Summary

On the latest episode of The Bioverge Podcast, Trevor Martin, Co-founder of CEO of Mammoth Biosciences, sits down with Neil Littman to discuss the power of CRISPR as a diagnostic and therapeutic tool, his company's efforts to discover new CRISPR enzymes, and how the company is building a therapeutic pipeline through partnerships and on it's own.

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Transcript

00:29
Danny Levine (producer)
Neil We've got Trevor Martin on the show today. For listeners not familiar with Trevor, who is he?

00:35
Neil Littman (host)
I am incredibly excited to welcome Trevor to the show today. If anything about the field of gene editing or CRISPR, chances are you've heard of Trevor Martin. He is the cofounder and CEO of gene editing company Mammoth Biosciences, which he founded at the ripe old age of 28. Jennifer Dougna is one of the cofounders of Mammoth and obviously she is one of CRISPR's original inventors. She won the Nobel Prize for it in 2020. For people who aren't familiar with Mammoth, they are pursuing CRISPR based diagnostics as well as therapeutics, which I think is which is pretty unique in the space. I'm incredibly excited to welcome Trevor to the show.

01:21
Danny Levine (producer)
CRISPR is thought of, I think, by most people as a therapeutic tool, but obviously it's got very broad applications. Where does Mammoth fit into the whole CRISPR landscape?

01:34
Neil Littman (host)
Yeah. I'm really excited to talk to Trevor about this. Just to set the stage for the discussion, right. Most folks have probably heard of CRISPR. There's probably very few that know what it actually stands for. It stands for clustered, Regularly Interspaced Short. Palindromic repeats. So that's a mouthful. People obviously just call it CRISPR for shorts, but it is widely recognized at this point for potential to treat diseases that's ranging from everything from cancer to inherited genetic disorders. It works just at a high level by slicing and dicing away the code that you want to take out in human DNA, and then you can replace that code with new edited functional code. What Trevor and his team at Mammoth are doing is exploring how that technology can use to diagnose disease through their diagnostics platform, but then also for ways to treat that disease through developing novel therapeutic applications.

02:36
Neil Littman (host)
I think it's a pretty unique vantage point from where Mammoth sits in the overall ecosystem. I'm excited to dive into some of what they're doing, both on the diagnostic side, also on therapeutic side, and they've announced some big partnerships recently, so I'm excited to explore those as well.

02:56
Danny Levine (producer)
I think there's a tendency in this industry to focus on high value applications, even if it takes a longer time to get there. Does it make sense to see what Mammoth is doing on the diagnostic side?

03:11
Neil Littman (host)
Absolutely. I mean, I think there's tons of potential here, both on the diagnostic side. So, if I'm not mistaken, mammoth's first diagnostic application was during the Pandemic for COVID. They had emergency use authorization for a CRISPR based diagnostic tool for COVID. My understanding is that is it looks very similar to the sensitivity and specificity of a PCR based test, but is easier to run. It's not exactly an at home test but it has much better sensitivity and specificity than antigen based test. It falls somewhere in between is how I think about it. But I want to ask Trevor that. I think there's a ton of applications in the diagnostic world and that's just for infectious disease, right? I mean, I think this technology is broadly applicable in terms of diagnosing a whole wide variety of diseases, not just infectious disease.

04:08
Danny Levine (producer)
What are you hoping to hear from Trevor today?

04:11
Neil Littman (host)
Yeah, so I'm hoping to hear about their vision for the future for Mammoth. I think it is pretty unique for them to do diagnostics as well as therapeutic. How do they think about the strategic direction of the company? Are they looking to establish more partnerships for therapeutic development? Are they doing stuff inhouse and developing their own therapeutics pipeline? How do they see CRISPR fitting into the broader ecosystem? A lot of gene editing, there are a lot of gene editing tools out there. There's a lot of companies tackling this space. Just curious, getting his 30,000 foot view on the broader ecosystem as well. Finally, I would certainly classify Mammoth as this new class of tech bio company. I'd love to understand if Trevor agrees with that. If so, what does that mean for him in terms of company culture and how they think about building and scaling a company like Mammoth?

05:06
Danny Levine (producer)
Well, if you're all set, let's do it.

05:09
Neil Littman (host)
Danny, trevor, thanks for joining us today. I am really excited to have you with us on the show today.

05:17
Trevor Martin (guest)
Yeah, thanks for having me. I'm excited to be here.

05:20
Neil Littman (host)
Today we are going to talk about your company, mammoth Biosciences, CRISPR It's utility as a diagnostic tool. Your recent partnerships with pharma and biotech companies to develop in vivo gene editing therapies which, as regular listeners of the show know, has been a recent theme on this podcast. I'm sure at this point, most folks have heard of CRISPR, and today I want to focus on what makes it such a powerful tool, not just for research, but diagnostics and therapeutic applications. Before we dive into all that, Trevor, let's spend a little time on the early days of Mammoth. Can you walk us through the early days and the origin story of Mammoth Biosciences?

