FUTURE BRIEF:Synthetic biology and biodiversity

September 2016Issue 15

Environment

Science for Environment Policy

The contents and views included in Science for Environment Policy are based on independent research and do not necessarily reflect the position of the European Commission.© European Union 2016

This Future Brief is written and edited by the Science Communication Unit, University of the West of England (UWE), BristolEmail: sfep.editorial@uwe.ac.uk

To cite this publication:Science for Environment Policy (2016) Synthetic biology and bidiversity. Future Brief 15. Produced for the European Commission DG Environment by the Science Communication Unit, UWE, Bristol. Available at: http://ec.europa.eu/science-environment-policy

1. 1. Introduction: What is synthetic biology?

2. 2. What are the applications of synthetic biology? 2.1 Synthetic biology in Europe

3. What are the potential impacts of synthetic biology on biodiversity?

4. Case study: new plant breeding technologies

5. What are the ethical issues associated with synthetic biology?

6. What are the safety issues associated with synthetic biology, and how can we manage them?

7. Regulatory implications 7.1 Research needs and areas for future development

8. Summary and recommendations

References

Contents

Science for Environment PolicySynthetic biology and biodiversity

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Images:Reproduced with permission by the relevant author or publisher, or otherwise publicly authorised for use.With thanks to the following creators:(iStock) Soybean, Diane Labombarbe; Cotton plant, kristina-s; Gene editing technology, a_crotty; Sheep, Capreola; Tobacco leaves, plalek; Fruits and vegetables, Fleren.(Flaticon) Freepik; Tomato, Roundicons; Cheese, Madebyoliver; Mouse, Carla Gom Mejorada.(Noun Project) Christopher Holm-Hansen; P J Souders; Yorlmar Campos; Cassie McKown; Icon Fair; Elliott Snyder; Tomas Knopp; parkjisun; Razlan Hanafiah; Chad Remsing; Arthur Shlain; last spark; NAMI A; Creative Stall. All infographics without sources were designed and produced by the Science for Environment Policy team at UWE.

AcknowledgementsWe wish to thank the Dr Todd Kuiken (North Carolina State University Genetic Engineering & Society Center) for his input to this report, and Dr Matthew Gentry (Swedish University of Agricultural Sciences, Uppsala) for his review. Final responsibility for the content and accuracy of the report, however, lies solely with the author.

ISBN 978-92-79-55109-3ISSN 2363-278XDOI 10.2779/976543

Introduction

What is synthetic biology?

All living organisms have a genome, which contains all the information necessary for that organism’s function. The genome is the complete set of genes in a cell or organism. Genes contain the information needed to make proteins, which perform the cellular functions necessary for life. For thousands of years, humans have deliberately altered the genes of plants and animals (Beadle, G.W., 1980; RSPCA, n.d.).

Selective breeding, a term first coined by Darwin in 1859, is a way of selecting for desirable traits and has been practiced since pre-history, beginning approximately

10 000 years ago (Clutton-Brock, 1981; West, B.R., 2002; Wood and Orel, 2001). Selective breeding has traditionally focused on species of wheat, rice and sheep for agricultural purposes, as well as domestic animals. Dogs are now the most genetically diverse species on Earth thanks to centuries of selective breeding by humans, beginning with the domestication of wolves (Adams, J. 2008; Anthes, 2013).

After the discovery of DNA in the 1950s, scientists began to learn rapidly about the genetic basis of characteristics and soon began to isolate and manipulate the genetic

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Glowing plant. Source: Ow et al. (1986) Science/AAAS Vol. 234, Issue 4778: 856-859. DOI: 10.1126/science.234.4778.856

Synthetic biology is an emerging field and industry, with a growing number of applications in the pharmaceutical, chemical, agricultural and energy sectors. It may propose solutions to some of the greatest environmental challenges, such as climate change and scarcity of clean water, but the introduction of novel, synthetic organisms may also pose a high risk for natural ecosystems. This Future Brief outlines the benefits, risks and techniques of these new technologies, and examines some of the ethical and safety issues.

material of organisms. Molecular biology techniques enabled scientists to take genetic material associated with a useful trait in one organism and insert it to another, and thus to develop new breeds of plants and animals more quickly than before (Synthetic Biology Project, 2015).

Building on understanding of how DNA is regulated, copied and repaired, molecular genetics advanced further in the 1970s when restriction enzymes were discovered (the scientists involved were later awarded the Nobel Prize for their efforts1). These enzymes cut DNA at a particular place which can then be combined with other stretches,

essentially allowing scientists to ‘cut and paste’ DNA. In 1972, the first paper was published using this recombinant DNA technique, reporting its application to produce transgenic bacteria (Cohen et al., 1972). The ability to insert foreign DNA into an organism’s genome, known under the umbrella term of genetic engineering, has since enabled the production of disease-resistant crops and bacteria that can produce the human hormone insulin.Techniques have continued to evolve at a rapid pace, including development of the Polymerase Chain Reaction (PCR) in the 1980s, which can produce millions of copies of DNA in a matter of hours. Further advances

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in DNA synthesis and cloning technology have made it much quicker and easier to construct and copy DNA.

With advances in technology and rapidly falling costs of DNA sequencing and synthesis, scientists begun to create entirely new sequences of DNA, allowing them to develop organisms with novel functions, such as producing fuels or pharmaceuticals. This latest development is termed ‘synthetic biology’, a field which shares features with modern biotechnology and builds on traditional molecular biology techniques to control the design, characterisation and construction of biological parts, devices and systems (CBD, 2015).

As well as molecular biology, synthetic biology interfaces with engineering, chemistry, physics, computer science and systems biology (ERASynBio, 2013) and is focused on developing more rapid and simple methods to produce genetically modified organisms (GMOs) by adding or removing genes, or creating genetic elements from scratch (European Commission, 2015; SCENIHR, SCCS, SCHER, 2014).

Unlike traditional genetic engineering, which typically involves the transfer of individual genes between cells, synthetic biology involves the assembly of new sequences of DNA and even entire genomes (Biotechnology Innovation Organization, 2016). The distinction between

Genetic engineering. © iStock / nicolas_

1. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1978/press.html

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synthetic biology and traditional genetic engineering is important. Although synthetic biology builds on the techniques of classical genetic engineering, many elements are entirely novel (and thus require fresh evaluation).

Synthetic biology aims to fulfill the goals of classical genetic engineering, but goes further, attempting to design life according to humanity’s needs (Engelhard, 2016). Indeed, synthetic biology involves designing and constructing new biological parts, devices and systems — going far beyond the modification of existing cells by inserting or deleting small numbers of genes. Cells can be equipped with new functions and entire biological systems can be designed. Compared to traditional GMOs therefore, synthetic organisms involve much larger-scale interventions, and it is important to bear this in mind when considering and debating the new field of synthetic biology (Engelhard, 2016).

Synthetic biology provides tools to better understand biological systems and can also produce valuable products, such as drugs, fuels, or raw materials for industrial processes or food. By reducing the time, cost and complexity of developing these products, the field represents opportunities for a range of industries and has been linked to future economic growth and job creation (ERASynBio, 2013). One report (McKinsey Global Institute, 2013) suggests that the field could be worth $100 billion by 2025.

Although the term came to prominence in the 1970s, there remains no universally accepted definition of synthetic biology.

A history of genetic modification

In 2013, the three independent EU Scientific Committees (Scientific Committee on Emerging & Newly Identified Health Risks — SCENIHR, on Consumer Safety — SCCS, and on Health and Environmental Risks — SCHER) were requested to adopt a set of three opinions addressing a mandate on synthetic biology from the European Commission (Directorates Health & Consumers, Research and Innovation, Enterprise and Environment).

