New biotechnology techniques can revolutionise agriculture, but the legislative picture remains confused

Several decades on from the bursting of the genomic bubble, the climate in Europe is now improving for plant biotechnology companies.

The legislative picture, and what officially defines genetic modification, is not straightforward. There is a ban specifically on the cultivation of genetically modified crops in some states in the EU. But, generally, biotechnology techniques are booming. (See box.)

Non-GM plant science in research laboratories and highly automated greenhouses is thriving. Among them is the Food Valley hub centred on Wageningen University in the Netherlands; FlandersBio in northern Belgium, where more than 220 biotechnology companies feed off the Flanders Institute for Biotechnology (VIB); a nucleus of universities and research facilities found in North Rhine-Westphalia, Germany; a community of researchers around Oxford in the UK; and a cluster in Lund, southern Sweden.

The debate on modified crops may shift if technological advances in molecular breeding force a redefinition of what it means to genetically alter a plant. Through the use of advanced DNA mapping and new targeted mutation of molecules, genes relating to fungal resistance, plant reproduction, and herbicide tolerance, for example, can be discovered and then selectively turned on or off, depending on the desired effect.

Europe leads the world in this field, with mostly small and medium-sized molecular breeding companies such as KeyGene, based in Food Valley, helping to usher in a new generation of biotech crops.

“We are experiencing what I call a ‘green gene revolution’,” says KeyGene chief executive, Arjen van Tunen.

‘Natural’ modification

It’s different from earlier biotechnology, says van Tunen, because genes aren’t being inserted from one species to another. New techniques concentrate on modifying genes that are natural to specific organisms.

At present, simple traits such as taste or size are easily identified, but more complex traits, known as quantitative traits, such as disease or drought resistance, are more difficult to identify in a crop plant.

“The trick is in determining which of those genes are directly linked to your trait of interest,” says van Tunen. “When you know all the sequences of the crop plant's 20,000 to 30,000 genes, then you try to select with computers a range of 10 to 20 genes that could be related to that trait.”

Since the 1980s, this kind of genomic analysis has been performed using DNA markers in a process called marker-assisted selection (MAS). More recently there’s been significant innovation in speed and accuracy, thanks in large part to sequencing technology developed by KeyGene and others.

DNA sequencing is now fundamental to agribusiness companies such as Monsanto, Dow Chemical and Syngenta. The technology also supports breeding programmes in the developing world, particularly in China, India and Brazil, where government spending on agricultural research is increasing. In 2010, KeyGene signed a deal for developing new hybrid rice seeds in India, and to van Tunen deals like this could soon be extended to Africa as well.

Next on the horizon for KeyGene are what’s known as whole genome profiling technologies. In five to 10 years’ time, van Tunen believes plant breeders will be directly using DNA sequences rather than DNA markers for the genetic improvement of their crops. The cost of genome profiling will drop further, thus enabling biotech expansion into the other crops such as sorghum, plantain and sweet potato.

The use of sequence-based breeding can be combined with a technique known as automated phenotyping, which, van Tunen says, means monitoring and recording plant growth “with robots, conveyor belts and analysing platforms … every day for months in a row”. The result is a composite pictureof an organism’s characteristics.

“Think of what then could be accomplished!” says van Tunen.

EU policy and innovation

Breakthroughs in targeted mutation developed by KeyGene, for example, are now making the identification and selection of favourable traits a fast and cost-effective process. This long-sought technique allows tailored changes in plant genes down to single pairs of DNA, potentially knocking years off development time. For now, targeted mutations (also known as genome editing),may or may not come under current EU definitions of GM.

These techniques are being “looked at by small and big gene breeding companies”, says René Custers, the regulatory affairs manager at VIB. “There are discussions ongoing at this moment whether those technologies fall within GM legislation or not. If they do, then it will be very difficult for these technologies to reach the market in Europe.”

This unsettled regulatory environment has had the effect of driving massive flows of investment out of Europe, says Carel du Marchie Sarvaas, director of Green Biotechnology Europe. BASF Plant Sciences recently announced it would move its headquarters to the US. Syngenta already did so in the mid-2000s, and others may yet follow, Sarvaas predicts.

Private investment in Sweden, Germany, the Netherlands and the UK continues but there’s very little in France, Italy or Poland. And, “these are big countries,” Sarvaas remarks.

