Biologists Emmanuelle Charpentier, Jennifer Doudna and Francisco Martínez Mojica, architects of the genome editing technique that is revolutionizing biomedical research, express their astonishment at the speed with which their brainchild is heading for the clinic. In as little as “one or two years,” Doudna believes, “we will see applications to cure eye and blood diseases, and quite possibly cystic fibrosis. Within five years, the technology will have developed beyond what we could ever have imagined.”
20 June, 2017
Mojica, Charpentier and Doudna are joint winners in the 9th edition of the BBVA Foundation Frontiers of Knowledge Awards in the Biomedicine category. This is the first prize the three have shared, which they received at a presentation ceremony on June 15 in Madrid alongside the laureates in the other seven award categories. On June 14, at a press conference in the BBVA Foundation, they talked about their respective contributions to the technique.
What they all singled out were, firstly, CRISPR’s rapid spread through the world’s biomedical labs and, with it, the speed at which it is beginning to be used in clinical trials in humans; secondly, the ethical dilemmas posed by its use; and, thirdly, the importance of basic science, the kind that “produces truly revolutionary results,” in the words of Mojica, who also criticized the lack of funds available in Spain for this kind of research.
“We have always struggled, but now we are even worse off,” he comments ruefully. “The money now is going into work that offers short-term benefits. Because, why fund something that will deliver results in fifty years? The problem is that when researchers work to a set goal, that is all they focus on, so marvels like CRISPR simply pass by unseen, or if they are seen they are ignored.” He admits to experiencing “some pressure” to get involved in the more applied side of CRISP investigation: “They tell me that by doing so I would have more chance of raising funds, that maybe I could expand my lab from two to four people.”
CRISPR exists because in the 1990s this Spanish microbiologist, then and now a senior lecturer in the Department of Physiology, Genetics and Microbiology at the University of Alicante, insisted on studying an odd detail he had detected in a bacteria on the Santa Pola salt flats. This obstinacy led him to a hitherto unknown aspect of the life of microorganisms, and it was on the basis of his findings that Emmanuelle Charpentier and Jennifer Doudna, French and American respectively, built the now famous technique of genetic “cut and paste” presented to the scientific community in 2012.
An old acquaintance, a reunion and a new conductor
CRISPR allows to modify the genome with an unprecedented precision, much more simply and economically than with any other biotechnological method. Charpentier, currently head of the Max Planck Institute for Infection Biology (Berlin, Germany) and a professor at the University of Umeå (Sweden), spoke this morning of her surprise at seeing that “only seven months after publishing the technique, papers began appearing from groups applying it in flies, yeast, worms, and a long list of other organisms. The community really grabbed hold of the technique and starting using it for their own purposes, and that is just fantastic.” She herself continues working with CRISPR for basic research, but, like Doudna, has also set up a biotech firm to explore applications.
Doudna, Professor of Chemistry and Molecular Biology at the University of California, Berkeley (United States), talked about the areas likeliest to see near-term benefit from the technique; specifically, ophthalmology and blood disorders like sickle cell disease, a genetic mutation that deforms red blood cells, leading to sluggish circulation and, at times, anemia or stroke. Cystic fibrosis is another potential target, an incurable genetic condition that affects the respiratory system.
Doudna pointed out that results of the first trials in cancer, begun in late 2016, should not be too long in coming. Oncologists at the university hospital in Sichuan, China, have injected a lung cancer patient with cells from his own immune system, previously edited with CRISPR to enhance their capacity to recognize and attack tumor cells.
An ethical red line?
Asked about ethical dilemmas, Charpentier is clear: “My view is that there is a red line we must not cross. CRISPR should be used purely as a therapeutic tool, and not to improve humans design or modify embryos.” Doudna, however, is more pragmatic: “I have been closely involved in the ethical debate over these past years and my opinion has changed. I have listened to many families dealing with hereditary diseases, and I now think that if we can help them by modifying the germline, perhaps we should.”
Mojica, meantime, had “no fixed opinion,” since ethical dilemmas are not a big thing in microbiology. He added, however, that embryo modification “might be justified in some cases, if there is no alternative,” echoing Doudna’s point that “in these kind of cases, it might be unethical not to intervene.”
A discovery that “rewrites the textbooks”CRISPR functions through a mechanism that “cuts and pastes” DNA sequences, and is derived from a natural mechanism that bacteria use to fend off viral attack. It was precisely this microbial immune system, whose existence no one had suspected, that Mojica (Elche, 1963) revealed to the world, after years mulling over a series of genetic sequences repeating at regular intervals in the genome of microorganisms. He gave these sequences the name of CRISPR, standing for “clustered regularly interspaced short palindromic repeats.”
Mojica solved the mystery with the discovery that between these repeat sequences lay fragments of viral DNA, a remnant of the bacteria’s past invaders. This lightbulb moment, which he describes as “the happiest by far in my scientific life,” showed the microbial CRISPR to be a vaccine against previously encountered aggressors, a defensive memory transmitted from generation to generation.
“It was something revolutionary, that no one had imagined,” Mojica recalls. “We ended up rewriting the textbooks. Science had always taught us that vertebrates were the only beings with acquired immunity and then – what do you know? – bacteria have it too.”
Mojica, who was doing this work with next to no funding because evaluators didn’t share his interest for an apparently minor byway of the microbial world, could not find a publisher for as long as two years – a number of leading journals turned the story down as lacking in interest.
He also reflected this morning that so immersed was he in his microbial world – which he still inhabits – that he “never imagined” that CRISPR would become the powerful tool it is today. “In 2012, a colleague at the lab brought me Charpentier and Doudna’s paper: Look, it turns out CRISPR can be used to edit genomes! We were all totally taken aback.”
In nature, the CRISPR/Cas9 mechanism destroys the phages attacking microorganisms by slicing their DNA; specifically, the CRISPR structure, containing fragments of the virus, detects the invader and steers the molecular “scissors” – the Cas9 enzyme – to the DNA region targeted for cleaving. Hence the technique’s full name of CRISPR/Cas9. In the lab setting, the virus DNA is replaced by a DNA fragment which marks the region of the genome targeted for modification. The resulting method not only cuts DNA with exquisite precision, it also pastes it back in, introducing new sequences if desired.