CRISPR's Gene Editing: Too Hot Not to Cool Down, A Little?

News coverage of the gene-editing technology CRISPR-Cas9 had until recently mostly been on its potential to repair or remove flawed genes, the ongoing clinical trial on human subjects in China and the one that will start next year in the U.S., and on the legal fight as to who controls its patents. The technology has been labeled "revolutionary and it has been predicted that it will change the face of modern medicine. But a new study titled “Unexpected mutations after CRISPR-Cas9 editing in vivo.” published in the journal Nature Methods has raised concern that CRISPR can also introduce unintended mutations into the genome. A study that sounded a broader alarm last year was widely criticised. What sort of effect will this new study have?

Clustered Regularly Interspaced Palidronic Repeat (CRISPR)-Cas9 allows researchers to alter DNA sequences and modify gene function. It has the potential to prevent genetic defects and curb the spread of a disease. The potential is so great that it has caused alarm about its potential misuse in breeding "designer babies" and superhumans.

The technology is thought to be worth billions of dollars. The patent fight has been between the University of California at Berkeley and the Broad Institute of MIT and Harvard. In 2017, the Patent and Trademark Office's Patent Trial and Appeal Board (PTAB) found in favor of the Broad Institute, and UC appealed to the U.S. Court of Appeal for the Federal Circuit. I covered both the PTAB ruling https://www.bna.com/gene-editing-patent-n57982084034/  and UC’s filing of its appeal https://www.bna.com/university-california-fight-n57982086696/ . A three-judge panel of the Federal Circuit heard oral arguments on April 30, 2018. Most prognosticators suggested that after the arguments they felt that the court would affirm the PTAB’s ruling in favor of the Broad Institute. Judge Kimberly Moore openly and dramatically questioned UC’s argument that its efforts showed a reasonable expectation that the technology would work. But, as I’ve suggested in this blog, prognostication based on oral arguments has been wrong on occasion. The court's ruling is due any time.

But around the same time as the PTAB ruling, the alarms about potential problems with CRISPR began to focus on its potential side effects. In May 2017, the journal Nature Methods published a Columnia University Medical Center study that suggested CRISPR can cause collateral damage to the genome. There was an outcry that the methodology of the study was flawed, and the journal on March 30, 2018 published a retraction.

In two papers in the same journal published this June 8, researchers described how they had sequenced the entire genome of mice that had undergone CRISPR gene editing in the team’s previous study and looked for all mutations. They found that CRISPR corrected a gene that causes blindness but also that the genomes of two independent gene therapy recipients had experienced more than 1,500 single-nucleotide mutations.

In a June 19 online chat, Sharon Begley, chief writer for science and discovery for STAT News, tried to put the two papers in perspective. She stated that the studies reported a possible link between CRISPR and a cancer-preventing protein called p53. "CRISPR did not turn cells cancerous. Instead, the two independent teams of scientists (at Novartis and the Karolinska Institute) reported cells already lacking a functional p53 were more likely to have their genome successfully edited by CRISPR." This would mean that the absence of p53 in a cell may make the CRISPR process easier but it also makes a cell more likely to be cancerous.

"[I]n the worst case," Begley stated, "the exact cells that seem therapeutic might, when returned to the patient, seed cancer. BUT the finding is preliminary. It needs to be confirmed by other investigators. Lots of mice have been CRISPR'd, and no one has reported any cancer epidemic in them." 

In a June 13 Bloomberg News article, Max Nisen, noting that it is very early in the technology's history, sounded a cautious note. "[T]he studies' findings are a reminder about how little we know about unintended consequences. And either way, these papers may have a cooling effect on investment, trial recruitment, and the FDA's [Food and Drug Administration's] willingness to give a broad or rapid green light to crispr testing."

Many breakthrough technologies have experienced setbacks and a longer development role than originally anticipated, Nisen noted.

Copyright 2018 by John T. Aquino