The body is filled with organ systems that generate spontaneous, rhythmic behaviours, such as the regular electrical excitation that causes the beating of the heart, neuronal firing in the brain leading to generation of thoughts and actions, phasic contractions of the gut to allow for digestion or timed contractions of the myometrium to accommodate a growing fetus. These patterns of activity are often well co-ordinated, and disruptions in their regularity or frequency (or ‘pace’) can lead to arrhythmias, seizures, dysmotility or preterm labour. Many of these rhythmic processes occur without our conscious knowledge, thus begging the question: who is setting the pace? This is especially challenging to answer in physiological systems consisting of complex, multicellular populations. Are there ‘pacemaker’ cells that act as conductors to an orchestra (i.e. do not play music themselves but cue other cells to perfectly co-ordinate performances)? Do some pacemaker cells act like drummers in a band (that is, set the beat and tempo for a group of musicians performing the music)? Or is some pacemaking an emergent property of a seemingly uncoordinated group of cells getting together and jamming (thus there being no real ‘pacemaker’ but rather synchronicity across players emerging from the summation of asynchronous performances)? This special issue of The Journal of Physiology consists of a collection of invited topical reviews from experts in the field of pacemaking across a diverse range of cell types and physiological systems, including the heart, nervous system, gastrointestinal (GI) and urinary systems, male and female reproductive tracts, exocrine organs such as the pancreas and salivary glands and the kidneys and lymphatics. This is timely as the field of pacemaking and rhythmicity continues to evolve at a rapid pace, due to recent advances in optogenetics and cell-specific genetic manipulation, which are making monitoring and targeting of specific pacemaker cell populations within intact tissues possible. The special issue opens with a general review for the non-expert on one of the most studied and simultaneously most vigorously contested areas of pacemaking in physiology: the origin of cardiac automaticity in the sino-atrial node (SAN) of the heart. MacDonald and Quinn (2026) explain how the regular heartbeat, so vital to life, requires a redundant and robust pacemaker system, originating in cells of the SAN that provide rhythmic excitation to contracting cardiomyocytes. The paper describes a series of what have traditionally been termed ‘clocks’, proposed to explain the mechanisms by which regular SAN excitation comes about, with the ‘membrane clock’ (excitation driven by activation of transmembrane currents in SAN cells) and ‘calcium (Ca2+) clock’ (intracellular Ca2+ cycling) being the two most historically contested explanations for the origin of cardiac pacemaker activity. The authors also explain that a third clock – the ‘mechanics clock’ driven by the heart's exquisite mechano-sensitivity (Quinn instead pacemaker currents (that are still to be identified) depolarise cells to action potential threshold. The following article by Wray and Taggart (2026) details pacemaking in the female reproductive tract. Similar to other papers in the special issue, the authors highlight how investigations into the generation and co-ordination of rhythmicity in the female myometrium have been hampered by limitations in the experimental identification of specific pacemaker cell populations. Ultimately the authors conclude that – at least in human myometrium – there is no fixed pacemaker cell or pacemaker region but rather spatially transient initiation sites of spontaneous activity. Regular phasic contractions of myometrium thus do not require a fixed pacemaker, with co-ordinated activity instead emerging from seemingly discrete areas of uncoupled activity, similar to the emerging pacemaker phenomenon proposed for other organs. The final paper in the special issue from Xiong and Garfinkel (2026) asks a pointed question: ‘are physiological oscillations physiological?’ Their prospective comments indicate the fact that many homeostatic processes in physiology are the result of oscillatory behaviours, for instance, cyclical increases and decreases in glucose levels that regulate insulin secretion, oscillating concentrations of enzymes required for glycolysis, maintenance of circadian rhythms and the keeping of biological time. The review calls on readers to recognise that homeostasis is perhaps not achieved only by negative feedback bringing systems back to equilibrium setpoints but that more dynamic homeostatic paradigms exist, involving stable oscillatory patterns. The authors argue that an oscillatory-based model for physiological homeostasis provides built-in controls that protect systems from desensitisation and avoid chronic elevations of harmful byproducts, and that the use of non-linear dynamic mathematics may enable investigators to identify novel oscillatory behaviours in cells and tissues. Overall, the collection of papers in the special issue highlights the critical role that pacemaking plays in complex, multicellular organ systems across the body, while providing an overview of our current mechanistic understanding of pacemaker function, ultimately offering a valuable perspective on the gaps in our knowledge and opportunities for further research in the field. We would like to thank all the contributing authors for their thorough and timely work and hope this issue will inspire future discoveries to help determine who exactly is setting the pace. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None. B.T.D. and T.A.Q. wrote the paper and agree to be accountable for all aspects of the work in ensuring that questions related to any part of its accuracy or integrity are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. This work was funded by the Irish Higher Education Authority Technological University Transformation Fund TUTFY2144 (to B.T.D.), the Canadian Institutes of Health Research (PJT-190009 to T.A.Q.), the Natural Sciences and Engineering Research Council of Canada (RGPIN-2022-03150 to T.A.Q.) and the Heart and Stroke Foundation of Canada (G-22-0032127 to T.A.Q.).
Drumm et al. (Sat,) studied this question.