Jennifer Doudna on CRISPR’s 10-Year Anniversary

Jennifer Doudna was staring at a computer screen filled with a string of As, Cs, Ts, and Gs—the letters that make up human DNA—and witnessing a debilitating genetic disease being cured right before her eyes. Just a year earlier, in 2012, she and microbiologist Emmanuelle Charpentier had published a landmark paper describing CRISPR-Cas9, a molecular version of autocorrect for DNA, and she was seeing one the first demonstrations of CRISPR’s power to cure a human disease. She was in the lab of Dr. Kiran Musunuru, a Harvard researcher who was eager to show her the results from an experiment he had just finished using CRISPR to treat the blood cells from a patient with sickle cell anemia. What the analysis revealed was something that few scientists had seen before: after using CRISPR, the mutation responsible for causing the patient’s sickle cell anemia was no longer detectable.

It was a thrilling validation of Doudna’s work as a co-discoverer of CRISPR, a technology that allows scientists to edit the DNA of any living thing with a precision that had never before been possible. In the case of sickle cell anemia, CRISPR spliced out a single aberrant letter from the 3 billion base pairs of DNA in a patient’s cells. With the mutated letter gone, the cells would, presumably, start forming healthy red blood cells that carry oxygen instead of the harmful versions that make the disease so painful for the 100,000 people living with the condition in the U.S.

“That was the moment when it really hit me that these patients wouldn’t have disease anymore,” Doudna says. “The concept of curing diseases that in the past were manageable at best was really a turning point.”

It has been 10 years since Doudna and Charpentier published the first paper describing the technology. During that decade, CRISPR has driven innovative thinking in nearly every aspect of life on earth. Scientists and companies are testing CRISPR not just to treat human disease, but also to improve plant crops and alter the populations of microbes in livestock that contribute to greenhouse gasses due to their methane emissions and ultimately to climate change. Drought and pesticide resistance, more carbon-friendly livestock, and lower-emission populations of gut microbes are all possible with CRISPR.

But those are its beneficial applications. As with any cutting-edge technology, the power to edit genomes has a dark side. While it holds promise for curing intractable genetic diseases, it could potentially also be used to impart certain traits, like eye color, hair color, intelligence, or specific physical attributes, which could then be passed on to future generations. Potential applications to cells like eggs, sperm, and embryos—where the changes can be inherited—keep Doudna up at night. She has spent the past decade evolving her own thinking about her role as a scientist and as the co-discoverer of an awesome technology that snatches the power of evolution out of the hands of nature and places it squarely in the unprepared arms of humankind.

“Ten years ago, I was in a very different place. I was a biochemist doing curiosity-driven research, which was what led me to working with CRISPR in the first place. I was teaching my classes, educating my students, and I wasn’t thinking in the context of society-level implications, legal implications, and ethical concerns,” she says. “Nothing I had done in my past work would have fallen in that bucket. But I had to grapple with the fact that CRISPR was different.”

Over the past decade, dozens of companies have emerged to take advantage of CRISPR to treat human disease, and Doudna’s nagging fear about CRISPR even came true; in 2018, a scientist used the technology to permanently alter the genomes of twin girls, despite Doudna and other leading scientists around the world having agreed to a moratorium on using CRISPR on embryos.

“I am always a little bit worried as more and more companies jump on the CRISPR bandwagon and start clinical trials,” she says. “What if those trials get ahead of themselves, and a negative event occurs that sets the whole field back?”

If the first 10 years of living with CRISPR were about working out the scientific challenges behind editing genomes, the next several decades will be about coming to terms with the technology’s revolutionary power. Doudna has now embraced her role, and obligation, to lead the right conversations involving the public, patients, scientists, and policy makers to ensure that the changes CRISPR produces ultimately do more good than harm.

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The technology that Doudna and Charpentier, who was then at the University of Vienna, first described in 2012 was breathtaking in both its power and simplicity. When opportunistic viruses insert their genetic material into bacterial genomes, using their hosts to churn out more copies of themselves, the bacteria respond with their own genetic defense: They generate repeated DNA sequences that sandwich the viral genes and provide instructions for powerful enzymes that can splice out the intruding DNA. Doudna and Charpentier’s teams worked out a way to apply the same strategy to targeting and snipping out specific portions of DNA in the human genome—namely those containing mutations responsible for genetic disorders like sickle cell anemia. CRISPR is programmed to edit DNA only at certain places, operating like a pair of molecular scissors equipped with enzymes that can cut the DNA, and a genetic GPS guide made up of another complementary genetic material called RNA that can find the designated DNA sequence.

