Solid State Nanopores – Building Blocks of Precision Medicine

Kyle Briggs shares how he and his cofounders are building the building blocks of precision medicine.

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  1. Can you tell our audience about yourself?

I am Kyle Briggs, an academic-turned-CEO building something unique: a deep tech biotechnology company that has been cashflow positive from day one. Our technology is built around a novel way to fabricate solid-state nanopores–tiny holes in thin glass membranes similar in size to a single molecule of protein or DNA that can be used to detect single copies of biomolecules.

This technology will be at the core of next generation single molecule sensing, which will revolutionize precision medicine.

I’ve been working in the nanopore space for more than a decade now, initially as an academic researcher. My focus during my time in a university lab has been on solid-state nanopores but has been varied within that scope, covering an eclectic collection of related work including novel methods to fabricate solid-state nanopores, various applications of the new technique, and development of new ways to analyze nanopore data. 

While I love the creativity and free exploration that characterized academic research, in my role as a researcher I have always tried to keep my focus on the practical potential impact of my work, preferring to develop technologies for which I could see a clear path out of the lab with a 5-10 year time horizon. 

I first started working with solid-state nanopores as a co-op student in the lab of Vincent Tabard-Cossa at uOttawa, and immediately began development of the controlled breakdown method of solid-state nanopore fabrication, a technology that continues to shape my career. It was immediately obvious to us that we had discovered something groundbreaking, and I stayed in the lab to develop it through grad school and even into a postdoc, ignoring all of the usual academic requirements to switch universities and supervisors for each degree, partly because Vincent is such an excellent mentor and teacher, and partly because I wanted to finish what I helped start and have a direct role in realizing the full potential impact of the technology.

I made the transition to industry about three years ago. The decision was motivated by the fact that we were getting regular inbound requests for purchase of our instrumentation from all over the world, and by the idea that we had taken our technology as far as we could academically. Continued progress required a commercial entity that could focus on solving the problems that don’t fit an academic mandate – the kind of hardware and software development and optimization that is critical to technological advancement but doesn’t generate enough academic papers to receive funding from that channel.. 

I was also very personally motivated. Having spent the time in academic research that I needed to develop the base of knowledge needed for my next challenge, I wanted to experience the process of building a deep tech company from the ground up. This idea of pursuing challenges for the sake of growth is the motivation for most of what I do: for me, the process of building something and learning from the process of doing so is the reward. Building Northern Nanopore has not disappointed in that regard—the pace of personal change that I have experienced over the past three years is by far the fastest and most rewarding I have ever experienced.

My role in the healthcare industry specifically lies very early in the technology funnel. Solid-state nanopores have enormous potential to drive developments in personalized medicine that I will discuss in detail later in the interview, but there is still R&D to be done.

  1. Can you tell our audience about Northern Nanopore Instruments?

Northern Nanopore is a deep tech biotech startup located in Ottawa, Canada. We consist of a founding team of four scientists, engineers, and deep tech enthusiasts, as well as research staff bringing the total team size to ten currently. 

The co-founders are a unique team: Matthew Waugh and I joined the lab of Vincent Tabard-Cossa at the university of Ottawa more than 10 years ago, just before the discovery of this technology, and we’ve been working to develop it in his lab ever since. Mathieu Gibeault joined us 8 years ago as a software consultant to the lab, and asked to join Northern Nanopore as a co-founder just a few months after incorporation. As a team, we have been working together for almost a decade on this specific technology, and that foundation of productive collaboration has been the cornerstone of everything Northern Nanopore has achieved since. 

We incorporated in March 2020, and have been cashflow positive since day one, selling scientific instrumentation which allows researchers to fabricate solid-state nanopores at the push of a button. As of now we have customers globally, with more than 30 systems installed across 15 countries. Our customer base is primarily academic researchers using solid-state nanopores for a variety of application development in labs globally, and we are starting to see uptake from industrial and national labs as well. 

Our customers are all doing something unique. Some are exploring genomics applications, seeking to detect and recognize particular DNA sequences. Others seek to detect and characterize target protein biomarkers of disease, or study their interactions with drug candidates. Still others are exploring synthetic biomolecules for digital information storage. The breadth of technology exploration being undertaken with solid-state nanopores makes for a unique challenge as well: our tools must be sufficiently general that they can be adapted to a wide variety of experimental contexts quickly and effectively, and I’m proud to say that to date, our tools have proven to be up to the task. Our tools consist of several main offerings:

Part of the process of building Northern Nanopore is to also build the nanopore community globally. To that end, we also make available a wealth of educational resources about solid-state nanopores, entirely free of charge. We have:

Our goal in developing all of these resources is to make clear that solid-state nanopores can be accessible to anyone and to thereby grow the field of researchers using solid-state nanopores for cutting edge research across multiple downstream healthcare opportunities.

