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OUTLOOK 28 June 2023

How genetically
modified
mosquitoes could
eradicate malaria
Gene-drive technology that can spread
antimalarial modifications throughout
mosquito populations is maturing, but
there are questions to answer before it
can be used in the wild.

Sam Jones

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Altering the genes of mosquitoes could prevent

them spreading malaria. Credit: Target Malaria

Malaria has plagued people for millennia. It

is referenced in ancient texts and has even
been detected in Egyptian mummies that
are more than 5,000 years old. During the
twentieth century alone, 150–300 million
people died from the disease worldwide.
And although technological and medical
advances have significantly reduced deaths
over the past couple of decades, in 2021 an
estimated 619,000 people died from the
disease. African countries are hit the hardest
— the region is home to 96% of malaria
deaths, with 80% of these being in children
under five years old.

“It shouldn’t be acceptable that children still

die of malaria, that expectant mothers still
get complications due to malaria,” says
Jonathan Kayondo, a vector biologist at the
Uganda Virus Research Institute in Entebbe.

RELATED
Malaria is caused by
Plasmodium
parasites that are
transmitted from
person to person by
Anopheles
mosquitoes — often
Anopheles gambiae,
Part of Nature Outlook: the primary vector
Malaria
in sub-Saharan
Africa. Many
approaches to malaria control focus on
mosquitoes. Insecticide-treated mosquito
nets and indoor spraying of insecticides, for
instance, have played a massive part in
malaria reduction. But still it persists. “We’ve
had great success over the past 20 years,
using the bed nets and spraying, but those
tools are not going to be enough to
eliminate malaria,” says Gregory Lanzaro,
director of the Vector Genetics Laboratory
at the University of California, Davis.

Many researchers, including Lanzaro, are

hopeful that part of the solution lies in
altering the genomes of Anopheles
mosquitoes. Scientists around the world are
exploring how to make lasting changes to
mosquito DNA that impair the insects’
ability to transmit malaria — either by
making them less hospitable hosts to
Plasmodium, or by interfering with their
reproduction to reduce or eliminate
mosquito populations. Interventions of this
kind have been in development for decades,
but their use in the wild could be now just
years away. Ecological and ethical concerns,
however, about how these modified
mosquitoes will be monitored, and by
whom, remain the subject of active and
contentious conversation.

A long history
Since the 1950s, researchers have
experimented with using radiation to
damage the DNA of male mosquitoes. The
intention is to render the insects sterile and
unable to reproduce in the wild, and thereby
reduce the number of potential disease
vectors. More targeted molecular
approaches, such as those undertaken by
the biotechnology company Oxitec in
Abingdon, UK, have been used to engineer
Aedes aegypti mosquitoes — a species that
transmits viruses such as Zika and dengue —
that produce female offspring that die
before they reach adulthood. This
intervention could temporarily suppress
wild mosquito populations by up to 96% in
some regions1.

So far, these efforts have not had much

success. One obstacle is finding a good
genetic target, says Maria Luisa Simoes, a
malaria researcher at the Institute of
Tropical Medicine Antwerp in Belgium.
Genes often have multiple functions, so a
well-intentioned change — such as deleting a
gene that helps Plasmodium to thrive in a
mosquito’s gut — could have undesirable
effects that make the modified mosquitoes
unable to compete with their wild
counterparts, and therefore unable to
spread their genes. “The ones that are in the
field have been there for millions of years,”
says Simoes. “If you are releasing a mosquito
that is already kind of weak, it will not make
it.”

Members of the Target Malaria team trial release

methods for mosquitoes in Burkina Faso. Credit:
Target Malaria

A bigger problem, however, is that the

effects of these interventions are typically
only temporary. When a modified mosquito
mates with a wild mosquito, only about half
of the young will inherit the modification.
Over generations, each of which lasts just a
couple of weeks for wild mosquitoes, the
number of insects with the modification
would dwindle. For genetically-modified
mosquitoes to make a sustained impact in
the wild, the chances of them passing on the
modification needs to be more than the
usual 50%. Enter, gene drive.

Gene drive was first proposed decades ago,

in the context of naturally occurring selfish
genetic elements — portions of DNA that
enhance their own transmission. One
example is sequences of DNA called
transposable elements. These are present in
a wide range of organisms, including
humans. Transposable elements can
replicate on their own and integrate
throughout an organism’s genome, causing
them to be passed on to offspring at rates
much higher than 50%.