06:02
Trevor Martin (guest)
Yeah, definitely. So, I mean, Mammoth has founded about four and a half, almost five years ago now with this very ambitious vision of what's really possible with CRISPR and this idea of really delivering on what we see as the true promise of CRISPR. I think especially Mammoths, there's a lot of focus on the kind of legacy, original systems that are maybe most famous in the CRISPR space. Things like CAS nine or CAS twelve. What was interesting is that people weren't really looking outside of that, whereas CRISPR actually is this very diverse technology that's found in many different organisms in nature, across these organisms that have needed to develop this adaptive immunity that CRISPR was originally evolved for. We had this idea and this vision that by leveraging these non traditional CRISPR systems beyond Cast Nine and beyond CAS Twelve, it wouldn't just be academically interesting, but it would actually enable new functionalities and new products that could be built that leverage their unique properties and overcame some of the challenges of things that we saw with the first generation CRISPR systems, and in particular at Mammoth.

07:19
Trevor Martin (guest)
Since the beginning, we've been focused on human therapeutics and human diagnostics. There's tons of applications outside of that. There's agriculture, there's met by manufacturing, there's all sorts of really exciting use cases. Internally, where we think we can have a huge patient impact is human therapeutics and human diagnostics. Within human therapeutics, as you mentioned at the beginning, really focused on unlocking permanent cures for genetic disease that can transform patient lives. In particular, that's going to require going in vivo. That's one of the hardest things to do. That's where we think, for example, in pioneering these things that we call ultra compact CRISPR systems, and we can get into what that is, that we uniquely enable that. On the diagnostic side, we've used CRISPR to invent the first new method of molecular detection in many years. What's exciting there is that we can now start to push closer and closer to the patient in this more accessible and decentralized fashion.

08:18
Trevor Martin (guest)
The gold standard of detection, things like lab based PCR that really high sensitivity and specificity, but pushing it in a more decentralized and more accessible manner. Those are some of the things that, from the very beginning of the company, we really think that unlocking these novel technologies, these novel systems, are really going to enable us to actually deliver to patients.

08:38
Neil Littman (host)
There's a lot there to unpack and dive into throughout the course of this show. I did want to ask, though, so Jennifer Doddna is one of the cofounders of the company. Just quickly, for those who aren't familiar with her work, she received the Nobel Prize in 2020 in chemistry, along with Emmanuel Sharpintier for the development of a method of genome editing, which is CRISPR. How did you hook up with Jennifer?

09:03
Trevor Martin (guest)
Yeah, so I'm really fortunate to work with an amazing cofounding team. So, as you mentioned, one of the cofounders of Mammoth is Jennifer Dodna, who won the Nobel Prize for her pioneering work in CRISPR. The other cofounders are, of course, myself and then the two star graduate students from Jennifer's lab, janice Chen and Lucas Harrington, who, along with Jennifer, are actually the inventors of many of the technologies we work with at Mammoth and develop. My background came from Stanford, where I was doing my PhD in biology, coming from more of a computational biology background. I actually just kind of read the papers that they were publishing and got really excited about the potential of the CRISPR technologies that they were building. Cold emailed Jennifer originally and was really excited to have her respond and introduce me to Janice and Lucas. We really hit it off in terms of sharing this vision of building a generational biotech company and that this was a unique opportunity where there is the technology, the founding team, and the opportunity to have this impact on patients lives over many years.

10:19
Trevor Martin (guest)
Definitely, I think a bit of a nontraditional background for me since I'm not one of the inventors of the technology. I think that shows that it's all about sharing that vision and kind of having that alignment around where the company can head. It doesn't have to be your PhD thesis, necessarily.

10:37
Neil Littman (host)
Yeah, and I love learning about this origin stories and the founding story of companies because it's never a straight line. So thank you for sharing. I think that's really interesting. I want to talk about your vision for the future in 1 second, but I just want to share a funny story. I'm not sure if you remember this, but I certainly remember you and I were actually connected back in 2018 as part of a JLABS event. Long story short, we never actually ended up meeting, which unfortunately for me, at this point, falls into our anti portfolio at Birds. Big missed opportunity, I think, from my perspective. No, that's okay. That's just the way these things go sometimes. You guys have obviously done incredible things over the years. Before we dive specifically into some of your technologies, I do want to just talk about your vision for the future.

11:30
Neil Littman (host)
You mentioned some of this, but it's described travelers, what your ultimate vision is for Mammoth and if that vision has evolved from day one or is it roughly the same since you founded the company?

11:44
Trevor Martin (guest)
Yeah, it's a great question and going back to some of what were talking about before, the vision really is to deliver on the promise of CRISPR and to do that by innovating around CRISPR systems and technologies and on therapeutic side, permanent cures in vivo, especially going extra hepatic. One of the areas that we pioneered at Mammoth beyond ultra compact systems is this space that we call CRISPR Plus. This includes things like base editing or gene writing or epigenetic editing and anything beyond double strand breaks, basically. We think that these methods are also going to have to go in vivo to really have their maximum impact. That's going to require having ultra compact systems so we can actually deliver them where they need to go. That's a kind of broad area that we think is really where the puck is headed in terms of having maximum impact on patients lives.

12:37
Trevor Martin (guest)
On the diagnostic side, again, really about kind of decentralizing, the ultimate in high quality, high sensitivity, high specificity molecular testing, whether that's for oncology or infectious disease or genetic medicine. It's this brand new method of molecular detection that we're leveraging. In terms of kind of the vision of the company, of course, from day one, you can't map out all the details, right? You're always going to have stuff that comes along, new things that are exciting, things you discover that maybe you didn't realize. What has stayed very consistent is that ambition to be across both curing and detecting disease and that ambition to drive it forward with novel technologies in addition to the amazing technologies invented by our cofounders that we licensed out of universities and to have that impact ourselves and to build a generational company, right? Not to just be a technology licensing shop or to just sit at the fringe of it, but really to fully invest in having that impact on patients lives both ourselves and with leading partners.