The current role of my company is to develop the hardware and software platforms that will enable and accelerate research, with the goal of enabling personalized medicine applications via single-molecule proteomics within the next five years. 

My current role as CEO in that endeavor is to keep us focused on the long-term vision, and to make sure the lights stay on enroute. Of course, given the time horizons involved these roles will no doubt evolve with the technology, and I am very excited to find out exactly how. I see a general trend in technology toward accessibility: the average person can use modern technology to achieve outcomes that not too long ago would have been impossible outside an expert lab setting, and what we are building will continue this trend in personalized medicine and precision diagnostics. 

  1. What problem is Northern Nanopore Instruments solving & how? 

This video explains it very well.

Solid-state nanopores are tiny holes in thin membranes similar in size to a single biomolecule like DNA or proteins. The idea is simple: if you run ionic current through the nanopore and a biomolecule passes through the pore, it blocks some of the current, and the shape of the blockage tells us something about the identity of the molecule that caused it. These are true single-molecule sensors, capable of detecting single copies of target biomolecules, a capability that enables much more sensitive detection of biomarkers all the way down to single copies of molecules. 

Solid-state nanopores have been promising disruptions to diagnostic medicine, DNA and protein characterization, drug discovery, and even the next generation of digital information storage. In all of these verticals solid-state nanopores play the role of the detector or reader that extracts the required information, so they are an incredibly versatile technology with potential for broad impact across multiple critical verticals that collectively represents hundreds of billions of dollars in some of the fastest growing fields on the planet. 

But despite this promise, they have been stuck in the lab, unable to make it into commercial utility. The issue is that until Northern Nanopore technology was discovered, fabricating a solid-state nanopore involved drilling it with the beam of an electron microscope, a million-dollar machine that requires manual operation by a highly trained user – a process that is incredibly difficult to automate and scale, and limited solid-state nanopore research to universities that had compatible shared TEM facilities already. This is a problem, because while the promise and value of the research outcomes accessible to solid-state nanopore research are not in question, the pace of the research that can be achieved with these legacy tools is too slow to realize it. 

The controlled breakdown method of nanopore fabrication replaces this with a purely electrical benchtop instrument that produces pores with higher precision and yield in less time and at a fraction of the up front infrastructure cost. Most importantly though, the process is now fully automated and can be parallelized. The equipment fits any research budget, and truly makes solid-state nanopore research accessible to anyone. Our goal is to provide the field the tools it needs to accelerate research with solid-state nanopores to realizing their incredibly varied promise. 

To give you a sense of the difference in scale, Vincent did his postdoc in solid-state nanopores before the method existed. He carefully made a small batch of nanopores every few months, which he guarded and reused, washing them religiously every time, for a year. 

A significant portion of his research time was simply dedicated to making sure that his pores survived the day of experiments because to make more would require days on the TEM, and could easily halt forward research progress as he waited for TEM access. This requirement also limited the experiments that could be done: some important molecules are more likely to clog and stick to a pore than others, and when pores are a precious resource, they are less likely to be applied to unknown molecular systems. 

In contrast, I did my grad work using the controlled breakdown method. During that time I averaged more than 100 pores per year, and if one of them failed I just set the equipment up to automatically make me a new one while I went to get a coffee.

In the short term, our technology solves the research bottleneck that has prevented solid-state nanopores from realizing their promise outside the lab. Our tools enable labs to make pores on demand as needed. Longer term, when you are able to assay the proteome of a living system you get a real-time snapshot of their health state and can accurately predict their response to a course of treatment on an individual level. 

This is the next step in human health, and solid-state nanopores will be a pivotal part of making it a reality. Our challenge from here is to scale the technology: taking it from single-pore operations in the lab to highly parallelized and automated systems that can be used by non-experts in a point of care setting.

  1. What have been the biggest achievements of Northern Nanopore Instruments? 

Northern Nanopore is a unique company, in that we are a cash-flow positive deep tech startup. Most investors will tell you that “cash-flow positive deep tech” is an oxymoron, and they would mostly be right. But whereas most deep tech companies build their technology quietly, choosing their downstream target application and building the complete solution before releasing anything, we took a different approach.

Everything we build accelerates our internal R&D,simultaneously providing us with a product that we can readily offer to the global research community, thereby expediting advancements in solid-state nanopore R&D worldwide. 

By building in the open like this, and by having many people use our products to perform cutting edge research, we get immediate validation that we are on the right track; we get opportunities to collaborate on research and access funding; we validate and establish the impact and potential of our technological contribution from day one; and we get non-dilutive capital to allow us to continue building and improving. 