The idea of using these portions of DNA to

spread genes throughout a population of
disease vectors, such as mosquitoes, was
first proposed in the early 1990s2. However,
researchers hit a problem: transposable
elements would sometimes land in
unfortunate places in an organism’s
genome. The consequences of interrupting
an existing genetic sequence by adding
transposable elements can vary from the
benign — changes in pigmentation in the
medaka fish (Oryzias latipes)3, for example
— to the decidedly harmful. In humans,
transposable elements that insert
themselves into certain genes are linked to
the blood cancer acute lymphoblastic
leukaemia, as well as the bone-marrow
condition Fanconi anaemia4. The problem
for researchers working on mosquito
control was that the transposable elements
would land somewhere in the insects’
genome that was immediately lethal,
preventing the modification from being
passed on. “We were working with that and
we were just getting clobbered,” recalls
molecular geneticist Anthony A. James at
the University of California, Irvine.

After decades of trying to improve the

insertion of selfish genes, the advent of
CRISPR–Cas9 genome editing in 2012 finally
gave scientists the tool they needed. These
molecular scissors can be used to precisely
place genetic sequences into the genome.
Researchers realized that if CRISPR–Cas9
was incorporated directly into an organism’s
DNA, it would allow a gene to be safely
copied from one generation to the next in
perpetuity (see ‘Engineering the odds’).

Credit: Alisdair MacDonald

In 2015, researchers at the University of

California San Diego were the first to use
CRISPR–Cas9 to create a gene drive in an
insect — the fruit fly5. Just months later, they
teamed up with James and other colleagues
to develop a gene drive in Anopheles
stephensi mosquitoes6. A team in Europe
soon followed with a gene drive in A.
gambiae7.

Replace or suppress
Scientists across the world are now working
to develop gene drives in mosquitoes to
stem the transmission of malaria. What
particular gene mutations the mosquitoes
will carry varies depending on the
researchers’ aims, and whether their goal is
to replace Plasmodium-carrying Anopheles
mosquitoes with those that cannot carry the
disease, or simply wipe out this type of
mosquito altogether.

Tibebu Habtewold, a malaria researcher at

Imperial College London, is pursuing a
population-replacement approach, in which
modified mosquitoes spread a desired
mutation throughout the wild population
until only modified mosquitoes remain.
Originally from Ethiopia, Habtewold is
currently working with the global scientific
programme Transmission Zero in Tanzania.
The goal is to introduce mosquitoes that
have been genetically modified to produce
two antimicrobial compounds in their gut
that block the transmission of Plasmodium
— one is found in skin secretions of the
African clawed frog (Xenopus laevis) and the
other is a toxin of the European honey bee
(Apis mellifera). In these modified
mosquitoes, which have been shown to be
successful in the laboratory8, the
antimicrobials delay the early-stage
development of multiple species of
Plasmodium. They probably do this by
interfering with the function of the
mitochondria, preventing the parasite
developing to the point at which it can infect
people.

In March, Transmission Zero announced

that it had introduced these genetic
modifications, without the gene-drive
element, into Tanzanian A. gambiae — the
first time a transgenic mosquito strain has
been made in Africa. Using mosquitoes from
the region where malaria is present is
important. “It should be local strains,” says
Habtewold, because even small differences
between the genomes of laboratory
colonies and wild mosquitoes could
interfere with the gene drive.

Simoes is also interested in introducing

modified insects that are less welcoming to
Plasmodium than wild mosquitoes. She is
hoping to achieve this by tinkering with the
immune system of Anopheles. Wild
mosquitoes are able to control the parasites
enough to live through the infection, but
not enough to prevent it from being
transmitted to people. Simoes is looking for
ways to alter the gene expression of
mosquitoes to allow their immune systems
to go further and wipe out the parasite. Last
year, Simoes and her colleagues used
CRISPR–Cas9 to delete the gene CTL49. This
gene is known to have a role in mosquito
immunity, and the researchers found that
the modified mosquitoes were highly
resistant to Plasmodium, decreasing the
likelihood that the parasite would survive
and spread to people.

Malaria researcher Tibebu Habtewold collects

transgenic mosquitoes in a purpose-built facility
in Bagamoyo, Tanzania. Credit: Tibebu
Habtewold

This mutation has yet to be combined with a

gene drive. However, another genetic
modification that makes mosquitoes
resistant to Plasmodium has. James and his
team have combined a drive with genes for
antibodies that target the parasite, and this
has been shown to reduce mosquito
infection10. This type of gene drive is now
being tested by the University of California
Malaria Initiative in Davis.

The non-profit research consortium Target

Malaria, which operates in Uganda, Ghana
and Burkina Faso, is taking a different
approach. Rather than replacing wild
mosquitoes with modified ones that cannot
spread malaria, they’re aiming to wipe out
Anopheles mosquito populations. This
could be done either by targeting genes that
affect a mosquito’s ability to reproduce, or
by skewing the female-to-male ratio so that
eventually there are not enough females to
sustain the population.