The first opinion concentrated on the elements of an operational definition of synthetic biology, while the two opinions that followed focus on risk assessment methodologies and safety aspects, and risks to

the environment and biodiversity and research priorities, respectively. The first lays the foundation for the two other opinions with an overview of the main scientific developments, concepts, tools and research areas in synthetic biology. Additionally, a summary of relevant regulatory aspects in the European Union, in other countries such as Canada, China, South America and the USA, and at the United Nations level, is included. This is available from: http://ec.europa.eu/health/scientific_committees/emerging/opinions/index_en.htm.

Although there is no universally accepted definition, that provided by the European Commission constitutes a robust framework for understanding synthetic biology.

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BOX 1. Definitions of synthetic biology

“The deliberate design of biological systems and living organisms using engineering principles”(Balmer & Martin, 2008)

“a) the design and construction of new biological parts, devices and systems and b) the re-design of existing natural biological systems for useful purposes”(Synthetic Biology.org, 2016)

“The design and construction of novel artificial biological pathways, organisms and devices or the redesign of existing natural biological systems”(The Royal Society, 2016)

“The use of computer-assisted, biological engineering to design and construct new synthetic biological parts, devices and systems that do not exist in nature and the redesign of existing biological organisms, particularly from modular parts”(International Civil Society Working Group on Synthetic Biology, 2011)

“A field that aims to create artificial cellular or non-cellular biological components with functions that cannot be found in the natural environment as well as systems made of well-defined parts that resemble living cells and known biological properties via a different architecture”(Lam et al., 2009)

“A new research field within which scientists and engineers seek to modify existing organisms by designing and synthesising artificial genes or proteins, metabolic or developmental pathways and complete biological systems in order to understand the basic molecular mechanisms of biological organisms and to perform new and useful functions”(The European Group on Ethics in Science and New Technologies, 2009)

“Synthetic Biology is the application of science, technology and engineering to facilitate and accelerate the design, manufacture and/or modification of genetic materials in living organisms” (SCENIHR, SCCS, SCHER, 2014)

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BOX 2.

Key terms

BioBricks: The technical standard for genetic parts, such as DNA, promoter sequences, protein domains and protein-coding sequences, which can be assembled to engineer biological systems. Over 20 000 parts are currently available in the Registry of Standard Biological Parts.

Biodiversity: The variability among organisms from all sources including terrestrial, marine and other aquatic ecosystems and the ecological complexes of which they are part (including diversity within and between species and of ecosystems).

Biotechnology: The application of in vitro nucleic acid techniques, including recombinant DNA techniques, that overcome natural physiological reproductive or recombination barriers and that are not used in traditional breeding and selection.

DNA-based circuits: The rational design of DNA sequences to create biological circuits with predictable, discrete functions, which can be combined in various cell hosts.

Gene drive: Genetic systems that circumvent the traditional rules of sexual reproduction and increase the odds that a gene will be passed on to offspring, allowing them to spread to all members of a population. Gene drive systems can be used to spread particular genetic alterations through targeted wild populations over many generations. By altering the traits of entire populations of organisms, gene drive systems have been posited as a powerful tool for the management of ecosystems.

Genetic engineering: The techniques/methodologies used for genetic modification.

Genetic material: Any physical carrier of information that is inherited by offspring, such as DNA.

Genetic modification: The processes leading to the alteration of the genetic material of an organism in a way that does not occur naturally by mating and/or natural recombination.

Genetically modified organism: An organism in which the genetic material has been altered in a way that does not occur naturally by mating and/or natural recombination.

Living modified organism: Any living organism that possesses a novel combination of genetic material obtained through the use of modern biotechnology.

Living organism: Any biological entity capable of transferring or replicating genetic material, including sterile organisms, viruses and viroids.

Protocell: The simplest possible component able to sustain reproduction, self-maintenance, metabolism and evolution.

Xenobiology: The study and development of life forms based on biochemistry not found in nature. This includes xeno-nucleic acids (synthetic alternatives to the natural nucleic acids DNA and RNA) and amino acids that are not found in the natural genetic code of organisms. Xenobiology could provide a biosafety tool by preventing interactions between synthetic organisms and the natural world (xeno-nucleic acids can prevent genetic exchange with wild organisms, as they cannot hybridise with natural genetic material).

Sources: Article 2 of the Convention on Biological Diversity; Cartagena Protocol on Biosafety; CBD 2015a; Pinheiro and Holliger, 2012; SCENIHR, SCCS, SCHER, 2014; Schmidt, 2010; Shetty et al., 2008; Wyss Institute, n.d.

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Generation of the DNA Construct

A. Milk Protein Promoter DNA: Allows for expression only in goat mammary glands.

B. Therapeutic Protein Gene: Encodes a protein known to treat disease in people.

C. Terminator Sequence: Assures that only the gene of interest is controlled by A.

D. Other DNA Sequences: Helps with the introduction of the new combination DNA strand.

New traits can be introduced into animals. Here’s how it works for animals engineered to produce a human pharmaceutical.

This new DNA strand is then introduced by any of a number of methods into an animal cell, such as an egg, that is then used to produce a genetically engineered animal.

The first genetically engineered goat is produced.

The offspring of the first genetically engineered goats, referred to as production animals, are milked. The milk is transferred to a purification facility.

The drug to be used to treat human disease is purified from the goat’s milk.

The DNA construct is created by combining A, B, C and D.

Native goat DNA

Native goat DNA 3

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FDA Consumer Health Information / U.S. Food and Drug Administration www.fda.gov/ForConsumers/ConsumerUpdates/UCM143980.htm

Genetically Engineered Animals

How goats are genetically engineered to produce ATryn ©FDA, US Food and Drug Administration, 2009http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm143980.htm

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2. What are the applications of synthetic biology?

Synthetic biology is still an emerging field but there are growing numbers of applications in the pharmaceutical, chemical, agricultural and energy sectors. In 2012, the World Economic Forum in Davos listed synthetic biology as an area which is likely to have a ‘major impact’ on the world economy in the future. The UK government has also named it as one of eight great technologies that will support future growth in the economy (Midven, 2016).

Commercial applications tend to focus on creating microorganisms (such as E. coli, baker’s yeast and microalgae) that can synthesise valuable products, such as fuels, food and pharmaceuticals. A notable example is the engineering of yeast cells that synthesise artemisinin, a drug used to treat malaria. American scientists first reported the engineering of yeast to produce the precursor of artemisinin in 2006, which could be transported, purified and chemically converted to the full drug (Ro et al., 2006). This process has since been enhanced and commercial production of semi-synthetic artemisinin is now underway by pharmaceutical company Sanofi (Paddon and Keasling, 2014), which may provide a model for the production of other pharmaceutical agents by synthetic biology.

In 2006, the EU Medicines Agency issued a license for a synthetically produced drug called ATryn, which is extracted from the milk of genetically engineered goats (EMA, 2015). ATryn is an anticoagulant, used to prevent blood clots in patients with a rare genetic disease. This therapeutic protein can be derived from the milk of goats whose genes have been altered to include a segment of DNA that instructs their cells to produce antithrombin — a protein that occurs naturally in humans. In 2009, the US also approved ATryn — its first approval for a biological product produced by genetically engineered animals (FDA, 2009; see facing page).

Other medical applications of synthetic biology include engineering bacteria to attack cancer cells (Anderson et al., 2006) and designing new antibiotics (ERASynBio, 2013).

