A research paper published a decade ago touched off a biomedical revolution that has made careers, spawned companies and drawn billions of dollars of investment. By the end of the year, the gene editing technology that paper described could win Food and Drug Administration approval as part of a powerful new treatment for sickle cell disease.
Now Nobel Prize-winning science, CRISPR gene editing is at the heart of the biotechnology industry’s latest Big Bang. It’s adaptable and efficient, putting the precise alteration of DNA within easy reach of academic scientists and drug startups alike.
Since 2012, when research by Jennifer Doudna and Emmanuelle Charpentier was published in Science, more than a dozen biotech companies have sprung forward to capitalize on the possibilities they and other scientists unlocked.
This new generation has joined early adopters CRISPR Therapeutics, Editas Medicine and Intellia Therapeutics, offering various twists and tweaks to improve on the original CRISPR technology. They’re also taking aim at a wider array of illnesses, from ALS to heart disease.
Many are led by or employ scientists and post-doctoral students trained in the laboratories of the University of California, Berkeley and the Broad Institute of MIT and Harvard, the academic institutions most closely linked to CRISPR gene editing research.
The research diaspora mirrors a broader trend in the life sciences. According to Feng Zhang, a member of the Broad and a pioneering CRISPR expert, the lines between academia and industry are “blending” more than before.
“The door is open in both directions,” Zhang said. “We need the flow of talent to be as porous as possible” to speed CRISPR research.
And, as happened with new drugmaking technologies before CRISPR, large pharmaceutical companies have moved in, placing bets on the technology’s potential.
“Large pharma is recognizing that this has the potential to be the future of medicine,” said Benjamin Oakes, co-founder and CEO of Scribe Therapeutics, an early-stage CRISPR drug developer now working with Eli Lilly and Sanofi.
The first glimpse of that future could come in early December, when the FDA is set to decide on approval of that sickle cell treatment, known as exa-cel and developed by CRISPR Therapeutics and Vertex Pharmaceuticals.
A biotech foundation
Often likened to a pair of genetic scissors, CRISPR editing at its simplest involves just a few specialized components. A strip of engineered RNA acts as a guide, shepherding the editing machinery to a corresponding stretch of DNA in a cell. If the sequences match, an enzyme called Cas9 will cut through the DNA double helix at that precise spot.
When this happens, the cell moves to repair the double-stranded DNA break. The process can inactivate the gene in question — useful for treating diseases caused by harmful protein production. Researchers can also take advantage of the cut made by Cas9 to correct the target gene or insert a new one by pairing the editing complex with a DNA template.
Exa-cel, Vertex and CRISPR Therapeutics’ drug, relies on the former approach. A patient’s own stem cells are collected and isolated in a laboratory, where CRISPR/Cas9 is used to cut a particular section of a gene called BCL11A.
This disruption causes the cells, once reinfused back into the patient, to produce high levels of fetal hemoglobin, an oxygen-carrying protein which the body stops making soon after infancy. High levels of fetal hemoglobin are thought to counteract the red blood cell sickling that’s characteristic of the disease and the cause of its symptoms.
Before CRISPR, gene editing was limited to older technologies like zinc finger nucleases, and transcription activator-like effector proteins, or TALENs.
Zinc finger nucleases are enzymes that also can cut specific gene sequences, while TALEN-based editing uses the eponymous protein to do the job. But both are expensive and time-consuming to produce and lack CRISPR’s specificity.
“The CRISPR revolution came around at the right time,” said Mitch Finer, CEO of Life Edit Therapeutics and former chief scientific officer of Bluebird bio, which has developed a rival sickle cell treatment to exa-cel. “It’s one protein, and all you have to do is change up the guide RNA. That’s what was so attractive.”
Doudna and Charpentier’s paper, as well as research by Zhang and others, led to the quick formation of a trio of companies focused on turning CRISPR science into new medicines.
Charpentier launched CRISPR Therapeutics in 2013 with Shaun Foy, a venture capitalist, and Rodger Novak, who had been an executive at Sanofi. Around the same time, Doudna joined other leading scientists in the field, including Zhang, George Church, David Liu and Keith Joung, to introduce Editas Medicine.
But Doudna quit Editas in 2014 as the co-founders tussled over who owned the intellectual property for CRISPR/Cas9. She later co-founded Intellia Therapeutics, working with Atlas Venture and Caribou Biosciences, a company she had launched several years prior.
According to Novak, academic innovation provided the necessary spark to start biotech’s CRISPR revolution, particularly as it came alongside the emergence of other technologies like messenger RNA and cheaper gene sequencing.
“Technology wise, around that time, there was some light on the horizon and things came together relatively nicely,” he told BioPharma Dive in a recent interview.
CRISPR Therapeutics, Intellia and Editas drove the translation of CRISPR into the clinic, achieving some of the field’s firsts. Exa-cel, for instance, became the first medicine made with the technology to be tested in humans in a biotech trial. And in 2021, Intellia proved CRISPR could work “in vivo,” or directly inside the body rather than via extracted cells.
