Industry Matters: CRISPR in hand, Mammoth Biosciences takes aim at diseases and diagnostics.

Mammoth Biosciences harnesses the power of the next generation of CRISPR products. Through its discovery of novel CRISPR systems, the company is enabling the full potential of its platform to read and write the code of life. With a distinguished team including co-founder and CRISPR-Cas genome editing co-inventor Jennifer Doudna, Mammoth is addressing challenges across healthcare, agriculture, environmental monitoring, biodefense, and more.

Lucas Harrington, co-founder and Chief Scientific Officer at Mammoth Biosciences set aside some time to discuss Mammoth’s technological platform as well as how working in a commercial lab compares with academia.

Lucas Harrington. (CREDIT: Mammoth Biosciences)

Coming from Jennifer Doudna’s is pretty good street cred when it comes to CRISPR. Can you discuss the ways your work now builds on what you learned there?

There’s a few principles that carry over and some things that are entirely new for our company.  One key thing that Jennifer taught us and it really carries over is just the power of curiosity. I think a lot of companies that don’t have the same kind of founding story often focus on what’s the straightest line to get to a product and get something into the clinic. With CRISPR at the stage that it’s in, just being able to really listen to the science and follow it to where it leads is a really powerful lesson.

You know the way that we approach our research as a company is pretty different, even if the problems are similar to what we were doing in our graduate work. It’s really a different scale and a different approach to tackling problems. A really well run company is like a super-organism, right? Everyone’s participating and contributing to a larger goal and moving toward that goal. It’s something that one individual wouldn’t be able to accomplish on their own. 

At Mammoth, we are basically taking the strategies that we were working on in grad school and scaling it up to an organization with 140-something people and trying to tackle much bigger problems than what we were able to do in the graduate lab.

At Mammoth Biosciences, you have a lot more people working with you and more resources. You have a lot more freedom as well. How is that compared with academia? 

I think a lot of times academia is framed as if you have complete autonomy over your research and you can do whatever you want. In reality, you are often constrained by resources and by government agencies that control the grants that you are getting.

In a company where resources are less constrained – although you’re still driving towards a product – I think you do have a little bit more freedom. Honestly, it’s counterintuitive to people that are in academia, but you really have the ability to research so long as you can justify the work that you’re doing as a business case for it. You are able to put more resources and take on other projects that maybe wouldn’t be supported in academic settings. You just need to be able to articulate the business case and the downstream outcome, whether it’s for patients or products. 

Who are the stricter taskmasters? Grant funders or investors?

That’s a good question. I would say the grant funders. I think that investors are more objective. If there’s a way to build a product that’s going to market and that is going to make business sense, then you can go and find the money to support that. With grants, a lot of times you end up having people just looking at the previous projects that you worked on and your publication record listing as your collaborators. 

Grant people are a little bit more narrow in terms of what they actually support. 

What was it like for you to co-found a company? Did any of your lab management experience prepare you for it?

Most aspects, I would say. I think the PhD teaches you some skills that are really critical to running a company and also helps identify where the opportunities are. You can have projects that last for 10 years and a PhD program that maybe aren’t that impactful. 

Same thing goes with a company. You have a lot of different opportunities in terms of what you can track down and it’s really about identifying where that key opportunity that’s going to be and the greatest ROI for your time and effort. In terms of, I think, everything that a PhD can teach you, but it doesn’t always, is really being able to work with a collaborative community. 

There’s a lot of times academic work ends up being a little bit more siloed and it’s one or two people working on a project. Janice and I, in particular, throughout our entire PhDs really were thinking about how we can support each other. How can we actually have this additive effect in terms of our efforts and bring in other collaborators that have complementary expertise? We were almost approaching team building as a kind of company exercise. 

I think that’s not always, not always the case, unfortunately. And a lot of times it does end up being someone in the lab alone just tinkering away at their experiments for six or seven or eight years. 

I think the people management aspect is definitely something that we’ve had to learn throughout scaling a company from four or five people up to 240. That’s not something you’re typically taught at any kind of scale and it’s not given a lot of attention in academia, which I think is a mistake, because people that are going to be successful in academia and move on to whatever the role is, are likely going to be managing fairly large teams. 

Training people in that aspect of business would better prepare people for diversity of careers even if they stay in academia. We’ve kind of had to learn as we go on that front and a lot of really great coaches and mentors that helped us along that path. But it’s not something that I was trained in a Ph. D. program for sure.

Can you tell me about Mammoth Biosciences and what your role is at the company?

Mammoth were founded four years ago, really on the principle of using the diversity of CRISPR to drive new products. We functionally have two major business units currently. One is in therapeutics and one is in diagnostics.

I wear two hats. There’s the co-founder hat that deals with how do we build the best business possible that’s going to have the funding and the support and kind of public recognition that it needs to sustain itself. 

The other hat I wear is leading the therapeutic side of the business. Mammoth has two sides, diagnostics and therapeutics. It was pretty organic, in terms of how these roles have worked out. There is definitely some like half switching here. 

Founders constantly say that they wear a lot of different hats and have to be comfortable with that. The big ones for me are managing the therapeutics team, and also stepping out of that role and putting on the co-founder hat where I provide a company wide perspective.

What is the scientific vision for the company?

