GENEWATCH
 
STERILE INSECT TECHNIQUES, GE MOSQUITOES AND GENE DRIVES
By Jaydee Hanson
 

from GeneWatch 30-1 | Jan-March 2017

One of the great temptations in any field is to promote your solution to a problem as the only solution. The recent application of gene drives to sterilize mosquitoes that transmit malaria or viruses like dengue and zika is an example of this tendency to first develop a technology and then look for applications that might justify its use.

For at least 70 years, scientists have been trying to sterilize insects to prevent them from spreading disease, especially mosquito-borne diseases like malaria, dengue and zika, an approach known as "sterile insect technique." Sterilizing some insects with irradiation has been successful in preventing their reproduction.[1] In the 1950s, it was used to rid the southeastern U.S. of the New World screwworm Cochliomyia hominivorax (Coquerel), a deadly parasite of livestock. During the next 43 years the technique was used to eradicate this screwworm from the U.S., Mexico, and Central America. Currently, the largest use of Sterile Insect Technique in the U.S. is for the control of Mediterranean fruit fly. Irradiated bollworms are also being released to control cotton boll weevils, and irradiated coddling moths are being released to help protect apples and pears.[2] Interestingly, Rachel Carson, in Silent Spring, warned that using the Sterile Insect Technique to control a population of insects that could rebuild from neighboring islands or other populations was especially challenging. Talking about a SIT effort to control houseflies in the Florida Keys, she wrote:

"In a test on an island in the Florida Keys in 1961, a population of flies was nearly wiped out within a period of only five weeks. Repopulation of course followed from nearby islands, but as a pilot project the test was successful....

 One of the problems of sterilization by radiation is that this requires not only artificial rearing but the release of sterile males in larger number than are present in the wild population. This could be done with the screw-worm, which is actually not an abundant insect. With the housefly, however, more than doubling the population through releases could be highly objectionable [to the local people]."[3]

 

Genetically Engineered Mosquitoes as a Sterile Insect Technique

It seems a bit ironic that the first effort to use genetically engineered insects as a sterile insect technique is occurring in the Florida Keys near where the house fly experiment occurred more than 50 years ago. Rachel Carson's observation about the need to release huge numbers of the altered insects has proven to be a big challenge for the company planning to release its genetically engineered mosquitoes. Oxitec, a company that grew out of research by Oxford scientists, has genetically engineered mosquitoes, flies, diamond back moths, and cotton bollworms to become sterile in the next generation. They planned to release their GE mosquitoes on the Key Haven, just north of Key West. The U.K. company (now owned by U.S. biotech giant, Intrexon), has a contract with the Monroe County Mosquito Control Board. However, local groups in Monroe County, led by the Florida Keys Environmental Coalition, organized an effort to block the release of the mosquitoes in Key Haven and forced the Mosquito Control Board to hold a referendum. On Nov. 8, the people of Key Haven voted against the release of mosquitoes on their island.[4] The coalition effort may have been one of the few places in the U.S. where supporters of Donald Trump and supporters of Hillary Clinton worked alongside each other and won. The Mosquito Control Board agreed on Nov. 19 that they would respect the vote in Key Haven. On Dec. 5, the U.S. Food and Drug Administration confirmed to lawyers at the Center for Food Safety that the FDA's approval only applied to Key Haven. If Oxitec wants to release its mosquitoes in the Keys, it will have to resubmit its application to the FDA.[5]

The problems of the Oxitec mosquito are likely a template for many of the problems that could come from using the gene drive technology to make mosquitoes sterile. The lack of independent scientific research on the release of GE mosquitoes constitutes a most troubling factor in the initiative to release billions of these insects. While the desire to control viral diseases like zika and dengue is understandable, Oxitec, the company manufacturing the GE mosquitoes, has not demonstrated that its release of the mosquitoes in Panama, Brazil, Cayman Islands and Malaysia has reduced disease.

No studies have been done to understand the unintended evolutionary effects of introducing new genes into a species. GE mosquitoes are intended to be sterile, but not all are. Eliminating Aedes aegypti, the yellow fever mosquito engineered by Oxitec, may open ecological space for Aedes albopictus, the Tiger Mosquito which carries the same diseases. Additionally, mosquitoes provide a food for animals and help pollinate plants. At least one orchid species depends on mosquito pollination. Genetically engineering mosquitoes to die off could put at risk species that rely on them, including threatened amphibians, bats and birds. The company only studied one of the many endangered species in the Keys to determine what effect that releasing the GE mosquito would have on the ecosystem. Prior to the cancelation of the GE releases on Key Haven, the Center for Food Safety and other groups filed a notice of a planned lawsuit on the failure to follow the strictures of the Endangered Species Act.[6]

In addition to potential threats to sensitive ecosystems and a lack of evidence to support the GE mosquitoes' efficacy at minimizing the spread of disease, there is little information about what ingesting these insects could do to people. So many mosquitoes are released in the Oxitec trials (millions are released multiple times a week) that people complain of being forced to breathe in and eat mosquitoes.

