Dr Bruno Martins

Assistant Professor

Email: Bruno.Martins@warwick.ac.uk

Phone: 024 765 22937

Office: B125

Research Clusters

Quantitative, Systems & Engineering Biology (Cluster Co-Lead)

Cells & Development

Environment & Ecology

Vacancies and Opportunities

For PhD and postdoctoral opportunities, and interest in potential collaborations, please contact me at the above email address.

Research Interests

Many organisms, from simple bacteria to complex mammals, have an internal ‘circadian’ clock that helps regulate essential life processes on a 24-hour cycle. The circadian clock is a network of interacting genes and proteins, which in turn interact with other processes in cells to switch genes on or off. Our goal is to understand both how and why the clock works together with these other processes, such as the cell cycle, metabolism or stress responses. To do so, we study the simplest known clock, which is found in photosynthetic cyanobacteria. By studying this simple system, we can establish general principles that we can then apply to more complicated organisms.

To test our hypothesis, we combine mathematical modelling – to quantitatively validate our understanding – with cutting-edge experimental techniques, including live imaging and synthetic biology. Our approach provides high-resolution data on the behaviour of individual cells (rather than whole populations averaged together). Differences between individual cells are often crucial to distinguish between hypotheses. It is also important that this data is dynamic, as otherwise causality is difficult to determine.

Understanding how the clock drives, and is in turn driven by, other cell processes is also the first step towards developing the capabilities to control it. Such control could be relevant for future research in other organisms as well as for applications in biomedicine and synthetic biology.

Research: Technical Summary

Our lab applies quantitative approaches to study the design principles of regulatory circuits and cellular physiology. Circadian clocks are special circuits that integrate intra - and extracellular inputs to generate and synchronise 24-hour rhythms of gene expression in many organisms. Our present focus is on understanding how the circadian clock of single-celled cyanobacteria is embedded within the regulatory fabric of the cell.

The circadian clock of the cyanobacterium Synechococcus elongatus is one of the simplest known clocks, consisting of just a few interacting and well characterised proteins. By studying this simple system, we can establish the principles of how clocks and other cellular processes interact in different physiological and environmental contexts. We can ask fundamental questions that are hard to answer in more complicated organisms, but still very relevant to these other systems. For example, how do the clock and the cell cycle interact with one another to coordinate growth, chromosomal replication and segregation, and cell division? How is the clock modulated by intracellular energy states, as well as extracellular environmental changes? Can we use synthetic biology to control the oscillatory dynamics of the clock and design new circuits?

We believe the best way to understand natural circuits and to build new ones is through an iteration of experiment and theory. Our approach is therefore highly interdisciplinary, combining single-cell microscopy, synthetic biology, microfluidics and mathematical models.

Biography

Assistant Professor, University of Warwick, 2020-present
Postdoc (Locke lab), University of Cambridge, 2013-2020
PhD in Systems Biology, University of Edinburgh, 2013
Licenciatura (BSc) in Engineering Physics, University of Lisbon

Publications

Ye, Chao, Micklem, Chris N., Saez, Teresa, Das, Arijit K., Martins, Bruno M. C. and Locke, James C.W. (2024) The cyanobacterial circadian clock couples to pulsatile processes using pulse amplitude modulation. Current Biology, 34 (24). 5796-5803.e6. doi:10.1016/j.cub.2024.10.047 ISSN 0960-9822.

Schwall, Christian P., Loman, Torkel E, Martins, Bruno M. C., Cortijo, Sandra, Villava, Casandra, Kusmartsev, Vassili, Livesey, Toby, Saez, Teresa and Locke, James C. W. (2021) Tunable phenotypic variability through an autoregulatory alternative sigma factor circuit. Molecular Systems Biology, 17 (7). e9832. doi:10.15252/msb.20209832 ISSN 1744-4292.

Ho, Po-Yi, Martins, Bruno M. C. and Amir, Ariel (2020) A mechanistic model of the regulation of division timing by the circadian clock in cyanobacteria. Biophysical Journal, 118 (12). pp. 2905-2913. doi:10.1016/j.bpj.2020.04.038 ISSN 0006-3495.

Martins, Bruno M. C., Tooke, Amy K., Thomas, Philipp and Locke, James C. W. (2018) Cell size control driven by the circadian clock and environment in cyanobacteria. Proceedings of the National Academy of Sciences of the United States of America, 115 (48). E11415-E11424. doi:10.1073/pnas.1811309115 ISSN 0027-8424.

