Something HUGE has been going on lately called "the CRISPR revolution”, and after doing some research and seeing its implications, I FEEL LIKE EVERYONE SHOULD KNOW ABOUT IT.
In short: CRISPR/Cas9 is a gene-editing tool that could (in theory) be used in the future to treat diseases like blood disorders, genetic blindness, HIV and even various forms of cancer! Scientists have successfully been applying this technique in animals and plants, are right now discussing (and sometimes ignoring...) the ethical issues regarding the clinical use of it in humans.
Jennifer Doudna, an American biochemist, was among the first to propose that CRISPR/Cas9 could be used to edit/reprogram genomic DNA. This is considered one of the most significant discoveries in the entire history of biology, and what it entails is mind-blowing. She will probably win a Nobel prize for it.
Many believe that we will see this technique enable significant medical breakthroughs in the next 5 to 10 years. In fact, CRISPR has already been used in China (where they are "a bit less subtle" about the ethical issues…) to treat over 80 people with different forms of cancer, and results should be available soon. Doctors at the University of Pennsylvania announced in 2018 that they will use CRISPR to modify T-cells (human immune cells) so that they become specialized in recognizing cancer, and fight it off.
CRISPR Therapeutics is one of the biggest companies in the world whose mission it is to develop transformative gene-based medicines. This company recently got green light from both the European Union and the United States to use CTX001 (an investigational therapy concerning the treatment of blood diseases like sickle cell anemia and beta-thalassemia) in humans.
If these first trials in humans go well, it might enable CRISPR Therapeutics to proceed with their plans to target other human diseases with CRISPR/Cas9, like cystic fibrosis, diabetes, Duchenne's muscular dystrophy and various cancers.
There are also good reasons why CRISPR could be used to treat genetic blindness. The specific mutations causing hereditary blindness are known, which makes it fairly easy to instruct CRISPR/Cas9 to find and edit that gene.
So how does CRISPR work?
The way Jennifer Doudna puts it, CRISPR/Cas9 is pretty much like how you would use WordPress, where you can spot spelling errors and simply edit them. If we know what gene is responsible for causing a certain effect (in medicine they look at genes that cause diseases/disorders), we can instruct CRISPR/Cas9 to find it in the DNA string, and cut it out.
Once the unwanted piece of genome is cut out, the cell will temporarily contain a damaged string of DNA. This doesn't go unnoticed, the cell will know about it and wants to repair it. It has two ways of doing so: the first way is to stitch both ends back together. This is called "non-homologous end-joining". The second way is to insert a piece of "donor DNA": this is called "homology-directed repair". Researchers often manually supply this bit of DNA in the hope that the cell uses it as replacement for the original (faulty) DNA. We don't really know exactly why some cells use the first method and others the second. That is kind of a problem on its own. Besides, when a cell uses"non-homologous end-joining", this often causes off-target editing and we are not sure what kind of effects those unwanted edits will have..
Off-target editing is not necessarily a deal breaker in situations where the patient has no alternative treatment options, but it sure stands in the way of the commercial goals of the companies using this technique.
Sidenote: Speaking of commercial goals, Broad Institute and University of California have been fighting over the CRISPR patent, and it is probably the most heated battle over inventorship that two educational institutions have ever had. Not surprising, because the leading companies in this field (CRISPR Therapeutics, Editas Medicine, and Intellia Therapeutics) have a combined market capitalization of €4.4B ($5B).
What's also important to note, is the fact that CRISPR doesn't simply spread out to other parts of the body once it's injected somewhere. The best way so far to achieve this, is by letting a virus into the body and infect cells with it. So once CRISPR has successfully spread throughout the body, we still have to deal with this virus...
Another concern is that Cas9 itself is derived from two infectious strains of bacteria:
- 1) The first one, [Staphylococcus aureus], often lives harmlessly lives on skin, and can in some cases cause staph infections.
- 2) The second one, [Streptococcus pyogenes], is the cause of strep throat but can also become a “flesh-eating bacteria” when it spreads to other parts of the body...
Considering this, it is no surprise that studies have confirmed that human cells have a pre-existing immune defense against Cas-9. So, chances are that this first iteration of CRISPR/Cas9 will turn out to be ineffective (if not dangerous) for most humans...
