We spoke to the organiser of our latest Interface Focus issue, Professor John Tyson at Virginia Polytechnic Institute and State University. He explains how living cells influence biological rhythms and make decisions. He also highlights why this topic is important to human health research, especially cancer biology.
Please can you briefly explain what you mean by time-keeping and decision-making in the context of cell biology?
Living cells are remarkably effective data-processing systems that receive information from outside and inside the cell, integrate concurring and conflicting signals, figure out an appropriate response, and implement the decision. Like your cell phone, a living cell processes information by means of ‘switches’ and ‘clocks’, but unlike electronic devices, the switches and clocks of a living cell are made up of thousands of protein molecules interacting by chemical reactions and diffusion in tiny volumes of the size of a single bacterium. Despite being knocked about by random fluctuations, these molecular control systems are amazingly successful about making the right decisions in the right places at the right times. How do they do it? This special issue considers the molecular mechanisms underlying some of the most interesting and important examples of time-keeping and decision-making in living cells. The contributions address each issue by powerful mathematical and computational methods without losing site of biological realities.
The issue is split into Parts I and II. How does the research covered in each part relate to the other one?
Part I focuses on biological rhythms; for example, the circadian clock that wakes you up each morning and brings on unshakable drowsiness during those interminable afternoon meetings. Other examples include cardiac pacemaker cells (which misbehave during atrial fibrillation), cell division cycles (which are out-of-control in tumours), and the inflammatory cycle (which may recur periodically in diseased states). Part II focuses on how cells make decisions. For example, in the egg chamber of a fruit fly, what mechanism selects one cell to become the ‘egg’ and the other 15 to become ‘nurse’ cells? How do cells of an embryo decide to become ectoderm or endoderm? Although clocks and switches are fundamentally different, they both regulate cellular processes, and their interactions are interesting and important. For example, stem cells in the dermis divide continuously to replenish the outer layers of the skin, but, if a stem cell’s DNA is damaged by sun light, a ‘decision’ must be made to stop the ‘clock’ and repair the damage or kill off the cell.
How can this issue inform our understanding of cancer biology?
‘Cancer’ is a spectrum of diseases in which normal controls over cell growth, division and differentiation are disrupted; the diseased cells reproduce uncontrollably, evade the immune system, attain the ability to move to other parts of the body, and eventually disrupt the function of some vital organ(s). Fundamentally, cancers’ roots lie in disastrous decisions made by growing, dividing, and differentiating cells. For example, unrepaired DNA damage induces mutations that make a cell unresponsive to anti-growth factors that normally restrain cell proliferation. Understanding how these decisions are normally made and then how they fail is central to a rational approach to cancer therapy.
Are there practical applications of the work in regards to health science and biotechnology?
In addition to cancer therapy, a better understanding of cell time-keeping and decision-making is crucial to many issues of human health: sleep disorders, developmental abnormalities, autoimmune diseases, cardiac arrhythmias, and metabolic disorders. In biotechnology, mathematical models of genetic switches help researchers to design artificial switching networks to control gene expression in organisms. For example, Michael Elowitz’s group at Caltech has recently described (Science 375:284, 2022) a flexible methodology for creating ‘synthetic multistable’ genetic control circuits in mammalian cells, using transcription factors that homodimerize to self-activate and heterodimerize to mutually inhibit one another. This technology is based on the ‘MISA’ motif (mutual-inhibition self-activation) that plays a major role in the contributions to Part II. Synthetic control systems, complemented by mathematical models, provide deep insights into cellular time-keeping and decision-making and routes to influence these processes for advancing human health and prosperity.
What are the future challenges and opportunities in this field?
At present, with their mathematical models and computer simulations, researchers are only scratching the surface of the complexity of the molecular regulatory networks that underlie cellular time-keeping and decision-making. In the near future, to gain better understanding and control of these networks, our modelling efforts must become more detailed, comprehensive and reliably predictive. These advances will require a highly educated, trans-disciplinary workforce; new methods of mathematical modelling, analysis and simulation; powerful computational facilities; experimental breakthroughs in quantitative data collection at the single-cell level in space and time; and extensive hardware and software for the curation and analysis of these data. The payoff is limitless, because we can hardly imagine today what implications a deep understanding of molecular and cellular control systems will have for future advances in human health care, agricultural productivity, and biotechnological innovations.
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Image credit: Microscape of Agate, by Professor Bernardo Cesare.