CRISPR is a story of fundamental discovery science, collaboration, and the harnessing of a powerful engineering technology that gives new hope and possibility to our society.Jennifer Doudna
by Marge d’Wylde
In a brief private ceremony on the morning of December 8, 2020, on her patio in California, Jennifer Doudna, the UC Berkeley Li Ka Shing Chancellor’s Chair in Biomedical and Health Sciences, and Professor of Chemistry and Molecular and Cell Biology, was awarded the Nobel Prize in Chemistry.
Nothing was ordinary about this event, even by Nobel standards. The annual Stockholm ceremony, replete with pageantry and an amazing banquet, was postponed due to the ongoing COVID pandemic until at least the fall of 2021. Only immediate family including her husband and fellow scientist Jamie Cate, son Andrew Cate, and sister Ellen Doudna were in attendance. Her sister Sarah Doudna attended by phone from New York. Barbro Osher, Sweden’s Honorary Consul General in San Francisco and a member of the UC Berkeley Board of Trustees, along with Anna Sjöström Douagi, Nobel Foundation VP of Science and Programs, drove from San Francisco to deliver the medal and hand painted diploma which had arrived from Sweden by diplomatic courier.
While the world was battling the COVID-19 pandemic, the Nobel Prize committee had quietly achieved a scientific milestone, awarding prizes in the physical sciences to three women The recipients included UCLA’s Andrea Ghez who shared the Nobel Prize in Physics “for the discovery of a supermassive compact object at the center of our galaxy” In addition, Doudna and Emmanuelle Charpentier, Founding and Managing Director, Max Planck Unit for the Science of Pathogens, shared the Nobel Prize in Chemistry for the “development of a method for genome editing”. Their research had revealed how the Cas9 protein, part of the CRISPR system in bacteria, targets viruses, and allows for the process to edit the genomes of many organisms, including humans.
In another first, Doudna and Charpentier shared the coveted prize without a male counterpart. In 2018, Frances Arnold (Ph.D. ’86, ChemE) was the first Cal alumna awarded the Chemistry Prize. Including the newest recipients, only seven women have won the Chemistry Prize since its inception in 1901.
According to the Nobel Foundation, since Doudna and Charpentier’s announcement of the CRISPR/Cas9 genetic scissors in 2012, their use has exploded. The tool has already contributed to many important discoveries in basic research in the human genome. Plant geneticists have used the technique to develop crops that withstand mold, pests, and drought. In medicine, clinical trials of new cancer therapies are underway, and the dream of being able to cure inherited diseases is about to come true. These genetic scissors have taken the life sciences into a new epoch already bringing breathtaking benefits to humankind.
CRISPR/Cas9 has opened a portal to a whole new way of viewing biotechnology, creating possibilities for using the technology in biotherapy, plant breeding, disease modeling, disease diagnostics, and much more. The technology is also yielding great insight into the functions and roles of different types of genes in relation to climate change.
An example of the climate mitigation using CRISPR is taking place with coral reefs, the most biodiverse and climate-sensitive ecosystem in the world. Coral reefs sustain about 25% of all the ocean’s fish and contribute to the livelihoods of over half a billion people. CRISPR has allowed researchers to identify which genes are involved in coral bleaching and to begin determining ways that can safeguard against this effect in the future.
The CRISPR discovery has also sparked the creation of innumerable startups, which have attracted hundreds of millions of dollars in investment worldwide in search of new cancer, hemophilia, and cystic-fibrosis treatments to name a few areas of experimentation. By 2019, over 15,000 research articles had been published inspired by CRISPR research.
According to Doudna, “It’s a great tool for scientists because it gives all of us that are working with biological systems a way to manipulate the genetic material that tells cells what to do and tells organisms how to behave and how to act. And so, this has been amazing as a technology for fundamental discovery. But beyond that, it also provides a tool that allows real manipulation of disease-causing genes. And I think that’s one of the ways that CRISPR is going to impact all of us in the coming years.”
Urgent research and technology needed to solve complex biotechnology challenges
In 2014, two years after the Nobel Prize-winning discovery was initially announced, Doudna thought the technology was mature enough to tackle a cure for the devastating hereditary disorder sickle cell disease that afflicts millions of people around the world. Some 100,000 Black people in the U.S. are afflicted with the disease. The Innovative Genomics Institute was formed as a partnership between the University of California, Berkeley and the University of California, San Francisco combining the fundamental research expertise and biomedical talent needed to work on the problem.
The new research team sought to repair the single mutation that makes red blood cells warp and clog arteries, causing excruciating pain and often death. Available treatments today typically involve regular transfusions, though bone marrow transplants can cure those who can find a matched donor.
After six years of work, the research team recently received approval for clinical trials by the U.S. Food and Drug Administration. This will enable the first trials in humans of a CRISPR-based therapy to directly correct the mutation in the beta-globin gene responsible for sickle cell disease.