The Oxitec mosquitoes are designed to cause a die off of the local mosquito population, and if new mosquitoes move into areas treated by the GE mosquitoes, then the company makes its money selling more of its GE mosquitoes. Gene drive mosquitoes, however, are intended to keep spreading their genes until ALL of the mosquitoes die off. This is one of the huge ecological challenges of the gene drive technique which will be discussed next.

 

Gene Drives as a Sterile Insect Technique

The largest  spending to create a mosquito-killing technology that relies on CRISPR Cas9 gene editing is coming from the Bill and Melinda Gates Foundation, which has dedicated more than $75 million to developing the technique. This sterile insect technique is designed to go through wild populations of mosquitoes and make them sterile with the intention of driving them extinct.

The Gates funded project is based at Imperial College, London and is attempting to put "gene drives" in to the DNA of mosquitoes that transmit malaria and make them sterile. Interestingly, locating the research in London is considered a geographical bio-control, as the mosquitoes do not naturally live in the UK.[7]

Gene drives are an experimental genetic engineering technique intended to overwrite Mendelian evolution by assuring that specific traits spread into every offspring in a population. Normally, only half of the population would inherit the traits from its parents.[8] If a gene drive were successful, the chosen traits would become dominant in a wild population in a few generations. A successful sterilization drive could push a population to extinction. Most of these artificial gene drives are developed using the gene editing system known as CRISPR cas9.[9]

While some of the more cautious CRISPR researchers argue that adequate environmental and human health safeguards need to in place before any gene drive organism is released into the wild,[10] other researchers insist that gene drives organisms (not necessarily mosquitoes) could be released as early as 2020.[11]

As tempting as it might seem to try to completely eliminate the mosquitoes that cause human malaria in Africa, which is now killing 450,000 people a year (mostly in Central African countries that have faced years of war and dire poverty), one must consider all of the possible consequences. Likewise, to eliminate bird malaria carried by Culex mosquitoes in Hawaii, the longer-term effects need to be fully considered.

The ecological effects of gene drives are at present unknown and hard to predict. Eradicating a single species of mosquito, moreover, as noted in the GE Oxitec mosquito, does not necessarily eliminate the disease, as other mosquitoes capable of moving into the niche of the first mosquito can also transmit many of the same diseases. The next mosquito might carry varieties of malaria less treatable with current medicines.

In the case of bird malaria in Hawaii, the Culex mosquitoes are believed to have originated in Latin America and came to Hawaii in the drinking water of whaling ships. We don't know the effect of causing the extinction of that species in Latin America where presumably there are birds, bats and other creatures that eat the adults, larvae or eggs of the mosquito. If the mosquito can get to Hawaii on whaling ships, it is likely that the gene driven form can get back to Latin America on a plane or ship.

Gene drives can thus undermine most of the principles of biological control. Previous biosafety practice encouraged testing GMOs in remote places like Hawaii to prevent environmental persistence. Gene drives are designed to override local conditions and supplant pre-existing species. Once the gene drive organism hops on a plane or ship, it can spread its genes beyond the isolated area into which it was released.

Some researchers, including Esvelt, have posited that it may be possible to reverse the gene drive effects, but this should not be tested after the organism is released into the environment.

 

No Release of Gene Drive Mosquitoes until containment and monitoring procedures are in place

Elsewhere in this issue of GeneWatch, Jonathan Latham argues that it may not be possible to control these gene drives, so we should ban their use. I share a lot of his concern that we may not be able to do this right, but would suggest a moratorium on the environmental release of gene drive mosquitoes to attempt to control human disease and provide for wild life conservation.

The Principles for the Oversight of Synthetic Biology[12] suggest that new organisms should be subject to a moratorium until rules are in place assuring that a "precautionary approach" is being taken, and until regulations are in place that address the ecological and human health implications of the release of the organism. Moreover, local people should be involved in a participatory  review of the technique. Alternative techniques should also be examined as a part of the review of the techniques used to make the new organism. Hypothetical claims about the reversibility of a technique need to be carefully tested. Strict international rules for the containment and handling of gene drive research on mosquito species must be in place even before laboratory testing begins. Mosquito eggs can survive long distance travel. The Asian Tiger mosquito is believed to have arrived in the U.S. as eggs attached to tires shipped across the Pacific. No mosquitoes should be able to escape the laboratory and hop aboard a ship or a plane.

