Synthetic Biology and New Breeding Techniques Are Genetic Engineering Technologies


Dear Friends and Colleagues

Synthetic Biology and New Breeding Techniques Are Genetic Engineering Technologies

Two new fields of genetic engineering (GE) that overlap with each other have emerged: synthetic biology and the so-called New Breeding Techniques (NBTs) (Item 1).

Synthetic biology (‘synbio’) often aims to remodel the chemical processes occurring within a cell, i.e., the metabolic pathways. It can lead to very different or largely new organisms. A number of synbio projects aim to redesign micro-organisms, e.g. for the production of transport fuels, plastics, chemicals or fragrances. Synbio processes are often automated, allowing the almost simultaneous production of thousands of slight variations to a vast number of individuals of one species. The sheer volume and mechanisation of the process distinguishes it from first generation genetic engineering, but fundamentally it is still genetic engineering.

Similarly, all NBTs involve genetic engineering. Some utilise old-style GE techniques, others represent newer or less used GE techniques. None of the ‘NBTs’ are, however, actually ‘breeding’ techniques.

New genome-editing tools such as CRISPR/Cas9 and CRISPR/Cpf1 are tools of synthetic biology, but are also referred to as NBTs. CRISPR is basically a readily programmed set of molecular gene scissors. Whilst genome-editing techniques such as CRISPR/Cas may cut at the target site, it may also cut ‘off-target’, disrupting other gene sequences. The resulting ‘off-target effects’ are by definition neither safe nor predictable. Furthermore, even the intended genetic change may give rise to other, unintended effects.

Proponents are keen to avoid the term GM/GE in relation to gene- and genome-editing techniques, lobbying for such modified organisms to be excluded from GMO regulation including risk assessments, detectability and labelling rules. This would mean giving up the scientific safeguards of the Precautionary Principle and exposing citizens and the environment to unpredictable risks.

Meanwhile, in the U.S., Monsanto has announced several licensing agreements for gene-editing technologies, while DuPont is developing gene-edited drought-resistant corn and wheat varieties. Such technologies are seen to be a driving force for mega-mergers of agrochemical giants like Monsanto and Bayer (Item 2). Last year, the U.S. Department of Agriculture (USDA) opted not to regulate the field-testing of a non-browning mushroomdeveloped using CRISPR/Cas9, creating the opening for such technologies to escape regulatory oversight.

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Item 1


Helena Paul, Elisabeth Bücking & Ricarda A. Steinbrecher
The Ecologist

Advocates claim that synthetic biology and the so-called New Breeding Techniques (NBTs) are distinct from genetic engineering (GE), write Helena Paul, Elisabeth Bücking & Ricarda Steinbrecher. In fact synthetic biology and NBTs carry similar risks to old-style GE, and even create novel hazards. The ‘new GE’ techniques – as they should be named – and their products deserve regulation at least as strict as those applying to GMOs.

With the development of new genetic engineering techniques, the ease and speed of creating genetically modified organisms (GMOs) has sharply increased, and the costs have gone down.

Scientists have acquired the ability to make deeper and more complex changes to the genetic makeup of living organisms.

Not only can DNA be rapidly sequenced but DNA strands can also be easily synthesised, taking digital sequence instructions directly from computers (and the internet).

This has led to the emergence of two new fields of genetic engineering that overlap with each other: synthetic biology (or synbio) and the so-called New Breeding Techniques (NBTs). In most cases both involve the use of old-style genetic engineering, but they also go much further.

So what precisely are these new techniques?

Synbio – redesigning micro-organisms

Synthetic biology or ‘synbio’ for short often aims to remodel the chemical processes occurring within a cell, also called metabolic pathways. It can lead to very different or largely new organisms. A number of synbio projects aim to redesign micro-organisms, e.g. for the production of transport fuels, plastics, chemicals or fragrances.

Synbio processes are often automated, which makes it possible to produce thousands of slight variations to a vast number of individuals of one species almost simultaneously. The sheer volume and mechanisation of the process distinguishes it from first generation genetic engineering, but fundamentally it is still genetic engineering.

Genetically engineered micro-organisms pose additional risks if they escape into ecosystems. They exchange, share and distribute information widely via horizontal gene transfer, even involving completely unrelated micro-organisms, and they multiply much faster than multicellular organisms.

