Organisms must continuously transform molecules found in their environment in order to extract the energy and building blocks necessary for life. While the second law of thermodynamics establishes that energy loss (dissipation) is an unavoidable feature of any energy / matter conversion process, we don’t yet know how it constrains a living system like a cell. Basic questions remain unanswered: What fraction of environmental ‘input’ energy is available to drive living processes and what fraction is lost to dissipation? How does this partitioning of energy vary with the physiological state of a cell (e.g. maintenance vs growth)? How does it vary with environmental conditions? This grant provides support to a collaboration between Pablo Sartori, a Principal Investigator at the Gulbenkian Institute for Molecular Medicine (Lisbon, Portugal), and Shashi Thutupalli, a Professor at the National Center for Biological Sciences (Bangalore, India), to address these questions by developing a thermodynamic framework to describe the energy and matter transformations that drive a simple living machine (a cell); transformations that are implemented by a complex network of chemical reactions collectively known as cellular metabolism. Experiments and theory that focus on a single-cell organism (a yeast) will measure and model its uptake of energy / matter (food), as well as the fraction of this energy that’s exported as (heat or chemical entropy) disorder to the environment. Measurements will be made for a range of environmental conditions and for two physiological states of a unicellular fungus (S. cerevisiae): maintenance and growth.The team will conduct a series of experiments that can separately measure how dissipation is distributed between 1) heat exchanged between cells and their surroundings, 2) chemical (entropy) exchanges between cells and their surroundings (nutrients in, waste out), and 3) biomass growth (nutrients transformed into new cellular components). Experimentally disambiguating these three contributions to dissipation will allow the team to develop and test far-from-equilibrium thermodynamic models of the underlying physical and chemical processes. To this end, Sartori and Thutupalli will develop both macroscopic (phenomenological) thermodynamic models and microscopic models of metabolic networks. ?They then intend to demonstrate how the macroscale models arise from systematically coarse-graining (averaging) the microscopic metabolic models. A successful project will result in a validated, predictive thermodynamic model that links cellular metabolism and energy dissipation across a range of environmental and cell-physiological conditions.