Kayondo, who leads the research for Target

Malaria in Uganda, wants to suppress
mosquito populations, in part, because he
worries that if mosquitoes are simply made
resistant to Plasmodium species, the
parasites could mutate and ultimately work
around their hosts’ bolstered defences. This
would land researchers back where they
started, or worse. “With replacement, in a
way, we are putting the pressure on the
parasite to do something,” he says. He also
points out that in places such as Uganda,
many other pathogens are circulated by
mosquitoes, not just Plasmodium. So even if
modified mosquitoes took over, they might
be vectors for some other disease.

James, however, thinks that population

replacement could be sufficient. Even if a
population of A. gambiae was highly
suppressed in a region, he says, it could
always come back. In an ideal scenario,
James sees replacement and suppression
being used in tandem.

For now, mosquitoes containing a gene

drive cannot be released outside of the
laboratory. If and when approval is given,
field trials will bring a whole host of
challenges that don’t exist in a lab setting,
including predators and insecticides. A 2019
pilot study by Target Malaria in Burkina Faso
released male mosquitoes that had been
genetically modified to be sterile, but did
not include a gene drive. It found that the
modified insects had lower survival rates
and were less mobile than their non-
modified counterparts11.

The bigger picture

As researchers continue to ready modified
mosquitoes for release, a number of ethical
and environmental considerations are
coming to the fore. For Michael Montague, a
biosecurity researcher at the Johns Hopkins
Center for Health Security in Baltimore,
Maryland, a crucial question is who will be
responsible for the technology once it is in
the wild. Gene drives are durable by design.
“It won’t wash away in a few generations,”
says Montague. Self-limiting or reversible
gene drives are being explored, but this
work is at a very early stage. As things stand,
Montague says, those who take the step of
releasing mosquitoes with a gene drive must
commit for the long haul. “The only way you
can manage the risk of something like this is
to keep your hand on the wheel,” he says.

That could become particularly

complicated if researchers in one country
introduce mosquitoes with a gene drive into
another. For example, if a US team released a
gene drive in sub-Saharan Africa, Montague
says, the local people would be dependent
on them managing it for hundreds of years.
“That sounds like colonialization,” he says.

This is partly why Habtewold feels so

strongly about building capacity to create
and manage modified mosquitoes in
Tanzania. In Africa, he says, “people are a bit
nervous with northern, white scientists
developing something and telling black
scientists in Africa to take it”. By developing
the science locally, with African scientists,
Habtewold is hoping that the local people
who stand to benefit the most from the
elimination of malaria will be receptive to
the use of gene-drive technology to do it. “I
believe, as an African, if you want to go any
further with gene drive that’s the way
forward,” he says.

RELATED
Lanzaro and his
colleagues, who are
hoping to one day
help to introduce
mosquitoes with
More from Nature gene drives in Sao
Outlooks
Tome and Principe,
also understand
how crucial local engagement is for a
project to be successful. The researchers
have been working on the island of Sao
Tome since 2018, establishing relationships
and trust with local citizens, government
officials and health-care workers. Ana
Kormos, programme manager at the
University of California Malaria Initiative,
frequently travels to Sao Tome, and says
that it is essential that the people who will be
affected play a part in the development
process and ultimately decide whether to
use gene-drive technology on the island.

Researchers are also questioning how

mosquitoes with a gene drive could affect
the ecosystems that they are a part of. Talya
Hackett, an ecologist at the University of
Oxford, UK, who works with Target Malaria,
is assessing A. gambiae’s place in the food
web in Ghana. “We’re looking to see if there’s
anything that really is getting a large
amount of its diet from Anopheles gambiae,”
says Hackett. She doesn’t think that will be
the case. “There are not really any species
that are expected to feed predominantly on
one species of mosquito.”

She and her colleagues are also investigating

whether the suppression of A. gambiae
could lead to an increase in other competing
insect populations, and if the mosquitoes
play a part in pollination. Both male and
female insects do feed on flower nectar, but
Hackett says that the data so far show that
mosquitoes don’t particularly interact with
pollen. “They’re basically nectar robbers,”
she says.

Hackett is optimistic about a population-

suppression approach, partly because the
ecological data look good, but also, she says,
because it would target just one species of
mosquito, unlike current broad-spectrum
insecticidal toxins that are used for
mosquito control. Those chemicals, she
says, are not species specific. “As an
ecologist, I’d say they have a huge amount of
unintended consequences.”

Many researchers are hoping that

mosquitoes with a gene drive will be used in
the wild in a matter of years, not decades.
But Kayondo warns against thinking that it’s
all that will be needed. “Those who think
gene drive is going to be a silver bullet, I
think they just haven’t seen how these things
have gone,” he says, referring to the rise of
insecticide and antimalarial drug resistance
(see page S26). “The mosquitoes and the
parasites, they will fight back.” It seems likely
that insecticides, antimalarial drugs and
vaccines will all have a part to play in malaria
elimination. But, it could be gene drive that
ultimately tips the scales in our favour, says
James.

Nature 618, S29-S31 (2023)

doi: https://doi.org/10.1038/d41586-023-
02051-4