Will a revolutionary DNA-editing tool end disease – or threaten humanity?

This story is part of the March 16 edition of Good Weekend.See all 14 stories.

Great discoveries – the ones that alter the course of human history – rarely happen with the sudden “Eureka!” moment you see in the movies: a lone inventor’s sudden flash of genius, giving birth to a fully formed breakthrough no one has ever thought of before. In the real world, giant leaps of technology – from the motor vehicle to the airplane, refrigeration to antibiotics, the computer to the mobile phone – happen far less dramatically. They usually begin with a thought bubble or rough sketch, followed by a series of frustrating false starts and dead-ends, the solution coming teasingly close for years before the triumphant discovery is finally made, more often than not with help from a few unsung collaborators along the way. While developing the light bulb, Thomas Edison (far from being a lone inventor, he employed at least 200 laboratory assistants) famously quipped, “I haven’t failed – I’ve just found 10,000 ways that won’t work.”

Until he found a way that did.

Professor Jennifer Doudna, a biochemist at the University of California, Berkeley, who helped make one of the most monumental discoveries in biology this century, spent years toiling in her lab, first at Yale, then Berkeley, hovering over microscopes, petri dishes and centrifuges, making a number of landmark findings, and winning accolades, before cracking the Big One in 2012: a new technique for editing DNA called CRISPR that can be used in virtually any field of science.

Doudna’s discovery is poised to radically advance the way medicine, agriculture and species protection is practised in the coming decades, in ways we can’t yet fully fathom because her CRISPR-driven biotech revolution is still in its infancy. But already, thanks to CRISPR, sufferers of pernicious, intractable diseases like sickle cell anaemia are being cured.

For someone who’s had a lifelong talent for making discoveries, Doudna, who turned 60 last month but looks younger with a bob of greying hair, a wide smile and unlined skin, is remarkably modest about her achievements, while keen to share the love with her collaborators and assistants. Ask Doudna something personal – an event in her youth, an early accolade – and you get small, clipped answers. Ask about her work – the actual science – and the words come somersaulting out. Behind any major discovery, she insists, lies years of medical research and collaboration between scientists. In fact, if Doudna (the first syllable rhymes with loud) has a signature word, it’s collaboration – with a capital C. “Collaboration is fundamental to the story of CRISPR,” she says in an extended video chat from her laboratory in California.

The game-changing collaboration for Doudna occurred in 2011 at a microbiology conference in San Juan, Puerto Rico, when she met Professor Emmanuelle Charpentier, a French microbiologist based in Sweden. One of the minor sessions at the conference was about a little-discussed immune response called CRISPR or “clustered regularly interspaced short palindromic repeats”. The pair strolled through the cobblestoned streets of old San Juan, trying to break down how CRISPR – a naturally occurring gene-editing process – worked, and how it might be manipulated in the lab. The two scientists decided to team up, Charpentier working from her lab in the snowy town of Umeå, 400 kilometres from the Arctic Circle in northern Sweden, and Doudna from hers in leafy Berkeley in northern California, sharing research ideas and swapping lab results. The more results they shared, the more Doudna was convinced they were on to Something Big.

The two women were intrigued by CRISPR’s cunning defence system, in which bacterial troops seize extracts of DNA from a viral invader, so they’re able to identify and kill the same virus in the future. When that virus returns to re-infect a bacterium, it docks with the recorded matching DNA strand. The bacterium then swiftly targets it with Cas9, a powerful enzyme, which chops the virus out. Presto! The bacterium is free of infection.

Doudna and Charpentier asked themselves: what if this hardwired immune response could be programmed, not just to identify and disable the genes of a virus, but to edit a genome with gene mutations, the ones responsible for inherited diseases like sickle cell anaemia, Huntington’s disease or muscular dystrophy? Doudna had already received acclaim for her work with RNA – the less famous, but vitally important cousin of DNA. (While DNA is fairly static, protecting the information it holds in the nucleus of our cells, RNA is more akin to a delivery person, making proteins that play an integral role in healthy cellular production and disease prevention.)

Doudna and Charpentier set about re-engineering a CRISPR-Cas9 system to target a specific section of DNA by loading it up with its own matching RNA sequence – once paired, the Cas9 enzyme would act like a pair of “molecular scissors” to snip out the faulty piece of DNA. Doudna recalls the excitement of that time: “I remember looking at the data and realising we could engineer a simpler version.” Doudna and Charpentier, who started using CRISPR-Cas9 on a jellyfish gene, successfully went on to use it on human cells.

A model of the groundbreaking technology developed by Professors Doudna and Charpentier, known by some as “genetic scissors”, whereby DNA can be cut and edited. Credit: Getty Images

In effect, Doudna and Charpentier had developed the master key for opening the DNA editing suite to practically all living things.