There must also be adequate monitoring procedures in place to detect accidental releases of these gene drive mosquitoes.

Only after these international rules are in place should testing move to the next phase, which is testing in large mesocosms that mimic the environment into which they might eventually be released. But these structures must be designed to effectively prevent the release of the mosquito until control strategies can be fully researched.

 

Alternatives to Gene Drive Mosquitoes
 

Bacterial "gene drives"

At the same time that the above research is being done, research on the alternatives must be advanced. Nature has already designed some "natural" ways of controlling mosquito fertility. One of these ways is by infection with the Wolbaccia bacteria. The EPA has already approved tests of two Wolbaccia infected mosquitoes in the Central Valley in California[13] and a test in Florida is expected soon.

Vaccines

Since most of the problems we are trying to solve are actually the diseases being carried by the mosquitoes, not the mosquitoes themselves, attention needs to be paid to other ways of eliminating the disease than by eliminating the mosquito. Yellow fever vaccines have been reducing the number of people who contract yellow fever from the so-called "yellow fever mosquito" for many years. Recently dengue fever vaccines have been developed and are now approved in some of the countries where dengue is most endemic. Last April, the World Health Organization recommended that any country where dengue is endemic use the first approved commercial vaccine, Sanofi's Dengvaxia.[14] Malaria vaccines have proven more difficult to develop, but are being tested.

Sanitation and medicines

Finally, it is important to remember that a good part of avoiding malaria or dengue or zika includes basic public sanitation strategies. Last year, I visited a woman in Managua, Nicaragua who is the de facto mayor of her shantytown slum. She and a group of women go from house to house making sure that any standing water is dumped so mosquitoes can't breed. She then takes the temperatures of the home's residents. If anyone has a temperature, she and her team make sure that they are enclosed in a mosquito net, so mosquitoes can't bite them and transmit their illness. Through such rigorous monitoring of her community, she has eliminated malaria, dengue and other mosquito borne diseases from her slum. This is an old fashioned but effective low-technology method for eliminating the disease. El Salvador saw 20,000 new cases of malaria at the peak of its civil war, but after more than 20 years, both liberal and conservative governments have made sure that everyone had access to the drugs that cure malaria. Two years ago, they no longer had endemic cases of malaria.

The world community needs to put its money in these proven alternatives and maintain a moratorium on gene drives as a way to control mosquito borne diseases until international regulations are in place. By that time, these other strategies may have completed the job without the help of GE and gene drive mosquitoes.

 

Jaydee Hanson is Policy Director, International Center for Technology Assessment. 

 

Endnotes

1. See http://www-naweb.iaea.org/Nafa/ipc/public/Sterile_Insect_Technique_book.pdf#page=14

2. Ibid. page 16.

3. Rachel Carson, Silent Spring, 1962. Available on-line at: https://archive.org/stream/fp_Silent_Spring-Rachel_Carson-1962/Silent_Spring-Rachel_Carson-1962_djvu.txt

4. http://www.centerforfoodsafety.org/press-releases/4568/this-election-keys-residents-vote-no-on-ge-mosquitoes

5. http://www.centerforfoodsafety.org/press-releases/4593/victory-ge-mosquitoes-will-not-be-let-loose-on-florida-community

6. http://www.centerforfoodsafety.org/press-releases/4580/advocates-challenge-fda-on-first-ever-ge-mosquito-release

7. Antonio Regalado, "The Extinction Invention" Technology Review, April 13 2016, available at: https://www.technologyreview.com/s/601213/the-extinction-invention/

8. National Academies of Science, Engineering, and Medicine (NASEM). "Gene Drives on the Horizon: Advancing Science, Navigating Uncertainty, and Aligning Research with Public Values, Washington DC: National Academies Press 2016 available at: https://www.nap.edu/download/23405

9. Andre Hammond, et al. "A CRISPR Cas9 gene drive system targeting female reproduction in the malaria mosquito vector, Anopheles gambiae," Nature Biotechnology 34, no. 1 (2016): 78-83

10. See Kevin Esvelt article in this issue.

11. GBIRd Project (Genetic Biocontrol of Invasive Rodents) led by Island Conservation International) Available at www.islandconservation.org/programcoordinator

12. International Center for Technology Assessment, Friends of the Earth, and ETCgroup. Principles for the Oversight of Synthetic Biology available at: http://www.icta.org/files/2016/09/ICTA_Principles_Oversight-Synthetic-Biology.pdf

13. See https://www.epa.gov/pesticides/epa-grants-extension-experimental-use-permit-wolbachia-mosquito

14. Dengue vaccine research". World Health Organization. Retrieved 18 April 2016. Available at: http://www.who.int/immunization/research/development/dengue_vaccines/en/


 
 
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