The fact that some of these modified organisms are very different from any naturally occurring organism means that there is nothing with which they can be compared, making meaningful risk assessment close to impossible.

‘New Breeding Techniques’ – just how ‘new’ are they really?

Companies, interest and lobby groups, some scientists, and the European Commission are giving the name of ‘New Breeding Techniques’ (NBRs) to a range of techniques and specific applications of GMOs. All NBTs involve genetic engineering. Some utilise old-style GM techniques, others represent newer or less used GM techniques.

Claims are being made that their products are not GMOs according to the EU legal definition, or that where they are GMOs, they should fall under the exemptions of the EU GMO regulations.

This is for example claimed by the NBT Platform – a coalition of companies developing products using these techniques including Syngenta. The opposite has been asserted by lawyers, scientists and NGOs, with France bringing the issue to the European Court of Justice.

Most of the NBTs proposed utilise old-style GM processes and techniques. They appear to include any type of GM application or technique that had not been commercialised by 2001, the year of the EU directives on GMOs. It includes for example ‘zinc finger nucleases’, a genome-editing tool first reported for plants in 2005 that relies strongly on old GM processes.

The use of ‘oligonucleotides’ to make small alterations in genomes has been around as a technique even longer, yet no commercial product was developed until quite recently. Though the herbicide tolerant CIBUS oilseed rape is available in the US, within Europe it is held up in the courts in Germany.

CRISPR – new, but not a breeding technique

Clearly new (2012) is the genome-editing tool CRISPR/Cas9, which is basically a readily programmed set of molecular gene scissors. It is comparatively cheap and easy, and is used by many researchers to make changes of a few letters of DNA at specific places of interest.

It is a tool of synthetic biology but is also referred to as a ‘New Breeding Technique’. Still newer (2015) is CRISPR/Cpf1, which works on the same principles as ‘Cas9’, but is a bit smaller and cuts through the DNA strands somewhat differently.

It is important to remember that a change of one single nucleotide in a gene can be sufficient to cause major malfunctioning of an organism, such as haemophilia (bleeding disorder), cystic fibrosis or sickle cell anemia in humans.

A single ‘point mutation’ can knock out or modify gene functions, resulting in missing or malformed proteins. Therefore even small ‘edits’ can have wide-ranging consequences.

If the CRISPR/Cas technique is used repeatedly, or to make many small alterations at once in parallel, or combined with other GM techniques, it is possible to make increasingly profound changes. This versatility makes it difficult to say whether the application of a particular technique will give rise to greater or smaller effects, and therefore involve greater or smaller risks.

The term ‘breeding’ is misleading here, since it is usually applied to reproductive processes, such as mating or controlled pollination and selection. However, none of the techniques put forward as ‘NBTs’ are actually ‘breeding’ techniques. Rather, they are genetic engineering techniques (NGETs), each bringing its own set of risks and uncertainties.

Precise and predictable? 

With genome-editing techniques such as CRISPR/Cas it is now possible to pre-determine to a high level of efficiency where to cut the DNA on a particular sequence of nucleotides in the genome in order to make a change.

This usually results in the loss or substitution of a few nucleotides at the cutting site, and hopes are that it will soon be possible to substitute or insert whole genes. Proponents suggest that this level of efficiency eliminates the unpredictability of old-style genetic modifications and resulting impacts.

Target precision is thus equated to predictability and safety of outcome. Wrongly so. Whilst this tool may cut at the target site, it may also cut ‘off-target’, disrupting other gene sequences. The resulting ‘off-target effects’ are by definition neither safe nor predictable. Furthermore, even the intended genetic change may give rise to other, unintended effects.

An accurate shot may intentionally ‘knock out’ the function of a gene, but the effects and repercussions of such knock-outs are yet to be fully understood. Another example: After the DNA is cut, so-called ‘templates’, introduced to direct the cell’s own repair mechanism, may accidentally insert themselves into the genome.

These unintended effects, and the inability to accurately anticipate the behavioural change resulting from altering a certain DNA sequence, mean that precision in determining the target site does not entail predictability in terms of biosafety outcomes.

So why not call it genetic engineering?