The duo won the 2020 Nobel Prize in chemistry for developing the gene-editing method. But by that time, Doudna—a professor in chemistry and molecular and cell biology at the University of California, Berkeley—was already a scientific rockstar. In the decade since she co-published the seminal paper, the number of students interested in logging time in Doudna’s lab has ballooned, due in equal parts to the burgeoning promise of CRISPR, and to the opportunity to add Doudna’s name to their resumes.

The Innovative Genomics Institute (IGI) at Berkeley is Doudna’s answer to the profound questions raised by the gene-editing technology she introduced to the world. The airy, light-filled facility has collaborative workspaces on each floor equipped with heavily used whiteboards. Every blank surface, including the glass walls of most offices in the building, is covered with scribbles reflecting the brainstorms of dozens of scientists and students involved in the Doudna lab. In order to capitalize on CRISPR’s promise, “I quickly realized very early on that there was so much to do that there was no way my academic lab could tackle it,” she says. “We would have to involve a much bigger team.” She shared her vision for an institute that convenes experts from virology, genetics, clinical medicine, agriculture, and climate—all focused on finding the most responsible ways to take CRISPR into the real world—with the dean. “CRISPR is something that will absolutely have a broad impact,” she recalls telling him, “and we have to make sure we are a player in that space.”

The promise of CRISPR also means that competition is fierce around every aspect of the technology—including its origin. Soon after Doudna and Charpentier published their paper, Feng Zhang, a molecular biologist at the Broad Institute of MIT and Harvard, published his description of CRISPR in eukaryotic cells, which include mammalian cells. That prompted a seven-year long patent dispute between the institutions: Berkeley and the University of Vienna claimed that their scientists came to the CRISPR breakthrough, and filed their patent application, first, while Broad said that their scientists got the technology to work in eukaryotic cells first. In February, the U.S. Patent and Trademark Office finally ruled in favor of the Broad, which could mean that the Broad will collect millions in licensing fees as CRISPR-based companies seek legal access to the technology. “The claims of Broad’s patents to methods for use in eukaryotic cells, such as for genome editing, are patentably distinct,” the Broad said in a statement. But the decision doesn’t end the dispute; Berkeley and the University of Vienna have filed an appeal.

Doudna has distanced herself from the battle, aside from providing lab notebooks and other documentation to support Berkeley’s and University of Vienna’s case. But she appreciates that such legal questions are part of the baggage that comes with a ground-breaking discovery like CRISPR. Many people who meet her for the first time ask about it, she says, including students at Berkeley. “The patent officer or judge—do they know the science well enough to be able to understand the nuances of something like this? These are questions I don’t have answers to,” she says. “I don’t think there is a lot of questioning in the scientific field of who did what and when, because you can read it in the peer-reviewed scientific literature, and it’s dated. I don’t lie awake at night worrying about it, I just carry on with what I see coming down the pike.”

Where CRISPR goes next

The first forays into treating human diseases with CRISPR have focused on conditions like blood cancers, in which doctors can remove cells from patients’ bone marrow, which produces immune and blood cells; edit them with CRISPR to remove unwanted mutations; and then return the “fixed,” healthy cells back to the patient. Doudna’s team is collaborating with researchers at the University of California, San Francisco and the University of California, Los Angeles to use a similar strategy to treat sickle cell anemia. One of Doudna’s several companies that she set up with former students, Caribou Biosciences, uses CRISPR to edit cancer-causing sequences out of the DNA of immune cells from patients with a variety of cancers, including non-Hodgkin lymphoma.

Scientists, including Doudna’s group, are continuing to refine the technology by finding ways to edit even more precisely. While CRISPR is effective, it’s not perfect at “making the type of change that you want to make at the desired position,” Doudna explains. Making it so is critical as CRISPR expands into trying to treat not just well-understood genetic diseases like sickle cell, but also more complex ones, like dementia and heart disease, that are the result of multiple changes in a variety of genes. With sickle cell, for instance, CRISPR edits out the single mutation responsible for the disease, after which the cells’ natural DNA repair mechanisms take over and fix the DNA, now with the correct sequence that can produce normally shaped and functioning red blood cells. But other conditions may require not just removing mutations but replacing them with more complex, correct sequences so that the cell can make the proper proteins or substances. That’s where ensuring that CRISPR is more precise, and able to deliver the appropriate corrected DNA to the right place in the genome in the right cells, is important—and still elusive. Another of Doudna’s former students, Ben Oakes, co-founded Scribe Therapeutics with her to refine how CRISPR can edit DNA more precisely. “We are really fixated and focused on how to [eventually] enable the use of CRISPR in the human body,” says Oakes. His team has pioneered a CRISPR system relying on a different enzyme, or DNA-cutting molecule, than the original CRISPR platform, and in animal models of ALS, the system seems to edit the targeted mutations more efficiently and contribute to a longer lifespan for the animals than the original CRISPR platform.

