John: Today we're excited to meet with Dr. Aneesh Acharya, Chief Commercial Officer at Molecular Instruments, a leader in spatial transcriptomics and molecular imaging technologies. With extensive experience at the intersection of science and commercialization, Aneesh has been pivotal in driving the adoption of innovative technologies that are transforming the landscape of molecular diagnostics and research. Thank you, Aneesh, for the time to speak with us today.

Aneesh: Thanks, John, for having me. It's a pleasure.



John: So, to start, one thing I'm curious about is how did Molecular Instruments get to where they are today?

Aneesh: That's a funny question for us. So, I am the Chief Commercial Officer at MI (Molecular Instruments), and I've been in that role for almost five years. But I've been with the leadership team for a lot longer. We spun out of Caltech in 2018, but even prior to that, our core technology was developed as part of our CEO's PhD thesis. And my thesis built on that, expanding on the applications of the core technology. When we first started, it wasn't even spatial biology – it was just bioimaging. We came into it trying to create tools for developmental biologists to study RNA expression in very challenging sample types that are still challenging today, like whole mount embryos that can be multiple millimeters thick – 1,000 to 10,000 times thicker than an FFPE tissue section. Since then, we've evolved into what’s now being recognized as spatial biology with more clinically relevant types of samples. But really, we've always been driven by making imaging of RNA or protein molecules easy and routine – and that’s what brought us here.

John: That’s very interesting. And as a quick follow-up, how have your products been used across such a diverse range of sample types in your work, particularly considering the relatively thick samples you can work with?

Aneesh: Honestly, you name it. I think people are sometimes surprised to learn that our users have published over 5,000 studies using HCR™ products. And the applications range from monolayer cells on a slide to tissue sections, whether it's FFPE or fresh frozen or fixed frozen, to whole-mount samples like zebrafish, jellyfish or other organisms. I think the record we've ever seen is a cleared mouse brain about a centimeter thick.  Same product, same reagents – just slightly tweaked protocols to make that work.

John: Great to hear that your technology can be applied to such a diverse range of samples. Could you walk us through how HCR™ RNA-ISH technology works, and highlight some of its key advantages? Additionally, what sets your solution apart from other commercially available options?

Aneesh: So, the main product we offer today is HCR™ RNA-ISH, which is essentially powered by two key technologies. The first is our probe design. Our HCR™ HiFi Probes are custom-designed based on user-submitted targets. For example, if someone wants to study RNA X in mouse, we can algorithmically design a probe set against that target, manufacture it, and provide full support. To give some context, we currently design around 1,200 custom probes each month, and warranty replacements are provided for fewer than 1% of them. Our probe design is highly efficient– we can typically go from start to finish with a new probe in just a couple of weeks. So that's one technology that enables our product.

The other key technology is the HCR™ part, which stands for hybridization chain reaction. This is the amplification platform that our team invented at Caltech and then incorporated into these products. In a nutshell, the HCR™ platform works like a computer program encoded in DNA. To generate signal, we build a large HCR™ polymer from very small components. It’s that physical size that really differentiates us from any other method out there. Our calling card has become this concept of being entirely protease-free. Unlike other techniques that require tissue digestion to allow bulky detection molecules to penetrate, we use small, easily diffusing hairpins. This means we can achieve powerful staining with just standard tissue prep.

There are actually quite a number of features, but we usually boil it down this way: it’s really simple, which makes it cost-effective – an important factor as we think about future clinical use and staying reimbursement friendly. It's also really fast. Compared to other methods, we’re nearly twice as fast in turnaround time, though I think we still need to be 10-times faster to be truly clinic-friendly. And it’s incredibly robust. By avoiding protease steps and heavy tissue digestion that other methods require, we’ve built a system that’s both efficient and reliable.



John: I always enjoy hearing about the clinical space when discussing ISH-based technologies.  As you know, pathology and clinical specimens are an area I’m particularly passionate about, given my background, and in following Molecular Instruments, I appreciate your “clinical-grade” standard. Would you please speak a bit more to this, and let us know how you deliver on this standard?

Aneesh: We really love to use that phrase in particular because today, RNA-ISH is just not there. There are clinical use cases but they're, well, almost like toy examples – they’re not nearly as ubiquitous as IHC has become in clinical practice. So, for us to succeed in the clinic, we’re focused on setting a new benchmark. Turnaround time is a huge part of that; in some cases, patients are on the operating table waiting for some readout to happen, so we need to get down to minutes instead of hours. Then there’s ISH performance – how consistently can you get the same results, and how well can you characterize things like the specificity and sensitivity of a new probe set? That's a major area of focus for us. And finally, cost is critical. We're proud to offer the least expensive ISH on the market, not because we’re cutting corners, but because we have to be competitive with IHC. If you're charging $100 per slide or more, you're just not there. So, for us, it’s all about those three angles: speed, performance, and cost.



