470 | Nature | Vol 584 | 20 August 2020
Article
A universal trade-off between growth and
lag in fluctuating environments
Markus Basan1,2,6 ✉, Tomoya Honda3,6, Dimitris Christodoulou^2 , Manuel Hörl^2 ,
Yu-Fang Chang^1 , Emanuele Leoncini^1 , Avik Mukherjee^1 , Hiroyuki Okano^4 , Brian R. Taylor^4 ,
Josh M. Silverman^5 , Carlos Sanchez^1 , James R. Williamson^5 , Johan Paulsson^1 ,
Terence Hwa3,4 ✉ & Uwe Sauer^2 ✉The rate of cell growth is crucial for bacterial fitness and drives the allocation of
bacterial resources, affecting, for example, the expression levels of proteins
dedicated to metabolism and biosynthesis^1 ,^2. It is unclear, however, what ultimately
determines growth rates in different environmental conditions. Moreover, increasing
evidence suggests that other objectives are also important^3 –^7 , such as the rate of
physiological adaptation to changing environments^8 ,^9. A common challenge for cells
is that these objectives cannot be independently optimized, and maximizing one
often reduces another. Many such trade-offs have indeed been hypothesized on the
basis of qualitative correlative studies^8 –^11. Here we report a trade-off between
steady-state growth rate and physiological adaptability in Escherichia coli, observed
when a growing culture is abruptly shifted from a preferred carbon source such as
glucose to fermentation products such as acetate. These metabolic transitions,
common for enteric bacteria, are often accompanied by multi-hour lags before
growth resumes. Metabolomic analysis reveals that long lags result from the
depletion of key metabolites that follows the sudden reversal in the central carbon
flux owing to the imposed nutrient shifts. A model of sequential flux limitation not
only explains the observed trade-off between growth and adaptability, but also allows
quantitative predictions regarding the universal occurrence of such tradeoffs, based
on the opposing enzyme requirements of glycolysis versus gluconeogenesis. We
validate these predictions experimentally for many different nutrient shifts in E. coli,
as well as for other respiro-fermentative microorganisms, including Bacillus subtilis
and Saccharomyces cerevisiae.To study the interrelationship between the rate of cell growth and
the rate of physiological adaptation (the latter being character-
ized by the inverse of the ‘lag time’ defined in Fig. 1a), we shifted
wild-type E. coli (Supplementary Table 1) between two minimal
media, each containing a single carbon source. Defined postshift
conditions and very rapid environmental changes were imple-
mented as ‘complete shifts’ that ensured that no preshift carbon
source was available to cells in the postshift medium (Fig. 1b). We
first investigated shifts from different glycolytic carbon sources
to acetate, a gluconeogenic carbon source that requires fluxes
through glycolysis to reverse direction. Because acetate is the
primary fermentation product of many bacteria, including E. coli,
it is naturally available to these bacteria upon exhaustion of the
primary carbon source.
We quantified these shifts by lag time, defined as the integrated
time lost during the adaptation to new conditions compared with
an immediate response (Fig. 1a). We found that the shifts produced
extended lags of up to 10 h (Fig. 1c, circles), much longer than the
doubling times in preshift and postshift media (less than 2 h), and
often included periods without detectable biomass production that
lasted several hours (Extended Data Fig. 1a). A notable correlation
emerged between the growth rate in the preshift medium and the lag
time (Fig. 1c, circles): fast-growing cells took a long time to adjust to
the new medium, whereas slow-growing cells resumed growth much
more quickly. The same relation was obtained when the preshift growth
was varied by titrating the uptake rates of lactose as an example of a
glycolytic carbon source (Fig. 1c, squares), suggesting that the rela-
tion between preshift growth and lag time depends on the carbon
influx rate rather than on the specifics of the preshift carbon sources.
A similar pattern was found for population growth dynamics with
chemostat-controlled growth rates^12. The data in Fig. 1c show that lag
times (Tlag) increased with increasing preshift growth rate (λpre), with an
apparent divergence at a critical growth rate, λ 0. Indeed, replotting the
data of Fig. 1c reveals an approximately linear relation (Fig. 1d, purplehttps://doi.org/10.1038/s41586-020-2505-4
Received: 4 April 2018
Accepted: 21 April 2020
Published online: 15 July 2020
Check for updates(^1) Department of Systems Biology, Harvard Medical School, Boston, MA, USA. (^2) Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland. (^3) Section of Molecular Biology, Division of
Biological Sciences, University of California at San Diego, La Jolla, CA, USA.^4 Department of Physics, University of California at San Diego, La Jolla, CA, USA.^5 Department of Integrative
Structural and Computational Biology, and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA.^6 These authors contributed equally: Markus Basan,
Tomoya Honda. ✉e-mail: [email protected]; [email protected]; [email protected]