CRISPR-Cas9 and Cancer: A Response from Dr. Kyle Fink (UC Davis Institute for Regenerative Cures)

June 23, 2018

On June 11, 2018, an article by Kristin Houser of Futurism was published: "CRISPR Could Help Us Cure Diseases. It Could Also Cause Cancer."

On June 11, 2018, an article by Kristin Houser of Futurism was published: "CRISPR Could Help Us Cure Diseases. It Could Also Cause Cancer." Kevin Jess (Vice President) of WeHaveAFace Canada and contributor of the WeHaveAFace Global Times online newspaper brought this to my (our) attention in a post on Facebook on June 22, 2018. WeHaveAFace quickly reached out to our friend Dr. Kyle Fink (UC Davis Institute for Regenerative Cures) for his response.  This is the Futurism article in its entirety, followed by Dr. Kyle Fink's response.

"CRISPR Could Help Us Cure Diseases. It Could Also Cause Cancer."

by Kristin Houser of Futurism

 

You know already about the promise for CRISPR-Cas9 — it might revolutionize fields from medicine to agriculture.

 

It might also eventually cause tumors.

 

That’s the takeaway from two new studies, published Monday in Nature Medicine. Both studies, one by Novartis and the other by the Karolinska Institute, focus on the gene p53, known to play a major role in tumor prevention by killing cells with damaged DNA. According to past research, most human tumors simply can’t form if p53 is working properly — some researchers refer to it as the “guardian of the genome.”

 

Unfortunately, p53 is also something of a natural defense against the kinds of changes to the genome made by CRISPR-Cas9. When researchers use CRISPR-Cas9 to snip and replace some DNA, p53 jumps into action, causing the edited cells to self-destruct. This renders the CRISPR edit essentially moot, which could explain why CRISPR isn’t terribly efficient.

 

Here’s the issue. When a CRISPR-Cas9 edit does stick, that could mean the cell’s p53 isn’t functioning the way it’s supposed to. And dysfunctional p53 may be a precursor to a host of cancers, such as those in the ovaries, colon and rectum, and the esophagus.

 

“By picking cells that have successfully repaired the damaged gene we intended to fix, we might inadvertently also pick cells without functional p53,” Emma Haapaniemi, one of the authors of the Karolinska study, said in a press release. “If transplanted into a patient, as in gene therapy for inherited diseases, such cells could give rise to cancer, raising concerns for the safety of CRISPR-based gene therapies.”

 

But don’t worry, the CRISPR revolution is far from over.

 

First: these are very early-stage studies presenting “preliminary results,” as biochemist Bernhard Schmierer, co-leader of the Karolinska study, told STAT News. “It is unclear if the findings translate into cells actually used in current clinical studies,” he added.

 

Second, the studies focus on just one type of CRISPR edit: replacing disease-causing DNA with healthy DNA (“gene correction”) using CRISPR-Cas9. While Cas9 is the most well-known CRISPR enzyme, there are others — Cpf1, for example — and we don’t yet know if they’d cause the same issues with p53.

 

We can also use CRISPR to simply knock out disease-causing DNA without replacing it (“gene modification”). This type of edit can stick even when p53 is functional, Haapaniemi noted. That’s the type of genetic change at the center of a number of high-profile CRISPR projects: CRISPR Therapeutics’ sickle-cell and thalassemia trials, Editas Medicine’s research to address blindness, and the University of Pennsylvania’s tumor-targeting T-cell research — the first trial of CRISPR in humans in the U.S.

 

The authors of the two new studies admit their research doesn’t mean CRISPR-Cas9 is “bad or dangerous.” We just need to proceed with caution.

 

Unfortunately, the finer details of these studies appear lost on the people holding the purse strings — a number of CRISPR-focused companies saw shares fall sharply following the studies’ release. Clearly, any link to the Big C is a big problem for CRISPR researchers, no matter how tenuous it might be.

 

The article references: STAT, Karolinska

Link to complete article: https://futurism.com/crispr-cancer-p53/

WeHaveAFace takes this reporting seriously as we directly support the Juvenile Huntington's Disease Research of Dr. Kyle Fink (UC Davis Institute for Regenerative Cures), and we reached out to him for his professional and first-hand experience using CRISPR/Cas9, and his opinion regarding the Futurism article.  

 

Here is Dr. Kyle Fink's response:

 

“While great excitement surrounds the world of gene editing using CRISPR/Cas9 for therapeutic purposes, as a research community we still have a lot to learn about how we apply this wonderful tools clinically. Specifically, two back to back publications in Nature Medicine have linked p53 expression with the ability to successfully engineer cells. A manner in which this data can be interpreted and is currently spreading through different science communication avenues is that due to the strong link between p53 and cancer is that the cells that are capable of becoming “edited” will be cells that are predisposed to uncontrolled growth and cancer-like phenotypes. While a major concern and hurdle for the field this is not something that was entirely unknown.

 

Editing of the endogenous genome requires DNA-repair mechanisms and these pathways have long been associated with p53 expression. Other approaches to engineer the genome, such as the use of Zinc Finger Nucleases, as developed by Sangamo performed “rule out tumorigenicity” studies which is a method to ensure that the edited cells do not give rise to cancerous-like phenotypes. Any trial moving forward would have to perform these long-term safety studies prior to starting a clinical trial with CRISPR/Cas9. It should also be noted that approaches to silencing the huntingtin allele at the RNA level, either specifically or non-specifically, from groups like WAVE, IONIS, and Roche would not encounter this concern.

 

Also, our group working on gene modifiers and Artificial Transcription Factors which target and remodel the DNA but do not cut it, this would also be avoided.  Long-story short or the take home message is: gene editing is extremely exciting and promising, however there are many hurdles including rigorous efficacy and safety studies that need to performed prior to delivering this in a person.” - Dr. Kyle Fink (UC Davis Institute for Regenerative Cures). 

WeHaveAFace believes that it is necessary to share such articles as the one in Futurism; however, we also feel that it is paramount that all aspects of CRISPR/Cas9 be brought to the forefront. This possible (and much-needed) treatment for Huntington's and Juvenile Huntington's disease might be on the horizon. We must have hope, be cautious, but most notably, we must also report the accuracies involved. 

 

Below is filmed visit with Dr. Kyle Fink at UC Davis Institute for Regenerative Cures, which can be seen in the award-winning documentary, "The Purple Road."