The term moratorium refers to a contractually agreed or legally mandated postponement. By a global gene drive moratorium, we mean a conditional moratorium on the release of gene drive organisms into the wild, agreed at the level of the UN Convention on Biological Diversity (UN CBD). Gene Drive Organisms are extremely new and so far untested in the wild. They are intended to breed with wild-living members of the same species to genetically modify or crash the whole population, with potentially devastating, unpredictable and far-reaching consequences for our ecosystems that are hard to predict before their release. Currently there is no viable and sufficiently proven way to stop them or reverse the change, should unforeseen problems arise- therefore we recommend a moratorium on their release until certain conditions are met. Click here for our recommendations for conditions that could justify the reversal of this moratorium.

The way genetically modified organisms have been developed so far, they should either not produce viable offspring, not be able to survive for long in the wild, or they have been prevented from pairing with wild conspecifics. However, in the case that they do reproduce with their wild counterparts, they are still governed by normal laws of genetic inheritance; i.e they can still be weeded out from the population over generations by natural selection if the engineered genes don’t help the organism survive or reproduce- and normally, altered genes will have a negative effect on the ability of the organism to survive.

While the release of GMOs is still fraught with risk and has many potentially severe environmental consequences, GDOs bring in other dangers altogether. They are not subject to the limiting mechanisms of natural selection. In contrast, Gene Drive Organisms are engineered to spread genes synthesised in the laboratory into wild populations or to eliminate naturally occurring genes1. Normally, these genes would not prevail under natural selection. However, GDOs pass their modified genes on even if this harms the species or offers no survival advantage2. Gene drives shift the place of genetic modification from the genetic engineering laboratory to nature: In the case of CRISPR/Cas9-based homing gene drives, the genetic engineering mechanism (CRISPR/Cas9) copies itself into the genome of the wild offspring each time a GDO reproduces – and keeps doing that over generations3. The ‘forced’ inheritance of even harmful genes caused by the gene drive induces a theoretically unstoppable “mutagenic chain reaction”4.

No. To our knowledge, genetically modified, synthetic Gene Drive Organisms have not yet been released into the environment. Gene drives are still at an early stage of development and have so far only been tested in the laboratory. Gene drives for manipulating sex distribution and lowering fertility in mosquitoes are the most advanced5. These gene drives are being developed as part of the Target Malaria project and are intended to decimate malaria-carrying Anopheles mosquitoes in West Africa. Release trials, originally planned for 2024, have been pushed back but are planned in sub-Saharan Africa within the next 10 years.

Often confused with gene drive but quite different, genetically-modified mosquitoes have been released: the GM male Aedes aegypti mosquito, developed by the British company Oxitec in order to reduce the population of mosquitoes transmitting diseases such as Zika, Dengue, Chikungunya and yellow fever, is currently fully licensed in Brazil and under a provisional use permit in the USA7. Eggs from the GM male mosquito are released into the environment, hatch, and then mate with wild females and produce only male offspring, causing a population crash and a reduction in numbers of biting, disease-carrying female mosquitoes. In contrast to gene drive, in which a genetic modification is designed to fixate (currently irreversibly) at levels close to 100% in the population through CRISPR/cas9 and ‘super-mendelian inheritance’, the ‘self-limiting’ gene in Oxitec mosquitoes is passed down according to the normal rules of inheritance with a 50% chance of inheritance. This means that, according to current research, the numbers of GM mosquitoes should reach effectively 0 after around 10 generations due to natural selection, unless the eggs of GM mosquitoes are consistently released in large numbers. This contrasts to gene drives, where the modification is designed to spread and persist in the wild population.

Another example of an altered, but not GM mosquito, is the Wolbachia-infected Aedes aegypti mosquito that is artificially infected with the Wolbachia bacterium and released to infect the wild population. Wolbachia has been shown to compete with viruses such as Dengue, making A. aegypti more resistant to it and reducing disease transmission8. Though they are often mistaken for gene drive, Wolbachia and Oxitech mosquitoes do not use gene drive technology.