There are also reams of synthetic biology studies that have possible benefits for the environment. There are projects underway to produce biosensors for polluted water for example (Aleksic et al., 2007). It is also possible to develop organisms that can process waste and purify water (and therefore restore damaged sites) by removing contaminants such as heavy metals and pesticides. One

group of scientists (Kane et al., 2016) recently developed E. coli able to degrade methylmercury, a toxic metal that can accumulate up the food chain.

Biofuels produced by engineered organisms such as algae could be a more sustainable alternative to fossil fuels, as they can be farmed without using arable land (Georgianna & Mayfield, 2012). As photosynthetic organisms, algae also remove CO2 from the air, reducing it into energy-rich hydrocarbons (Schmidt, 2010). Synthetic biology has for some time been hailed as a potent contributor to food security, by developing new crop varieties that are resistant to pests or that have enhanced nutritional value.

Although synthetic biology may have benefits for society, there are many scientific uncertainties surrounding the development of synthetic life, cells and genomes, especially in terms of their impact on the environment..

Algal biofuel ©Flickr/Sandia Labs 2008. CC BY 2.0.

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2. What are the applications of synthetic biology?

BOX 3. The case of glowing plants

As well as applications which promise to solve grand societal challenges, there are concerns about purely commercial applications.

The ‘Glowing Plant project’ began as a Kickstarter project to engineer the thale cress (Arabidopsis thaliana) to emit light, using synthetic variants of genes from fireflies and jellyfish. This was the first crowdfunding campaign for a synthetic biology project. It was successfully funded and is now available to the American public to pre-order, in the form of the already grown plant or its seeds.

According to the developers, the plants could one day be used to light streets at night, thus saving energy use and reducing CO2 emissions. However, others say the project is ‘frivolous’ and has limited value to society (Callaway, 2013).

Beyond this, there are concerns about the risk this project may represent, as it provides an example of the unregulated release of a synthetic organism. The glowing plants are not regulated by the US Animal and Plant Health Inspection Service (APHIS) as they are not deemed to pose a risk (Callaway, 2013). This is because the APHIS jurisdiction to regulate GM plants depends on the use of a ‘plant pest’, and the technique does not use any elements that meet the definition of a plant pest within the US Plant Protection Act2.

GLOWING PLANTS: A TIMELINE

2. US Department of Agriculture, Animal and Plant Health Inspection Service (2000) Plant Protection Act. Text available from: http://www.aphis.usda.gov/brs/pdf/PlantProtAct2000.pdf

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Although a regulated plant pest (agrobacterium, able to transfer DNA to plants and therefore used frequently in genetic engineering) was involved in the process, it was used to modify the foreign genes before producing plants for distribution. Once the team showed the designs worked using the bacteria, they inserted the same DNA sequence into the plant using a gene gun (Shin, 2013), which is generally considered safe and does not rely on plant pests. The Glowing Plant therefore does not use genetic material from a plant pest, does not use a plant pest as a recipient organism, and no plant pest is used to modify the genes of the host plant (Synthetic Biology Project, 2015). The transgenic plant consequently does not satisfy any of the regulatory criteria that would be subject to the oversight of APHIS (Evans, 2014).

Although the USDA does not appear to have any regulatory concerns about the project, scientists and policymakers have questioned its societal value and risks — including the impact on public opinion of synthetic biology and the need to apply the precautionary principle.

It is unclear whether these plants pose any risks to human health or the environment, but allowing their entry to the market based on the absence of plant pests rather than an assessment of potential risk is of concern to many. A lack of regulation in future commercial projects could be more risky, and poses important ethical and legal questions.

For now however the risk remains hypothetical, as the team at glowingplant.com are yet to produce a completely functional glowing plant, highlighting the difficulties of producing working genetic elements in complex living systems (Regalado, 2016).

http://www.glowingplant.com/

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Europe is well placed to take advantage of the ‘synthetic biology revolution’ due to its leading academic institutions and strength in biotechnology research. Researchers in Bristol, UK are developing a toolkit of novel proteins which could be used as building blocks for biomaterials, including hollow spheres able to carry drugs (Bromley et al., 2008). Elsewhere, a collaborative team involving researchers from Belgium, France and Germany has developed a strain of E. coli with the T bases in its DNA replaced by an artificial base. This provides proof of concept for the use of xeno-nucleic acids and may have potential as a safety mechanism, whereby synthetic organisms are dependent on lab-supplied nutrients for survival (ERASynBio, 2013).

Europe is also home to the European Molecular Biology Laboratory (EMBL), which has the highest citation impact in molecular biology and genetics outside of the US, and the European Bioinfomatics Institute,

which provides the world’s most comprehensive range of freely available molecular databases. Furthermore, in 2013, there were an estimated 150 companies engaged in synthetic biology research in Europe, including those working on agricultural, environmental, medical and food applications (ERASynBio, 2013).

Although synthetic biology may have benefits for society, there are many scientific uncertainties surrounding the development of synthetic life, cells and genomes, especially in terms of their impact on the environment.

An inventory of synthetic biology-based products and applications, covering the US and Europe, is available via the Synthetic Biology Project’s website (http://www.synbioproject.org/cpi/). This tool allows citizens, researchers and policymakers to explore products on or close to market. Although not comprehensive, this inventory provides a good overview of currently available synthetic biology based products and the companies that produce them.

2.1 Synthetic biology in Europe

Synthetic Biology projects funded by the Sixth Framework programme for NEST (New and Emerging Science and Technology):

BioModularH2 This project aims to use synthetic biology to produce hydrogen, by designing devices that use the natural ability of cyanobacteria to produce hydrogen as a by-product of atmospheric nitrogen fixation.https://www.shef.ac.uk/synbio/biomodularh2

BioNano-Switch Aims to develop a biosensor using biological molecular motors. The project hopes to facilitate ‘lab-on-a-chip’ technologies — which enables operations that normally require a laboratory, on a miniature scale, such as infectious disease diagnosis.http://synbiosafe.eu/project/bionano-switch/

Eurobiosyn Working on the synthesis of oligosaccharides from E. coli, chemicals which are used to create many pharmaceuticals.http://www.eurobiosyn.org

FuSyMem Cell membranes are important in sensory perception, drug action and signal recognition. This project aims to understand and ultimately control cell membranes to develop applications such as biosensors.http://archiveweb.epfl.ch/fusymem.epfl.ch/

NANOMOT This project aims to engineer building blocks that can be assembled into controllable ‘nano-engines’, with lab-on-a-chip technologies and chemical nanoreactors as potential applica-tions.http://synbiosafe.eu/project/nanomot/

PROBACTYS Aims to construct a bacterial cell containing coordinated genetic circuits that can transform chloro-aromatic chemicals into high-added-value products.http://www.2020-horizon.com/PROBACTYS-Programmable-bacterial-catalysts(PROBACTYS)-s20599.html

SYNTHCELLS SYNTHCELLS aims to bio-engineer minimal cellular constructs with applications including bioreactors and drug delivery systems.http://cordis.europa.eu/project/rcn/85168_en.html

Table 1. Source: Pei et al., 2012

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3. What are the potential impacts of synthetic biology on biodiversity?In many ways synthetic biology presents a dilemma; it may propose solutions to some of the greatest challenges facing the environment, such as climate change and scarcity of clean water, but also poses a high risk for natural ecosystems. The introduction of novel, synthetic organisms may therefore have both constructive and destructive effects on the conservation and sustainable use of biodiversity.

