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Mammoth Biosciences Developing CRISPR-Based Disease Detection for At-Home, Hospital Use

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NEW YORK (GenomeWeb) – Mammoth Biosciences, a biotech startup cofounded by CRISPR researcher Jennifer Doudna, made a splash when it came out of stealth mode late last month with backing from several venture capital firms, a license for CRISPR technology from the University of California, and a plan for a CRISPR-based disease detection platform that the company said would have both at-home and hospital-use versions.

Though the firm didn't specify how much money it had raised, the fact that it's backed by the likes of Mayfield, NFX, 8VC, AME Cloud, Wireframe, Kairos, and Boom Capital was enough to lend it a certain significance. And Doudna's name — she also chairs Mammoth's scientific advisory board — certainly suggests that this company knows what it's talking about when it comes to CRISPR technology.

What the company is aiming to build is a CRISPR-based platform, initially using Cas12 and Cas13 to look for DNA and RNA in a bid to detect various diseases, Mammoth Cofounder and CEO Trevor Martin told GenomeWeb. The possibilities, from infectious disease detection to cancer biomarker detection, are almost limitless, he added. And although the initial focus of the platform is healthcare, future possibilities include applications for genotyping, agriculture, forensics, the oil industry, and more. The platform would be able to utilize any CRISPR-Cas protein with a purpose.

"We're excited to create our own tests for these applications, but we're also excited to partner with other institutions, corporations, or entities that have biomarkers, but need help to actually commercialize them, to bring their biomarkers into the clinic or into people's homes. So it's a two-pronged strategy," Martin said. "The beauty of CRISPR is that it's programmable, and switching out the guide RNA, you can make it target a different indication. If you have a biomarker, we can design a guide RNA for that biomarker."

Further, he added, Cas proteins could be multiplexed to detect several nucleic acids, or even DNA and RNA, simultaneously.

"For the at-home version of the platform," Martin said, "our vision is to not have a device. It would be like a pregnancy test. You wouldn't have a dedicated reader, just a strip of paper that changes color to give you the result. Some might need a cheek swab, some might need urine, some might need spit, depending on the disease, and then you would use an app on a smartphone or go to our website to interpret the result."

For the platform used in the clinic, he added, the lab-based format would make it more flexible. Depending on the disease and the requirements of the test, the format could be paper-based, a well-based format, or anything in between.

"It's a really simple concept, but the implications are really huge," Martin said. "You can imagine with emerging diseases like Zika or H1N1 [influenza] — there are diseases emerging around the globe all the time, and this is the kind of technology that can really enable rapid development of a diagnostic test and can really help prevent the emergence of those diseases. And more generally, this is going to transform the US healthcare system, but it's going to change lives fundamentally in the developing world. It's really going to open access to molecular-level information in the developing world, so we're really excited about partnerships on that side."

The company is actively looking for partners to create tests for its platform. Martin said Mammoth is envisioning creating revenue-sharing partnerships and used the Apple iOS model as an analogy — Mammoth provides the platform like Apple provides the App Store. Now the company is hoping to find test developers just like Apple found app developers.

Sound familiar?

If this is all sounding a bit familiar, there's a reason for that. The Broad Institute's SHERLOCK (Specific High sensitivity Enzymatic Reporter unlocking) platform — developed in the lab of Doudna's CRISPR rival Feng Zhang — works in much the same way Mammoth's CRISPR platform will.

SHERLOCK was first described in April 2017, when the Zhang lab reported its efforts to build on research Doudna had done in October 2016 on Cas13a. This March, researchers from Zhang's lab published a paper in Science describing the latest refinements to SHERLOCK: It now has four-channel single reaction multiplexing using orthogonal CRISPR enzymes, quantitative measurement of input down to 2 attomolar concentration, a 3.5-fold increase in signal sensitivity through a combination of Cas13 with auxiliary CRISPR-associated enzyme Csm6, and a lateral flow readout.

In other words, SHERLOCK now uses Cas12a, Cas13a, and Csm6 to detect both DNA and RNA, and now has a much easier-to-interpret paper readout that the Broad compared to a pregnancy test.

Further, the Broad researchers tested SHERLOCK's new features in the contexts of both infectious disease and cancer, and Zhang lab researchers Jonathan Gootenberg and Omar Abudayyeh told GenomeWeb at the time that one of the major visions the Broad had for SHERLOCK was to turn it into both a field-deployable tool that could be used during outbreaks, and a clinic-based diagnostic for treating cancer patients.

Indeed, SHERLOCK has already shown its utility in the field. Late last month, Broad researcher Pardis Sabeti and her colleagues demonstrated that it can be deployed as a diagnostic tool to detect Zika virus in the field, and can distinguish between the four Dengue virus serotypes as well as region-specific strains of Zika from the 2015 to 2016 pandemic.

Further, Gootenberg and Abudayyeh noted the ease with which different tests could be designed for the SHERLOCK platform. "The really great thing about the SHERLOCK assay is how easy it is to redesign and deploy," Abudayyeh said in March. "We've shown that we can detect dozens of different targets and we can design these assays in as little as a week. That speaks to how robust it is, and how well it works for each given set of CRISPR RNAs. It's as easy as designing a new CRISPR RNA and then showing that it works."

The Broad declined to comment on the similarities between SHERLOCK and Mammoth's platform. And when asked about the comparison in a follow-up email, Martin didn't respond. Their respective reticence to comment isn't entirely surprising — the Broad has been locked in a legal battle with the University of California over the ownership of the intellectual property underlying a great deal of CRISPR technology.

For its part, Martin said Mammoth is confident in its IP strategy for its platform and is now focused on making sure the technology has the biggest impact possible.

The company didn't provide a timeline for production of either the clinical or at-home versions of its platform, nor did it provide a price point. Martin noted that the pregnancy test is serving as Mammoth's model for affordability and accessibility for the at-home version, and that the company is currently sourcing the best and most affordable way of manufacturing the needed parts.