Overflow metabolism refers to the seemingly wasteful strategy in which cells use fermentation instead of the more efficient respiration to generate energy, despite the availability of oxygen. Known as Warburg effect in the context of cancer growth, this phenomenon occurs ubiquitously for fast growing cells, including bacteria, fungi, and mammalian cells, but its origin has remained mysterious despite decades of research. Here we study metabolic overflow in E. coli and show that it is a global physiological response used to cope with changing proteomic demands of energy biogenesis and biomass synthesis under different growth conditions. A simple model of proteomic resource allocation can quantitatively account for all of the observed behaviors and accurately predict responses to novel perturbations. The key hypothesis of the model, that the proteome cost of energy biogenesis by respiration exceeds that by fermentation, is quantitatively confirmed by direct measurement of protein abundances via quantitative mass spectrometry.

A central aim of cell biology was to understand the strategy of gene expression in response to the environment. Here, we study gene expression response to metabolic challenges in exponentially growing Escherichia coli using mass spectrometry. Despite enormous complexity in the details of the underlying regulatory network, we find that the proteome partitions into several coarse-grained sectors, with each sector's total mass abundance exhibiting positive or negative linear relations with the growth rate. The growth rate-dependent components of the proteome fractions comprise about half of the proteome by mass, and their mutual dependencies can be characterized by a simple flux model involving only two effective parameters. The success and apparent generality of this model arises from tight coordination between proteome partition and metabolism, suggesting a principle for resource allocation in proteome economy of the cell. This strategy of global gene regulation should serve as a basis for future studies on gene expression and constructing synthetic biological circuits. Coarse graining may be an effective approach to derive predictive phenomenological models for other ‘omics’ studies.

During the formation of tissues, cells organize collectively by cell division and apoptosis. The multicellular dynamics of such systems is influenced by mechanical conditions and can give rise to cell rearrangements and movements. We develop a continuum description of tissue dynamics, which describes the stress distribution and the cell flow field on large scales. In the absence of division and apoptosis, we consider the tissue to behave as an elastic solid. Cell division and apoptosis introduce stress sources that, in general, are anisotropic. By combining cell number balance with dynamic equations for the stress source, we show that the tissue effectively behaves as a viscoelastic fluid with a relaxation time set by the rates of division and apoptosis. If the system is confined in a fixed volume, it reaches a homeostatic state in which division and apoptosis balance. In this state, cells undergo a diffusive random motion driven by the stochasticity of division and apoptosis. We calculate the expression for the effective diffusion coefficient as a function of the tissue parameters and compare our results concerning both diffusion and viscosity to simulations of multicellular systems using dissipative particle dynamics.active fluids | fluctuations | growth processes | source stress M any biological processes, such as organ development or cancerous tumor growth, involve the remodeling of tissues by cell division and cell death or apoptosis. For many years, emphasis has been put on the regulation of growth by signaling pathways such as growth factors and its genetic control (1, 2). Recently, however, the importance of the mechanical properties of tissues has been realized (3-7). It has been shown, for example, that during the development of the fruit fly Drosophila, the expression of some of the essential genes can be strongly modified by the application of external forces that change the local mechanical stresses acting on the cells in the growing organism (8). At certain stages of development, such as gastrulation, the spatial distribution of mechanical stresses also seems to play a role in controlling the pattern of gene expression (9). Quite similarly, in tumor progression, gene expression is related to the stress distribution in the tumor (7,10).The rates of cell division and cell death depend on many biological parameters, but they also depend on the local cell density or pressure in the tumor. It has recently been argued that the tissue pressure at which cell death exactly compensates cell division is an important parameter that could be related to the invasiveness of a tumor in a host tissue (11). Such a pressure has been called homeostatic pressure, and the corresponding tissue steady state, the homeostatic state. This pressure is defined as the isotropic part of the stress acting on cells directly and is not related in any simple way to the hydrostatic pressure.From a mechanical point of view, a tissue is a complex system where the growth due to cell division and cell death interferes with the elastic de...