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Home Tests in Mind, Doudna Startup Races Rivals in CRISPR Diagnostics

Xconomy San Francisco — 

[Updated 4/26/18, 2:20pm ET. See below.] The gene-editing technology CRISPR-Cas9 has captured the world’s attention with the possibility of fixing tough diseases and altering human traits. While experimental medicine, ethical worries, and an epic patent battle have attracted most of the headlines, the field’s pioneers have advanced new types of CRISPR to detect and diagnose diseases.

A new diagnostics company called Mammoth Biosciences has licensed technology from the lab of Jennifer Doudna of the University of California, Berkeley. Currently sharing lab space with other startups in a San Francisco incubator, Mammoth has venture dollars behind it but isn’t saying how much. Doudna is cofounder and chair of Mammoth’s scientific advisory board.

Mammoth has been hiding in plain sight for months, but a new willingness to talk—although not too much—comes soon after research groups led by Doudna and Feng Zhang of the Broad Institute of MIT and Harvard published in February side-by-side papers in the journal Science. Each group described its own use of a CRISPR-based system to detect traces of disease in human samples.

In an interview this week, Mammoth CEO Trevor Martin says his new firm is aiming to commercialize cheaper, faster tests that would be easy enough to use at home and hospitals alike, with infectious disease likely first on its list. His example: giving a child a quick test for strep infection before sending her to school.

Martin (pictured) is a 29-year-old Stanford University graduate student who was in the spotlight last year for his data-driven dissection of an influential pro-Trump channel called The_Donald on Reddit.

He says he and cofounder Ashley Tehranchi, Mammoth’s CTO, set out a year ago to build a diagnostics company, not necessarily a CRISPR company. Mammoth will develop some diagnostic tests itself, says Martin, but in other areas such as cancer detection, where he says there are “awesome partnership opportunities,” Mammoth could stay behind the scenes and provide the underlying CRISPR technology, based on the Doudna team’s DETECTR system, to others.

[Updated with this paragraph.] The Broad, meanwhile, is also working to license its CRISPR diagnostic technology, which is called SHERLOCK. The SHERLOCK group published an update today in Science. They say that their technology is “poised” to be deployed in the field and “allow real-time tracking of microbial threats.” It doesn’t require lab equipment to distinguish infection among related viruses, such as members of the flavivirus family that includes Zika and Dengue viruses. Harvard University geneticist Pardis Sabeti, who was instrumental in tracking recent Ebola and Zika outbreaks, has led efforts to tune the technology as well to differentiate between virus strains, such as the four serotypes of dengue that could strike with varying severity, or the Zika mutation that causes microcephaly. The Broad Institute said today that Sabeti and colleagues want to test the system in Nigeria, which has seen a wave of Lassa fever cases recently.

When asked about licensing and spinouts, spokesman David Cameron emailed this statement to Xconomy: “Broad is developing a framework to ensure the SHERLOCK diagnostic platform is easily accessible in the developing world, where the need for fast, inexpensive, reliable, field-based diagnostics is the most urgent.”

It’s not immediately clear if the CRISPR diagnostics will lead to a new patent fight between the Broad and Berkeley camps. The current battle over the origin and ownership of CRISPR-Cas9, with royalty riches from future medical, industrial, and agricultural products at stake, is about four years old. A special U.S. patent board ruled in favor of the Broad in early 2017, triggering an appeal by Berkeley. A major hearing is scheduled next week.

In Europe, Doudna and allies have fared better.

New York Law School professor Jacob Sherkow follows the case closely and says “A similar, almost mirror-image scenario” is a possibility with the dueling diagnostics. “So who knows?” says Sherkow. “Maybe another Doudna vs. Zhang patent dispute. The world is strange.”

As with the previous work of Doudna and Zhang, their diagnostics work has similarities. Both are working with new enzymes—the “scissors” that bacteria naturally use in self-defense to cut up the genetic material of invaders like viruses. Instead of the Cas9 enzyme, SHERLOCK and Mammoth, using DETECTR as its foundation, use variations of Cas12 and Cas13. The former cuts DNA, the latter cuts RNA, which is important because some viruses use RNA rather than DNA to carry their genetic code, and in some diseases the RNA produced by switched-on genes are important clues to diagnosis.

In these systems, when the CRISPR machinery finds a match with a suspected pathogen, it spurs a frenzy of snipping. A tiny signal that is engineered into the CRISPR machinery is also triggered, like a tripwire, and becomes readable. Think of a pregnancy test that changes color over several minutes. In fact, the groups are incorporating their technology into paper strips that, after contact with a person’s blood, saliva, or urine, could produce a result quickly. How quickly is yet to be determined. Martin says Mammoth’s “vision in the long term” is to produce results in 30 minutes. When pressed about a first product, which he says is coming “in a few years,” Martin declined to answer.

Both groups are pursuing infectious disease applications. Zhang and colleagues have detailed SHERLOCK testing for Zika and dengue virus as well as signs of lung cancer in blood samples, and they position SHERLOCK for use “in settings where power or portable readers are unavailable.” Doudna’s group showed that they could detect traces of cancer-causing human papillomavirus in human samples.

Another name for Cas12 is Cpf1, which Zhang and several others first characterized in a publication in 2015. Months later Editas Medicine (NASDAQ: EDIT), of which Zhang is a cofounder, announced it had licensed exclusive rights to use CRISPR-Cpf1 for human medicines.

It’s hard to tell if the Broad’s jump on Cpf1/Cas12 could extend to other applications like diagnostics, says Sherkow. “It depends on what is claimed in the patent,” he says. The patent office has not yet granted a patent related to Cpf1/Cas12.

“I can’t go too deep into intellectual property,” Martin says when asked about rights to the new CRISPR diagnostic tech. “I’m confident we have freedom to operate on Cas12 in our particular detection applications because we have the priority dates on the necessary parts.” His claim could not be verified, and he declined to go into more details.

Mammoth is backed by Mayfield, NFX, 8VC, AME Cloud, Wireframe, Kairos and Boom Capital.

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