Rethinking cell growth models

Abstract

The minimal description of a growing cell consists of self-replicating ribosomes translating the cellular proteome. While neglecting all other cellular components, this model provides key insights into the control and limitations of growth rate. It shows, for example, that growth rate is maximized when ribosomes work at full capacity, explains the linear relation between growth rate and the ribosome fraction of the proteome and defines the maximal possible growth rate. This ribosome-centered model also highlights the challenge of coordinating cell growth with related processes such as cell division or nutrient production. Coordination is promoted when ribosomes don't translate at maximal capacity, as it allows escaping strict exponential growth. Recent data support the notion that multiple cellular processes limit growth. In particular, increasing transcriptional demand may be as deleterious as increasing translational demand, depending on growth conditions. Consistent with the idea of trade-off, cells may forgo maximal growth to enable more efficient interprocess coordination and faster adaptation to changing conditions.

Size control in mammalian cells involves modulation of both growth rate and cell cycle duration

“…A possible interpretation of this observation is that the average exponential (or faster than linear) growth is the result of multiple compensatory processes. The factors that could modulate growth rate at the single-cell level in a sizedependent manner are to date unknown and could involve, as recently hypothesized, the limitations of protein synthesis rate for large cell sizes (M. Kafri et al 2016), nonlinear metabolic scaling with cell size (Miettinen & Bjorklund 2016) or physical constraints on volume growth via the addition of surface area (Glazier 2014), or dynamic changes in cell/substrate adhesion, cell spreading and cortical tension.…”

Principles of cellular resource allocation revealed by condition-dependent proteome profiling

“…To interpret the observed scaling relation between ribosome content and growth rate, we used the growth-law connecting the specific growth rate  with the proteome fraction r a encoding ribosomes that are actively translating at any given time:   r a . Here,  denotes the rate of translating a ribosome (Kafri et al, 2016a;Maaløe, 1979;Scott et al, 2010). Written differently, this growth-law predicts the linear scaling we observe, with r =    r 0 where r is the ribosomal fraction, and r 0 =r-r a , being the proteome fraction encoding ribosomes that are not actively translating at any given time.…”

“…Ribosomes are the major resource consuming process in cells. Theoretical concepts developed over the past decades demonstrated that growth rate is maximized when all expressed ribosomes are fully employed in translation (Bosdriesz et al, 2015;Dekel and Alon, 2005;Kafri et al, 2016a;Keren et al, 2013;Klumpp et al, 2013;Koch, 1988;Li et al, 2014;Maaløe, 1979;Scott et al, 2014;Scott and Hwa, 2011;Scott et al, 2010;Shah et al, 2013;Vind et al, 1993). Under these conditions, ribosome content dictates growth rate: the specific growth is defined by the fraction of proteome which codes for ribosomal-associated proteins.…”

A bacterial growth law out of steady-state

“…For example, the proteome fraction for carbon utilization, , is a decreasing linear function of growth rate, and + is approximately constant across growth rates on limiting carbon. These laws generated vigorous research (Bosdriesz et al, 2015;Giordano et al, 2016;Kafri et al, 2016;Maitra and Dill, 2015;Pavlov and Ehrenberg, 2013;Towbin et al, 2017;Weiße et al, 2015), with mathematical models that explain phenomena such as dependence of cellular content on antibiotics (Scott et al, 2014) and the switch between carbon utilization strategies Mori et al, 2017a).…”