When it comes to containing coronavirus spread, every minute counts, as people can infect others without showing any symptoms. But many patient samples can take days, if not longer, to be shipped and run through molecular diagnostic tests at lab facilities experiencing backlogs. Rapid serology tests can check for the presence of antibodies in minutes, but it can take several weeks from initial infection for a person to develop an immune response.
Two groups of Forbes Under 30 alums, operating on different coasts, are racing against time—and each other—to develop the next generation of rapid Covid-19 diagnostic tests that won’t require a lab setting. These tests, which rely on the gene-editing technology Crispr, could be used at-home and provide results in minutes on a strip of paper, similar to a pregnancy test.
The West Coast effort is led by Mammoth Biosciences co-founders and 2019 Under 30 honorees Trevor Martin, Janice Chen and Lucas Harrington. The East Coast effort, called STOPCovid, is led by Omar Abudayyeh and Jonathan Gootenberg, who run a joint lab out of the McGovern Institute at the Massachusetts Institute of Technology. The two scientists are cofounders of Sherlock Biosciences and were 2018 Under 30 honorees.
In theory, Crispr-based tests are the perfect trifecta: simple, fast and affordable. In practice, it’s more complicated. The biochemistry underlying the technology is usually carried out at specific temperatures in sterile lab settings, requiring pipettes, heat blocks and space to prevent cross-contamination. Miniaturizing an entire lab bench into a hand-held device is akin to moving from the vacuum-tube computers of the 1960s to an iPhone in a matter of months.
Mammoth Biosciences CEO Trevor Martin describes the current Covid-19 diagnostics landscape as a “tale of two cities.” His hope for Crispr-based diagnostics is to “unite” the accuracy of molecular tests with the speed of serology tests.
His vision got one step closer to reality last month as South San-Francisco-based Mammoth announced a collaboration with GlaxoSmithKline Consumer Healthcare to develop, scale and commercialize a Crispr-based Covid-19 test that could eventually be sold over-the-counter for at-home use.
The GSK partnership is a “watershed moment” for Crispr-based diagnostics, says Ursheet Parikh, a partner at the Mayfield Fund, Mammoth’s largest investor. “It’s one thing for a lot of emerging companies to move fast with it. It’s another thing for a large mainstream company to internalize that and want to bet on it,” he says. Mammoth, which was co-founded by Crispr pioneer Jennifer Doudna, has raised $70 million to date.
The technology pairs a Crispr-associated protein with a snippet of RNA code from the virus that acts as a guide. If the Crispr enzyme recognizes the guide sequence in the sample, it cuts the RNA apart and simultaneously activates a signal.Two lines will appear on the paper test strip, indicating the presence of SARS-CoV-2, the virus that causes Covid-19, if the signal is activated.
The benefit of Mammoth’s diagnostics platform, known as DETECTR, is it can quickly adapt to new diseases by switching out the Crispr enzymes and target sequences, which is what happened in January as the company pivoted to develop a Covid-19 test. Less than three months later, Mammoth’s CTO Janice Chen co-authored a paper published in Nature Biotechnology, demonstrating the platform could detect the virus with a high-level of accuracy in less than 40 minutes across 83 patient samples.
But the method outlined in the paper requires two different temperature settings for amplifying the virus and the Crispr detection step. “The real magic comes into how you integrate that all into a handheld disposable system,” Chen says.
She declined to provide details on how Mammoth will go about this process, but the ultimate goal of the GSK partnership is to combine the steps in a handheld device for use in a clinic or at-home that can generate a readout in around 20 minutes. The companies say they plan to apply for an emergency use authorization from the U.S. Food and Drug Administration by the end of the year.
Omar Abudayyeh and Jonathan Gootenberg frequently use the word “simple” when describing the vision for their Crispr-based diagnostic test for Covid-19. Picture a device, they say, about the size of an iPhone. A person will insert a nasal swab or spit sample into it, and, within twenty minutes or so, the device will indicate whether the person has Covid-19. The results, printed on a strip of paper, will be easy to understand: one line and its negative, two lines and its positive.
They haven’t gotten there yet, but Abudayyeh and Gootenberg are making progress out of their joint lab at MIT’s McGovern Institute in Cambridge, Massachusetts, where they’ve figured out how to combine two crucial steps—usually performed at different temperatures—into one.
The key? Finding a Crispr protein that could sustain being heated up to 140℉ (60℃). They found a solution with AapCas12b, an enzyme derived from a bacterium found in spoiled fruit juice, with which they could combine amplifying the viral RNA and Crispr detection into one step. But in order to move from the lab to the home and achieve the desired cost-savings, they will need to figure out a battery-powered or plug-in heating system, to get the device to the needed temperature.
“It’s going to be hard to miniaturize a PCR machine and make it incredibly cheap,” says Abudayyeh, referring to the thermal cyclers needed to amplify DNA or RNA in the lab setting that are around the size of a microwave.
“By switching to something that requires a constant temperature, we can start thinking about devices that are basically the size of an iPhone,” he says. Abudayyeh estimates the cost of the chemistry at around $1 per test at scale, while it’s around $6-7 on the small scale they are working at now. The device would be an additional cost.
The STOPCovid effort started in January, when Abudayyeh and Gootenberg teamed up with Feng Zhang of the Broad Institute of MIT and Harvard. (All three scientists are co-founders and equity holders in Sherlock Biosciences.) In February, they released an open access two-step protocol using the Crispr technique they invented, known as SHERLOCK, in combination with paper strips.
But the initial feedback they received from collaborators was that the protocol was still too complicated—iit required multiple steps that included mixing up fluids and risked contamination of samples in an at-home setting.
“We had a big vision for at-home testing and we knew that we had to reduce the fluid handling number of steps to really make it easier-to-use,” says Abudayyeh.
This vision is what pushed the team to reduce the reaction to one 140℉ step. They’re calling the new protocol STOP, or SHERLOCK Testing In One Pot.
Gootenberg says they’ve gotten more than 150 requests for test kits from “people all around the world,” including Italy, Spain, several military groups and the CDC. The protocol is only authorized for research purposes only and will likely start in point-of-care settings, such as pharmacies or workplaces, before it would be available for at-home use.
The hope is that these groups can figure out how to further refine the protocol as they continue to develop the self-contained handheld device. “We’re trying to just make this as accessible as possible so people can, use it, build upon it and make it hopefully something that globally has an impact,” Gootenberg says.