Jack may be young, but his field is younger still. Professor Emmanuelle Charpentier published a monumental discovery in 2011. In 2020, Professor Charpentier, along with Professor Jennifer Doudna, received the Nobel Prize for harnessing a bacterial tool capable of chopping up the DNA of invading viruses. This tool, called CRISPR/Cas9, combines molecular “scissors” capable of cutting out DNA with a guidance system that specifies which sections of DNA are to be cut.
Since then, the field has grown exponentially, with increasingly engineered versions improving on the original. Now, versions of CRISPR/Cas9 include base editors capable of changing a single letter of DNA and prime editors capable of changing a whole sequence.
“The CRISPR/Cas-based techniques we’re currently using were popularized around the time I was graduating high school,” explains Jack, “But since then, the platform has gone through six or seven monumental upgrades, yielding better editors all the time. Now we’re looking to see how we can tweak existing discoveries or start from the ground up to design new ones to suit particular diseases.”
As our understanding of these gene editing systems has progressed, so too has our ability to modify and tailor these tools for various applications. Scientists now have more ways to modify gene editing tools to be more efficient, precise, and, in some cases, more compact. The ability to optimize along these various parameters is especially critical for therapeutic applications of gene editing to treat or potentially cure human genetic diseases.
“In around a decade, we’ve gone from being able to change perhaps ten parameters to billions. You could waste a lot of time trying to screen billions to trillions of these optimisations. That’s where I can draw on the years of expertise our lab has gained, which helps me to navigate that landscape.
“Initially, the field had to poke around in the dark, but now there are massive data sets that allow us to make quicker and more informed decisions. We can design an editor that has the characteristics we want and is capable of targeting a specific change in the DNA. But to reach that end product, we have to go through a multi-stage selection process.
“We rule out sub-optimal options at each stage, iteratively honing our strategy through screening thousands of options until we settle on a final set of editing tools with the best combination of qualities for our particular application. After choosing an optimal variant, we make sure they behave properly in mice and cells derived from human patients with cardiomyopathies.”
Jack’s work in tailoring gene editors is a critical undertaking as the CureHeart team collectively work towards developing cures for inherited heart muscle diseases. To be successful as medicines, gene editors must be precise, efficient, and capable of safe delivery into cells. Given that inherited heart muscle diseases can arise from various mutation types across different genes, the ability to tailor gene editing tools is critical.
