Possible applications of gene drive organisms

Gene drives are opening up numerous new applications. Current research is focused on three areas:

  • the control of disease vectors
  • the removal of invasive species from sensitive ecosystems
  • the control of so-called pests in agriculture.

 

 

 

 

Gene drives to eliminate disease vectors

Infectious diseases such as malaria, dengue fever and borreliosis are transmitted to humans by mosquitoes or ticks. Combating these vectors has long been part of disease prevention. Gene Drives are expected to take these efforts to a new level.

Malaria

The malaria pathogen is spread by several species of Anopheles mosquitoes. A concerted global program of malaria control using mosquito nets, insecticides and medicines has helped push back the disease in many regions of the world, reducing deaths by about half between 2000 and 2015.¹ In 2016, the World Health Organization (WHO) identified 21 countries with the potential to reach the goal of zero indigenous malaria cases by 2020.

In the process, 37 countries have already been certified as malaria-free, most recently Sri Lanka (2016), Paraguay (2018) and Algeria (2019)². China, Malaysia, El Salvador and Iran are also well on their way to achieving the three-year malaria-free status required for certification. Other factors for successful control of the disease include, above all, strong political will, a functioning health system, good training of medical personnel, national programs for education and prevention activities, medical surveillance programs, rapid and correct diagnosis and treatment, and rapid responses to outbreaks that do occur.³ But there remain 87 countries where such measures have not been adequately implemented. In 2017, more than 200 million people contracted malaria, and more than 400,000 people died from it. Sub-Saharan Africa is the hardest hit, with mortality particularly high among children under five.⁴ Gene Drives are intended to remedy this situation by massively reducing the number of Anopheles mosquitoes in Africa and thus also the transmission of malaria. Target Malaria, an international research consortium, is playing a leading role in the development of such gene drives. The consortium has a budget of around 100 million U.S. dollars, most of which comes from the Bill & Melinda Gates Foundation and the Open Philanthropy Project.⁵  ⁶ Target Malaria's plans have already reached the stage where the first model projects have been launched in Burkina Faso, Mali, Ghana and Uganda.

Lyme disease

In temperate climates, the use of gene drives against the infectious disease Lyme disease is being considered. In the U.S., Lyme disease spread rapidly in 2018, affecting about 300,000 people annually.⁷ For Germany, according to a projection from 2017, the number of new cases is estimated at about 100 000 per year. ⁸The disease is triggered by Borrelia bacteria, which often infect wild mice and are transmitted to humans by ticks. If the infection is not detected in time, a chronic disease can develop that is difficult to treat. 

On two islands in the northeastern United States, a project was launched in 2016 that aims to interrupt the transmission of the disease with the help of genetic engineering. The target of the genetic manipulation is not the ticks as carriers, but the native white-footed mice, which are the most important host for Borrelia in these regions. An intervention in the immune system is supposed to make the mice resistant and interrupt the transmission chain of Borrelia. After a citizen survey on the islands of Nantucket and Martha's Vineyard in Massachusetts, USA, a majority rejected the use of gene drives. Instead, plans now call for the mass release of genetically modified mice to mate with their natural counterparts and crossbreed Lyme disease resistance into the population. However, should trials on larger land masses be planned in the long term, the use of Gene Drive mice would again be up for debate.⁹

There are several alternative strategies to prevent the transmission of Lyme disease to humans apart from gene drives and other genetic engineering methods. Infection can already be prevented by simple means: by wearing suitable clothing, applying anti-tick medication and regularly scanning the body. For a short time in the past, a vaccine was already available, but it was taken off the market again due to lack of interest.

Using gene drives to combat invasive species

Humans have carried off numerous animal species to foreign islands and continents, where they have become a serious threat to native flora and fauna. Major problems are caused, for example, by introduced rats and mice, which significantly decimate smaller animals and the breeding of native birds. Conventional measures such as hunting, trapping, or poison baiting have been able to drive invasive species off small islands. On larger land masses, these measures reach their limits. Gene drives are intended to offer an alternative here.

