CRISPR Gene Editing: Proofreaders and Undo Buttons, but Ever "Safe" Enough?

News about genetic engineering continues to emerge at a dizzying pace. In recent weeks, a handful of reports suggest that the suite of new “gene editing” tools may have so-called “proofreaders” and “undo” protocols that increase technical safety. At the same time, a growing consensus seems to be emerging that looks beyond immediate technical safety to the long-term and social implications of modifying the genes of human embryos for the purpose of “enhanced” reproduction.

Is CRISPR safer?

A November 13 story in The Scientist, headlined Cas9 Proofreads Gene Edits, canvassed two recent research publications (in Nature and Science) co-authored by CRISPR co-discoverer Jennifer Doudna. The take-home message was that the Cas9 protein – the molecule charged with making cuts to DNA in the CRISPR/Cas9 gene editing complex – may have certain built-in mechanisms that work against off-target cuts. The headline’s metaphorical imagination conformed to the headline used by UC Berkeley in its related November 12 press release: CRISPR-Cas9 gene editing: check three times, cut once.

The same day, VICE Motherboard reported on work done by researchers at UMass Medical School (published in Molecular Therapy) that “used a ’non-cutting’ version of the protein Cas9” to research the genetics of muscular dystrophy. In contrasting the UMass team’s research with the typical function of CRISPR/Cas9 complexes, VICE’s Melissa Cronin wrote descriptively,

Usually, CRISPR is a cutting machine, hacking away at pathogenic genes. But sending a weed-whacker into a delicate genome to cut away hundreds of spots is risky, and could result in mistakes.

On November 16, Nature News described research by a team including George Church and Kevin Esvelt on gene drive – a technology that can amplify specified genes in populations by altering inheritance probabilities –  with the headline: Safety upgrade found for gene-editing technique. A few days earlier, Sharon Begley had reported in STAT on increasing concerns with gene drives with the headline Why FBI and the Pentagon are afraid of gene drives. The “undo button” proposed by Church, et al.’s research, or what Scientific American referred to perhaps appropriately as a “kill switch” [paywall], was, it seems, more of the unforeseeable same. The so-called upgrade was “sending a second gene drive out to undo the effects of the first.”

Is there an emerging consensus against CRISPR-ing future people?

These recent headlines may “calm some fears about the technology.” But even if the promised safeguards function as advertised, they wouldn’t necessarily prevent gene editing tools from effecting unforeseeable and irreversible changes to human genomes or ecological systems – not to mention the fabric of our society. Gang Bao, professor and bioengineering researcher at Rice University who studies the genetics of sickle cell disease, recently noted:

In the germline, off-target effects might persist for generations and could lead to long-term changes in the genome. Until we know the full consequences of gene editing, it would be a huge mistake to use it to modify the germline.

Jennifer Doudna has long been cautious of the potential for CRISPR technology to go awry. Just days prior to her most recent publication, she was quoted by Michael Specter in The New Yorker story The Gene Hackers on its potential to “do more harm than good”:

"I lie in bed almost every night and ask myself that question," she said. "When I’m ninety, will I look back and be glad about what we have accomplished with this technology? Or will I wish I’d never discovered how it works? … I have never said this in public, but it will show you where my psyche is,” she said. “I had a dream recently, and in my dream”—she mentioned the name of a leading scientific researcher—“had come to see me and said, ‘I have somebody very powerful with me who I want you to meet, and I want you to explain to him how this technology functions.’ So I said, Sure, who is it? It was Adolf Hitler. I was really horrified, but I went into a room and there was Hitler. He had a pig face and I could only see him from behind and he was taking notes and he said, ‘I want to understand the uses and implications of this amazing technology.’ I woke up in a cold sweat. And that dream has haunted me from that day. Because suppose somebody like Hitler had access to this—we can only imagine the kind of horrible uses he could put it to."

Many voice concern that eugenics in the modern age could be as pernicious as the twentieth-century variety, even if it is submerged in the shiny casing of individual consumer decisions. Nathaniel Comfort’s historical essay Better Babies (Aeon, November 17) argues,

Scientific medicine rescued eugenics, turning human perfection from a social programme [of who to mate with and who to sterilize] into a biotechnical problem. … CRISPR must be seen as the latest step in this history of promises: the promise of ending genetic disease, of designer babies, of the self-direction of human evolution.

Other recent stories have echoed these concerns: Would you edit your unborn child’s genes so they were successful? (The Guardian UK), The Risks of Assisting Evolution (The New York Times), The Crispr Quandary (The New York Times Magazine), Experts debate: Are we playing with fire when we edit human genes? (STAT). More and more observers and stakeholders appear to be taking a cautious position on this technology. In that STAT story, a number of notables were asked where they stood on the issue of germline editing. Pushing the discussion beyond research gaps in technical safety, NIH director Francis Collins explained:

[P]reimplantation genetic diagnosis already offers a practical and much less ethically challenging option for most couples seeking to avoid the birth of a child with a serious genetic disorder. … Do we want to accept the scenario that only those with financial resources get to ‘improve’ the genomes of their children?

Collins concluded that there was a “profound paucity of compelling cases” where germline editing could overcome a balance that “leans overwhelmingly against human germline engineering.”

Bioethics professor R. Alta Charo is co-chair of the recently announced committee charged with producing a “consensus study” after the upcoming National Academies “international summit on human gene editing.” This makes her comments, published by the University of Wisconsin Madison’s news office, particularly interesting:  

Changes to germ line cells will affect all subsequent generations. Ethically, it offers possible benefits to — but imposes risks on — people who were never involved in the original decision. And whatever happens, good or bad, will reverberate down the generations. ... germ line engineering is, in my opinion, the least likely gene editing application in the near term — potentially forever. Established methods could, a lot more simply, avoid some grievous or fatal genetic defects. You could adopt a child or use donor sperm and eggs. Or you could use in vitro fertilization and pre-implantation genetic diagnosis for embryo selection to avoid bringing a child into the world who will suffer with a serious disease.

All these recent comments suggest that even as researchers rush to proclaim they’re solving CRISPR’s technical limitations, its long-term consequences and social implications can’t be ignored.

Previously on Biopolitical Times:

• Gene Editing and Eugenics (Opinions Vary)
• Considering CRISPR: Putting a thumb on the scale?
• Fast Forward-Pause-Stop: The 3-Speed Human Germline Debate
• Putting Ourselves in Harm’s Way: Thoughts on Pinker and the Role of Bioethics
• The Science and Ethics of Genetically Engineered Human DNA

Image via Flickr/Nate Bolt