While the research may sound a tad obscure, its practical, real-world applications are massive. When the pair published their findings for peer review in the journal Science in June 2012, it not only sparked a frenzy of interest in the international scientific community, but a stampede of new biotech research. That’s because Doudna’s peers recognised CRISPR’s spectacular promise – and how they might edit the cells of plants, animals and people themselves. In effect, Doudna and Charpentier had developed the master key for opening the DNA editing suite to practically all living things. A tsunami of scientific papers by other researchers swiftly followed, detailing the use of CRISPR in editing a host of different organisms. “It was a moment when it was clear things were about to change pretty dramatically,” says Doudna with a half-smile – and characteristic understatement.

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Since becoming one of the most famous scientists on the planet, Doudna now divides her life into “before CRISPR” and “after CRISPR”. In 2014, she shared a stage, not only with Charpentier, but with movie star Cameron Diaz and then Twitter CEO Dick Costolo, to receive a Breakthrough Prize in Life Sciences, which included a $US3 million cheque each for the pair’s research (the annual awards are funded by tech titans such as Mark Zuckerberg, Jack Ma and Sergey Brin). The following year, Doudna was listed by Time magazine as one of its 100 most influential people. In 2017 she published a book, A Crack in Creation, with Samuel H. Sternberg, a biochemist and former member of her lab; four years later, revered US journalist Walter Isaacson wrote a biography of Doudna, The Code Breaker, which became a bestseller.

Professors Jennifer Doudna (left) and Emmanuelle Charpentier with a model of CRISPR-Cas9. The pair won the Nobel Prize for Chemistry for their contribution to its development.Credit: AP

But the biggest accolade of all came via a 3am phone call in the thick of a COVID-19 lockdown. It was May 2020, and the call was to inform her that she and Charpentier had won the Nobel Prize in Chemistry. What’s more, they were the first joint female winners. At first, Doudna thought it was a prank call, but a flood of congratulatory phone calls and messages followed, and by 7am she was fronting a socially distanced press conference. “It was a moment of great joy, but it wasn’t that easy to celebrate – we were in the middle of lockdown,” she recalls. “A few of us got together in the laboratory later that day.”

Doudna says the most gratifying aspect of winning the Nobel has been witnessing an increase in the number of young people entering the sciences. In recent years, the number of women enrolled in university STEM (science, technology, engineering and mathematics) subjects across the US has increased by about 30 per cent. She believes the Nobel Prize “has really made a difference in attracting young people to the field. I’ve noticed this across the board.”

Until Doudna and Charpentier’s gene-editing technology came along, the ability to make changes to human, animal or plant DNA – literally, the building blocks of life – sounded, if not exactly like science fiction, still a long way off, a little like artificial intelligence only a few years ago. CRISPR allows an organism’s DNA – from plants to animals to humans – to be edited, like blocks of text in a word-processing document or scenes in a film. Just like a bad word or movie moment, a faulty gene causing an inherited disease can be deleted and replaced with a better one (healthy DNA). While there had been gene-editing tools before CRISPR, they were labour-intensive, time-consuming and often unreliable.

“Earlier technologies for genome engineering meant that for every experiment, you had to design a new protein, test it, and if it didn’t work, make it again,” Doudna explains. “This could take many weeks, and it’s also very expensive, which meant most academic labs didn’t have the resources to do that work. After CRISPR came along, it became possible to generate the new molecules you needed for an experiment within an afternoon or a day, fairly easily and inexpensively. Almost any lab doing any kind of molecular biology now has this tool.“

What makes CRISPR so exciting to scientists is that the possibilities for applying the technology seem limitless, from revolutionising the treatment of diseases to making plants more drought and pest-resistant – critical attributes as climate change advances at an ever-quickening pace. Some of the most promising work in agriculture is now being undertaken by plant scientists in China, where CRISPR is being used to develop tomatoes that are less susceptible to heat stress, wheat that is less prone to mildew, and rice crops that are not only higher-yielding, but also resistant to fungal infection.

In early 2022, the Chinese government published a set of guidelines for the approval of gene-edited plants and, in May last year, gave the green light to farmers growing a gene-edited soybean, enhanced with heart-healthy oleic acid – quite something for a country that for decades outlawed genetically modified crops. (Advocates of CRISPR insist gene editing is a less risky and more “natural” method of boosting food production than genetic modification, which introduces foreign genes into a plant to boost quality and production, while gene editing works with existing genes.) Bear in mind that all this is happening while the use of CRISPR technology has still barely begun in earnest. Brad Ringeisen, the executive director of the Innovative Genomics Institute at Berkeley, which Doudna set up, told USA Today last year that the rise of CRISPR was “unmatched and unparalleled” in science. “It’s changed the way we do biology.”

