Nature: Encourage the innovatorsIn Washington:
International scientific academies will be discussing the issue of human-germline editing in Washington DC on 1–3 December. Now is, therefore, a good time to encourage the general public to become well informed on key issues, which may get muddled by out-of-date facts or loose phrasing. This technology is poised to transform preventive medicine. Rather than talk about the possibility of banning alteration of the human germ line, we should instead be discussing how to stimulate ways to improve its safety and efficacy. I hope to rectify some common misconceptions.
... Those who want to ban human-germline editing should also consider that such a move would do little to allay concerns about ethically dubious attempts to 'enhance' humans. To think that there is not already a cadre of IVF clinicians poised to engage in such practices, perhaps even supported by governments, is to ignore, for example, the history of doping in sport. These kinds of ambitious individuals and institutions are unlikely to be dissuaded by an agreement made on their behalf by others with a different view.
... the concept of a ban on germline editing does not make sense. There is already a ban on using medical technologies in humans until they are proven safe and effective in appropriate animal trials. Then, following human trials, they can only be applied to the general population for those conditions for which their use has been demonstrated. Banning human-germline editing could put a damper on the best medical research and instead drive the practice underground to black markets and uncontrolled medical tourism, which are fraught with much greater risk and misapplication. Instead, the generally high safety and efficacy standards of regulatory agencies should be encouraged rather than saddled with pessimistic assumptions about the trajectory of promising approaches.
NYTimes: Scientists Place Moratorium on Edits to Human Genome That Could Be InheritedNote who the author of the Times piece is ;-)
An international group of scientists meeting in Washington called on Thursday for what would, in effect, be a moratorium on making inheritable changes to the human genome. The group said it would be “irresponsible to proceed” until the risks could be better assessed and until there was “broad societal consensus about the appropriateness” of any proposed change.
The group also held open the possibility for such work to proceed at some point in the future by saying that as knowledge advances, “the clinical use of germline editing should be revisited on a regular basis.”
The meeting was convened by the National Academy of Sciences of the United States, the Institute of Medicine, the Chinese Academy of Sciences and the Royal Society of London. The academies have no regulatory power, but their moral authority on this issue seems very likely to be accepted by scientists in most or all countries. Similar restraints proposed in 1975 on an earlier form of gene manipulation by an international scientific meeting in California were observed by the world’s scientists.
The participation of the Chinese Academy of Sciences is a notable coup for the organizers of the meeting, led by David Baltimore, former president of the California Institute of Technology, given that earlier in the year Chinese scientists seemed to be racing ahead independently toward clinical alterations to the human germline. ...
Meanwhile, the technology continues to advance:
MIT News: MIT, Broad scientists overcome key CRISPR-Cas9 genome editing hurdleSee also
... In a paper published today in Science, Feng Zhang and his colleagues report that changing three of the approximately 1,400 amino acids that make up the Cas9 enzyme from S. pyogenes dramatically reduced “off-target editing” to undetectable levels in the specific cases examined. Zhang is the W.M. Keck Career Development Professor in Biomedical Engineering in MIT’s departments of Brain and Cognitive Sciences and Biological Engineering, and a member of both the Broad Institute and McGovern Institute.
Zhang and his colleagues used knowledge about the structure of the Cas9 protein to decrease off-target cutting. DNA, which is negatively charged, binds to a groove in the Cas9 protein that is positively charged. Knowing the structure, the scientists were able to predict that replacing some of the positively charged amino acids with neutral ones would decrease the binding of “off target” sequences much more than “on target” sequences.
After experimenting with various possible changes, Zhang’s team found that mutations in three amino acids dramatically reduced “off-target” cuts. For the guide RNAs tested, “off-target” cutting was so low as to be undetectable. ...
WIRED: ... Today, on the first day of an international summit on human gene editing in Washington, DC, MIT researchers announced that they have tweaked a Crispr protein to reduce those off-target effects. It’s the latest in a series of improvements to the Crispr system that, together, are inching the error rate down toward practically zero.
... On face of it, the MIT paper is yet another molecular nuts and bolts study with a barely scrutable title (“Rationally engineered Cas9 nucleases with improved specificity”). Crispr is essentially a pair of DNA scissors, and Cas9 is the protein in the Crispr system that unzips DNA and runs along looking for its target by matching the DNA sequence against a snippet of its guide RNA. When Cas9 finds its target, snip snip. The problem is that Cas9 will sometimes think it’s found a target even when up to five of the guide RNA’s approximately 20 letters do not match the DNA—hence the off-target mutations.
Feng Zhang, another scientist with a claim to CRISPR’s invention as a gene-editing technique, and his colleagues at MIT changed one part of Cas9 slightly so its guide RNA binds fewer mismatched DNA sequences. This improved Cas9’s specificity by about 25-fold at the sites they tested. Zhang’s lab, along with that of other labs of Harvard, have come up with several other ways to make Cas9 better behaved, such as pairing up Cas9s so they only work in twos and both guide RNAs match.
With these improvements, Harvard geneticist George Church estimates that Crispr’s error rate, best-case scenario, could be just 1 in 300 trillion letters of DNA. (The rate can vary quite widely in different types of cells and with different guide RNA designs.) Even at the higher end, that’s comparable to the spontaneous mutation rate in humans, says Church.
He asserts that off-target mutations are already a solved problem. With typical Churchian flair, he says, “I’m beginning to feel like this is hitting a fly with sledgehammer. I think the thing is already dead.” Even if not all scientists agree about off-target mutations yet, solving the problem of Crispr’s non-specificity is looking more like a question of when rather than if. ...