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Rewriting the code of life

Entering CRISPR gene-editing technology's second decade

CRISPR Gene Editing Kevin Davies .

The 2020 Nobel Prize in Chemistry was awarded to two women who pioneered a new genetic technology that has captured the public imagination and revolutionised science. Kevin Davies tells the story of how CRISPR changed the future in less than a decade.

 

When the international phone call came, at precisely 2:53 am Pacific time, the country code showed the UK, not Sweden. Heidi Ledford, a reporter for the journal Nature, had the unexpected honor of informing a groggy Jennifer Doudna that she’d won the 2020 Nobel Prize for Chemistry, sharing it with her former collaborator, French microbiologist Emmanuelle Charpentier.[1] ](Doudna had slept through the official call from Göran Hansson, Secretary General of the Royal Swedish Academy of Sciences.)

“What a testament to Doudna’s work ethic,” Ledford tweeted later. “I certainly wouldn’t have taken a call from me at that hour.”

Hansson had more luck reaching Charpentier, who was working in the same time zone in her office at the Max Planck Unit for the Science of Pathogens in Berlin. After gleefully receiving the news, Charpentier encountered some Nobel bureaucracy as she was asked to confirm her date of birth, address and sworn to secrecy for an hour or so until the official public announcement. She reflected the rollercoaster ride she, along with the rest of the international community studying CRISPR, had been on for the past decade. The science had moved so fast, she said, “I was losing the notion of time.”

During the livestreamed public announcement from Stockholm, Hansson broke the suspense by announcing that the 2020 Nobel Prize in Chemistry “is about rewriting the code of life…” With those electrifying words, it was clear that CRISPR had won -- a mere eight years after Doudna and Charpentier’s immortal joint publication in Science laid out the molecular toolset for “the development of a method for genome editing.” The Nobel committee likened CRISPR-Cas9, a repurposed bacterial anti-viral defense system, to “genetic scissors” capable of rewriting the genetic code of any organism, including humans.

Watching the announcement via YouTube on my phone before dawn in my New York apartment, I was almost as stunned as the winners. My book Editing Humanity – a deep dive into the CRISPR revolution, its heroes, rivalries, applications, and controversies -- had been published just 24 hours earlier!

Hansson broke the suspense by announcing that the 2020 Nobel Prize in Chemistry “is about rewriting the code of life…” With those electrifying words, it was clear that CRISPR had won.

In the book I had stopped short of predicting who would win for CRISPR, but noted it was important first to distinguish in which category the Prize would be given: Chemistry or Medicine? Charpentier, a microbiologist by training, expressed surprise that she had won for Chemistry, but that decision narrowed the likely winners. In the sleeve of color photos in the book, the only individuals I devoted a full page to were Doudna and Charpentier. Both photos were taken from my iPhone in Manhattan: Doudna opening the World Science Festival, cradling a molecular model of the Cas9 nuclease “scissors”; Charpentier outside a French bistro, posing with my previous book, The $1,000 Genome.

 

Jennifer Doudna and Emmanuelle Charpentier

Jennifer Doudna and Emmanuelle Charpentier, © Kevin Davies

 

Both women were swept up in a whirlwind of well-wishes and hastily organized press conferences, convened under COVID-19 restrictions. A beaming Charpentier posed for photographers next to a bust of Max Planck in the lobby of her institute. She relished her success and nonchalantly said the Nobel was not really a surprise – many people had predicted she would eventually win the big one. “I was extremely emotional,” she said. “I could not believe it -- even though I knew it would happen one day.”

Doudna and Charpentier made history by becoming the first two women to share a Nobel Prize. Both recognized the symbolism of their success. “I think it’s very important for women to see a clear path,” Charpentier said. “The fact that Jennifer and I were awarded the prize today can provide a very strong message for young girls.” Doudna agreed: “Both Emmanuelle and I felt proud of our gender that morning and just happy that we were sending a message collectively to girls and others who have felt excluded from the STEM fields that their work can be recognized.”

The Nobel committee likened CRISPR-Cas9, a repurposed bacterial anti-viral defense system, to “genetic scissors” capable of rewriting the genetic code of any organism, including humans.

Behind closed doors, the Nobel committee doubtless wrestled with the question of whether to include a third recipient for the Chemistry prize. Two years earlier, the Kavli Prize in Nanoscience was shared by Doudna, Charpentier, and a Lithuanian biochemist, Virginijus Šikšnys. But there was no call from Stockholm to the Lithuanian, or Francisco Mojica, the Spanish microbiologist, or Feng Zhang, the Chinese-American genome engineer at the Broad Institute, or any of the other heroes of the young CRISPR revolution.