“Why are they leaving?” he asks. “Because they have a very unfriendly regulatory and political climate.

“Because of an anti-GM atmosphere politically [if not strictly in terms of legislation] in Europe, billions in research funds have gone out – and they are not coming back. That’s bad for European jobs and growth and has a knock-on effect on other companies and technologies.”

Still, that doesn’t mean European biotech isn’t expanding.

In February 2012, VIB announced its largest collaboration effort yet. Involving 20-full-time researchers at Ghent University and in collaboration with BASF Plant Sciences, the TopYield Project is expected to supply a number of large-scale commodity crops into Monsanto field trials in the US.

Also in 2012, the BASF-Monsanto partnership paid off with the first genetically improved drought-tolerant maize to reach the US corn belt with large “ground breaker trials” in order to familiarise farmers with the new product. By using biotechnology methods – gene discovery and gene modification – a gene for drought-resistance was introduced into maize in order to provide tolerance to water deficiency. “This enables the plant to grow and develop even during prolonged periods of inadequate water supply,” says Thomas Deichmann of BASF Plant Science.

“The introduced gene was found in cold-tolerant bacteria. Further analysis of the gene showed that it can also help plants in stress situations such as drought.”

Amazing!

Maize is the world’s leading crop in terms of seed market value, and yield enhancement is the most important value driver for growers, seed companies and technology providers. Other crops BASF and Monsanto are working on include soy, rapeseed (canola) and cotton. Also high in the BASF portfolio are rice and wheat, seed markets that are less developed but are expected to represent a substantial growth opportunity for the years to come.

Formed only in 1998, German chemical giant BASF's plant biotech division jumped into the fray relatively late.

“From the start the idea was not to get into the first generation market – focused primarily on agroeconomic benefits for farmers such as resistance against insects or herbicide tolerance – but to focus on second and third generation products,” says Deichmann.

Third generation plant biotech involves developing so-called functional foods that contain valuable proteins and compounds, a field known as plant molecular farming. It’s a potentially lucrative market as demand for healthy ingredients soar – such as omega-3 oils found in rapeseed and canola. BASF and Cargill say that by the end of the decade they will have a new rape seed oil with extra omega-3 fatty acids on the market. Demand for omega-3 supplements – already a $1bn-a-year market – is growing 12% annually.

Syngenta and the future

In many ways 2011 was a watershed year for the plant biotech industry. That’s when value-added crops for drought tolerance and improved health hit the marketplace after decades of research and regulatory wrangling.

“The talk was there a long time. There were products before offering super benefits as with papaya in Hawaii,” says Sarvaas, referring to the stunning success of two papaya varieties first sown commercially in 1998, “but never a large-scale commercial release of products with immediate societal benefit.”

Potatoes and squash have been engineered to resist viral pathogens. Other examples include a genetically modified cassava enhanced with protein and other nutrients, while golden rice, developed by the International Rice Research Institute (RRI), has been discussed as a possible cure for vitamin A deficiency.

But if a turning point can be marked between first and subsequent generations of biotech, it remains the case that the biggest investments mainly are in the large commodity crops of maize and soy. First generation is reaching maturity, but even so the industry is very much still in its growth phase, says Michiel van Lookeren Campagne, head of biotechnology at Syngenta.

Recounting a period in the early 1990s when expectations from new genetic knowledge were set too high, van Lookeren Campagne says now the industry is truly beginning to deliver as the new ideas and techniques come on stream.

“There was, perhaps, from a market point of view, a bit of over-expectation then for the speed at which that could be implemented. In fact, we are living now in the era where it is really making an impact on agricultural productivity.

“Where we used to be able to have a genetic gain of 1% per year of yield improvement through conventional breeding, we can really now step it up and double or triple that by applying [DNA] markers.”

At present, Syngenta is the world’s largest agribusiness company, spending $3.6m a day on R&D in high-performing seed and crop protection products (that control pests). Maize remains its number one seed product, accounting for roughly 20% of the company’s entire $13.3bn in sales recorded in 2011. Leading the way in maize are two new products, Enogen, for enhanced biofuel, and Agrisure Artesian, a seed bred to reduce by 15% the volume of crop lost to drought.

