Editing DNA could be genetic medicine breakthrough

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A new way to make powerful changes at will to the DNA of humans, other animals and plants, much like how a writer changes words in a story, could usher in a transformation in genetic medicine.

Scientists are not just excited about this recently discovered technique because it can snip and edit DNA with precision. It can also do the job more easily and cheaply than other gene-editing methods, making possible research that has historically been difficult, experts say.

Now some of the biologists who unlocked this tool, derived from the immune system of bacteria, are forming companies around it. Although this molecular system, known as Crispr, is not fully understood, researchers believe it can be harnessed to create therapies for intractable genetic diseases.

One of those scientists, UC Berkeley Professor Jennifer Doudna, was part of the team that in 2012 first demonstrated the technique. It is now employed by two companies she has co-founded: Caribou Biosciences in Berkeley, and Editas Medicine in Cambridge, Mass. The latter started last year with $43 million in venture capital. Another company, the aptly named Crispr Therapeutics in Switzerland, has $25 million in the bank, and other biotechnology companies are experimenting with the procedure.

"In principle, this is a technology that could enable correction of genetic mutations that would otherwise lead to disease," said Doudna, a professor of chemistry and biochemistry and molecular biology, in a telephone interview. She was among several experts who spoke at a UC Berkeley conference on the subject last month.

Ethical concerns

But because the method is in its infancy and has little precedent with the agencies that regulate medicines, it will almost certainly be a long time before a Crispr-based therapy makes it to market.

Its potential risks also concern some bioethicists.

"In the very worst case, technologies that can cause permanent inheritable changes in people bring you very close to the risk of modern eugenics," said Pete Shanks, a consultant who blogs about the topic for the Center for Genetics and Society, a bioethics watchdog organization in Berkeley. "Pretty much everyone agrees that we should avoid that. How we do that, comes the question."

The technique operates on the recent discovery that bacteria, like humans, have an immune system that remembers viruses that have attacked before. To protect themselves, bacteria chop up and incorporate short fragments of foreign invaders' genetic code so they know to destroy a virus should it strike again. It is their equivalent of developing vaccines.

Those new fragments in the bacterial genome add up to an "unusual structure," first reported in the late 1980s by scientists who called them "clustered regularly interspaced short palindromic repeats" - Crispr for short. But Crispr's role, to fight infections, wasn't confirmed until 2007.

Interest in Crispr intensified two years ago. While investigating how Crispr works, Doudna's team discovered a way to use the system to slice up any DNA sequence of their choosing.

After selecting an area to be cut, scientists deploy a DNA-like molecule called "guide RNA" to bind to the DNA sequence in question. Also bound to the guide RNA is a protein that cuts the DNA, which usually ends up inactivating the gene. Researchers can also throw additional DNA into the mix to change a gene.

A 'tour de force'

After Doudna's team published their findings in Science, they and other scientists set out to see if Crispr could be used to edit DNA in the cells of organisms besides bacteria. It has since been shown to work in humans, mice, zebrafish, fruit flies, monkeys and others.

The procedure was labeled a "tour de force" in a 2012 review in the journal Nature Biotechnology.

But Crispr is not perfect: It does not always bind to the intended DNA targets. Nor is it the only gene-editing method.

Two others - zinc-finger nucleases and transcription activator-like effector nucleases - also allow scientists to snip DNA at a particular region of a genome and insert an alternative piece of DNA. But Crispr's proponents say those methods require comparatively more work to direct proteins to the desired targets.

So far, Editas has not revealed how it might use Crispr to treat diseases. But Doudna, who is not involved with the company's operations, said, "What's on everybody's radar - and it's certainly no secret - is blood disorders that involve genetic mutations might be very attractive ones to treat with this technology."

A treatment for sickle cell anemia or beta thalassemia, for example, could involve engineering a patient's blood cells to express a correct version of the hemoglobin protein, then putting those cells back into the person, she said.

Doudna is also a scientific adviser to Caribou, whose dozen or so employees work in a life-sciences incubator in Berkeley. It wants to use Crispr to develop products for companies in fields such as basic research and drug development.

No ownership

"Something challenging but also incredibly exciting is how many other people are working on this technology at the same time," CEO Rachel Haurwitz said. "There's no opportunity for any company to own this technology right now."

Some scientists have set their sights beyond drugs for humans. In July, researchers and policy experts proposed to fight malaria by genetically engineering the mosquitoes that carry the lethal disease. Crispr could be used, they said, to make the insects resistant to the malaria parasite or to engineer them to be infertile.

But Doudna expressed concern that such an experiment on the ecosystem "is going to have a ripple effect you can't always predict."

It is just one example of the murky boundaries that scientists, ethicists and regulators will have to clarify as Crispr's possible uses multiply.

"We're moving here into potentially very dangerous areas," Shanks said, "which potentially may also be very useful."