Limitations of CRISPR | Top 6 reasons clinical trials only focus on some diseases

Limitations of CRISPR | Top 6 reasons clinical trials only focus on some diseases

May 24, 2018 0 By Santiago
Reading Time: 6 minutes

China started CRISPR clinical trials already in 2015. The US came shortly after. Why so few diseases targeted? What are the limitations of CRISPR technology?

Damn, this CRISPR-thing escalated fast. In 2013, we could read the first reports of the genome-editing tool CRISPR-Cas9 being used in human and mouse cells and just two years later it was suddenly possible to change genes in fertilized eggs with it. To top that, clinical trials with CRISPR started in China the same year. That’s two freaking years after we started using it on cells in culture dishes. Let me be clear by saying that I’m not talking about living animals. I’m talking from cells in a dish to humans in two years!  

Nevertheless, at least 11 clinical trials with CRISPR have been initiated in China. And with 86 reported cancer patients having received CRISPR therapy, it’s clear that the race between China and the Western countries (whatever countries that would include) is ON. Prepare the popcorn, because shit’s going to get crazy.  

To summarise, these are the main types of CRISPR clinical trials that are being done right now:  

1. Genes of immune cells are changed and activated to attack for example lung cancers. 

2. Gene mutations of blood disorders like hemophilia are corrected.    

Amazing, for sure! CRISPR clinical trials for the win! Still, considering the ongoing East vs. West competition and the overall attention CRISPR has received, only a few conditions are tested right now. Only a handful of disorders are taken into consideration for CRISPR clinical trials. The question is why CRISPR is limited. And the answer might surprise you… it’s not the lack of Russian participation in the race. Nope, it is…  

What are the limitations of CRISPR technology?

Guys, let’s have a look at it in the form of a list! I know we’ve done it before, but damn it was fun! So, ladies and gentlemen, here you have the top six reasons only some types of disorders are treated in CRISPR clinical trials! …for the moment. (Order is somewhat random).  

Reason #1: Blood is easy  

That’s right, the blood’s easy to manipulate. And the above mentioned clinical trials (numbers 1 and 2) include using CRISPR in blood cells. That’s right, immune cells are blood cells. White blood cells, to be more specific. 

And here’s the thing with blood cells: we can extract them from the body, grow and manipulate them outside of it and then reinsert them. This is true for both white and red blood cells. Take hemophilia for example. It’s caused by red blood cells containing one gene-mutation that prevents blood from clotting. Here’s the CRISPR-fix: We tap the blood out of the body, correct the gene by using CRISPR, and reinsert the blood to the body.  

We cannot do the same with other cells. Let’s say we need to correct a gene in your liver. Take out the liver and you’re dead. That’s the number one reason why blood cells are so easy to manipulate compared to other tissues. It’s just bloody easy…

limitations of crispr blood

But there are more reasons.   

Reason #2: It can be tricky to target the sick cells 

You can see where I’m going with this one and it’s pretty related to the above-mentioned reason. Whenever you work with extracted blood cells you’re working with the odds on your side, as far as the delivery of CRISPR to the right cells is concerned. I mean, the cells are there. They’re in front of you. Targeting the wrong cells should be pretty much impossible.  

The problems become apparent when you want to deliver the CRISPR system into cells inside the body: Lungs, kidneys, liver, intestines, brain, heart, etc. How do you target these? And if you know that, then how much CRISPR can you safely administer? Not too little, it needs to have an effect, but for science sake, not too much either! Too much can result in nasty effects like toxicity, increased risks of off-target cutting (explained below) or the risk of targeting other tissues.   

For this reason, it can be a risky business to administer CRISPR directly to the tissues of your body. It’s easier to take the organ out and manipulate and then reinsert.

Try to do the same with the heart for example. The heart is easy to take out. Fixing and successfully reintroducing it to your body is the tricky part.

Ask Toni Braxton. She’ll tell you all about the process of unbreaking hearts (if you know what I mean). 

Reason #3: You have an adaptive immune system 

I mentioned this potential issue in a previous blog 

But Mr. Embassy, give me a brief summary of the whole thing, I don’t want to click the link and leave this page.  