Promising trials

Syngenta is also looking at molecular level development, which can, for example, promote longer plant roots to reach water and nutrients in less fertile, drought-prone areas. Thus far, promising field trials using this technique with wheat have shown a 15-25% yield increase, with 15% less irrigation required.

Agrisure is not a GM crop (or “trait”) but uses molecular breeding to bring naturally available genes together through the use of advanced knowledge of gene functions. “There are plenty of examples of agronomic and quality traits, such as Agrisure Artesian, which are non-GM,” says van Lookeren Campagne. “GM just adds new tools to the arsenal.”

Much of this work is taking Syngenta beyond biotech and into new types of chemistry, another prong in what’s referred to as second generation crop enhancement. This involves specific molecular level modification. An example of such a molecule is Moddus, which promotes longer plant roots to reach water and nutrients in less fertile, drought-prone areas. Thus far, promising field trials with wheat have shown a 15-25% yield increase, with 15% less irrigation required.

Such complexity and its associated cost are driving ongoing consolidation in the industry. It’s taking place particularly on the seed side, where advanced breeding techniques in crops such as rice are highly sought after. The production of rice, the staple for more than half the world’s population, has kept pace so far with consumption, but yields will have to keep rising and stocks kept at healthy levels if huge shortfalls are to be avoided.

In this regard, Syngenta’s $523m bid for Devgen, a Belgian developer of hybrid rice, is seen as crucial to the Swiss company’s growing seed ambitions.

“They use new breeding approaches that are very complementary to our assets,” says van Lookeren Campagne. “We are number one in rice from the crop protection point of view and we wanted to complement that with a stronger position from the seed development point of view.”

Crucial rice yields

Rice yields have more than doubled over the past half century, but according to the International Rice Research Institute in the Philippines, rice yields will have to rise another 11% by 2019 just to keep rice prices steady.

Syngenta has said that it aims to increase its engagement with smallholder farmers. Significantly, it’s making a big play in Africa where – as former UN secretary-general Kofi Annan has pointed out – 60% of the world’s uncultivated arable land remains untapped.

Syngenta’s stated target over the next decade is to build a $1bn business in Africa that reaches out to more than five million farmers, with productivity gains of 50% or more.

The company says it will do so by offering improved seeds, as well as herbicides, fungicides and insecticides, with particular attention focused on smallholders in Tanzania through the Southern Agricultural Growth Corridor of Tanzania (Sagcot). Tanzania’s southern corridor links the port of Dar es Salaam to Malawi, Zambia and the Democratic Republic of Congo. However, due to a lack of infrastructure – including road, rail and power – connection with some of the richest farmland in Africa has been impossible.

As co-founder of Sagcot, Syngenta has co-developed a blueprint for how $2.1bn of private investment will be catalysed over a 20-year period, alongside public sector commitments of $1.3bn.

“We can bring the knowledge, tools, technology and services farmers need whatever the size of their field or the type of cropping system,” said Syngenta’s chief executive, Mike Mack, at the 2012 G8 Summit. “Africa needs a fully integrated approach to crops because there is no single technology solution.”

When is it GM?

The definition of when a substance is GM – with all the connotations – and when it is not can be confusing. In many respects, opinion is split exactly where the line lies.

Modern plant breeding – known as molecular breeding – may use techniques of molecular biology to select, or in the case of genetic modification, to insert, desirable traits into plants. The distinction is important if one accepts the broadest definition of GM crops to include any organism with artificially altered genes.

Traditional plant breeding at its core is the deliberate interbreeding (crossing) of closely or distantly related individuals to produce new crop varieties, including the crossbreeding of traits (genes) from one variety or line into a new genetic background. Thus, plant breeding has always involved the “artificial” alteration of genes.

Most scientists argue for a more precise GM definition distinguishing between cross-species breeding (ie insertion) and selection of genes from the organism’s already-existing genetic composition.

Advances in molecular biology, have greatly improved the selection or screening process, thus opening up a genome editing pathway into new biotech methods such as mutagenesis – whereby targeted mutations turn on or off single pairs of DNA.

Biotechnology, then in its broadest terms, includes both GM techniques of cross-breeding insertion, as well as newly developed methods that encompass a wide-ranging selection process for identification and breeding that turns on or off genes already present in an organism’s own genetic makeup.