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22 October 2018Biotechnology

Gene-editing: a block on further development

In late July, Europe’s highest court handed down a much-awaited ruling on gene-editing which was met by an uproar from parts of the scientific community.

For Huw Jones, professor of translational genomics for plant breeding at Aberystwyth University in Wales, the EU has essentially “turned back the clock on innovation”. This is unlike many other countries that have signalled that, with certain conditions, gene-edited crops are not be regulated by genetically modified organisms (GMO) laws.

After awaiting regulatory clarification for years, researchers and developers were shocked by the court’s decision to subject genome-editing techniques, including CRISPR/Cas9, to more stringent regulations.

On July 25, the Court of Justice of the European Union (CJEU) held that genome-editing falls into the GMO category, meaning it’s covered by the GMO directive.

This means that organisms obtained by mutagenesis, the technique where the genome of a living species is altered without the insertion of foreign DNA, must fulfil the obligations laid down by the GMO directive.

GMOs must be authorised following an assessment of the risks which they present for human health and the environment. They are also subject to traceability, labelling and monitoring obligations—each presenting an onerous task for those looking to develop and sell these techniques.

Confédération paysanne, a French agricultural union, had alleged that herbicide-resistant seed varieties posed a significant risk to the environment and human and animal health, in the same way as GMOs obtained by transgenesis—the process of introducing an exogenous gene into a living organism.

While the CJEU concluded that organisms obtained by mutagenesis are GMOs, it added that older techniques of mutagenesis with a “long safety record” are exempt.

“This decision is both illogical and bad for plant breeding innovation. It encourages older forms of random mutation breeding, which it exempts from GMO regulations, but effectively blocks modern, targeted approaches, which it defines as GMOs and demands disproportional levels of safety data,” says Jones.

Finally, the CJEU noted that EU member states can legislate on such GMOs, provided they do so in a manner that is compliant with EU law.

“The court had to use a limited toolbox (the 2002 directive),” explains Geert Glas, senior IP counsel at Allen & Overy. “Fundamentally, the court had to say ‘we have no specific rules, so we will apply the old rules to a new scientific reality’.”

He says that applying the directive to new techniques of mutagenesis is like comparing apples with pears (the new tools being pears).

Glas adds: “In the end, the CJEU interprets the law but does not make the law. The court however went quite far in limiting the scope of the mutagenesis exemptions.”

What was the industry hoping for?

“The seed sector in Europe had hoped for a clarification that finally acknowledges that these technologies can be applied in different ways, leading to different results that may, and in fact should, be treated differently by the regulator,” says Garlich Von Essen, secretary general at the European Seed Association, a trade organisation representing the seed industry.

While some of these techniques lead to a regulated GMO, others do not, and this differentiation can be made only when we do not solely look at technologies but also consider the final outcome of the process, he explains.

This is the approach most other countries across the globe have taken, says Von Essen, now that they realise that the “rather simplistic approaches of the old GMO rules aren’t fit for purpose for the next era of plant breeding innovation”.

In a further blow to the sector, the judges of the CJEU overturned the opinion of advocate general Michal Bobek, who had proposed “exactly such a more differentiated, more end result-oriented interpretation of the EU legislation”, concludes Von Essen.

Biotech industry group EuropaBio had been hoping for a ruling that would provide the legal certainty and predictability that are essential for the EU’s public and private research into innovations that can address EU and global challenges.

“Instead, this ruling brings genome-editing into the EU’s GMO regulatory framework, which has never been properly or efficiently implemented,” warns Beat Späth, director of agricultural biotechnology at EuropaBio.

Below, LSIPR outlines some of the effects this decision might have.

Expelling innovation

The bottom line is the ruling doesn’t ban gene-edited organisms, but it does make it less straightforward to develop and bring them to market, and introduces significant uncertainty, claims Daniel Rowe, senior associate at Dehns.

These sorts of considerations add costs and risks, he adds, which will put off many investors so the flow of money into research and development in this area will dwindle.

The current GMO framework is characterised by lengthy and sometimes scientifically unjustified assessment procedures, explains Späth. He adds that it even allows for national bans on the cultivation of GM crops for non-scientific reasons.

Späth goes on to say: “The EU has essentially expelled GM crop innovation, and now runs the risk of locking out the benefits of genome-editing from Europe.”

“The EU has essentially expelled GM crop innovation, and now runs the risk of locking out the benefits of genome-editing from Europe.”

Von Essen agrees, adding that even for maize or oilseed rape, today, no applications for cultivation of GMOs are pending in the EU.

Not only is the authorisation procedure “notoriously cumbersome and slow” but it’s politicised, alleges Von Essen, with members states now having the right to ban the cultivation of GMOs on their own territory even following an EU-level approval.

Of the current 28 member states, 19 have introduced blanket cultivation bans in their national laws, he says.

Jennifer O’Farrell, partner at Boult Wade Tennant, provides a counterpoint: she doesn’t believe that the additional restrictions will stifle innovation and, for the products that obtain approval, the rewards will continue to be great.

“There may even be an increase in the profitability of successful products, which is expected to maintain the incentive to innovate in this area,” she adds.

In principle, the authorisation process should be reasonably straightforward for gene-edited organisms which are considered to be indistinguishable from naturally produced organisms, says Rowe.

He adds: “It is only those edited organisms which bring in heterologous traits that would face significant scrutiny and possible refusal of consent. As long as researchers stick to essentially naturally produced products, they should not see too much impact on their activities. Of course, convincing non-technical investors of such nuances will be tricky.”