Benefits

Several synthetic biology applications aim to respond to environmental challenges, including those associated with energy, wildlife and agriculture. These may have indirect or direct positive impacts on biodiversity. For example, some GM crops have provided both livelihood and conservation benefits (Redford et al., 2014). Bacillus thuringiensis (Bt) cotton — genetically modified to produce an insecticide — has been shown to reduce pest damage in developing countries such as India, contributing to agricultural growth in small-scale farms. Several other GM, insect-resistant and herbicide-tolerant crops have benefitted farmers in developing countries by increasing yield (Carpenter, 2010; Waim and Zilberman, 2003).

In this way, synthetic biology could reduce the impact of human land use on biodiversity, by, for example, reducing the need for pesticide use (which can have negative impacts on non-target wildlife). Furthermore, habitats currently unavailable to wildlife due to energy installations for example could be made available by the introduction of new methods of energy production, such as algae that use carbon to produce fuel (Redford et al., 2014). Biofuels have also been posited to reduce reliance on

non-renewable energy sources and thus mitigate climate change (CBD, 2015; Redford et al., 2014), which has negative effects on biodiversity.

Applications in bioremediation could benefit biodiversity. Bacteria such as Rhodococcus and Pseudomonas naturally consume and breakdown petroleum into less toxic byproducts. Synthetically engineered microbes could be used to degrade more persistent chemicals such as dioxins, pharmaceuticals, pesticides or radioactive substances (which might otherwise be sent to hazardous waste landfills). A team at the Spanish National Center for Biotechnology are engineering microbes that survive in harsh conditions by replacing non-essential genes with metabolic circuits that direct microbes away from simple sources of carbon (such as glucose) towards

industrial chemicals (Schmidt, 2010). The application of these bacteria could remove pollutants that are currently persistent, and more rapidly, thus helping to restore damaged sites and facilitate conservation.

Synthetic biology can be used to synthesise products currently extracted from plants and animals. Engineering biosynthetic pathways provides an alternative and cost-effective method of

Clover in a field margin CC0 @Pixabay /glarcombe

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producing drugs of natural origin, such as morphine and aspirin (Khalil and Collins, 2011). This may reduce the pressure on species that are currently threatened by hunting or harvesting (CBD, 2015).

The ability of synthetic biology to restore genetic diversity and even extinct species has been widely reported. Using synthetic biology to re-create extinct species has captured the imagination of the public, through projects such as ‘Revive and Restore’ (The Long Now Foundation, 2015). No longer solely the realm of science fiction, the restoration of extinct species has become a subject of valid scientific research and planning. Although DNA can only survive for limited periods, it has been found and sequenced for wild horses that have been extinct for 700 000 years, and work has already begun to bring back the passenger pigeon and woolly mammoth (Charo and Greely, 2015; The Long Now Foundation, 2015). While this aspect of synthetic biology has understandably garnered lots of attention, there are concerns that such projects may distract attention (and funds) from more deserving and essential conservation projects. There are unclear benefits, and unknown long-term risks, due to the restoration of previously extinct species.

More immediate benefits could be derived from protecting at-risk species by genetically modifying bees to be resistant to pesticides or mites for example (Redford et al., 2014). Synthetic biology could be used to engineer solutions to other threats to biodiversity, including infectious diseases like white nose syndrome, a fungal disease that affects hibernating bats.

It is also possible to use synthetic biology for control of disease vectors. Using gene drive systems, it is possible to change the genomes of populations of mosquitoes to make them less dangerous (e.g. resistant to the parasite that causes malaria) (Ledford and Callaway, 2015). Gene drive systems can also be used to lessen the threat from other insect vectors of diseases, reverse pesticide resistance or eradicate invasive species, which are significant threats to biodiversity (Redford et al., 2014).

Risks

While there are certain opportunities for protecting biodiversity, there are also risks to consider. The escape or release of novel organisms into the environment could radically and detrimentally change ecosystems. Genetically engineered microbes could have adverse effects in the environment due to their potential to persist and transfer their genetic material to other microorganisms. The organisms may become invasive, and, by exchanging genetic material, form hybrids that out-compete wild species. Indeed, the transfer of genetic material to wild populations is a major risk. Genes could be transferred through horizontal or vertical gene transfer, which could lead to a loss of genetic diversity and the spread of harmful characteristics. Even without genetic transfer, these organisms could have toxic effects on other organisms such as soil microbes, insects, plants and animals. They may also become invasive and have an adverse effect on native species by destroying habitat or disrupting the food web for example (CBD, 2015).

Many of the supposedly beneficial applications of synthetic biology could also have negative side-effects. For example, gene drive systems designed to suppress populations of disease vectors could have unintended consequences for biodiversity, such as introducing new diseases by replacing the population of the original disease vector with another (CBD, 2015). Using

Wooly Mammoths: a target for de-extinction © iStock/Aunt_Spray

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BOX 4. Synthetic biology and the Aichi Biodiversity Targets

Synthetic biology may both contribute to the Aichi Biodiversity Targets (shown in green) and impede progress towards them (shown in red).

Address the underlying causes of biodiversity loss (Targets 1-4)• May promote a transition to more sustainable consumption and production• The ability to change the genetics of an organism may change people’s perceptions of nature

and biodiversity• Distract policymakers from addressing the underlying causes of biodiversity loss

Reduce direct pressures on biodiversity and promote sustainable use (Targets 5-10)

• New potential for ecological restoration• Synthetic organisms in agriculture may reduce land conversion and protect wild habitats• Organisms may become invasive

Improve the status of biodiversity by safeguarding ecosystems, species and genetic diversity (Targets 11-13)

• Synthetic organisms may threaten protected areas• Restoring extinct species may help to meet targets for conservation while still allowing new

extinctions to occur, due to a counter-balancing effect• Society may become less willing to support efforts to protect endangered species• May make off-site conservation more attractive than on-site, reducing support for existing

protected areas

Enhance the benefits from biodiversity and ecosystem services (Targets 14-16)

• Could remove justification for conservation by providing ecosystem services such as clean water and air

• Private ownership of genetic material may restrict access for public benefit

Adapted from Redford et al., 2013

gene drives to change entire populations very rapidly could have other unforeseeable implications, including potentially devastating effects on entire ecosystems.

Similarly, while replacing natural products with synthetic ones could reduce pressure on natural habitats, it could also disrupt conservation projects and displace small-scale farmers (CBD, 2015). Saffron for example is usually picked from crocus flowers

in Iran, but can now be synthetically produced by yeast. Each hectare of natural saffron growing in Iran provides jobs for around 270 people a day – replacing that with synthetic versions therefore threatens livelihoods (ETC Group, 2016). A growing range of products (such as palm oil, rubber and artemisinin) are beginning to be provided by synthetic biology, which may deprive farmers of their only source of income and raises serious and complex issues of global justice.

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Another major concern relates to the large-scale increase in the use of biomass. A large number of synthetic biology applications involve organisms that convert biomass into valuable products. Cellulosic biomass, such as wood and grass, represents a renewable source of sugars that can be used as feedstock for fermentation. Several microorganisms can naturally degrade cellulosic biomass, but with synthetic biology, organisms can be engineered to convert the sugars in biomass into useful products, such as fuels or pharmaceuticals (French, 2010; French et al., 2013). Although use of feedstock could benefit the environment by representing a shift away from non-renewable resources, increased demand for biomass could also lead to increased extraction of biomass from agricultural land (CBD, 2015). Fuel production may require particularly large amounts of biomass, which could reduce soil fertility and structure and contribute to biodiversity loss due to the conversion of natural land (CBD, 2015). Indeed, a number of studies suggest that extracting biomass from existing agricultural practices is already causing a decline in soil fertility and structure (CBD, 2015).