Proponents of genetic engineering are keen to circumvent the public scepticism surrounding GMOs. They want to avoid the term GM in relation to gene- and genome-editing techniques in particular, hoping that such modified organisms will be excluded from GMO regulation.

Clearly, this would be completely inappropriate, since these resulting GMOs would then not be subject to risk assessment, detectability and labelling rules. It would mean giving up the scientific safeguards of the precautionary principle and exposing citizens and the environment to unpredictable risks.

Genetic engineering, whether it’s called GM, Synbio or NBTs, involves the application of an engineering mindset to the natural world. It means that living things are seen as composed of parts that may be disassembled and reassembled in an ‘improved’ or novel form.

Living organisms are being re-imagined as data and software platforms. They may be added to or removed from an ecosystem, be reshaped or reprogrammed – without taking into account what impacts such changes have on the whole system.

Proponents claim that GMOs, including the new techniques, are essential to help feed a growing global population, develop plants that can withstand climate change and replace fossil fuels with better alternatives.

However, what would be the consequences of such approaches? Moreover, none of these promises have so far been fulfilled in over 20 years of GMO crop research and development. Proponents respond that we (society) need to reduce or remove regulation and increase the speed of application.

The problems predicted by GMO critics, on the other hand, have to a large extent materialised. These include the contamination of non-GM crops; the emergence of pesticide-resistant pests and secondary pests (in response to pesticide-producing GM crops), requiring ever more pesticides; and the development of herbicide-tolerant persistent weeds, sometimes in invasive proportions (in response to herbicide-tolerant GM crops).

These have all had negative impacts on farmers and communities, including serious health impacts from the multiple spraying of toxins (herbicides and pesticides), eg Argentina.

Now we need effective regulation more than ever!

Our ability to make ever greater changes to the genetic makeup of living organisms should not blind us to the reality: our incomplete knowledge of these organisms and their interactions, and the dangers involved in trying to adjust nature to our needs and ‘improve’ it by engineering it.

This is why the first step should be to use clear and applicable language rather than misleading terminology.

Secondly, the EU should clarify that existing GMO law applies to these new GM techniques. The European Court of Justice is likely to do so as a result of a recent referral from a French court.

Thirdly, the EU – and Britain, post Brexit – should adapt its GMO risk assessment procedures to the intricacies of the new GM techniques, which are likely to require more rather than less scrutiny.

Item 2


Twilight Greenaway

Gene editing technology is being heralded as a game-changer, but it raises serious questions as five of the Big Six agriculture and chemical companies seek to merge.

When the CEOs of both Monsanto and Bayer met with Donald Trump to talk about their potential merger just three days before the inauguration, they made some big promises. If the union between the world’s largest seed company and the German multinational chemical, pharmaceutical, and life-sciences company is blessed by antitrust regulators, the companies have pledged to add 3,000 high-tech American jobs and to combine—rather than consolidate and trim—their R&D budgets to the tune of $16 billion over the next six years, or $2.7 billion a year.

The two companies have been locked in a dance since May 2016, when Monsanto rejected Bayer’s initial $62 billion offer. Then, last fall, the merger reappeared in the news in a noteworthy chain of events.

On September 14, Bayer upped its offer to $66 billion and Monsanto accepted, putting a third major seed company merger on the table, beside ChemChina’s $43 billion takeover of Syngenta and Dow Chemical’s intended merger with DuPont. On the day it was announced, the Washington Post called the Bayer-Monsanto deal the “mega-deal that could reshape [the] world’s food supply.”

Less than a week later, spokespeople for the companies behind all three mergers were asked to testify before the senate judiciary committee, on what senator Chuck Grassley (D-Iowa) called a “merger tsunami.” Then, just two days later, Monsanto announced it had licensed the rights to use CRISPR/Cas9 gene editing—a technology that has been called the “Model T of genetics” for its power to change the way we live.

This rapid-fire timing may have been a coincidence, but it also may be a sign of what’s to come. And it’s just one of many indications that CRISPR/Cas9 and other next-generation gene editing technologies will likely be at the forefront of the seed industry in the years ahead. Some even see gene editing, which is said to be simpler, less expensive, and more consumer-friendly than traditional genetic engineering, as one factor driving the mergers. And while that’s up for debate, it’s clearly an important part of the strategy for companies looking to control, and profit from, the world’s seeds.