The Genetic Biocontrol of Invasive Rodents (GBIRd) project, which is supported by seven universities, authorities and non-governmental organizations from the USA and Australia, is investigating whether this approach is promising. GBIRd aims to address the question of whether invasive mice can be eradicated through gene drives and under what conditions this intervention would be acceptable. The bulk of the project is funded by the U.S. military's Defense Advanced Research Projects Agency (DARPA) to the tune of $6.4 million. ¹⁰Among the most active members of GBIRd is the small conservation organization Island Conservation. It has been dedicated to the protection of seabirds for 25 years and says it has already rid 63 islands of rodents. So far, this has been done using conventional methods, but Island Conservation believes that further progress will require the use of gene drives.¹¹

The first steps in this direction were taken at the University of California in San Diego, USA, when gene drives for mice were developed there for the first time in 2019.¹² However, the developers encountered an unexpected phenomenon: CRISPR/Cas9 was able to cut the DNA strand in all test animals, but only in females did the repair mechanism kick in, which actively spreads 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. 

New Zealand's former government also showed interest in using gene drives. The country's unique flora and fauna suffer great damage from introduced rats, stoats and the Australian fox cusu. With the Predator Free 2050 program, the New Zealand government pursued the goal of eradicating all invasive predators by 2050. The measures have already been successful on more than 100 smaller islands. To achieve success on the main islands as well, the use of gene drives was considered. 

In light of the consideration of using gene drives for invasive species eradication in New Zealand, two gene drive developers published an article in 2017 warning against hasty releases and the use of gene drive organisms in conservation.¹³ Since the change of government that same year, there has been greater restraint in New Zealand in this regard. Before Predator Free returns to the topic, the many technical, social and ethical considerations and regulatory hurdles first have to be explored and overcome.¹⁴

The discussion on gene drives in the International Union for Conservation of Nature (IUCN)

In view of the possibility of using gene drives to remove introduced invasive species from sensitive ecosystems, the International Union for Conservation of Nature (IUCN), also known as the World Conservation Union, has also been discussing how to deal with this technology since late 2015.

At its General Assembly in Hawaii in September 2016, IUCN adopted a resolution¹⁵ that, among other things, mandated IUCN to prepare a scientific report on the implications of synthetic biology and gene drives for biodiversity conservation. Based on this scientific report, IUCN originally intended to take a position on the role of gene drive technology for nature conservation at its subsequent General Assembly in 2020.

In part through public protest and at the urging of global conservation luminaries¹⁶ , IUCN committed in its 2016 resolution to refrain from any support or endorsement of research, field trials, or use of gene drive technology until this report is available. 

The report, entitled ‘Genetic Frontiers of Conservation’¹⁷, was published in May 2019 and was met with harsh criticism from IUCN member organizations as well as conservation and development organizations around the world. An analysis conducted by the research and advocacy organization ETC Group¹⁸ concluded that a majority of the report's authors were known proponents of genetic engineering and should not have been engaged by IUCN, in part because of their economic self-interest in developing the technologies studied. In a subsequent open letter signed by 231 civil society organizations and several scientists, the report was criticized as "regrettably one-sided", "biased", and "inappropriate for the intended policy discussion". This report, they said, is not consistent with the precautionary considerations of the Hawaii resolution. The undersigned organizations therefore called on IUCN to commission another scientific report based on a precautionary analysis of the risks of the technology and to wait until such a counter-report is available before taking a decision¹⁹ on the issue. In a similar vein was the request of an October 2019 letter from 23 IUCN members to the IUCN Council. According to its signatories, more time is needed for a fundamental, comprehensive, balanced discussion based on the precautionary principle, with greater involvement of IUCN members, prior to any IUCN decision-making.²⁰

Confronted with this criticism, the IUCN Council withdrew its plan to adopt a position already at its membership process originally planned for June 2020. Instead, principles²¹ for the discussion on the topic were defined in a consultation open to members. These are to be voted on at the IUCN World Conservation Congress in 2021 and serve as the basis for a position on the topic until the following Members' Congress. 

Gene Drives in Agriculture

In the long term, agriculture could become the most important field of application for gene drives – a fact that has so far hardly been noticed by the public. Patents on CRISPR-based gene drives list hundreds of animals and plants whose containment or eradication could increase agricultural yields. However, a number of hurdles would still have to be overcome along the way.

Patent applications for use in agriculture

At least six patents on gene drives refer to specific applications in agriculture. The focus is on controlling pests and weeds and reversing herbicide resistance. Two key applications come from leading developers of the CRISPR/Cas-based Gene Drive, the research groups led by Kevin Esvelt²² and Ethan Bier²³. Numerous claims are also filed in a patent by Bruce Hay's group²⁴. Most of the claims are general, but one patent already contains detailed goals and methods that enable commercial use.

