CRISPR: Editing genes becomes a reality

Samuel H. Sternberg, PhD: “It allows you to really think about treating disease in a different way. Instead of persistent treatments that might require daily or weekly administration, you could turn to a one-time treatment that edits enough of the patient’s cells at the DNA level to eliminate the causative mutation at its source.”

Renowned biochemist Samuel H. Sternberg, PhD, explained CRISPR-Cas9 technology and how it could dramatically change medical treatments when he delivered his address as the Guest Speaker at the Plenary session Friday.

The world is on the cusp of a breakthrough in treating diseases caused by genetic mutations because of CRISPR-Cas9, a technology that enables biochemists to edit defective genes inside cells. CRISPR-Cas9 gene editing technology is being tested in clinical trials, and its story of great promise is told in understandable terms in a new book, A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution written by Dr. Sternberg and biochemist Jennifer Doudna, PhD.

Redefining treatment options

“The real dream would be to deliver CRISPR-Cas9 to patients for monogenic diseases, like cystic fibrosis or sickle cell anemia. It allows you to really think about treating disease in a different way. Instead of persistent treatments that might require daily or weekly administration, you could turn to a one-time treatment that edits enough of the patient’s cells at the DNA level to eliminate the causative mutation at its source,” said Dr. Sternberg.

Dr. Sternberg explained CRISPR-Cas9 technology and how it could change medical treatments when he delivered his address as the Guest Speaker at the Plenary session Friday. He and biochemist Jennifer Doudna, PhD, are the co-authors of the book about CRISPR, A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution.

Dr. Sternberg earned his PhD in chemistry from the University of California, Berkeley, where he worked in Dr. Doudna’s lab as its team advanced the use of CRISPR-Cas9 for gene editing. He is now a scientist and group leader of technology development at Caribou Biosciences, Inc.

Molecular “scissors”

“Certain CRISPR systems comprise Cas9, a protein molecule, and RNA, a polymeric molecule,” Dr. Sternberg said in an interview about his talk. “You can think of these two molecules forming a tight interaction or tight complex that acts like a pair of molecular scissors,” he said. “This complex has two properties. The RNA sequence acts like a pair of GPS coordinates to allow the complex to home in on a very particular sequence of DNA inside of cells. The Cas9 protein acts like the scissors in that it has the property of being able to cut DNA into two pieces. In the context of bacteria, that molecular scissor function is used to actually eradicate viral DNA during an infection. If you use those same properties inside of human cells, you can tap into a cell’s natural ability to repair broken strands of DNA.”

As challenging as it is to bring together Cas9 and RNA, programming the molecular machine to find mutated gene sequences in cells that cause disease is just as big of a test. The mutated DNA sequence is not just removed. Instead, Cas9 cuts the mutated DNA sequence to start a subsequent DNA repair process.

“That damage acts as a hot spot that kicks the cell into this repair mode where you can now harness that damage to initiate the replacement of the mutated sequence with a healthy sequence that eliminates the mutation,” Dr. Sternberg said. “Using standard techniques in biotechnology, we can deliver CRISPR-Cas9 into human cells by packaging the molecules into something called a vector, essentially an artificial mini-chromosome.”

The human cells interpret the vector DNA as their own, then produce the Cas9 protein and the RNA, which homes in on the mutated gene sequence. The damaged DNA initiates the process to edit the mutated gene sequence and begin the repair.

What’s ahead?

“The real challenge moving forward in terms of converting this into something that is going to be effective in the clinic is the delivery,” Dr. Sternberg said. “How can you introduce these molecules into living patients who already have this disease? How can you precisely edit enough cells in the body for there to be a reversal of the symptoms?”

Another challenge he identified is to make the tool accurate enough that it finds and edits only the mutated gene sequence and not other similar sequences. If another gene sequence is promiscuously damaged, the editing process could actually create new mutations.

The first CRISPR clinical trials have begun in China, where the technology is being used to generate gene-edited immune cells that are transplanted into patients to target various cancers through immunotherapy. Other clinical trials are planned in the U.S. and China. These trials involve ex vivo therapies, where immune cells are edited outside the body, expanded, and transplanted back into patients.

The next big step would be in vivo treatments in humans. Several research facilities and multiple companies are working on that technology.

“I think that in the next couple of years we are certainly going to see numerous trials beginning for these ex vivo therapies. It is going to be a bit slower on the in vivo front because the safety and delivery challenges are much greater,” Dr. Sternberg said. “There has been so much momentum on the tool development front that when it comes to editing cells in the laboratory, the technology is working fantastically. Now it’s just a matter of seeing if the efficiency of the editing tools inside the body is going to be high enough.”

Return to AAD Daily articles

Top