DNA with two cuts, each with highlighted ends.

Can we treat diseases with Cas12a (CRISPR)? Modifying multiple genes.

A Swiss team figured out how to modify multiple genes in one cell using the gene-editing CRISPR system Cas12a. What do the findings mean for disease treatment strategies? Can we now treat diseases with Cas12a?

In May, during our Amsterdam S.H.I.T. Show, we talked about the gene-editing CRISPR-Cas systems and how they enable you to cut DNA almost anywhere you want. The tools promise great things for future disease-fighting! But we, of course, had to immediately poop all over the happy party and point out the many problems in our way of treating diseases with CRISPR-Cas. One of them is that many conditions, including cancer, result from multiple genetic events, which means we need to target or change several genes to treat the disease. We call these multifactorial or polygenic (multiple genes) disorders.

Well, while we were speaking, a team of Swiss researchers looked into just that – polygenic changes. The team managed to figure out how to modify multiple genes in a cell at the same time. The findings appeared in the scientific journal Nature Methods and showed how the researchers used Cas12a, a type of CRISPR-Cas that differs from the commonly used Cas9, to edit (mutate) or repress (silence) genes. 

What’s so special about Cas12a?

Let’s recapture: the CRISPR-Cas gene-editing tools rely on a so-called Cas protein that can cut DNA and a short molecule that guides the DNA-cutting protein to the right place on the cell’s DNA. Researchers commonly introduce a plasmid, a circular DNA molecule, that codes for the Cas protein and the guide. Notice that I wrote “the guide.” Meaning ONE guide that drags the DNA-cutting protein to one place of the DNA.   

With the recent findings, we can, for the first time, introduce a circular DNA that encodes SEVERAL guides. We no longer rely on one change at a time. In the true spirit of the 21st century, crank the volume up, and amplify everything at once; no patience is needed because more is finally more! 

Can we treat diseases with Cas12a?

As soon as the news got out, I received a message from a friend saying, “It seems like polygenic will soon be a non-issue.” And I must admit, they seem to have solved the polygenic targeting. Congratulations to the Swiss team!  

But as far as disease treatment goes (which I believe this friend referred to), I’m still wondering: are we there yet? Are we even close enough to the non-issue scenario? I feel like such a Grinch by just typing those questions [stop stealing the fun!]

Now, don’t take me wrong. I find the discovery super-exciting! I believe the new findings can improve research and are probably very useful for certain clinical therapies. For example, as the institute of the research team behind the study points out, the new approach has great potential to improve stem cell therapies. 

Researchers can use the new approach to edit, repress, or even activate multiple genes simultaneously. In other words, they can now manipulate genetic networks important for creating stem cells from normal cells (so-called reprogramming) or create normal (differentiated) cells from stem cells. [Actually, not a bad topic for later]. Why is this so great, you ask? Well, you can use the approach in replacement therapy to quickly force cell programming to create the type of cells you need to replace. You can next use the cells to replace diseased cells in your body with healthy ones.  

It will take time before we can treat diseases with Cas12a

However, at the moment, we’re still at the research level with this, and the approach applies far from most disease treatments. We haven’t solved polygenic issues with these findings. Here’s why:

Genes can have multiple purposes.

Just as many genes can affect one condition – as in polygenic examples – one gene may have many responsibilities. Just look at sickle cell disease caused by one gene mutation. While the affected patients have a higher risk of anemia and blood clotting, they also have some protection against malaria, a parasite-caused disease. Battling one of the conditions will ultimately also affect the other. 

In other words, by adding complexity to your gene-editing approach (in this case, the number of targeted genes), you may also increase the risk of affecting conditions unrelated to the disease you’re battling.

ON/OFF states don’t define you.

We might fix diseased cells by turning on or off specific genes, but this switch mode doesn’t always apply. Certain conditions depend on gene expression levels. It’s easy to believe that our realities are binary (ON or OFF; 0 or 1; good or evil), but the truth is that our lives are within spectra. My previous research focused on a protein that cancer cells enjoyed in the right amounts. Not too little and not too much; just enough. In Swedish, we have a special word for this: “lagom.” And, according to the Swedish mantra, lagom is good… But that’s not the point! The point is that, although I don’t know how widespread the preferences for “lagom” are among different diseases, I imagine that they’re more common than we think.  

The off-target effects.

Ahh, these famous off-target effects that the Embassy loves to point out as soon as CRISPR-Cas is on the news. But they are a real concern, especially when introducing the tool to the clinic. And, while Cas12a is typically considered more specific than Cas9, it doesn’t escape the problematics of off-targets, which is the editing of an unintended genomic site, for example, a gene. I think the considerations for off-target effects become increasingly important with polygenic targeting. 

And more…

Anyway, I recommend you check out THIS post to get more reasons why the CRISPR-based technologies (including Cas12a) are not ready to treat all diseases. 

Don’t think I’m trying to find flaws in all optimistic CRISPR news just because happiness in my surroundings bothers me. I don’t want to steal Christmas from anyone or be a party pooper. My intentions are pretty simple: Although awesome, CRISPR is not a miracle cure, we still have a lot more to learn, so we also need more patience, and things are not binary (ON/OFF). And that’s OK! 

Until next time, let’s reconsider the more is more mentality. Here at the Embassy, we many times enjoy that less is more.   

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