Arbor Biotechnologies

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WINSTON YAN: We're from Arbor Biotechnologies. I'm Winston Yan. I'm the Head of Operations.

DAVID SCOTT: And I'm David Scott, Co-founder and Head of Research.

WINSTON YAN: Arbor is a company that's founded upon the premise that there is an incredible amount of natural diversity out there that can be harnessed to power impactful applications in human health and sustainability.

DAVID SCOTT: Yeah, and what we're really looking to do is to bring new discoveries that we find from large-scale genomic data to real impact in these specific problem domains.

WINSTON YAN: So one of the first areas that we're harnessing that natural diversity in is in discovering new CRISPR enzymes. So CRISPR enzymes have been this remarkable revolution in our ability to edit the genome, and we think that there is a tremendous amount of greater diversity that can be harnessed for applications in gene therapies, in diagnostics, and beyond.

DAVID SCOTT: Winston and I, as graduate students at MIT, had really been thinking about, how do we go out and really leverage this opportunity of expanding genomic data and the ability to actually create technologies and high-throughput from that we can mine from that data? Where we started that conversation about really turning this into a company was with our advisor, Feng Zhang.

And we're really fortunate that, for our enthusiasm about this problem space, that we were able to share it with Feng and also with our fellow co-founder, David Walt, who really shared a passion for this particular biodiscovery vision as well. And I think together, that's been such an exciting pathway, the four of us being able to, from the founding of the company until now, realize this vision.

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WINSTON YAN: Yeah, I think the best way to think about our technologies is we're integrating a number-- four different features that may have existed in parts. But in putting them together, we get many more gains of efficiency and power. So the first is harnessing the large scale of genetic data. We're collating all sorts of microbial, whether it's short or fragments in sequences or the whole genomes, into a large database that we can use computational power to effectively search.

The second thing is that we are using gene synthesis very effectively to create from scratch these systems that we may not be able to isolate, but we can now just create de novo to translate that computational power to actual experimental settings. And then, we have the experimental platform, where we're really capitalizing on next-generation sequencing, as well as just new high-throughput assay modalities, to effectively test out in a much greater scale all of the different hypotheses that are generated from that computational platform.

So all in all, by integrating it into just one single platform, we're able to get much more greater efficiency and integration of all of those features for empowering the discovery of new bioactivities. So our discovery platform has been highly productive, even within the short time we've established Arbor. In the past 18 months, we've discovered two new RNA editing systems and also three new DNA editing systems, all to enable a broader range of editing capabilities and functionalities to expand that tool box in CRISPR.

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DAVID SCOTT: Yeah, so why we think this is the right time for a project like this is that Winston and I really been students during our graduate studies of kind of observing trends of new data streams that are emerging and new opportunities to leverage those data streams. And a specific couple of trends that we were watching a lot for a number of years were the increasing amount of gene synthesis that really had the potential to encode many different biological systems that could enable really powerful technologies.

And at the same time, we're really watching this trend of gene synthesis and how all of a sudden, we didn't actually have to have our hands on any of these organisms that we have the genetic code for. We just had to be able to synthesize them, and the cost of synthesizing them was dropping exponentially. And together, those trends really illuminated for us this macro opportunity, where we then realized if we could just create the ability to be able to efficiently search through that genetic information for systems that could enable needed biotechnologies in the world and then pair that with an experimental platform that could allow us to be able to realize those biotechnologies from our searches, we felt like together, we could create a really impactful company around that concept and these trends.

WINSTON YAN: Yeah, it's really a fantastic time to be existing at this intersection of computational and experimental science, and the opportunity really is that nature, over billions of years, has evolved so many impactful biotechnologies that is literally out there in the world. And that just contains a multitude of capabilities that humans can't even engineer right now. So by searching that broad diversity of all the trends that Dave mentioned, we have this opportunity to go in and find the most impactful tools and find, really, the optimized tools for different solutions.

So one of the ways that we're differentiated from the competitors is just that integration between the computational side and the experimental side. And what that enables us to do is take advantage of this huge, exponential growth of data and not just collapse it down to a few candidates. But in having this very integrated platform, we can remove all the bottlenecks along the way so we can come up with the most number of potential new enzymes that could be turned into these impactful products.

DAVID SCOTT: Yeah, I think the general idea is that this new data stream of all of this genetic diversity that we're seeing right now, there are a lot of people trying to figure out how to utilize it, and-- but I think for a really wide variety of problems. And I think that what we've really focused on is being able to bring this particular data stream to applications in genome editing. And I think that that is something that we've really tried to build a scale of our search and experimental processes there that really do put us in a position to uncover diversity and uncover new functionality for genome editing that I think we're uniquely positioned to find and bring to the world.

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DAVID SCOTT: Yeah, so one of the things that we're particularly excited about is that in the first 18 months of the company, we were able to realize the discovery of multiple new CRISPR systems that had never before been studied. And what we were able to find is two RNA-editing CRISPR systems and three DNA-editing CRISPR systems, cumulatively, that enable these opportunities for sensitive diagnostics and also the treatment of genetic disease. And we can get into a few more specifics of how they're actually differentiated for these applications.