13:44
Neil Littman (host)
I think it's an incredible vision. Trevor so let's dive into some of the details. Typically when people talk about CRISPR, it's often in conjunction with a protein called Cats Nine. However, CRISPR, as you mentioned, really actually comes in a variety of different flavors. Before we dive into the different permutations, I just want to make sure our listeners are on a level playing field. Can you talk about CRISPR in general and why it's such a powerful gene editing tool and then we can talk about the CAS Nine and other permutations of that protein.

14:18
Trevor Martin (guest)
Yeah, so CRISPR has a lot of really great properties and as you mentioned, there's many different flavors. Probably the most famous beam CAS nine. I think fundamentally one of the things that has really caused an explosion in the field of CRISPR is the programmability and accessibility of the technology. It's not the first way, ever since you're gene editing, right? There's stick fingers and other technologies that have come before it, but it's definitely just orders of magnitude more programmable. I think that has caused an explosion of development of the space and people using new methods being developed on top of it. It becomes this very virtuous cycle of developing the technology and making it better and better. Where I think now I think of CRISPR really fundamentally as kind of this almost search engine for biology. You can program it with this piece of technology called the guide RNA.

15:17
Trevor Martin (guest)
That guide RNA directs it to a certain sequence so that's DNA or RNA and tells it to only go to that specific, say, location in the genome that you want to edit and not go anywhere else in the genome or not bind to any other locations. That's a very powerful concept because we can very easily design, manufacture and program those guide RNAs. That allows us to very rapidly iterate and kind of direct this CRISPR technology in a very programmatic and reproducible way to different therapies different diagnostics, different agricultural edits you want to do. You don't even have to use the kind of builtin scissors on the CRISPR protein. That's how some of the first editing was done is through double strand breaks where you're leveraging these builtin scissors that come with this programmable CRISPR protein to cut the DNA at the location where the guide RNA told it to go.

16:17
Trevor Martin (guest)
Through the repair of that cut there's various ways that you can have the editing done. Now people, including Mammoth are moving beyond that and doing things like base editing where you fuse on a deaminate so that you can actually change a single base pair or epigenetic editing or other areas where you're now using the CRISPR system as this kind of vehicle for delivering that functionality and leveraging that search capability of the protein that I think lies at the core of what makes it special.

16:48
Neil Littman (host)
Focusing on CAS Nine specifically, why is that not an all in one solution? Are there certain limitations of CAS Nine that you need to engineer around?

17:01
Trevor Martin (guest)
Yes, I think definitely we're lucky that CAS Nine is a great system and there's really great pioneering work being done with it including in the clinic. Now, I think in general, if you just look at the history of CRISPR though, that's the first system to be discovered and developed. There's no reason to expect out of all the flavors of CRISPR that would necessarily be the best or the only one that ends up being effective. In general, I think CAS Nine is a great technology and a great system but it does have real limitations whether that's kind of bringing it in vivo because of its size or that's trying to get the highest fidelity possible or that's the targeting and can you reach all the locations in the genome? There's many different things you might want to look at. I think it just goes back to that philosophy of how do you have the broadest portfolio of kind of multiple CRISPR systems so that you can choose the right technology for the right disease, whether that's going in vivo with an ultracompact system or that's even going beyond double strand breaks and using base editing or gene writing?

18:08
Trevor Martin (guest)
At Mammoth, we don't have this philosophy that a lot of companies have that there has to be like one ring to rule them all. It's either like all CAS Nine or all not CAS Nine or all double strand breaks or all not double strand breaks. I think we want to be driven by the science at the end of the day. Right. You want to be able to choose the right technology for the disease that's going to have the maximum impact. Maybe for some disease it is CAS Nine that's the right technology, especially, let's say, if you're going ex vivo or for another disease, like, you really need to use an ultra compact system because you're going in vivo and you're trying to develop a permanent cure. For some disease, you're using a double strand break because a knockout is the right way to approach it.

18:42
Trevor Martin (guest)
Or for another thing, you're using base editing. I think it's about having access to all these different technologies so you can be driven by the disease biology and not driven by what you kind of happened to license out of the university ten years ago.

18:55
Neil Littman (host)
Yes, Trevor, I mean, there take a note of really important points there to dive into, but I want to pick up on the threat as the platform because a lot of what you've done at Mammoth is building this platform for discovering new cast enzymes, if I understand it correctly. Could you talk about maybe some of the properties you look for in other cast enzymes? What have you found today? What are you developing in terms of this product suite of other types of cast enzymes that could be more precise tools?

19:27
Trevor Martin (guest)
Yeah. The foundation of the company and the way we've been able to build up what's become the broadest and most diverse portfolio of CRISPR systems and technologies in the industry is through our pioneering work in mining, discovering, developing and engineering CRISPR technologies. The kind of grist for that mill is what we call metagenomic data. This data can come from all sorts of environments. Like it could be a hot spring, it could be a volcano, it could be a desert. There's all sorts of places. What you do is you sequence kind of all the microbes in that environment. Because CRISPR has evolved to be this adaptive immunity functionality, you'll have tons of potential CRISPR systems in these sequencing databases. At Mammoth, we have been able to build up extremely comprehensive industry leading database. And that's including the public data. We also strike deals privately to get exclusive access to data for things that we think will be particularly enriched based on our very extensive, now experienced mining through these databases.

