AFM Nano-Robotic DNA Sequencing via Compressive Feedback
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Solution Overview
Problem
Current DNA sequencing technologies, particularly third-generation nanopore-based methods, face challenges such as high DNA strand passing speed, measurement noise, and the inability to control DNA movement speed, leading to inaccuracies and increased costs, especially in single-cell sequencing where rare cell populations' information is lost.
Innovation Solution
An Atomic Force Microscopy (AFM) based nano robotic system with a novel semantic compressive feedback control system and Generative Adversarial Tri-model (GAT) machine learning scheme for precise motion control and data analysis, allowing for sub-nanometer position measurement and multiple measurements without a liquid environment, improving accuracy and reducing sequencing costs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If nanopore-based sequencing is used, then long DNA strands can be sequenced without PCR amplification, but the DNA strand passing speed is high and cannot be controlled, leading to measurement inaccuracies
Solution Approach 1:
Instead of moving the DNA strand through a fixed nanopore (conventional approach), the patent inverts the approach by keeping the DNA strand stationary on a substrate and moving the sensing probe along the DNA. This allows precise control of the measurement process and multiple measurements at the same position, improving accuracy while maintaining sequencing capability.
Solution Approach 2:
The patent employs feedback control mechanisms to track and control the probe's movement along the DNA strand, ensuring accurate positioning for measurement. The system uses feedback from position detection to adjust and control the scanning speed and position, enabling precise measurement of electrical properties at each base position.
2Length of moving object
If nanopore-based sequencing is used, then long reads are achieved, but measurement noise increases and multiple measurements cannot be performed
Solution Approach 1:
The patent performs preliminary actions by establishing a controlled measurement environment where the DNA strand is fixed on a substrate before sequencing. This allows repeated measurements at the same position, enabling signal averaging and noise reduction while maintaining long read lengths.
Solution Approach 2:
The system enables continuous measurement along the DNA strand with the ability to return to previous positions for repeated measurements. This continuous scanning capability with pause-and-measure functionality allows multiple measurements at each position, improving signal accuracy without sacrificing read length.
3Measurement precision
If PCR-based sequencing is used, then base pair detection accuracy reaches 99.9%, but it is costly, time-consuming, and requires lots of samples
Solution Approach 1:
The patent extracts and eliminates the need for PCR amplification step from the sequencing process. By directly measuring electrical properties of DNA bases in their native state without amplification, the system achieves high accuracy while reducing cost, time, and sample requirements significantly.
Solution Approach 2:
The patent replaces the chemical PCR amplification mechanism with a direct physical measurement approach using electrical property detection. Instead of relying on enzymatic replication, the system uses electrical sensing to directly read base information, improving efficiency while maintaining accuracy.
4Measurement precision
If PCR-based sequencing is used, then high accuracy is achieved through amplification, but it cannot sequence single cells without losing rare cell subpopulation information
Solution Approach 1:
The patent extracts and eliminates the PCR amplification step that causes information loss. By measuring DNA bases directly in single cells without amplification, the system preserves all original information including rare cell subpopulations, achieving both high accuracy and complete information retention.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The system achieves sub-nanometer motion tracking accuracy, reduces sequencing costs, and enhances the speed and convenience of single-cell sequencing by eliminating feature extraction and calibration processes, enabling more reliable and efficient DNA sequencing.
Implementation Method 1
measures the current between the two base contact points
Implementation Method 2
The robot motion is controlled by a novel semantic compressive feedback control system capable of sub-nano meter motion tracking accuracy
Implementation Method 3
The measurement data is analyzed by a novel Generative Adversarial Tri-model (GAT) machining learning scheme in order to obtain the DNA sequence
Data Source
AI summary
A nano scale robotic system for single cell DNA sequencing of a strand of DNA positioned on a slide utilizes an atomic force microscope (AFM) having an end effector in the form of a cantilever with a tip. The AFM causes its cantilever tip to scan over the base pairs of the DNA strand. A pair of spaced-apart electrodes at the tip makes contact with opposite sides of the DNA strand and the current between bases of the DNA strand is measured by a current measurement system connected to the electrodes. An artificial intelligence-based data analytic system determines the DNA sequence based on the current from the current measuring system. The AFM tip is guided over the DNA strand by comparing compressed desired intensity local scan images and compressed actual intensity local scan images and using the difference to control the location of the tip.