Abstract

ABSTRACTA single change in DNA, RNA, proteins or cellular images can be useful as a biomarker of disease onset or progression. With high-throughput molecular phenotyping of single cells, it is now conceivable that the molecular changes occurring across thousands, or tens of thousands, of individual cells could additionally be considered as a disease biomarker. Transition to a disease state would then be reflected by the shifts in cell numbers and locations across a multidimensional space that is defined by the molecular content of cells. Realising this ambition requires a robust formulation of such a multidimensional ‘cell space’. This is one of the goals of the recently launched Human Cell Atlas project. A second goal is to populate this ‘cell space’ with all cell types in the human body. Here, I consider the potential of the Human Cell Atlas project for improving our description and understanding of the cell-type specificity of disease.

Highlights

  • Can we attribute a disease to a cell type? If so, what molecular features of a cell type best predict a disease state? Could we pinpoint the origin of a disease both to a particular cell type and to a defined developmental time point? Answers to these questions will help to deliver on the promise of new therapies, those that target disease onset or progression, by taking advantage of the distinctive features of cell types

  • This would allow a specific cell type to be annotated across multiple species, and enable researchers to rank cell types by their ‘molecular drift’, the degree by which each cell type’s molecular features have changed since the species’ last common ancestor. These analyses could predict the degree by which a cell population in one species models the same population in another, a useful metric when justifying the use of models. In framing this discussion, I have avoided a previous description of the Human Cell Atlas as a periodic table for biology (Regev et al, 2017)

  • While the periodic table of chemical elements is useful in predicting reactions between multiple elements, we are not likely to use cell atlases to predict the details of multicellular function in the near future

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Summary

Introduction

Can we attribute a disease to a cell type? If so, what molecular features of a cell type best predict a disease state? Could we pinpoint the origin of a disease both to a particular cell type and to a defined developmental time point? Answers to these questions will help to deliver on the promise of new therapies, those that target disease onset or progression, by taking advantage of the distinctive features of cell types. Most of the heritability of traits and complex diseases can be explained by variants that only indirectly alter the functions of core diseaserelated genes (Boyle et al, 2017) This implies that, even with finely resolved cell-type data, explaining the molecular mechanisms underlying complex disease genetics will remain a substantial challenge. Diseases that originate at inaccessible developmental stages, for example, will not be informed by the Human Cell Atlas project because the samples are to be drawn predominantly from adult individuals. To address this shortcoming, organoids, which, by their nature, model organ development, could provide some insight. Comparison would take advantage of orthology relationships and could project cells of one species into the cell space of the other, or

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