When Bas Teusink and Douwe Molenaar came to the VU University, about a decade ago, they had just published a thought-provoking paper on how microbial physiology can result from optimal allocation of biosynthetic resources, such as ribosomes, RNA polymerases, amino acids, energy, etc., in order to maximise growth rate (https://doi.org/10.1038/msb.2009.82). Roughly at the same time, a paper from Terry Hwa’s lab was published providing experimental evidence for the potential of thinking in terms of allocation of limited biosynthetic resources — regardless of any optimality assumption (https://science.sciencemag.org/content/330/6007/1099). Some of those ideas can be traced back to the ideas of Kjeldgaard, Schaechter and Maaløe several decades ago (e.g. O. Maaløe, An analysis of bacterial growth, Developmental Biology Supplement, 3, 33-58, 1969). Many of developments of the last decade have now been reviewed by us in FEMS Microbiology Reviews (https://doi.org/10.1093/femsre/fuaa034).
What has become clear in the last decade is that the assumption of maximal (per capita of specific) growth rate is a very powerful one to understand the behaviour of (model) microorganisms, such as Escherichia coli and Saccharomyces cerevisiae. Why they express certain metabolic pathways, to which degree they tune expression of proteins, what the fitness effects are of unneeded protein expression, and what limits growth can all be predicted in the current theoretical framework, which matches experimental data remarkably well.
This review also indicates the great potential of theory in microbiology and the likely universality of the underlying causes of many metabolic behaviours.
We hope that you enjoy reading the review, we certainly had a lot of fun writing it, and performing some of the research mentioned in it.
Growing cells in constant conditions at a fixed exponential growth rate in a shake flask — balanced growth — is arguably the most basic experiment in microbiology. We are so used to it that we sometimes forget to realise that this is not at all so obvious.
Not only the average growth rate remains fixed, but also the average cell size at birth and division. Either this emerges for free, and no active homeostatic mechanisms are required, or balanced growth requires evolved regulatory mechanisms. Analysis of experimental data, using a deceptively, simple theory, by Susan et al. , indicates that active homeostatic mechanisms are at work during steady-state growth and that without those balanced growth would be possible.
That cell-size homeostasis mechanisms exist and are required for balanced growth was already known — mostly from work by Suckjoon Jun’s lab. But what about growth-rate homeostasis? Do active mechanisms exist that maintain a constant average (and variance) of single-cell growth rate? Here we show that that is indeed the case for Bacillus subtilis.
We also found that its cell cycle is composed out of two phases. A first one, during which cells with variations in birth size correct size differences — they behave as “sizers” — and a second one during which cells behave as “timers” — they grow for a nearly fixed duration.
Our most surprising, and novel, finding was that cells experience a great disturbance of growth rate at division, with smaller cells outgrowing larger ones, while at division that growth rate variation has largely disappeared and growth rate became independent of cell size at birth.
So, also a growth-rate homeostasis mechanism is at work in Bacillus subtilis— like it is for cell size. How it works, we are currently figuring out.
You can find our paper here: https://www.cell.com/current-biology/fulltext/S0960-9822(20)30544-3.
- Susman, L., Kohram, M., Vashistha, H., Nechleba, J.T., Salman, H., andBrenner, N. (2018). Individuality and slow dynamics in bacterial growth ho-meostasis. Proc. Natl. Acad. Sci. USA 115, E5679–E5687.
For those of you who do not know Daan. He is a PhD student in our lab, working on a mathematical theory about optimal metabolism for microbial growth-rate maximisation and its experimental testing. One of the principles underlying his theory is optimal allocation of limited resources for the synthesis of metabolic enzymes. What turns out is that Daan is also an expert in allocating his own limited resources.
Daan is a talented road cyclist. A decade ago he competed with riders who are currently riding the tours of Italy, France and Spain. (I regularly wish I had those skills, but let us not go there.) During multiple day cycling events, which can even last several weeks, it is all about staying fit and focussed, while your body is slowing draining resources, which you cannot readily supplement with food. We call this fatigue. Cyclists learn how to the optimise their balance of performance and fatigue, which is one closely associated with optimal resource allocation. Recently, Daan has added a new resource-allocation trick on his sleeve.
He started duathlon, a run then bike then run event. Duathlon is a growing sport in the Netherlands and highly popular in the USA. It is closely related to triathlon, an Olympic sport. During a run-bike-run it is all about allocation of energy resources. Daan found an optimal way of solving this problem during last weekend’s European Championship (EC), in Vejle (Denmark), by focussing on what he does best.
Daan cycles better than he runs. His strategy during the EC was to save resources during the first run, go as fast as possible on his bike, and then run until he can no longer stand. And what a wise choice this was! After the first run he was amongst the slowest, he was the fastest cyclist and was 5th when crossing the finish line. We congratulate Daan with this major achievement!
For more information about the Vejle EC Duathlon 2018 see this link.
Here you see Daan riding earlier this year when he won the Duathlon in Geluwe (Belgium).
We hope you like the paper, it is here. We had a great time working on it! Its amazing how quantitatively balanced growth and protein expression of microorganisms can be studied with simple shake flasks, a flow cytometer, some useful statistical tricks, and a titratable fluorescent reporter protein, which Niclas engineered all by himself.
Go and see it here, we hope you like it! We tried to give a fairly comprehensive overview of some of the mechanisms underlying phenotypic variation and diversification in populations of microorganisms and how phenotypic variation influences fitness.
On March 28 we have an exciting number of presentations scheduled by yeast experimentalists and theoretical systems biologists trying to work out the underlying principles of metabolic regulation. You are welcome to attend this meeting. For more information, go and see the meeting information here.
On Wednesday, June 29, Frank gave his inaugural speech for this University Research Chair in Interdisciplinary Life Sciences. The speech was in Dutch and with it came a written text. The day ended with a party where Frank received two wonderful gifts from the department and other colleagues: a glider (sailplane) flight and a picture of Frank explaining his Fabulous Fundamental Formula of Fitness, printed on wood.
You can download the written text (in Dutch) by clicking: inaugurele rede.
Susanne will defend her thesis on May 24 and today we received copies of it! This work is a successful collaboration with the Joachim Goedhart and Dorus Gadella, both from the University of Amsterdam.
You can find it here: Our new Current Opinion in Microbiology Review
It discusses how different cultivation methods can be used to select mutant bacteria with improved macroscopic growth parameters and our current understanding of whether such parameters trade off.
For more information see: O2 building information