However, the commercialization of gene drives faces a fundamental problem: its spread cannot yet be contained, either spatially or temporally. Individual releases could result in the transboundary spread of GDO into neighboring ecosystems for decades. The classic business model of agribusinesses, which is based on continuous sales of the products, would be difficult to apply under these conditions. 

In theory, its use appears commercially interesting in two scenarios: A gene drive could eliminate natural resistances that wild plants have developed to common herbicides. An agribusiness could then profit from increased sales of the herbicide because they would become usable again. Another scenario would be for large agricultural associations to fund the development of a gene drive that would benefit all association members.

Examples of applications in agriculture

The use of gene drives would be conceivable for almost every field crop and for numerous farm animals or so-called pests. In three cases, there are already concrete plans.

In three cases, there are already concrete plans:

  • The cherry vinegar fly 

Originally native to Southeast Asia, the cherry vinegar fly (Drosophila suzukii) has spread worldwide and causes significant crop losses in numerous fruit varieties. It lays its eggs in nearly ripe, undamaged fruit with thin skins. In 2008, the cherry vinegar fly reached California and caused more than $38 million in damage to cherry orchards the very next year. According to calculations, these losses can rise to over $500 million annually in the western United States. Since 2011, it has also appeared in Germany, threatening the harvest of cherries, grapes, raspberries, blackberries and strawberries. In 2013 the California Cherry Board, an association of California cherry growers, began funding research on a gene drive with $100,000 annually. A group of researchers at the University of San Diego, USA, developed a so-called Medea Drive. The flies' offspring are not viable. This can affect one or both sexes.

In initial laboratory experiments, a high number of modified flies was necessary to establish the Medea Drive in the population. In addition, many fly populations in the wild have natural resistances that would probably strongly hinder the spread of the Medea Drive. The researchers therefore suspect that a very large number of modified cherry vinegar flies would have to be released to keep the Medea Drive in the population for several years. No field tests have been planned yet. The patent applied for in 2017 on this Medea Drive also covers other species of tropical fruit flies as well as mosquitoes of the genera Anopheles and Aedes, which transmit malaria and numerous viral diseases.

  •  Leaf fleas and huanglongbing 

    Other potential target organisms for a gene drive are leaf fleas. In 2005, bacteria that infect citrus trees and render their fruit inedible were detected for the first time in the USA. It is spread by introduced Asian leaf fleas, which ingest the bacteria while sucking plant sap and can then infect other trees. Within three years, the disease, called Huanglongbing, has spread across most of Florida's growing regions, with citrus production plummeting by 70 percent. Europe has so far been spared from the disease, but spread cannot be ruled out. Citrus growers in California are considering the use of gene drives to protect their plantations. One option would be to release gene drive leaf fleas that cannot transmit the bacteria. A research project on this was completed in 2017 and identified a number of genes that could prevent transmission. However, a gene drive has not yet been established from this.

Gene drives for the eradication of plant lice

Other potential target organisms for gene drives are plant lice. In 2005, bacteria that attack citrus trees and make their fruit inedible were detected for the first time in the USA. The bacteria are spread by Asian plant lice that infest citrus trees. When they suck the sap of plants, they take up the bacteria and can then infect other trees. Within three years, the disease, which goes by the name of Huanglongbing, has spread over most of Florida’s growing areas, with citrus fruit production falling by 70 per cent.30 Europe has so far been spared the disease, but its further spread cannot be ruled out.31

Citrus fruit producers in California are considering the use of gene drives to protect their growing areas.32 One possibility would be the release of gene drive plant lice, which cannot transmit the bacteria. A research project on this was completed in 2017 and has identified a number of genes that could prevent transmission. However, a gene drive has not yet been established.33

 

  • The New World screwworm fly 

The New World screwworm fly (Cochliomyia hominivorax) is found primarily in the Americas and lays its eggs near body cavities or open wounds of mammals and birds. The hatching larvae feed deeply into the tissues of infested animals, causing severe inflammation. The New World screwworm fly also infests livestock such as cows, sheep, and goats, which can die from the inflammation without veterinary treatment. The screwworm fly was eradicated from the continental United States and Central America in the 1960s by releasing sterile male flies. To prevent new introductions from South America, a protected zone was established in Panama, but it is very costly to maintain. Scientists at the University of North Carolina, USA, therefore proposed the use of gene drives. It could also be used to eradicate the screwworm fly in South America. In 2019, an international group of researchers was able to apply CRISPR/Cas9 in the screwworm fly for the first time, altering a gene in the fly that is crucial for the development of the fly's sex. This resulted in females that had male sexual characteristics and were presumably sterile. This intervention is a first step toward developing a CRISPR/Cas-based gene drive that would aim to completely eradicate the screwworm fly. 

