In 2018, there were 228 million cases of malaria worldwide. The overwhelming majority of those cases – more than 90% – were in sub-Saharan Africa, where the disease is endemic. Nearly half a million of those infected died from the disease.1
Those numbers are devastating, but that is still far fewer cases and deaths than there were in the early 2000s. "Beginning around 2010, there was a concerted effort led by numerous organizations, [including] the World Health Organization, to eradicate malaria from endemic countries," Stephanie James, PhD, Director of Science at the Foundation of the National Institutes of Health (FNIH), told ASH Clinical News.
The approach was multipronged – encouraging the use of bed nets and insecticides to prevent the spread of the mosquito-borne disease and providing access to appropriate antimalarial drugs to treat the illness. Although it was initially successful, progress on the initiative stalled in 2018. The techniques responsible for the progress of the previous decade no longer have the same impact on the parasites or on the mosquitoes who carry the disease.
Now, researchers are looking at a new technique to eradicate malaria: Engineering mosquitoes with a "gene drive" – a gene that when inserted into mosquitoes (or other organisms) will be passed on to nearly 100% of the offspring in the next generation, rather than just half the offspring – that rapidly spreads a mutation that removes the insects' ability to spread the malaria-causing parasite. This is still an investigational technique and one that has generated controversy.
"We have not yet reached the stage where we can release the gene-drive mosquitoes into the population," Charles Mbogo, PhD, Founder and President of the Pan African Mosquito Control Association (PAMCA), told ASH Clinical News. "But there are several other approaches, such as the sterile insect technique, that have been used in agriculture for many, many years and worked very well."
ASH Clinical News spoke with Drs. James and Mbogo, as well as other scientists working in the field of infectious disease and gene editing, about innovative – and controversial – efforts to control this bloodborne parasitic disease.
Old Problems, New Solutions
Controlling malaria today is quite challenging, and many of those challenges are a result of resistance that has evolved to the methods that worked in years past. For example, malaria-transmitting mosquitoes are no longer susceptible to some of the pesticides used to keep them out of homes and beds. The malaria parasites have developed resistance to some of the drugs used to treat patients once they contract the disease. Bed nets were once a highly effective intervention, but now malaria-transmitting insects have started biting earlier in the evening before people go to bed, or later in the morning after they have risen.
"It's widely recognized now that we need new tools for malaria control to overcome these issues," said Dr. James, who works on the FNIH's GeneConvene Global Collaborative, a project to determine best practices for using gene editing to improve public health.
In addition to these biologic problems, Dr. Mbogo said, "our health systems are not strong enough to diagnose malaria." He explained that some of the cases are occurring in rural areas, where there is no electricity, making examination of blood smears under microscopy virtually impossible. "Countries are now trying to use rapid diagnostic tests in those areas, but because of the financing – which is another major challenge – some of the countries may not be able to afford [to test people] all across the country," he said.
Clinicians and researchers in malaria-endemic sub-Saharan Africa are also fighting another disease: sickle cell disease (SCD).2 While the heterozygous trait for sickle cell may confer some protection against severe malaria, when patients with homozygous SCD are infected with malaria, they tend to have poor outcomes. Malaria parasites infect the red blood cells and cause a host of hematologic complications that can be especially detrimental to people living with SCD, including severe anemia and thrombosis. Thrombocytopenia also is a well-documented and frequent complication in malaria – occurring in an estimated 50 to 80% of patients.
Gene Drive Goals
Rather than focusing on patient-level interventions, investigators are now targeting the source of the infectious parasite – the mosquitoes themselves. "There is a widespread call for development of innovative new tools," said Dr. James. "We think that genetically modified, and specifically gene drive–modified mosquitoes, have an important role to play there. Because the preventive measures are actually carried by the mosquitoes themselves, it would protect everyone living in the region regardless of their access to medical care."
Genetically modifying one mosquito won't change malaria prevalence, so scientists need to create a gene drive. While gene drives sometimes occur naturally, advances in gene editing have made it easier than ever to develop gene drives quickly and efficiently.
Researchers have identified two potentially powerful ways to use the gene drive to minimize the effects of malaria in sub-Saharan Africa, one that suppresses the population and one that modifies the population, Dr. Mbogo explained.
In the first approach, scientists insert a self-destructive gene into the population that causes the malaria-transmitting species of mosquitoes to die out. The other idea is to use a gene drive that makes mosquitoes incapable of transmitting disease; in one example, Italian researchers inserted a mutation that alters the organism's mouth so it cannot bite humans.3 By genetically modifying the mosquito population, the vector isn't killed, but it becomes unable to transmit disease, Dr. Mbogo said.
The gene-drive idea is about 70 years old, said Michael Santos, PhD, GeneConvene Director and Associate Vice President of Science at FNIH. "The drive is a naturally occurring phenomenon but engineered gene drives have never been introduced into any wild population," he said.
"[Gene drive approaches] would protect everyone living in the region regardless of their access to medical care."
