CRISPR Retooled as a Genomic Search Engine

Mammoth Biosciences wants to turn CRISPR into a Google-like utility, one that will detect genes in the genome the way the predominant search engine finds information on the web. The company anticipates that the most popular search terms will consist of genes indicative of disease.

Despite its name, Mammoth is still a tiny biotech startup. If it is to realize its massive ambitions, the company will need to grow. It has yet to develop a finished product, gain regulatory approval, and commercialize its technology. To reach these goals, Mammoth is developing a management team that has the requisite heft.

“We see CRISPR as the best search engine in biology,” says Trevor Martin, Ph.D., Mammoth’s co-founder and CEO. “It’s easily programmable and intuitive, like Google’s search function.”

“When you look at diagnostics, what you see is the equivalent of the ENIAC,” he remarks, referring to a general-purpose electronic computer that was built in the 1940s and used by the military. Diagnostics, he suggests, may be following the example of early computing; that is, diagnostics has started incorporating improvements that only hint at what is yet to be achieved in terms of power and availability: “There’ve been tremendous technological advancements in healthcare, but a lot of them haven’t trickled down to the hospital.”

According to Dr. Martin, Mammoth’s ultimate goal is to make CRISPR-based diagnostic tests as easy to use as home pregnancy tests.

“We envision [our tests] being used at point of care and at all different levels in the healthcare continuum, whether in a hospital, a drug store, or a home.” That means incorporating the technology into a simple test and a small format.

The benefit of this approach, he says, is widespread availability: “CRISPR detects any nucleic acid, so it’s very accessible. You don’t need a giant machine to get results.” The ability to function without sophisticated equipment may enhance the platform’s value wherever such equipment is lacking, which is much of the world.

A Different Vantage Point

CRISPR revolutionized gene editing. Dr. Martin expects similar results when the technology is applied to diagnostics. “In polymease chain reaction (PCR) systems, you have primers, but with CRISPR, you also have the enzyme helping out,” he notes, “which makes it versatile and effective for diagnostics.

“We want to personalize diagnostics, so specificity matters,” he continues. “We want to identify not only the presence of an organism, but its strain.” A February 2018 paper in Science, by CRISPR pioneer and Mammoth co-founder Jennifer Doudna, Ph.D., showed the chemistry works. “We can use CRISPR to identify genes and even single single-nucleotide polymorphisms,” Dr. Martin asserts.

The technology uses Cas12 to bind and cut DNA, and Cas13 to recognize and cut RNA. When teamed with guide RNA—an RNA molecule matching the sequence the test is designed to find—CRISPR becomes a detection platform.  When a match is found, Cas12 or Cas13 breaks apart a reporter molecule, causing it to change color and thus signal the presence of the DNA of RNA sequence in question. Dr. Martin envisions test formats from reagent kits for hospital uses as well as one that uses a smartphone to detect the color change in liquid.

Mammoth is continuing its basic research and refining its approach to diagnostics. It has used its prototype CRISPR diagnostics platform first to detect human papillomavirus in human patients and then to determine whether the strain is oncologically relevant. “That’s a double whammy,” Dr. Martin exclaims. “That’s actionable.”

Many diagnostic tests today rely on cultures, which can take several days to grow. Others use PCR or gene sequencing. Dr. Martin says Mammoth’s CRISPR diagnostics platform has the potential to diagnose patients faster than those approaches.

Piggybacking on CRISPR’s Success

Dr. Doudna developed the CRISPR diagnostics system in her laboratory at the University of California, Berkeley. “We followed papers from her laboratory,” Dr. Martin recalls. “We knew this was the technology that would make a revolution in diagnostics possible.

“She and her graduate students were also extremely entrepreneurial and excited about commercializing the technology. We talked and found we shared a vision to create really powerful diagnostics tools, so we decided to team up and do this together. That’s when Mammoth Biosciences was formed.” The company incorporated in the spring of 2017 and officially launched in June of this year.

In those few months, it has attracted some high-profile investors from the high-tech community. Apple CEO Tim Cook and Grail CEO Jeff Huber may be the most notable. The company raised $23 million in funding from the Silicon Valley investment firm Mayfield, the venture firms NFX and 8VC, among others.

“We always want to work with the top investors,” Dr. Martin declares. “As long as we execute and work toward our goals, we will attract top-tier investors. We’re excited to work with people who have experience in building great companies.” That means not just Silicon Valley investors but also those with deep expertise in the diagnostics industry.

The hoopla surrounding CRISPR since its introduction undoubtedly helped Mammoth. Piggybacking on a known technology removes some of the hurdles new technologies face, and fundraising within the high-tech community means that potential investors accept a high degree of risk. And as technology and healthcare lines begin to blur, a whole new group of investors is opening to biotech. But the biotech and the high-tech communities are different, which means that high-tech investors must learn to be patient as the technology inches toward the clinic.

Broad Applications

“With any platform technology, you want to have the right first application of the technology. We’re working to identify where it can add the most value. Healthcare, therefore, is our first target market,” Dr. Martin maintains.

Despite that priority, healthcare may not be the first commercialized application. That’s because developing a medical diagnostic test faces stringent regulatory hurdles that are not present to the same extent in other industries. Therefore, the company also is developing its CRISPR platform for industries outside of healthcare that need to detect nucleic acids.

For example, Dr. Martin says, “CRISPR diagnostics can be used in agriculture to identify the genotype of pathogen or bugs in the soil, in restaurants to detect microbes that evade routine cleaning, or in forensics. It also may be used to monitor water supplies.”

“We’ll never be experts in all these markets,” he acknowledges. “To scale effectively, we need to partner.” As a nascent company with a small scientific advisory board, Mammoth is tapping into the expertise of its investors, Dr. Martin points out: “Tim Cook, for example, heads a company that builds products people love. We strive to do the same. We want to leverage our investors’ expertise.”

Right now, Mammoth is spearheaded by the five scientific founders and is growing its scientific team. As with many biotech startups, managerial expertise may be lacking now but should evolve later. “We’re continuously growing, finding people excited about the future of diagnostics,” Dr. Martin says.

The next milestone is to complete the prototype. Dr. Martin says the small team is working “aggressively” to this point. It’s too soon to speculate about when the technology will be ready for regulatory review, however.