Nautilus: Igniting a proteomics revolution!

Nautilus was conceived with the goal of revolutionizing proteomics and making comprehensive, high throughput assessment of the proteome accessible to all researchers and clinicians. While many successful companies have come from incremental thinking and advancement, to accomplish our audacious goal we needed start with a blank sheet of paper. The leaps in proteomic technology and innovation that have and will continue to come from Nautilus are powered by cross-disciplinary thinking and collaboration – two characteristics vital to true breakthroughs. Indeed, these have become core values at Nautilus. In this series of blog posts, we’ll give you an inside view on how cross-disciplinary thinking and collaboration have and will continue to propel us into a proteomics-powered future.
 

A new path for proteomics inspired by the intersection of science and magic

Our scientific co-founder, Parag Mallick, is not just an accomplished professor at Stanford but also a professionally trained magician. As you’ll see below, his truly diverse but deep expertise enabled him to devise the technology that would become the core of the Nautilus platform. 

Parag set out to create Nautilus after being consistently disappointed with the proteomics status quo. Traditional and emerging proteomics technologies like mass spectrometry, affinity arrays, and protein sequencing have made it clear that the proteome is highly dynamic and have enabled fundamental advances in our understanding of cell biology in both health and disease. However, these techniques are ill equipped for comprehensive assessment of the proteome for a few key reasons:
 

• They are too insensitive to measure the majority of the proteome – in the best case, routine measurements only cover ~30% of the proteome. This makes it very difficult to compare protein levels across samples as researchers may not even be able to measure the same subset of the proteins across all samples. It is also rarely possible to measure modified proteins and proteoforms.

• They are too low-throughput to meet researchers’ demands – For instance, clinical researchers may want to look at the proteomes of thousands of tumor samples to assess proteomic differences amongst patients. This could take months with current technologies.

• They are difficult to use – It can take a ton of time for even a highly trained postdoctoral researcher to get up to speed on the techniques necessary to use current proteomics technologies. 

Frustrated by these issues, Parag set out to think of ways to solve his proteomics conundrum. At first, incremental thinking dominated. As a scientist who firmly values the deep understanding that comes from building upon past work, Parag looked for ways he could improve traditional proteomics technologies. Yet, no matter how hard he tried, he could not conceptually tweak mass spectrometry or other technologies enough to solve the problems outlined above.
 

Feeling as if he hit a wall, Parag decided to clear his head; he got out of the lab and went on a road trip. Separated from the standard trappings of the academic world, Parag’s magician mind took hold. As a magician, Parag knew that people can be misled by the obvious or traditional. Indeed it is such distraction that makes magic tricks possible. By thinking about incremental advances in current technologies, Parag was being misled into thinking there were no alternatives. By putting on his magician’s hat, he could set the obvious aside. As he says:
 

“As a magician, you have to have a healthy disregard for the impossible. Instead of taking the impossible for granted, you have to ask ‘All right, well, is it really impossible? Does it have to be impossible? How could I make it possible?’“

Focusing on traditional techniques made it seem like radical advances in proteomic sensitivity, throughput, and accessibility were impossible. So, like a good magician, Parag stepped away from the obvious and thought of an entirely new way of measuring the proteome. After returning from his road trip, he had an epiphany involving the use of relatively non-specific protein binding reagents (affinity probes) that would become the theoretical basis of the Nautilus’ platform.
 

You can learn more about the technology behind the Nautilus Platform here, but, in brief, the platform isolates individual proteins on billions of landing pads on a nano-fabricated array – one protein per pad. By flowing affinity probes binding short motifs over these proteins and computationally assessing their patterns of protein binding, the platform is designed to systematically identify the proteins on each landing pad. Identifications are based on predicted binding patterns developed from known protein sequences and machine learning algorithms. By simply counting up how many times a protein is identified on an array, the platform is expected to determine protein abundance across a wide dynamic range. The user will ultimately get a simple list of identified proteins and their abundances.

This is nothing like current proteomics technologies which generally identify pieces of proteins in aggregate, destroy the proteins in the process, and have poor dynamic range. According to calculations based on the size of our arrays, the known sequences of proteins in the human proteome, and the design of our affinity reagents, our platform should be able to quantify ~95% of the proteome from a human cell or body fluid sample. 

Our current prototype, developed over five years after Parag’s epiphany, is remarkably similar to Parag’s original vision. His cross-disciplinary thinking and willingness to look beyond the traditional set the foundations for what Nautilus is today.

In the next post in this series, we’ll discuss how interdisciplinary thinking allowed us to achieve this growth.