â€”Stephanie James, PhD
These approaches are being explored entirely in the lab, Dr. Santos added. "There's laboratory work on both of these kinds of approaches that have demonstrated that, at least in principle and under laboratory conditions, it is possible to accomplish those goals at high enough rates that they could [have an impact] on controlling malaria rates in the field."
Labs around the world have designed studies to at least partially mimic the environment in which the mosquitoes will eventually be released. For example, in the Italian experiment, researchers created a hot, humid lab and fed genetically modified mosquitoes warm cow's blood to test a gene drive that caused mosquitoes to become sterile and unable to bite. The study showed that the gene was likely to disappear within 3 years of being introduced, meaning its impact on the overall environment might be temporary.4
In experiments in a London lab, researchers were able to develop a gene drive that eliminated the population of mosquitoes in a cage after 11 generations by guaranteeing mostly male offspring (only female insects transmit malaria).5
Risk Versus Reward
These scientific developments have been met with pushback about unforeseen effects on the environment. Typically, scientists try to prevent genetically engineered organisms from spreading their mutations; with gene-drive approaches, wide spread of the mutation is the goal.
Environmental groups criticized a September 2019 project led by the research consortium Target Malaria, in which a group of 10,000 genetically modified sterile male mosquitoes were released into a small village in Burkina Faso.6 Researchers tracked the insects for a year to understand how they would interact with the natural environment upon release, and in the end there weren't enough mosquitoes to spread their genes to the entire population of mosquitoes in the area.
There are myriad concerns about genetically modifying an organism in such a way that the gene will permeate the species, and then releasing it into the wild. "Those include risks to biodiversity, risks to ecosystem diversity and pollination, or even risks to human and livestock health – for example, changes in the fitness of the mosquitoes to be able to carry other diseases," said Dr. Santos.
To help minimize known and unknown risks of gene editing, scientists are also designing controls to keep the experiment from running amok. For instance, in the Italian experiment, investigators engineered the genes to lose potency over time.
"The research community is very aware of those concerns and is working hard to address them," Dr. James added.
From the Lab to the Field
Drs. James and Mbogo were part of an international working group that described a pathway to safely test the gene-drive mosquitoes.7 These recommendations include completing laboratory and cage experiments, identifying potential risks, mathematically modeling different outcomes and conducting limited releases in geographically isolated areas. The working group also emphasized the need for transparent testing strategies, plans to mitigate damage, and self-limiting gene drives.
"It is important to recognize this is a proposed pathway," Dr. James said, but eventually, regulators will decide what scientists can and cannot do.
In the U.S., gene drives would need oversight and involvement by biosafety and health authorities. For example, in the U.S., since a gene drive acts on mosquitoes, it is most closely related to a pesticide, so it would likely fall under the Environmental Protection Agency's purview. However, because its hopeful outcome is to improve health, the FDA would need to be involved, as well.
A gene drive presents the type of scientific scenario that can instill fear in the general public – the kind with the potential to lead to a cascade of unforeseen changes in the environment – so the FNIH's GeneConvene Global Collaborative is working to ensure that any solutions are thoroughly vetted before being deployed into the world.
"The collaborative is intended to help the community address some of these important issues and challenges and develop a set of best practices and guidance that will help to ensure that this research is pursued responsibly and safely," Dr. James stressed. â€”By Emma Yasinski
- World Health Organization. Fact Sheet: Malaria. Accessed October 14, 2020, from https://www.who.int/news-room/fact-sheets/detail/malaria.
- Ferreira A, Marguti I, Bechmann I, et al. Sickle hemoglobin confers tolerance to Plasmodium infection. Cell. 2011;145:398-409.
- Stein R. Scientists release controversial genetically modified mosquitoes in high-security lab. NPR, February 20, 2019. Accessed October 14, 2020, from https://www.npr.org/sections/goatsandsoda/2019/02/20/693735499/scientists-release-controversial-genetically-modified-mosquitoes-in-high-securit.
- Pollegioni P, North AR, Persampieri T, et al. Detecting the population dynamics of an autosomal sex ratio distorter transgene in malaria vector mosquitoes. J Applied Ecol. 2020:57:2086-2096.
- Simoni A, Hammond AM, Beaghton AK, et al. A male-biased sex-distorter gene drive for the human malaria vector Anopheles gambiae. Nat Biotech. 2020;38:1054-1060.
- Diabate A. Target Malaria. Target Malaria proceeded with a small-scale release of genetically modified sterile male mosquitoes in Bana, a village in Burkina Faso. July 1, 2019. Accessed October 14, 2020, from https://targetmalaria.org/target-malaria-proceeded-with-a-small-scale-release-of-genetically-modified-sterile-male-mosquitoes-in-bana-a-village-in-burkina-faso/.
- James S, Collins FH, Welkhoff PA, et al. Pathway to deployment of gene drive mosquitoes as a potential biocontrol tool for elimination of malaria in sub-Saharan Africa: recommendations of a scientific working group. Am J Trop Med Hyg. 2018;98:1-49.