There are many hurdles to overcome in the development of gene drives; these depend on the species to be modified, but also on the gene drive used. Here are just a few examples:

Development of resistance to the gene drive

CRISPR/Cas-based gene drives search for a clearly specified DNA sequence at which they are supposed to cut the genetic material. Even single mutations to this sequence can therefore make the target unrecognisable to them. The organism thus becomes resistant to the gene drive. Such resistance can arise if the DNA double-strand break produced by CRISPR/Cas9 is incorrectly repaired by the cell and changes the target sequence9. However, resistance could also occur naturally, especially in populations with high genetic diversity.

Unexpected effects of CRISPR/Cas9

Many gene drives use the genetic engineering tool CRISPR/Cas9 to create a double-strand break at predetermined locations in the genome. However, this tool does not work flawlessly. CRISPR/Cas9 can change the activity of the target gene in an unpredictable way, increase the mutation rate in the genome, lead to unexpected mutations or be disrupted in its function by emerging resistances. For example, there are increasing reports of so-called off-target effects, unintended changes to non-target sequences, which can occur when using the CRISPR/Cas system10,11.

Decreased fitness of gene drive mosquitoes

One issue encountered already is that heterozygous carriers of the gene drive (those that have one copy of the gene) in the tested mosquitoes, are much less biologically fit than their wild counterparts. That means that they have decreased rates of survival and egg production in comparison to the non-GD mosquitoes. This effect has been observed in many of the mosquito populations that Target Malaria are working on12,13. This finding is thought to be due to gene expression working in a different way to expected, with CRISPR-Cas9 being active in every cell, rather than as it should which is just in the sexual cells shortly after reproduction. Together with showing us that we know far less about the workings of the genome than we thought, which should make us pause and consider before proceeding, these fitness effects could prove enough to stop the gene drive spreading through the population and preventing it from working as planned.

Gene drives in mice / mammals:

An experiment with mice showed: CRISPR/Cas9 was able to cut the DNA strand in all test animals, but only in females did the repair mechanism also set in, actively spreading the new DNA segments in the genome. The gene drive was therefore only successful in one of the two sexes, and even there it only achieved an efficiency of about 70 percent14. The gene drive in this form is probably not suitable for manipulating free-living populations.

Gene drives in plants:

A number of technical challenges still need to be overcome before gene drives can be applied in plants. Plant cells usually repair the double-strand break caused by CRISPR/Cas9 in their genome with fault-prone mechanisms. This prevents the preparation of the gene drive in plants. In addition, many plants have significantly longer generation times than insects and thus the population-level effect of a gene drive would not become visible for many years. Therefore while the development of gene drive technology in plants is underway, it is presenting many challenges. A recent paper by Zhang et al.15 demonstrates this; after the team initially thought they had successfully engineered a gene drive system in the model plant Arabidopsis, their paper was retracted in June 2022 as they discovered that the drive system had in fact been passed down to later generations with a significant mutation in its genetic code.

Though gene drives have demonstrated some efficacy in a laboratory or cage environment, they are currently untested in the wild. Once released into the wild, a gene drive organism is intended to breed with and spread in free-living populations and could spread rapidly over large distances. Recent simulations have shown that even a release of as few as two gene drive organisms using a low-threshold gene drive system into some wild populations could be enough to cause the gene drive to reach levels of almost 100% in the population. With no current well-researched and reliable way to reverse or recall them, even a small field trial in nature would be essentially the same as releasing them16,17,18. Therefore the discussion about possible consequences and risks is still largely speculative.

However, in the event of a release, the incalculable diversity and complexity of the natural habitats and ecosystems affected will make the prediction and control of possible risks significantly more challenging19. Even with a comprehensive risk assessment, the nature of intervening in a complex system such as an ecosystem means the effects are unpredictable and not linear. They could range from no effect if the gene drive construct did not perform in the wild, to ecosystem collapse if it was successful but had unintended consequences, with a whole range of effects possible in between.

In the EU, Directive 2001/18 regulates under which conditions genetically modified organisms (GMOs) may be released into the environment. It is undisputed that gene drive organisms are GMOs.

