New CRISPR Findings Raise Concerns Before Technology’s Clinical Debut

A pair of studies that investigated the effect of CRISPR-Cas 9 on a key protein that regulates cell growth and protects against cancer has sent shockwaves through the growing corner of the biotech sector that draws on this technology and has caused investors to reassess the safety of the method.

Two groups of researchers independently reported in the journal Nature Medicine in June that CRISPR-Cas9 sometimes negatively interacts with p53, a protein regarded in some molecular genetics textbooks as “the guardian of the genome” for its role in preventing genome mutations and resisting cancer.

The findings come as more advanced studies push use of the technology into the clinic and the public eye. A small number of trials for CRISPR-based therapies have been slated to start in the U.S. this year, with nearly a dozen already underway in China. However, the U.S. Food and Drug Administration (FDA) has now halted a clinical trial to treat patients with sickle-cell disease using a CRISPR-based therapy, which would have been the first study in the U.S. to use the technology. Other trials have been slated at Stanford Univ. and the Univ. of Pennsylvania with no definite start date yet. Experts believe a dozen or more trials could begin in the U.S. by the end of next year.

The problem stems from a DNA damage response led by p53 within the cell, which can be activated by certain applications of CRISPR technology. When some potential CRISPR therapies are applied to a group of cells, cells with functioning copies of p53 detect the CRISPR modifications and stop growing, allowing cancer-prone cells that lack the p53 machinery to continue to proliferate. These cancerous cells could then be introduced into a patient.

“This study teaches us that genome-edited cells should be studied carefully for p53 mutation and other potential dangers in the genome before they can be used in therapeutic applications,” says Ahmet Yildiz, an associate professor of physics and molecular cell biology at the Univ. of California, Berkeley, who did not participate in the two studies in question.

Selecting for p53 dysfunction

The CRISPR, or clustered regularly interspaced short palindromic repeat technique, draws on a function of the adaptive immune systems of bacteria to thwart viruses. CRISPR-associated proteins, known as Cas nucleases, are directed to make cuts in the genome where new material can be inserted.

Bacteria use CRISPR as a type of defense system — tagging viral genetic material so that other Cas proteins can identify and deactivate the virus the next time it attacks. In multi-celled organisms, however, the Cas9 nuclease is combined with guide RNA to allow researchers to make cuts at specific targets along the genome and remove or change the DNA at that location.

Cells are typically grown in culture and transfected with the CRISPR system. In past attempts to use CRISPR in human cells, some types of human cells did not yield many transformed cells that were viable...