Ok, ok. Here’s a short version. A preliminary pre-print publication, that was not peer-reviewed (that is, not reviewed by other researchers before being published) recently suggested that the immune cells in your body can potentially recognize the CRISPR protein Cas9 as an invader. Why? Because the CRISPR system that we use to cut DNA is after all derived from common bacteria. A natural pathogen to us. That means that your immune cells could potentially neutralize the DNA-cutting protein Cas9, making it useless. In a worst-case scenario, it could even cause systemic inflammation in your body.   

Obviously, this would also be the case for CRISPR introduced blood cells. However, since the genes, in this case, can be modified outside of your body, it’s easier to control the presence of Cas9 in them before reintroducing them to the body.  

Reason #4: CRISPR may cut off target

Question number one whenever presents CRISPR results is “What about the off-target effects?”. This is an essential issue. There is a real risk that Cas9 not only cuts the gene you intend to manipulate but also starts cutting the wrong DNA-sequence. That’s an off-target effect. Outside of the real target.  

In a laboratory setting, this is not as big of a problem. Did you get an off-target mutation you say? Fine, redo the experiment. Take a new population of cells and use a CRISPR to target the same gene, but this time with a different target. One that doesn’t cut off target. A more trustworthy target. Dump the first one!  

However, as you can imagine this is not an alternative when we’re treating patients. Once you’ve created a cut in a patient’s DNA (on or off-target) it’s there. No REV-button. Best case the off-target doesn’t make a difference. But the worse case you created an additional mutation in your DNA that could make things worse.

We have to be 100% sure that we don’t cut and mutate other genes than the intended ones when we treat patients. A single off-target cut can lead to disastrous outcomes. Right now, however, it’s impossible to guarantee anything.

Reason #5: We don’t always know what to fix 

Now let’s say that we can target CRISPR anywhere in the body and that we know the exact amount of CRISPR to use. Let’s also assume that we can, with 100% certainty, avoid an immune reaction from the body, off-target effects, and long-term negative effects. Still, one more problem left to deal with: WHAT do we target?  

Sure, some genetic disorders require only one well-known gene mutation, a so-called single gene disorder, for example, Cystic fibrosis or hemophilia (see above). However, take cancers for example. We sometimes find several mutations that could be contributing to the disease. Many times, we don’t know how many of the mutations in a particular cancer are essential for its survival. Heck, sometimes we don’t even know exactly what causes a disease. What’s the so-called driver mutation?

So, it’s not just the limitations of CRISPR technology that restricts clinical trials, but sometimes also the limitations of our biological knowledge.

Reason #6 (and some last words): The tool has only been available for a short time 

Guys, it’s time to calm down. I know that there are hopes for the CRISPR tool, I know we are in the midst of an epic race between East and West. But check this out: the technology is young. 2013 was just a couple of years ago. The same year Sharknado premiered, and we all talked about it for a week or so. Feels like yesterday, I feel you. But I think we’re expecting too much in too little time. I guess that’s what being human is about.  

Nevertheless, we need to calm the f*ck down and realize that there are a lot of decisions and improvements to be made before we can put our trust in CRISPR. Especially in the clinics. There are obviously fewer restrictions for these things in China compared to here, but let’s not get caught up in the race. We need to realize that there are risks with CRISPR treatments at this point. Otherwise, we’ll end up with more inpatient fools, trying to inject themselves with CRISPR. Here’s a piece of bonus advice: Don’t do it!  

Woah… That got heated… Let’s tone it down a notch and end on a good note. I do find the CRISPR-tool amazing and I think we’ll be able to save many lives and suffering in the (maybe not too far) future. I’m as excited as anyone else. I even think we’ll experience plenty of advancements with CRISPR and CRISPR clinical trials in the coming years. Let’s just chill for a moment and let it happen. Artificial intelligence and the robotics field is allowed a relatively slow development. Let’s have patience with something that can both cure or kill us. I think it’ll be worth it…

Has anybody seen Sharknado 2 by the way? I hear it’s better than the first one.  

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