20:37
Trevor Martin (guest)
And that's just step one, though. You have to apply machine learning and bi informatics to pull out the punitive CRISPR technologies and systems that are in these databases. We really kind of pioneered this techniques. One of the things that separates Mammoth is that we're not just looking for things that look like CAS Nine or CAS Twelve. That's where a lot of the industry is focused, is kind of look like very similar functionality systems. We really are pushing the envelope of what's possible and that requires deep understanding of CRISPR functionality and what actually can create a functional CRISPR system. Even with the best spy informatics, though, and the best machine learning pipelines, it's still a needle in the haystack. We actually have a whole floor of our building that has a bunch of high throughput robotics systems that actually then, in the wetlab environment, screen these for their potential, whether that's as an editing modality or diagnostic modality, or whether it's an ultra small property, all sorts of things that we look for.

21:39
Trevor Martin (guest)
That is really required in order to pull out the systems that are actually going to be functional at the end of the day. Even with the best buying from Edison, the best screening, the best database, we still have to do an immense amount of engineering on top of that. That's what really turns these into these leading kind of novel CRISPR technologies. The ones that we're talking about include things like CAS 14 and CASP. It's really this entire kind of comprehensive pipeline that we've pioneered at Mammoth that's required to go from metagenomic sequencing data all the way through to really great, let's say, editing CRISPR system.

22:21
Neil Littman (host)
In terms of the technology, it's probably fair to say that most people are focused on therapeutic potential of CRISPR. However, your initial focus at Mammoth was on the diagnostic applications of CRISPR. What do you see as the potential for CRISPR as a diagnostic tool? What advantages might it have over other types of tests?

22:44
Trevor Martin (guest)
We've always been focused on detecting and curing disease since the beginning, obviously, with the pandemic. I think we obviously have done a ton of pioneering work that's been public around the diagnostic side of the business, but we've been really cranking away and have been able to generate amazing data on therapeutic side since the early days of the company as well. I think that's one of the things that makes Mammoth unique is that we take this broad view of CRISPR, right, because I think whether it's therapeutics or diagnostics or agriculture, people really do segment into these areas and there can be advantages to that. What makes Mammoth special is that we have this incredibly diverse and broad portfolio of crystal systems and technologies that allows us to think in this kind of more ambitious way about what really is the promise of CRISPR. In terms of the diagnostic kind of capabilities of a lot of these novel, CRISPR systems that we work with, I think what's really exciting there is that for the first time, we're able to have to not make this choice that we've all seen during the pandemic of oh, do we want something that's as accurate as possible?

23:58
Trevor Martin (guest)
Okay, that's like in the lab, that means we're going to have to wait longer time, it's like totally different process, or do we need a result quickly at our doctor's office, even at home, antigen type tests, things like that. We're going to sacrifice on the quality, right? It's not going to be as sensitive, it's not going to be as specific and I think what's exciting is that CRISPR based diagnostics allow us to kind of have our cake and eat it too, in terms of ultra high sensitivity and specificity, but in these more decentralized formats, because this is a simple chemistry that's isothermal. I think that is really kind of a sea change in what's possible in molecular testing. They'll have applications across a bunch of different areas. The obvious one, of course, is infectious disease. During the pandemic, we've published multiple papers showing how CRISPR based diagnostics can be effective for detecting things like COVID-19.

24:52
Trevor Martin (guest)
These are really great proof of concepts for the power of the technology. We even were able to achieve an emergency use authorization, actually the world's first high throughput CRISPR based emergency use authorization for detection of COVID-19. That really proves that CRISPR is a molecular diagnostic technique that can go head to head with these technologies that have been in the market for decades, that are more complex. I think that looking forward, there's lots of exciting applications, but anywhere where you're trying to detect DNA or RNA, whether that's genetic medicine, whether that's oncology, whether that's infectious disease, I think there's really exciting applications of CRISPR diagnostics across them.

25:35
Neil Littman (host)
Yeah, I think that's incredibly exciting and I just want to spend another minute on that because I'm just really fascinated by this. I believe that the COVID diagnostic test was, if not the first one of the first that you've developed. As you said, you got the emergency authorization for that. I'm really interested in how you mentioned that, how it compares to the tests that we're more familiar with. Right. The antigen based tests and the PCR tests. There are pros and cons with each approach. It sounds like, if I'm understanding it correctly, you have the sensitivity and specificity of something like a PCR test, but it's more accessible and can be I mean, it's not an at home test specifically, but it's an easier to use, maybe a quicker turnaround time than a traditional lab based test. Maybe just dive into of sensitivity specificity compared to antigen based tests and the PCR based test that we're all more familiar with.

26:35
Trevor Martin (guest)
Yeah, exactly. I think kind of the crux of it is that CRISPR is incredibly specific and leveraging this really unique property that we pioneered that enables CRISPR based diagnostics, which is kind of this molecular shredder functionality. You're able to actually create both a readout and an amplification using the CRISPR technology. At the highest level, the way it works is that you program the CRISPR protein with a guide RNA the same as you do for editing and therapeutics. Now you're programming the guide RNA to be specific to a sequence you're trying to detect, rather than a sequence in the genome that you're trying to edit. That could be a sequence that's specific to COVID-19 and not found in flu or the human genome. This is, to be clear, all taking place ex vivosis in a test tube that someone has spit in or something like that.

