Repairing defective genes in humans has been a tantalizing idea in medical research for decades, with far more disappointment than success. But now new methods of DNA engineering are giving scientists precise ways to delete or edit specific genetic sequences.

One especially promising method was inspired by the nifty way that certain bacteria fend off viruses. When a virus infects a bacterium, it mimics the viral DNA and inserts it into its own bacterial genome. This has the effect of forming “clustered regularly interspaced short palindromic repeats,” or CRISPRs. CRISPRs essentially immunize the bacteria against the virus, because the next time the bacteria is infected, it recognizes the viral DNA and makes a short RNA sequence that guides an enzyme called a nuclease to render the virus harmless by cutting its DNA.

In 2012 scientists adapted the CRISPR bacterial defense system into a gene-editing tool that could be tuned precisely to target any gene. Because they can use it to knock out genes or repair mutations, this technology is helping scientists better understand the connection between genetics and disease. And some research could ultimately lead to treatments and other medical applications.

Preventing disease

This year Eric Olson’s lab at the University of Texas Southwestern used CRISPR to prevent Duchenne Muscular Dystrophy (DMD) in mice. In humans, DMD is caused by mutations in the dystrophin gene. Olson’s team used mice that had been altered to have a defective dystrophin gene. They injected single-celled mouse embryos with CRISPR gene-editing ingredients, including a correct dystrophin DNA template. The treated mice showed less muscular damage and had better grip strength than untreated mice.

Also in 2014, Jinsong Li at the Chinese Academy of Sciences in Shanghai used CRISPR to edit out a cataract-causing mutation in the Crygc gene in the kind of stem cells that eventually develop into sperm cells in mice. The treated cells were then injected into the testes of infertile male mice, where they developed into immature sperm cells. These cells were collected and used for in vitro fertilization of mouse egg cells. Once injected into female mice, the treated cells developed into 39 live pups—all of which had the corrected Crygc gene and did not develop cataracts. This treatment approach is unlikely to be used in human patients, since cataracts can be addressed in far easier ways. However, this study indicates it is possible to prevent disease-causing mutations from being transmitted from one generation to the next.

Curing disease

It is much easier to prevent disease by editing the genome of embryos than to cure disease by gene editing in adult animals, which are made up of billions of cells. However, this year Daniel Anderson’s group at MIT used CRISPR to treat adult mice with the inherited liver disease hereditary tyrosinemia I. These mice, like humans with hereditary tyrosinemia I, have a mutation in the Fah gene. Anderson’s team delivered CRISPR to the mice via an injection in a vein in their tails. The CRISPR treatment initially corrected the Fah gene in only one out of every 250 liver cells. However, 33 percent of liver cells had the correction after 30 days, probably because the liver has a high rate of cellular turnover, and the cells with normal Fah were healthier than the cells with the mutated gene. Having normal Fah in only one-third of the liver cells was still enough to leave the mice with much less liver damage than untreated mice.

This approach worked because the liver filters all blood, so anything injected into the blood has a high chance of making its way into liver cells. Delivering CRISPR by venous injection is less likely to work in other organs. Anderson says the group is “actively working to develop therapeutically relevant delivery systems for genome repair to a range of tissues.”

Turning genes on

Until recently, CRISPR had largely been used to edit out mutations. Now Feng Zhang and colleagues at MIT and the Broad Institute have altered a key enzyme in the CRISPR system to turn genes on. They showed how the gene-activating technique could be used to figure out which genes conferred resistance to a melanoma drug. Many other applications could be possible as well; the team has made a library of 70,290 guide RNAs—the sequences that guide enzymes to the proper place—that collectively activate every gene in the human genome.

The takeaway

CRISPR gene editing has the potential to become a powerful new medical treatment. But, as in other types of gene therapy, delivery systems need to be refined before this technology can realize its full potential.

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