 

Open questions on the use of gene drives in plants

In theory, gene drives could also be used in plants. The U.S. National Academies of Science identified the foxtail plant Amaranthus palmeri, which has developed into a resistant ‚superweed‘38 in the USA beginning in the 1990s due to the excessive use of herbicides such as glyphosate. Amaranthus palmeri37 is a dioecious plant, which produce either male or female flowers. Researchers recently identified a gene that controls the formation of female flowers.39 Should it become possible to switch off this gene by means of a gene drive, only male plants could be formed and make natural reproduction impossible.

Another theoretical possibility would be the withdrawal of resistance to common pesticides, which has developed in dozens of plant species and which poses major problems for industrial agriculture. Behind these resistances are genetic changes that are often well researched and could theoretically be reversed by a gene drive.40

Before gene drives can be used in plants, however, a number of technical hurdles still have to be overcome. For example, CRISPR/Cas9 works only very inefficiently under these conditions, since plant cells usually repair their genome with error-prone mechanisms.41 Moreover, many plants have significantly longer generational cycles than insects: the effect of a gene drive would therefore only be felt after many years. And finally, the seeds of some plants can survive in the soil for years and significantly delay the breakthrough of the gene drive.42 The utilisation of gene drives in plants is not yet possible with the current state of knowledge.

 

This figure illustrates the areas in which gene drive organisms are being developed or considered for agricultural application.

  • Gene drives to eradicate rats, mice, cockroaches and moths that infest grain silos.
  • Gene drives to eradicate the New World screwworm fly, which lays its eggs in the body cavities and wounds of cows and other farm animals.
  • Gene drives to eradicate the Cherry Vinegar Fly, which lays its eggs in ripe fruit, such as cherries.
  • Gene drives to eradicate leaf fleas, which spread Cirtrus Greening Disease (Huanglongbing) in citrus fruits.
  • Gene drives to eradicate nematodes that cause plant diseases.
  • Gene drives to decimate the cabbage moth.

Gene Drives as biological weapons

The release of gene drive organisms could have widespread and long-lasting negative effects on ecosystems and societies. For this reason alone, gene drive organisms could be misused as biological weapons against plants, animals and humans. The direct development of gene drive organisms for hostile purposes is also conceivable.

  • Gene drive organisms as bioweapons 

A release of gene drive organisms could, in theory, have large-scale and long-lasting negative effects on ecosystems and societies. The release of gene drive organisms for civilian purposes could therefore cause conflict or lead to misuse. The targeted development of gene drive organisms for hostile purposes is also conceivable.

One way that gene drive organisms could be used as bioweapons would be to use them to eradicate important beneficial insects for agriculture in a particular region. However, until gene drive organisms and their harmful effects can be narrowed down spatially or temporally, there are few convincing scenarios for government gene drive weapons programs.

Despite these challenges, the U.S. military's Defense Advanced Research Projects Agency (DARPA) is one of the largest funders of gene drive research and is financially involved in almost every gene drive research project. The DARPA research program, titled Safe Genes, sets out to control, limit, or recover GDOs from the environment. There are numerous gray areas in the spectrum between unexpected negative effects of gene drive organisms in nature, their misuse, and the deliberate development of gene drives for hostile purposes: While the effect of a gene drive organism might be considered positive in a particular region, its consequences might be considered undesirable or negative in other affected regions, leading to insurgency or conflict. 

Conflict from the use of gene drive technology in the environment could also be triggered by a lack of public (or international) consensus on a release of gene drive organisms in one's own or neighboring countries. Resulting damages, such as crop loss, biodiversity loss, or unintended health, social, or economic effects, can lead to conflict if there is no adequate compensation for them. Even the unintended presence of a GDO in a country that has not consented to a release can lead to interstate conflict or diplomatic crises. For these reasons, experts at the UN Biological Weapons Convention have been monitoring and discussing the issue for years.

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