Thursday, June 04, 2015

The CRISPR way to danger

The sudden burst of interest in the ethics of human genome editing has come about because of the recent arrival of a new gene editing technique called CRISPR, and there is an excellent Nature News feature up about it, which notes warnings and misgivings from scientists about how it could go wrong.

Some extracts:
 CRISPR is causing a major upheaval in biomedical research. Unlike other gene-editing methods, it is cheap, quick and easy to use, and it has swept through labs around the world as a result. Researchers hope to use it to adjust human genes to eliminate diseases, create hardier plants, wipe out pathogens and much more besides. “I've seen two huge developments since I've been in science: CRISPR and PCR,” says John Schimenti, a geneticist at Cornell University in Ithaca, New York. Like PCR, the gene-amplification method that revolutionized genetic engineering after its invention in 1985, “CRISPR is impacting the life sciences in so many ways,” he says....

Biologists have long been able to edit genomes with molecular tools. About ten years ago, they became excited by enzymes called zinc finger nucleases that promised to do this accurately and efficiently. But zinc fingers, which cost US$5,000 or more to order, were not widely adopted because they are difficult to engineer and expensive, says James Haber, a molecular biologist at Brandeis University in Waltham, Massachusetts. CRISPR works differently: it relies on an enzyme called Cas9 that uses a guide RNA molecule to home in on its target DNA, then edits the DNA to disrupt genes or insert desired sequences. Researchers often need to order only the RNA fragment; the other components can be bought off the shelf. Total cost: as little as $30. “That effectively democratized the technology so that everyone is using it,” says Haber. “It's a huge revolution.”

Now the warnings:
“This power is so easily accessible by labs — you don't need a very expensive piece of equipment and people don't need to get many years of training to do this,” says Stanley Qi, a systems biologist at Stanford University in California. “We should think carefully about how we are going to use that power.”...

“People just don't have the time to characterize some of the very basic parameters of the system,” says Bo Huang, a biophysicist at the University of California, San Francisco. “There is a mentality that as long as it works, we don't have to understand how or why it works.” That means that researchers occasionally run up against glitches. Huang and his lab struggled for two months to adapt CRISPR for use in imaging studies. He suspects that the delay would have been shorter had more been known about how to optimize the design of guide RNAs, a basic but important nuance.

 ...Doudna has begun to have more serious concerns about safety. Her worries began at a meeting in 2014, when she saw a postdoc present work in which a virus was engineered to carry the CRISPR components into mice. The mice breathed in the virus, allowing the CRISPR system to engineer mutations and create a model for human lung cancer4. Doudna got a chill; a minor mistake in the design of the guide RNA could result in a CRISPR that worked in human lungs as well. “It seemed incredibly scary that you might have students who were working with such a thing,” she says. “It's important for people to appreciate what this technology can do.”

Andrea Ventura, a cancer researcher at Memorial Sloan Kettering Cancer Center in New York and a lead author of the work, says that his lab carefully considered the safety implications: the guide sequences were designed to target genome regions that were unique to mice, and the virus was disabled such that it could not replicate. He agrees that it is important to anticipate even remote risks. “The guides are not designed to cut the human genome, but you never know,” he says. “It's not very likely, but it still needs to be considered.”

As the article later notes, it might end up being a case like the earlier excitement about gene therapy falling apart, when researchers discovered it was a lot trickier to administer that hoped, and could kill.

This seems very likely to me.

My hunch, expressed in an earlier post, was that working on the molecular genetic scale is never likely to be easy and would be readily capable of having unintended consequences on other bits of the gene.  Seems I was right:
Yet many scientists caution that there is much to do before CRISPR can be deployed safely and efficiently. Scientists need to increase the efficiency of editing, but at the same time make sure that they do not introduce changes elsewhere in the genome that have consequences for health. “These enzymes will cut in places other than the places you have designed them to cut, and that has lots of implications,” says Haber. “If you're going to replace somebody's sickle-cell gene in a stem cell, you're going to be asked, 'Well, what other damage might you have done at other sites in the genome?'”

Keith Joung, who studies gene editing at Massachusetts General Hospital in Boston, has been developing methods to hunt down Cas9's off-target cuts. He says that the frequency of such cuts varies widely from cell to cell and from one sequence to another: his lab and others have seen off-target sites with mutation frequencies ranging from 0.1% to more than 60%. Even low-frequency events could potentially be dangerous if they accelerate a cell's growth and lead to cancer, he says.
What's more, I wouldn't be confident that even the successful removal of certain bits of DNA which cause disease might not turn out to have other, non desired, effects, but no one in the article addresses that.  

As the article goes on to also explain, the technique has the potential to bioengineering animals that always pass on the new characteristic, leading to the possibility of completely eradicating species very quickly.  But at what ecological cost?

So libertarians can get as uptight as they like about bioethicists who are philosophically opposed to editing the human genome for permanent changes down the line, but they ought to look at the real and practical issues with the process because they get too excited about its potential.

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