Yes, I think that the main goal of driving new products that are based on the diversity of CRISPR I think, is really the founding of the company. To make it a little bit more specific, on the therapeutics front our goal is to ultimately address all genetic diseases, continually chipping away at what diseases we can address.

On the diagnostics end, it’s really about making data about people’s genomes accessible to them, and in different environments as well. 

That includes going from a centralized lab, like exists today, to highly accurate home tests. Right now you’re really presented with the dilemma of having either something that’s very accurate that comes from a lab or having something that’s not so accurate in home environment. I think we’re really trying to create the best of both worlds. That means providing highly accurate and actionable information in a completely decentralized testing process. 

Your company’s platform revolves around CRISPR. For people who aren’t familiar exactly with it and what it does, can you just provide some background as to what it does, what the advantages are, and what it offers?

CRISPR fundamentally is a way for us to program biology. It gives us the tools that allow us to find a certain sequence which we put into our CRISPR and then it has a certain effect. 

At the heart of both of our products, it is that CRISPR component that allows us to treat the genome like a text editing document. When it’s discussed in the media, CRISPR is presented as a singular thing.  In reality, there’s hundreds of thousands of different kinds of CRISPR out there. They all have different features and different attributes. 

What we do is we mine through all those different systems and when we have a particular application, we go and find the right tool for that job. It’s kind of like the toolbox analogy, where pretty much everyone right now is working with just a toolbox that has one tool in it. It has a hammer. A hammer works great if you’re doing a particular task, but you really need that full toolbox to be able to address more genetic diseases. To be able to do more things with it entails building out that toolbox and then driving towards products once those new tools are established.

One of the concerns with CRISPR relates to unwanted downstream substitutions. Is there a way to mitigate that now?

There are different strategies, each depends a little bit on the particular diseases that you’re going after or targeting. One of the main ones is just to improve the accuracy of the CRISPR protein itself or the CRISPR system itself. 

There’s a few different ways you can do that. One way I had mentioned earlier, going back to the previous answer with these hundreds of thousands of CRISPR systems. It is actually going and making that a criteria that you identify the system that you’re going to work with. So really defining that as a priority and going and looking at those 100,000 systems and saying which ones are better or worse according to that metric.

The other way is through engineering. We can go in and once we have a system that’s working well, we can start to tinker with it and change the components of the system of the protein until it becomes more more accurate. A lot of that becomes very computationally intensive and you’re going in and basically designing new CRISPR systems that can improve accuracy. 

Those are the ways that people have approached it so far.

You mentioned that a lot of different crispers exist. From your experience, are there are there certain crispers have sort of like workhorses that kind of rely on a lot

There are about 100,000 different CRISPR systems. We narrow that down, and for each project, we don’t go back into that 100,000 and try to find a new one. It’s usually looking at our databases of top lead CRISPR systems for a particular application, and then choosing from that menu, which system is going to do the job. 

Mammoth has designed a COVID-19 diagnostic. Can you discuss that product, and how it differs from the current tests that are available?

With COVID, Mammoth has a few different products that we’re working on the diagnostics front. With COVID, we were alerted by one of our collaborators back in 2020, Charles Chu, over at UCSF who got some of the first patient samples. This was before it was really in the news. He was like you should probably pay attention to this. I think it’s going to be an important thing for diagnostics. 

That’s really when we shifted most of our efforts from our previous targets over to COVID. The immediate need that we recognized, the thing that we have our DNA  for  emergencies authorization is a what we call it’s called Boost. That is the product name. 

Essentially, it is a way to take an existing cloud automation infrastructure that might be in any centralized lab and increase that capacity and turnaround time for what you would do with typical RT-PCR. Basically take that same infrastructure and swap out the chemistry, take out the RT-PCR and put in CRISPR.

That was definitely something that we thought was supercritical, especially at the height of the pandemic. How can we get more testing without sacrificing accuracy? Looking forward, what we’re really looking to do is to, again, move the lab testing paradigm from something where you go to your testing facility, wait two weeks and get your result to something where you can really get actual information either in a physician’s office or in a clinic or even in your home by just getting it from a pharmacy. 

We definitely wanted to focus on just quality products that we can deliver in a centralized facility. That’s really where we’re headed long term.

We’ve designed assays that identify Omicron with just a single nucleotide chain. You can actually go in and design a CRISPR that targets regions of the virus to tell you which of those strains you have. 

That’s pretty powerful information. When you think about all the different strains that are popping up and how concerned someone should be when they when they have a COVID infection, if it’s just going to be a cold or if it’s going to be something that’s more serious that they should probably go and talk to their, their physician about.

You touched on this briefly before. What’s the promise of CRISPR technologies? Why should the general public care how? How it would end up improving their lives?

Yeah, I think the COVID test is a great example of where people will actually see and touch it. But I think the most, probably the biggest impact that people will see is hopefully that they don’t actually see it. The way that CRISPR therapeutics Friant right was the way that our entire healthcare system has been built is really about, okay you have this disease so let’s put you on medication for the rest of your life. What CRISPR really has the opportunity to do is go in and address that underlying genetic cause of the disease and really cure it. People can go on living their life and not think about the disease.

It’s a pretty incredible time in biology. We have these tools that does away with people living on a form of life support, for lack of a better lack of a better phrase, and is able to really cure diseases.


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