Still, it is only the very beginning of the CRISPR revolution! According to many scientists, there are probably ways around these problems. For example, instead of delivering CRISPR/Cas9 into the body, you take cells out of the body, use CRISPR to edit their genes in a lab, and return Cas9-free cells. This is actually the method that CRISPR Therapeutics is using for curing the blood disorder Thalassemia.
We could also use CRISPR in places the immune system doesn’t reach. Sites like these are called immunoprivileged, and human eyes are one of those sites. This means that Cas9 is less likely evoke a immune response there, and therefore it will probably be more effective and cause less side-effects. This is the reason why researchers think that CRISPR/Cas9 could help cure blindness.
Also, there are many other bacteria that use a CRISPR system. It might be a matter of time before researchers find another bacterial protein that can do the same job as Cas9, without provoking an immune response in humans.
Neurologist Nicole Déglon (from the Lausanne University Hospital in Switzerland) and her team are in the early stages of treating Huntingon’s disease using CRISPR. They actually devised an alternative to CRISPR, and I absolutely love how they named it: KamiCas9. It includes a “self-destruct button” for Cas9. So right after the target genes are edited, it will target Cas9 and no more DNA-dicing enzyme will be produced. Déglon’s team found that using KamiCas9 reduces the amount of unwanted (off-target) edits by 75%!
It is interesting to think about what else we might be able to do with CRISPR (outside of treating genetic diseases with it) when we start to master the trade. There are talks about "designer babies", where it's speculated that using this technique in human embryos could in the future prevent baldness, enhance IQ or create perfect eyesight. Imagine that we can... Should we do it? If CRISPR is going to be as easy as some people claim it will be, I don't think there will be anything we can do to stop people from using it.
But all the speculation and ethical issues aside, what's actually most important about CRISPR is that it gives researchers an efficient way of doing better research. It's not a secret that we actually don't know that much about how our cells work. Like I said before, we don't really know exactly why some cells use one DNA repair method, and other cells another. Imagine what else we don't know.
We still don't know exactly what the precise genetic architecture is of many diseases we want to cure. We cannot simply come up with a hypothesis and cut out some pieces of DNA to see what happens. If it goes wrong it could be passed down to next generations before we even know what the long term effects are of having those genes edited.
Jennifer Doudna is very aware of this and calls for a global debate on the ethical issues while putting all human CRISPR trials on hold. In reality though, it is really hard to stop the whole world from doing clinical trials. For example, in November last year, a Chinese researcher named He Jiankui had not only allegedly made the first crispr-edited babies; he would have done so in secret, the editing wouldn't have been executed right and the parents wouldn't have been informed about the risks. So yeah, Jiankui became the center of a global firestorm. Doudna was horrified by this story: "[I'm] really disappointed that the international guidelines that many people worked so hard to establish were ignored."
To conclude, this is the most astonishing discovery of this era, and I think we will be hearing more from it soon, whether it is about progress in research or more controversial implications.
Hope you guys found this article interesting! I did my best to explain a complicated body of research in a way hopefully most of you understand. If you still have any questions, feel free to leave a comment below or contact me!
Sources:
https://www.fool.com/investing/2018/11/30/why-crispr-therapeutics-stock-is-up-65-so-far-in-2.aspx https://www.fool.com/investing/2018/10/11/why-crispr-therapeutics-stock-is-heading-higher-to.aspx https://www.labiotech.eu/tops/crispr-technology-cure-disease/ https://www.theatlantic.com/science/archive/2018/01/crispr-humans-immune-system/549974/ https://www.parkerici.org/research_project/cancer-fighting-t-cells-created-using-crispr/ https://www.nature.com/articles/d41586-018-05177-y https://www.wsj.com/articles/china-unhampered-by-rules-races-ahead-in-gene-editing-trials-1516562360 https://www.clinicaltrials.gov/ct2/show/NCT03399448 https://www.ncbi.nlm.nih.gov/pubmed/29856031 https://www.labiotech.eu/features/crispr-patent-dispute-licensing/https://www.theatlantic.com/science/archive/2018/12/15-worrying-things-about-crispr-babies-scandal/577234/https://twitter.com/tictoc/status/1067772480511766528