Another day, another CRISPR issue to worry about.
Shares of gene-editing biotechs CRISPR Therapeutics (NASDAQ:CRSP), Editas Medicine (NASDAQ:EDIT), and Intellia Therapeutics (NASDAQ:NTLA) sank on Monday following the publication of a paper identifying the possibility that the use of CRISPR-Cas9 can cause significant unintended gene mutations. All three biotechs are exploring the use of the CRISPR-Cas9 gene-editing approach to treat -- and potentially cure -- various diseases.
What does this latest potential CRISPR issue mean? And what should you do if you either own shares of the CRISPR-focused biotechs or are thinking of buying these stocks?
Understanding the problem
CRISPR-Cas9 has been touted as the biotech discovery of the century. CRISPR stands for clustered regularly interspaced short palindromic repeats. This refers to DNA sequences discovered in certain types of bacteria that read the same forward and backward and are separated by regular stretches of what's called "spacer DNA" (a kind of DNA that doesn't provide instructions for building proteins).
Some bacteria use a CRISPR-associated system (CAS) protein known as Cas9 to target and slice specific sections of DNA in viruses as a self-defense mechanism. Over time, scientists figured out how to build their own guide RNA (ribonucleic acid) to harness CRISPR-Cas9 to edit DNA sequences. CRISPR-Cas9 was hailed for its accuracy, cost-effectiveness, and simplicity.
However, a paper published on July 16, 2018, by Wellcome Sanger Institute scientists Michael Kosicki, Kart Tomberg, and Allan Bradley in the scientific journal Nature Biotechnology raises a serious concern. The researchers found that using CRISPR-Cas9 to edit DNA in mouse cells and in a human differentiated cell line caused extensive unintended changes in DNA sequences that were relatively far away from the target DNA sequence. Those other unintended changes could potentially cause cancer or other diseases.
If all of this sounds familiar, it should. A similar issue was raised in May 2017. Another scientific article published in Nature Methods found unexpected mutations in DNA following the use of CRISPR-Cas9 to edit genes. The stocks of CRISPR Therapeutics, Editas Medicine, and Intellia Therapeutics plunged on that news, just as they did this week.
However, the findings of the paper were quickly challenged. By July 2017, the editors of Nature Methods had issued "an editorial expression of concern" about the paper's conclusions. The authors subsequently retracted the paper in March 2018 after determining that the genetic changes observed in the two mice that were part of the research couldn't definitively be attributed to the use of CRISPR-Cas9 to edit genes.
The fundamental problem with that research was that the scientists didn't appropriately control for genetic variation the mice that were used. That's not an issue with the research performed by the Wellcome Sanger Institute team. They first tested on mouse embryonic stem cells and hematopoietic progenitor cells, but also saw similar off-target gene mutations in an immortalized human female retinal pigment epithelial cell line.
There have also been other potential issues identified with CRISPR-Cas9. In January 2018, a scientific paper suggested that human immune responses could impact the effectiveness of the gene-editing method. In June, two different papers published in Nature Medicine pointed to the possibility that CRISPR-Cas9 could cause an increased risk of cancer.
What investors shouldn't do
It's certainly concerning that using CRISPR-Cas9 could result in unintended DNA changes. This idea is akin to going into surgery for a tonsillectomy and ending up with one of your kidneys removed inadvertently. Not a good situation.
However, investors shouldn't panic. More research is needed to determine how serious the potential of off-target genetic mutations really is. If there were flaws in the way the Wellcome Sanger Institute scientists performed their testing, other scientists will find them. That's exactly what happened with the report last year about concerns with significant numbers of unplanned DNA changes.
On the other hand, investors shouldn't ignore the latest concern about CRISPR-Cas9. The Wellcome Sanger Institute research was much different than the research in the paper published in 2017 that was ultimately retracted. Again, additional research will determine how worrisome the issue really is.
What investors should do
The best thing for investors who already own stocks of CRISPR-focused biotechs is to simply wait and watch. The share prices of CRISPR Therapeutics, Editas, and Intellia bounced back some on Tuesday. This rebound could stem in large part from the reactions of the biotechs themselves.
CRISPR Therapeutics told Reuters that it doesn't "use the methods described in this Nature Biotechnology paper" and hasn't seen similar findings in its own research. Intellia Therapeutics said in a statement that the company "does not believe that these findings significantly impact the path forward for CRISPR-based therapeutics." Editas responded that it wasn't "significantly concerned" over the findings published in Nature Biotechnology.
All three biotechs have been monitoring for potential off-target mutations resulting from the use of CRISPR-Cas9 in their own research in light of the controversies. Editas, for example, has stated in the past that it has "detected no off-site targets" with the use of its lead CRISPR-Cas9 candidate, EDIT-101, in treating genetic eye disease Leber congenital amaurosis type 10.
But could this or another issue potentially derail CRISPR-Cas9? It's possible. While the gene-editing method has been researched extensively for several years, it hasn't been used in U.S. clinical studies yet. More problems could arise. Investors who are considering buying CRISPR-focused biotech stocks should keep this in mind. CRISPR-Cas9 has huge potential, but also comes with huge risks.