A woman in Tanzania under a mosquito tent with a relative who was being treated for malaria. With gene drives, it may be possible to kill off a mosquito population or make the population resistant to malaria parasites.CreditUriel Sinai for The New York Times
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 favored 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,” a group of Harvard biologists
wrote last year in the journal eLIFE.
A much discussed application of gene drives would help rid the world of pest-borne diseases like malaria, dengue fever and 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 this month 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 favor 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.
Planning a Gene Drive
Researchers are studying a powerful technique of spreading desired genetic changes through wild animal, insect or plant populations.
INHERIT (first pic)
A genetic change made to one parent usually has a roughly 50 percent chance of being passed down to offspring.
But a novel technique called a gene drive system may be able to increase the odds of spreading a genetic change to all offspring, and eventually through an entire population.
MATCH AND CUT (2nd pic)
A gene drive is a segment of engineered DNA that typically contains a guide sequence, a gene for an enzyme called Cas9 and any desired genes that researchers want to spread in the population.
If the guide sequence matches a stretch of DNA inherited from the wild parent, the wild DNA will be cut by the Cas9 enzyme.
REPAIR AND COPY (3rd pic)
The cell rushes to repair the cut in the wild DNA, using the matching strand of DNA from the genetically modified parent as a template.
Once repaired, the wild DNA will contain both the Cas9 gene and the desired genes.
SPREAD (4th pic)
Because the gene drive effectively inserts itself into any wild DNA it is paired with, a single copy from one parent is enough to spread the gene drive and its desired genes to all offspring.
The technique has worked in the lab, but researchers are exploring the ethics and risks of releasing a gene drive into the wild.
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 no gene drive organisms have yet been released, biologists cannot yet assess how well they will work and what degree of risk they may pose.
The issue of risk, rather than effectiveness, has dominated discussion for the last several months. Biologists are eager to see the benefits of the technology realized, and wish to avoid any consequences that might erode public confidence or get gene drive systems off on the wrong foot, as has happened with genetically modified foods. Several articles published in the last few months propose specific safety precautions and call for full public discussion of gene drives, along with speedy regulation.
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 last month.
A Gene Editing Advance
A gene drive refers to any process that biases the usual pattern of Mendelian inheritance, in which a gene has a 50 percent chance of making it to the 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 in Sunninghill, England, 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 concluded. “Given the suffering caused by some species, neither is it obviously one to be ignored.”
An endonuclease is an enzyme that cuts at a specific site the DNA of the chromosome with which its gene’s own chromosome is paired. Because DNA breaks are very threatening to genome integrity, cells rush to repair them, often by using the other chromosome of a pair as a template. In doing so, they copy the gene for the endonuclease into the joint made between the two broken ends of the cut chromosome. If this repair occurs in a germ line cell, both eggs and sperm will carry the endonuclease gene together with any cargo genes that genetic engineers may have attached to it.
Because it is hard to change the natural site at which a homing endonuclease cuts DNA, Dr. 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 defense 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.
After recovering from their amazement that organisms as small as bacteria possessed an adaptive immune system,
biologists realized that they could take over the Cas9 endonuclease and make it cut DNA at any site of their choosing by providing it with a synthetic guide sequence instead of one from the Crispr library.
The use of Crispr-Cas9 for genome editing was first published in 2012 by Jennifer Doudna of the University of California, Berkeley,
and Emmanuelle Charpentier, now at the
Max Planck Institute for Infection Biology in Berlin.
But Feng Zhang, of the Broad Institute in Cambridge, Mass., was the first to file a patent, which Berkeley lawyers are challenging.
Photo
CreditJames Gathany/Centers for Disease Control and Prevention
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 cell’s DNA repair machinery paste in new sequences, usually a gene of interest, in the process of annealing the two cut ends of the DNA molecule.[...]
