CRISPR pioneer Jennifer Doudna shares her outlook for the groundbreaking gene-editing tool

It’s been less than five years since University of California, Berkeley, biochemist Jennifer Doudna and colleagues unveiled the gene-editing tool CRISPR in Science (2012, DOI: 10.1126/science.1225829), but its use among researchers across the globe has already exploded.

Last April, for example, Sichuan University scientists announced that they had used CRISPR to program T cells from the immune system of a person with lung cancer to kill tumor cells (Nature 2016, DOI: 10.1038/nature.2016.20988). And late last year, a UC Berkeley team reported harnessing the technology to correct the genetic mutation responsible for sickle cell anemia in stem cells from patients with the disease (Sci. Transl. Med. 2016, DOI: 10.1126/scitranslmed.aaf9336).

Doudna didn’t set out to develop a far-reaching gene-editing tool years ago. Initially, her team wanted to uncover the role of CRISPRs—short for “clustered regularly interspaced short palindromic repeats”—which are repetitive sequences of RNA hidden in the genomes of many bacteria.

Eventually, Doudna; Emmanuelle Charpentier, now the director of the Max Planck Institute for Infection Biology; and coworkers discovered that CRISPRs help bacteria fight viral infection. Bacteria snag bits of an invading virus’s RNA and tuck them into CRISPRs, the team found. If the virus strikes again, these modified CRISPRs bind to the pathogen’s DNA, signaling to the enzyme Cas9 to come and dice up the foreign genetic material. The researchers realized they could harness this machinery to cut and paste target DNA fragments at will, as long as they introduced the appropriate designer RNA sequences.

What started as a small project “aimed at something seemingly unrelated … led to a very different direction,” Doudna said during the Kavli keynote address on April 3 at the ACS national meeting in San Francisco. C&EN caught up with Doudna at the meeting to discuss the importance of curiosity-driven basic research and her outlook for CRISPR.

How do you think CRISPR will impact chemistry, including how chemists conduct research?

The convergence of chemistry with other disciplines to tackle interesting problems in science is exciting. More and more, I see chemists using gene editing to make precise changes to molecules, such as proteins. That allows them to connect discoveries made using purified biomolecules outside cells—enzymes reacting in lab vessels, for instance—to what you would find in a living organism. That’s really amazing. With better chemical understanding of the way these enzymes operate, it will be possible to use them in ways that they don’t seem to be deploying in nature.

The ability to make changes to the DNA of plant cells also opens up opportunities both in research and in solving problems in agriculture. That includes helping plants defend themselves against infection, drought, and other climate-change-related issues from a chemical perspective. With CRISPR, you understand the precise changes that you’re making to DNA—at the level of individual base pairs—rather than randomly introducing changes by exposing plant seeds to chemicals that cause DNA mutations.

In drug discovery, one of the big challenges for chemists is determining the targets of small molecules. Now, you can potentially very rapidly figure out the targets by using CRISPR to query cells on a genomewide scale. You can disrupt certain genes and then ask if cells are still susceptible to the small molecules. I’m excited about that as an important research application but also as a practical way of doing drug discovery.

Most CRISPR work has so far been carried out in the lab. What real-world applications of CRISPR can we expect to see first?

We can do gene editing on cells ex vivo—meaning outside the organism—and the edited cells can then be reintroduced to the body, which gets around the challenge of drug delivery. For clinical use, we’ll probably see treatments like this that involve immune cells in the blood first, since they can be collected outside the body.

In agriculture, we’ve already begun seeing products that have been created using precision gene editing. That brings up a bunch of regulatory challenges. The U.S. Department of Agriculture has decided that plant products created using CRISPR that don’t introduce foreign DNA are not considered genetically modified, which has led to lots of discussion. In other countries, the regulation of GMO plants is different, so I think people are being pushed to reevaluate how these are defined based on the opportunities we now have with CRISPR.

What improvements would you like to see made to the technology?

Where we’ll likely see advancements being made is in deploying CRISPR to do more specific kinds of things. One is using it not to cleave DNA directly but to make a direct chemical modification to DNA, whether it’s changing one nucleotide base into another one or adding a methyl group.

What ethical issues will researchers need to consider in their applications of CRISPR?

CRISPR has made possible genetic changes in individual organisms and even made it possible to pass along changes to offspring. This raises ethical concerns, particularly regarding human embryo or germ-line editing that might lead to permanent changes in the DNA that can be passed on to future generations. I’ve been actively involved in discussing these issues. As scientists, we need to explain what we’re doing and why we’re doing it, not dictating how these discoveries and technologies should be used. We need to participate in those conversations with the public. This is important, especially now, when there’s a lot of questioning about scientific knowledge, the value of facts, and how scientific data are used to help governments make decisions about regulations and funding.

In February, the U.S. Patent & Trademark Office upheld patents awarded to the Broad Institute of Massachusetts Institute of Technology and Harvard University for the use of CRISPR in eukaryotic cells. About a month later, the European Patent Office announced plans to award a patent to the University of California that covers a wide range of CRISPR uses. How do you see the patent battle playing out in the years ahead?

Patents around important technologies typically are complicated. It takes a while to sort them out, and CRISPR is no different. Honestly, I think it will take a while before the patent situation is resolved in different countries. The exciting thing for me is that we’re seeing rapid deployment of the CRISPR technology both in academic settings and in companies. That’s leading to real advances for various diseases. There are exciting uses in agriculture and in fundamental research. None of that is being hampered by the current patent situation.

CORRECTION: This Q&A was updated on April 21, 2017, to correct the affiliation of the team that used CRISPR to fix the genetic mutation responsible for sickle cell anemia in patients’ stem cells. It is UC Berkeley, not Stanford.