Cell types as species: Exploring a metaphor

Abstract

The concept of “cell type,” though fundamental to cell biology, is controversial. Cells have historically been classified into types based on morphology, physiology, or location. More recently, single cell transcriptomic studies have revealed fine-scale differences among cells with similar gross phenotypes. Transcriptomic snapshots of cells at various stages of differentiation, and of cells under different physiological conditions, have shown that in many cases variation is more continuous than discrete, raising questions about the relationship between cell type and cell state. Some researchers have rejected the notion of fixed types altogether. Throughout the history of discussions on cell type, cell biologists have compared the problem of defining cell type with the interminable and often contentious debate over the definition of arguably the most important concept in systematics and evolutionary biology, “species.” In the last decades, systematics, like cell biology, has been transformed by the increasing availability of molecular data, and the fine-grained resolution of genetic relationships have generated new ideas about how that variation should be classified. There are numerous parallels between the two fields that make exploration of the “cell types as species” metaphor timely. These parallels begin with philosophy, with discussion of both cell types and species as being either individuals, groups, or something in between (e.g., homeostatic property clusters). In each field there are various different types of lineages that form trees or networks that can (and in some cases do) provide criteria for grouping. Developing and refining models for evolutionary divergence of species and for cell type differentiation are parallel goals of the two fields. The goal of this essay is to highlight such parallels with the hope of inspiring biologists in both fields to look for new solutions to similar problems outside of their own field.

The evolving definition of plant cell type

“…Cell biologists find this concept useful to have a dynamic, inclusive, and multifaceted definition of cell type, where facets include cell origin and lineage history, function, morphology, location, interactions, and molecular features (including genetic variation, epigenome, transcriptome, posttranscriptional modifications, non-coding RNAome, proteome, post-translational modifications, metabolome, and cellular localization). As with defining species, implementation is difficult when traits are incongruent, and researchers prioritize them differently (Doyle, 2022).…”

“…Recently, Domcke and Shendure (2023) proposed an explicitly lineage-based definition of cell types and their relationships that they contend will serve cell biology better than transcriptional cell types organized into atlases. In looking for an organizing principle for cell types, they reject the transcriptomic approach as inherently phenetic and thus suffering from arbitrariness in defining entities, as is true in species biology (Doyle, 2022), as well as lacking an objective means of distinguishing state from type. However, they also reject the Arendt et al (2019) evolutionary approach as being impractical due to the divergence of cell types across highly diverse species and the difficulty of defining the CoRC.…”

“…We conclude that although the transcriptomic cell type concept (Zeng, 2022) is prevalent in the animal cell atlas community, the approach has recognized limitations. Thus, the debate over what constitutes a cell type in theory, and how to identify cell types in practice, is likely to continue for the foreseeable future, like the debate over species (Doyle, 2022).…”

“…Their answers varied widely; although most agreed that "cell type" was a critical concept, at least one felt that only cell states exist (Clevers et 2017). This diversity of opinions on how to fit natural variation into human-designed categories has been likened to the problem of defining "species" (reviewed by Doyle, 2022). How has that debate evolved, and what can plant scientists learn from it?…”