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. The Harvard researcher Dr. Kiran Musunuru was waiting to share with her results of an experiment using CRISPR for the treatment of sickle cell disease. 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. The cells should now be able to make healthy red blood cell that contain oxygen and not the harmful variants that are so severe for 100,000 American patients.
“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.”
Doudna, Charpentier and others published the original paper that described the technology 10 years ago. CRISPR was a catalyst for innovation in almost every area of human life. CRISPR has been used by companies and scientists to not only treat human disease but to also improve plants and reduce the amount of methane emitted from livestock. This contributes to climate change and greenhouse gasses. CRISPR makes it possible to have more drought-resistant and less-emitting livestock.
These are the benefits of this technology. The power to modify genomes is not without its dark sides, as with all cutting-edge technologies. Although it has potential for treating difficult genetic conditions, the technology could also be used to pass on certain characteristics, such as intelligence or eye color to other generations. Potential applications to cells like eggs, sperm, and embryos—where the changes can be inherited—keep Doudna up at night. Doudna has worked for the past ten years to develop her ideas about science and her role in discovering an incredible technology that takes evolution out of the hands nature and places it directly into the hands and arms of humanity.
“Ten years ago, I was in a very different place. CRISPR came to me because I was an avid researcher in curiosity, and that is what made me a biochemist. 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 is now accepting her obligation and embracing the role of leading the conversations that involve patients, scientists, policy makers, and the general public to ensure the CRISPR-related changes ultimately benefit more than hurt.
Doudna Charpentier (then at the University of Vienna) first described technology in 2012. It was remarkable in its simplicity and power. Opportunistic virus inserts their genetic material into bacterial genes, causing them to make more copies. Bacteria respond by creating repeated DNA sequences. These DNA sequences sandwich the viruses and contain instructions that allow for the creation of powerful enzymes that will splice the 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 can edit DNA in certain areas only. It acts like a pair molecular scissors with enzymes capable of cutting DNA and a complementary genetic guide called RNA which can locate the appropriate DNA sequence.
They won the Nobel Prize for Chemistry 2020 in Chemistry for their invention of the gene-editing technique. 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. Light-filled, airy space features collaborative spaces on every floor that are equipped with used whiteboards. Every empty surface in the building is covered with scrawls that reflect the ideas of the Doudna laboratory’s dozens of students and scientists. 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. Feng Zhang (a Broad Institute of MIT/Harvard molecular biologist) published his CRISPR description in eukaryotic cell. This includes mammalian cells. This sparked seven years of patent disputes between the two institutions. Berkeley claimed the breakthrough and then filed their patent application. Broad claimed their scientists had developed the technology in eukaryotic cell. The U.S. Patent and Trademark Office ruled in Broad’s favor in February. This could result in the Broad collecting millions of licensing fees from CRISPR-based businesses seeking legal access to this 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. She understands however that legal issues are part and parcel of a groundbreaking discovery such as CRISPR. She says that many people, even students, ask her about CRISPR when they meet them for the first times. “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.”
Emmanuelle Charpentier and Jennifer Doudna, shown onscreen, were named the recipients of the 2020 Nobel prize in Chemistry, during a press conference at Royal Swedish Academy of Sciences in Stockholm (Sweden), Oct. 7, 2020.
Henrik Montgomery—TT via AP
What’s next for CRISPR
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. CRISPR is expanding beyond treating well-understood diseases such as sickle cells to include complex genetic conditions like heart disease and dementia that result from multiple gene mutations. 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. Other conditions might require more than just the removal of mutations. The cell may need to be able to make proper substances or proteins by replacing the defective sequences with complexer, better ones. 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. Oakes’ team pioneered a CRISPR method that relies on a different enzyme or DNA-cutting molecule than the original CRISPR platform. In animal models of ALS the system appears to be more efficient in editing targeted mutations and has a greater lifespan than the original CRISPR.
That will hopefully be the case in people as well, as more scientists find ways to use CRISPR directly inside patients’ bodies. Intellia Therapeutics was founded by Doudna in 2014. Its scientists tested an intravenous CRISPR-based treatment for transthyretinosis. This rare condition is caused when abnormal proteins build up along nerves or organs. According to the company, it was tested on a limited number of patients and resulted in an increase of 93% in the blood level of the affected gene in the liver. This treatment was reported by the company 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.
Environmental health transformation
It’s not just humans who are getting the CRISPR treatment. The world’s biggest crops are, too. Little sprigs are growing in small plastic containers, tucked inside dozens of incubators that can be kept at room temperature, on the IGI’s first floor. All the plants in this exhibit are seedlings that represent the future agriculture: pesticide resistant wheat and drought-resistant rice.
Researchers are looking for new ways to improve yields and allow crops to withstand harsh environments that could otherwise cause their death. 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. Although the work is still early, Cho is very proud of the CRISPR-modified rice variety that the team created to reduce carbon dioxide and water exchange in plants. This makes it less tolerant of low-water environments. He’s shipped the seeds to Colombia for farmers to plant in the first field test of the drought-resistant crop.
Cho continues to add features to CRISPR’s list. 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. CRISPR has the potential to improve human health and the overall health of the Earth. “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. Doudna believes that the biggest challenges in the climate crisis are carbon emissions. Getting to net zero requires cultivating plants and animals that take more carbon out of the atmosphere, as well as raising 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.
Jennifer Doudna is seen here, centre, being interviewed by the International Summit on Human Genome Editing held in Hong Kong on Nov. 27, 2018.
Isaac Lawrence—AFP/Getty Images
CRISPR’s dark side
While Doudna finds such explorations “fun,” she is also keenly aware of CRISPR’s power. She had nightmares shortly after publishing her paper in which Adolf Hitler visited her to find out more about CRISPR. If the right people had the power to modify genes, it could result in medical abuses. It could also lead to eugenics in which anyone could choose for any characteristic, even those that affect intelligence or physical appearance. 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. Scientists had previously agreed to suspend such experiments due to 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]It was something I had tried to prevent and thought about, but it happened. How do we manage that?”
Many years later, it is still not clear what the answers are. 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. He violated medical regulations by manipulating consent documents, according to a Chinese court. “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. This was an older version of gene edits that had less control than CRISPR. However, it has led to promising drug treatments and vaccine candidates. With the assistance of Baltimore and other top scientists, Doudna drafted guidelines on how to apply CRISPR and reached an agreement on a 2015 moratorium on the use of CRISPR in the embryo-editing 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.”
CRISPR: The Future
Doudna insists that CRISPR and the editing of genomes can have a positive effect on human health. 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.”
It could also be applicable 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. The lab had been federally accredited to offer diagnostic tests by September and was able to begin testing underserved areas and frontline workers 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. CRISPR had the opportunity to make use of this pandemic to detect and track new infection suspects. This surveillance could help public-health professionals better forecast where additional resources and testing will be needed.
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. CRISPR has the potential to reduce the carbon emission from the animals’ microbiomes, which could be the source of most of the climate-related problems.
Doudna recognizes that the scientific sovereignty of humans over their planet is irrevocable. CRISPR-based treatments of human diseases are on the horizon. She has been in touch with the U.S. Food and Drug Administration to discuss the possibility. They have assured her that they will be able to tackle the complex questions that editing human DNA poses. Doudna believes that CRISPR technology will move in the right direction because of the open and transparent dialogue she’s been advocating for over the last 10 years. However, it is not possible to control CRISPR completely.
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 arrived in Napa Valley for one of the first ever CRISPR meetings. 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. It was the first time I had realized there was both a pre-CRISPR version of me and an after CRISPR. My life had forever changed, and so had the world.”
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