Numerous “technical constraints” have led to delays in commercialisation, say Argentine government scientists. Report: Claire Robinson

Announcing the passing into law of the Genetic Technology Act, which removes regulatory safeguards around a whole subclass of GMOs, notably those produced using gene editing, the Westminster government breathlessly enthused that the UK had now joined “Argentina, the US, Australia and Japan”, which “have already enacted similar legislation, driving innovation on a global scale and helping fight the greatest challenges facing the world”.

I can’t pretend that GMWatch was waiting with bated breath for the “new GM”-based “innovation on a global scale” that was supposed to be pouring out of these countries, especially given the dismal performance and fate of the handful of gene-edited crops that they've released.

But the history of GM crops has settled into a pattern of hyped reports of supposed successes continuing for a good few years before they give way to sad tales of technology failure. So at this early stage of the “new GM” journey, we were expecting something reasonably upbeat about gene-edited GM crops from these deregulatory pioneering countries.

What we didn’t expect just yet is the catalogue of abject failure that’s detailed in a recent article by Argentine government scientists, published in the journal Plant Science and titled, “Multiple challenges in the development of commercial crops using CRISPR/Cas technology”.

While we're constantly told by lobbyists and their friends in political circles that overly onerous regulations are what’s been holding back gene editing from fulfilling its promise, the authors of the article explain that the main factor is rather various “technical constraints” that have led to “a concerning delay in the commercialization of [gene-]edited plants”. It seems scientists are having difficulty engineering desirable traits into plants and bringing marketable lines of plants to market.

Technical problems in getting engineered traits into plants

The authors explain that the commercial profitability of herbicide-tolerant and Bt insecticidal first-generation GM crops was enabled by three factors:

1. These are genetically simple traits that are easy and cheap to engineer into plants.
2. It's also easy to check that the traits have stably integrated into commercialisable high-performing (“elite”) plant varieties, reducing the cost of molecular analysis.  
3. These are dominant traits, meaning that they will definitely appear in the offspring if one of the parents contributes it. That’s even the case if the plant to be engineered has many sets of chromosomes (“multiploidy”), meaning that any genetic modification has to be targeted to all sets.
The authors state that finding these three features together is rare in both older-style transgenic and new gene-edited traits.

Technical problems in producing commercialisable edited varieties

The authors point out that there is a “common belief in the scientific community” that directly gene editing elite varieties avoids the lengthy processes of transferring desired genetic material and developing a viable commercial variety that have impeded the development of older-style GMOs. This is certainly a claim that GMWatch has heard the deregulation lobby repeating to politicians. But these assertions are false, the authors explain. Just as with older-style GM crops, developers of new gene-edited crops must work to ensure stable expression of the edited trait over several generations, reliable inheritance of the trait, absence of undesired traits, such as growth penalties, due to the unpredictable genome-wide effects of the genetic transformation (pleiotropy), and absence of undesired effects due to unintended chromosomal rearrangements.

Unsurprisingly, the authors point out, the process of “optimizing the transformation of particular elite germplasm, producing and characterizing edited events in this background under field conditions, seed increment, and cultivar registration is a lengthy process”.

There is also the problem of multiple foreign DNA fragments that unintentionally get inserted into gene-edited plant cells during the editing process. These may persist in the final plant to be marketed. That’s a problem if the plant is claimed to be “transgene-free", which is one of the most common claims made in favour of gene-edited plants and a principal reason advanced for exempting them from existing GMO regulations. Identifying and removing these fragments is expensive, even after several rounds of backcrosses assisted by high-throughput genomic analysis tools, the authors state, and even then, “the absence of foreign DNA cannot be completely confirmed”.

Single-copy genes and dominant mutations needed

The authors state that incorporating multiple edited copies of genes into plants can be costly (not to mention, given their previous points, technically difficult). Therefore they advise that focusing on a single-copy gene as the editing target “may be the most effective approach” to hasten the production of commercially viable edited varieties.