John: Thinking ahead, if we consider that Molecular Instruments technology has made its way into the clinical space, what type of health care institutions would you anticipate may lead the charge?

Aneesh: Yeah, we've seen some success with university-affiliated clinics and hospitals in that space. I think they hit the right balance of looking to try new tools and innovations, while also being price sensitive enough that our pitch around being reimbursement-friendly really resonates. For us, we're going to take things, I would say, with deliberation, with careful consideration and respect for what it means to go to the clinic. Right now, we're making our first steps as a lab, developing site-specific tests that don't require any significant QC implementations above what we already do today for our research users. But moving toward an IVD is definitely on our radar, and it's something we'll likely pursue with a partner.



John: So, let’s learn a little more about Molecular Instruments, in terms of where you were, where you are now, where you're headed, perhaps some things we can look forward to?

Aneesh: I love that question because we really believe a company should have a mission, or at least something that they're driving towards, even if they're not there yet today. And for us, I’d say it’s really two things. First, as a small, agile, and focused company, we’re committed to advancing this concept of ‘clinical grade.’ How do we continue to make our products better – not just by adding more plex, but by improving the performance and accessibility of those technologies? Because when you make those advancements, it helps out the research users too.

Here's a quick example, maybe a bit in the weeds, but it’s something we’re really focused on: we want to eliminate harmful reagents from our buffers. Traditional ISH has always required some pretty toxic reagents that require proper ventilation, storage, and very specific waste disposal. We're working to remove those components from the buffers so people can do ISH anywhere, and waste can just go down the standard drain without special handling. I know that's a very specific example, but that's the kind of thing we're really concentrated on.

The other thing I’d mention, is this growing community around spatial biology and mid-plex to high-plex assays – like 10 to 15 targets or more. We partner with quite a few companies like Bruker Spatial Biology, RareCyte, and a few others to integrate world-class RNA imaging into their existing protein imaging workflows. And we're excited to continue expanding our reach through partnerships with companies looking for that kind of solution.



John: That’s great, especially considering the unique focus on reagents. It nice to see a focus on reducing potential impact to users and the environment as you develop your products. So Aneesh, what are some examples of more impactful applications currently underway?

Aneesh: The two that we've seen are use cases where having really good ISH is helpful. First, the LDTs that I referenced before, I think is a good example of that where we have our first four 1-plex assays that are now reimbursed. These assays enable more accurate diagnoses and treatment selection for patients in ways that weren't possible with previous ISH methods and is impossible with IHC alone. It’s a perfect combination of performance, cost, and reliability. The second area we're investing a lot in the future for is co-detection. Researchers and clinicians are increasingly looking to study both RNA and protein together. Previously, they’ve had to pick between RNA or protein detection. We don't try to fight that battle with anybody – instead, we want to complement existing assays. If a user has a working 5-plex protein assay and wants to add a sixth target that either doesn't have a reliable primary or isn’t even translated (like a splice junction), our kits let them easily sequence that in without disrupting their existing assay. It’s about trying to make ISH feel like just another channel you can use with your IHC or IF, enabling more comprehensive analysis without compromise.



John: When we consider launching new products like the HCR™ Pro kits, how do you balance wanting everything to be perfect with the need to get something out there quickly, especially when customers are already asking for more features?

Aneesh: What we try to do is stay true to the technology and our original goals. But you're also building the plane as you fly it, and that requires some level of compromise – you have to decide what to prioritize. And you know, from the scientist and engineer perspective, we always aim to maintain the highest quality, but we also need to know where it’s okay to make those trade-offs. For example, when we launched the HCR™ Pro kits, we started the launch at the beginning of last year, but the full launch with all of our platform and hardware partners didn’t really wrap up until the beginning of this year. We launched a product that was not ready to fully compete – just a 1-plex ISH assay. We knew there would be immediate demand for 2-plex, short targets, and other features, but we had to skip that because it wasn’t ready yet. I think it’s all about finding that balance between holding onto your scientific ideals, generating revenue, making an impact, and getting traction as soon as you can.



John: To wrap up, Aneesh, one last question for you. Any important lessons you've learned along the way in getting to where you are, considering your transition from academia to commercial leadership?

Aneesh: I think something I never truly appreciated when I was in academia, and even now, I still learn it over and over again, is just how noisy the scientific community is when it comes to communication. It’s really, really hard for good ideas to break through and stick with people. And you know, we've been distributing these kits for over a decade, and we’re still not as well-known as we’d like to be. In a space dominated by a small number of gigantic corporations, with a bunch of small players like us trying to make a dent, being really focused, repetitive, and diligent with our messaging has been a really important learning for us.



John: Well, thank you so much, Aneesh. Such a pleasure to meet with you!

Aneesh: Thank you! This was great!

Contact Information for Molecular Instruments:

• To learn more about Molecular Instruments, please reach out to info@molecularinstruments.com or visit the Molecular Instruments website at www.hcrimaging.com