Jul 17 2023

Using Genetic Engineering To Fight Malaria

Despite robust efforts to fight it, malaria remains one of the most significant infectious diseases affecting humans. According to UNICEF – ” In 2021, there were 247 million malaria cases globally that led to 619,000 deaths in total. Of these deaths, 77 per cent were children under 5 years of age.” Efforts to minimize malaria cost about $7 billion per year, through vaccination, drug therapy, and spraying pesticides to kill the mosquitos that carry the disease. Mosquito populations are developing resistance to the pesticides, however, which could raise the costs of control, while available funds can fluctuate.

One potential solution is using genetic engineering to fight malaria, and there are several approaches being developed that are close to being ready for deployment. They all use an approach known as a gene drive, which causes a desired trait to spread more quickly through a population than regular Mendelian genetics would allow. This idea is actually 60 years old, but newer techniques, such as CRISPR, are making it much easier and more powerful.

With sexual reproduction, each offspring has two sets of chromosomes, one from each parent. So organisms have two copies of each gene (each copy is called an allele). They then pass one of their two copies onto each offspring. Mendelian genetics assumes that there is a 50% chance for each allele to be inherited, and this is mostly true. The gene drive phenomenon refers to situations in which one allele has an advantage over the other, so it is more likely to be inherited. There are naturally occurring gene drives, but we’re going to focus on the latest synthetic gene drive, which involves CRISPR.

As a reminder, CRISPR is the latest technique for altering or inserting genes into DNA. The CRISPR component can target a specific sequence of DNA, and it is attached to another element (such as Cas9) which then makes a cut at the desired location. Normal cellular DNA repair then fixes the cut, inserting the desired sequence in the process. The CRISPR-Cas9 system is quick, cheap, and easy resulting in nothing less than a revolution in genetic engineering and research.

Some recent gene drive systems incorporate CRISPR. Essentially they include a CRISPR-Cas9 sequence in an allele, which then automatically inserts the desired genetic sequence into the inherited allele. Therefore spread of the desired gene is not left to chance, but is engineered to spread rapidly through a breeding population. This works particularly well in a rapidly reproducing species like mosquitos. Recent research shows that this approach is highly effective, with the desired alleles spreading through a test population at >90% in just 3 months.

So what genetic modifications are researcher thinking of driving through the mosquito populations that spread malaria? There are about 3,000 species of mosquito, and only a few of which spread malaria to humans. So one idea is to reduce or even eradiate those species using a gene drive approach (the same goal as using pesticides, but with much greater precision). There are two basic approaches to achieve this goal that I have seen. One is to spread a gene that renders the offspring sterile. A more recent approach is to spread a genetic modification that prevents offspring from developing along the female pathway, so essentially all offspring are male. This has two benefits. First, only the female mosquitoes bite humans. So a mostly male population would spread malaria much less. But also, with fewer females, this would drastically reduce the overall population.

Another approach is to spread genes which counter resistance to pesticides. This can help maintain the efficacy of using pesticides to control mosquito populations. This seems like the least effective approach – just treading water with existing approached to control malaria.

The latest research sounds the most promising to me – using CRISPR-Cas9 gene drive to spread malaria resistance to the mosquito populations. Malaria is a parasite, a protozoa with four species affecting humans – Plasmodium falciparum, P vivax, P ovale and P malariae. The parasite infects and reproduces in humans, partly in the blood. When a mosquito feeds on the blood of an infected human they take in the parasite, but they are unaffected by it themselves. They then spread the parasite to the next human that they bite. The mosquitoes themselves are under no selective pressures to evolve resistance to the malaria parasite because it does not negatively affect them.

Therefore, instead of trying to kill the carrying mosquitoes, we can CRISPR them to have resistance to the malaria parasite. Instead of spreading the protozoa, they will kill it. The introduced genes are for monoclonal antibodies which will attack the Plasmodium. In the recently published study, the gene drive did not affect the fitness of the alteredĀ Anopheles coluzzii mosquito but did reduce the fitness of Anopheles gambiae who were less competitive than the wild types (not ideal but not a deal killer).

The next step is to release altered mosquitoes into the wild and let the gene drive get to work. Ideally, within a few years the antibody producing alleles will spread widely in the mosquito populations, drastically reducing the spread of malaria. The only hurdle now is regulatory. The same bodies that regulate GMOs must review the data for safety, but also health organizations must also review the data and approve this approach as a health intervention.

I understand the caution over releasing genetically modified organisms into the wild, specifically ones that are designed to spread their genetic alteration through a population. The precautionary principle has its uses, but also has its limits. We need to consider the risk vs benefit alongside the risk of other approaches. In this case, what is the realistic risk of spreading a gene through a mosquito population that confers antibodies to malaria? It would involve something completely unanticipated. Further, how does this compare to the risk of not taking this step, allowing malaria to continue to cause human disease, and continuing with the program of pesticide use, which is becoming increasingly difficult?

Absolutely we need to do due diligence on this one. But if a thorough review of the evidence does not find any specific risk, I don’t think we should avoid using these gene drive approaches simply out of fear of the unknown. Also, as the technology develops, malaria may be just the first of many vector-spread human diseases that we could address with this approach. As a public health strategy, using gene drive technology to address vector-borne illness could be as huge as vaccines. I suspect, however, that it will also attract just as many conspiracy theorists.

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