance. Another way may be through in silico analysis or through good old laborious research. The knockin mutation is a dominant one. This means that for most cases it does not matter if an existing gene has been edited or if a modified version has been introduced to the genome through genetic engineering.

Side note — Put your bet on the winning horse.
As for Knockout and also for Knockin, random mutagenesis can actually get the same results with two disadvantages and one tremendous advantage. The disadvantages are the need for an efficient screening mechanism for the trait and the collateral damage to the genome that can mask the advantage of a specific mutation. The advantage is that in mutagenesis (as with all other methods from what known as “conventional” breeding) we seek for what has succeeded and not what should succeed. This means that in genetic editing (as with molecular breeding in general as it applies today) a research is required prior to editing, and only after the gene has been edited can you know if the genetic modification led to a successful trait. While in mutagenesis you simply look for plants who demonstrate the successful trait. If a genetic modification that was not expected to contribute was the one that led to the advantage trait, it will be noticed. This can be compared to horse racing. If we will study the characteristics of all the competing horses and their track record, we can increase the chances of choosing the winning horse dramatically. But if we will just bet on all of the horses, winning will be much easier.

4. Insertion of a sequence
Overall this capability is no different from genetic engineering. There is one essential difference, which is the ability to target the insertion within the genome. There is also a technical difference as the insertion with CRISPR is mediated mainly through NHEJ (non homologous end joining) or in more rare cases with HDR (Homology Directed Repair), while in genetic engineering insertion is mediated through recombination. This option has not yet been implemented in the breeding industry, but it does have some success in the peer reviewed literature.

So these are CRISPR’s main capabilities. But when referring to the knockout and knockin capabilities, which constitutes the realistic uses for CRISPR, we must mention the greatest disadvantage of the technique. CRISPR has no real ability to fundamentally widen the range of genetic traits within the genome, and genetic diversity is the building block of plants breeding. There are certain improvements and refinements in relation to existing technologies, but CRISPR is lacking the true ability to break the boundaries of plant species. Knocking out genes is the main use of this technology today and changing genes activity through editing is very limited in the practical level and very hard to implement.

It is important to note that this does not mean that genetic editing is not a breakthrough in general, it is simply not a breakthrough in agriculture breeding. In medicine, for example, CRISPR can constitute a real revolution . But here lies the great difference between medical and agricultural technology, we don’t really care about the fate of plants. In agriculture, plants are just a platform for us to produce food. We don’t care if plants will “suffer” because of a genetic treatment. We don’t even care to kill almost all of the plants in a breeding process, as long as in the end we will get one successful plant. This is why we don’t really care if a specific genetic alteration won’t be successful, we will just try again. And this is why methods of much broader genetic impact such as transgenesis or mutagenesis will bring a greater value for agriculture.

So it seems that from a technological point of view, genetic editing does not have the potential of genetic engineering. But what about the second part of the argument in favor of genetic editing. What about the breakthrough in regulation and public discourse? Even if genetic editing will not realize the full potential of genetic engineering, could it be delivered to the fields more easily?

This argument is heard a lot in the scientific community and even in the literature. Let’s analyze the possible change in regulations and the opposition to biotechnology in the public debate.

Starting from the technical level — CRISPR (like most of the genetic editing methods) is not mediated through recombination, but rather through NHEJ and HDR. This is while the leading opposing regulatory agencies worldwide define GMO only if it was mediated through recombination.
The European commission, for instance, define many techniques as GMO (in Directive 2001/18/EC ) but then it is exempting out all of those which are not mediated through recombinant nucleic acid (ANNEX I A). The Cartagena protocol, which is adopted by many biotechnology opposing organizations, Defines LMO (Living Modified Organism) as a crop bred through what they consider to be “modern biotechnology” :

  1. In vitro nucleic acid techniques, including recombinant deoxyribonucleic acid (DNA) and direct injection of nucleic acid into cells or organelles, or
  2. Fusion of cells beyond the taxonomic family.

