What prompted Mammoth Biosciences’ entry into the diagnostic and therapeutic space?

We are excited about augmenting the toolbox of CRISPR proteins beyond the initial systems like Cas9 for several reasons. First, we see potential for new products that can be built with the properties of these proteins, as evidenced in our pioneering work with CRISPR-based diagnostics, which was something people did not think was possible just a few years ago. Second, we believe we can unlock new iterations of pre-existing therapeutic ideas through our pioneering of ultra-small CRISPR systems. These are systems that are physically smaller than the Cas9 and have important delivery implications to enable potentially new in vivo therapies.

What are the benefits of Cas14 and CasΦ nucleases over Cas9 when it comes to genome editing?

These systems are smaller, which allows for novel methods of delivery. We can start to achieve some of the holy grails of editing, like looking for permanent cures rather than just treatments. They also have a better targeting range. This is because CRISPR proteins have PAM sequences that limit where the individual protein can go, not unlike a postal code. By having a more diverse PAM sequence the protein can go to more regions in the genome, which is particularly transformative when you want to make multiple edits on the same protein.

What are the mechanics of your CRISPR-based high throughput COVID test, and how does it compare to a PCR test?

Fundamentally, the test leverages the idea of CRISPR as a search engine for biology. One can program CRISPR proteins with a guide RNA, which is a molecule that directs the search for a specific sequence, such as a gene that you want to edit to cure or treat a disease. For example, the sequence can be unique to a particular COVID variant and, once programmed, CRISPR will use its built-in scissors to edit the genes. In the case of diagnostics, these molecular scissors can also be used to read-out and amplify a test’s signal. This diagnostic technology works like a molecular shredder on a sample by cleaving tons of single-stranded nucleic acid when the Cas enzyme binds to the sequence its been programmed to identify, which, as a result, strengthens the test’s signal. This ability to detect nucleic acids renders it a molecular test with a degree of sensitivity and specificity that rivals more standard tests like the PCR. 

How long had Mammoth worked on developing this test before FDA approval, and how will it help pandemic relief efforts moving forward?

We began working on CRISPR-based diagnostics when the company was founded and have continued to leverage the fundamental work done previously at Berkeley in our co-founders’ lab. While it was impossible to have foreseen COVID as a specific target, we always believed in the accessibility of testing for infectious diseases. Hence, leveraging the technology to address the pandemic was a natural progression, evidenced by how quickly we published the first available data of a CRISPR-based test for COVID.

The impact on COVID testing and future pandemics will be substantial given the wide spectrum of accessibility the technology affords. CRISPR-based diagnostics are also advantageous because one can create new tests relatively quickly to combat new variants. This is a brand new testing technique that we hope will become foundational towards fighting future pandemics.

How does CRISPR technology democratize access to diagnostic testing?

CRISPR increases accessibility across the whole spectrum of testing, from the lab to the doctor's office. This should extend to patient testing at home in the long term, which is an area that has been highlighted throughout the pandemic. One of the things we’re excited about with CRISPR diagnostics is being able to provide tests that are both accurate, like a PCR test, and accessible, like an antigen or antibody test, with the goal of providing a product that is both affordable and easy to use.

Looking forward, how does Mammoth plan to evolve?

Our primary goal is to continue to develop the CRISPR toolbox and advance the technology from a diagnostic and therapeutic standpoint, making an impact by leveraging CRISPR technology with our network of partners. What will be exciting over the next few years is continuing to advance CRISPR’s capabilities to patients, in both diagnostics and therapeutics. Ultimately, we aim to fine tune this foundational technology that can be applied to innumerable challenges across a variety of industries, making biology become more like software and programming.