Gene Drive FAQ

Overview of questions:

 

  • Why are you calling for a global moratorium on gene drives? What does this mean?
  • Have genetically modified gene drive organisms already been released into the wild?
  • What is the difference between genetically modified organisms and genetically modified gene drive organisms?
  • What are the technical hurdles in the development of gene drives?
  • What would be the consequences and risks of releasing gene drives into the wild in the future?
  • Can gene drive organisms be released in the EU?
  • What is CRISPR/Cas?
  • What are ‘new genetic engineering techniques’ as opposed to ‘old’ genetic engineering techniques?
  • Do gene drives also occur in nature? Are there natural gene drives?
  • What do you mean when you say that a gene drive triggers a genetic engineering chain reaction?
  • Why do gene drives change the rules of evolution?
  • What is the precautionary principle and why is it necessary to apply it in connection with the release of gene drive organisms?

 

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Why are you calling for a global moratorium on gene drives? What does that mean?

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). Click here for our recommendations for conditions that could justify the reversal of this moratorium.

Have genetically modified gene drive organisms already been released into the wild?

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 advanced. 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 are planned in Burkina Faso over the next few years.

However, releases of Gene Drive-like insects, both GM and non-GM, have already taken place. These include, for example, the release of mosquitoes in Australia that are infected with (Wolbachia) microbes, reducing the fertility of their offspring, sometimes over generations. Another example is the release of genetically modified sterile mosquitoes by the company Oxitec, e.g. in Florida or California. Both examples are not gene drives.

 

Further information on the state of development of gene drives here:

Target Malaria – Your approach: https://targetmalaria.org/what-we-do/our-approach/

Target Malaria – Your project area: https://targetmalaria.org/about-us/where-we-operate/

What is the difference between genetically modified organisms and genetically modified gene drive organisms?

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. The use of GMOs should therefore remain limited in space or time outside their place of origin in the laboratory. These genetically modified organisms should not survive in nature any more than their modified genes.

The gene drive approach breaks radically with these considerations: genetically modified organisms that inherit gene drives, unlike conventional GMOs, aim to spread genes synthesised in the laboratory into wild populations or to eliminate natural genes. They do so even if this harms the species or offers it no survival advantage. Normally, these genes would not prevail under natural selection. 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 – over generations. The ‘forced’ inheritance of even harmful genes caused by the gene drive induces a theoretically unstoppable “mutagenic chain reaction”.

What are the technical challenges in the development of gene drives?

There are countless hurdles 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 sequence. 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 system.


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 percent. 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. The effect of a gene drive would only take effect after many years. The realisation of a gene drive in plants is not yet possible with the current state of knowledge.

What consequences and risks would a future release of gene drives into nature imply?

Gene drives are at an early stage of development. The discussion about possible consequences and risks is therefore still largely speculative. However, numerous critical points are already emerging that need to be considered before a possible release. Once released into nature, a gene drive organism actively spreads in free-living populations and can spread rapidly over large distances. The incalculable diversity of the natural habitats and ecosystems affected will make the prediction and control of possible risks massively more difficult.

According to the current state of science, the outcome of the experiment would no longer be controllable by humans. All manipulations of this kind on animals, plants and entire ecosystems would be irreversible.

Click here for a description of the ecological risks.

Can gene drive organisms be released in the EU?

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, 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 still in the future, 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

How does a gene drive work?

So-called homing gene drives based on CRISPR/Cas9 are the most common variant of synthetic gene drives. Such a gene drive consists of at least two components: the Cas9 gene scissors and a messenger molecule. In addition, a new or modified gene can be introduced. 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 messenger 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 homing. 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.

What is CRISPR/Cas?

CRISPR/Cas is a so-called ‘new’ genetic engineering technique discovered in 2012 by molecular biologists Emanuelle Charpentier and Jennifer Doudna. 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 and an associated protein called Cas (which is an acronym for CRISPR-associated). Cas can make a double-strand break in DNA at a searched DNA target sequence, whereupon 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.

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

What are ‘new genetic engineering techniques’ as opposed to ‘old’ genetic engineering techniques?

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. Where in the genome the introduced DNA was inserted is left to coincidence.

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.

Do gene drives also occur in nature? Are there natural gene drives?

No. Not all natural gene systems follow Mendel’s rules of inheritance. 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). They are sometimes also called ‘selfish’ genetic elements because they can spread in the genome without benefiting the species. In the course of evolution, plants, animals and humans have found a way to deal with these genetic elements: Some gave rise to important functional, usually regulatory, units. In many other cases, mechanisms have been developed to silence the ‘jumping genes’ in the genome. Transposons are often referred to as naturally occurring gene drives. Genetically engineered synthetic gene drives have been developed along their lines, but are different in key aspects of function and purpose from their natural counterparts.

In some publications, for example, Wolbachia bacteria are referred to as ‘natural’ gene drives. This is not quite correct: Wolbachia is a bacterial infection of insects that can be inherited over generations. Wolbachia bacteria occur naturally in the cells of certain insects, e.g. fruit flies. They reduce the reproductive capacity of infected insects. Unlike synthetic gene drives, this approach does not use genetic engineering. 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.

Genetically engineered, synthetic gene drives, on the other hand, are artificial genetic elements that come with specific, human-determined purposes and functions. They have not evolved and adapted through evolutionary processes. They are not ‘selfish’ but serve human interests. Evolutionarily established control mechanisms are often ineffective here. Synthetic gene drives set a “mutagenic chain reaction” in motion.

What do you mean by saying that a gene drive triggers a genetic chain reaction?

The term “gentechnische Kettenreaktion” is the German interpretation of the English term “mutagenic chain reaction”, which was influenced by the Gene Drive inventors Valentino Gantz and Ethan Bier. By this term we mean that the genetically modified genes of an organism provided with 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.

Why do gene drives change the rules of evolution?

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 of genetic traits described by Gregor Mendel together with Alfred Russel Wallace. In natural selection, mainly those genetic traits prevail in populations and species that serve the survival of the species or the adaptation to a specific environment. With gene drives, however, genetic traits that serve purely human purposes and offer no survival or adaptation advantage would now also be able to establish themselves in a population.

What is the precautionary principle and why is it necessary to apply it in connection with the release of gene drive organisms?

The precautionary principle is the guiding principle of environmental policy at the German, EU and international levels and defines the legislator’s discretionary powers and room for action to avoid risks to the environment, e.g. through new technologies. The principle is that even if knowledge about the nature, extent, probability or causality of environmental damage and hazards is incomplete or uncertain, preventive action should be taken to avoid them from the beginning.

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. In the context of this campaign, we therefore recommend the introduction of exclusion criteria for the authorisation of gene drive organisms to implement 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.

 

Further information here:

 

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.