Cells and Networks in Flux: Rethinking Ontogenesis and Pathogenesis.

Publication/Presentation Date

9-1-2026

Abstract

Organ and tissue functions emerge from the coordinated activity of cell networks. Therapeutics that act on pathogenic cell networks, modulating their cellular interplay, follow naturally. Over several decades, our laboratory has developed a series of approaches for rewiring cell networks, culminating in a class of cell surface-directed signal converter proteins (SCPs) that do so by modulating juxtacrine and autocrine signaling in and among their nodal cells. A first such SCP has now produced encouraging clinical data for cancer immunotherapy. Yet, these early network-directed fusion proteins rest on a deliberately simplified picture: discrete end-cell types plugged into graphically tractable networks. That picture is increasingly at odds with what computational cell typing and spatiotemporal analytics, along with epigenetics, now reveal-a hyperdiverse, plastic, experience-shaped cellular landscape embedded in dynamic, multiway networks. Setting the stage for a next generation of network modulators, an extended cell differentiation synthesis is proposed, which formalizes paracell ultradifferentiation and aging-associated differentiation phases. According to this model, cells are ever evolving, and no two cells are alike. A richer cellular ontology forces a more elaborate network ontology, with paralogous networks and their shifting subnetworks opening a concrete design space for next-generation network-directed SCP therapeutics. This exploration calls for a willingness to embrace complexity more fully and borrow freely from conceptual fields close and afar.

Volume

196

Issue

9

First Page

1821

Last Page

1836

ISSN

1525-2191

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

42425304

Department(s)

Administration and Leadership

Document Type

Article

Link to Full Text

Share

COinS