27:29
Trevor Martin (guest)
If that CRISPR protein that's now been programmed with the sky DNA that's specific to the sequence you want to detect if and only if it finds its target. It successfully finds, let's say, COVID-19 sequence, then it doesn't just cut the sequence that it's bound to like a kind of classical editing CRISPR system. It actually turns on this kind of molecular shredder functionality and it cleaves all the single stranded DNA or RNA depending on the protein, that it can get its hands on. That can be leveraged in a lot of different ways. The simplest is some reporter molecule where it's like a clenched floor for and if it's cut, it releases some color and that can be both a readout so let's say color metric and that's an amplification. It's going from binding a single example of the sequence you're trying to detect to cutting many other sequences as a result of that.

28:23
Trevor Martin (guest)
That's kind of the fundamental principle of CRISPR based diagnostics.

28:28
Neil Littman (host)
So cool. Okay, so let's shift gears then and talk about what you're doing in the realm of therapeutics, some of the partnerships that you have announced recently. I'm always curious about partnerships. One of the hazards of spending so much of my career doing business development. I mean, you've already said your application has lots of broad applicability, right, that's spanning things like agriculture, environmental monitoring, food safety, bio threats. I guess at a high level, I'd love to understand how you think about partnering at a strategic level. What do you think about in terms of what makes for a compelling partnership as you think across these different verticals and different applications for your technology?

29:19
Trevor Martin (guest)
Yeah, it's a great question. I think the first part is vision alignment in terms of where is this technology going to have an impact and kind of what are the maybe even additional technologies that could be brought to maximize that impact. When you're looking at partnerships, it's always really great if there are synergistic things like delivery methods or other technologies that can be brought to bear by either both parties into the collaboration. In terms of that vision alignment, a big part of it is also where are you directing it, right? The partner bringing in domain specific expertise in a disease area that would be very difficult or time consuming for you to build up? They've really lived in that space and have a ton of expertise they can bring to bear to help accelerate the time that it will take to bring this therapy to the patients that need it the most.

30:18
Trevor Martin (guest)
I think beyond that, you have to really look for cultural fit between the. Teams. Ideally, this is a partnership that hopefully will last a very long time, and it takes a long time to bring a drug to patients. Right. It's like a journey with its ups and its downs and sideways. That means that you have to have a really great working relationship between the partners. Very similar to looking at an investor, right? You're looking at do you share the same vision? Do you have the same ideas around where this can go and are you going to enjoy working together? Right? Those are some of the high level things, yeah.

30:56
Neil Littman (host)
All critical aspects. Let's dive in and see how this is played out. You have announced two therapeutic focused partnerships. One was in January of this year, where you announced a partnership with the pharma company Bayer to help strengthen their genes and cell therapy platform with a specific focus on liver diseases. Can you talk about that partnership and the benefits of partnering with a company like Bayer?

31:24
Trevor Martin (guest)
Yeah, so we have, as you mentioned, well, two public partnerships on therapeutic side, one with their and one with Vertex. I think both are incredibly exciting and great foundational deals for the company, a, for the reasons I mentioned before, around cultural alignment, around vision alignment. In terms of the Bayer partnership, what we can say there is that it's in vivo focused, starting with the liver. Bayer has done a lot of really foundational work building out like a cell and gene therapy franchise, acquiring Ask Bio, acquiring other companies. I think that is really exciting to help build that foundation for that franchise. On the Vertex side, also in vivo focused for some specific undisclosed targets. Vertex has immense experience in the CRISPR space, has done deals with CRISPR Therapeutics, for example, really understands the technology and very exciting to work with them to tackle in vivo applications.

32:36
Neil Littman (host)
For Bayer specifically, since you have publicly announced that you're focusing on liver diseases, I'm curious, how did you decide to focus on liver as the initial target disease and target area of interest? Was that driven from Bayer? Was that a combined decision? I'm always curious how you narrow down on a specific indication or focus.

32:59
Trevor Martin (guest)
So it starts with liver focus. I think in general, it's always a collaborative decision, right, where you want to start a partnership and where you want it to go. I think in general, just speaking broadly about the space, when you're going in vivo, liver is kind of really the obvious place to start. There's a lot of really great pioneering work that's been done by some of the first generation companies. For example, in the liver for various targets. It's somewhere that you have multiple really great delivery options. It's really a great kind of launching pad for in vivo applications in general. I think all those things in the broadest sense make liver like a very attractive place to start, whether that's for your in programs or for partnerships or otherwise.

33:50
Neil Littman (host)
Yeah. Bayer, you mentioned some of the acquisitions, but both Bayern and Vertex are I think, kind of deep into the space, right. Gene editing, selling gene therapy. I mean, Bay acquired Blue Rock Therapeutics for their induced blood bone stem cell platform a few years ago, and Vertex acquired SEMA and you mentioned some other partnerships. I do want to pick up on the point that you made, the in vivo gene editing, maybe could you compare and contrast in vivo compared to the ex vivo approach, which I think is more typically done these days? How does it differ in terms of maybe production cost, delivery, the ability to treat a broader range of patients, for example, any number of areas?

