Concept

In cells, proteins do the lionshare of the signaling, regulating, and metabolizing. Put another way, almost everything that cells do are by virtue of a complex synchrony of proteins. Recently methods for sequencing proteins have improved through methods developments of different techniques. New technologies here have higher potential than those for DNA/RNA sequencing because proteins are the application layer to DNA/RNA’s transmission. This means that proteins are inherently more valuable to understand. Below is a brief investigation of the technology.

Longer Description

Current protein sequencing technologies, including mass spectrometry (fragmenting and ionizing proteins then extrapolating size from how quickly they move in air) and Edman degradation (sequential removal of amino acids which are identified post-removal), are limited by low sensitivity, high costs, and technical challenges with low-abundance proteins and complex post-translational modifications (PTMs).

New single-molecule protein sequencing (SMPS) platforms bypass these limitations by offering high-throughput, real-time analysis of individual protein molecules. Put simply, new methods can, in a more parallelized manner look at individual amino acids to be able to more deeply understand proteins and in some cases their associated modifications (post-translational modifications).

These approaches manifest as fluoro-sequencing, nanopore sequencing, and (non-commercialized) quantum tunneling which propose higher sensitivity, digital quantification, and PTM detection. Not only this but, projecting these methods into the future pave the way to single-cell proteomics.

Key components of the most advanced systems include:

1. Fluorescence-based methods: Fluorescent labeling of specific amino acids combined with Edman degradation enables the identification of amino acid sequences with high precision.
2. Nanopore technology: By threading proteins through nanopores, individual amino acids and PTMs can be detected based on electrical signals. This method also promises label-free sequencing of full-length proteins.
3. Reverse translation: of protein sequence information into a DNA (Encodia).
4. Quantum tunneling: Detecting proteins by measuring the tunneling current through protein molecules, which offers real-time, label-free identification.

Considerations for venture businesses building here:

• Switching costs: Despite the promise of SMPS, mass spectrometry remains dominant in proteomics. Widespread adoption will depend on demonstrating superior cost-effectiveness and throughput. Might be a longer lag time depending on the hardware cost which make us more bullish on nanopore-based methods.
• Talent constraints: Like other burgeoning technology landscapes the vast majority of new-age sequencing knowledge is from 10 labs so extra important to capture talent from these as the industry starts to mature.

Other thoughts

• Business Model: Companies should consider if they will focus solely on sequencing technology (selling to labs and biotech firms) or if they will develop a vertically integrated platform that includes data analysis and application-specific solutions, such as diagnostics. Proteins are such a valuable modality that it bucks my normal intuition to go vertical.

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