Oxford Nanopore's roadmap to proteomics
By Lakmal Jayasinghe, Chief Scientific Officer, Oxford Nanopore Technologies
Today, I shared my perspective on how protein sensing with Oxford Nanopore technology has the potential to transform our ability to understand proteins. At Oxford Nanopore, our teams have been working on this vision for many years — but today marked the first time we’ve publicly outlined our journey: from biomarker analysis to our bold (yet realistic) ambition of full protein sequencing.
This year’s London Calling conference was my first in the role of Chief Scientific Officer, and I was immensely proud to share this next, pivotal phase in our company’s development — particularly one which I’m so personally passionate about.
I can hardly believe that only 12 years ago, there were still many people who thought that using nanopores to sequence DNA was impossible. Yet here we stand today, enhancing our existing multiomic sequencing platform by bringing our passion for endless innovation and scientific progress to the field of proteomics.
If we are to empower research and improve health, we need to read all of the building blocks of human beings, not just DNA and RNA.
Exploring the next frontier
During my PhD at the University of Oxford, I engineered proteins for various applications, and now, I’m proud to be part of a team building a system to sequence them. Yes, DNA and RNA analysis has shown us the potential of ‘what could happen’ and ‘what is starting to happen’ at a cellular level. However, proteins are the essential molecules that perform nearly every function, including building and repairing tissues, supporting immune defence, and regulating biological processes.
There are, of course, already protein analysis technologies out there, generating fantastic knowledge and being used regularly in healthcare and industry. However, the technology space has an opportunity to move forwards to provide richer data, faster, and more affordably and accessibly.
We are at the cusp of an exciting new frontier, but where do we start?
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Oxford Nanopore roadmap to full proteomics
Today, most available methods in proteomics that don’t involve mass spectrometry are indirect, which in many cases means that the actual readout is DNA. Our goal is to go beyond this and directly read and identify native proteins, just like we do with DNA and RNA — read the real molecule, not a proxy. Our teams are developing two complementary approaches for protein analysis using nanopores to do this.
The first approach is peptide-based detection. Here, proteins are digested into peptides, and one or more peptides per protein are analysed based on their amino acid composition. The resulting signal enables accurate protein detection.
Secondly, we are working towards our longer-term goal of full-length protein identification, where entire proteins are passed through the nanopore without digestion, generating a characteristic signal that reflects the overall composition and structure of the intact protein.
Our focus today, and the area that I will go into further detail on, is peptide-based detection — a method for which we have already developed a complete, end-to-end workflow.
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Peptide-based detection
Our peptide-based detection approach is a free-running system that captures peptides between two DNA handles. A DNA motor protein is then used to translocate the peptide through the nanopore. The nanopore used in this approach not only generates a distinct signal from the peptide, but also reads DNA to Q20+ accuracy. This enables simultaneous sample barcoding and identification at the DNA level, allowing multiplexing and streamlined analysis. We have optimised this method for two key applications:
1. Detection of protein biomarkers
Detection of protein biomarkers in complex samples, allowing not only the detection of the presence or absence of target proteins, but also absolute quantification. We envisage that this could enable potential use in clinical panels, and you can see an example of where we’ve looked at disease panels in my presentation below. Deployed effectively, this method could unlock the detection of biomarkers at ultra-low concentrations.
2. Protein barcoding
Protein barcoding: a scalable tool for life science research, enabling quantification of the relative abundance of tagged proteins in a sample and allowing multiplexing of assays or screening variant libraries. We see easy implementation, high scalability, and minimal impact on protein structure on protein function (unlike some other methods) as the key advantages of this approach.
If you would like to hear more about these, you can watch my talk here.
Why insight-rich proteomics matters
The potential impact of our work on proteins is significant, especially for healthcare settings. Many diseases result from protein dysfunction rather than DNA mutations, and disease progression can also be more clearly assessed through the wider proteome.
Proteins are, in fact, so remarkable as a real-time indicator of health or disease that full-length protein sequencing could — in some cases — effectively cut out the DNA and RNA middlemen to achieve a clear biological picture all by itself. This could enable even faster therapeutic development and earlier disease detection.
If protein detection can be performed using portable Oxford Nanopore devices in a more distributed manner — directly in clinics and surgeries, at the point of need — rather than waiting days or weeks for results from centralised laboratories, the impact could be truly transformative.
We are some way off from that world as I write this today; however, this vision provides just a glimpse the potential advances that proteins could unlock for clinical and pharmaceutical applications.
A multiomics approach
A broader benefit of our expansion into directly reading proteins will be the possibilities for multiomic analysis across our platform. We are committed to our goal of accessibility, and, with this, providing inherently modular platforms. Moving forwards, the simple change of a nanopore will allow a single device to sequence DNA, RNA, or proteins, without the need to redesign the entire system or hardware. This flexibility will allow rapid innovation and expansion into new applications while maintaining the same core technology.
As a multiomics company, I fundamentally believe that proteins are the natural next step for us to explore, and this is the beginning of what I know will be an exciting journey for Oxford Nanopore. We are only just unlocking the full potential of protein analysis. I can’t wait to see the transformation these approaches could enable, from research labs to real-world clinical settings.
Find out more and express your interest in proteomics
Watch my talk here to find out more about our protein work to date here.
Express your interest in proteomics here.