Malaria. When we hear this word, we instantly picture people dying. We see malnourished children and poverty. This is one of the deadliest diseases in the world, affecting 220 million people every year and killing 400,000 .
How does Malaria work?
Malaria is caused by the plasmodium parasite. Mosquitoes infected with the parasite bite humans, infecting humans’ liver and red blood cells, compromising the immune system. Then another mosquito bites the person, carries the virus, and spreads it to more people and so on . There have been many past medications to treat Malaria but all of them have only achieved limited, if any, success. Malaria is most common in sub-Saharan Africa, but also is prevalent in South Asia, the Middle East, and other countries with large mosquito populations .
In recent years, CRISPR gene drives have been an area of interest in the realm of malaria treatment.
What is CRISPR?
As you may know, CRISPR is a gene editing technology that can be thought of as a copy and paste for genes. CRISPR has had a significant impact on cancer treatment and other medical innovations. In fact, Jennifer Doudna and Emmanuelle Carpentier won the Nobel Prize this year for CRISPR research. It has recently been a subject of research for Malaria cures.
How does CRISPR work?
CRISPR deploys an enzyme called Cas9 to cut DNA strands. Cas9 will cut pretty much any DNA. However, its specificity comes from guide RNA, also known as gRNA. Cas9 interacts with gRNA, which binds to DNA through base pair matching. When the gRNA binds to the DNA strongly enough, the DNA is cleaved by Cas9 [3, 4]. For Malaria, CRISPR is proposed to be utilized in the form of gene drives. Gene drives are a relatively new topic and it is an open area of research with limited literature. But let’s talk about what we know.
What are gene drives?
Gene drives utilize CRISPR to insert and spread genetic modifications through a population at an abnormally high rate. The gene drive will be engineered into an organism’s genome. The offspring will then inherit one chromosome from the gene drive parent and another normal one. During early development, the CRISPR portion of the drive finds and cleaves the normal gene out of the normal chromosome. The drive gene is then used as a template to synthesize a complementary strand on the formerly normal gene. This leads to the offspring inheriting two copies of the modified gene .
Since 2014, scientists have engineered CRISPR-based gene-drive systems in mosquitoes, fruit flies and fungi, and are currently developing them in mice . Trials with mammals generally report a 70-75% success rate in accurate gene drive copying . Although there is much research necessary, gene drives are on the path to success.
How do CRISPR gene drives impact malaria treatment?
There are 2 main proposed ways to insert gene drives into the mosquitoes.
First, population control. This is where the drives are designed to spread female infertility due to alteration of the doublesex gene, where female mosquitoes cannot reproduce and thus cannot spread the plasmodium parasite throughout the population. This is strategic because it will drastically reduce mosquito population, mathematically reducing risk of contracting malaria .
The other approach is alteration. This is where the drives are designed to make mosquitoes resistant to the plasmodium parasite, thus not getting infected at all. These are strategic because they eliminate the spread of plasmodium, rather than just reduce mosquito population .
Let’s contrast standard inheritance and gene drive inheritance to recap. In standard inheritance, offspring get one copy of each parent’s chromosome, leading to a 50% chance of inheriting the mutation. With gene drives, the gene is present on both of the inherited chromosomes, leading to 100% chance of inheritance . As you can see, gene drive inheritance is far more efficient to spread a mutation across a population.
Where are we now in the development of this treatment?
The World Health Organization has outlined a path of progression for CRISPR malaria treatment.
The first stage is the laboratory. This is where gene drive research is now. This is where gene drives are being tested in a laboratory setting without being released anywhere .
The second stage is field testing. This is important because to ensure gene drives will actually work, they have to be tested outside of the lab setting, possibly in a large cage or island. Researchers report that they should be ready for this phase soon, in the next 1-5 years .
And then phase 3, coordinated releases. This is where the gene drive mosquitoes are released and observed while scientists will make changes if needed .
In order to do this, there are many steps to be taken. To begin with, countries with high malaria prevalence should develop insectaries. Tests should also be simulated with non gene drive mosquitoes before gene drive mosquitoes. This is to accurately get an understanding of the process.
The exciting future of gene drives
CRISPR gene drives are a very promising cure for malaria reduction. Since this is an active and novel innovation with great potential, more research should be coming. We should all be very optimistic about the future of CRISPR gene drives as a viable measure for malaria prevention.
 Mayo Clinic, . “Malaria.” Mayo Clinic. Mayo Foundation for Medical Education and Research, February 3, 2021. https://www.mayoclinic.org/diseases-conditions/malaria/symptoms-causes/syc-20351184#:~:text=Malaria%20spreads%20when%20a%20mosquito,and%20infect%20red%20blood%20cells.
 Roser, Max, and Hannah Ritchie. “Malaria.” Our World in Data, November 12, 2019. https://ourworldindata.org/malaria.
 PLOS. “Safer CRISPR Gene Editing with Fewer off-Target Hits.” ScienceDaily. ScienceDaily, July 9, 2020. https://www.sciencedaily.com/releases/2020/07/200709141619.htm.
 Walsh, Michael. “How Can CRISPR Genome Editing Shape the Future of Cancer Research? - Cancer Research UK - Cancer News.” Cancer Research UK - Science blog, April 12, 2021. https://news.cancerresearchuk.org/2018/01/12/how-can-crispr-genome-editing-shape-the-future-of-cancer-research/.
 Empinado, Hyacinth. What Is a Gene Drive? YouTube. YouTube, 2015. https://www.youtube.com/watch?v=75iP50LEHrU.
 Scudellari, Megan. “Self-Destructing Mosquitoes and Sterilized Rodents: the Promise of Gene Drives.” Nature News. Nature Publishing Group, July 9, 2019. https://www.nature.com/articles/d41586-019-02087-5.
 Fong, Joss, and Matthews, Dylan. The Bold Plan to End Malaria with a Gene Drive. YouTube. YouTube, 2018. https://www.youtube.com/watch?v=P0HPHUzsHbI.