Last week the European Union cleared the way for the ChemChina–Syngenta takeover, suggesting the other two mergers may be imminent. If that happens, the resulting three companies would control nearly 60 percent of global seedstocks (including as much as 80 percent of U.S. corn seeds) and 70 percent of the global pesticide market. And these companies are also making a bid to control much more than seeds and pesticides. Monsanto, for example, is already making a play to control many other facets of modern agriculture—including tools for precision planting and high-tech weather prediction.

So while much of the media coverage of gene editing has pointed to its potential to break molds and change the genetic playing field, when it comes to agriculture, it will likely follow a more familiar path: CRISPR and other similar technology will most likely be used by scientists mainly to continue developing seeds that withstand consistent doses of pesticides and herbicides on large, industrialized farms.

“Monsanto has been conducting research with genome-editing techniques for years, and we are excited to be integrating additional technology from licensing partners in to this body of work,” Tom Adams, biotechnology lead for Monsanto, said in an email. Over the past year, the company has announced several licensing agreements that will allow it to access gene-editing technologies, such as CRISPR/Cas9 and CRISPR-Cpf1 (which is said to be more precise), as well as a tool from Dow AgroScience called EXZACT™ Precision Technology® Platform,  among others.

Although Adams said this work is still in its early days, he added, “we believe that genome-editing techniques have great potential to improve and unlock capabilities across our leading germplasm and genome libraries to enable a wide variety of improvements across crop systems.” However, he added, “We do not view it as a replacement for plant biotechnology.”

Gene Editing vs. Genetic Engineering

Since 1996, Monsanto has released a series of genetically engineered herbicide-resistant seeds, beginning with Roundup Ready soybeans in 1996, and moving on to corn, cotton, sugar beets, canola, and more. Today, Roundup Ready crops account for over 94 percent of the soybeans and 89 percent of the corn grown in the United States.

As these products have come to dominate the farm landscape, weeds have also become resistant to Roundup. According to the Weed Science Society of America, “overreliance on herbicides with a single mechanism of action to control certain weeds has led to the selection of weeds resistant to that mechanism of action.” Similarly, incidents of pesticide resistance have also been on the rise.

As a result, farmers often find themselves on what critics call a pesticide treadmill, where each new form of resistance requires a more powerful solution. Companies have spent the last several years working on pesticides and herbicides with “stacked traits,” and the seeds that are resistant to them. Gene stacking involves combining two or more genes of interest into a single plant. In the case of Monsanto, that has meant, for instance, breeding seeds that tolerate both glyphosate and a second herbicide called dicamba.

The main difference between gene editing and classical genetic engineering is that the former allows scientists to manipulate the genetic makeup of an organism—by changing or “knocking out” the function of a gene—without introducing genes from other organisms. This last part is key, because it’s often the combination of parts of various organisms—such as genes from bacteria added to corn to create herbicide resistance or genes from an arctic flounder added to strawberries to make them able to withstand cold weather—that has made the public wary of GMOs in their food.

But the image of CRISPR/Cas9 and other gene editing tools as an “entirely pristine” technology that rules out all foreign DNA isn’t entirely accurate, says Maywa Montenegro, a Ph.D. candidate in Environmental Science, Policy, and Management at University of California, Berkeley.

“They aren’t wrong in saying CRISPR doesn’t need to introduce foreign DNA, but it absolutely can. That’s what it’s very good at,” she said. “But it’s also important for people to understand that you can create huge, impactful changes in a plant’s functioning without introducing anything foreign.” De-activating, or knocking out, a gene function, can significantly change the plants and animals involved.

In the case of the mildew-resistant wheat developed in China, for instance, scientists were able to introduce “targeted mutations” using CRISPR/Cas9 without inserting new genes. In another example, Cibus, a San Diego-based startup, has produced (and commercialized) an herbicide-resistant canolausing another early gene-editing technique called Rapid Trait Development System (RTDS).

The company also says it has other crops, such as herbicide-resistant rice and flax seeds, in the pipeline. DuPont is also working with the Berkeley-based start-up Caribou Biosciences (founded by Jennifer Doudna, one of the founders and patent-holders of CRISPR/Cas9 technology) to develop gene-edited, drought-resistant corn and wheat varieties.

