Does the answer to eradicating malaria – the biggest killer on the planet – lie with gene editing its mosquito carriers? Martin Fletcher investigates
No disease in history has killed more humans than malaria. Now, genetic scientists say they are close to defeating its carrier, the mosquito. Is this a life-saving breakthrough? Or arrogant meddling with nature? Martin Fletcher reports
Deep in the basement of a bland-looking building on Imperial College’s South Kensington campus is a humid, windowless suite protected by two steel doors and an electronic security system. It is called the ‘Insectary’.
Inside, thousands of mosquitoes are kept in small cubes of white netting, which are themselves stored in eight large stainless-steel cubicles whose temperature, humidity and light are carefully controlled. Scientists study wriggling mosquito larvae beneath microscopes. Students pore over trays of pupae. Lab assistants make up the vials of sugar water on which the male mosquitoes feed. The female mosquitoes suck from tiny drums of heated human blood obtained from nearby hospitals.
This is no ordinary laboratory. It is the nerve centre of the most innovative attempt yet made to eliminate malaria – a scourge that, even today, kills a child every 90 seconds. It is where scientists are developing what could prove to be the ultimate weapon against malaria-bearing mosquitoes. They are seeking to harness ‘gene-drive’ technology to render those long-legged, glassywinged insects incapable of reproduction so that their populations crash.
The mood is one of suppressed excitement. ‘I think it’s on the way to success, but not guaranteed sufficiently that I’d say all other research should stop,’ says Austin Burt, an understated professor of evolutionary genetics at Imperial. He heads a project called Target Malaria, which employs 130 scientists in 14 institutions in Europe, Africa and North America.
‘I’m convinced it will work… We have made tremendous progress in the last two years,’ says Andrea Crisanti, a genial professor of molecular parasitology at Imperial, who has helped Burt develop the technology over the past 15 years.
‘Gene-drive could be one of those transformative tools that makes the end of malaria possible,’ says Martin Edlund, chief executive of the pressure group Malaria No More. ‘It could save millions of lives, prevent billions of cases and unlock trillions of dollars in economic productivity by helping to end one of the world’s oldest and deadliest diseases.’
The Bill & Melinda Gates Foundation, which often backs risky projects that governments shy away from, has shown its confidence by pumping $70 million into the project since 2005.
But perfecting the science, hard as that is, will be just the start. It cannot be deployed without the support of governments and peoples. And although it could eliminate not only malaria, which kills nearly half a million people a year, but any number of other deadly diseases, including yellow fever, dengue and Zika, it is already generating fierce opposition reminiscent of the furore over genetically modified foods.
More than 170 environmental and other civil-society organisations have demanded a moratorium on what they call ‘genetic extinction technology’. They argue that it could have dire unintended consequences, or be hijacked for all manner of nefarious purposes – including, just conceivably, the development of bioweapons.
‘We should not be playing God in the garden with things scientists admit they do not fully understand,’ says Dana Perls, senior food and technology campaigner at Friends of the Earth.
Nothing in history has killed as many humans as malaria – not wars, famines, plagues or natural disasters, or probably all of those combined. Hippocrates described its symptoms 2,400 years ago. It plagued ancient Rome. It stalled the advance of white colonialists into sub-saharan Africa. It helped Haiti’s former slaves to defeat Napoleon’s mighty army and win independence in 1803. It held back the development of America’s Deep South. It wrecked the first – French – attempt to build the Panama Canal. In 1906, two years after the United States took that project over, 21,000 of the 26,000 workers were afflicted by malaria.
It was not until the end of the 19th century that doctors discovered that malaria – a distortion of the Italian words mala aria or ‘bad air’ – was a pathogen transmitted by mosquitoes. Specifically, the female mosquito alights on human skin and, using her sharp proboscis, searches for blood. When she nicks a tiny vessel, she inserts a substance that prevents coagulation. She then sucks out the blood she needs for reproduction.
When the saliva she leaves behind contains the plasmodium parasite, those parasites migrate to the liver, where they mature and multiply. About a week later, tens of thousands of parasites escape into the bloodstream and attach themselves to red blood cells. The blood cells eventually rupture and the victim is hit by the full force of malaria – headaches, vomiting, violent shivering, extreme fever and sweating. The most unfortunate, usually babies and children, suffer delirium, coma and finally death.
The mosquito may be just a few millimetres long, but it is man’s deadliest enemy. The Gates Foundation has calculated that approximately 10 people a year are killed by sharks, 100 by lions, 1,000 by crocodiles, 10,000 by tsetse flies, 50,000 by snakes and 475,000 by other humans. Mosquitoes kill roughly 725,000 – mostly through malaria but also through diseases like dengue and yellow fever. ‘When it comes to killing humans, no other animal even comes close,’ Bill Gates has said.