The purpose of gene drive organisms is to spread independently in the environment, to cross with wild conspecifics and to pass on their modified genes to as many offspring as possible in order to spread them throughout the entire population of a species. Because this is clearly contrary to the current provisions of Directive 2001/18 with regard to the precautionary principle for the protection of the environment mentioned therein and the opt-out option available to Member States (EU Directive 2015/412), an authorisation for the release of a gene drive organism into the environment should not be possible under European law. Every release of a GMO, of course, requires such an authorisation.

However, this assumption has not yet been officially confirmed by EU bodies or the European Court of Justice, because the political debate on the regulation of gene drive technology is still in its infancy at the European level. As concrete applications for the use of gene drive technology in the EU are yet to be decided, the political debate has so far focused mainly on the EU’s position in the negotiations of the UN Convention on Biological Diversity (CBD) and on the preparation of criteria for the risk assessment of the technology.

Previous statements and positions of the European institutions on gene drives are described here: Status of the regulation of gene drive organisms at EU level.

More detailed comments on the interpretation of Directive 2001/18/EC with regard to gene drives can be found here: The European Genetic Engineering Law

A synthetic “gene drive” is an overarching term for several genetically engineering tools that spread a desired modification in the genome of a population. They increase the likelihood that the offspring would inherit the modification. There are different types of such tools that are usually categorized into low or high threshold drives which require few or many, respectively, released engineered individuals for the wild population to be manipulated20. So-called homing gene drives which use the CRISPR/Cas9 tool are the most common variant of synthetic gene drives and are considered to be low threshold drives. Such a gene drive consists of at least two components: the Cas9 gene scissors and a guide molecule (guide RNA). In addition, a new or modified ‘payload’ gene can be introduced, which codes for a desired trait.

The gene drive is first introduced into the genome of the target organism, e.g. a mouse, in the laboratory. This gene drive becomes active after fertilisation of the egg cell and identifies a target sequence in the non-manipulated chromosome with the help of the guide molecule. There, Cas9 induces a double-strand break. Natural repair mechanisms in the damaged cell then try to repair the break with the help of a template. The gene drive on the genetically modified chromosome serves as a template: it is very likely to be copied completely and incorporated within the target sequence on the previously unmanipulated chromosome. This targeted process is called homing21. In addition to the integration of the gene scissors at the target position, existing gene sequences can be switched off and/or new ones additionally inserted. This process ultimately results in all offspring inheriting a copy of the gene drive. The gene drive becomes active anew with each reproduction – also in all following generations – and theoretically only comes to a stop when the target sequence has disappeared from the entire population. In other words, when every wild type target gene has been replaced by the gene drive construct.

CRISPR/Cas is a so-called ‘new’ genetic engineering technique discovered in 2012 by molecular biologists Emanuelle Charpentier and Jennifer Doudna22. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats, which is actually used in the immune system of bacteria to defend against viruses. The two scientists who discovered it then turned this mechanism into a biotechnology tool. CRISPR consists of two components: a search tool for DNA sequences (guide RNA) and an associated protein called Cas (which is an acronym for CRISPR-associated). Cas is a DNA enzyme that can make a double-strand break in DNA at a searched target sequence. Once the break happens, repair mechanisms in the cell can then repair this break in 3 possible ways. Biotechnologists then make use of these three repair mechanisms to either switch off existing gene sequences, to insert only a single base pair or to insert a completely new DNA sequence. As well as in gene drive technology, CRISPR/Cas is in use or proposed for use in genetics research, biotechnology and medicine.

Further information here: Centre for Genetic Engineering and the Environment.

The differences between old and new genetic engineering are in the tools and mechanisms used and the targeting and nature of the desired genetic modification. ‘Old genetic engineering’ refers to procedures that introduce one or more genes of an organism of the same or a different species into the DNA of an organism using bacterial plasmids or gene guns at one or more random locations in the DNA. With these ‘old’ genetic engineering techniques, the site in the chromosome where the introduced DNA is inserted cannot be specifically and accurately chosen.

New genetic engineering methods are a series of instruments with names such as CRISPR/Cas, zinc finger nuclease or Talens, which also have to be introduced into the DNA before they can become genetically active there. These methods are commonly called “gene scissors” because they make it possible to cut DNA sequences at a specific point. The resulting cellular repair mechanism is then used by biotechnologists to switch off individual genes, change their function or insert new gene sequences. Through these new mechanisms, more specific and targeted deletions, additions or modifications can be made. It is worth noting that a body of literature is arising that points to on and off target effects from CRISPR that are not intentional- that means that CRISPR/Cas9 has been shown to ‘mistakenly’ make cuts and changes in chromosomes either in the wrong place, or make wrong modifications in the intended target site23.