But they also hit difficulties, too. Progress was greatest in rare diseases of the eye and blood, areas of the body that are relatively easier to reach — shaping which conditions the companies aimed for first. CRISPR/Cas9, with its proclivity to cut through both strands of DNA, also isn’t the best tool to address every kind of genetic mutation, spurring research into other approaches.
New directions
As gene editing research advanced, scientists unearthed different techniques for editing DNA as well as other CRISPR-associated enzymes to do the job.
Their discoveries led to a stream of academic literature on how CRISPR could be improved and made more precise. Zhang and researchers working with him at the Broad studied Cas12 and Cas13. Joung, at his lab at Massachusetts General Hospital, engineered CRISPR/Cas9 systems to better avoid off-target effects. Liu and his team published in 2016 and 2019, respectively, landmark papers on base and prime editing, which offered ways to edit single nucleotides without cutting both DNA strands.
“We now have at our disposal more capabilities, so that we can pick the best one for the disease we're trying to treat,” Zhang said.
He likened the advancements to a bigger toolbox, containing just the right equipment for specific jobs. “If your house didn't have water, there’s a problem with the pipe, and instead of fixing the pipe you get water from somewhere else — that’s the approach that's taken with current sickle cell disease treatments,” Zhang said, referring to exa-cel and Bluebird’s treatment, which uses an engineered virus to add a new gene to patient stem cells.
“With more tools in the toolbox, we'll have a better chance of being able to fix the pipe,” Zhang added.
The discoveries led to new companies, like Beam Therapeutics, which was founded by Liu, Zhang and Joung to develop base editing into medicines. A group of venture investors and life sciences researchers including Joung started Verve Therapeutics in 2018. And Liu later co-founded Prime Medicine around prime editing.
These companies, and others, were launched even as legal battles continued between the Broad and Berkeley over rights to the original CRISPR invention. (Federal patent officials issued a ruling in 2022 determining the legal rights to the foundational technology belong to the Broad.)
The Broad has said it believes in “open access” to CRISPR research. Since 2014, the institution has granted licenses to companies and scientists looking to build on the existing technology.
An expanding group of venture firms, including Arch Venture Partners, F-Prime Capital, GV, Atlas Venture and Newpath Partners, has emerged as common backers of this second generation of CRISPR companies.
The value of private financings also swelled. Early on, CRISPR-focused biotechs raised between $15 million and $43 million in their initial Series A rounds. Their successors often raised much more: Prime Medicine emerged from stealth in 2021 with $315 million in hand from its Series A and B rounds, for instance.
The influx of money helped fund grand ambitions and broad development goals. “I certainly would love to become the next Vertex or Biogen,” Keith Gottesdiener, then the CEO of Prime Medicine, said in a 2021 interview with BioPharma Dive.
Some of these later companies also benefited from going public during a peak in biotech valuations. Beam went out in 2020, followed by Verve in 2021, when it hit Wall Street with one of the year’s largest IPOs. Even in 2022, when the sector was experiencing the beginnings of a funding drought, Prime Medicine was able to pull off an IPO.
Still, these companies haven’t gotten far in the pursuit of treating people. Beam began testing a “first-of-its-kind” gene editing medicine for cancer in September, the first time a base editing medicine has entered human trials.
Many biotech licenses to CRISPR technology tie back to Berkeley or the Broad
An expanding ecosystem
CRISPR is now no longer the domain of just a handful of biotechs. A larger ecosystem exists, as more gene editing startups have continued to crop up.
These companies are working with other CRISPR enzymes, such as Cas12, Cas13, Cas14 and CasΦ, and aim to sidestep problems like delivery and off-target editing. (Older gene editing companies, like Editas, Caribou and Beam, are also experimenting with new enzymes, too.)
This fresh slate of Cas molecules has emerged along with a new generation of scientists. Researchers who completed their PhDs and post-doctoral fellowships under gene editing pioneers like Doudna, Zhang and Liu are launching companies of their own.
“Abandoning false modesty, we're UC Berkeley,” said Fyodor Urnov, a professor of molecular and cell biology at UC Berkeley and an expert in genetic medicine. “We're the best public research university in the world. It's an elite training school.”
For example, Janice Chen and Lucas Harrington, two Berkeley researchers who worked with Doudna on a 2018 paper detailing Cas12, founded Mammoth Biosciences with her and a Stanford University colleague, Trevor Martin. Based in the San Francisco Bay Area, Mammoth is now working with both Cas14 and CasΦ proteins, which are smaller than the original enzyme.
“We’re still developing tools to understand what are high standard edits, or what are other off-target edits,” said Chen, now Mammoth’s chief technology officer. “The technology is advancing, but then also the tools to understand the safety profile.”
In its early days, Mammoth focused on both diagnostics and medicines, believing CRISPR could improve upon existing methods in identifying cancer targets or viral infections. The biotech partnered with Vertex in 2021, and Bayer a year later. It has since trimmed back its diagnostics work.
