"TO GET TO work in the morning, Omar Akbari has to pass through a minimum of six sealed doors, including an air-locked vestibule. The UC Riverside entomologist studies the world’s deadliest creature: the Aedes aegyptimosquito, whose bite transmits diseases that kill millions each year. But that’s not the reason for all the extra security. Akbari isn’t just studying mosquitoes—he’s re-engineering them with self-destruct switches. And that’s not something you want accidentally escaping into the world.
The technology Akbari is designing is something called a gene drive. Think of it as a way to supercharge evolution, forcing a genetic modification to spread through an entire population in just a few generations. Scientists see it as a powerful tool that could finally vanquish diseases like malaria, dengue, and Zika. But US defense agencies see something else: a national security issue.
Last year, former director of national intelligence James Clapper added gene editing to a list of threats posed by “weapons of mass destruction and proliferation.” In July, the US Defense Advanced Research Projects Agency awarded $65 million in four-year contracts to seven teams of scientists, including Akbari, to study gene-editing technologies. The commitment officially made Darpa the world’s largest government funder of gene drive research. Most of that money is going toward designing safer systems and developing tools to counter rogue gene drives that might get into the environment either by accident, or with malicious intent.
That danger may be more real than scientists first thought. Four years ago, when Harvard biologist Kevin Esvelt first suggested the idea of building gene drives with the newly discovered Crispr gene editing system, he was thinking about extinction. Specifically, preventing endangered wildlife from disappearing by spreading a fertility-reducing gene through the invasive animals competing with them for resources. Conservation biologists took the idea and ran with it; they're now considering gene drives to save native birds in Hawaii, New Zealand, and the Farallones. But now, Esvelt is saying they should slow down.
That's based on the results of a new mathematical model he and his colleagues published on Thursdayon the bioRxiv preprint server.Taking into account things like how often Crispr screws up and the likelihood of protective mutations arising, their work shows how gene drives could be ruthlessly aggressive. Just a few engineered organisms could irrevocably alter an ecosystem. While Esvelt doesn't view the technology as inherently threatening, he is now preachingthat it deserves a bold new caution in how it's applied.
"The primary risk posed by gene drive technology is social," he says. "Unethical closed-door research, unwarranted fears, or unauthorized releases of gene drives will damage public trust in science and governance." He still thinks gene drives have potential to save threatened species and battle public health threats. But researchers will have to invent safer forms of the technology first. That's where the Darpa money comes in. Until very recently, gene drives have been largely theoretical—safe ones even more so. But with the new funds, scientists like Esvelt and Akbari are starting to put together the pieces to test them in real life. That starts with bugs that have a gene editor baked into their DNA from the moment of conception. In a paper published Tuesday in the Proceedings of the National Academy of Sciences, Akbari did that for the first time in Aedes aegypti, creating mosquitoes encoded with the bacterial Cas9 enzyme.
These mosquitoes were born with white eyes instead of black ones, after Crispr/Cas9 cut out genes associated with eye pigment.
MICHELLE BUI/UC RIVERSIDECas9 is the DNA-chopping half of the Crispr gene editing system. So Akbari’s team just had to inject the other half—a bit of guide RNA—into the embryos, for Cas9 to automatically execute its patented snipping action. When they deleted a cuticle pigment gene, the mosquitoes turned from black to yellow. How about a wing development gene? Welcome to the world, flightless blood sucker. Good luck crawling your way to a human meal.
These modifications were just for show. But the skeeters with built-in Cas9 will be an important tool as we learn how to best disrupt mosquito populations. Scientists estimate they’ve only probed about 5 percent of the Aedes aegpyti genome. Which means no one knows what the vast majority of mosquito genes actually do. Now they’ll be able to more easily screen knockouts gene by gene. Maybe they’ll find one that makes the mosquito mouth a hospitable home for malaria. Or one that turns off their taste for human blood. The goal is to disrupt the animal—and the ecosystems they’re a part of—as little as possible while still eradicating disease. If you’re going to play God, the idea goes, use a light hand.
In addition to advancing a new way to study mosquito physiology, these strains represent an important building block for efficient gene drives. Normally, the technology would require expressing both Cas9 and the guide RNA together in the same location. But that could make the drive system invasive and uncontrollable. One way to control them is to keep the components separated in the genome. And that’s what Akbari is working on: a less virulent version called a split-gene drive.
His team has already started the process by breeding these Cas9 strains with mosquitoes encoded with guide RNAs. “The only way to keep the drive spreading is to continuously release Cas9 into the population,” Akbari says. “That makes it confinable to a laboratory setting or self-limiting in the wild as the drive will depend on the presence of Cas9 which gets inherited in a Mendelain fashion.”
