CRISPR Gene Editing Can Trigger Tumors, Two Studies Warn
CRISPR-Cas9, a form of “molecular scissors,” allows for very precise DNA editing, i.e., the removal, addition or altering of sections of a DNA sequence
While CRISPR-Cas9 gene editing is more precise in that you can target a specific area of the genome, two recent studies warn the gene editing process can trigger cancer
When you cut the two double helix strands of the DNA, the injury triggers the cell to activate a gene called p53 — a “biochemical first-aid kit” that either mends the DNA break or signals the cell to self-destruct; so, either the genome edit is mended or the cell dies
In instances where the cell survives and accepts the edit, it does so because it has dysfunctional p53, and p53 dysfunction has been shown to significantly increase your risk of cancer
CRISPR stock dropped between 5% and 13% within days of the findings’ publication
Editor's Note: This article is a reprint. It was originally published June 26, 2018.
The discovery of the gene editing method known as CRISPR1 eventually led to a novel gene editing tool called CRISPR-Cas9,2 a form of molecular scissors that allows for far more accurate DNA editing for the removal, addition or altering of sections of a DNA sequence. A layman's explanation of the technology is presented in the video above.
CRISPR is the acronym for clustered regularly interspaced short palindrome repeat, and its function was initially discovered in 1993 by Spanish researcher Francisco Mojica.3 Mojica hypothesized CRISPR is an adaptive immune system, which has since been confirmed.
Two decades later, in 2013, the technology known as CRISPR-Cas9 was successfully used to edit the genome in eukaryotic cells for the first time, demonstrating targeted genome cleavage could be achieved in mouse and human cells.
As reported by Nature4 in 2016, "Researchers use CRISPR-Cas9 to make precise changes to genomes that remove or edit a faulty gene. It has worked on nearly every creature on which they have tested it, including human embryos."
In the wake of these discoveries, a number of CRISPR-based companies have sprung to life with the hopes of furthering gene editing in everything from food and medicine5 to eventually producing "designer babies" that have had unwanted genetic traits edited out.
However, while CRISPR-Cas9 gene editing is more precise in that you can target a specific area of the genome, two recent studies call for a rethink, as the process of gene editing can trigger cancer.6,7 As noted by STAT News8 these findings could be "a potential game-changer for the companies developing CRISPR-based therapies."
CRISPR Editing Triggers Tumor Growth The two studies9,10 were published in Nature Medicine, and present a sobering warning to scientists hell-bent on defeating nature. It appears that cells whose genomes are successfully edited by CRISPR-Cas9 have carcinogenic potential, turning them into proverbial ticking time bombs. As reported by STAT News:11
"CRISPR has already dodged two potentially fatal bullets — a 2017 claim12 that it causes sky-high numbers of off-target effects was retracted13 in March, and a report14 of human immunity to Cas9 was largely shrugged off as solvable.15 But experts are taking the cancer-risk finding seriously."
Indeed, CNBC16 and Market Watch17 reported CRISPR stock dropped between 5 and 13% within days of the findings' publication. The two studies — one performed by scientists at the Karolinska Institute18 in Sweden and Cambridge University in the U.K., the other by the Novartis Research Institute in Boston19 — both found the same thing.
When you cut the two double helix strands of the DNA, the injury triggers the cell to activate a gene called p53, described as a "biochemical first-aid kit" that either mends the DNA break or signals the cell to self-destruct. As noted in the featured article, "Whichever action p53 takes, the consequence is the same: CRISPR doesn't work, either because the genome edit is stitched up or the cell is dead."
Cutting the Genome Activates Repair-or-Kill Mechanism
According to the Novartis team, p53 lowers CRISPR efficiency seventeenfold in pluripotent stem cells — stem cells that can turn into virtually any other cell and are therefore a primary candidate for the development of therapies targeted at a wide array of diseases. This helps explain previous findings that suggest CRISPR isn't nearly as efficient as initially hoped.
According to STAT News, "CRISPR is woefully inefficient, with only a small minority of cells into which CRISPR is introduced, usually by a virus, actually having their genomes edited as intended." Emma Haapaniemi, who led the Swedish team, noted that since cutting the genome is what activates p53, genome editing becomes a very difficult undertaking.
Importantly, both teams discovered that in instances where the cell actually survives and accepts the edit, it does so because it has dysfunctional p53, and p53 dysfunction has been shown to significantly increase your risk of cancer. Mutations of this particular gene are thought to be responsible for:20
* 50% of ovarian cancers
* 43% of colorectal cancers
* 38% of lung cancers
* 33% of pancreatic, stomach and liver cancers
* 25% of breast cancers
"By picking cells that have successfully repaired the damaged gene we intended to fix, we might inadvertently also pick cells without functional p53. 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," Haapaniemi told the New York Post.21 The Catch-22 of Gene Editing
In other words, even if scientists become exceptionally adept at accurately cutting out and inserting new DNA sequences, when the process works as intended, it's because p53 fails to do its job, which significantly raises the risk of cancer formation.
It's a real Catch-22 that puts a significant damper on the idea that we can customize the genome to our own liking simply by cutting and splicing DNA sequences. It appears nature has built-in fail-safe systems for this eventuality. As noted by the Novartis team, "it will be critical to ensure that [genome-edited cells] have a functional p53 before and after [genome] engineering."
All hope is not lost, however. It's possible that these findings may be applicable only when you replace disease-causing DNA with a healthy DNA sequence, and not when you're just removing a piece of the DNA sequence, so CRISPR may still be useful in some instances. As explained in the featured article,22 the genome can be edited with CRISPR in two different ways:
1. Non-homologous end joining (NHEJ), also referred to as gene disruption. This is where a disease-causing section of DNA is simply cut out and not replaced. NHEJ is currently being used by CRISPR Therapeutics in their development of a treatment for sickle cell disease. Others are working on treatments for cystic fibrosis and severe immunodeficiency using gene disruption