Combined with our free educational resources, this allows us to build our future market as we build Northern Nanopore, and ensures that when we get to the downstream applications in healthcare that the technology will already have years of third-party validation behind it. And I am genuinely proud of the impact that our tools are having globally and the fact that we have operated profitably for three years as a deep tech startup. 

While the large majority of our operations are funded through our sales, we have raised other non-dilutive capital from other sources, mainly Canadian government funding agencies focused on supporting entrepreneurship, technology translation, and Canadian small businesses operating abroad. Our YoY growth between 2021 and 2022 was about 300%. Together, this enabled us to double the size of our team over the last year (from 5 to 10), and we will be seeking to continue this trajectory into 2023. In total, our capital breaks down as about ⅔ sales and ⅓ non-dilutive grant funding.

A major challenge for us has been the continuous debate between time to market and dilutive capital. The debate relates primarily to how far we want to take our internal R&D before seeking external investment. On the one hand, we have demonstrated that we can bootstrap very effectively and everything we do builds value for a raise. On the other hand, we are in a space where time to market is important, and an injection of capital would provide an accelerant toward our long term goals. To date, we have elected to build with non-dilutive capital, but this is shifting, and we are currently in discussions with several pre-seed and seed-stage VC funds.

The main challenge in getting to this point hasn’t been product-market fit (we got that right from the start) or even finding customers (at this point, they mostly find us), but rather it has been what I think of as overcoming a language barrier. The founding team consists of scientists and engineers: people who by nature are conservative in our estimation of the potential of our work, and who are trained to speak primarily to technical audiences–a combination that makes for challenging conversations with investors in particular, who are used to hearing people promising them the moon and who mentally divide all the numbers they hear by 10. As a result, the first few pitches I attempted to give were met with blank stares. Nobody understood a word of the story I was trying to convey. Since then, with the help of many (very patient) mentors and through delivery of a lot of very bad pitches, we have been able to get to a point where we can more effectively convey our vision.

  1. What have been the biggest challenges for Northern Nanopore Instruments & how did you overcome them?

Deep tech involves a long and complex roadmap that constantly evolves as new information and technology comes to light. For example, while our operations in the research space have been and will continue to be a core part of our strategy, it is not immediately obvious to someone hearing about us for the first time how selling research instruments to academic researchers gets us closer to healthcare applications of solid-state nanopores. 

This makes for an interesting communications challenge when attempting to pitch the long-term vision and give an explanation of where we are now in the same pitch–without the context that comes from 10 years in the field, it is difficult to connect the ideas, requiring either that we only tell a partial story, or that we spend a lot of time providing that context. It has been a constant struggle for me to pitch Northern Nanopore effectively as a result. 

Overcoming this is an ongoing challenge, but mainly relies on feedback from a network of mentors and people to whom I have delivered pitches. There is a balance to be struck between the scientist role and the CEO role, and I have been fortunate to have excellent mentors and teachers in both. I love having chances to pitch Northern Nanopore’s vision to people, even if they are not potential investors, for the simple reason that all the feedback I get is a valuable part of the process. 

It is easy as a subject matter expert to forget what is and is not obvious to your audience, and understanding where my audience is misunderstanding my story allows me to improve it.

  1. What are you most excited about in healthcare at present? How do you anticipate healthcare will change in the next 5 years?

Personalized medicine enabled by single-molecule proteomics is the future of healthcare.

If you’re tracking innovations in healthcare then you would be familiar with the genomics story: from the first human genome at $3B, 2007 onwards saw the cost of sequencing dropped like a rock, down to about $200 today. What enabled this is the advent of massively parallel sequencing, followed shortly by single-molecule sequencing, and the whole transformation took about 15 years. 

Proteomics today is where genomics was in about 2006: after decades of stagnation based on mass-spectrometry and centralized lab proteomics, we are just now starting to see the emergence of massively parallel protein sequencing technologies, with single-molecule technologies in the research pipeline. I anticipate that the next 10-20 years will do for proteomics what analogous technologies did for genomics. 

The value proposition of proteomics generally is simple: whereas the genome provides a blueprint of biological potential, the proteome provides a real-time snapshot of the health state of an individual. Whereas genomics can guide treatment decisions and identify disorders to be managed, proteomics will allow accurate, real-time prediction of the effectiveness of a particular treatment at the level of the individual patient. The implications of this are massive, and will be felt across the entire healthcare industry. 

As a couple of examples, a recent study concluded that the success rate in oncology drug trials for going through all 4 trial stages is just 1.6%. Once you average over the costs of failed trials, the cost of one fully successful drug is north of $500M. 

But hidden in those numbers is an interesting insight: many failed drugs are actually very effective in a subset of the trial group but perform poorly on average. The reason lies in the individual proteomes of those patients–information which, if available, actually increases the chance of success to almost 11%, for a specific subset of the trial group. 