MORE ON GENE DRIVES
Teams at the Broad Institute and Harvard Medical school are screening and compiling a suite of chemical off-switches to block gene editors like Crispr/Cas9 and Talens. At UC Berkeley, Jennifer Doudna’s group is hoping to find anti-Crispr proteins to inhibit unwanted gene-editing activity, which would help design resistance-proof gene drives. While the military’s involvement has some in the public concerned about weaponized, Crispr-ized superskeeters, Esvelt sees defense department support as the only way to advance gene drive technologies safely, at least for the time being.
The Darpa program explicitly prevents the release of gene-drive organisms and requires participants to work under stringent biosafety conditions—hence Akbari’s six-door entrance and exit routine. Perhaps one day he’ll have the molecular tools to come and go without concern. But for now, they’re still the safest thing between his gene-drives and the world outside."
UCR RESEARCHERS ARE GENERATING GENETICALLY ENGINEERED INSECTS TO HELP PREVENT THE SPREAD OF INFECTIOUS DISEASES. PDF
Read full article here. pdf
Dr. Akbari quotes:
“I found both of [the studies] exciting in different ways,” molecular biologist Omar Akbari of the University of California, Riverside, says. “I really hope to see these technologies tested in the field.”
CRISPR-based methods do involve putting more complicated molecular machinery into cells, Akbari says, but they could also prove more reliable than the new approach, which relies on complex mating dynamics. “I think gene drive is probably a more powerful technology that’s portable across species,” he says.
ucr_today__ucr_uc_davis_center_to_fight_vector-borne_diseases.pdfUCR, UC Davis Center to Fight Vector-Borne Diseases Center is Powered by $8 Million CDC Grant. pdf
WE ALL DREAM TO SPLICE THE GENES
The CRISPR//Cas9 gene editing tool has quickly earned a reputation as a revolutionary technology, and its merits support the clout. This year has, in fact, seen so many CRISPR-related breakthroughs that it’s worthwhile to take a step back and take in all of the many accomplishments.
1. This week, circulating reports about the successful application of gene-editing human embryos in the US were confirmed by a research paper published in Nature. The researchers “corrected” one-cell embryo DNA to remove the MYBPC3 gene — known to cause hypertrophic cardiomyopathy (HCM), a heart disease that affects 1 in 500 people.
2. This year, scientists successfully used gene editing to completely extract HIV from a living organism, with repeated success across three different animal models. In addition to the complete removal of the virus DNA, the team also prevented the progress of acute latent infection.
3. Semi-synthetic organisms were developed by breeding E.coli bacteria with an anomalous six-letter genetic code, instead of the normal four-base sequence. Additional gene editing was implemented to ensure that the new DNA molecules were not identified as an invasive presence.
4. The CRISPR method successfully targeted the “command center” of cancer — called the hybrid fusion — which leads to abnormal tumor growths. A “cut-and-paste” method allowed the creation of a cancer-annihilating gene that shrinks tumors in mice carrying human prostate and liver cancer cells.
5. Scientists also slowed the growth of cancerous cells, by targeting Tudor-SN, a key protein in cell division. It’s expected that this technique could also slow the growth of fast-growing cells.
6. Gene editing techniques have also made superbugs kill themselves. By adding antibiotic resistant gene sequences into bacteriophage viruses, self-destructive mechanisms are triggered which protect bacteria.
7. Gene editing may even make mosquito-born diseases an extinct phenomenon. By hacking fertility genes, scientists have gained the ability to limit the spread of mosquitoes — a success they credit to CRISPR’s ability to make multiple genetic code changes simultaneously.
8. Using CRISPR, researchers have edited out Huntington’s disease from mice, pushing the symptomatic progression of the condition into reverse. Experts expect this promising technique to be applied to humans in the near future.
9. Outside of the medical field, CRISPR might also provide a more abundant and sustainable biofuel. By connecting several gene-editing tools, scientists engineered algae that produce twice the biofuel material as wild (or “natural”) counterparts.
10. Very recently, the first-ever “molecular recorder” was developed — a gene editing process that encodes a film directly into DNA code — and with this ability, scientists embedded information into an E.coli genome.
11. Last but not least, and on the macro-scale, the US Defense Advanced Research Projects Agency (DARPA) invested $65 million in a project called “safe genes,”designed to improve the accuracy and safety of CRISPR editing techniques. In addition to serving the public interest of avoiding accidental or intentional (cue ominous music) misuse, the seven research teams will remove engineered genes from environments to return them to baseline “natural” levels.