Identifying the mosquito as the vector allowed the developed world largely to eliminate malaria by the mid-20th century through better drainage and sanitation, the isolation of malaria patients (to prevent mosquitoes biting them and then passing the virus on), insecticides, window screens and the development of the anti-malarial drug chloroquine. In the 1950s, the World Health Organization (WHO) launched a drive to eradicate malaria elsewhere by dousing developing countries in DDT – almost literally. Initially that campaign worked, and more than two dozen countries eliminated the disease – with adverse environmental consequences down the line. But the mosquito is a formidable opponent. It began developing resistance to the insecticide, as the plasmodium parasite did to chloroquine. Funding dried up. The programme was suspended in 1969. Malaria returned with a vengeance.
The second great drive against malaria began in the early 2000s, using new tools: 1.65 billion bed nets treated with modern insecticides; a fresh set of drugs based on artemisinin; and a rapid diagnostic test that could be deployed in the field.
Again, the drive worked well for a while. Globally the number of malaria cases fell from 262 million in 2000 to 214 million in 2015, and deaths from 839,000 to 438,000. Then progress stalled. In 2016 there were 216 million cases of malaria and 445,000 deaths – a slight rise on the previous year. Once again mosquitoes have developed resistance to the insecticides used in bed nets, and there are signs that the parasite is developing resistance to drugs containing artemisinin, too.
Europe has eliminated indigenous malaria, but a few scientists have warned that mosquitoes bearing the malaria and dengue pathogens could reach southern Europe if global warming continues. Malaria has largely retreated to its strongholds in sub-saharan Africa, but there it is thriving, often in poor, ill-governed or conflict-ridden countries lacking sanitation and proper health services. International funding for efforts to counter malaria has also levelled off despite the WHO goal, adopted in 2015, of reducing malaria deaths by 90 per cent by 2030.
In short, says Jeff Chertack, senior programme officer at the Gates Foundation, ‘We can’t rely on the tools we have today to end malaria. We need new tools with a longer duration and increased effectiveness in difficult settings.’
One could be the development, after decades of research, of an antimalarial vaccine called RTS,S, but it has to be taken in four doses over many months and has a low success rate. The other is the new method of attacking the mosquito pioneered at Imperial by Profs Burt and Crisanti: gene-drive technology.
In 2000 Prof Crisanti, an Italian in his early 60s, became the first scientist to insert engineered genes into malarial mosquitoes, though at that stage all they did was turn the mosquitoes’ eyes a fluorescent green to show that the technique worked in principle. Three years later, Prof Burt, a Canadian in his mid-50s who moved to Britain from California in 1995, published a Royal Society paper suggesting that Dnacutting enzymes could be used to develop a gene-drive technology that could be deployed against those mosquitoes.
The idea was to use a synthetic gene to cut a mosquito’s DNA sequence at a precise point and paste itself into the gap, thereby replicating itself in both the mosquito’s relevant chromosomes so it is bound to be passed on to the insect’s progeny. Normally genes stand a mere 50/50 chance of being passed on.
The two men began to collaborate, and they were helped enormously by the subsequent development of CRISPR, a revolutionary gene-editing tool that made it far easier to produce the required enzymes.
The mosquito may be just a few millimetres long, but it is man’s deadliest enemy
The Imperial team is targeting just three of the 3,500 species of mosquito – anopheles gambiae, coluzzii and arabiensis, which spread malaria in sub-saharan Africa. It is exploring the use of genes that will either reduce the females’ fertility, or ensure that their progeny are predominantly male (only females bite humans). Mosquitoes reproduce rapidly, so those genes could cascade through a mosquito population in a couple of dozen generations, or less than two years.
This ‘population suppression’ effectively reverses the evolutionary process, which normally favours genes that help a species survive. It would implant genes designed to do the exact opposite. ‘It’s like a genetic disease of the mosquito. It’s spreading despite the harm it’s causing to the mosquito,’ Prof Burt tells me in his office on Imperial’s Silwood Park campus, near Ascot.
Unlike conventional measures to combat malaria, it would be simple, self-sustaining and relatively cheap. It would not require a functioning health system, political stability or government funding to work. ‘It takes human frailty out of the equation, and humans are the weak point in fighting malaria,’ says Prof Crisanti in his South Kensington office. Prof Burt’s team has already created infertile mosquitoes in the Insectary, and ones that can only breed males. It is now grappling with the problem of their evolving resistance to genetic alteration. It also has to find ways of crossing its lab mosquitoes with wild ones, and to that end has built a large lab in Terni, Italy, that mimics the climatic conditions of sub-saharan Africa.