Brain drain

Will Europe lag behind? In short, the answer seems to be yes. The only question for Von Essen is at what point the lag will become fully evident.

“Companies will quite quickly concentrate plant breeding innovation (PBI)-related research innovation activities outside of Europe,” he says.

Just one day after the ruling, German company BASF essentially ruled out pursuing genetic plant editing in the EU. In 2012, BASF moved its plant research operations to the US from Germany, but this year it agreed to acquire Bayer’s seed business.

Bayer will also avoid trying to bring gene-edited crops to European markets. After the company bought Monsanto, chief executive Wernser Baumann said the combined group would not develop genetically modified crops for commercial use in Europe.

Von Essen expects this position to become the rule, not the exception.

He adds: “The relocation of PBI-related research and innovation activities (and consequent product development and marketing) will be easier for those entities that already possess respective facilities outside the EU.”

The ones that will suffer most are the smaller and more regionally or even locally focused European companies, cautions Von Essen.

It’s important not to underestimate the effect of this ruling on the human resource base of Europe’s plant breeding.

Rowe notes that overall investment in the area will inevitably drop, so less work will be funded. Of the work that goes ahead, early stage work will probably carry on much the same, but field trials could move overseas, he adds.

Glas concurs, adding that the end stage of innovation is likely to suffer, but that it’s unlikely to have as big an impact on preliminary research.

If researchers decide it’s more convenient to do all their research in less regulated jurisdictions, this could lead to a ‘brain drain’.

“But what is worse is the fundamental message the ruling sends to anybody considering a career in plant sciences in Europe: ‘you’re not welcome here’. That may prove the most devastating effect in the longer term."

Von Essen expects Europe will see short to medium-term relocation of research and innovation personnel of both companies and institutes to other countries.

“But what is worse is the fundamental message the ruling sends to anybody considering a career in plant sciences in Europe: ‘you’re not welcome here’. That may prove the most devastating effect in the longer term,” he concludes.

Trade complications and negotiations

Problems may begin to arise for exporting countries as their gene-edited crops, cultivated as conventional varieties, become illegal GMOs when they arrive in the EU.

Tactical concerns need to be taken into account. Glas, who has consulted with a number of scientists, notes that distinguishing products which have been obtained by targeted mutagenesis from products that have been obtained in a different way is very difficult.

This could further complicate trade, particularly for commodity crops, where the EU will need to develop specialist detection methods and exporters will need clarity that the presence of grain from gene-edited varieties would be accepted by EU member states, says Jones.

O’Farrell explains that while additional regulation regarding distribution and marketing of their products is an additional hurdle for importers, there are numerous advantages associated with gene-edited crops.

She adds: “This suggests that importers who are able to successfully navigate the regulations will continue to reap the rewards, and the incentive for producing crops which receive regulatory approval is unlikely to decrease.”

As a consequence of having to ensure that their export products are free of non-authorised organisms, third countries might have to choose whether to allow the cultivation of non-authorised organisms, even for internal use (because of a contamination risk), advises Rowe.

He warns that developing nations might choose to decline gene-edited crops that could help towards meeting their internal food-related issues for fear of losing access to EU markets for their export crops and animal products. This, in turn, could cool research into such crops/livestock globally.

“On the other hand, the EU might find itself isolated with third nations choosing to trade less regulated gene-edited products among themselves,” he adds.

That’s not all: trade between Europe and the US may also be affected, given the US’s stance on gene-editing.

In March, the US Department of Agriculture confirmed that it will not regulate foods created with gene-editing technology, as long as the plants could otherwise have been developed through traditional breeding techniques.

Agriculture remains a sticking point between US and EU trade talks, potentially creating a further barrier to peace.

However, the full impact of the ruling remains unclear and depends on how the European Commission chooses to interpret and act in response to the CJEU’s ruling, concludes Späth.

A better way forward?

“It is perfectly possible to devise a good, proportionate and transparent regulatory policy that would simultaneously ensure safety and stimulate research and innovation,” asserts Jones.

There are some risks: technology can also introduce heterologous traits or unintended “off target” changes, bringing the same concerns as classical genetic modification.

And while Rowe believes that the biotech industry’s use of gene-editing to shape our agricultural future should come under some scrutiny, he doesn’t consider that using “woefully out of date” legislation is the best way forward.

His idea of a better way would be to create purpose-built legislation that is designed with modern gene-editing technologies. This would take into account the different concerns which arise depending on how the technology is used and offering different levels of regulation depending on the risks posed.

However, while O’Farrell believes the ruling presents a challenge to the agritech industry, she believes that a suitable balance has been struck.

“In this case it appears as though a suitable balance has been struck since the availability of patent protection will always drive innovation, while the present decision from the CJEU ensures that the distribution of potentially controversial products is appropriately regulated,” adds O’Farrell.

As uncertainties abound, it’s obvious that the decision from Europe’s highest court could change the future of the gene-editing landscape in Europe and perhaps affect the rest of the world.

“The very clear and unusually outspoken reactions of many of our colleagues in public research, our customers, European farmers and growers, and partners along the EU agri-food chain show the wide agreement that the ruling now has to be accepted from a purely juridical point of view, but that its wider socioeconomic consequences are unacceptable,” says Von Essen.

“To turn an old saying around: if it’s broken, fix it. How it can be fixed to me is still uncertain 
and will require long and difficult discussions. But we will try to fix it, that much is certain,” he concludes.