According to the civil society organisation the ETC group (2010), biomass-based economies will develop, which are market driven and — unlike biodiversity-based economies — view nature in terms of its commercial value and profit potential. They suggest that major changes to land-use will occur, such as increases in the number of plantations in former forests (a major source of biomass), which have little value for biodiversity and significant negative impacts on water and soil.

These land-use changes may also have adverse impacts on food and livelihood security (Redford et al., 2014). The increased production of biomass could reduce access to local natural resources and cause small, self-sufficient farms to be replaced by large-scale commercial farming (CBD, 2015).

Finally, there are deeper concerns that synthetic biology may act as a ‘sticking plaster’ rather than providing a profound solution to biodiversity loss. In other words, synthetic biology may distract policymakers, scientists and industry from the deeper underlying causes of biodiversity loss.

Biofuel feedstocks @Flickr/Idaho National Laboratory 2013. CC BY 2.0.

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4. Case study: new plant breeding technologies

A separate although interconnected issue is that of new plant breeding techniques, which aim to create new traits in plants using genetic engineering. Unlike synthetic biology — which generally involves major genetic changes (such as altering entire metabolic pathways) — plant breeding typically involves smaller changes, such as changing individual genes or even bases in DNA.

Innovation in plant breeding is deemed by many to be essential to meet the challenges of population growth and climate change. Plant breeding techniques have been around for decades, but a number of very new techniques (developed after the 2001 review of the EU Directive on the deliberate release of GMOs) are creating concern, and are surrounded by legislative uncertainty.

These new techniques differ from the methods traditionally used to create GMOs (such as transgenesis) because they involve specific and targeted changes to the genome, and do not involve any foreign DNA. Traditional transgenic plants contain genes from another species, such as maize containing proteins from Bacillus thuringiensis to make it resistant to insects. Mixing genetic materials between species that could not hybridise naturally has previously generated concern among the public and regulatory agencies (Holme et al., 2013).

Two newer (and potentially safer) techniques are cisgenesis and intragenesis. Unlike transgenesis, cisgenesis involves transferring genes between members of the same species, or closely related species that could crossbreed naturally. The term cisgenic plant, introduced less than 10 years ago, can be defined as ‘a crop plant that has been genetically modified with one or more genes isolated from a crossable donor plant’ (Schouten et al., 2006). As such, cisgenic crops contain only the gene(s)

of interest (Espinoza et al., 2013) and are more similar to crops that may occur by conventional breeding.

While cisgenesis is the transfer of genes from the same or closely related species, intragenesis is the insertion of a reorganised region of a gene from the same species (EASAC, 2015), and is therefore further removed from traditional breeding. Although it also describes the introduction of a gene that originates from the same or a crossable species, intragenes are hybrids, which means they may contain elements from different genes. Intragenesis enables the development of new genetic combinations, and thus GMOs with more innovative properties (Espinoza et al., 2013). Both methods provide viable alternatives to transgenic crops.

In 2012, the European Food Safety Authority (EFSA) reviewed the risk of cisgenic and intragenic plants by comparing them to conventional plant breeding techniques. The Panel established that similar hazards are associated with cisgenic plants and conventionally bred plants. However, plants created through intragenesis may present novel hazards. Overall, they concluded that the frequency of unintended effects may differ based on the breeding technique used and risks must be assessed on a case-by-case basis (EFSA, 2012a).

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The genetics ofplant breeding

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Classical selective breeding

Conventional cross-breeding between species that could breed naturally

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Genome editing techniques (A-B)

New plant breeding techniques (B)

A

B1

A further technique is engineering with the ‘zinc finger nuclease’, a class of enzymes that cut DNA in targeted places and use the natural machinery of the cell to repair the break. This can be used to edit existing genes and insert new ones (Carroll, 2011). The EFSA Panel also assessed the risk of plants developed using the zinc finger nuclease 3 technique, which allows the integration of gene(s) into a predefined insertion site in the genome of the recipient species. The Panel concluded that its existing guidance documents can be used for plants developed using this technique. Furthermore, as the zinc finger nuclease inserts DNA to a predefined region, they deemed it to have less risk of disrupting genes and/or regulatory elements than transgenesis. Although there is some risk of off-target, unintended genetic changes, these are expected to be fewer in number and similar in type with respect to mutagenesis techniques used in conventional breeding (EFSA, 2012b).

Zinc finger nucleases were the first targeted gene-editing technique, although more sophisticated techniques have been developed since — such as transcription activator-like effector nucleases (TALEN), restriction enzymes that can be engineered to cut almost any DNA sequence (Boch, 2011) and the CRISPR/Cas9 system (which enables precise genomic modifications in a wide variety of organisms; see box 5).

Applications using these new techniques are already in use. In the US, agricultural trait development company Cibus has used new plant breeding techniques to create herbicide-resistant oilseed rape. The variant (which does not contain any foreign material) was planted in the US in 2015. The US has also approved a potato variant with reduced bruising and browning, developed using RNA (a nucleic acid like DNA) that reduces the expression of the enzymes responsible for these processes (a method

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B2

B3

called RNA interference, which also does not involve foreign DNA) (EASAC, 2015). In the EU, field trials in Belgium and the Netherlands have bred potatoes resistance to the fungus responsible for ‘late blight’ using cisgenesis (EPRS, 2016).

There are many possible benefits to these new techniques: increasing yield, improving crop quality, developing resistance to pests and diseases, creating plants that use resources more efficiently or can adapt to environmental

extremes, crops with enhanced nutritional quality, increasing genetic diversity and reducing crop losses (ADAS, 2015; EPRS, 2016; STOA, 2013).

However, there are certainly downsides to consider. As well as the potential unforeseen risks that may occur due to unintended genetic changes or gene transfer, some argue that these new plant breeding techniques are incompatible with organic farming, which by definition excludes GMOs, and may therefore threaten

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BOX 5. CRISPR/Cas9: A genetic modification power tool

As well as applications which promise to solve grand societal challenges, there are concerns about purely commercial applications.

Clustered regularly-interspaced short palindromic repeats (CRISPR) is an emerging genetic modification technique that has the potential to rapidly and precisely modify the genes of crops, animals, and even the human germline.

CRISPR are DNA sequences found in bacteria that can be used to edit genes. In concert with the Cas9 enzyme, CRISPR can cut the genome at any location of choice. A modification of the system has recently allowed researchers to change not just genes, but individual bases within genes (Komor et al., 2016). This is an important tool for synthetic biologists, but also a challenge to the international regulatory landscape.

CRISPR has been used for medical purposes, fuelling a new generation of gene therapy. In April 2015, scientists reported use of the technique to edit human embryos, sparking an ethical debate. In agriculture, CRISPR is being used to engineer wheat and rice resistant to disease and create vitamin-enriched fruit crops, and CRISPR-based gene drive systems could be used to eradicate populations of disease-carrying mosquitoes. Such environmental applications raise many concerns, including how to recognise a modified organism (as the changes made by CRISPR are difficult to differentiate from changes obtained by conventional breeding) and how changing or removing entire populations — and stores of genetic material — may affect the rest of the ecosystem. The major changes to genetic information enabled by CRISPR-Cas9 could have major impacts on biodiversity, especially if used on organisms with rapid reproduction cycles such as insects, microbes or annual plants. Furthermore, because it is difficult to identify these synthetic organisms, it will be challenging to monitor or control them. In the context of plant breeding, there is fear that these techniques will have significant economic consequences for the organic sector.

