Biochemical signaling networks are fundamental to all forms of life; they serve as the control system for cell operating processes, the cell cycle, gene expression, tissue formation, and many other aspects.

Abnormalities in biochemical signaling networks are signifiers of disease, causes of disease, and methods for treatment of disease (see for example Signalling Defects and Disease, Defects in Signaling Pathways Can Lead to Cancer and Other Diseases, Kinase-Disease Associations, among others). Examples include the full spectrum of Cancers, Alzheimer’s, Diabetes, Multiple Sclerosis, Tuberculosis, Hepatitis, eye and organ diseases (including heart, liver, kidney), Asthma, Epilepsy, Bipolar Disorder, Osteoporosis, Rheumatoid Arthritis, Schizophrenia, and many others.

There have been ongoing efforts to create small-scope highly-approximated computational models of portions of a few selected pathways of biochemical signaling networks. These have been interesting and illustrative, but there is an opportunity to make and use such computational models for importantly so very much more than appears to have been contemplated.

For almost two decades, long before current popularity and years before the contemporary Systems Biology community, NRI has self-funded its own R&D into next-generation methods and technologies for:

• Accurate measurement of rate constants in absolutely essential context of molecular
  crowding,
• More accurate large-scale nonlinear numerical computational frameworks that do not impose
  inaccuracies of forced linearization, equilibrium, S-models, non-temporal Boolean-logic
  simplifications, etc.
• Accurate complexity-simplification approximations for high-gain feedback and saturation
  conditions,
• Modeling the effects of allostery (varying large molecule conformation) on signaling,
• Merging and splitting of dynamical models,
• Signaling pathway cross-talk modeling,
• Powerful rich-feature interactive large-scale model execution environments,
• SBML exchange of enhanced signaling, metabolic, and genomic models,
• Additional technologies, proposed protocols, approaches, tools, applications, and
  industrial opportunities that at this writing remain proprietary.

NRI feels its evolving work in this area has become extremely valuable and is seeking funding to considerably expand the pace, scope, disclosure, and productization of this work.

A select few aspects of NRI’s work in these areas are represented in the patent assets listed below.

Issued Patents

Title	Patent Number	Application Number	Priority Dates	PDF	Text Only	Related Patents
Computer System and Microfluidic Instrumentation for Next-Generation Biological Signaling Network Research and Applications	9,646,133	13/157,304	06/09/2010	PDF	Text	Biochemical Signaling Network Modeling and Instrumentation
Nonlinear and Lie Algebra Structural Analysis System for Enzyme Cascades, Metabolic Signal Transduction, Signaling Pathways, Catalytic Chemical Reaction Networks, and Immunology	8,660,823	12/767,794	04/26/2009	PDF	Text	Biochemical Signaling Network Modeling and Instrumentation

Pending Published Applications

Title	Publication Number	Application Number	Priority Dates	Publish Date	PDF	Text Only	Related Patents
Computer system and microfluidic instrumentation for next-generation biological signaling network research and drug discovery	2017/0235872	15/586,166	05/03/2017		PDF	Text	Biochemical Signaling Network Modeling and Instrumentation
Stepwise and Blockwise Biochemical Network Laboratory Breadboard Systems and Techniques for Signaling, Disease Research, Drug Discovery, Cell Biology, and Other Applications	2019/0025297	14/485,791	03/15/2013		PDF	Text	Biochemical Signaling Network Modeling and Instrumentation
Modular Biochemical Signaling Laboratory Breadboard for Disease Research, Drug Discovery, Cell Biology, and Other Applications	2014/0273045	14/216,420	03/15/2013	09/18/14	PDF	Text	Biochemical Signaling Network Modeling and Instrumentation
Split, Break, Substitute, and Fragment-Splice Operations for Computer Models of Enzyme Cascades, Metabolic Signal Transduction, Signaling Pathways, Catalytic Chemical Reaction Networks, and Immunology	2014/0129196	14/150,010	04/26/2009	05/08/14	PDF	Text	Biochemical Signaling Network Modeling and Instrumentation

Pending Unpublished Applications

Title	Application Number	Priority Dates	Related Patents
Systems and Methods for Combining Machine Intelligence and NextGeneration Computational Biochemical Network Dynamical Models	16/853,736	04/19/2019	Biochemical Signaling Network Modeling and Instrumentation
Rate-Constant Invariance Simplifications for Analysis Systems of Biochemical Signaling Networks, Metabolic Networks, Catalytic Chemical Reaction Networks, and Immunology	13/957,370	08/01/2012	Biochemical Signaling Network Modeling and Instrumentation