In addition, major crops resist being engineered with traits that are genetically “recessive” (not dominant). So gene-edited crop developers should focus on dominant mutations.

Given the above list of technical problems with crop gene editing, GMWatch asks: Why did the scientists advising the UK government and the EU Commission on their GMO deregulatory agenda omit to point out these cautionary facts? Why did they choose instead to paint a picture of unimpeded agricultural progress if only those pesky GMO regulations were removed? Will they be held accountable for misleading the politicians?

“Give us your money"

The authors note that first-generation GM crops were developed by big companies with large investments justified by equally large profits. But with gene editing, the landscape is different: there is an “absence of simple traits offering huge profits”. Breeding companies prefer to focus on “conventional traits that are accepted as non-transgenic in any country”. Meanwhile, “researchers generate numerous edited traits with biotechnological purposes, without considering possible downstream limitations" of a technical nature. As a result of these issues, there is a lack of investment in crop gene editing. The authors say the way to plug this gap is by pouring in public money, to “encourage public-private projects with high technical feasibility”.

The authors do not explain why the public should shoulder the risks that industry refuse to take in order to shore up an already-failing venture, especially when any profits from intellectual property rights and royalties will accrue to the industry.

The public has been sold the line that this technology is such a sure-fire bet that all governments need to do is to take their foot off the regulatory brake for it to rapidly deliver remarkable results – even including promptly solving the current food price crisis.
 
But now we’re being told that the technical difficulties are so great that the public needs to wade in and heavily subsidise it – or it won’t be going anywhere much.

Hope over experience

In a seeming attempt to explain away forty years of relative failure of first-generation GM crops, the authors state in their conclusion that while “plant genetic engineering can provide significant economic benefits”, there are still “many challenges to overcome in order to translate transgenic prototypes into commercially viable genetically modified crops”. In spite of this, they somehow retain the faith that a new generation of gene-edited crops will provide “enormous economic and ecological benefits in the face of global environmental change”.

In light of the many serious difficulties facing the gene-edited crop venture highlighted by the authors, this statement appears – to borrow Samuel Johnson's definition of second marriage – a triumph of hope over experience.

During the UK government’s frenzied runup to GMO deregulation, we were aghast that they held up Argentina – a former fertile breadbasket turned into a toxic no-go area by GMO agriculture – as a role model. The new paper – despite the authors’ attempts to rescue the image of GM technology – provides a potent immunisation against further idolatrising of Argentina and other countries that have rushed over the GMO deregulation cliff.

Doomed to fail

Commenting on the new paper, molecular geneticist Prof Michael Antoniou said, “The authors’ recommendation that gene editing should focus on single-gene dominant traits (an example would be herbicide tolerance) smacks of desperation to save an already failed technology. Gene editing has been sold to politicians and the public as the way to easily and rapidly engineer traits like drought or heat tolerance and disease resistance into crops and thus meet sustainability goals.

“However, such traits are genetically complex in nature, meaning that they have at their basis the coordinated functioning of many genes, or even the balanced functioning of the entire genome of the plant – a concept known as omnigenics. I highlighted this feature of genetically complex traits in a previous GMWatch article as something that gene editing could simply not deliver. The only way to succeed is by bringing together the families of genes that underpin a complex trait through natural breeding.

“Therefore the Argentine scientists’ admission that they are facing many challenges in commercialising gene-edited crops – we presume particularly those with complex traits – comes as no surprise. The biological realities of life don’t allow you to introduce complex traits by manipulating one or a few genes through gene editing. Attempts to do so are doomed to fail, regardless of how much money you pour into the venture.”


The new paper:
Ayub N, Soto G (2023). Multiple challenges in the development of commercial crops using CRISPR/Cas technology. Plant Science 335: 111809. https://www.sciencedirect.com/science/article/abs/pii/S0168945223002261