Šikšnys’ chances of a Nobel would likely have been higher had his own landmark paper in 2012 not been rejected by his first-choice journal, like an Olympic hopeful tripping on the last lap. Mojica was, perhaps to his relief, spared the media frenzy that would have engulfed him had he shared the prize and about which he had very mixed feelings. By contrast to the champagne celebrations in Berlin and Berkeley, the mood at the Broad Institute that fateful morning was somber as researchers and staff digested the news of Zhang’s omission. (Zhang and Harvard Medical School geneticist George Church were the first scientists to demonstrate CRISPR’s ability to edit human DNA in January 2013.) “Take that, U.S. legal system,” was how the late Sharon Begley opened her Nobel Prize story in STAT, alluding to the protracted patent dispute over the invention of CRISPR gene editing, pitting Zhang’s institute against those of the Nobel Prize winners.[2][ii]

Sadly, the COVID-19 pandemic meant that for the first time in 120 years, there would be no royal gala in Stockholm. While Charpentier received her gold medal from the Swedish Ambassador in Berlin, Doudna hosted a short, improvised ceremony on the back patio of her Berkeley home, with her husband (UC Berkeley professor Jamie Cate), son, and sister looking on proudly. Berkeley capped Doudna’s award with another precious gift: a parking space reserved exclusively for Nobel laureates. “After 18 years, I can finally park on campus,” Doudna joked.

Güneş Taylor discusses the potential of CRISPR technology.

Precision Medicine

The 2020 Nobel Prize was validation of the vast potential of CRISPR not only as a dazzling, ubiquitous tool for basic biomedical research but also as a potent new form of precision genetic therapy. We didn’t have to wait long for that potential to become reality.

In December 2020, researchers at CRISPR Therapeutics published clinical results on a small number of patients with sickle-cell disease and beta-thalassemia in the New England Journal of Medicine.[3][iii] Pride of place belonged to Victoria Gray, an African-American from Forest, Mississippi, who was the first sickle-cell patient to volunteer in the trial. Hematologist Haydar Frangoul and colleagues conducted an experimental therapy on Gray’s extracted bone marrow cells, using CRISPR to engineer a genetic tweak that would activate the otherwise dormant fetal globin gene, in effect replacing the faulty beta globin gene. The therapy produced a safe and sustained boost in Gray’s fetal hemoglobin levels, which has lasted now for some two years. Most experts consider that a cure – a “once-and-done” lifetime therapy. Choosing his words carefully, genome editing pioneer Fyodor Urnov (now a colleague of Doudna’s at the Innovative Genomics institute) concluded that the study was “borderline utopian.”[4] iv]In a progress update earlier this year, CRISPR Therapeutics announced that more than 20 patients have been successfully treated to date.

Remarkably, 2021 has seen several more exciting reports showing the preclinical and clinical potential of CRISPR. In January 2021, David Liu, NIH director Francis Collins, and colleagues reported the use of another genome editing technology loosely based on CRISPR, called base editing, to increase the lifespan of a mouse model of progeria, a premature aging disease.[5] The prospect of treating children with this rare genetic disorder is suddenly within reach. Liu’s group has also used base editing to repair the specific mutation in beta globin in animal models of sickle cell disease – what Beam Therapeutics CEO John Evans calls “the most famous point mutation in all of human genetics.”

But the biggest excitement in CRISPR circles so far centers around results reported by Intellia Therapeutics, another of the first wave of CRISPR biotech companies. Intellia’s initial focus has been on treating a rare progressive liver disease called ATTR amyloidosis, in which amyloid deposits build up to toxic levels in organs and tissues. Using a new non-viral delivery vector, Intellia performed the first successful in vivo gene editing therapy – directly injecting the CRISPR construct into the patients’ body. The results on the first half-a-dozen patients, also published in the New England Journal [6]i], were superb, providing hope not only for patients with this disease but also a proof of principle for the safety and efficacy of direct CRISPR injections. The next week, the stock price of Intellia and many of its competitors surged. This spectacular progress is all the more remarkable as it comes less than 10 years from the first description of the genetic scissors.

This spectacular progress is all the more remarkable as it comes less than 10 years from the first description of the genetic scissors.

Long-term follow-up and vigilance of these and future patients is of course mandatory, but talk of a CRISPR cure for sickle-cell and other genetic disorders is not out of bounds. Human genetic engineering was proposed almost half a century ago, in 1972, by Ted Friedmann. “We have a 50-year track record of developing and monitoring how well all these [genetic therapies] are doing,” says Urnov. Volunteers like Victoria Gray are true heroes, he says. “At the end of the day, a human being has to agree to be CRISPRed.”

 

CRISPR Controversy

Threatening to overshadow all this progress is the lingering fallout from the notorious “CRISPR babies” scandal. In 2018, a 30-something Chinese scientist shocked the world by announcing that he had edited the genomes of a pair of newborn twins, Lulu and Nana, in an unsafe and unnecessary attempt to grant them HIV immunity. The work, conducted in almost complete secrecy, dismayed and disgusted virtually the entire scientific and medical establishment. Even the Chinese establishment turned against this renegade researcher. Among a long list of transgressions, perhaps the most egregious was voiced by Qiu Renzong, a senior Chinese bioethicist: “How could [he] change the gene pool of the human species without considering the need to consult other members of the human species?”

