In the late 1980s, scientists at Osaka University in Japan noticed unusual repeated DNA sequences next to a gene they were studying in a common bacterium. They mentioned them in the final paragraph of a paper: "The biological significance of these sequences is not known."
Now their significance is known, and it has set off a scientific frenzy.
The sequences, it turns out, are part of a sophisticated immune system that bacteria use to fight viruses. And that system, whose very existence was unknown until about seven years ago, may provide scientists with unprecedented power to rewrite the code of life.
In the past year or so, researchers have discovered that the bacterial system can be harnessed to make precise changes to the DNA of humans, as well as other animals and plants.
This means a genome can be edited, much as a writer might change words or fix spelling errors. It allows "customising the genome of any cell or any species at will," said Charles Gersbach, an assistant professor of biomedical engineering at Duke University.
Already the molecular system, known as CRISPR, is being used to make genetically engineered laboratory animals more easily than could be done before, with changes in multiple genes. Scientists in China recently made monkeys with changes in two genes.
Scientists hope CRISPR might also be used for genomic surgery, as it were, to correct errant genes that cause disease. Working in a laboratory - not, as yet, in actual humans - researchers at the Hubrecht Institute in the Netherlands showed they could fix a mutation that causes cystic fibrosis.
But even as it is stirring excitement, CRISPR is raising profound questions. Like other technologies that once wowed scientists - like gene therapy, stem cells and RNA interference - it will undoubtedly encounter setbacks before it can be used to help patients.
It is known, for instance, that CRISPR can sometimes change genes other than the intended ones. That could lead to unwanted side effects.
The technique is also raising ethical issues. The ease of creating genetically altered monkeys and rodents could lead to more animal experimentation. And the technique of altering genes in their embryos could conceivably work with human embryos as well, raising the spectre of "designer babies."
"It does make it easier to genetically engineer the human germ line," said Craig C. Mello, a Nobel laureate at the University of Massachusetts Medical School, referring to making genetic changes that could be passed to future generations.
Still, CRISPR is moving toward commercial use. Five academic experts recently raised $43 million to start Editas Medicine, a company in Cambridge, Massachusetts, that aims to treat inherited disease. Other startups include Crispr Therapeutics, which is being formed in London, and Caribou Biosciences in Berkeley, California.
Agricultural companies might use CRISPR to change genes in crops to create new traits. That might sidestep the regulations and controversy surrounding genetically engineered crops, which generally have foreign DNA added.
The real frenzy started in 2012, when a team led by Emmanuelle Charpentier, then at Umea University in Sweden, and Jennifer A. Doudna of the University of California, Berkeley, demonstrated a way for researchers to use CRISPR to slice up any DNA sequence they choose.
Scientists must synthesise a strand of DNA's chemical cousin RNA, part of which matches the DNA sequence to be sliced. This "guide RNA" is attached to a bacterial enzyme called Cas9. When the guide RNA binds to the corresponding DNA sequence, Cas9 cuts the DNA at that site.
The cell tries to repair the cut but often does so imperfectly, which is enough to disable, or knock out a gene. To change a gene, scientists usually insert a patch - a bit of DNA similar to where the break occurred but containing the desired change. That patch is sometimes incorporated into the DNA when the cell repairs the break.
Would this work in organisms besides bacteria? "I knew it was like firing a starting gun in a race," Doudna said, but sure enough, by early 2013 scientists had shown it would work in human cells, and those of many other animals and plants, even though these species are not known to have CRISPR-based immune systems.
"I don't know any species of plant or animal where it has been tried and it failed," said George Church, a professor of genetics at Harvard Medical School. "It allows you to do genome engineering on organisms that are very hard to do otherwise."
In the past, making an animal with multiple genetic changes usually required creating separate animals with single changes and then crossbreeding them to produce offspring with multiple changes. With CRISPR, multiple genetic changes can be made in one step, by putting multiple guide RNAs into the cell.
"It just completely changes the landscape," Doudna said. Berkeley scientists used to farm out that work to specialised laboratories or companies. Now, she said, "people are able to make mice in their own labs."
There are other techniques that can do what CRISPR does, though CRISPR is "the easiest by far," Church said.
It is likely to be a few years before CRISPR is tested in people. For now, there is a lot more to learn about it.
Chase L. Beisel at North Carolina State reported that CRISPR could be used to kill one strain of bacteria in a mixture of strains, by targeting a sequence unique to that strain. That might one day lead to antibiotics that can kill the bad bugs without also killing the good ones.
David S. Weiss of Emory University found that some bacteria use Cas9 to silence one of their own genes, rather than that of a virus, to help them evade detection by their host's immune system.
The pace of new discoveries and applications is dizzying. "All of this has basically happened in a year," Weiss said. "It's incredible."
New York Times