With the general rule of “not techniques used in traditional breeding and selection;”

So technically, even with regulators which are more conservative, it seems that there is a loophole for genetic editing. Worldwide there are already some examples of regulation authorities which exempt CRISPR from the regulations. It is seen in the US and even in Israel . Although so far only for Knockout traits. On the other hand, in the EU it is still under a debate (for many years), although it is not supposed to be regarded as a GMO according to the regulation. In New Zealand the Supreme Court has ruled that the conclusion of an official professional committee that exempted CRISPR partly from the regulations will not be considered, since this is a matter that must be decided on the political level .But this is of course only a regulatory loophole. If the regulators will agree that CRISPR should be considered under the terms of regulation, then those terms will simply be changed.
There is also the notion that regulators will simply understand that there is no rationale in regulating CRISPR or genetic editing in general. After all, we are talking about a technique that leads to a much smaller change in the DNA than with “traditional” genetic engineering. Those are genetic variations that could occur event without any intervention. In fact, the greater accuracy and the minimal intervention are also supposed to answer the arguments of the opposing side in the public debate. But here lies the great failure, the one for which we refer here to the regulators together with the public debate. These are all logic-based arguments, but logic has nothing to do with this debate (nor with the regulations). This debate is based on emotions, mainly fear. Bringing logic to this debate is as useful as bringing a knife to a gun fight.

Ballistic analysis

Let’s analyze the basis for this opposition. The great failure that stands behind the barriers for agriculture biotechnology is based on a logical fallacy. Based upon this logical fallacy, a bias was formed, when the bias allows the blocking of biotechnology. Let us delve deeper into these two components that builds the barriers for biotechnology, starting from the logical fallacy.

The romantic perception of the field
the source of most of the negative attitude for agricultural biotechnology (as with any progress in agriculture and sometimes progress in general) is a romantic perception of what is called nature (although this perception has almost nothing to do with what nature is actually is). Nature is actually the part of the environment with minimal human intervention. Agriculture practice, no matter how traditional it may be, is just the opposite. Growing of only one plant while eliminating the rest of the vegetation (plus the insects and the entire ecosystem). The processing of the soil, from heterogeneity to homogeneity, and in general, the change of the environment to fit the plant. This is exactly the opposite of nature. The anti-biotech side wants to return to nature, but in nature they will not find tomatoes, oranges, or corn. Crops do not exist in nature nor do they have the ability to grow there. Nature as it referred to by the opposition to GMO’s is actually something else. It is oil painted fields, it is a chapter in an old book, and it is a picture that has not been modernized. It is a romantic perception of what was before the technological progress. It is fueled by aversion from the unknown that progress toward us so quickly. It is an understandable fear. Science and technology has complicated our lives. No one can fully understand even half of the processes concerning our lives any more. It is not a call to get back to “Nature” as it is a call to get away from progress. The graphics will always highlight the dissonance between the open field and the lab (Picture 1). The most commonly identified object with graphics of those opposing genetic engineering is the syringe, when in fact there is no use for it in genetic engineering (except for transient expression uses). It is what symbolizes the penetration of the unknown.

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Picture 1 — Left : Greenpeace activists demonstrating against genetic engineering (GE) crops wearing biological protective clothing. Right — Friends of the earth poster praising organic agriculture