Like Zhang, Mammoth’s founders see the latest iterations of CRISPR as a toolkit.
“We want to have the right technology available for the disease so we can be driven by the science and the disease biology,” Martin said. Then, “it’s not that we have a hammer, so everything has to look like a nail. We can choose the right technology for the disease, rather than having to fit everything into a certain box.”
Doudna is also associated with other biotechs such as Scribe Therapeutics, which she co-founded with Oakes, one of her former students. Oakes, who once studied zinc finger nucleases, came to Berkeley in 2013 after the publication of that first CRISPR/Cas9 paper by Doudna and Charpentier.
“That problem that we were brute force working to solve was solved in a much more elegant way,” said the Scribe CEO, who co-authored a paper on CRISPR/CasX in 2019.
The backing of young researchers by scientists at Berkeley and the Broad has helped along the evolution of new CRISPR-based technologies. So, too, has the technology’s spread throughout the scientific community, despite the legal battling over CRISPR patents between Berkeley and the Broad.
“Licensing the technology, on a non-exclusive basis for different areas, has been really, really good,” said Zhang, of the Broad. “It’s accelerated research and application development.”
Setbacks and public sentiment
The rapid growth of the gene editing sector has come with its share of research stops and starts.
As the initial companies raced to begin clinical trials, federal regulators in the U.S. proceeded more warily. In 2018, the FDA paused Vertex and CRISPR Therapeutics’ plans to start their first study of exa-cel. Editas also ran into delays when the FDA imposed a partial clinical hold for its sickle cell disease therapy in 2021.
Both Beam and Verve had similar problems as they tried to advance their base editing programs into clinical testing, receiving clinical hold orders from the FDA last summer and fall.
The temporary pauses reflected regulatory caution on the safety of CRISPR gene editing and its use in humans. In particular, the FDA appears to be closely watching tests of in vivo CRISPR medicines for any signs CRISPR changes could be inadvertently made to sperm or egg cells — so-called germline edits.
“Our view is that this is the FDA taking a very considered view of the space,” said Intellia CEO John Leonard in response to questions on an August call about a recent request made by the agency.
Intellia conducted testing of its first in vivo candidate outside of the U.S., and recently scrapped plans to include U.S. patients in testing of its second following the FDA’s ask. The company intends to open up U.S. trial sites as part of late-stage studies it’s now preparing.
Other safety concerns have cropped up too, such as with Graphite Bio’s sickle cell treatment nula-cel, which the company stopped testing after reporting a serious side effect.
In most cases, though, the FDA has lifted the holds it’s imposed, allowing testing to advance and paving the way for the agency’s current review of exa-cel.
That looming approval decision will again put CRISPR gene editing squarely in the public eye. While biotechs are using the technology to treat diseases solely via edits to somatic cells, the field is still shadowed by the actions of Chinese scientist He Jiankui. In 2018, He stunned the scientific world by announcing he had edited a pair of embryos that were implanted and brought to term, sparking condemnation and renewed calls to restrict germline editing.
Even before the controversy, the Broad had put in place safeguards against experiments like He’s. Now, the institution maintains “any human clinical use must be consistent with all laws and regulations,” and does not license their technology for editing human egg and sperm cells.
Looking ahead
Even as a down biotech market has stressed young drugmakers, gene editing companies continue to draw investment.
Prime’s IPO, for example, raised $175 million last October — a rare IPO success in a down year. New gene editing companies continue to emerge, too, such as Tome Biosciences and Tune Therapeutics.
Others, meanwhile, are applying CRISPR principles in different ways. Boston-based Chroma Medicine, which raised $135 million in venture funding this March, is crafting drugs to alter the epigenome.
From an R&D perspective, researchers in the field hope to make advances in several areas. First, prove that CRISPR-based gene editing can work in a wider variety of diseases. Many of the initial programs are for eye-related conditions, sickle cell disease or beta thalassemia, but there are many other possible targets, said Urnov, who co-founded Tune and consults with Vertex.
Second, delivery remains a challenge. Current genetic medicines can readily reach those parts of the body that are easily accessible, such as the eye, blood or liver. As a result, diseases affecting other tissues, like the muscle and brain, remain challenging to treat, even if the genetic errors causing them are well understood.
And there are still concerns about the possibility of off-target edits with CRISPR-based therapies. The FDA’s ongoing review of Vertex and CRISPR Therapeutics’ medicine could give a window into the agency’s comfort with this risk.
From an industry perspective, commercialization of genetic medicines remains a question mark. While they promise dramatic benefits, their high price tags and complex manufacturing could present marketing hurdles. Outside of Novartis’ spinal muscular atrophy drug Zolgensma, sales of the gene replacement therapies approved to date have not taken off.
“The for-profit sector really understands how to commercialize medicines where you put the patient on a lifetime of treatment,” said Urnov. With gene therapy, most patients will likely receive treatment once.
“At the end of day, patients aren't going to care about the modality,” Chen said. “They just want to know: is it safe and does it work? That's the ultimate end goal.”
Ned Pagliarulo contributed reporting.
