Scientific research: Gene editing has put biological research on a new trajectory

In the late 2010s eight macaque monkeys were born at a laboratory in Shanghai. At first they seemed much like the other infants in the colony, but differences soon became obvious. They were much more active at night than their peers. Their hormones were unusual, too. Melatonin, which typically oscillates with the day-night cycle and aids sleep, was all over the place. Cortisol, a stress hormone, was perpetually high. Then their behaviour took a turn: they sat frozen in corners for long periods of time, fled in fear from their caretakers, and began burying their little heads in their hands—all signs of mental illness.

The root of their malaise was a genetic experiment. When the monkeys were single-celled embryos, scientists had used CRISPR editing tools to silence, or “knock out”, a gene that helps regulate the body’s internal clock. Its disruption is linked to psychiatric conditions, such as bipolar disorder, which are notoriously difficult to study on the genetic and molecular levels. The deeply unpleasant lives of Shanghai macaques are part of a push to understand how genes shape brain disorders and to devise drugs for them.

This could have been done with old technology, but it would have been laborious. Scientists can breed knock-outs using “gene targeting”, a hugely inefficient process that first inserts DNA into stem cells and then into embryos. For mice, it takes a year. CRISPR can do the job in a month. The same is true for adding, or “knocking in”, genetic mutations. Manipulations in both animals and cells have become so quick and easy that scientists can model a host of diseases in the lab, tease apart intricate genetic mechanisms and create huge studies linking genes with diseases.

Hold the anchovies

CRISPR might be on the cusp of transforming medicine and agriculture, but in research things have already changed. Almost 9,000 scientific papers mentioned CRISPR tools in their abstracts in 2024, up from 300 in 2013. Since 2012 Addgene, a non-profit repository of DNA reagents, has shipped more than 300,000 CRISPR preparations to 5,000 organisations in around 100 countries. “You can just simply order everything you need,” says Robin Lovell-Badge, a developmental biologist at the Francis Crick Institute in London. CRISPR RNA is about as hard to get as the pizzas researchers order when working on gene editors into the night.

That is a serious time-saver for scientists interested in fundamental biology, such as Dr Lovell-Badge, whose work concerns sexual development. In the 1990s he discovered that a gene on the Y chromosome called SRY acted as a switch that turned embryos, which by default develop as female, onto the path of male development. But it was not until the arrival of CRISPR in the 2010s that he and others figured out how it actually works. Through knock-out experiments in mice they showed that SRY, via an “enhancer” gene, activates another gene called SOX9, which ultimately drives the development of the testes.

Knock out that activation of SOX9 with CRISPR and “you now get XY females,” he says. This sometimes happens naturally in humans. Other scientists recently checked the genomes of a handful of people who had developed the opposite sexual characteristics of their chromosomal sex. Their mutations were almost exactly the same as those Dr Lovell-Badge had put into his mouse embryos with CRISPR. Those people now know the genetic cause of their unusual development.

Everyone carries their own genetic variants, usually where one base has been swapped for another. Though all these variants can be easily found with genome sequencing, it is often not known which are benign and which are harmful. But in recent years CRISPR has sped up the task of telling them apart. Greg Findlay, a colleague of Dr Lovell-Badge at the Crick Institute, is using the tool to tackle a gargantuan task: he wants to understand every single variation in the human genome that is associated with disease.

Counting only mutations in genes which are implicated in disease, this would mean knocking in 30m DNA variants, Dr Findlay says. Using CRISPR and a new type of gene editing called prime editing, he now runs massive, high-throughput screening experiments, in which thousands of variants are knocked into cells and analysed. “We’ve gone from testing these variants in genetics one at a time to testing large pools,” he says. “Now we’re trying to do experiments that are close to 100,000 variants.”

His results have begun to explain previously baffling symptoms. In 2024 he published a paper going through 2,268 base-swap variants of VHL, a gene involved with suppressing tumours, and showed how particular variants led to different forms and severities of kidney cancer. More such CRISPR-enabled mass screens might help doctors check for variants and tweak treatment accordingly.

But even if Dr Findlay is able to scale up his experiments, the job is probably too big. There are substantial parts of the genome that are poorly understood, and which may host large numbers of disease-causing variants. And multiple variations in the same gene—or different ones—can interact. “Even if we could test a million variants, it’s still nowhere near the 10bn or whatever that are possible,” he says.

To lessen the load, he plans to feed his data to an artificial intelligence (AI) model. If the model trains on all the information he has already generated, he hopes that it will make increasingly accurate predictions about mutations he has not yet tested. DeepMind, Google’s AI company, put out a model in 2023 called Alpha Missense that does this kind of prediction. It was benchmarked against an experimental data set which took ten years to generate, but with the massive gene-editing screens now possible, a data set of that size could be made in a couple months, he says.

I am the one who knocks

He is not the only one energised by CRISPR’s potential to create big genetic screens. Silvana Konermann, the director and co-founder of the Arc Institute, a non-profit research institute in California, has pioneered a CRISPR screen using a tool that can systematically switch genes on or increase their activity—what one might call “knocking up”. Such powers mean she can flip the traditional CRISPR screen on its head. Rather than start with a genetic variant and see what its outcome is, she can take an event, like exposure to a drug or a pathogen, and see which genes do and do not influence how the body responds.

Take SARS–CoV–2. In 2022 Dr Konermann and her Arc co-founder Patrick Hsu developed a CRISPR screen in which human lung cells had genes either knocked out by classic CRISPR or knocked up using the activation tool. The cells were then infected with SARS–CoV–2, and the team were able to say which genes in the human cells helped or hindered the virus. The virus struggled to infect the cells in which the genes responsible for making mucus proteins were more activated. Such variation in gene activity could help explain why some people suffered greatly from covid while others got through the pandemic unscathed. Some probably had very active mucus genes.