The standalone technique

Side note-Herbicide tolerance , A Case of absurdity .
Herbicides are nothing new to the practice of agriculture, and nor is the resistance of weeds. Still, the use of herbicides in agriculture is seen by many as something related only to biotechnology. The association is mainly due to varieties that are resistant to the Glyphosate herbicide, and to the company who previously had a patent for this product, Monsanto.
In 2007, Greenpeace organization (one of the leaders of the global anti-GMO movement) published a report titled: “Bayer CropScience contaminates our rice”. The report describes how the strain Liberty Link developed by Bayer which is resistant to the gluphosinate herbicide have “contaminated” other strains stocks.
One of the more surprising strains that Greenpeace defended was the Clearfield 131 by BASF. It is surprising because this rice strain has also been developed to be tolerant to another herbicide, imadazolinone. BASF kept the way this strain bred under ambiguity stating it was made “Using conventional breeding techniques”. But the fact is that this strain was bred through chemical mutagenesis. And so Greenpeace basically defend one herbicide tolerant strain from the “contamination” of another, only because one was bred using mutagenesis and the other through transgenesis.
If you think that the level of this double standard aimed at biotechnology methods is something that only the anti-GMO movement fall into, think again. This is exactly the way regulatory authorities around the world are working, although we would expect that they would operate professionally. While the mutagenized Clearfield 131 is grown in the US as in the EU without any regulatory need, the transgenic Liberty Link rice had to go under regulatory process In the US and the EU.
The peak for this absurd is reached with the cv127 soy strain by BASF. This strain is a transgene developed to be herbicide tolerant to imidazolinone. The gene that was used here is also a mutated ALS gene as with the Clearfield strain but this time from Arabidopsis thaliana. Meaning that the genetic result is the same (minus the collateral damage to the DNA by mutagenesis in the Clearfield rice). And yet, the cv127 soy had to go under regulatory process in the US and its cultivation was banned in the EU while no regulatory test was required prior to the cultivation of the Clearfield strains.

Bringing the guns

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Picture 2 — Covers of professional agricultural reports
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Picture 3 — Commercial advertisements for Bayer’s Liberty Link and Monsanto’s Bollgard crops
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Picture 4 –Up- Satellite images of the agriculture area near O’neill Nebraska. Down- regions in the south of Brazil’s rainforests that have been deforested for agriculture activity.(Google maps)

In addition, we must understand that this discussion can never be solved when only the advanced biotechnology methods are referred to. There is nothing without any risk, so actual risk can be measured only in comparison. For example, an airplane itself is a vehicle with many risks involved with using it. But if we have to complete a journey of a certain length, we must examine the risk with regard to the alternatives. If the train, car and bicycle are more dangerous to carry out the journey with, then the aircraft is the safest option even if there are some known risks associated. The same holds for plant breeding. We have to go through the journey because the agricultural goals are going to change if we want to or not. The quantity and composition of food required will vary, the environment will continue to change and make agriculture practice more difficult (while agriculture practice will continue to affect the environment). Pathogens will advance in the arms race against crops. We are on a journey to maintain the security of the food supply, and the journey is in full swing. Even if today there is an ability to feed the entire world adequately, the risks for the next year are real. Fungi such as the UG99 wheat rust strain can be triggered by an environmental que each moment, causing an epidemic that will affect the food security for a vast part of humanity, even in the developed world. When it will break out we will have to deal with it, using one of the different breeding methods exist (not necessarily the advanced biotechnological ones).
If we will continue to hide the other methods from the public debate, we could not argue that advanced biotechnology is a safe practice. We can continue to claim that genetic engineering has been tested for decades for its safety and its impact on agriculture, but what has really been tested so far is not the method, those were just the products. Therefore, if a specific trait has been tested for decades, it only means that new traits should go through the same path to cultivation. Let’s face the facts, we cannot guaranty full safety for this technology. It all depends on what we will do with it (just as with any other technology).
Specific studies have shown a greater difference in the overall expression pattern of plants bred through Mutagenesis, as well as with hybrids when compared to genetic engineering. A report by the National Academy of Sciences states that the methods most likely to create non-targeted traits in plant breeding are actually the various random mutagenesis methods and not genetic engineering. It is only when the accuracy of biotechnology is presented in comparison to the other breeding techniques, it is translated to a higher degree of certainty. And uncertainty is what drives the primal fears behind the public debate. These are not the dangers of elevating the level of toxic compounds or creating new allergens (dangers that can be diagnosed immediately) that feed fear. There is no fear of allergenic exposure of populations to new agricultural species or toxicity in the introgression of solenoids . The primal fear is from the unknown. Health hazards that occur after a long period of latency (primarily cancer) are the real fuel of fear in this debate. Therefore, an article on oncological risks from genetically modified strain has led to a much stronger impact (even after it was retracted) compared to the findings of allergen in a transgene soybean during its regulatory assessment (Picture 5).

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Picture 5 — Google Trends analysis of online searches of the retracted Seralini article (blue line) and the article of the allergenic transgene soybean (red line).

Get into the fight. Now!

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