“Pausing” biological time: its molecular mechanisms, biological functions, evolutionary origins, and implications in biomedicine

Much of the collective understanding on biological time control has historically shaped around the progression of time (e.g. on cell cycle, circadian clock, segmentation clock, and on). Considerably less effort is devoted to research on the suspension of biological time such as cellular arrest, quiescence, senescence, dormancy, and suspended animation. Unravelling the molecular circuits and metabolic sustenance programs that underlie these cellular states holds significant biomedical promise, as they are implicated in phenomena as diverse as aging (e.g. senescence), cancer progression (e.g. post-metastatic dormancy), stress adaptation (e.g. suspended animation), and shaping tissue architecture (e.g. the quiescence in polyploidy). Understanding how biological time can be “paused” will also open the doors for investigating how cells decide between progressing vs. suspending their biological time.

Metabolic licensing of animal development: an experimental model for understanding the choice of progressing versus suspending biological time

All animal embryos undergo cleavage cycles to achieve a critical cell mass before transitioning to morphogenesis: an irreversible developmental commitment that begins with gastrulation and leads to differentiation and organogenesis. Classic views on the molecular basis of this developmental commitment have emerged from mechanisms involved in chromatin remodeling and zygotic genome activation, which help establish downstream body patterning and axis-determination. As such, a paradigm centering on genetic cues from nuclei has been established for the morphogenetic licensing of development. Recent studies, however, paint a more complex picture for the upstream control of morphogenetic commitment, as they reveal an unexpected set of cytoplasmic products related to mitochondrial biology. Together with reports that oxygen depletion (i.e., anoxia) can suspend the early development of various animals, these hint at a pivotal role for oxygen metabolism in an organism’s ability to progress through or suspend its biological time. Yet, whether there is a bona fide metabolic program that license morphogenesis, and if so, how this is achieved chemically, remains unknown.

Our group has recently discovered in fruit flies that a mitochondrial redox switch licenses the onset of morphogenesis. With hydrogen peroxide at its chemical basis, we find that — like anoxia — both a wholesale and targeted depletion of mitochondrial oxidants can reversibly suspend development and do so only at the onset of morphogenesis, but not after. As we further reveal that this oxidant switch is in action at the onset of morphogenetic events in vertebrate embryos and Ichthyosporea (a close relative of animals), such broad evolutionary conservation promises to help us reveal potentially generalizable biochemical requirements that underlie the metabolic licensing of animal development. Since embryos enter into a reversible state of suspended animation when such requisites are not satisfied, the metabolic licensing of animal development provides us with an excellent experimental model to also investigate the molecular programs that underlie the suspension of biological time.

Research direction #1: What are the exact molecular and chemical mechanisms that determine whether an embryo proceeds with morphogenesis or enters suspended animation?

Research direction #2: What biological roles do oxidants play that make them so critical for deciding whether development proceeds or is suspended?

Research direction #3: What are the evolutionary and physiological implications of coupling oxygen availability and oxidant metabolism to developmental commitment?

Research direction #4: What adaptive metabolic and biochemical programs allow embryos to maintain viability in prolonged states of suspended animation?