Regulatory authorities around the world are considering the social, ethical and environmental.implications of this system. Indeed, this is an international issue, as organisms and effects could easily spread across borders. A recent report from the US National Academies concluded that laboratory studies conducted to date are not sufficient to support a decision to release gene-drive modified organisms into the environment, recommending field research to refine CRISPR/Cas-9 based gene drives and to understand how they might work under different environmental conditions (National Academies, 2016b). Similarly, a policy report from the Netherlands’ National Institute for Public Health and the Environment (Westra et al., 2016) concluded that the use of gene drives is a cause for concern, and that current methods for assessing the risks to human health and the environment are insufficient.

Source: Ledford, 2015.

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its development. Other arguments include increased production costs for farmers and reduced freedom of choice for breeders, farmers and consumers (IFOAM, 2015).

Associated with these potential downsides, there is an intense debate regarding whether these newly bred plants should come under EU legislation on GMOs. The testing and release of genetically modified plants is tightly regulated in the EU in order to prevent negative effects on human or environmental health, which some argue constrains innovation and agricultural potential.

As these new techniques involve precise changes to the genome and do not involve foreign DNA, some suggest that they should not be regulated by existing GMO legislation. The European Academies Science Advisory Council (formed by the national science academies of EU Member States) for instance argues that plants produced through these methods are different from GMOs produced previously, as they enable precise and targeted changes in the genome. For several of the techniques, the resultant plant does not contain any foreign genes and could also be developed by conventional breeding (EASAC, 2015). As such, EASAC recommended that new breeding techniques (when they do not contain foreign DNA) should not fall within the scope of GMO legislation and that the EU should regulate the agricultural trait or product rather than the technology itself.

Several other bodies have supported the view that the safety of new crop varieties should be assessed based on their characteristics, not how they are produced (EPRS, 2016). The US National Academies also recommends that the product, not the process, should be regulated and emphasises a tiered approach to risk assessment based on likely risk to human health or the environment — regardless of how the plant was bred (National Academies, 2016a). Likewise, Schouten (2006) argues that, as cisgenic plants are similar to traditionally bred plants, they present similar safety concerns and should

be exempt from regulations for GMOs. Overall, the plant breeding industry argues that these new breeding techniques should not be subject to GMO legislation (EPRS, 2016).

However, as they are still techniques of genetic modification, others suggest that they should be subject to the traceability and labelling requirements (Regulations EC 1829/2003 and 1830/2003) that apply to GMOs. The German Federal Agency for Nature Conservation (BfN) for example argues that the fact that the modifications are carried out purposefully and lead to incorporation of new genetic material into a host organism is more important than the fact that the mutations could also occur naturally, and therefore that the techniques should fall under the GMO legislation (EPRS, 2016).

The International Federation of Organic Agriculture Movements (IFOAM) EU Regional Group recently developed a position paper on New Plant Breeding Techniques, recommending that the European Commission considers these techniques as GMOs. The paper cites concerns such as unknown consequences for biodiversity and economic damage to the organic farming sector (IFOAM, 2015). Should they not fall under GMO legislation, it could mean that it would be for the Member States to decide. This could be problematic, as national authorities do not yet have the capacity to properly evaluate potential impacts. The European Parliamentary Research Service (EPRS, 2016) recently published a brief on the applicability of EU legislation on GMOs to new plant breeding techniques, which discusses these arguments in more detail.

The debate is ongoing and the European Commission has been requested to clarify whether GM regulations apply to these new techniques (see also section 7. Regulatory implications, p. 28)

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5. What are the ethical issues associated with synthetic biology?Beyond the impacts on biodiversity discussed above, synthetic biology raises complex ethical issues. Wider use of synthetic biology could generate shockwaves in the global economy, causing a shift towards biotechnology-based economies, or those based on the use of biological resources. This may have particularly significant impacts on the rural economy and low-income tropical countries (Redford et al., 2014), which could be sources of biomass (needed as feedstock for synthetic biology processes). Synthetic biology could provide benefits to these areas, or further reinforce inequities in trade, depending on the policies in place. Furthermore, natural products that are currently grown or harvested in low-income countries could be displaced by industrial production with the help of genetically engineered organisms. Government policies in both high- and low-income countries will have a large influence on these new bio-economies and the social impacts they have (CBD, 2015a).

There are many questions about the use of synthetic biology techniques, how they are controlled and who will profit from their use. Many ethical and economic issues are related to the role and place of synthetic biology in the fair and equitable sharing of benefits arising from the use of genetic resources, which is the third objective of the CBD. While the Nagoya Protocol3 provides a framework for the fair sharing of benefits arising from the use of genetic resources, it is not clear whether it would be applicable to all synthetic biology (Bagley & Rai, 2013). For example, the Nagoya Protocol would not seem to cover digitally stored genetic information which may be used as a basis for synthetic biology, and as such would not capture an increasingly important dimension of the potential value of genetic material. This issue may have to be addressed by the Parties to the Protocol.

Yet another and broader ethical concern is how the ability to engineer biology may affect people’s perception of nature, and the value they attribute to it. Synthetic biology aims to create living organisms from scratch

and therefore challenges ideas about what is natural (Calvert, 2010). It may reduce how much people value what are now precious natural resources, and reduce support for conservation efforts in the expectation that extinct species can be brought back to life.

Linked to this are philosophical debates about the creation of life, prompting fears about scientists ‘playing God’; concerns that have been voiced since the beginning of modern biotechnology (Dabrock, 2009). In 2010, a team of scientists led by Craig Venter (Gibson et al.) produced an entirely synthetic genome and introduced it to bacteria without any genetic material, allowing the cells to grow and replicate. In 2014 (Malyshev et al.) the first entire living organism with artificial DNA was produced, when a team engineered E. coli to replicate a genetic code containing unnatural base pairs – representing the first organism to propagate an expanded genetic alphabet. More recently (Hutchison et al., 2016), Venter’s lab built a bacterium with the smallest genome of any free-living organism, a cell that is able to survive and self-replicate with just 473 genes. (For comparison, humans have around 21 000 genes and even the fruit fly has around 17 000 (Kimball, 2016)). The construction of ‘life’ in this manner raises questions about what ‘life’ really means and our relationship with the natural world.

3. https://www.cbd.int/abs/

Hedgehog and cowslip @Pixabay/TomaszProszek

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The line between changing the genetics of an existing organism and creating an entirely new being is blurred, prompting some scientists to find a definition of ‘life’ — what it is, where it begins, and how complex it must be. To assist this, some have proposed a modified version of a Turing test (which is used to test whether a machine’s intelligence is equivalent to a human) for life imitation. While this may have some use, such a definition is unlikely to allay deeper concerns about the blurring of the boundary between the synthetic and the natural (Balmer & Martin, 2008), especially as machine learning is starting to rival world-class human game players.

As this section highlights, beyond the immediate safety issues, there is a need for robust ethical governance of synthetic biology to protect the environment and

society. To assist with this, the newly established Scientific Advice Mechanism (SAM) has been given the mandate to provide independent and high quality scientific advice to the European Commission. SAM is now hosting the secretariat of the European Group on Ethics in Science and New Technologies (EGE)4, which was requested by the President of the Commission to provide independent advice on the scientific, ethical, legal, governance and policy implications of synthetic biology in 2008. An opinion on the ethics of synthetic biology adopted by the EGE in 20095 concluded that the responsible development of synthetic biology must be based on ethical principles, enshrined in conventions and declarations. The general framework developed in this opinion remains valid, although an update to take account of the most recent developments in the field could be valuable.

4. https://ec.europa.eu/research/ege/index.cfm 5. Opinion n°25 17/11/2009: http://ec.europa.eu/archives/bepa/european-group-ethics/docs/opinion25_en.pdf

6. What are the safety issues associated with synthetic biology, and how can we manage them? As the field continues to develop at breakneck pace, there are huge uncertainties regarding not only what the potential of synthetic biology may be, but also the risks it may pose. The accidental release of GMOs into the environment is a clear concern, as organisms could evolve, proliferate and interact in unexpected ways, potentially adversely affecting ecosystems. There are many scientific uncertainties and potential unforeseen consequences to do with the manipulation and transfer of genetic material, such as the integration of modified cells with living organisms or transfer of genetic material to wild organisms.