The most widely discussed food produced using gene editing today is a non-browning mushroomdeveloped using CRISPR/Cas9 at Pennsylvania State University. The mushroom received a great deal of media attention last spring, when the Penn State scientists received a letter from the U.S. Department of Agriculture (USDA) informing them that the agency would not be regulating its field testing.

At the time, a number of media outlets reported that the mushroom had “escaped regulation,” suggesting that gene editing was not only remarkably different than tradition genetic engineering in crucial ways, but that it also might be the key to avoiding government oversight. But on both accounts, the reality may be less cut and dried.

Will Gene-Edited Seeds be Regulated?

Doug Gurian-Sherman, director of sustainable agriculture and senior scientist for the Center for Food Safety (CFS), says the letter USDA sent to Penn State about the non-browning mushroom was just one of over 30 that went out at that time in response to requests by a variety of entities working with gene-editing technology.

While the USDA did clearly mention the fact that the mushroom didn’t contain any foreign DNA in its response, that wasn’t the only reason it abdicated its regulatory authority. Just as important, it seems, is the fact that the mushroom was not in any way considered a “plant pest.” (Think Bt corn, which is engineered to express an insecticide in the field.)

You see, when it comes to regulating GMO crops, plant pests have been at the heart of the USDA’s regulation approach; all other genetically engineered products fall under the auspices of either the U.S. Food and Drug Administration (FDA) or the Environmental Protection Agency (EPA). (A document from the Pew Charitable Trusts includes a handy chart detailing which agency is supposed to regulate what types of organisms.)

In fact, the letter sent to Penn State concluded with this sentence: “Please be advised that the white button mushroom variety described in your letter may still be subject to other regulatory authorities such as the FDA or EPA.”

So gene editing was by no means the only factor at hand. “As soon as they put genes in from any plant pest they would immediately become regulated by USDA,” said Gurian-Sherman.

Of course, exactly how the FDA plans to regulate gene editing is yet to be seen. Since January, the agency has been seeking public input on the topic in both medical research and agriculture. One core question at hand is whether gene editing will be considered “genetic engineering.” And at a time when a growing number of consumers want to know exactly what’s in their food—and around 90 percent of Americans say they want to see genetically engineered ingredients in food labeled—this is as much a question of consumer demand as it is a question of regulation.

“We already see lots of people who are supportive of genetic engineering, calling [gene editing] ‘advanced breeding,’” said Gurian-Sherman. But, he added, “In terms of most of the legal definitions of genetic engineering that are out there right now, it applies. I think it is a legitimate area for argument whether this is generally safer or not or more acceptable, but they clearly don’t want to label it genetic engineering.”

According to Michael Hansen, senior staff scientist at Consumers Union, “the FDA’s documents now clearly say their definition of bioengineering is the same as the definition of modern biotechnology held by Codex Alimentarius.” That’s the “Food Code” established by the U.N. Food and Agriculture Organization and the World Health Organization. The Codex definition refers to any organism made using “the application of in vitro nucleic acid techniques.” And since gene editing does precisely that, Hansen believes the answer is clear: Gene editing should be seen as genetic engineering.

But not everyone agrees. In an editorial last January, for instance, the editors of Nature endorsed “the principle of transparency in the production of genome-edited crops and livestock…with no further need for regulation or distinction of these goods from the products of traditional breeding.”

U.C. Berkeley’s Montenegro describes CRISPR/Cas9 as a kind of Swiss army knife with the potential to be paradigm-shifting. But, she adds that, for that reason, it calls for a lot more scrutiny and regulatory oversight

Hansen agrees. Using gene editing, he said, “You can identify a key sequence you want to cut. But wherever that sequence occurs in the genome, you would get a cut. And you will also get a cut at sequences that look similar.”

Hansen also points to the fact that scientists have experienced at least some off-target effects with most gene editing technology to date. He points to the case of an effort to destroy the HIV virus with CRISPR/Cas9. Although scientists engineered T-cells with CRISPR to recognize and destroy HIV, he said, “it took the HIV just a couple of weeks to evolve resistance to CRISPR.”

And in a recent effort to artificially synthesize a new genome for E. coli, a group of scientists decided not to use gene editing because, they wrote, “these strategies…likely would introduce off-target mutations.”