“If you have a single gene that’s been well-defined as causing a disease, it’s a great potential target for something like CRISPR.”

Jennifer Doudna

Late last year, the US Food and Drug Administration approved the first gene therapy using CRISPR for the treatment of sickle cell anaemia – the inherited blood disease – in patients 12 years and older. Blood cells, Doudna explains, can be “harvested, edited and then reintroduced to patients”. While it has led to a cure in some patients suffering from sickle cell anaemia, it is still an expensive and involved procedure, requiring a bone-marrow transplant and chemotherapy to allow the edited cells to take hold. Still, it’s a tremendous breakthrough. Given that most of the more than 7000 defined rare diseases result from a single faulty gene, these are now prime first-wave targets for the technology.

Doudna with her Nobel Prize medal.Credit: Courtesy of the Innovative Genomics Institute

“Many of the clinical trials in progress currently with CRISPR are targeting those kinds of rare diseases,” Doudna tells me. “And one reason is that if you have a single gene that’s been well-defined as causing a disease, it’s a great potential target for something like CRISPR.” The truly rewarding aspect, she adds, is that these rare diseases have tended not to be the focus of research and trials by pharmaceutical companies, because the numbers aren’t there for healthy profit margins. Genetic diseases of the eye have also been a focus for CRISPR applications: as Doudna explains, “it’s easier to deliver to the eye than to other parts of the body.”

For cancers and heart disease, CRISPR could, in the near future, offer sufferers the possibility of prevention as well as cure. “I’m very excited about the potential for CRISPR to become a prophylactic kind of treatment,” she says. “In other words, helping people not only deal with existing disease but actually prevent future disease. So for example, there are already efforts to edit genes involved in hypercholesterolemia – high cholesterol. This is one of the major causes of cardiovascular disease, as you probably know, so if it were possible to create changes in a person that prevented heart disease in the future, I think that would be incredible.”

“It’s a very effective and cheap tool, which has enabled many labs that couldn’t have done molecular research in the past to do so.”

Professor Paul Thomas, director of the South Australian Genome Editing Facility

While CRISPR therapy for heart disease and cancer is still in development, the coming decade is likely to see many therapies move out of the lab and into hospitals and doctors’ surgeries. The beauty of gene therapies, too, is that they offer the possibility of a permanent, drug-free cure, saving sufferers from a lifetime of medication. That’s because gene therapy tackles the cause of the rare disease rather than the symptoms. A single dose could offer lifelong protection from a disease or cancer.

Professor Paul Thomas, director of the South Australian Genome Editing (SAGE) Facility at the University of Adelaide, estimates at least 100 labs across Australia are now using CRISPR technology in a range of fields, and the number is increasing by the month. “It’s a very effective and cheap tool, which has enabled many labs that couldn’t have done molecular research in the past to do so,” he says. “It’s been a game-changer.”

Thomas’s lab is using CRISPR technology for its research on the inherited diseases, retinitis pigmentosa and Duchenne muscular dystrophy, which are caused by “mistakes” in specific genes. CRISPR offers the possibility that these diseases can be stopped in their tracks or cured with a single “knock-out” therapy. “CRISPR is both a research tool and a therapeutic tool,” he says. “It is a little molecular machine – allowing genetic modification of cells or animals to investigate a disease and develop new therapies.”

Thomas met Doudna when she visited Victoria in 2018. “She is a superstar in the world of science, but she was very down-to-earth and so keen to share her knowledge,” he says. “I wasn’t surprised when she went on to win the Nobel Prize.”

Doudna as an undergraduate at Pomona College, outside Los Angeles, in 1985.Credit: Courtesy of the Innovative Genomics Institute

Doudna’s bloodline runs thick with impressive academic credentials. Her father taught literature at the University of Hawaii; her mother lectured on history at a community college. When she was seven, her family moved from Washington DC, where she was born, to Hilo, a small town on the spectacular north-eastern corner of the big island of Hawaii. She spent much of her time exploring the local rainforests and was fascinated by how plants and animals interacted. She found her calling during high school when a good friend of her father’s at the University of Hawaii, Professor Don Hemmes (now Professor Emeritus), offered her a chance to work in his research lab over the summer break. “I absolutely loved it,” Doudna recalls. “It was a wonderful opportunity to see how a lab worked.”

Another prime inspiration for the teenager was reading James Watson’s book, DNA: The Secret of Life, which reinforced her fascination with biology. She graduated from Pomona College outside Los Angeles in 1985 and earned a PhD from Harvard Medical School four years later. She is married to Jamie Cate, also a professor of chemistry at Berkeley (the couple met in the early 1990s at the University of Colorado as graduate students) and they have a 22-year-old son, Andrew, also at Berkeley, where he’s studying electrical engineering.

