Illuminating pulses of living cells

NUS biological scientists have unravelled principles underlying pulsatile cell dynamics, a key step towards understanding biological networks.

Cortical oscillations are like the breathing cycles of the cells. A team of scientists led by Prof Min WU from the Department of Biological Sciences and Mechanobiology Institute, NUS used fluorescently labelled proteins to visualise periodic travelling waves in the membrane of leukaemia cells. Their research identified key elements of these pulses that can be used to tune the cellular rhythm like a dial.

Many biological functions rely on the establishment and maintenance of biochemical rhythms. Some examples include the cell cycle, which enables regular turnover of new cell growth. Many organisms, including humans, follow a 24-hour cycle of activity and rest based on circadian rhythms. On the cellular level, rhythmic oscillations in the cell membrane are linked with changes in cell shape, locomotion, and development. Based on mathematical principles, oscillations are generated from pulses of activity from an activator coupled with that of the inhibitor, and the inhibitor is essential for determining the spatio-temporal pattern of oscillation. Despite the ubiquitous presence of these oscillatory dynamics, mechanistic understanding of such phenomena, especially the molecular identities of the inhibitors, is largely lacking.

Using oscillations as readouts for the system and optogenetics to perturb the system, this work demonstrated the fundamental role of lipid metabolism in setting cortical oscillations, which represents a key step towards understanding both the components and the topology of the biological networks.

Aside from the importance of cortical pattern formation in regulating fundamental biological processes such as cell growth and migration, many of the key regulators of the process have immediate medical relevance. Lipid kinase PI3K p110δ is the most sought-after clinical PI3K target for blood cancer drug development. This study shows, for the first time, that its activity is encoded by the frequency of cortical oscillations. The inhibitors identified in the study, lipid phosphatases SHIP1 and synaptojanin 2, are also involved in the formation of leukaemia and other cancers. The model presented in the study in terms of amplitude and frequency-based information processing could be used as a novel blueprint for designing better therapeutic strategies.

Image shows the emergence of traveling waves in a single cell, visualized by a lipid biosensor for PIP3.

Image shows graduate students XIONG Ding (left) and XIAO Shengping (right), first and second author of the study, performing the imaging experiments.

Reference 

Xiong D; Xiao SP; Guo S; Lin QS; Nakatsu F; Wu M*, “Frequency and amplitude control of cortical oscillations by phosphoinositide waves” NATURE CHEMICAL BIOLOGY Volume: 12 Issue: 3 Pages: 159-166 DOI: 10.1038/NCHEMBIO.2000 Published: 2016