WINSTON YAN: Yeah, exactly. These new CRISPR systems, they have new functional properties as well as just useful characteristics that could enable-- we're really expanding the toolbox here so those new capabilities can enable a broader diversity of applications that previously hadn't been enabled.

DAVID SCOTT: And some of those new capabilities of these systems include new ways that they're actually able to make edits to RNA and DNA. They could actually allow them to reach new targets that haven't been able to be accessed by previous enzymes or to be able to make functional manipulations to those targets that allow our enzymes to better be able to function as therapeutics.

Additionally, many of our enzymes are actually smaller than those that have preceded them in the CRISPR space. So this really opens up an opportunity for some of the systems coming out of Arbor to actually enhance the ability to deliver gene therapies to specific target tissues that have maybe been difficult to reach previously.

WINSTON YAN: Well, I guess the specific example is enzymes that are DNA-editing, such as Cas12i, they really have their actual, physical size of the protein is smaller. So this can be better enabled to be packaged into the state-of-the-art viral vectors, such as adeno-associated viruses, where there's a certain packaging limit and to fit in all the components that are necessary for a therapeutic gene edit, there's a limit to the size of the protein.

So the conventional proteins that are used, such as the SP-Cas9, the one that is the most widely-used flavor, there's challenges due to the size of the protein. So by finding a whole diverse array of sizes, of different editing capabilities, and the target ranges, we hope that we're just expanding the therapeutic range that you can hit with gene editing.

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WINSTON YAN: The Cambridge environment's really second-to-none, right? Just from this hot spring of academic thought and engagement, as well as for the collab-- the interdisciplinary company that we want to build, it's impossible, really, to just be siloed in different functional domains, like biochemistry, molecular biology, computer science. And we really think that the academic ecosystem of Cambridge is a model of how all of that connects together, and we want to build a company that takes the best of this interdisciplinary collaboration and takes, also, the best of academia but supported with the scale and the resources of an industrial setting.

So the benefit we see of working with the ILP and the STEX25, the companies as well as the whole program, is that we really want access to the partnerships, the advising, as well as the network of other companies. Specifically with the partners, what we would like are two things. The first is if you have needs in CRISPR, if you are interested in working with new DNA and RNA capabilities to expand your gene editing or even start your gene editing capabilities internally, we'd love to talk to you and see if there's an ability to form a partnership.

The second is going beyond CRISPR into the other enzymatic needs that are just-- are possible to be discovered within the natural world. We'd love to just start those initial conversations around discovery, and what could a new capability that we could discover from nature look like?

DAVID SCOTT: I think, in general, the ideal partner for us, just like I was saying earlier, we really want all of the discoveries we make to be able to reach a point of having an application in the real world. And because of that, then what we really think is ideal with our partners is someone who can help us propel our discoveries towards real-world applications. And a great illustration of that is Vertex, who's our new collaborator that we-- from a deal that we launched last year, to take some of our DNA-editing nucleuses towards therapeutic applications. And Winston, you can probably expand on some of the things that we're really excited about there.

WINSTON YAN: The Vertex partnership really has been an ideal one for us because they're not only visionaries in terms of what they want to do with gene therapies, but they have a commitment and just a real plan of what they plan-- what they want to do with these nucleus discoveries that Arbor is generating. So I think from our perspective, they have been this archetype of a great partner. And we would love to find more folks who are very interested in gene editing capabilities that we've discovered with CRISPR and have a definite plan of how they can translate those into applications that eventually impact patients and human health.

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WINSTON YAN: The trajectory of Arbor has been, I think, a very rapid one. For us in the beginning, even within a few months of starting the company and setting up our wet lab, we were able to show that our discovery platform has unique and productive potential. So in the past two years, we've had two publications, one in Science and other in Molecular Cell, describing these new discoveries.

And the partnership with Vertex really has enabled us to take that first translational step into turning discoveries into something that can really impact humans or patients as products. I think for us, that is a theme that we want to continue of not just ending at the discovery but translating that further from these early-stage glimpses of what nature has to offer into real products that can have that benefit on the world.

DAVID SCOTT: The vision of Arbor is big. We really want to be able to take these new genetic data streams and be able to uncover a wide variety of different bioactivities that could enable very much-needed biotechnologies in the world. But in order to do that in the long-term, we can't-- we have to be able to start somewhere focused, and we have to be able to create market value and also human value, value by getting products out to the world and having them be impactful.

So where we really see an initial opportunity for that is within genome editing. We think this is one of the great medical advances of the current day and maybe of our time. And we think that being able to enable new treatments for genetic diseases with partners like Vertex is a phenomenal area where we can really show in our early discovery efforts that the systems that we're mining from this genetic diversity are really having-- are reaching patients and making a difference.

And we think that over the longer term, as we kind of see these major value inflection points and impact inflection points for some of our early discovery efforts, that will allow us to take resources and to be able to put them back into growing the breadth of our discovery into new areas of biology, long-term.

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