As well as the accidental transfer of genes to wild populations, there is also the possibility of intentional destructive activity, such as engineering genes that quickly spread

through populations (gene drives) to cause the spread of disease. Other potential malicious applications include production of biological weapons (e.g. modified pathogenic viruses) or microorganisms engineered to produce toxins.

Bioterrorism could have destructive effects on the environment© iStock /Bernd Wittelsbach

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Although the design and production of entirely novel pathogens for malevolent purposes is unlikely, there are reasons to take the threat seriously, as anyone can potentially access public DNA sequences, design DNA using free software and order it for delivery (although this requires rare expertise, and checks are in place to ensure that sequences of pathogens cannot be ordered). Out of this has arisen a debate about publishing studies which could have security implications, such as the description of vaccine-resistant mousepox (Jackson et al., 2001) and the artificial synthesis of the polio virus (Cello et al., 2002).

There is an understandable danger here, but publishing such studies could also have benefits for science and banning them raises complex censorship issues. Another protective mechanism is for companies that synthesise DNA to screen all sequences for toxicity before processing an order (EGE, 2009). In fact, the International Gene Synthesis Consortium (http://www.genesynthesisconsortium.org/) — a consortium of the world’s leading gene synthesis companies — already screen the sequences of synthetic gene orders and the customers who place them to help prevent the misuse of this technology. An alternative solution may be for the scientific community to ‘self police’ research for malevolent intent or for situations when legitimate research could be misused (Atlas, 2009).

To mitigate the possible negative impacts, there are also several methods of control that can be used on the synthetic organisms themselves. Firstly, organisms used for research purposes can be kept in confined conditions, with measures in place to prevent contact

with the external environment. They can also be placed under contained use outside of labs, using physical measures to limit their exposure to the environment.

Applications where organisms are intended for release into the environment will have different and potentially greater safety concerns than those intended for restricted use. Thus, as well as physical restrictions, more sophisticated techniques to contain organisms are being explored, such as ‘integrated biocontainment traits’, which act as built-in safety controls. Examples include ‘kill switches’, which cause the death of the engineered organism on a particular signal, such as the introduction of a chemical. A kill switch activated in the presence of the chemical IPTG (commonly used as a trigger in molecular biology) has been demonstrated in engineered microbes in soil, seawater and an animal model (Knudsen et al., 1995). Other inducers include heat and sugar molecules (Moe-Behrens et al., 2013).

Other control measures include engineering bacteria to be dependent on nutrients and self-destruct mechanisms that are triggered once the population density exceeds a certain threshold (Balmer & Martin, 2008). A further possibility is the inclusion of nucleic acids containing elements not found in nature (xeno-nucleic acids), which cannot mix with naturally occurring organisms (CBD, 2015a).

While there are clearly a range of control strategies in place, no biocontainment strategy can eliminate risk, which highlights the importance of robust risk and safety assessment methods.

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BOX 1. Do-it-yourself (DIY) synthetic biology

As technology advances, synthetic biology has become simpler to use than traditional molecular biology techniques — and more affordable. In concert with this, its user base has expanded from scientists to interested amateurs, creating the ever-expanding field of ‘DIY Biology’.

There are thousands so-called DIY biologists worldwide, increasingly organised in formal groups. DIYBio.org for example (founded in 2008) has over 2000 registered members in over 30 countries. In the EU alone, there are over 15 countries registered, each with their own website. Most activities involve teaching and workshops, but some involve lab-based experiments.

Recent advances include ‘Cello’, a piece of software that allows people who are not trained biologists to design biological systems (Nielsen et al., 2016) and ‘Bento Lab’, a DNA analysis kit suitable for beginners the size of a laptop (Bioworks, 2014).

There are some concerns that citizen scientists may not follow the risk assessment and biosafety procedures required by the professional community. However, it requires not only materials but also knowledge to create biological systems that may cause harm, and there is no reason to expect the DIY Biology community to cause more harm than anyone else (Kuiken, 2016). Furthermore, the community has developed its own code of conduct (diybio.org/codes), which, alongside the ‘Ask a biosafety professional your question’ portal, demonstrates its sense of responsibility (ask.diybio.org).

In 2015, in its second opinion on risk assessment methodologies and safety aspects, the three European Commission Scientific Committees concluded that, in principle, DIY Biology does not pose a hazard to humans or the environment. Realistically, the greater threat is likely from state-level biological warfare programmes (Balmer & Martin, 2008).

However, because it is becoming more popular, established safety practices must be maintained. An independent biosafety body could be used for verification, and it is important that newcomers undergo the same biosafety training as professionals (European Commission, 2015). It is also important to proceed towards robust codes of conduct and regulations for safe and responsible research, developed through public dialogue.

In the EU, genetic engineering experiments can only be performed in GM-authorised labs, which places limits on DIY biology. Several groups in Europe already begun the process to create a certified lab for genetic engineering projects. For example, a Netherlands group began the process in 2013 and groups in Denmark and France are planning to follow suit (Seyfried et al., 2014).

The benefits of a responsible DIY Biology community in Europe could be far-reaching, raising public awareness of science and creating a participatory innovation process, perhaps developing products that would not have been conceived of by science or industry (Seyfried et al., 2014).

Sources: Kuiken, 2016; SCENIHR, 2015.

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7. Regulatory implications

As discussed earlier in this brief, synthetic biology may have unintended negative effects in the environment. Unanticipated interactions with natural organisms could create risks which must be addressed by legislation if synthetic biology is to be used responsibly.

Due to the novelty of the field and how rapidly it is changing, there are questions as to whether existing regulations can adequately address the risks and implications of synthetic biology. Synthetic biology falls under a number of regulatory mechanisms, but most were established before the field fully developed and therefore were not intended to cope with its impacts.

At the most recent meeting of the CBD’s Subsidiary Body on Scientific, Technical and Technological Advice, the advisory group agreed on a common understanding of the terms components (parts used in a synthetic biology process, such as a DNA molecule) and products (the output of a synthetic biology process, such as a chemical substance). Both of these elements are not living, unlike the final element of the triad: organisms. The group agreed that the organisms, components and products of synthetic biology fall within the scope of the Convention and its three objectives. This agreed terminology — organisms, components and products — will be valuable in future political deliberations.

However, there are many grey areas. Living organisms developed through current applications are similar to living modified organisms (LMOs) defined by the Cartagena Protocol on Biosafety. However, the non-living components are not regulated by this protocol, and there may be cases in which there is no consensus on whether the application is living or dead (e.g. protocells). And, as the field evolves beyond techniques to manipulate nucleic acids in vitro to cause heritable changes, the methods used to assess the risk of LMOs may become inadequate (CBD, 2015).

There is also discussion of how existing legislation on GMOs fits into this. Although synthetic biology results in genetic modification (altering the genetic material of existing cells in a way that does not occur naturally) and therefore should be subject to existing EU GMO legislation, several elements of synthetic biology escape the existing GMO regime. As a result, is has been suggested (Engelhard, 2016) that new regulation is needed — which either extends the scope and risk assessment or existing regulations, or takes the form of entirely new regulation that addresses biotechnology more broadly (including GMOs,

synthetic biology and possible new breeding techniques). Although the former would be simpler in political terms, perhaps the latter would be more appropriate to match the new risks presented by synthetic biology.

