What’s Luck Got to Do with It: Single Cells, Multiple Fates, and Biological Nondeterminism

Abstract

The field of single cell biology has morphed from a philosophical digression at its inception to a playground for quantitative biologists, to a major area of biomedical research. The last several years have witnessed an explosion of new technologies, allowing us to apply ever more of the modern molecular biology toolkit to single cells. Conceptual progress, however, has been comparatively slow. Here, we provide a framework for classifying both the origins of the differences between individual cells and the consequences of those differences. We discuss how the concept of “random” differences is context dependent, and propose that rigorous definitions of inputs and outputs may bring clarity to the discussion. We also categorize ways in which probabilistic behavior may influence cellular function, highlighting studies that point to exciting future directions in the field.

Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance

“…Resistance can result from a secondary mutations 3,4 , but other times there is no clear genetic cause, raising the possibility of non-genetic rare cell variability 5–11 . Here, we show that melanoma cells can display profound transcriptional variability at the single cell level that predicts which cells will ultimately resist drug treatment.…”

Single-Cell Virology: On-Chip Investigation of Viral Infection Dynamics

“…The era of biology at the single-cell level is underway (Gawad et al, 2016; Heath et al, 2016; Kolodziejczyk et al, 2015; Saadatpour et al, 2015; Symmons and Raj, 2016). Most studies have relied on some physical method of separation to isolate single cells followed by interrogation of individual cells for some property: RNA, protein, etc.…”

Mammalian gene expression variability is explained by underlying cell state

“…Similarly, single‐cell organisms and viruses were shown to utilize heterogeneity at the population level to create diverse phenotypes, such as bet‐hedging strategies in changing environments (Veening et al , ; Vega & Gore, ; Rouzine et al , ). While variability can provide useful functional heterogeneity in a multicellular organism or cell population, it is not necessarily always beneficial (Raj & van Oudenaarden, ; Symmons & Raj, ). Unregulated stochastic events, i.e., noise, can limit cells' ability to respond accurately to changing environments and can introduce phenotypic variability that can have a negative contribution to overall fitness.…”