Skip to main content
Premium Trial:

Request an Annual Quote

Nautilus Biotechnology Early-Access Users Exploring Platform's Discovery Proteomics Potential


NEW YORK – Proteomics firm Nautilus Biotechnology has been working with early-access users at Brigham Young University, the University of Southern California, and the Buck Institute for Research on Aging to explore potential applications of its technology.

While Nautilus has largely highlighted its platform's capacity for in-depth targeted analyses to date, the projects being pursued by these users suggest the Seattle-based company is progressing toward its goal of enabling proteome-scale experiments.

Nautilus' platform uses chips functionalized with DNA origami structures that allow researchers to deposit single proteins in extremely dense arrays, enabling single-molecule analysis of as many as 10 billion individual proteins. The company analyzes the arrayed proteins by iteratively staining the sample with semi-specific affinity agents and then using machine learning to make identifications of the individual proteins based on the patterns of affinity agent binding observed. Because the platform uses single-molecule technology, proteins are quantified simply by counting them following identification.

According to Nautilus, the company's approach could enable single-molecule analysis of the proteome at a depth and scale surpassing existing technologies like mass spectrometry. Some researchers specializing in mass spec-based proteomics have questioned these projections, however, and Nautilus' early timelines for the platform have proved overly optimistic. The company initially said it aimed to measure 2,500 proteins per run by early 2022, to measure up to 10,000 proteins per run by late 2022, and to analyze full proteomes by the middle of 2023. It missed the first two deadlines and does not appear to be on track to hit the third.

One major struggle Nautilus has faced in reaching proteome-scale experiments is obtaining the required affinity agents. The company has said it expects its machine learning approach will be able to identify greater than 95 percent of the human proteome with the binding data collected from around 300 cycles of probing. It inked deals with outside firms, including affinity reagent provider Abcam, to develop binding agents for the platform, but these arrangements have been less successful than hoped.

Perhaps due to these difficulties, most of the research collaborations Nautilus has publicized thus far have focused on deep analysis of a small number of proteins, an application where the company believes it will have an impact because of its ability to measure proteins at the single-molecule level and to distinguish between different protein variants, including forms altered by post-translational modifications and genetic mutations.

The recently announced batch of early-access users, on the other hand, are notable for their interest in using the platform for proteomic discovery purposes, which suggests that Nautilus is making progress toward broader analyses as it approaches a planned 2024 commercial launch.

The researchers will receive access to the Nautilus system as part of the company's "First Access Challenge," in which it solicited proposals from interested scientists and selected three groups.

Nicholas Graham, assistant professor of chemical engineering at the University of Southern California and one of the early-access users, said he plans to use the technology for discovery work in glioma. Specifically, he will look for proteins linked to the sensitivity of cancer cells to arginine deprivation.

"There are some clues in the literature about which proteins regulate [this sensitivity], but we suspect that there are many undiscovered regulators, and we are hoping that Nautilus' platform will help us identify them," he said.

Graham said his lab currently uses mass spec for this sort of discovery work but is interested in seeing if Nautilus' platform can help it identify proteins not typically seen in mass spec experiments, which, he noted, are "biased toward abundant proteotypic peptides."

"We are very interested to see how the proteins identified using Nautilus' platform compare to those we see by LC-MS," he said. "We hope [it] will increase the depth, specificity, and quantitative accuracy of our proteomic methods."

Joanna Bons and Jordan Burton, postdoctoral fellows in the lab of Buck Institute researcher Birgit Schilling, are likewise planning to use the platform for discovery work, in their case for characterizing proteomic changes linked to cisplatin-induced acute kidney injury.

Burton said that the lab has previously used mass spec to characterize proteomic changes caused by acute kidney injury due to ischemic reperfusion injury and are now looking to explore cisplatin-induced injury in mouse models using the Nautilus technology.

"We want to really deeply characterize these proteomes … and we think that with this platform, we will be able to get really deep insights into the proteomes of the mouse kidneys and this condition," Bons said.

Burton said the single-molecule nature of the platform was particularly appealing. "We're hoping that we see some overlap in our mass spectrometry data and the Nautilus data, but we are also hoping that we see some things that are different in the Nautilus data … because those [proteins that] we haven't been able to access via mass spectrometry could be incredibly important for the discovery of novel therapeutics for these diseases," he said.

The third group of early-access users, which comprises BYU researchers Samuel Payne and Pam Van Ry, plans to use the Nautilus system to characterize organoid models of pulmonary fibrosis developed in Van Ry's lab.

"We're just really excited to see the depth [of analysis] and what we can see from it," Payne said. "We're going to send organoids and sorted cell types from the organoids to try to get a comprehensive picture of what is happening."

Van Ry said the researchers are also hoping Nautilus' platform can provide a more in-depth, targeted look at several proteins where modifications and splice variants are thought to play a role in pulmonary fibrosis.

These early-access projects will provide an indication of where Nautilus' technology stands in terms of providing proteome-scale data. Parag Mallick, the company's cofounder and chief scientist, noted that "many of the questions that are being asked in these projects are really about sensitivity and dynamic range."

"One of the key strengths of the platform is scale, measuring billions of molecules," he said. "And each of these [projects] took advantage of that in a unique way."

All three projects will be characterizing proteins in cell samples, which is less challenging from a dynamic range perspective than plasma — a sample type mass spec has historically struggled with.

Mallick previously said that Nautilus has demonstrated the ability to affix up to 10 billion individual proteins to its chips using biological samples including cell lysates, which could in theory allow it to analyze proteomes across a dynamic range larger than is possible using current mass spec approaches. The company has yet to demonstrate — at least in any publicly published data — how the platform performs in actual discovery proteomics experiments, however.

In the meantime, Nautilus has made progress in expanding the scale of its platform's measurements. In November, Mallick said it was able to "routinely perform experiments involving many dozens" of iterative probing cycles, though this would leave it short of the roughly 300 cycles it projects are needed to hit nearly full proteome coverage.

Mallick said this week that Nautilus remains on track for a 2024 platform launch but declined to say how many affinity agents would be available for use at that time or what number of proteins it would be able to characterize.