Document Type

Article

Publication Date

8-20-2026

Comments

This article is the author’s final published version in American Journal of Pathology, Volume 96, Issue 9, 2026, Pages 1821-1836.

The published version is available at https://doi.org/10.1016/j.ajpath.2026.06.005. Copyright © 2026 The Author(s).

 

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.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

PubMed ID

42425304

Language

English

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