No. One of the most common arguments put forward for the use of gene drives are that they occur naturally. It is true that not all natural gene systems follow Mendel’s rules of inheritance and some similarities to gene drive constructs can be observed in nature For example, in plants, animals and humans, there are genetic elements that copy themselves with the help of enzymes into other parts of the genetic material, spread independently and thus increase the frequency of their inheritance. These include so-called ‘jumping genes’ (transposons)24. They are sometimes also called ‘selfish’ genetic elements because they can spread in the genome and bias their own inheritance. Therefore transposons are often referred to as naturally occurring gene drives.

However, there are major and consequential differences. It is now known that they can play an important role in cellular function 25 and gene expression 26. Furthermore, their targets in the genome are not random and usually avoid areas most essential for the development of the organism27. It is clear therefore that, far from being random, and a nuisance to the organism, the phenomenon of transposons has been harnessed by natural selection to play a key role in the regulation and evolution of the genome. In contrast, a synthetically engineered gene drive plays no such beneficial role and is engineered instead from the perspective of what benefits humans, usually into an area important for the development of the organism. They have not evolved and adapted through evolutionary processes and are not ‘selfish’, instead serving human interests and setting a “mutagenic chain reaction” in motion28. Thus gene drives are likely to bypass the process of naturally-selected, careful balance and regulation of transposons that aids the organism.

In some publications, Wolbachia bacteria are also referred to as ‘natural’ gene drives. This is not quite correct: Wolbachia is a bacterial infection of certain insects (e.g fruit flies) occurring naturally in the cell, that can be inherited over generations and that either reduce the reproductive capacity of insects it infects, or makes them more resistant to certain infections29. Unlike synthetic gene drives, this approach does not use genetic engineering, instead using a process called transfection. This means that the risks of genetic side effects associated with genetic engineering through cross-breeding and interaction with wild populations are not relevant in Wolbachia interventions.

The term “genetic chain reaction” is derived from the term “mutagenic chain reaction”, which was coined by the Gene Drive inventors Valentino Gantz and Ethan Bier30. By this term we mean that the genetically modified genes of an organism engineered with a Gene Drive in the laboratory are passed on unstoppably and irrevocably – similar to a chain reaction – to all offspring and in turn to all their offspring until all individuals of a wild population or species carry these genes. With the current state of gene drive development, we do not have the ability to stop or recall this process if started.

Gene drives ignore the rules of inheritance discovered by Gregor Mendel.  These describe, among other things, that the probability of inheriting a genetic trait from two (homozygous) parents to their offspring is about 50%. Gene drives, however, establish “super-Mendelian” inheritance. This means that through a gene drive up to 100% of all offspring – over generations – inherit a certain genetic trait.

In addition, another key mechanism of evolution is also altered by gene drives: the mechanism of natural selection described by Darwin and Wallace. In natural selection, genes that improve the biological fitness of an organism (the ability to survive and reproduce in an environment) are favoured and selected for, and those that negatively affect it are selected against. It is a simple concept whereby when a gene (which codes for a trait, for example white or brown coats in mice) has a negative impact on an organisms chances of survival or reproduction, it is then by its nature less likely to be passed down to the next generation. When a gene has a positive effect on the survival or reproductive chances of an organism, the organism is more likely to survive and reproduce, and therefore pass down the gene to the next generation31.

With gene drives, however, this system is circumvented and even genes and traits that offer no survival advantage, or even reduce the organism’s fitness, will (if the gene drive works) establish themselves in a population. With this development, theoretically any trait can be spread and passed on in a population without it being selected against and other ‘fitter’ organisms outcompeting it, which would usually be quickly weeded out by natural selection. An example of this is the ‘X-Shredder’ gene drive in the Anopheles mosquito which ensures that no females are born, developed by Andrea Crisanti and his research group at Imperial College London. The team showed that a captive population can be eliminated using gene drive within 9 months32.

