Cell Ion Channel Parameter Inference From Voltage Readings
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Solution Overview
Problem
Current methods are inadequate for identifying genetic mutations in ion channels that affect electrical activity in cells, particularly in neurological diseases like Alzheimer's and brain cancer, as they lack a direct assay to link electrical function to underlying genetic mutations, and ethical considerations prevent electrophysiology on human brains, necessitating a single-shot assay for ion channel inference.
Innovation Solution
A computer-implemented method using recursive piecewise data assimilation to optimize a state vector based on membrane voltage readings, iteratively adjusting the membrane voltage variable to corresponding readings, and applying constrained non-linear optimization to determine biological parameters of ion channels, ensuring a unique and accurate estimation of ion channel conductances and other parameters.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If genetic sequencing is used to identify ion channel mutations, then gene mutations can be detected, but the method cannot determine how these mutations affect electrical function
Solution Approach 1:
The patent introduces electrophysiological measurements as an intermediary to bridge the gap between genetic sequencing and functional impact. By measuring electrical properties (membrane voltage, action potential waveforms) in cells expressing the gene of interest, the method translates genetic information into functional data, revealing how mutations affect ion channel behavior without requiring direct observation of the mutated protein.
Solution Approach 2:
The patent replaces direct structural analysis of ion channels with electrical measurement techniques. Instead of attempting to visually or structurally analyze the mutated protein, the method substitutes electrical property measurements (conductance, voltage thresholds, action potential characteristics) as proxies for functional assessment, enabling indirect but accurate determination of mutation effects.
2Loss of information
If patch-sequencing methods are used to correlate gene mutations to morphological characteristics, then qualitative correlation is achieved, but the method is time-consuming and lacks quantitative precision
Solution Approach 1:
The patent replaces time-consuming morphological analysis with rapid electrical measurement techniques. By using patch-clamp electrophysiology to directly measure ion channel conductance and electrical properties, the method achieves quantitative assessment of mutation effects without requiring extensive time for morphological characterization or complex image analysis.
Solution Approach 2:
The patent shifts the measurement focus from static morphological parameters to dynamic electrical parameters. By measuring conductance, voltage thresholds, action potential duration, and other electrophysiological properties, the method obtains quantitative data that directly reflects functional impact, enabling faster and more precise mutation characterization.
3Measurement precision
If voltage clamps are used to study ion channels, then electrical function can be measured, but the method requires multiple pharmacological manipulations and is very time consuming when the affected ion channel is unknown
Solution Approach 1:
The patent employs cells expressing the gene of interest as their own control system. The cells naturally express the ion channel(s) being studied, eliminating the need for external pharmacological manipulations to activate or inhibit specific channels. This self-expressing system allows direct measurement of the target ion channel's electrical properties without time-consuming drug application and withdrawal protocols.
Solution Approach 2:
The patent isolates and measures specific ion channel properties through targeted electrophysiological protocols. By using selective ion channel blockers or activators in a systematic manner, and by analyzing specific electrical parameters (resting membrane potential, action potential characteristics, conductance steps), the method segments the complex electrical behavior into measurable components, reducing the need for multiple sequential pharmacological manipulations.
4Measurement precision
If electrophysiology is performed on healthy human brain cells, then direct functional data would be obtainable, but ethical considerations and paucity of samples prevent this
Solution Approach 1:
The patent creates functional copies of human brain cells through induced pluripotent stem cell (iPSC) technology. By reprogramming somatic cells from patients into iPSCs and differentiating them into neuronal cells, the method generates ethically acceptable cell models that replicate human neuronal function. These copies can be studied in detail without violating ethical constraints, while maintaining relevance to human biology.
Solution Approach 2:
The patent introduces iPSC-derived neurons as an intermediary system between patient samples and ethical research constraints. These intermediary cells preserve the genetic and functional characteristics of human neurons while providing an ethically permissible platform for study. The intermediary model allows functional assessment of ion channels in a controlled laboratory setting without requiring direct manipulation of human brain tissue.
Data Source
AI summary
The disclosure relates to a computer-implemented method for determining values of biological parameters of a cell, comprising: receiving membrane voltage readings of the cell corresponding to N time points; for a state vector comprising the biological parameters and a plurality of interdependent and time-dependent state variables, including a membrane voltage variable: setting an initial guess of the state vector and parameters; performing an optimization of the state vector by: setting the membrane voltage variable to be equal to a corresponding membrane voltage reading at a number of time points within the N time points; determining an updated value of the state vector by optimizing an objective function that operates on values of the membrane voltage variable and corresponding membrane voltage readings; and repeating the optimization with: the initial estimate of the state vector set to the updated value of the state vector; and the membrane voltage variable set to be equal to a corresponding membrane voltage reading at fewer time points within the N time points.