34:34
Trevor Martin (guest)
Yeah, totally. And I think you're right. Most of the space is focused on vivo right now. I think where the puck is going is in vivo. It's exactly for the reason we talked about when we started the call. It's how do you get to permanent cures, right? Like one time treatments, if you just think about patient quality of life and what's really transformative for them, that's the kind of thing that really is the Holy Grail. If you want to do that, you have to go in vivo and in many cases, you have to go beyond the liver as well. I think in general, when we think about Envo versus exevo, again, it's not necessarily one ring to rule them all. I think obviously there'll be exciting applications in both areas. I think a lot of the focus on ex vivo has been because there are just technical challenges to going in vivo, right?

35:21
Trevor Martin (guest)
Especially we think about delivery. The way we have overcome the delivery challenges at Mammoth is by pioneering this whole space of ultra compact systems that really can leverage both existing and new delivery techniques in new ways. You're thinking about one time permanent cure, like single dose, this really is all very attractive in terms of both the patient's perspective and in terms of how you're having to manufacture things like compared to exevo and are you doing autologous or allergenaic and how quickly you're able to turn this around. I think in general, there is a lot of really great work going on both sides. At Mammoth, definitely we really see the future as going in vivo in particular.

36:13
Neil Littman (host)
Trevor, as a Lord of the Rings fan myself, I appreciate your one ring analogy. Let's talk about therapeutic applications in terms of your strategic direction. So, as you mentioned, I think one of the special things about Mammoth is your focus on the underlying technology. You can develop therapeutics, you can develop diagnostics. There's a huge potential green field for the development of the underlying core technology. As you think about therapeutic applications, is that something you envision doing solely through partnerships or do you envision developing your own therapeutics potentially at some point in the future? How do you think about that?

36:55
Trevor Martin (guest)
Yeah, so Mammoth is fundamentally a biotech company. We're definitely fully invested in our own clinical pipeline and internal programs. We're not one of those companies that blast our pipeline on our website today. That's an area where we are intensely focused and are investing a lot because in addition to working with partners who can, of course, accelerate and bring in additional expertise, at the end of the day, we really are excited about building our own holy earned therapies as the foundation of the company. I think along those lines, we really are focused on differentiated pipeline as well. Right. Really thinking about we have these novel CRISPR technologies and systems, what are the things where we can be first in class and best in class and that other people just can't tackle? I think that's what we're really excited about is enabling the things that others cannot, especially.

37:54
Trevor Martin (guest)
Yeah.

37:55
Neil Littman (host)
Trevor, let's take a step back for a minute and look at things from the 300 foot vantage point. The whole area of genetic medicine is moving, I think, extremely rapidly, and there seems to be an expanding toolbox of approaches where do you see CRISPR ultimately fitting in to the overall landscape?

38:16
Trevor Martin (guest)
Yeah. So obviously a manifest. We see CRISPR very broadly as this kind of almost search engine for biology where it's really fundamentally the best way to send any editing you want to anywhere in the genome, whether that's double strand breaks from using the native scissors, whether that's additional functionality use to it, whether it's a d*** use or something like this editing or genetic editing or whatever it is. I think fundamentally that kind of programmatic search engine functionality is incredibly compelling for a wide variety of applications. I think, especially when you're thinking about permanent cures and one time in Viva treatments, that's where CRISPR can especially shine. The work that we're doing at Mammoth is particularly focused on that. I think the hope is that using CRISPR, we can get to that point where you don't even have to worry about redosing stuff. Right. It's really a one and done, and I think it's very difficult for other technologies to accomplish that.

39:22
Trevor Martin (guest)
Again, it's not going to be all one thing or all the other, but I think especially for those next generation applications, it's really hard to imagine doing it without CRISPR.

39:36
Neil Littman (host)
Yeah. I mean, no question there's this massive potential here, and you've outlined a lot of those reasons. Let's shift gears and pick up on something you talked about a little earlier in the show, which is how you're merging the biology and the chemistry with things like artificial intelligence and bioinformatics. I think about that merger, there's become common nomenclature in our industry for the type of company you're building. And I love your viewpoint, right. It's really called tech bio these days. Number one, do you see yourself as a tech bio company? If you do, what does that term even mean to you?

40:16
Trevor Martin (guest)
Yeah, it's interesting. I think a lot of people have different definitions for the term. Yeah, we definitely see ourselves as leveraging technologies and learnings and as much as we can across industries. Right. I think that to me is a lot of the spirit of tech bio is how do you build a platform company. It's not a single product like a small molecule. Let's say it's a technology where after you build your first therapy you've learned things that you can actually help build your second or third or fourth theory. You're not always starting from zero. Right. I think that is going to be a sea change in how we develop drugs and therapies for patients. Because right now it's you have a small molecule, you get across the line and now for the next one you're kind of back to the beginning and it's going to take you just as long likely to develop it for another indication.

41:09
Trevor Martin (guest)
Whereas things like CRISPR, because you're using the same system, maybe even the same delivery method and you're changing out just the guide RNA in some cases, depending on what different diseases you're targeting, that is just completely different. We might even have to think differently about the regulatory path. In terms of just the scientific risk, that is so exciting to actually have something that's programmatic and then it becomes a big question of okay, what are you targeting? Right? That's where also a lot of the machine learning and artificial intelligence methods come in is like what are the genetic bases of more complex disease? Right? As CRISPR starts to knock off monogenic diseases and kind of these things where we already have an understanding of the biology, there's going to be all the more pressure to understand, okay, well, what's the genetic basis of complex disease so that we can then target that and help cure those diseases with CRISPR.

