The most powerful tool in the history of biology was, in part, worked out by people trying to make better yogurt. In the early 2000s, at the food company Danisco, scientists had a costly, unglamorous problem. The bacteria used to ferment milk into yogurt and cheese — workhorse cultures such as Streptococcus thermophilus — were regularly wiped out by viruses called bacteriophages, souring entire production batches. To fix it, the researchers began studying how these bacteria defended themselves. What they uncovered turned out to be nothing less than a bacterial immune system, and within a decade it would let biologists rewrite the code of life almost at will.
The clues had been accumulating quietly for years. Back in 1987, Japanese researchers sequencing a gene in the gut bacterium E. coli had noticed something odd nearby: a series of identical short DNA sequences, repeated over and over, separated by "spacer" segments that were all different. Nobody knew what they were for. Similar strange repeats turned up in one microbe after another over the following years, scattered through the genomes of bacteria and their relatives, the archaea. In 2002 the pattern was finally given a suitably forgettable name: Clustered Regularly Interspaced Short Palindromic Repeats — CRISPR for short. It was, at that stage, a curiosity in search of a purpose.
The immune system in a bacterium
The dairy work helped crack the mystery. In 2007 the Danisco team, including Rodolphe Barrangou and Philippe Horvath, showed experimentally what the spacers were: snippets of DNA captured from viruses that had attacked the bacterium in the past. When a bacterium survives a viral infection, it files away a piece of the invader's genetic code in its CRISPR region, like a mugshot. If that virus ever returns, the bacterium uses the stored sequence to recognise and destroy the matching viral DNA. The spacers, in other words, were a genetic memory of past infections — a molecular immune system, complete with a set of cutting enzymes named Cas, for "CRISPR-associated".
The crucial leap came in 2012. Jennifer Doudna, a biochemist at Berkeley, and Emmanuelle Charpentier, a French microbiologist then working in Sweden, had been unpicking how one of these enzymes, Cas9, actually worked. They showed that the system could be reduced to two essential parts: the Cas9 protein, which does the cutting, and a "guide" molecule of RNA that steers it to a precise location in the genome. Crucially, they demonstrated that the guide could be redesigned to target virtually any DNA sequence a researcher chose. In effect, they had turned a bacterial defence mechanism into a programmable pair of molecular scissors.
Rewriting life
The implications were staggering, and biology moved with rare speed. Where editing a gene had once been slow, costly and hit-and-miss, CRISPR-Cas9 made it cheap, quick and precise enough for an ordinary university lab. Within months, groups around the world — notably including Feng Zhang at the Broad Institute — had shown it working in the cells of plants, animals and humans. A bitter and long-running patent dispute followed over who was first to make it work in complex cells, a reminder of just how valuable the technique had become.
The applications arrived quickly. Researchers have used CRISPR to engineer disease-resistant crops, to alter mosquitoes, to hunt for the genetic roots of illness, and to develop treatments for inherited blood disorders such as sickle-cell disease, the first of which won regulatory approval in Britain and the United States by the mid-2020s. It also raised some of the sharpest ethical questions in modern science. There is a firm line, widely observed, between editing the ordinary cells of a consenting patient and editing the germ line — the eggs, sperm and embryos whose changes are inherited by every future descendant. In 2018 a Chinese scientist named He Jiankui shocked the world by announcing he had edited the genomes of twin baby girls to try to make them resistant to HIV. The act was condemned across the scientific community as reckless and unethical, and he was later imprisoned.
In 2020 Doudna and Charpentier were awarded the Nobel Prize in Chemistry "for the development of a method for genome editing" — a rare case of the prize going to two women, and unusually swift recognition for work only eight years old. The award traced a line that ran, improbably, from the spoilage of fermented milk to the ability to edit the human genome.
It is a fitting origin story for the genomic age. The tool that may one day cure hereditary disease was first glimpsed not in a gleaming genetics institute but in the humble, ancient business of turning milk sour — a reminder that the deepest secrets of life are often hiding in the most ordinary places.
Quiz nuggets
- CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats; the acronym was coined in 2002.
- Researchers at the food company Danisco, studying yogurt bacteria such as Streptococcus thermophilus, showed in 2007 that CRISPR is a bacterial immune system against viruses.
- Jennifer Doudna and Emmanuelle Charpentier published their landmark paper on programmable CRISPR-Cas9 gene editing in 2012.
- Cas9 is a protein that cuts DNA, steered to its target by a guide molecule of RNA.
- Doudna and Charpentier won the 2020 Nobel Prize in Chemistry for developing genome editing.