The Carrier As the Cure

AT ONE POINT DURING THE INTERVIEW, Kaushal Kumar had deliberately calmed himself. The former Joint Director and Head of the Centre for Medical Entomology and Vector Management at the National Centre For Disease Control, who had spent much of his life studying mosquitoes, had been speaking much too rapidly, discussing what appeared to be a favourite subject of his, the danger posed by the Aedes aegypti mosquito. He lowered his voice and enunciated his words carefully, as though he wanted the weight of each word to be felt.

“People say communalism, corruption and all these things are dangerous to the country,” he told me over the phone a few years ago. “But, I say, you’ve got it wrong. The most dangerous thing is this aegypti.”
This aegypti (or the Aedes aegypti mosquito) is the primary cause behind dengue, chikungunya, yellow fever and the Zika virus. Originally a species from Africa, it probably arrived on Indian shores, like it did elsewhere in the world, aboard ships transporting goods during the two World Wars. It has since overrun the healthcare defences of many countries, particularly India’s, which is believed to annually contribute one of the highest numbers of dengue cases globally.

The Aedes aegypti hovers low, drinks our blood even during the day, usually low on our legs and away from our gaze, biting several times during a single feeding. And they breed prolifically almost anywhere, from drains, buckets and flower vases with some water in them to even tiny objects like a discarded half-consumed coconut shell with a little rain water in it. One researcher, the head of the zoology department at JES College in Maharashtra’s Jalna district, Laxmikant Shinde, once told me that he has even found Aedes aegypti mosquitoes breeding in overturned bottle caps with a teaspoon of water.

We have thrown everything at it. We have sprayed powerful insecticides, employed mosquito-larvae-eating fish, lit mosquito-repellant coils that burn our eyes, fumigated our houses, lathered our bodies with unpleasant lotions, guarded our homes with window screens and our beds with nets, tried developing malaria and dengue vaccines for humans, and charged at them with electric rackets, rolled-up newspapers and the front of our palms. We always fail. The puddles fill again, stronger resistance to insecticides develops and they learn to dodge our swatting palms.

But work currently going on at the recently established Tata Institute for Genetics and Society (TIGS) suggests that we are looking at the issue of mosquito-borne ailments the wrong way. We don’t need to kill mosquitoes. We need to immunise them (against the dengue, chikungunya and other viruses for Aedes aegypti mosquitoes, and the malaria virus for Anopheles mosquitoes).

TIGS was set up a few years ago as a partnership between the Tata Trusts and the University of California, San Diego (UCSD), which has been at the forefront of some of the most promising work around using genetics to control vector-borne ailments. According to SK Dasgupta, the Group Leader of Field Applications at TIGS, mosquitoes can be genetically modified in a laboratory in such a way that they would become immune to carry the germs of diseases like malaria and dengue. These GM mosquitoes can then be released into the open, where they would mate with wild mosquitoes and pass on this genetic trait down the generations. The researchers here use what is known as active genetics that allows them to bypass natural selection and plug in a gene that passes through the population faster than a mutation handed down by the usual process of inheritance. Within a fairly short time, theoretically, all mosquitoes could develop this immunity. “The technology has been demonstrated [in a lab], the proof of concept has been done,” he says. The question is whether, away from the controlled setting of a lab, it would work in the real world where genetically modified (GM) mosquitoes will have to compete with other wild mosquitoes in securing mates.

According to Dasgupta, they are currently trying to develop these GM mosquitoes in their lab in India. Their current focus is on the Anopheles mosquito, which transmits malaria, but they will also be using this method to deal with the Aedes aegypti.

Releasing these mosquitoes into the open is still some way away. More work needs to be done both in the lab and in controlled outdoor settings, he says. The technology also has to be tested for safety, along with consultations with the Government for policies and regulations to be set up. “I don’t think [GM mosquitoes are] going to be a silver bullet,” he says. “India is such a huge country, the population density is so high. We will probably have to use this method in conjunction with many of the other pre-existing and emerging methods [of malaria and dengue control].”