42:01
Trevor Martin (guest)
Internally at Mammoth, of course we use a lot of these techniques, whether that's for finding and characterizing CRISPR systems or designing things like guide RNAs. I think more broadly it's really this idea of is your 2nd, third and fourth product going to be informed by that first one and you're going to have a higher likelihood of success and be able to move more quickly. That's where we're also building on the shoulders of giants of many of these legacy companies that are doing these pioneering work with things like CAS Nine. Right. To me those are kind of the key elements of things like tech.

42:37
Neil Littman (host)
Bio and I really love that way of thinking and maybe just dive in one more step. I think that an often overlooked area that I don't think is talked about enough is company culture. How do you think about your culture at Mammoth? Because it really does seem to span different disciplines. I mean, I'm sure you have some software engineers and maybe hardware engineers and you have biologists and chemists. How do you think about merging all those various disciplines together in a culture?

43:04
Trevor Martin (guest)
Yeah, that's a great question and I think that is the key. Early on in the company's lifecycle, we wrote down a set of values around what do we care about, like how we want to work together. One of the key things that we decided on at that time is that I think we're 510 people when we first did that is that the company was going to grow and we didn't want to just have a fossilized culture. Right? We want to be true to the things that we care about, but we also want the next hundreds of people, thousands of people that will join the company to be additive and to not just have the same culture, but a better culture as we grew. So, like, always be improving. It very similar to how we think about improving products. I think that's a very powerful philosophy.

43:50
Trevor Martin (guest)
We've continued to update our company values over time. One of the key ones as we think about updating them is to try and use them in decision making. It's all fine and well to have them on the wall or wherever, but at the end of the day, one of the most powerful ways to leverage them is decision making. If you find yourself constantly not using a value for decisionmaking or using some other metric for decision making, then you should really think carefully about is that an adjustment that you want to make? Some classic examples that we've gone through when we first wrote the values, we had fun as a value. Not that there's no fun at Mammoth, there's plenty of fun, but when you're making decisions, you often choose to do things that are not fun. Right? And why? Well, because you really care about the outcome.

44:36
Trevor Martin (guest)
Like, you think you could really help patients or you think this is a really important thing that has to get done. That makes you rely on more things like the mission of the company. The vision of the company is a key lens that you want to make decisions through. I think it's through constant refinement, like necessarily having some savvy vision of exactly what the culture looked like ten years from now. From the beginning. I think that's the key, and the only thing I'll add to that is at the end of the day, culture is, like, hiring and really trying to find people that you really respect, that you really want to work with, and that, I hate to say, at the end of the day, you'll have fun working with. Right. No matter if it's something really hard or something really easy. I think that's the key is finding the people that you want to build the company with.

45:25
Neil Littman (host)
Trevor, I love that advice and you sounds like you live this every day, but that idea of distilling the culture down to something practical, which is how to use your decisionmaking ability. So I really love that thought process. Okay, whichever. We could probably talk for another two or three days about all this stuff. I do want to be cognizant of your time and wrap up. I want to end with one final question for you. I believe you started the company when you were 28, and so any advice for young entrepreneurs who are either starting out their entrepreneurial journey or who are thinking about building the next generation of healthcare companies?

46:07
Trevor Martin (guest)
Yeah, definitely. I think that more and more now, we're seeing a lot of scientific founders and that's definitely near and dear to my heart. I think often times, whether you're a PhD and Masters in undergrad or whatever it is, way too many shut the door on themselves rather than waiting on someone else to shut it for them. I think that there is incredible potential for people to build really generational companies starting from an academic background or a PhD background. I think that as there's hopefully more success stories like Mammoth and other companies where generational companies are built with that type of background, I think people seeing that will help them understand that is something they can do and that is a real path that you can take. You don't have to kind of pass off the technology to a big corporation or to others to really help it reach its full potential.

47:05
Trevor Martin (guest)
In fact, I think it's the opposite. The way these technologies do reach their full potential and have their maximum impact is by having the scientists involved in the leadership of the company. I think beyond that's a big part of, I think, increasing the diversity in the space as well as having more examples of people that look like the diversity of the United States that have founded successful companies. I think that's the most powerful thing. I think in general, there's never been a better time for especially like an academic entrepreneur to strike out and really see the impact that they can have building a company that's going to deliver a new technology to the market. I just encourage people to make that jump and that there is a very supportive community around that. That was probably one of the most surprising things for me because I came into it without knowing anything about the industry.

48:03
Trevor Martin (guest)
There are just a ton of people that really want to help really want companies to succeed, and you just have to kind of walk through the door. That's the first step.

48:13
Neil Littman (host)
And Trevor, I could not agree more. I think with that, we better wrap up. So, Trevor Martin, cofounder and CEO of Mammoth Biosciences, thank you so much for joining us on the show today.

48:23
Trevor Martin (guest)
Yeah, thanks for having me. It's fun.

48:28
Danny Levine (producer)
Well, what did you think?

