Gene drives: New hope against diseases, pestsGene drives filled with malaria-resistance genes could prevent its spread through mosquito bites
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LYING IN WAIT: A woman tends to a relative being treated for malaria at a medical centre in Kirando, Tanzania. Biologists are developing a revolutionary genetic technique that may provide an unprecedented degree of control over insect-borne diseases and crop pests. NYT
Biologists in the United States and Europe are developing a revolutionary genetic technique that promises to provide an unprecedented degree of control over insect-borne diseases and crop pests.
The technique involves a mechanism called a gene drive system, which propels a gene of choice throughout a population. No gene drives have yet been tested in the wild, but in laboratory organisms like the fruit fly, they have converted almost the entire population to carry the favoured version of a gene.
Gene drives “could potentially prevent the spread of disease, support agriculture by reversing pesticide and herbicide resistance in insects and weeds, and control damaging invasive species,” Harvard biologists wrote in the journal eLIFE. A much discussed application of a gene drive would help rid the world of pest-borne diseases like malaria, dengue fever, Lyme disease.
A gene drive designed to render a population extinct is known as a crash drive. A crash drive being developed for mosquitoes consists of a gene engineered into the Y chromosome that shreds the X chromosome in the cells that make the mosquito’s sperm, thus ensuring that all progeny are male. Unless the drive itself is damaged through mutation, the number of females would be expected to dwindle each generation until the population collapses.
Biologists led by Andrea Crisanti and Tony Nolan at Imperial College London reported in the journal Nature Biotechnology their development of mosquitoes with gene drives that disrupt three genes for female fertility, each of which acts at a different stage of egg formation.
Because the female mosquitoes are infertile only when a copy is inherited from both parents, the gene drives would be thoroughly disseminated through a population before taking their toll. They could “suppress mosquito populations to levels that do not support malaria transmission,” the authors wrote.
The mosquitoes are not yet ready for release. Because natural selection will heavily favour any wild mosquitoes that acquire resistance to the gene drives, the researchers need to prevent such resistance from arising. One approach would be to target two or three sites in the same fertility gene, giving natural selection a much higher barrier to overcome.
Another approach is to endow mosquitoes with genes that make them resistant to the malaria parasite. Last month, biologists at the Irvine and San Diego campuses of the University of California reported introducing a gene drive with a cargo of malaria-resistance genes into mosquitoes. Such genes, if successfully propelled throughout a wild mosquito population, would render a region free of the malarial parasite, which could no longer spread via mosquito bites.
In agriculture, biologists envisage gene drive systems that could destroy or modify insect pests, and reverse genetic resistance to pesticides in species that had acquired it. Gene drives may also be used to squelch populations of harmful invasive species like rats.
Gene drives have two major technical limitations. They will work only in sexually reproducing species, which effectively rules out bacteria. Second, they spread significantly only in species that reproduce quickly, meaning they would be of no practical use in elephants or people.
Because a single escaped organism carrying a gene drive system “could alter a substantial fraction of the wild population with unpredictable ecological consequences, the decision to deploy a gene drive must be made collectively by society,” a group of scientists, led by George M Church of Harvard Medical School, said in Nature Biotechnology in November, 2015.
A gene drive refers to any process that biases the usual pattern of Mendelian inheritance, in which a gene has a 50 per cent chance of making it to next generation. Several gene drive processes exist in nature but are hard to manipulate.
In 2003, Austin Burt, a biologist at a branch of Imperial College London essentially laid out the whole theory of gene drives and their possible applications based on natural gene drives known as homing endonucleases. “Clearly, the technology described here is not to be used lightly,” he said. “Given the suffering caused by some species, neither is it obviously one to be ignored.”
Since it is hard to change the natural site at which a homing endonuclease cuts DNA, Burt’s proposed gene drive systems could not easily be put into practice. All that changed three years ago with the invention of Crispr-Cas9 gene editing. The technique is based on a natural system that evolved in bacteria as a defence against invading viruses.
