I took a step towards eradicating malaria 🦟🥊

Crafting a futuristic cure for malaria through CRISPR-Cas9-based gene drives

Vector-borne diseases such as malaria are unquestionably some of the deadliest in the world.

The current cure? Next to nothing.

Here’s a thought- What if we… shift our focus?

➜ Instead of focusing on curing individuals, why don’t we edit the malaria right out of the mosquitoes?

But first, what exactly is malaria? 🤔

Malaria is a serious and potentially life-threatening disease that is caused by five different species of Plasmodium parasites. The most severe and deadly form of the disease is caused by Plasmodium falciparum. Though many myths do exist, the only way malaria can spread is through bloodstream transfusion- a fancier way of saying via mosquito bites.

Though many of us are fortunate enough to never have faced the fear of malaria, it’s unquestionably a HUGE issue. The World Health Organization (WHO) has identified malaria as a major public health problem causing hundreds of thousands of deaths each year.

WHO reports in 2022 state that malaria takes one life of child under the age of 8 every minute.

Being the most prevalent in tropical regions such as Southern Africa, India and the Middle East, malaria is renowned for sky-high mortality and morbidity rates. Being such a devastating disease, malaria can do severe damage such as commonly causing organ failure, seizures, and death.

With billions of deaths worldwide, it’s shocking that to this day, no concrete cure exists. Attempts to cure individuals such as vaccines and anti-malarial drugs have gone in vain. This is largely due to the devastatingly fast progression of this disease, the speedy reproduction rate of mosquitoes and the drug resistance of multiple malaria strands.

Knowing this, why can’t we editing the malaria out of the mosquito itself?

Using a gene-editing tool called CRISPR and the Cas9 enzyme, making mosquitoes malaria-resistant is actually possible. Furthermore, with the use of a phenomenon called gene drives, any edits made to a singular mosquito can be passed on to offspring.

The above would be the most feasible solution, here’s a quick summary as to why:

1. Large, fast impact 🌎. Mosquitoes reproduce very quickly. Genetically changing their DNA to no longer carry malaria receptive genes will allow both them and their (~100+) offspring to be malaria-free.
2. Ethical 🩺. This would not harm the mosquito in any way. Editing their genetic sequences have no negative affect on them nor their ability to carry out normal functions.
3. Essential 🤲. Such a solution is absolutely needed. This entirely eliminates individuals from getting malaria- It’s a huge plus.

A little more depth on CRISPR and the Cas9 enzyme ➜

The entirety of this solution is based on the gene-editing tool, CRISPR and the Cas9 enzyme. In brief, CRISPR-Cas9 is a gene editing technology. It allows precise changes to be made to the DNA of living organisms, including humans, plants and even mosquitoes. CRISPR-Cas9 system is based on a bacteria which is fully equipped with a natural defense system.

By using guide RNA (gRNA), the CRISPR-Cas9 system can target a specific sequence of DNA, and then the Cas9 enzyme cuts the DNA at that precise location. As a whole, this allows us to add, remove, or replace specific genes or DNA sequences from organisms.

A diagram demonstrating how the Cas9 enzyme and gRNA are placed in an ongoing sequence. This placement is required for precise edits and sequence bonding in the DNA.

For a more depth, reference my previous article: https://harini-saravan.medium.com/crispr-cas-9-the-molecular-%EF%B8%8F-of-the-body-72ac47937d4d

And what are gene drives?

Gene drives are a tool made through the intersection of genetic engineering and inheritance studies. This technique enables a particular trait/gene to be spread rapidly throughout a population and selected for in an individual's offspring, many times with the use of CRISPR-Cas9 technology.

The way gene drives work is through manipulating the CRISPR-Cas9 gene editing system to introduce the desired modification into the DNA of an organism. This is done by using CRISPR-Cas9 to introduce a new allele of a particular gene. Through this process, the allele is inserted/modified in a way which causes it to be passed on to the vast majority of offspring. With this new guarantee, a much larger population has the chance of inheriting desirable traits rather than the usual 50% or less chance during natural conception (based on inheritance patterns for typical Mendelian traits).

Once a gene drive is introduced into a population, it can have the potential to spread rapidly to the point of even dominating entire populations by completely altering their genetic makeup. This is undoubtedly useful as it has countless potential benefits from boosting disease resistance amongst a population, eliminating the disease-carrying ability of insects and even creating desirable traits in agriculture to produce higher/healthier yields.

A visual display of how gene drives influence offspring in a given population. In this given case, disease-resistant wheat crops (indicated in green) and their path of inheritance is represented in pedigree charts.

Now… How does this apply to malaria?

I’ll be explaining every part of my path to this solution thoroughly through the course of 3 stages; Research, Exploration and Creation.

Stage 1: Research 🧬

Initially, to come up with my base idea, I referenced back to a conversation I had with the CEO of SwitchHealth, Marc Thomson. While he was walking through his thought process when coming up with a new product he mentioned 2 key things; Need and Passion. In simplicity, this new product should have the ability to have a large impact (need amongst individuals) and you must be completely passionate about this product (love for learning, even through the hurdles.

With this in mind, I started brainstorming until I came upon malaria. A disease which affects so many people is devastatingly in need of a solid cure and, I’m wholeheartedly determined to learn about it.

Through the research stage, my main goals were to uncover all the pieces needed to form a possible cure, deeply understand the science behind all those pieces and make sure this was feasible IRL. Being domain-specific helped a ton in terms of clear, concise goals and learnings.

In brief, the main parts I set out to do deep learning on are the different strands of malaria, malaria’s composition, the science behind gene drives, filling the gaps in my biological knowledge on chromosomes, inheritance, alleles and the enzymatic background of editing mosquito DNA.

Here are some of my top ressources/references;

Gene drives gaining speed - Nature Reviews Genetics

Malaria

Plasmodium falciparum

CRISPR Gene Drives: Eradicating Malaria, Controlling Pests, and More

Stage 2: Exploration 🚀

After gathering my thoughts and developing profound background knowledge, I started exploring various platforms to construct my theoretical solution. I say theoretically as I’m not (yet!) able to perform such experiments in a lab. Due to this, making an online simulation was my next-best option.

In this simulation, I had the goal of getting as realistic, precise and visually coherent as possible so with that in mind, I started exploring some platforms. I quickly found Benchling, a platform used for biotechnology research. The learning process was undoubtedly hard as this part is where all the technicalities come into play.

As I kept trying different ways to receive my wanted outcome, I learnt that the gene sequence of a specific mosquito/malaria strand- Plasmodium falciparum Hb3 was available in Benchling. With this knowledge, I had everything set up to create my edits and back them up.

Stage 3: Creation 💡

To begin my simulation, I started by exporting a sequence of the Plasmodium falciparum Hb3 sequences into my workspace. As previously mentioned, there are 5 strands of malaria parasites, Plasmodium falciparum being the deadliest due to the long-term complications it causes to the bloodstream. I specifically chose this strand as it’s singlehandedly responsible for over 90% of fatal cases and overall morbidity.

I then inputted the needed information to make a cut:

1. The sequence is called Plasmodium falciparum
2. The specific gene number is Hb3
3. The enzyme cut with the highest chance of eradicating the malaria spreading trait is called TspRI
4. In one base-length strand, 2 overall cuts are made

An image of my simulation on Benchling demonstrating gene edits to the Plasmodium falciparum Hb3 sequence

Check out my video featuring a comprehensive guide to this project ➜

You’ve made it to the end! Thank you for reading :)

If you enjoyed this article, consider liking it and leave a comment!

Check out my other articles and LinkedIn @http://linkedin.com/in/harini-saravan! ♥️