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For the last 15 years, Austin Burt and Andrea Crisanti have worked tirelessly to genetically engineer the perfect mosquitoes. The two scientists are at the most radical end of a spectrum of researchers currently working to eradicate malaria, a disease that killed 435,000 people, most of them children, in 2017.
Not content with blocking the parasite that causes malaria, as some scientists are attempting, Burt and Crisanti want to perpetuate a modified gene – a so called "gene drive" – in a mosquito population that will render females sterile, until the species is wiped out. In another 15 years, they believe, their mutant mosquitoes will be released all over Africa.
“I hope to see it in my lifetime. I think the only thing that we need is to show its effectiveness in a small, isolated proof of principle example. And then I think everybody will want to use it,” 64-year-old Crisanti says.
The scientists are the two most prominent figures in Target Malaria, an initiative dedicated to halting the disease from its base at Imperial College London and with local partners in Burkina Faso, Mali and Uganda.
They are very aware that their work is viewed as audacious, even dangerous. Friends of the Earth called for a moratorium on gene drives at a UN meeting on biodiversity in November 2017, referring to their work as “exterminator technology”.
“It’s a GMO (genetically modified organism) technology. It’s a GMO technology that spreads. It’s a GMO technology that reprograms sex. It’s a GMO technology that can be used to eliminate malaria,” Crisanti summarised, rattling off the reasons why his work causes alarm and wonder in equal measure.
Prior to arriving at Imperial College London within a year of each other (Crisanti in 1994; Burt in 1995), the two men slowly worked their way into the same field. Crisanti trained as a medical doctor in Italy before switching to a PhD in immunology, and working on a doomed project for a malaria vaccine in the late 1980s at the University of Heidelberg. His interest then turned to how mosquitoes carry and transmit malaria, and how this capability is passed down the generations.
Burt grew up in Winnipeg – “in the middle of Canada, lots of mosquitoes in the summertime” – before moving to Montreal to study, completing a PhD in biology at McGill University in 1990.
“Austin and Andrea are incredibly different in their style, which reflects both their personalities but also the fact they come from very different cultural backgrounds – the cold province of Winnipeg for Austin and the warm and hectic Rome for Andrea,” says Delphine Thizy, a close colleague.
Thizy describes Burt as a “listener” who is “very measured in what he says”, to the point where occasionally “there are silences in the middle of a discussion”. It’s difficult to shake him from his Canadian modesty at times, she adds.
Beyond his brief description of Winnipeg, Burt is reluctant to speak too much about his background, carefully steering the conversation back to science. “It’s an interesting combination, because I'm Italian and I’m much more communicative and open. He is more reserved, and I think this worked out nicely,” Crisanti says.
Burt builds models to project how Crisanti’s insects will react when released into the wild, and oversees Target Malaria’s overall organisation, also acting as its spokesman. Crisanti runs closer to the mad scientist stereotype, at his most content in a lab, where he hatches his re-programmed mosquitoes. “Let's say I'm not a field person. I recognise myself; I have this limit,” he says.
For years, Burt worked with yeast enzymes, observing how “selfish genes” managed to perpetuate themselves with a greater probability than the standard 50-50 chance. He idly wondered whether these genes, known as homing endonucleases, could be copied and reconfigured for other uses, in a thought experiment he adapted for a groundbreaking 2003 paper.
“If you could engineer them to recognise new [DNA] sequences, well, then you could use them as a gene drive system in an animal, like a mosquito. So I was just connecting dots,” Burt explains. He wanted not only to edit mosquitoes’ DNA, but to embed the insects’ eventual destruction into their genes. Only females from certain species of Anopheles mosquitoes transmit the malaria parasite via their bites, so skewing the population male would minimise this risk.
Burt’s paper drew widespread attention among evolutionary biologists, and he invited Crisanti to join him in applying for a grant from the Bill and Melinda Gates Foundation, cementing their partnership. The grant was approved in 2005, and a cash injection of $8.9 million allowed the pair to take the theory and prove it could work in a lab. Crisanti describes the impact as “immense”.
“If you need a resource, you get it, if you need a technology, you get it, if you need equipment, you get it. We were left with the notion that success is only up to us.” This commitment has since increased, hitting $75 million in 2016 and allowing the construction of laboratories in Burkina Faso, Mali and Uganda, from which the mosquitoes are one day due to be released.
Jonathan Kayondo, principal investigator for Target Malaria in Uganda, says the diversity of the 140-person team globally is “unusual, but also necessary due to the scale of the work involved”. The teams in these three African nations have spent decades collecting the baseline data required to feed into Burt’s models and inform Crisanti’s lab work.
“You also need expertise in terms of genetic studies, entomological studies in the field. We understand the local mosquito population, the dynamics and seasonality,” Kayondo adds. Once gene drive mosquitoes can survive in the wild and are correctly adapted to the environment, which is not yet the case, they will be let loose among the existing insect population.