The trials, which are expected to take four years, will be led by physicians at UCSF Benioff Children’s Hospital Oakland and UCLA’s Broad Stem Cell Research Center, who plan to begin this summer to enroll adult and adolescent patients with severe sickle cell disease.
The Innovative Genomics Institute’s clinical diagnostics laboratory, which was built last year under Doudna’s leadership to provide free COVID-19 testing to the Berkeley community, will play a key role in analytical support for the trial by developing diagnostics to monitor patient well-being and track the efficiency of the treatment.
“We are motivated to work toward a cure that can be accessible and affordable to patients worldwide,” Doudna said of the trials.
In a 2019 Time article, Doudna stated, “There’s a possible future where genetic disease is a thing of the past, where we routinely sequence DNA and treat harmful mutations as an outpatient procedure. But we must ensure that in this future, everyone will have access to these new technologies and there’s a consensus on rules to regulate whether and how this technology is applied to the human germline.”
Development of CasX and treatments for genetic based diseases
Many companies developing CRISPR gene-editing therapies use variations of CRISPR-Cas9, the original gene-editing system described in 2012. Since then, Doudna’s research group and others have looked for alternative Cas enzymes with better or different properties for gene editing beyond Cas9. One result of their search was finding a distinct family of RNA-guided genome editors dubbed CasX.
Discovered in 2016 by Jill Banfield and Doudna in some of the world’s smallest bacteria, the protein is similar to Cas9, but significantly smaller: a big advantage if you’re trying to deliver a gene editor into a cell.
In 2018, Doudna, Benjamin Oakes, UC Berkeley biochemist David Savage, and former Doudna postdoc Brett Staahl co-founded Scribe Therapeutics (Scribe) to create gene-editing therapies based on CasX.
“CasX has some features that could give it an upper hand over Cas9 as a gene-editing therapy,” Oakes explains. “For one, CasX is a smaller protein than Cas9, which should make it easier to get into cells in the human body with gene-therapy delivery vessels like adeno-associated viruses.”
Rather than “shoehorning” enzymes that evolved to work well in bacteria but not in humans into treatments for human disease, Scribe is engineering CRISPR molecules from scratch. This will allow the company to address problems seen in traditional CRISPR, such as safety, efficacy and off-target effects, where the treatment edits untargeted parts of the genome, causing harmful side effects.
Although Scribe continues to improve CasX, it has started working on gene-editing therapies for neurodegenerative disease with versions of the enzyme that it has already created. In October 2020, Scribe announced a partnership with Biogen to create CasX-based therapies for genetic forms of amyotrophic lateral sclerosis (ALS) and an option to work on another undisclosed neurological disease target.
CRISPR testing and the COVID-19 pandemic
In 2020, at the height of the pandemic, Doudna, and other members of the Innovative Genomics Institute, convened to discuss what they could do to help battle COVID-19. During that meeting the group decided to pivot their projects and convert the research labs into an automated COVID testing facility expanding existing efforts to develop CRISPR-based diagnostics and genetic medicines that might help mitigate the pandemic.
Literally overnight the clinical diagnostics laboratory was turned into a lab that could test for COVID-19. Under Doudna’s leadership, free COVID-19 testing was rolled out to the Berkeley community. Doudna commented, “In a typical year, if you tried to map the trajectories of all of the scientific projects in even one department at a large public institution like UC Berkeley, you’d find lines going in all directions at once. What happened last year was different. With a shared vision, a diverse team of professors, postdoctoral researchers, engineers, graduate students and volunteers all willingly put their personal and professional projects on hold to do something that had never been done before.”
The science behind a PCR-based COVID-19 test was right in the team’s comfort zone but spinning up a clinical laboratory was another matter entirely. Doudna continues, “Looking back, I’m still in disbelief at how quickly the team was able to safely overcome massive technical, logistical and physical barriers. In just three weeks, we secured lab certifications, developed new software and hardware with industry partners, ran the first of thousands of tests, received philanthropic funding to support lab operations, and started two dozen additional research projects, including a new rapid, point-of-need COVID test.”
Riding the wave of the bio revolution
Doudna’s scientific research and startup endeavors are revolutionizing the biosciences. In addition to her innovative research work, she is co-founder of a number of companies including: Mammoth Biosciences, Caribou Biosciences, Intellia Therapeutics, Editas Medicine, and Scribe Therapeutics.
These companies are tackling some of the biggest challenges that the world is currently facing. Mammoth is working on a new type of COVID-19 test; Caribou is pursuing novel cancer therapies; publicly traded Editas is pursuing treatments for ocular, neurodegenerative, and blood diseases as well as cancer therapies; and Scribe Therapeutics is running trials for a CRISPR based approach to treat sickle cell disease.
Doudna is a biochemist, scientific leader, mentor, and entrepreneur. But most importantly, she is a scientist still focused on research and running her lab. In an article last year for C&EN magazine, Doudna commented, “I love the science. When I wake up in the morning, that’s the first thing I’m thinking about, and when I go to bed at night, that’s usually the last thing I’m thinking about.”