Mosheiff, Noga, Martins, Bruno M. C., Pearl-Mizrahi, Sivan, Grünberger, Alexander, Helfrich, Stefan, Mihalcescu, Irina, Kohlheyer, Dietrich, Locke, James C. W., Glass, Leon and Balaban, Nathalie Q. (2018) Inheritance of cell-cycle duration in the presence of periodic forcing. Physical Review X, 8 (2). 021035 . doi:10.1103/PhysRevX.8.021035 ISSN 2160-3308.

Martins, Bruno M. C., Das, Arijit K., Antunes, Liliana and Locke, James C. W. (2016) Frequency doubling in the cyanobacterial circadian clock. Molecular Systems Biology, 12 (12). 896. doi:10.15252/msb.20167087 ISSN 1744-4292.

Martins, Bruno M. C. and Locke, James C. W. (2015) Microbial individuality : how single-cell heterogeneity enables population level strategies. Current Opinion in Microbiology, 24 . pp. 104-112. doi:10.1016/j.mib.2015.01.003 ISSN 1369-5274.

Mac Gabhann, Feilim, Martins, Bruno M. C. and Swain, Peter S. (2013) Ultrasensitivity in posphorylation-dephosphorylation cycles with little substrate. PLoS Computational Biology, 9 (8). e1003175. doi:10.1371/journal.pcbi.1003175 ISSN 1553-7358.

van Nimwegen, Erik, Martins, Bruno M. C. and Swain, Peter S. (2011) Trade-offs and constraints in allosteric sensing. PLoS Computational Biology, 7 (11). e1002261. doi:10.1371/journal.pcbi.1002261 ISSN 1553-7358.

Research Projects

Title	Funder	Award start	Award end
Circadian regulation of cell division in cyanobacteria: mechanism and function	BBSRC	01 Aug 2021	28 Aug 2025

Teaching / Student Supervision

I am happy to receive enquires about PG Research projects in my group, please contact me at the above email address. At the moment I am offering the projects detailed below. You can apply to these through the MIBTP PhD Programme (deadline 16th January). Other sources of funding are available. Please get in touch with me to discuss.

The coupling between the circadian clock, metabolism and the environment: a systems’ approach

Secondary Supervisor(s):Professor Orkun Soyer(University of Warwick)

University of Registration:University of Warwick

BBSRC Research Themes:Understanding the Rules of Life (Microbiology)

Project Outline

The circadian clock is a gene circuit that generates 24-h cycles of gene expression in many organisms in anticipation of daily cycles of sunlight and temperature. In the cyanobacterium S. elongatus, which has the simplest clock we know of, most of the genome is under clock control. The cyanobacterial clock regulates many processes inside the cell, including metabolism, photosynthesis or the cell cycle. While the clock anticipates environmental change, it is also influenced by a variety of signalling cues. Light and temperature transitions reset the clock state, but the effect of these signals on clock proteins is relayed through more fundamental quantities, such as redox metabolites and ATP/ADP ratios. These cues can be said to characterise the global energy state of the cell, but on the other hand the clock controls expression of most photosynthetic and metabolic proteins. This dynamic and bi-directional coupling between the circadian clock and metabolism likely holds the key to understanding the evolutionary significance of clocks at the most fundamental level (1, 2).

General Aim and Methodology

The aim of this project is to characterise the cross-talk between the circadian clock and metabolism and understand how this cross-talk coordinates cellular growth and division under different environmental scenarios. Using fluorescent reporters, the joint dynamics of the clock and metabolic enzymes will be measured using time-lapse microscopy (3) and microfluidics for thousands of individual cells. Cellular energetics (e.g. ATP/ADP ratios) will be monitored through ratiometric fluorescent reporters. These measurements will provide a comprehensive timeline of physiological changes throughout the 24-h cycle and of how cells allocate metabolic resources to time growth, cell division and DNA replication, which will allow us to create an integrated model of the coupling between the clock and metabolism. We will test this model using a combination of genetic and environmental perturbations in microfluidic devices. These results will allow us to understand why clocks offer a selective advantage, and thus reveal a mechanistic ‘logic’ that can be applied to other systems.

References

A. M. Puszynska, E. K. O’Shea, Switching of metabolic programs in response to light availability is an essential function of the cyanobacterial circadian output pathway. eLife 6, e23210 (2017).

G. Pattanayak, M. J. Rust, The Cyanobacterial Clock and Metabolism. Curr Opin Microbiol 18, 90–95 (2014).

B. M. Martins, A. K. Das, L. Antunes, J. C. Locke, Frequency doubling in the cyanobacterial circadian clock. Molecular Systems Biology12, 896 (2016).