The ability to stratify trial groups by the presence or absence of a set of context-specific protein biomarkers has the potential to dramatically reduce the cost and time involved in getting new drugs approved for specific subsets of the population. 

As things stand, however, the cost and time associated with accessing that information with existing technologies is too high to be useful. And while the numbers change slightly in drug discovery contexts outside of oncology, the core message generalizes well: being able to cost- and time-effectively stratify patients by proteomic phenotype will completely change the way we approach drug discovery. 

Another area where the same capability will be felt is in management of acute kidney injuries. Currently the marginal cost of hospitalization involving acute kidney injury versus hospitalization without it is about $8B in the US alone, and the mortality rate is high. Among the many challenges involved in treating AKI, simply being able to identify the proteomic phenotype of the injury quickly could save a hundred thousand lives and $2B in the US alone every year. Right now, the process of identifying the biomarkers needed is too expensive and too slow to be impactful, but tools that enable point of care identification of context-specific protein biomarkers will change that. 

These are just two examples among many, including some I’m sure I haven’t even considered yet. There is no aspect of human healthcare that will not be impacted by this technology. When I am asked what I do and I only have a few seconds to work with (and my audience is old enough to have a chance of getting the reference), I tell people that “I’m building a tricorder”. Point of care proteomics will be pretty close to that in terms of the treatment modalities it enables once fully realized. 

  1. What are your favorite educational resources, and how have they influenced you?

The process of building a company, and the mentors and teachers I’ve had in the process, has been the driver for the fastest pace of positive personal change I have ever experienced. When I started the process I had many blind spots: a general disregard for the importance of soft skills; an inability to effectively communicate with non-technical audiences; and an arrogant approach to work that could be summarized as “if you want it done right, do it yourself”. The last three years have thoroughly challenged all of those, for the better. And while I no doubt continue to have blind spots of which I have yet to be made aware, the constant push that comes with building a deep tech company continues to afford me opportunities to find and address them.

When we first started, it became quickly apparent that it was not possible to do it all myself, even if I wanted to. One of the many things I love about my team is that they are all highly effective people: if they tell me that something will be done, I have confidence that it will get done and it will get done well, without any further thought on my part. That security is the cornerstone of our effectiveness as a company, and the idea of allowing myself to trust others to perform at their best without trying to look over their shoulders has been one of the most valuable lessons I’ve learned in this process. 

I am fortunate to have an excellent team of co-founders and mentors that have assisted me in this. My former PhD supervisor and now co-founder Vincent Tabard-Cossa has been an incredible teacher and mentor for the last decade, but I will spare you the book I could write about the numerous positive influences his presence in my life has had on my development. Suffice it to say that there is a reason I spent 10 years working with one academic advisor.

Early in the process, prior even to our formal incorporation, I was introduced to Greg Lane, a mentor who did our intake interview for the University of Ottawa Entrepreneurship Hub incubator. What started with a commitment to 3 hours of his time over the course of 4 months turned into weekly conversations that have happened consistently over the last 3 years, and his guidance and wisdom, particularly on engaging effectively with people and related soft skills development, has been invaluable. 

There are many other mentors who have contributed and who I cannot possibly list comprehensively. I have found that the mentors who bring the most value and who stay engaged are the ones that do not provide direct answers or instructions. Rather, they challenge assumptions and make me defend the thought processes that led to a particular decision. And while I cannot claim to have always followed their advice (for better or worse), the thought process that informs those conversations has been and continues to be an invaluable tool.  

I’ve never been much of a podcaster. I think I threaded a half-generation needle that missed podcasts completely. For books, I have always had an aversion to what I think of as “soft skills self help books” but that has been challenged recently as well. After much coaxing from my partner I read “7 Habits of Highly Effective People” and it has actually had an impact on how I approach work. I may have to bite the bullet and explore the genre more carefully. 

Above all, though, the biggest driver of all my learning is just doing. Getting comfortable with making mistakes and learning from them is key to personal growth in any context. 

  1. Do you have any other key messages for the audience?

What surprised me the most about the process of building a company is just how welcoming and supportive the entrepreneurship community has been. The community is full of experienced, responsive people who are happy to share their hard-earned knowledge (their “scar tissue” as one mentor puts it).  Even beyond Ottawa, the number of people who respond enthusiastically to my cold request for a 30-minute conversation is astonishing.

I’ve received wisdom and advice from people all over the world. Angel investors, scientists, founders from all stages of startup development, and the C-suites of companies across the entire economic scale have taken time out of their day to talk to me.

When I ask why, the answer is universal: 

“Because when I was where you are, someone did the same for me. Pay it forward.” 

I look forward to my chance to do so.

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