There is also another way of using GM mosquitoes, championed by researchers at the UK’s Imperial College. Using a somewhat similar method, it spreads not an immunising gene but a sterilising mutation that can theoretically wipe out an entire mosquito species.

Last year, in an advanced test, researchers under the aegis of Target Malaria Project released up to 10,000 GM sterile male Anopheles gambiae mosquitoes in Burkina Faso. According to them, the risks, if any, are negligible because the mosquitoes are sterile and would die within months. ‘If this is successful, there will be further phases and eventually scientists are thought to be planning a more advanced release of mosquitoes engineered with gene-drive technology to spread sterility and eventually eradicate the vector for the disease,’ reported The Guardian.

The results of that test are yet to emerge but many aren’t convinced about the method. Some researchers are sceptical whether it is even possible to wipe out an entire species, while others worry about its ethical concerns. Mosquitoes aren’t known to play any vital role in the environment, except perhaps as reports have shown, in the Arctic tundra where they serve as a significant food resource for birds.

According to Dasgupta, any of the mosquito species by itself is not key. There are several other mosquito species, he says, which can fill a void in case a particular species is eradicated. Furthermore, as some researchers point out, mosquito species like the Aedes aegypti do not belong in many of the places they are currently found in. They reached there because of the emergence of sea travel.

The method the researchers at TIGS and UCSD are working on does not seek the elimination of any species. It is also believed to be superior in another way. “We won’t need to keep releasing GM mosquitoes all the time,” Dasgupta explains. “In the other method, even though mosquitoes may be wiped out from a certain area, newer mosquitoes from elsewhere will invariably come. So to deal with that, more of these GM mosquitoes will have to be released every once in a while.”

Governmental permission for larger tests could be challenging to secure. The political opposition in India to GM technology in farming has been at the cost of crop yields. If we extend it to GM insects, the cost may be even more severe. There is no reason to be optimistic. Gangabishan Bhikulal Investment and Trading (GBIT), which is owned by the Barwale family that also owns Mahyco which produces seeds, learnt it the hard way. A few years ago, they tied up with Oxitec (a company partly owned by the University of Oxford and later bought over by the US synthetic biology firm Intrexon) to begin work on a GM mosquito programme.

Here, according to a source familiar with this programme who requested anonymity, male Aedes aegypti larvae were bred with a lethal gene. This gene, however, is kept inactivate by dosing the larvae with an antibiotic, tetracycline. When released into the wild, they mate with wild mosquitoes but their offspring, deprived of tetracycline, die before they can reach adulthood. Over time, the population of Aedes aegypti would decline.

India is such a huge country, the population density is so high. We will probably have to use (GM mosquitoes) in conjunction with many of the other pre-existing and emerging methods (of malaria and dengue control),” says SK Dasgupta, Tata Institute for Genetics and Society

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“You tell me,” the source asks, “Are we anywhere close to dealing with [vector-borne diseases]? Present methods are woefully inadequate. So many people die every year. But for some unscientific reasons, we haven’t been allowed to carry on and the project is now stalled.” Only male GM mosquitoes were to be released, the source explains, because male mosquitoes do not bite humans, and in this way, humans did not need to fear being bitten by a GM organism.

According to the source, tests in the lab were successful. Male GM mosquitoes were mating with wild female mosquitoes, the source says, and a majority of their offspring, as expected, also died. Outdoor caged trials were successfully carried out, but at the next stage, an open field caged trial, the Government balked and approvals weren’t granted. If things had gone according to plan, the source says, they had hoped to begin tests in two villages with a small human population by 2019.

Oxitech has gone on to release GM Aedes aegypti mosquitoes in Panama and Brazil, without triggering any of the dire consequences predicted by environmentalists. The company claims these releases have led to significant decline in mosquito populations in those areas. But they have also had setbacks, for instance in the Cayman Islands, where, according to reports, the project was abandoned because the female mosquito population did not decline.