Techniques

Single-cell time-lapse microscopy and microfluidics.
Computational work including quantitative image analysis, time-series analysis, writing short routines for automated microscopy acquisition and possibly modelling (depending on the background and interests of the student).
Microbiology and molecular genetics.

A mathematical model of cell cycle regulation by the cyanobacterial clock: integrating quantitative data, machine learning and stochastic models

Secondary Supervisor(s):Professor Daniel Hebenstreit (University of Warwick)

University of Registration:University of Warwick

BBSRC Research Themes:Understanding the Rules of Life (Microbiology)

Project Outline

Circadian clocks are regulatory networks that generate 24-h rhythms in gene expression and other cellular processes in many organisms in anticipation of daily environmental cycles. The simplest and best characterised clock in nature is that of the cyanobacterium S. elongatus, which consists of only 3 proteins – KaiA, KaiB and KaiC – forming a post-translational loop. The cyanobacterial clock regulates many processes inside the cell, including metabolism, photosynthesis, cell growth and the cell division cycle. There is extensive evidence that the distribution of cell division times has modes at certain clock phases, with consequences for cell size and cell cycle homeostasis (1). While phenomenological models of this clock-cell cycle coupling have been proposed (2,3), a mechanistic understanding remains elusive. Clock modulation of the temporal and spatial dynamics of specific ‘cell division proteins’ is a likely mechanism. Homologous molecular mechanisms have been shown to rate limit cell size, hence cell division, in other bacteria and there is evidence of clock output signals regulating the divisome (4). The cell division cycle and the circadian clock are two ubiquitous intracellular oscillators exhibiting a degree of synchrony – yet not always cycling at the same frequency – across all circadian systems. A mechanistic model of this coupling is lacking. The well characterised cyanobacterial clock and the single-cell data our group has been obtaining offer us an opportunity to build the first model of this kind and reveal rules and principles that could apply to other organisms, including plant crops and humans.

General Aim and Methodology

This project will use a multidisciplinary approach combining integrating single-cell microscopy data with computational analysis (analysis of time-series, stochastic modelling, and machine learning and AI-driven approaches) to shed light on a complex biological system. The aim of this project is to clarify how the circadian clock regulates cell division by creating a data-driven, mechanistic model of clock-cell cycle coupling actions under various environmental conditions and genetic perturbations. We will take advantage of extensive pre-existing and new data generated in the lab, where the spatial and temporal dynamics of fluorescently tagged proteins can be measured at single-cell level. We will use information theory and machine learning/AI-based approaches to identify the key characteristics of cell physiology and protein dynamics that best predict the coupling between the clock and the cell division cycle. We will then use these lessons to build upon and improve on previous models of the circadian clock (5) and cell division (3). Our final objective is to build an integrative mechanistic model that explains the origin of correlations between clock state, protein expression and cell growth-division properties, and generates new predictions and hypotheses that could be tested under environmental and genetic perturbations. These results will allow us to understand how and why these two fundamental oscillators, the circadian clock and the cell cycle, are interlinked and thus reveal a mechanistic ‘logic’ that can be applied to other systems.

References

Yang Q, Pando BF, Dong G, Golden SS, van Oudenaarden A. Circadian Gating of the Cell Cycle Revealed in Single Cyanobacterial Cells. Science. 2010 Mar 19;327(5972):1522–6.

Martins BMC, Tooke AK, Thomas P, Locke JCW. Cell size control driven by the circadian clock and environment in cyanobacteria. Proc Natl Acad Sci. 2018 Nov 8;201811309.

Ho PY, Martins BMC, Amir A. A Mechanistic Model of the Regulation of Division Timing by the Circadian Clock in Cyanobacteria. Biophys J. 2020 Jun 16;118(12):2905–13.

Dong G, Yang Q, Wang Q, Kim YI, Wood T, Osteryoung KW, et al. Elevated ATPase Activity of KaiC Constitutes a Circadian Checkpoint of Cell Division in Synechococcus elongatus. Cell. 2010 Feb 19;140(4):529–39.

Paijmans J, Lubensky DK, Wolde PR ten. A thermodynamically consistent model of the post-translational Kai circadian clock. PLOS Comput Biol. 2017 Mar 15;13(3):e1005415.

Techniques

Quantitative image and time-series analysis.
Mathematical modelling and dynamical systems.
Information theory.
Machine learning and AI