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About five years ago, when the gene-editing tool CRISPR was just starting to sweep labs around the world, a famously brilliant scientist encouraged two of his grad students to just play around and tinker with it.
"A lot of things that we try fail," says one of those students, Jonathan Gootenberg. "And that’s OK. Because sometimes you find these things that are really, really awesome."
Though they might not seem so awesome at first.
CRISPR is often compared to a word processor that can hunt down the genetic equivalent of a specific word in a text and precisely slice it out. The grad students found that a particular molecular ”scissors” — an enzyme called Cas-13 — would slice RNA, the chemical cousin of DNA, at the right spot, but then, willy-nilly, go on to cut RNA all over the place.
"There was actually a time when we were like, ‘Should we even publish this?'" says Gootenberg’s research partner, Omar Abudayyeh. "'It’s really weird. It doesn’t really align with what we wanted for these enzymes, which is targeted cleavage, not ‘cleave everything.’ ”
But the scientist, Feng Zhang, a CRISPR pioneer and a leading researcher at the Broad Institute and MIT’s McGovern Institute, saw potential importance there.
"He recognized that this is a unique feature that we should publish, and it could be useful one day," Abudayyeh says. "We wanted to kind of hide it under the carpet because 'Ah, this is not what we want!' And months later, we realized that it could be used for detection."
Those runaway scissors could be used for diagnostic tests: Once they're triggered to start cutting by the presence of, say, a specific germ, the continued cutting can also turn on fluorescent molecules that signal “Germ detected!”
They called the method “Sherlock.” Like CRISPR, it’s an acronym. (If you must know, it stands for “Specific High-Sensitivity Enzymatic Reporter unLOCKing.”)
In 2018, the team helped found the company Sherlock Biosciences to start developing CRISPR diagnostic tests — a new use for CRISPR, beyond the advances it has brought in genetic diseases and research ranging from cancer to agriculture.
Then this year, the pandemic hit. Now, with coronavirus tests in short supply around the country, CRISPR could help. Sherlock Biosciences is using the gene-editing system in coronavirus tests approved for use in health care — the first CRISPR product to reach the market.
The company hopes to come out with an at-home coronavirus test next year. Others are on the CRISPR-coronavirus case as well.
Like the World Series
The Sherlock company's push to develop a CRISPR-based coronavirus test "felt like being in the World Series — it really did," says Principal Scientist Christine Coticchia. "Because there was so much on the line every day. You plan so much, you train so much — and then it comes down to the day, it comes down to the data."
Adds Sherlock Biosciences CEO Rahul Dhanda, to office laughter: "For Christine, it felt like it was going to be the World Series and she was the pitcher."
Dhanda says in normal times, it would have taken the company at least another couple of years to bring a CRISPR test to market. But in February, with the pandemic looming, he appealed to the board to let Sherlock Biosciences shift nearly overnight to develop a coronavirus test as quickly as possible.
"And each of them, to their credit, responded by saying, 'This is the mission of Sherlock, to solve these problems,' " he says.
When Dhanda told the Sherlock staff, he saw them all turn their chairs simultaneously toward their desks to face their computers and "start putting together the plan on how we’re going to pull this off. When we say a pivot, there was a literal pivot of chairs at the same time there was a pivot of the company towards a new goal."
In Sherlock's lab on a recent day, scientist Paul Carlson was tweaking the coronavirus test to try to make it faster and more sensitive. He’s been working long hours — with no complaints.
So rarely in science do you get to work on something with such an immediate need.Paul Carlson, Sherlock Biosciences
"So rarely in science do you get to work on something with such an immediate need," he says. "When you're going through your PhD or other types of school, the motivation for work is always, ‘Well, maybe in five years or 10 years or 20 years this will be useful in developing a product.' "
Basic research with longer-term goals does lead to breakthroughs, he says, but these days, his work could already prove useful in just a week or a month.
The Sherlock coronavirus test got temporary federal approval -- called an emergency use authorization — in May. Research associate Joel Mowatt says the CRISPR tests could help both with the national shortage of tests and with concerns about testing accuracy.
"With the increase of numbers recently, you can tell that some people don’t believe that it’s truly real," he says. "So it’s kind of cool to just try to put a little confidence back into the public eye."
Sherlock Biosciences is partnering with a manufacturer to produce kits for testing in medical labs — an initial batch of 30,000, Dhanda says, that could scale up to millions if there’s demand.
It also just announced a deal for on-the-spot COVID tests with a company whose chlamydia and gonorrhea tests come back within about half an hour, ideally while the patient is still in the doctor's office.
There’s competition. Trevor Martin, CEO of Mammoth Biosciences in South San Francisco, points to a recent paper Mammoth published on using its own tests in patients, "where we actually showed that Mammoth’s CRISPR-based diagnostics are an extremely effective tool for testing for COVID-19," he says. "And anyone in diagnostics can tell you that real patient samples are really the gold standard."
Martin says Mammoth is working as quickly as possible to bring their CRISPR tests to market.
"The way we think about it is really putting things out there that are effective and fill a gap in the market," he says, "and there’s a lot of gaps in the market right now."
The biggest gap
Probably the biggest gap is the need for quick, cheap, accurate coronavirus tests that can be done at home or at the entrances to a school or nursing home or stadium.
MIT professor and Sherlock Biosciences co-founder Jim Collins predicts rapid progress on that front from a new technology — called “INSPECTR” — that would use synthetic biology methods to make a test on a simple paper strip.
"In a matter of a small number of months," Collins says, the company "will be in a position to introduce an INSPECTR-based test for COVID-19."
Gootenberg and Abudayyeh have their own lab now at MIT’s McGovern Institute, and are working seven days a week on the challenge of COVID testing.
They’re focused in part on developing a device "akin to something as small as maybe like a Coca-Cola can," Abudayyeh says, "and that someone could do daily testing with every day for very low cost, around maybe five to ten dollars."
They’re also still exploring various CRISPR enzymes — those "scissors" that do the molecular cutting — including one isolated from spoiled fruit juices.
"Because, you know, nature’s got a ton of amazing secrets in it," Gootenberg says.
If there’s a moral to this story, it’s the importance of continuing to explore and try to understand the natural world, he says. It's important both because you never know when a basic science discovery like CRISPR could pan out, and because you never know when a natural phenomenon like the coronavirus could have a huge and terrible impact on people’s lives.
This segment aired on July 10, 2020.
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