It intends to stage trial runs with risk-free mosquitoes. It needs to study how fast and far the synthetic genes would spread in natural conditions, and whether that spread could be contained or reversed if necessary. It is working closely with authorities and local communities in three African countries – Burkina Faso, Mali and Uganda – where, with their permission, it eventually hopes to release several bucketfuls of genetically modified mosquitoes in villages 10 or 15 miles apart.
But that will not happen soon. Prof Burt says there is still a ‘long slog’ ahead. He reckons it will be 2023 before Target Malaria is ready to seek approval for deploying its gene-drive mosquitoes. And that could well be where the real battle begins. ‘If you asked me 10 years ago I’d have said the science was the harder problem. Now I think the biggest roadblock is getting the technology in the field,’ says Prof Crisanti.
The first problem is the lack of a supranational regulatory authority for a technology whose impact will ignore national boundaries: if genedrive technology works, the genocidal mosquitoes will spread rapidly across Africa. Burt says Target Malaria is encouraging the African Union to explore the issues involved with its member states. The United Nations Convention on Biological Diversity is also seeking to draw up rules.
The second is the growing opposition of environmentalists to gene-drive technology. They fret about the elimination of entire species, the damage that could do to ecosystems, and the possibility that other harmful species could fill the
ensuing void. They worry that gene drives could jump across species, or cause dangerous mutations and other unforeseen consequences.
The environmentalists’ concerns are not limited to the elimination of anopheles mosquitoes. They say that gene-drive technology could be used against any species that reproduces sexually and fast, and that is deemed to be a nuisance: worms, pests, ticks, rodents, invasive fish. They fear that it could be exploited for commercial gain by the giants of industrial agriculture, or used by rogue states to create mosquitoes that produce toxins or spread designer plagues. That scenario is not entirely far-fetched. In 2016 James Clapper, then US director of national intelligence, added gene-drive technology to a list of threats posed by ‘weapons of mass destruction and proliferation’. The US Defense Advanced Research Projects Agency (DARPA) has reportedly invested $100 million in gene-drive research.
‘The application of such irreversible and risky technology should have global oversight and a requirement for transparency that doesn’t exist at the moment,’ says Perls of Friends of the Earth.
‘Target Malaria should prepare itself for a great deal of robust interrogation and resistance,’ adds Mariam Mayet, executive director of the African Centre for Biodiversity. She calls it a ‘neocolonial project designed and conceived in the West and telling us what’s good for us’.
Ali Tapsoba, head of an organisation called Terre à Vie in Burkino Faso, told me, ‘There are so many unanswered questions ahead of us that we do not accept gene drives. We have our own know-how to solve our health problems. Our forests are full of healing plants and we would prefer to have a good policy for the hygiene and sanitation of our environment rather than leaping towards the unknown.’
Prof Burt, whose gene-drive project is the world’s largest, certainly does not dismiss these concerns, though he believes some are unwarranted. He says the anopheles mosquito plays no key role in any ecosystem, and that using gene drives for terrorism would be extremely difficult.
He insists that Target Malaria, a non-profit organisation, is advancing cautiously, consulting widely and being as transparent as possible. Its job is simply to develop the tool and let others decide whether to use it, he says. ‘It’s not up to me or Imperial College whether to release these mosquitoes. It’s up to the Africans to decide.’
Prof Crisanti ‘strongly believes that this technology will help mankind to eliminate malaria’, and sees no problem with humans destroying species of mosquito to achieve that goal. ‘We are part of this complex system of life on earth. We’re in competition with the mosquito. If we use our brains that’s part of the evolution game. Why do we have to introduce a moral component?’
Of gene-drive’s critics, he says, ‘They mostly sit in comfortable offices in San Diego or San Francisco. I’d like them to live in the bush in Africa where malaria is a problem every day. I think the decision whether to use this technology or not should be left to the people who have the problem.’
They also need to consider the alternative, Prof Crisanti suggests: ‘What about the moral issue of doing nothing and leaving all those people dying of malaria?’
Bill Gates made a similar point in a recent Reuters interview. ‘Malaria itself is quite controversial. It kills about 400,000 kids a year,’ he noted. At a forum on the subject earlier this year, he described seeing a child convulsed with seizures in a Tanzanian hospital. ‘With the state of science and the wealth of the world, that should really be an affront. We really shouldn’t accept that this disease can continue.’
‘Target Malaria is a neocolonial project designed in the West, telling us what’s good for us’
A mosquito draws blood from a human
From left Professors Andrea Crisanti and Austin Burt; screening genetically modified mosquito larvae at Imperial College; Anopheles gambiae mosquitoes.