Buzz kill

Does the answer to erad­i­cat­ing malaria – the big­gest killer on the planet – lie with gene edit­ing its mosquito car­ri­ers? Martin Fletcher in­ves­ti­gates

The Daily Telegraph - Telegraph Magazine - - Contents -

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

Pho­to­graphs by Richard Ansett

From left Pro­fes­sors An­drea Crisanti and Austin Burt; screen­ing ge­net­i­cally mod­i­fied mosquito lar­vae at Im­pe­rial Col­lege; Anophe­les gam­biae mos­qui­toes.

Newspapers in English

Newspapers from UK

© PressReader. All rights reserved.