SPECIALSECTION
INTRODUCTION
THE SCIENTIFIC LITERATURE CONTAINS AN ENORMOUS BODY OF WORK IN WHICH large numbers of cells have been broken open and homogenized to prepare samples for biochemical characterization and, certainly, much has been learned from such studies. But more recently, it has become possible to monitor events in single cells, thus allowing investigators to test whether existing “averaged” readings of the state of many cells from traditional large-scale assays accurately represent the behavior of the individual cells being studied. Such single-cell measurements are providing a wealth of information—sometimes unanticipated and often previously obscured—about how cells respond to perturbations or signals. In this special issue, three Reviews provide examples of fundamental insights into cellular regulation that are revealed when it is possible to measure enzymatic activity, transcriptional responses, or the metabolic state in individual cells. An obvious advantage of single-cell measurements is the ability to measure variations or “noise” in the responses of the individual cells to similar or identical conditions. In many instances, it is possible to monitor the time course of cellular responses. Gene transcription can be particularly noisy, with bursts of RNA synthesis occurring in some cells but not others of the same population. Thus, fundamental questions arise about the nature of these systems. Perhaps variation in response is advantageous in conserving resources or in assuring that some cells survive in a changing environment. Or it may be that biophysical constraints of small numbers of molecules and the characteristics of the enzymes at work dictate such variability as unavoidable. Sanchez and Golding review recent work in model systems, from bacteria to animal cells, that attempts to resolve whether the kinetics of transcription are encoded in the architecture of promoter sequences in DNA—and might therefore vary throughout the genome—or are determined by physical or biophysical properties that would impose more global constraints throughout the cell. Levine et al. explore another previously hidden phenomenon. Continuous measurements of protein activation show that many undergo asynchronous pulsatile responses, which are obscured in average measurements from a population of cells. They discuss how cellular circuits are wired to produce such responses and what the advantages of such control systems might be. Zenobi highlights methodological advances, particularly in mass spectrometry, that are enabling quantitation of the abundance of molecular components of single cells. Challenges abound for the goal of making simultaneous measurements to characterize the rapidly changing metabolic state of individual cells. But the promise of new insights across a broad range of disciplines is sustaining a steady effort to tap into the large store of new knowledge lying hidden within the confines of single cells.
Downloaded from www.sciencemag.org on January 22, 2014
CREDIT: DINA FADDAH AND RUDOLF JAENISCH/THE WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH
Cells Go Solo Single-Cell Biology CONTENTS Reviews 1188
1193
1201
Genetic Determinants and Cellular Constraints in Noisy Gene Expression A. Sanchez and I. Golding Functional Roles of Pulsing in Genetic Circuits J. H. Levine et al. Single-Cell Metabolomics: Analytical and Biological Perspectives R. Zenobi
See also more cell biology in this issue: Research Articles on pages 1202 and 1203 and Podcast
– L. BRYAN RAY
www.sciencemag.org SCIENCE VOL 342 6 DECEMBER 2013 Published by AAAS
1187
INTRODUCTION
THE SCIENTIFIC LITERATURE CONTAINS AN ENORMOUS BODY OF WORK IN WHICH large numbers of cells have been broken open and homogenized to prepare samples for biochemical characterization and, certainly, much has been learned from such studies. But more recently, it has become possible to monitor events in single cells, thus allowing investigators to test whether existing “averaged” readings of the state of many cells from traditional large-scale assays accurately represent the behavior of the individual cells being studied. Such single-cell measurements are providing a wealth of information—sometimes unanticipated and often previously obscured—about how cells respond to perturbations or signals. In this special issue, three Reviews provide examples of fundamental insights into cellular regulation that are revealed when it is possible to measure enzymatic activity, transcriptional responses, or the metabolic state in individual cells. An obvious advantage of single-cell measurements is the ability to measure variations or “noise” in the responses of the individual cells to similar or identical conditions. In many instances, it is possible to monitor the time course of cellular responses. Gene transcription can be particularly noisy, with bursts of RNA synthesis occurring in some cells but not others of the same population. Thus, fundamental questions arise about the nature of these systems. Perhaps variation in response is advantageous in conserving resources or in assuring that some cells survive in a changing environment. Or it may be that biophysical constraints of small numbers of molecules and the characteristics of the enzymes at work dictate such variability as unavoidable. Sanchez and Golding review recent work in model systems, from bacteria to animal cells, that attempts to resolve whether the kinetics of transcription are encoded in the architecture of promoter sequences in DNA—and might therefore vary throughout the genome—or are determined by physical or biophysical properties that would impose more global constraints throughout the cell. Levine et al. explore another previously hidden phenomenon. Continuous measurements of protein activation show that many undergo asynchronous pulsatile responses, which are obscured in average measurements from a population of cells. They discuss how cellular circuits are wired to produce such responses and what the advantages of such control systems might be. Zenobi highlights methodological advances, particularly in mass spectrometry, that are enabling quantitation of the abundance of molecular components of single cells. Challenges abound for the goal of making simultaneous measurements to characterize the rapidly changing metabolic state of individual cells. But the promise of new insights across a broad range of disciplines is sustaining a steady effort to tap into the large store of new knowledge lying hidden within the confines of single cells.
Downloaded from www.sciencemag.org on January 22, 2014
CREDIT: DINA FADDAH AND RUDOLF JAENISCH/THE WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH
Cells Go Solo Single-Cell Biology CONTENTS Reviews 1188
1193
1201
Genetic Determinants and Cellular Constraints in Noisy Gene Expression A. Sanchez and I. Golding Functional Roles of Pulsing in Genetic Circuits J. H. Levine et al. Single-Cell Metabolomics: Analytical and Biological Perspectives R. Zenobi
See also more cell biology in this issue: Research Articles on pages 1202 and 1203 and Podcast
– L. BRYAN RAY
www.sciencemag.org SCIENCE VOL 342 6 DECEMBER 2013 Published by AAAS
1187