Clearly, future developments in synthetic biology will require changes to existing regulation, or entirely new legislation, and there is a pressing need to explore other biosafety frameworks and identify the gaps in current risk assessment methodologies. There is also a need to think creatively about the potential unforeseeable events that could occur. Some argue that no-one can yet fully understand the risks that synthetic biology poses to the environment, or even what information is needed to perform risk assessment (CBD, 2015; Dana et al., 2012).

Overall, existing biosafety frameworks and the general principles of the Cartagena Protocol on Biosafety provide a sound basis for risk assessment of the living organisms, components and products developed by synthetic biology now and likely to be developed in the near future. However, they should be updated and adapted for future developments and applications. It is important to assess other regulatory frameworks that cover components and products, such as EU chemicals legislation, and address any remaining gaps under the CBD.

Convention on Biological Diversity SBSTTA: agreed terminology, April 2016Terminology Living or

non-living? Does Cartagena Protocol apply?

Components(parts used in a synthetic biology pro-cess, such as a DNA molecule)

Non-living No

Products(the output of a synthetic biology process, such as a chemical substance)

Non-living No

Organisms (developed via applications of synthetic biology, similar to living modified organisms)

Living Yes

Source: 20th meeting of the SBSTTA documents

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In order to understand the potential ecological effects of synthetic organisms, and thus regulate them effectively, four areas of research have been proposed (Dana et al., 2012), to: 1) understand the physiological differences between natural and synthetic organisms; 2) consider how engineered microorganisms might alter habitats, food webs or biodiversity; 3) determine the rate at which synthetic organisms evolve and whether they could persist, spread or alter their behaviour in natural environments; 4) understand gene transfer by synthetic organisms (for example, whether synthetic organisms could transfer antibiotic resistance).

In its opinion on the ethics of synthetic biology, the EGE makes a number of recommendations for the assessment and regulation of synthetic biology. The group recommended that the use of synthetic biology be conditional on safety issues and that risk assessment be conditional for financing of research. It also recommends the development of a Code of Conduct for research on synthetic organisms which should ensure, for example, that organisms cannot survive autonomously if accidentally released into the environment. For organisms that are developed for environmental applications, ecological impact assessment studies should be performed and authorisation procedures for synthetic biology derived materials should take into account risks for the environment and people.

The EGE discusses the existing regulatory framework as ‘fragmented’ and says it may be not sufficient to regulate current and emerging aspects of synthetic biology. It re-iterates the importance of acting now to develop a robust governance framework for synthetic biology in the EU, which should address all relevant stakeholders and make clear their responsibilities (EGE, 2009).

More recently (2014), ERASynBio (a European Research Area Network, originally funded by the European Commission) proposed a vision for European Synthetic Biology, which also discussed the principles of good governance, highlighting the importance of transparency, participation and accountability in policy. The vision also suggests that regulation should consider issues of safety and controls on synthetic organisms, and that scientists should be required to demonstrate consideration of environmental risks, ethical and social issues before proceeding with their work.

The European Commission also supports the need to conduct research on the impacts of the organisms, components and products of synthetic biology, including socioeconomic, cultural and ethical considerations. It aims to identify and reconcile knowledge gaps, and identify how these impacts relate to the objectives of the CBD. In its third opinion, the Scientific Committees to the European Commission discussed the risks to the environment and biodiversity related to synthetic biology processes and products, and identified gaps in knowledge that may prevent reliable risk assessments (SCENIHR, SCCS, SCHER, 2015b).

The gaps they identified included a lack of information and tools to predict the properties of complex unnatural biological systems, and to measure the differences between natural and engineered organisms. They also discussed new genome editing methods that allow scientists to produce lots of variants at the same time. Although these methods allow more accurate and precise changes than traditional techniques, they are also producing organisms at an unprecedented scale and speed, which may create new challenges for risk assessment.

Based on the major scientific gaps they identified, the Committees made a number of recommendations for future research. Vitally, they concluded that more work is needed to develop standardised techniques to monitor the survival of organisms in the environment. Indeed, the need to develop monitoring systems for the organisms, components and products of synthetic biology is key, as emphasised in the recent recommendations from the CBD’s Subsidiary Body on Scientific, Technical and Technological Advice (CBD, 2016).

As a party to the CBD, the EU has to clarify its position on synthetic biology. Key elements include adopting an operational definition of synthetic biology and

evaluating the tools available to detect and monitor the organisms, components and products of synthetic biology — and their impacts on biodiversity. Finally, in terms of regulation, the Nagoya and Cartagena Protocols may need to be re-assessed, in order to determine if changes are needed to protect access and benefit sharing, and effectively assess the risks posed by synthetic biology.

7.1 Research needs and areas for future development

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8. Summary and recommendations

Synthetic biology is a new and exciting field with a vast range of potential applications, which might have benefits for biodiversity. However, there are also many scientific uncertainties surrounding the manipulation and transfer of genetic material, which may have matching adverse consequences for biodiversity. There are also complex ethical issues to investigate, including how synthetic biology may fundamentally change our perception of the natural world. Several things will be key to surmounting the challenges presented by synthetic biology.

For example, an exploration of synthetic biology commissioned by the UK Biotechnology and Biological Sciences Research Council highlighted the importance of public engagement for achieving (responsible) progress in the field. This requires involving the public in research and demonstrating, but not overstating, the societal benefits of applications. Public acceptance of synthetic biology will inform policy, funding and regulation and therefore how the issues are framed is very important. Mainstream media coverage to date has focused on extraordinary stories of de-extinction, neglecting the more nuanced benefits (or risks) for biodiversity and complex ethical and social implications (Redford et al., 2014). As well as accurate reporting, the scientific community should openly debate the implications of their work and engage with society about the issues it may raise (Balmer & Martin, 2008).

It is also imperative that a robust governance framework is in place before synthetic biology’s newest applications come to fruition. This will involve an in-depth review of the existing regulations as well as the development of new measures for environmental release, biosafety and biosecurity (Balmer & Martin, 2008).

While it seems that the existing regulatory instruments — such as the Cartagena Protocol — are broad enough to address current issues in synthetic biology, there are questions about whether they will continue

to be fit to protect biodiversity in the future. There is a need for further discussions to explore other existing biosafety frameworks and identify possible gaps in regulations that need to be addressed and how. It is also important to develop risk assessment protocols for the unlikely but highest impact consequences on biodiversity. Negotiations are ongoing within the CBD to achieve these goals.

Whatever is decided, regulations should be continually updated and coordination between Member States will be vital. Underlying this, the precautionary principle must be central to addressing the threats to biodiversity. In the EU, the precautionary principle plays a key role in policy design: applied as a tool to follow developments in a sector and continuously verify that the conditions for the acceptability of a given innovation are fulfilled (EGE, 2009). In the case of synthetic biology, the precautionary principle is an important element of ethical debates and legal decision making and will help to protect the environment from harm.

“The growing innovative powers of science seem to be outstripping its ability to predict the consequences of its applications,” warned the European Environment Agency in 2001. Synthetic biology provides a prime example of technology outpacing regulation, and highlights the need to identify the risks posed by new and emerging technologies via early warning systems. As with many such technologies, it is too early to foresee all the possible developments of synthetic biology. Developments could generate unexpected (and undesirable) side-effects. Synthetic organisms that are initially useful could later turn out to have harmful and wide-reaching effects (Engelhard, 2016).

Likened to Pandora’s box, it is important that action is taken now to ensure synthetic biology is safely implemented. This sector could revolutionise the way our industries and economies function, placing policymakers in a unique position to protect the environment throughout the transition.

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