Far-Red Light Activated Chimeric Receptor Tyrosine Kinase

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Solution Overview

Problem

Current optically controllable receptor tyrosine kinases (RTKs) are activated by visible light, which poorly penetrates animal tissues, necessitating invasive methods for deep-tissue light control and gene transcription regulation.

Innovation Solution

Development of a chimeric polypeptide comprising an extracellular light-responsive polypeptide, a transmembrane domain, and an intracellular domain of a receptor tyrosine kinase, where the light-responsive polypeptide, when associated with a chromophore, switches states upon far-red light illumination, activating the intracellular domain.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If visible light is used to activate optically-controlled RTKs, then the RTKs can be activated with light, but the light poorly penetrates animal tissues requiring implantation of optical fibers and tethering animals

Engineering Contradiction:

ImproveRTK activationVSAvoidinvasive procedures

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent changes the wavelength parameter of light from visible range to far-red range (650-780 nm), which has superior tissue penetration properties. This parameter change allows non-invasive deep-tissue light control while maintaining RTK activation capability, resolving the contradiction between reliable activation and ease of operation.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces a bacterial phytochrome (DrBphP) as an intermediary light-responsive polypeptide that mediates far-red light detection and transmembrane signal transmission. This intermediary enables the use of far-red light (which penetrates tissue well) to control RTKs, eliminating the need for invasive optical fiber implantation while maintaining reliable activation.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Illumination intensity

If cyanobacterial phytochrome Cph1 is used for far-red light control, then far-red light control is achieved, but the chromophore PCB is not naturally present in mammalian cells and needs exogenous supply

Engineering Contradiction:

Improvefar-red light controlVSAvoidexogenous chromophore supply

Core Design Contradiction:

Illumination intensityVSDevice complexity

Solution Approach 1:

The patent uses Deinococcus radiodurans bacteriophytochrome (DrBphP) which utilizes biliverdin as its chromophore. Biliverdin is a natural endogenous molecule in mammalian cells that serves as a heme degradation product. This self-service approach eliminates the need for exogenous chromophore supply while maintaining far-red light control capability.

Inventive Principle:

Principle #25Self-service

Solution Approach 2:

The patent achieves homogeneity by using a chromophore (biliverdin) that is naturally present in mammalian cells, eliminating the heterogeneity introduced by exogenous chromophore supply. This makes the system more suitable for in vivo applications where consistent, maintenance-free operation is required.

Inventive Principle:

Principle #33Homogeneity

3Reliability

If diffusible ligands are used to activate RTKs, then RTK activation is achieved, but non-targeted action leads to undesirable effects and diminishing efficiency

Engineering Contradiction:

ImproveRTK activationVSAvoidnon-targeted action

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent replaces the chemical diffusion mechanism (ligands moving through tissue) with an optical mechanism (far-red light activation). This substitution allows spatially and temporally precise control of RTK activation only in targeted cells, eliminating the non-targeted effects associated with diffusible ligands while maintaining reliable activation.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

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

Enables non-invasive, spatially and temporally precise control of RTK activity with far-red light, allowing for reversible modulation of downstream signaling and potential applications in therapy and research.

Implementation Method 1

the light-responsive polypeptide, when associated with a chromophore, is capable of switching from a first state to a second state when exposed to illumination by a wavelength

Methodology Applied

Scientific EffectPhotoisomerization: Photochromism

Data Source

PatentUS20250051398A1Fusion constructs optically controllable by far red light and methods of use thereof

Publication Date: 2025.02.13 UNIVERSITY OF HELSINKI

AI summary

This disclosure provides a generalized approach for engineering receptor tyrosine kinases (RTKs) optically controlled with far-red light, named eDrRTKs, by targeting a bacterial phytochrome (e.g., DrBphP) to the cell surface and allowing its light-induced conformational changes to be transmitted across the plasma membrane via transmembrane helices to intracellular RTK domains. The ability to activate eDrRTKs with far-red light enabled cross-talk free spectral multiplexing with fluorescent probes operating in a shorter spectral range, allowing for all-optical assays, including non-invasive stimulation in the brain of a live animal. The disclosed engineering approach can be applied beyond RTKs to any membrane receptors, channels, surface antigens, or membrane antibodies that share high similarity with RTKs in mechanisms of their activation.