Gene drives can be characterized in different ways depending on the trait33. First, they can be either suppression or modification/alternation drives34. Suppression drives intend to reduce the number of individuals in a population or to eradicate it. On the other hand, modification drives aim to introduce new traits or change the genome of a population, by adding or deleting genes. Another way to characterize gene drives is by the number of released engineered individuals.  A low threshold drive would require only a small number of engineered organisms to be released into the wild population in order for the gene drive construct to be dominant in most of the population. They are considered potentially invasive gene drives, self-sustaining and better suited for large populations. Examples of low threshold drives the doublesex gene or X-shredder as developed by Target Malaria- a low number (around 2.5% of the size of the target population) will spread uncontrollably and create intersex females or stop them developing at all, thus crashing the population35. High threshold/threshold dependent drives will dominate in a population only if a large amount of GDOs are released, for example at a ratio of 60% of the total wild population. They are drives that are thought to be less invasive, local and better suited for small populations like on islands36. Examples of such systems are underdominance, toxin-antidote or Medea.

Gene drives can also be characterized through their mode of action. There are homing based drives like CRISPR/Cas. They rely on the DNA’s repair mechanism called homology directed repair (HDR) where the broken (wild type) chromosome is repaired by copying the DNA sequence from the corresponding homologous (modified) chromosome. Another system is the toxin-antitoxin Medea (maternal effect dominant embryonic arrest). The toxin is a microRNA targeting an embryonic essential gene. It is expressed during the oogenesis of Medea carrying mother. The antidote is a recoded version of the targeted gene that is “immune” to the “toxin”. The antidote is expressed during the formation of the embryo and only in those that inherit the Medea element. Thus, half of the embryos from a Medea heterozygote female die. A payload gene can be linked to this system. The different systems for gene drives are at different levels of development and all face their own challenges and offer their own benefits. Perhaps the furthest developed and closest to being deployed is the Doublesex gene drive in mosquitoes. This construct disrupts a gene vital to development and causes females to develop as intersex and sterile.

The precautionary principle is the guiding principle of environmental policy at the German, EU and international levels and defines the legislator’s powers and room for action to avoid risks to the environment and health, e.g. through new technologies. In principle, when there are reasons for concern regarding potential negative consequences on the environment or on public health from a proposed intervention or technology, and the stakes are high, uncertainty around the science or potential unforeseen consequences, one should act in a precautionary or preventative way to stop potential harm to the environment and health from the beginning, in order to safeguard our natural environment for generations to come.

The PP applies when the environment or public health is potentially at high risk due to a new technology. In this case the principle dictates that policymakers should act to prevent any harm from occurring pre-emptively, which could potentially mean prohibiting the use of a new technology when there is serious cause for concern. Gene drives should meet the criteria of the precautionary principle in at least three ways: firstly, the risk of detrimental environmental (and therefore human health) consequences is extremely high with no tested way to reverse the damage. Secondly, the science behind gene drive and the possible consequences is still in its infancy.

This principle is stated in Article 191 of the EU Treaty on the Functioning of the European Union. In its 2000 Communication on the Precautionary Principle, the European Commission emphasises the importance of the precautionary principle as an essential element of EU policy on risk prevention. In Germany, the precautionary principle is explicitly regulated in Article 34(1) of the Unification Treaty as a self-obligation of the legislature and is thus applicable federal law. The precautionary principle is also written into Article 20a of the German Basic Law. The Rio Declaration of the United Nations Conference on Environment and Development in 1992 determined in Article 15 to apply the precautionary principle for the protection of the environment.

The precautionary principle, as also defined in the EU Genetic Engineering Directive 2001/18/EC, can only work if effective measures can actually be taken to protect the environment and human health in cases where this appears necessary. Retrievability (controllability in time and space) is a crucial prerequisite for this, and so far there is no working mechanism for this in regards to gene drive technology. In the context of this campaign, we therefore recommend the introduction of exclusion criteria for the authorisation of gene drive organisms, in order to uphold the precautionary principle in the context of environmental risk assessment. This would mean: If in the course of an environmental risk assessment of gene drive organisms it is determined that retrievability is not guaranteed, this should be an exclusion criterion for authorisation. The risk assessment should then be terminated and any release of the gene drive organism prohibited.