“Andrew loved Australia when he came with me on my last visit,” she tells me. (Doudna came to Melbourne with her son for a series of engagements in 2018, and the pair will return, this time to Sydney, for Doudna’s talk on “The Gene Editing Revolution” at the Sydney Opera House on May 21, held in conjunction with the Sydney Writers’ Festival.)

As with any new technology, we’ve barely begun to understand how the full effects of CRISPR will play out in the coming decades – specifically, any threats it may pose to the natural world of humans, animals and plants. It’s one thing to prevent someone with an inherited gene for cystic fibrosis from developing the disease, it’s quite another to make changes that will be passed on to future offspring. If it’s okay to lower an unborn child’s future risk of dementia, for example, is it okay to edit for a higher IQ, greater height and athleticism? Even if Western countries introduce regulations and laws against designer babies, what’s stopping authoritarian countries from creating an elite population with enhanced intelligence, beauty or other traits? The prospect of CRISPR being used to manipulate the genes in human embryos, sperm or eggs, so that these can be passed to future generations, is what keeps scientists like Doudna up at night. “The idea that you would affect evolution is a very profound thing,” she told The New York Times in 2015.

Around that time, scientists in China reported that they had used CRISPR to double the muscle mass of a dog. Since then, they’ve used the technology to develop faster-growing, disease-resistant pigs, goats and cows and genetically altered twin cynomolgus monkeys. If that wasn’t enough wading into ethically murky waters, a Chinese researcher in 2018 claimed to have altered the genomes of twin baby girls to make them resistant to infection by HIV. Making changes to embryos like this – in effect making permanent alterations to the genome – was taking CRISPR into uncharted terrain. “We were concerned that scientists were racing ahead to use CRISPR,” Doudna tells me. “In human embryos, making heritable changes means permanent changes in the germline, which can be passed on to future generations.” In any case, the announcement sparked a blaze of outrage from the international scientific community, which regarded it as a gross breach of medical ethics. Perhaps chastened, the Chinese Society for Cell Biology issued a statement calling the research “a serious violation of the Chinese government’s laws and regulations and the consensus of the Chinese scientific community”. The doctor in question was sent to prison for “illegal medical practices” but has since been released and is staging something of a comeback, using CRISPR for his work on muscular dystrophy.

“You can’t really put a lid on the process, even if you wanted to.”

Jennifer Doudna

Doudna has been lobbying policymakers and the international scientific community to prevent this ethical line from being crossed. In 2019, she led a group of prominent scientists asking for a global moratorium on gene editing of eggs, sperm or embryos. Three years later, on the 10th anniversary of CRISPR, Doudna told Time magazine: “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. 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.”

Doudna tells me she now sees herself as an ambassador for CRISPR so that it achieves positive, rather than negative outcomes in the world – and that global governance of the process is maintained through clear guidelines. But, she concedes, “You can’t really put a lid on the process, even if you wanted to.”

Doudna’s fight to control how her invention is used hasn’t been restricted to reining in rogue scientists testing the limits of what’s right: she has also had a battle protecting the intellectual property of her discovery. It was a surprise to many when the first major patents for CRISPR were granted not to Doudna but to Feng Zhang, another pioneering researcher at the Broad Institute of MIT and Harvard in Massachusetts, who published a paper after Doudna, but claimed he got his technology to work in cells with a nucleus before she did.

Whoever wins – Doudna has launched an appeal against the ruling – will stand to collect untold millions in licensing fees from companies paying for the legal right to use CRISPR technology. While Doudna won’t be drawn on the patents war, which is continuing, she says that “patents are important because they allow investments in a technology that often takes years to develop. Investors want to know that at the end of that investment timeline, they’re going to recover value from that investment. And for that, you need to have patents.”

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At a time when trust in science and facts appear to be eroding, when misinformation is rampant thanks to social media, Doudna is determined to use her platform thoughtfully, to show the public the power of gene editing, while not glossing over its potential perils. At stake, she believes, is “nothing less than the future of our world”. But she remains optimistic. “CRISPR has already cured people of the devastating sickle-cell disease, and it’s created rice plants that are resistant to both diseases and drought,” she said in a TED Talk late last year. “The next world-changing advance with CRISPR will actually come from using it in a way that will allow us to go to the next level by editing genes beyond just in individual organisms. We now have the ability to edit entire populations of tiny microbes called microbiomes that live in or on our bodies … in humans, dysfunctional microbiomes are associated with diseases as diverse as Alzheimer’s and asthma.” And, potentially, bowel diseases including ulcerative colitis, which have been linked to unhealthy biomes.

“Things have really changed in the time I’ve been doing science professionally,” Doudna reflects. “There are many more scientists involved in our field, and they’re from all over the world, so if you want to lead, you have to stay abreast. Above all, I really want to see this technology used to help people.”

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