The bacteria store DNA samples from these invasive viruses in a DNA library, called Crispr, that is part of their genome. When a virus attacks, endonucleases such Cas9 (Cas stands for Crispr-associated) are primed by the Crispr library to cut viral DNA of the same sequence.
The Crispr-Cas9 technique gives biologists unprecedented power to edit DNA. With the ability to cut DNA at a specific site, they can let the DNA repair machinery paste in new seque-nces, usually a gene of interest, in the process of annealing two cut ends of the DNA molecule.
Multiple risks
With the Crispr-Cas9 technique, laboratories all over the world, including many with no expe-rience in confining potentially hazardous orga-nisms, could now generate gene drive systems. A flurry of articles urging caution began to appear from other biologists, who noted that if a fruit fly with a gene drive system escaped from a laboratory, it could affect fruit flies worldwide.
In a Science article last August, Church and others recommended steps for avoiding accidental release, including having more than one confinement strategy. With strong safeguards, they wrote, “we hope to build a foundation of public trust for potential future applications.”
A harder issue than containment is how to assess the ecological effect of gene drive systems. Even something as apparently benign as eliminating mosquitoes could have ecological effects “because mosquitoes interact with other spe-cies,” said Kevin Esvelt, a Harvard biochemist.
It may seem that once a gene drive system is released, it can never be recalled. But this may not be entirely true. Biologists are working on the concepts of “reversal drives” and “immunising drives.” A reversal drive would cut out an errant drive and restore the target organism almost to its previous state. An immunising drive would attack and pre-emptively change the DNA sequence targeted by the rogue drive.
Risks aside, there is no guarantee that gene drives will work as well in the field as they do in the laboratory. Wild populations of mosquitoes, say, may have much genetic variation at the target site of a gene drive system. Those with a variant target site would escape the drive and might have a selective advantage over it.
Resistance will arise, as to any change that reduces a species’ fitness. But biologists could respond by releasing many drives into a wild population, each assigned to a different target. Even if a drive comes to dominate a whole population, biologists expect it will eventually be eliminated by fitter genes. But a response would be to keep releasing new drives. “I think we’ll be able to make this work,” Burt said.
The technique involves a mechanism called a gene drive system, which propels a gene of choice throughout a population. No gene drives have yet been tested in the wild, but in laboratory organisms like the fruit fly, they have converted almost the entire population to carry the favoured version of a gene.
Gene drives “could potentially prevent the spread of disease, support agriculture by reversing pesticide and herbicide resistance in insects and weeds, and control damaging invasive species,” Harvard biologists wrote in the journal eLIFE. A much discussed application of a gene drive would help rid the world of pest-borne diseases like malaria, dengue fever, Lyme disease.
A gene drive designed to render a population extinct is known as a crash drive. A crash drive being developed for mosquitoes consists of a gene engineered into the Y chromosome that shreds the X chromosome in the cells that make the mosquito’s sperm, thus ensuring that all progeny are male. Unless the drive itself is damaged through mutation, the number of females would be expected to dwindle each generation until the population collapses.
Biologists led by Andrea Crisanti and Tony Nolan at Imperial College London reported in the journal Nature Biotechnology their development of mosquitoes with gene drives that disrupt three genes for female fertility, each of which acts at a different stage of egg formation.
Because the female mosquitoes are infertile only when a copy is inherited from both parents, the gene drives would be thoroughly disseminated through a population before taking their toll. They could “suppress mosquito populations to levels that do not support malaria transmission,” the authors wrote.
The mosquitoes are not yet ready for release. Because natural selection will heavily favour any wild mosquitoes that acquire resistance to the gene drives, the researchers need to prevent such resistance from arising. One approach would be to target two or three sites in the same fertility gene, giving natural selection a much higher barrier to overcome.