48:30
Neil Littman (host)
I thought that was a really wonderful and wideranging discussion with Trevor. You've heard us talk about his vision for the future with Mammoth. My key takeaway is, I guess I really think about Mammoth as a core platform technology company that is utilizing CRISPR in its whole broad variety of potential applications, which include diagnostics and therapeutics. You heard Trevor and I talk a lot about each of those areas, but it sounds like each of those areas is really an offshoot of the underlying power of their core technology, which is based around CRISPR. To me, I think it's really exciting. There's tremendous potential here. Mammoth has already accomplished a lot of things in their short time, and I think they're just getting started.

49:19
Danny Levine (producer)
It seems to me that one of the powers that they have is really their ability to identify novel cast enzymes, which may better suited for different applications. How much of a competitive advantage is that?

49:35
Neil Littman (host)
You heard Trevor talk about this. I mean, it sounds like quite a big competitive advantage, right. When people talk about CRISPR associated with the CAS Nine protein, I think what most people don't realize is that there are a whole wide range of permutations of CRISPR and there are other proteins that are not necessarily CAS Nine or maybe don't look like CAS Nine. They all can have more specificity for different targets or for different applications. There are definitely limitations around CAS Nine, and that just happened to be the first one that came about. And so that's why everyone uses it. That's why it's well known. It is certainly not, if you listen to Trevor, not an all in one solution. I think what they're doing is developing this toolkit of other enzymes. I really think it provides a powerful extension of the CRISPR system. It sounds proprietary to what they're doing.

50:37
Neil Littman (host)
So I think it's pretty powerful.

50:40
Danny Levine (producer)
If you think of the early days of Biotech, the first generation companies were going to do AG and industrial diagnostics and therapeutics, and then found themselves spread too thin and focused on high value applications, which were therapeutics. What do you think of the challenges of capitalizing on a broadly applicable technology like CRISPR? Does that multi pronged approach here makes sense?

51:07
Neil Littman (host)
Yeah, it's a really good and difficult question that all companies with this type of broad platform applicability have to face at some point or another. There are a lot of other companies that have, as you mentioned, Danny, pursued different areas so that's agriculture or environmental monitoring or buyer threats or whatever it may be. I think in one sense those other areas might be a distraction. I think if you go about doing it correctly, I think there's a lot of value that could be accrued there. The way that I would think about doing that is through partnerships. I don't necessarily know if that's how Mammoth is thinking about that. We didn't really get that much into it. I do think based on Trevor's comments, there is such broad applicability of the platform technology and they want to realize the full potential of CRISPR. It sounds like they're going to be pursuing all these different areas and obviously they are highly focused now on therapeutics and the diagnostic I guess more what I would call human health element.

52:16
Danny Levine (producer)
You can see Mammoth building a business around licensing and partnering, but Trevor was clear that it's developing its own therapeutic pipeline. He didn't get into a lot of specifics but seems to have a very clear vision of what he'll be pursuing. How does that complicate the business model?

52:36
Neil Littman (host)
Well, it's a different business model, right? Obviously diagnostics is a very different business model than therapeutic. Therapeutic development. It's own animal, it takes its own unique team with their own skill set, has its own regulatory challenges, and so it is its own unique business that is different than diagnostics. We didn't get into a lot of details because I don't think a lot of those details are public. Even as Trevor said, I'm pretty sure they don't even show their pipeline on their website. It sounds like they're pretty secretive about this. Yeah, I mean, if you're developing therapeutics, you need to have the team capable of doing that to understand all the preclinical tests that need to be performed. Ind enabling studies. What are the regulatory considerations for moving these therapeutics forward? I don't know. It sounds like they probably have a lot of those pieces in place because they're doing it today.

53:32
Neil Littman (host)
But yeah, I think it is different. It could also complement some of the diagnostics business that they have.

53:40
Danny Levine (producer)
It's still early days for this technology, but where do you expect it to have its biggest impact?

53:47
Neil Littman (host)
Well, as Tremendous said, and I tend to agree with him, I think in vivo gene editing is ultimately where this technology is going to have its biggest impact. That is going to be in the realm of developing therapeutic. I think we are just scratching the surface of what's possible and we can start with monogenic diseases and we are in many cases, but I think there's applicability beyond that. There's a long way to go to realize the full potential here. I really do think, as Trevor said, skate to where the puck is going, the old Wayne Gretzky analogy. I think it's moving towards in vivo editing. It sounds like Madness is deeply involved in pursuing those applications.

54:37
Danny Levine (producer)
Well, until next time.

54:39
Neil Littman (host)
Thanks Danny.

54:43
Speaker 1
Thanks for listening. The Bioburg podcast is a product of Bioburging, an investment platform that funds visionary entrepreneurs with the aim of transforming healthcare. Bioberge provides access and enables everyone to invest in highly vetted healthcare startups on the cutting edge of innovation, from family offices and registered investment advisors to accredited and nonaccredited individuals. To learn more, go Neil bioverge.com this podcast is produced for Biofourge by the lead media. Music for this podcast is provided courtesy.

55:22
Danny Levine (producer)
Of Jonah Levine Collect.

55:24
Speaker 1
All opinions expressed in this podcast by participants are solely their opinions do not reflect the opinion of Biobridging or its affiliate. The participants opinions are based upon information they consider reliable. Neither BioBridge or its affiliates warranted completeness or accuracy and it should not be relied on itself. Nothing contained in accompanying this podcast shall be construed as an offer to sell, a solicitation of an offer to buy, or a recommendation to purchase any security by BioBridge, its portfolio companies or any third party. Past performance is not indicative of future results.