UC Riverside-led Team Wins $14.9 Million to Battle Disease-carrying Mosquitoes
"DARPA award is the largest ever for a UCR researcher"
DARPA funds UCSD gene drive research against mosquito-borne diseases
Building the Safe Genes Toolkit
Small Pest, Big Battle
UC San Diego Researchers Join $14.9 Million Fight Against Disease-transmitting Mosquitoes
Defense department pours $65 million into making CRISPR safer
How will we keep controversial gene drive technology in check?http://www.sciencemag.org/news/2017/07/how-will-we-keep-controversial-gene-drive-technology-check
DARPA Awards $65M to Improve Gene-Editing Safety, Accuracy
Zika, dengue, yellow fever: UC Riverside researcher gets $14.9 million to thwart disease-carrying mosquitoes
UC Davis Joins DARPA-funded “Safe Genes” Program
UC San Diego researchers selected for DARPA project against mosquito-borne diseaseshttps:
UC Zika research aims to ‘collapse’ mosquito populations
Importantly these guidelines may be adopted in the future to help provide information to stakeholders regarding regulatory oversight of articles, including substances, for use in or on mosquitoes (e.g. genetically modified mosquitoes or perhaps even gene drives).
Click here for a pdf of the document.
"Examples of New Animal Drugs (regulated by FDA)
Dr. Akbari Quoted
"This year, his advocacy has begun to bear fruit. Researchers and policymakers worldwide have been discussing the technology, and a report from the US National Academies of Sciences, Engineering, and Medicine urged that gene-drive research proceed, but cautiously. Omar Akbari, who studies gene drives at the University of California, Riverside, believes Esvelt’s outreach has focused public attention — and attracted funding — for a nascent technology at just the right time. “I attribute that to Kevin,” says Akbari. “It’s difficult for a scientist to do what he’s done.”
Nova Next - For Gene Drives, Resistance May Be Inevitable. pdf
Professor Akbari said this about how the severity of the effect of resistance in gene drive is dependent on the ultimate goal:
"If you’re able to block all disease [Dengue] transmission for a few weeks, that could essentially eliminate the virus. So you don’t need it to last indefinitely [versus if the goal was to create a lasting alteration for a disease like Zika]. "
The best way to get rid of mosquitoes? Turn them all into males. pdf
www.wsj.com/articles/mosquitoes-are-deadly-so-why-not-kill-them-all-1472827158Mosquitoes Are Deadly, So Why Not Kill Them All? pdf
Zika virus’s spread adds urgency to gene editing that could allow scientists to program the insects to die off, but the idea is fraught with quandaries.
"Prof. Akbari at UC Riverside is using Crispr/Cas9 to design a gene-drive system that would inactivate a fertility gene in female Aedes aegypti mosquitoes and then pass on the inactivated gene. That would sterilize future generations of females.
He hopes to test the system within the next several months. “We’re working as fast as we can,” Prof. Akbari says."
www.deutschlandfunk.de/die-gen-bombe-kettenreaktion-gegen-zika-malaria-und-co.740.de.html?dram:article_id=363534 - pdf; Translated -pdf; mp3
"Omar Akbari, University of California Riverside: "If you want to destroy a biological kind in the world, for example, Aedes aegypti, the Zika supercarrier, this is now possible A new technique turns off vital genes of the mosquito and spreads itself in a way. . chain reaction Sometime breaks the whole population together - and you have eradicated this way."
San Diego Union Tribune. A path forward for gene drive technologies. pdf
"UC Riverside’s Akbari put in a plug for more research dollars in Southern California to develop and test gene drive technologies.“Developing these systems takes a lot of effort and time and they are very complex,” Akbari said. “So funding the right groups would be important, and opening up larger collaborative efforts.
“In California we have a pretty good team of people working on this goal. We have Bruce Hay at Caltech, Tony James at UC Irvine, Ethan Bier, and me. We’re all really close to each other, about an hour’s drive of each lab. So I think having a collaborative grant where we could come together and work on these technologies would be really nice, and we don’t have that yet.”
Nova Next. Editing Out Pesticides. pdf
“We’re taking multiple approaches. The ideal approach would be to eradicate the pest—develop a catalytic gene drive system that you could release into a population that can spread invasively,” says Omar Akbari, a molecular biologist at UC Riverside. “And as it spreads, the population declines without the use of insecticides.”
UCR Today. Rio Olympics from A to Z. pdf
Professor Akbari said this about Zika and the Olympics:
“It is estimated that 1/2 million visitors will travel to Brazil for the 2016 Olympics, and it is important that these travelers exercise extreme caution as related to Zika. In Brazil, Zika still poses a significant threat with a total of 166,000 suspected cases, and counting, thus far. As recommended by the CDC, pregnant women should avoid the games completely, and individuals with pregnant partners should abstain from sexual contact for the duration of the pregnancy, and upon returning home from the games. In addition, all visitors should take the necessary steps to prevent mosquito bites, both during the games and for several weeks after returning home.”