THE INDIAN COUNCIl of Medical Research (ICMR) has now begun to work on another method. In this method, championed by the Australian entomologist Scott O’Neill, who heads the non-profit World Mosquito Program (WMP) headquartered at Monash University, mosquitoes do not need to be eradicated or genetically modified. With just a slight biological tweak, where the Aedes aegypti mosquito is infected with a microbe, the insect can instead be recruited to eradicate the viruses it otherwise spreads.

The microbe they are infected with, Wolbachia, is a common bacterium in the insect world. It however does not naturally occur in Aedes aegypti mosquitoes. When Aedes aegypti mosquitoes are infected by it, O’Neill discovered some years ago, the microbe blocks the dengue virus from replicating in the tissues of mosquitoes. Since the virus does not replicate, transmission to humans cannot occur. In this method, mosquitoes are artificially infected with the microbe in the lab and then set loose in the wild, where they hopefully pass this dengue-blocking microbe down the generations.

Here too there are two ways of using Wolbachia. In the first method, preferred by WMP, thousands of both male and female Wolbachia-carrying Aedes aegypti mosquitoes are released in an area in the hope that the microbe is passed down the generations. In the alternative method, thousands of only male Wolbachia-carrying mosquitoes are released. It has been found that when a wild female mosquito mates with such a Wolbachia-carrying male, it is unable to reproduce. ‘We prefer the former method because the deployment of mosquitoes only needs to be done once and not in an ongoing way which means it is very cost effective,’ O’Neill says over email. ‘In the suppression approach, the mosquito population rebounds very quickly, which means you need to keep reapplying the released mosquitoes, which makes scaling very challenging and expensive. It also requires much larger numbers of mosquitoes to be produced and released.’

So far, according to O’Neill, their programme is currently being undertaken in 13 countries. ‘The effectiveness we are currently measuring ranges from 98 per cent reduction in dengue through to 46 per cent reduction depending on the site,’ he says. ‘These estimates of reduction are likely conservative as some of the deployment areas are still small and heavily affected by people movement in and out of the deployment site.’
The ICMR has been working with WMP since last year. Wolbachia-carrying mosquito eggs were transferred to the ICMR, according to O’Neill, where researchers were able to hatch them, get them to successfully mate with Indian mosquitoes, leading to Wolbachia-carrying local strains. It is believed that field tests with this new strain will begin in a few months.

The success of these methods, if it is ever carried out to its fruition in India, will depend on how well locals support it. This method requires a lot of community support. In some areas, for instance, in the Australian city of Townsville, the researchers had around 7,000 families rearing around 4 million Aedes aegypti mosquitoes. Each family hosted a tub of Aedes aegypti eggs in their yard, stocked with fish food to nourish them before they took flight. It helps that this method does not require genetic tweaking and is seen as a more natural intervention. O’Neill says he expects similar support in India.

Not everyone is convinced the method will work in India. SR Prabagaran, an associate professor at the biotechnology department in Coimbatore’s Bharathiar University, along with two other researchers, Sivaraman Balaji and S Jayachandran, claims to have found Aedes aegypti mosquitoes in places like Coimbatore and Madurai with naturally occurring Wolbachia. This bacterium, it is believed, does not occur naturally in Aedes aegypti mosquitoes. And Prabagaran worries if this trait in local mosquitoes will lead to unforeseen complications.

The three researchers spent the last four years combing through Coimbatore and Madurai, scooping out mosquito larvae from stagnant water pools and studying them in a lab. According to their study, published in FEMS Microbiology Letters earlier this year, at least around 80 per cent of Aedes aegypti mosquitoes they examined in Coimbatore naturally possess Wolbachia.

“No studies have been done to find out what happens if [a living modified organism] like a Wolbachia-carrying mosquito is released into a wild population which already carries a type of Wolbachia,” he says. “What I am saying is our knowledge and competency in this subject are premature for field evaluations.”

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Lhendup G Bhutia

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