That will hopefully be the case in people as well, as more scientists find ways to use CRISPR directly inside patients’ bodies. In 2014, Doudna co-founded Intellia Therapeutics, and its scientists have tested a CRISPR-based intravenous treatment for transthyretin amyloidosis, a relatively rare disease involving the buildup of an abnormal form of a protein in organs and along nerves, causing damage to the heart and nervous system. The treatment, tested in a small number of patients, successfully edited the target genes in the liver and led to an up to 93% drop in blood levels of the abnormal protein a month after the infusion, the company reported in June. It’s the first demonstration of the safety and efficacy of CRISPR-based editing in a patient’s body, and “how to take something that is incredibly powerful in the test tube or petri dish and make it start to behave like medicine,” says Intellia president and CEO Dr. John Leonard.

Transforming environmental health

It’s not just humans who are getting the CRISPR treatment. The world’s biggest crops are, too. On the first floor of the IGI, little sprigs of rice, wheat, corn, banana, cassava, and other plant species are sprouting in plastic containers tucked into dozens of refrigerator-sized incubators. The plants are all seedlings representing the future of agriculture: drought-resistant rice, pesticide-resistant wheat, and better-tasting tomatoes.

Scientists are searching for ways to boost yield and help crops withstand punishing environmental conditions that would otherwise kill them. Myeong-Je Cho, director of IGI’s plant genomics and transformation facility, is trying to suss out the genes responsible for making plants susceptible to certain pests or fungi—or those that make them dependent on an abundant and consistent rainfall—and tweak them using CRISPR to become hardier and able to produce higher yields. The work is still in the early stages, but Cho is proud of a rice variant the team has modified with CRISPR to genetically reduce the amount of pores that the plant uses to exchange carbon dioxide and water with the environment, thus making it more tolerant to low-water conditions. He’s shipped the seeds to Colombia for farmers to plant in the first field test of the drought-resistant crop.

The list of features that Cho is hoping to edit with CRISPR is long and continues to grow. He is working on knocking out a gene that could be responsible for making wheat vulnerable to a fungal disease; he’s growing corn that could be genetically resistant to herbicides, allowing farmers to control pests without harming the crop; he’s also using CRISPR to remove genes responsible for producing solanine, a neurotoxin in potatoes that helps protect the tuber from insects and disease but can cause vomiting and paralysis of the central nervous system in people. His group is also working with Innolea, a French seed company, to develop sunflowers that produce oil with a better consistency and tweaking the tomato plant’s ethylene gene, which is responsible for controlling ripening, to develop a more delicious fruit.

Solving agriculture’s biggest blights wasn’t part of Doudna’s initial agenda. But CRISPR can improve not just human health, but also the health of the planet. “It’s an unusual experience, being able to bridge all different disciplines of science—from plant biology and commercial agriculture to people working to treat human diseases—yet all of these problems are potentially treatable or can be addressed using CRISPR,” she says.

Editing genes could also play a role in what many world leaders see as humankind’s most urgent problem: climate change. As Doudna sees it, the most daunting challenges of the climate crisis boil down to carbon emissions, and achieving net zero will ultimately depend on cultivating plants that can pull more carbon from the atmosphere and raising animals that release less. At IGI, Jill Banfield, a Berkeley professor and microbiologist who first introduced Doudna to the odd phenomenon in bacteria that was CRISPR, is currently exploring ways to edit genes in millions of bacteria living in microbiomes like the cow gut in order to manipulate the amount of methane—a potent greenhouse gas—they release. It’s still early work, but could provide one way to reduce the effects of climate change.

CRISPR’s dark side

While Doudna finds such explorations “fun,” she is also keenly aware of CRISPR’s power. Soon after she published her paper, she had nightmares in which Adolf Hitler came to her to learn about how CRISPR works. In the wrong hands, the power to edit genes could lead to medical abuses and even eugenics, in which people could select for virtually any feature, including those involved in physical appearance and intelligence. In 2018, her fears about using CRISPR to tweak human genes were realized when she received a shocking email from the Chinese scientist He Jiankui, who told Doudna that he had used CRISPR to change the DNA in human embryos, and that as a result, twin girls had been born—the first people on record to have their genomes permanently altered by CRISPR. Up to that point, scientists had agreed to a moratorium on such experiments, because of deep ethical concerns. “It’s hard to explain my emotions on seeing that,” says Doudna. “It was a feeling of horror, because this was the scenario that we [the scientific community] had been thinking about and trying to mitigate against, and now it actually happened. How do we manage that?”