How indeed. The health of the twins (and a third gene-edited baby born 6 months later) is unknown. The scientist at the center of the scandal is currently serving a 3-year prison sentence.

Figuring a way out of this debacle is a priority. In September 2020, a blue-ribbon commission set up by the National Academies of Sciences, Engineering and Medicine (NASEM) and the UK’s Royal Society released its findings on the future of Heritable Human Genome Editing (HHGE).[7][vii] The commission concluded that there were certain rare circumstances in which it could condone the editing of human embryos, such as where couples with a serious genetic disease could not have a biologically healthy child by any other means (such as preimplantation genetic diagnosis). But the report stressed that much more research was required to ensure that genome editing could be performed safely in human embryos. “There are reports of unintended events including deletions and off-target events that would not be desirable,” said Rockefeller University president Rick Lifton, who co-chaired the commission. “So there’s quite a long road to go.” The final decisions would belong to individual countries after broad public debate, not scientists alone.

Neither the NASEM report, nor the recently published World Health Organization report, can guarantee that another rogue operator won’t try to push the hereditary genome editing envelope once more.

Following publication of that report, I invited dozens of CRISPR experts and bioethicists to share their reactions for an article in The CRISPR Journal.[8][viDoudna hailed the findings and said, “we must continue an inclusive, transparent public dialogue.” Zhang called the report “an inspiration for a future where the commitment to maximizing human benefit and trust in science transcends international boundaries to improve the lives of those suffering the most.” But others judged the commission’s conclusions premature. J. Benjamin Hurlbut called the report “more opiate than solution.” New York University bioethicist Art Caplan said the commission was “putting the technical cart before the ethical horse.” And sociologist John Evans, author of The Human Genome Editing Debate, likened the report’s premise to building an expensive bridge to a remote island with public money, and then saying society can decide to not use it. “The builders of the report want the pathway to be used, or why would they build it?” Another major concern was that legal uses of HHGE would further expand societal divides and discrimination, creating a rift between the “haves” who receive editing for serious diseases or designer babies, and the “have-nots” who are not afforded – or cannot afford – this privilege.

But neither the NASEM report, nor the recently published World Health Organization report, can guarantee that another rogue operator won’t try to push the hereditary genome editing envelope once more.

 

Conclusion     

Two decades ago, the term “CRISPR” was first proposed in an email exchange between a couple of European microbiologists. They weren’t interested in personalized medicine or cures for genetic diseases, merely trying to understand the origin and function of a mysterious pattern of DNA sequences buried in the genome of some species of bacteria. They coined the acronym for “Clustered Regularly Interspaced Short Palindromic Repeats” to describe this genetic curiosity, gloriously unaware that CRISPR would become the subject of Congressional hearings, a Jeopardy! question, a Dwayne Johnson movie, an Emmy-nominated documentary, and a Nobel Prize. Such is the unfathomable value of funding unfashionable basic research, which can (and often does) lead to wondrous serendipitous discoveries such as CRISPR.

Today, the developers of CRISPR gene editing are acclaimed for fueling a scientific, medical and biotechnology revolution that has captured the public imagination, is literally curing patients of devasting genetic disorders, and looks poised to transform the generation of gene-edited plants and crops to help combat the threat of pests and climate change and feed the planet. Where, one wonders, will CRISPR gene editing take us in its second decade?



[i]

[1] GEN. “Doudna Talks Nobel Success and Women in Science.” December 3, 2020. https://www.genengnews.com/topics/genome-editing/doudna-talks-nobel-success-and-women-in-science/[ii]

[2] Sharon Begley & Elizabeth Cooney. “Two female CRISPR scientists make history, winning Nobel Prize in chemistry for genome-editing discovery.” STAT October 7, 2020. https://www.statnews.com/2020/10/07/two-crispr-scientists-win-nobel-prize-in-chemistry/

[iii][3] Frangoul H. et al. “CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia.” New Engl. J. Med. 384, 252-260 (2021). https://www.nejm.org/doi/10.1056/NEJMoa2031054

[iv][4] Urnov, F.D. “The Cas9 Hammer---and Sickle: A Challenge for Genome Editors.” CRISPR Journal. 4, 6-13 (2021). https://www.liebertpub.com/doi/full/10.1089/crispr.2021.29120.fur

[v][5] Koblan, L.W. et al. “In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice.” Nature 589, 608-614 (2021). https://www.nature.com/articles/s41586-020-03086-7

[vi][6] Gilmore, J.D. et al. “CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis.” New Engl. J. Med. June 26, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2107454

[vii][7] National Academies of Sciences. Heritable Human Genome Editing. September 2020. https://www.nap.edu/read/25665/chapter/1

[viii][8] Angrist, M. et al. “Reactions to the National Academies/Royal Society Report on Heritable Human Genome Editing.CRISPR Journal 3, 332-349 (2020). https://www.liebertpub.com/doi/full/10.1089/crispr.2020.29106.man

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