Amid Nobel Prize Suspense, Making Sense Of Latest Gene-Editing News

Xconomy National — 

There was a meeting Monday in Washington, D.C., to discuss some of the latest advances in gene editing, a field that has profound medical, agricultural, social, and ethical implications for society. At the lunch break, the webcast played over and over a genteel piece of classical music—Albinoni’s string concerto No. 4 in G major, to be exact—as if you’d called the offices of Masterpiece Theatre and got stuck on hold.

It was a short breather, one could say, from the chaotic pace that gene editing is undergoing at the moment. Or, in musical terms, perhaps it was a prelude to a Nobel Prize for some of the field’s pioneers, as Thomson Reuters predicted last month. (The prize for physics could be announced by the time you read this; the prize for chemistry, Wednesday.)

Convened by the U.S. National Academies, Monday’s meeting was also a warm-up for an international summit in December to hammer out ethical rules for gene editing in the germline—eggs, sperm, and embryos—which has spawned fears that babies will be designed for looks or intelligence, or new organisms will be unleashed into the wild with irreversible consequences.

“We live in remarkable times, and I salute the academies for taking steps to get ahead of this issue,” said Fyodor Urnov, senior scientist at Sangamo Biosciences (NASDAQ: SGMO), whose work has helped bring a treatment for HIV infection into clinical trials, the first and only gene editing program to get that far.

For those who can’t immerse themselves 24/7 in gene editing, following along can sometimes feel like watching multiple freight trains speed past while deciphering tiny print on the sides of each boxcar. The past few weeks have been particularly wild, with movement on the scientific, business, legal, and ethical fronts, so let’s dip into some of the most provocative and intriguing advances.

—New Tools For Gene Repair: The tools of gene editing all have one thing in common: scissors. That is, proteins called enzymes that cut DNA. How those scissors work, how accurately and deeply they cut, and how well they can get to their intended spot are all degrees of difference within the various gene editing systems. In CRISPR/Cas9, the ridiculously easy-to-use gene editing system that has taken the bioresearch world by storm, the Cas9 enzyme mainly comes from the bacterium S. pyogenes. It works pretty well in basic research labs, but as the technology moves toward human therapeutic uses, many researchers have been scrambling to find better versions of Cas9 from other bacteria or different enzymes entirely that might have different properties. (After all, you need more than one type of scissors for various household duties.)

Most recently, Feng Zhang of the Broad Institute of MIT and Harvard University and colleagues published details of an enzyme, Cpf1, which they found by searching through bacterial libraries. (CRISPR is based on the defense system bacteria and archaea use against invasive viruses.) When the paper came out in late September, I wrote about the potential benefits of Cpf1 over Cas9 that Zhang and colleagues outlined in the paper. They were careful to not to overstate those benefits, and outside observers were also circumspect in their appraisal.

Dana Carroll, considered a gene editing pioneer, called Cpf1 “a nice addition to the array of tools we have, but I’m not going to drop Cas9 and pick up the new platform.”

“We’ll have to see how things develop,” said Carroll, a biochemist at the University of Utah whose work on gene editing well predates the CRISPR/Cas9 discoveries. “Based on this paper, there doesn’t seem to be an immediate advantage to the Cpf1 system.”

(It should be noted that Carroll has backed the scientists, led by the University of California, Berkeley’s Jennifer Doudna, who are contesting Zhang and the Broad in the big CRISPR patent dispute. More on that fight, including a new development, later.)

However, Carroll noted one potential practical advantage to the Cpf1 discovery: Cpf1 requires a shorter guide than Cas9 to usher it to the right spot in the genome. Zhang and colleagues noted that the shorter guide could require less material to manufacture if and when Cpf1-based systems scale up into broader research and potentially therapeutic uses. Carroll agreed.

Another potential advantage Zhang and colleagues highlighted was Cpf1’s different cutting mechanism. Cas9 makes “blunt-end” cuts—it snips right through both strands of DNA at the same place. Cpf1 makes staggered cuts, as if the blades of its scissors were misaligned. Because of the different ways cells repair cuts in DNA, which they do all the time, the misaligned cuts are actually a good thing if you’re trying not just to snip out a gene but replace it with a new one.

For making new medicines, replacement is a big deal. It means far more genetic diseases, beyond the ones that can be cured by just snipping out a bad gene, could be treated.

“To repair genes is the holy grail of unlocking all the potential for this technology,” said Vic Myer, the chief technology officer of Editas Medicine, in an interview that took place before Zhang’s Cpf1 paper came out. (Zhang is a scientific cofounder of Editas, which is just a few blocks away from Zhang’s lab in Cambridge, MA.)

But cells prefer to fix themselves in a rather messy way at the cut site. (Imagine a wound healing with an ugly scar.)  This cellular preference makes fusing in a new gene very tricky. It’s proving difficult to do this replacement—or recombination, in gene-speak. Myer said Editas is working … Next Page »

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