The organisation has hired stakeholder teams to raise awareness and obtain consent for a future release, as any unintended side effects on the ecosystem will not be felt in major North American or European cities, but in the communities where Target Malaria will begin its trials.
Overseeing the stakeholder teams’ work is Thizy, a former aid worker turned consultant who spent years helping mining and energy companies to improve relations with citizens living close to their operation sites. “Burt understood the need for stakeholder engagement and decided to ask funders to support it early days,” she tells me via email. “I am not objective, but I’d say it is as important as the work done by my amazing colleagues in the lab.”
Thizy was hired in 2014, and channels the concerns of groups in Burkina Faso, Mali and Uganda to the local scientists and also back to Target Malaria headquarters, where they are considered and factored into the research and planning already underway.
“When I go to visit the communities, the concerns are often about the vector – could another vector replace Anopheles gambiae [a malarial mosquito species] if it is reduced, could a modified mosquito become a better vector for malaria or other disease?” Thizy explains. “It is very much focused on health implications and I think it’s because malaria is something very central in people’s lives.”
The teams also translate the concept of gene drive into local languages, and explain the expected impact on the malarial mosquito population.
Last June, around 1,000 farmers marched against genetically modified mosquitoes in Burkina Faso, saying they were concerned about the human and environmental impact of gene drive. Friends of the Earth has called for a blanket ban on the technology.
“In Africa we are all potentially affected, and we do not want to be lab rats for this exterminator technology,” says Mariann Bassey-Orovwuje of Friends of the Earth Africa. “We are giving notice now that potentially affected West African communities have not given their consent or approval to this risky technology.”
The United Nations Convention on Biological Diversity, which has 150 signatories, decided in November it would not back the critics’ demand for a moratorium on gene drives, but cautioned that mosquito releases would be considered on a case-by-case basis, and would require community consent.
The problem lies, Burt believes, in the relative lack of understanding about gene drives’ many forms, or “flavours”, and commensurate levels of environmental exposure. “So there's low threshold, high threshold, split, daisy, tethered, integral, and sex limited,” he says. Some gene drives would happen in one large burst, others in a series of smaller, timed releases, for example. Target Malaria already supports consent, regulation and community engagement with its plans, he adds, and “no predator specialises in this particular species of mosquito”.
Crisanti takes a more philosophical view of his critics, heavily influenced by his background in evolutionary biology. “Species have gone and emerged continuously, so to defend the stability of the environment is something that, for me, is not valid,” he says. Our “limited lifespan” as humans often leaves us with a very short-term view of such processes, he adds, and malaria’s horrific toll should be emphasised a lot more often by scientists attempting to win the gene drive argument. “I think this battle that will be won on moral grounds, not on the basis of convincing about technicalities.”
Burt and Crisanti are not alone in exploring the use of a gene drive to eradicate malaria. Scientists at University of California San Diego and UC Irvine have developed a proof of concept for a gene drive that would make mosquitoes resistant to the parasite that causes the disease, focusing on South Asia.
Kevin Esvelt, who leads the Sculpting Evolution Group at Massachusetts Institute of Technology, developed the “daisy drive” concept, which only spreads locally, to tackle rodents. Esvelt was also first to see the potential of CRISPR gene-editing technology in the field of evolutionary biology, and has warned the public about its unchecked power. He has said, however, that malaria provides an imperative for a gene drive “that just doesn't exist for almost any other class of problem”.
CRISPR has sped up every aspect of life in the lab, but technology is less cutting edge out in the field. “We're still using basically 100-year old technology to collect mosquitoes,” Burt says. “There's room for bright people to be making a contribution there, so that we can be monitoring this thing on some larger scale at a reasonable cost and reasonable approximation to getting the data in real time”.
For now, gene drive technology is dealing with a far graver challenge than regulatory hurdles, community consent or collecting bodies. It does not yet work, largely due to the naturally occurring resistance that builds in genes through generations.
Target Malaria took its biggest step in 15 years last September, when it published a paper explaining how the team wiped out a population of mosquitoes in eight generations without any resistance to an edited “doublesex” gene, which determines whether a mosquito is male or female.
The researchers found that males who carried this modified gene showed no changes, and neither did females with only one copy of the modified gene. But females with two copies of the modified gene showed both male and female characteristics, failed to bite and did not lay eggs. The transmission of the edited gene from generation to generation was almost 100 per cent, proving that in a lab setting at least, resistance could be overcome.
Burt had assumed this demonstration would happen sooner. “I wouldn’t have guessed it would take 15 years, but that was probably naïvety on my part more than anything else,” he says. He hopes to conduct field trials for gene drive mosquitoes in the next five years, and wants to roll out the project across Burkina Faso within a decade. “It's quite possible that most scientists think they're going to live to see the fruits of their labour,” he says, hopefully.
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