Despite these concerns, CFS’s Gurian-Sherman says there are big questions about how regulatory bodies under the Trump administration will choose to respond to the technology. For one, he says, gene editing could be much harder to test for.

“Detecting [transgenic] engineered changes, for a molecular biologist is really, really easy,” he said. But some of these [gene edits] are not going to leave much of a fingerprint, if at all, and they’re going to be very hard to trace,” he said. “So something like the kind of testing the Non-GMO Projectdoes probably wouldn’t be possible in foods edited with CRISPR.”

Ultimately, Monsanto appears to be preparing for the possibility of regulation. When Lux Research, an independent technology research and advisory firm, looked into the Monsanto-Bayer merger in December, they surmised that gene editing was an important part of Monsanto’s appeal to Bayer, but that it was by no means the only technology they’re banking on.

“Monsanto’s advantage in the space is that they’re super diverse and they have their hands in all the cookie jars,” said Laura Lee, the author of Lux’s report. “So they’d be able to advance traits using CRISPR, or if the regulatory bodies step in and decide to classify CRISPR as genetic modification or put a harmful label on it, they’ll have of other options.”

“More Accessible” Technology

While CRISPR and other gene editing tools are seen as more affordable and more efficient, they’re also being touted as more accessible than traditional genetic engineering—and they are already being used in small private laboratories.

“We think the fact that this science is accessible to and being explored by many researchers across the public and private sectors is exciting—and will only improve the types of products that will ultimately be accessible to farmers,” said Monsanto’s Tom Adams.

Indeed, most traditional genetically engineered traits take years and cost millions to produce (an average of $136 million to be exact). So bringing that number down could bring more constituents into the fold, despite the consolidation at the top.

But seeds produced this way will still be subject to strict intellectual property fines, says Gurian-Sherman. “[CRISPR] won’t be as controllable by the big companies, but the patenting (or lack thereof) could really be a limiting factor for smaller companies,” he said. Case in point, a non-exclusive license to use CRISPR/Cas9 is valued at $265 million.

Of course, if that license is used to create a handful of seed traits, it could be more than worth the investment for a company like Monsanto—particularly if it can deliver on sought-after traits such as drought tolerance. And it might lead one to deduce that a newly merged company such as Monsanto-Bayer would use gene editing to bring down its overall R&D budget.

But that’s not necessarily the case, says Montenegro. In addition to facing pressure from the Trump Administration to spend mightily in the U.S., she points to an economic phenomenon called Jevons paradox, wherein technology makes a process more efficient, but that efficiency ends up leading to increasing demand. (Jevon first observed the phenomenon while observing the coal industry of the 19th Century.)

Another important question is whether this more accessible technology will be put to use to create seeds designed for alternative or more sustainable farming systems.

Montenegro says she has heard from one plant breeder at the University of Minnesota who was interested in using CRISPR/Cas9 for participatory plant breeding—a tactic involving farmers that is often used in the developing world—and to breed plants that could be amenable to diversified organic farming systems. But she says it’s not likely that a wider playing field will change the basic premise of the bulk of the work done using gene-editing technology—which is to engineer seeds used on large-scale industrial farms.

“While I don’t want to foreclose the possibility of using CRISPR for agroecology, [companies and institutions] are underinvesting and undercutting basic agroecology research to such a large degree that even the lower-hanging fruit hasn’t yet been picked,” Montenegro said. This “massive asymmetry” makes her doubtful that the technology will help researchers tread new paths when it comes to sustainable practices.

Gurian-Sherman is no more optimistic. “There are ways you can breed or adapt crops for sustainable agricultural systems that don’t rely on inputs like fertilizers and pesticides as much,” he said. “You can breed crops that attract natural enemies, or take advantage of the slower release of organic nutrients from cover crops and manure. I can go on and on about traits that are valuable to sustainable farming. But that’s not going to be of interest to these companies because they’re actually antithetical to their business models.”

Consumers Union’s Hansen says the current excitement about gene editing reminds him of the very early days or genetic engineering. “In the late 80s and early 90s, they were saying they’d be able to do everything with GE. Thirty years later, all you have is herbicide-tolerant plants and Bt plants. Or that’s the vast majority.”

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