– The German Federal Environment Agency on the precautionary principle

– Regulations of the UN Convention on Biodiversity on the precautionary principle

– European Environment Agency, 2013: Late lessons from early warnings

– Decision 14/19 on synthetic biology of the UN Biodiversity Convention on the application of the precautionary principle to gene drives (para 11)

– Resolutions of the European Parliament on Gene Drives in the Context of the Precautionary Principle

– von Gleich, Arnim: Steps Towards a Precautionary Risk Governance of SPAGE Technologies Including Gene Drives. in: von Gleich, Arnim / Schröder, Winfried (2020): Gene Drives at Tipping Points.

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2N. Wedell, T. A. R. Price, and A. K. Lindholm, ‘Gene Drive: Progress and Prospects’, Proceedings of the Royal Society B: Biological Sciences 286, no. 1917 (18 December 2019): 20192709, https://doi.org/10.1098/rspb.2019.2709.

4V. M. Gantz and E. Bier, ‘Genome Editing. The Mutagenic Chain Reaction: A Method for Converting Heterozygous to Homozygous Mutations’, Science 348, no. 6233 (24 April 2015): 442–44, https://doi.org/10.1126/science.aaa5945.

5Ethan Bier, ‘Gene Drives Gaining Speed’, Nature Reviews Genetics, 6 August 2021, https://doi.org/10.1038/s41576-021-00386-0.

6Lea Pare Toe et al., ‘Small-Scale Release of Non-Gene Drive Mosquitoes in Burkina Faso: From Engagement Implementation to Assessment, a Learning Journey’, Malaria Journal 20, no. 1 (December 2021): 395, https://doi.org/10.1186/s12936-021-03929-2.

7Emily Waltz, ‘First Genetically Modified Mosquitoes Released in the United States’, Nature 593, no. 7858 (13 May 2021): 175–76, https://doi.org/10.1038/d41586-021-01186-6.

8Peter A. Ryan et al., ‘Establishment of WMel Wolbachia in Aedes Aegypti Mosquitoes and Reduction of Local Dengue Transmission in Cairns and Surrounding Locations in Northern Queensland, Australia’, Gates Open Research 3 (8 April 2020): 1547, https://doi.org/10.12688/gatesopenres.13061.2.

9Tom A. R. Price et al., ‘Resistance to Natural and Synthetic Gene Drive Systems’, Journal of Evolutionary Biology 33, no. 10 (October 2020): 1345–60, https://doi.org/10.1111/jeb.13693.

11Dominik Modrzejewski et al., ‘Which Factors Affect the Occurrence of Off-Target Effects Caused by the Use of CRISPR/Cas: A Systematic Review in Plants’, Frontiers in Plant Science 11 (23 November 2020): 574959, https://doi.org/10.3389/fpls.2020.574959.

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16,19M. Dolezel et al., ‘Gene Drive Organisms. Implications for the Environment and Nature Conservation. A Joint Technical Report of the EPA/ENCA Interest Group on Risk Assessment and Monitoring of GMOs’ (Vienna, Austria, 2019), https://www.umweltbundesamt.at/fileadmin/site/publikationen/rep0705.pdf.

17Simon, Otto, and Engelhard, ‘Synthetic Gene Drive: Between Continuity and Novelty: Crucial Differences between Gene Drive and Genetically Modified Organisms Require an Adapted Risk Assessment for Their Use’, EMBO Reports 19, no. 5 (May 2018), https://doi.org/10.15252/embr.201845760.

18Johannes L. Frieß, Arnim von Gleich, and Bernd Giese, ‘Gene Drives as a New Quality in GMO Releases—a Comparative Technology Characterization’, PeerJ 7 (3 May 2019): e6793, https://doi.org/10.7717/peerj.6793.

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36,37Champer, Buchman, and Akbari, ‘Cheating Evolution: Engineering Gene Drives to Manipulate the Fate of Wild Populations’, Nature Reviews Genetics 17, no. 3 (March 2016): 146–59, https://doi.org/10.1038/nrg.2015.34