Another approach is to endow mosquitoes with genes that make them resistant to the malaria parasite. Last month, biologists at the Irvine and San Diego campuses of the University of California reported introducing a gene drive with a cargo of malaria-resistance genes into mosquitoes. Such genes, if successfully propelled throughout a wild mosquito population, would render a region free of the malarial parasite, which could no longer spread via mosquito bites.
In agriculture, biologists envisage gene drive systems that could destroy or modify insect pests, and reverse genetic resistance to pesticides in species that had acquired it. Gene drives may also be used to squelch populations of harmful invasive species like rats.
Gene drives have two major technical limitations. They will work only in sexually reproducing species, which effectively rules out bacteria. Second, they spread significantly only in species that reproduce quickly, meaning they would be of no practical use in elephants or people.
Because a single escaped organism carrying a gene drive system “could alter a substantial fraction of the wild population with unpredictable ecological consequences, the decision to deploy a gene drive must be made collectively by society,” a group of scientists, led by George M Church of Harvard Medical School, said in Nature Biotechnology in November, 2015.
A gene drive refers to any process that biases the usual pattern of Mendelian inheritance, in which a gene has a 50 per cent chance of making it to next generation. Several gene drive processes exist in nature but are hard to manipulate.
In 2003, Austin Burt, a biologist at a branch of Imperial College London essentially laid out the whole theory of gene drives and their possible applications based on natural gene drives known as homing endonucleases. “Clearly, the technology described here is not to be used lightly,” he said. “Given the suffering caused by some species, neither is it obviously one to be ignored.”
Since it is hard to change the natural site at which a homing endonuclease cuts DNA, Burt’s proposed gene drive systems could not easily be put into practice. All that changed three years ago with the invention of Crispr-Cas9 gene editing. The technique is based on a natural system that evolved in bacteria as a defence against invading viruses.
The bacteria store DNA samples from these invasive viruses in a DNA library, called Crispr, that is part of their genome. When a virus attacks, endonucleases such Cas9 (Cas stands for Crispr-associated) are primed by the Crispr library to cut viral DNA of the same sequence.
The Crispr-Cas9 technique gives biologists unprecedented power to edit DNA. With the ability to cut DNA at a specific site, they can let the DNA repair machinery paste in new seque-nces, usually a gene of interest, in the process of annealing two cut ends of the DNA molecule.
Multiple risks
With the Crispr-Cas9 technique, laboratories all over the world, including many with no expe-rience in confining potentially hazardous orga-nisms, could now generate gene drive systems. A flurry of articles urging caution began to appear from other biologists, who noted that if a fruit fly with a gene drive system escaped from a laboratory, it could affect fruit flies worldwide.
In a Science article last August, Church and others recommended steps for avoiding accidental release, including having more than one confinement strategy. With strong safeguards, they wrote, “we hope to build a foundation of public trust for potential future applications.”
A harder issue than containment is how to assess the ecological effect of gene drive systems. Even something as apparently benign as eliminating mosquitoes could have ecological effects “because mosquitoes interact with other spe-cies,” said Kevin Esvelt, a Harvard biochemist.
It may seem that once a gene drive system is released, it can never be recalled. But this may not be entirely true. Biologists are working on the concepts of “reversal drives” and “immunising drives.” A reversal drive would cut out an errant drive and restore the target organism almost to its previous state. An immunising drive would attack and pre-emptively change the DNA sequence targeted by the rogue drive.
Risks aside, there is no guarantee that gene drives will work as well in the field as they do in the laboratory. Wild populations of mosquitoes, say, may have much genetic variation at the target site of a gene drive system. Those with a variant target site would escape the drive and might have a selective advantage over it.
Resistance will arise, as to any change that reduces a species’ fitness. But biologists could respond by releasing many drives into a wild population, each assigned to a different target. Even if a drive comes to dominate a whole population, biologists expect it will eventually be eliminated by fitter genes. But a response would be to keep releasing new drives. “I think we’ll be able to make this work,” Burt said.