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Does this look like genetic engineering to you? Crystal Structure of Cas9 in Complex with Guide RNA and Target DNA. By Hiroshi Nishimasu, F. Ann Ran, Patrick D. Hsu, Silvana Konermann, Soraya I. Shehata, Naoshi Dohmae, Ryuichiro Ishitani, Feng Zhang, and
Does this look like genetic engineering to you? Crystal Structure of Cas9 in Complex with Guide RNA and Target DNA. By Hiroshi Nishimasu, F. Ann Ran, Patrick D. Hsu, Silvana Konermann, Soraya I. Shehata, Naoshi Dohmae, Ryuichiro Ishitani, Feng Zhang, and Osamu Nureki via Wikimedia Commons (CC BY-SA).
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'New Breeding Techniques' and synthetic biology - genetic engineering by another name

Helena Paul, Elisabeth Bücking & Ricarda A. Steinbrecher

4th April 2017

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.

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 neither safe nor predictable. Even the intended genetic change may give rise to other, unintended effects.

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. [1] The opposite has been asserted by lawyers, scientists and NGOs, with France bringing the issue to the European Court of Justice. [ [2]

Most of the NBTs proposed utilise old-style GM processes and techniques. [3] 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' [4], 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. [5]

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, [6] 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. [7] 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. [8]

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.

 


 

Helena Paul is co-director of EcoNexus >and> has worked for 25 years on issues including indigenous peoples' rights and tropical forests; oil exploitation in the tropics; biodiversity, including agricultural biodiversity; patents on life and genetic engineering (GE); climate change and geoengineering; and corporate power.

Dr Elisabeth Bücking> is a biologist, trained in Molecular Biology. She has worked on mycorrhizae and soil fungi in the Forestry Research Institute of Baden-Württemberg/Germany. She is a founding member of the "Gene-ethical Network" and serves presently as an adviser to farmers' associations.

Dr Ricarda Steinbrecher is a biologist, geneticist and co-director of EcoNexus. She has worked on GMOs since 1995, especially UN-led processes on Biosafety, the risk assessment of genetically engineered organisms and synthetic biology. She's a founding member of the European Network of Scientists for Social and Environmental Responsibility and works with civil society and small-scale farmer groups world-wide.

References

1. Legal Briefing Paper: 'The regulatory status of plants resulting from New Breeding Technologies'. NBT-Platform 2013.

2. Spranger TM. 'Legal Analysis of the applicability of Directive 2001/18/EC on genome editing technologies'. Commissioned by the German Federal Agency for Nature Conservation. October 2015.

Krämer L. 'Legal questions concerning new methods for changing the genetic conditions in plants'. Legal analysis commissioned by Arbeitsgemeinschaft bäuerliche Landwirtschaft (AbL), Bund für Umwelt und Naturschutz (BUND), etc. September 2015.

IFOAM EU et al. 'Joint Position: New techniques of genetic engineering'. February 2017.

3. Econexus December 2015. 'Genetic Engineering in Plants and the "New Breeding Techniques" (NBTs) - Inherent risks and the need to regulate'. Technical Briefing, by RA Steinbrecher.

4. A 'zinc finger nuclease' (ZFN) is a designed protein that has two functional components: i) a DNA recognition and binding domain, and ii) a DNA cutting domain, cutting one strand only. The genetic instructions for building such a ZFN is inserted into an organism as a transgene via genetic modification. See also Econexus NBT briefing.

5. Econexus December 2015. 'Genetic Engineering in Plants and the "New Breeding Techniques" (NBTs) - Inherent risks and the need to regulate'. Technical Briefing, by RA Steinbrecher.

6. Gene drives are designed to alter or eliminate whole populations, engineer ecosystems by altering species in it, or eradicate whole species all together.

7. J. Heinemann et al. (2014). 'Sustainability and innovation in staple crop production in the US Midwest'. International Journal of Agricultural Sustainability 12(1): 71-88 and J. Heinemann et al. (2014). 'Reply to comment on sustainability and innovation in staple crop production in the US Midwest'. International Journal of Agricultural Sustainability, 12(4): 387-390.

D. Hakim, 'Doubts About the Promised Bounty of Genetically Modified Crops', New York Times, October 29, 2016.

8. Vazquez M, Maturano E, Etchegoyen A, Difilippo F and Maclean B (2017). 'Association between Cancer and Environmental Exposure to Glyphosate'. International Journal of Clinical Medicine, 8, 73-85. doi: 10.4236/ijcm.2017.82007.

'Declaration of the 3rd National Congress Of Physicians In The Crop-Sprayed Towns'. Oct 2015.

 

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