Gene Scientists Don't Fear the Latest Crispr Snag

(Bloomberg View) -- It can feel shocking when someone disparages a golden person, thing or technology -- and in recent years, no emerging technology has glittered as brightly as the gene-altering technique known as Crispr. So some investors were apparently jolted earlier this month when MIT Technology Review ran a news item headlined “Uh-Oh -- Crispr Might Not Work in People.”

Any technology that’s never been tested in clinical trials runs that risk. With Crispr, there has yet to be a single human experiment in the U.S. or Europe. Human experiments are just beginning in China, but American researchers say they don’t have complete information on how those are turning out.

Crispr still promises to transform agriculture, manufacturing and other endeavors, but making it “work” in people -- presumably by treating diseases -- presents a different challenge, since human lives are on the line.

The news item under the “might not work” headline described an unpublished but credible study out of Stanford University, which used samples of human blood to demonstrate that some forms of Crispr-based therapies might set off a dangerous immune response.

One of the authors of the paper, Stanford pediatrics professor Matthew Porteus, said the take-home message isn’t that Crispr might not work in people, but that it might work in principle, and that a scientist somewhere might make a fatal mistake and that could set everything back for years.

That is, there are probably ways scientists could proceed to test Crispr that would save lives and heal the sick, and other ways that would accidentally harm or even kill people. Scientists are now standing at the frontier. There are no obvious signposts showing the safest possible road to take.

History is littered with warnings. It was a violent immune response called a cytokine storm that killed an 18-year-old patient at the University of Pennsylvania nearly 20 years ago, when researchers started testing a similarly pioneering DNA-altering technique known as gene therapy. Jesse Gelsinger, one of the first test subjects, suffered from an incurable but immediately life-threatening genetic disease. In hindsight, the experimental trial he entered was too rushed, and the version of gene therapy used was not safe enough.

Porteus himself is working with FDA to start clinical trials of a Crispr-based therapy for sickle cell disease. The key difference between Crispr and more traditional gene therapy, he said, is in its precision. The original version of gene therapy relies on viruses that have been modified to insert desired genes into the DNA of patients. In Crispr-based therapies, scientists use a bacterial protein called Cas9 to snip a patient’s DNA in a chosen place, where scientists can introduce a corrected or altered version of a gene.

His experiments, however, showed that many people already have immunity to the Cas9 proteins, which they probably got after being infected with Cas9-carrying staph and strep bacteria. That immunity, he said, may or may not lead to a dangerous reaction in patients, but it’s something to be very careful of. He and other scientists say it’s not a deal-breaker, even for people with immunity to those proteins, because there are other proteins that could be adapted to do the job.

Some of the first human experiments in the U.S., including the ones he plans on sickle cell patients, will use the Cas9 proteins on blood cells outside the body, so there’s little chance the immune system will cause any trouble. When the altered blood cells are put back into patients, the hope is that they will begin producing healthy hemoglobin, rather than the faulty sickle-cell version.

A somewhat darker view came across in a STAT headline that proclaimed Genome-editing companies play down Crispr paper, as concerns drive down shares. This hints at a potentially nefarious trade-off between patient safety and money.

I talked this over with McGill University medical ethicist Jonathan Kimmelman, who specializes in the risks of medical experiments and has written a book about them centered on the Jesse Gelsinger case. Of course, he says, money isn’t the only thing that might prevent medical researchers from being perfectly objective -- there’s the desire to be heroes, to beat rivals, and to help patients. A bigger concern is the fact that whatever is driving scientists, they can have blind spots just like everyone else.

Indeed, many other seemingly promising medical technologies have caught scientists up short with unintended consequences, he said, from fetal tissue transplants for Parkinson’s disease causing jerky involuntary movements, to targeted cancer therapies showing heart toxicity.

Sometimes scientists get focused on one potential problem, and then miss something else that’s right in front of them, he said -- the way people in a famous psychology experiment failed to spot a gorilla strolling through the frame of a film.

Kimmelman says anyone who wants to anticipate the future of new medical technology could benefit from stepping back and looking at the overall success rate for novel medical technologies -- where they proved better than existing medicine, how they met or failed to meet expectations, and what, if anything went wrong. Stanford’s Porteus made a similar observation. Technological hurdles are inevitable. But while some investors may let themselves get tossed around by every wave reported in the headlines, most scientists are taking a longer view.

This column does not necessarily reflect the opinion of the editorial board or Bloomberg LP and its owners.

Faye Flam is a Bloomberg View columnist. She has written for the Economist, the New York Times, the Washington Post, Psychology Today, Science, New Scientist and other publications. She has a degree in geophysics from the California Institute of Technology, and has been a Knight-Wallace fellow at the University of Michigan.

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