Years later, there still are no easy answers. In the controversial experiment in China, the twins’ father was HIV positive, and He edited a gene believed to contribute to resistance to HIV, in an effort to protect the children from the virus. But a Chinese court determined that He manipulated consent documents and questioned whether the parents were fully informed of the nature of the study; ultimately, He was jailed for violating medical regulations with his unorthodox experiment. “What was so horrifying was realizing that this was an experiment that had been done on human beings that had never even been done in animals,” says Doudna. “It brought back Mengele,” she adds, referring to the Nazi physician who experimented on prisoners, including twins, at Auschwitz during World War II. I thought, ‘Oh my God, I don’t want the technology I am involved in to be doing that.’”

After initially feeling that she was not qualified to tackle the bigger social and ethical implications of CRISPR, Doudna realized that with the remarkable discovery also came a responsibility that she couldn’t shirk.

“Here we are sitting on this powerful technology, and more and more scientists are adopting it, yet most people outside of the scientific community have no idea about it and what it can do,” she says. “What do I do, call my Senator? I had no idea. There was nobody to ask.”

So she turned to other Nobel laureates—including David Baltimore, who had struggled with similar ethical questions after he and others discovered how to manipulate DNA to recombine its sequences in different ways. It was a crude, earlier version of gene editing with much less control than CRISPR affords, but which has contributed to drug treatments and promising vaccine candidates. Doudna, with the help of other leading scientists including Baltimore, drafted guidelines for how and when to best apply CRISPR, and agreed on a moratorium in 2015 on using CRISPR for the type of embryo-editing that He conducted. But without a way to enforce such guidelines, Doudna believes that CRISPR’s next battles will be in public opinion and legal settings as the public, courts, and regulatory bodies confront which applications of CRISPR cross ethical and cultural lines. “We are going to have to forge a path and figure it out,” she says. “This powerful technology allows us to change the essence of who we are if we want to. I’m not a hyperbolic person, but I’m trying to alert people to the fact that this is really going to change things.”

The future of CRISPR

Doudna adamantly believes that CRISPR, and editing genomes, whether human or otherwise, can be beneficial. While changing DNA does have serious consequences, if it’s applied only to individual genomes and not to cells—in humans, at least—that can be inherited, she views CRISPR as a type of molecular accelerant to the process of natural selection. “CRISPR makes it possible to get to a genetic condition or change genes in an organism faster than if we were to wait for evolution to do it,” she says. “When we’re dealing with something like climate change, where time is of the essence, it means we can do things faster than waiting for the natural process to take its course.”

That could also apply to pandemics. When her lab researchers were desperate to continue their time-sensitive work during the early COVID-19 lockdowns in 2020, part of Doudna’s team at IGI developed a diagnostic COVID-19 test for all of Berkeley’s staff, students, and faculty in just three months. By September, the lab was federally certified to provide diagnostic tests and began testing frontline workers and underserved communities in the Bay Area. Using CRISPR-based strategies not to edit genomes but to identify pathogens, IGI’s scientists were able to quickly detect new variants by picking out changes in SARS-CoV-2’s genetic sequences, and in May, the lab launched a new assay that can detect which variant of the virus patients are infected with when they test positive. The pandemic provided an opportunity for CRISPR to flex its muscles as a tool for potentially tracking and detecting new infectious disease culprits, as well as variants as COVID-19 continues to spread. Such surveillance would allow public-health experts to better predict where and when to dedicate additional testing and treatment resources.

Doudna recently reread her landmark 2012 paper, and admits that while she had a sense then that it was “kind of a moment,” she could not have envisioned the profound ways CRISPR is now transforming the world. CRISPR is making us rethink genetic diseases: it’s now possible to contemplate curing, rather than treating for a lifetime, genetic conditions like sickle cell anemia or vision problems like macular degeneration. The dialogue about climate change has also been redirected, given the possibility that CRISPR could help address major sources of organic carbon emissions at their source, in the gut microbiomes of animals.

There is no turning back the clock on the incredible scientific sovereignty that humans now have over their world, and Doudna is keenly aware of her responsibility in making sure that power is wielded through thoughtful collaboration. She is talking with the U.S. Food and Drug Administration about CRISPR-based therapies for human diseases that appear to be coming fast, and is reassured that the agency is trying to stay ahead of the thorny questions editing the human genome will pose. However, while Doudna is optimistic that the transparency and open dialogue that she has advocated for the past 10 years about CRISPR will push the technology in the right direction, she is also aware that it will be impossible to completely control CRISPR.

It wasn’t until a few years after publishing her paper that the enormity of what she had discovered, and the weight of responsibility that came with it, finally hit her. Doudna was in Napa Valley, attending one of the first-ever CRISPR meetings, and had arrived a few hours early so decided to take a hike. As she reached an overlook with a spectacular view of the valley, “I suddenly felt profoundly sad,” she says. “I should have felt happy—I was in a gorgeous setting and was fortunate to be there. But I hadn’t really had a moment like that to myself in a long, long time. I reflected for the first time that there was a before-CRISPR for me and an after-CRISPR. My life had forever changed, and so had the world.”

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