Growth strategies beyond microbes

In Systems Biology Lab, my colleagues, and I myself, work a lot on different aspects of microbial life, and our “lenses”, or the viewpoint, is inherently quantitative. Overall, to enable quantitative research, one needs to be able to assert tight control onto system in question. As the scientific community, we were able to transform microbiology into a highly quantitative science, since, to our delight, typical lab microbes are very convenient to deal with, when we aim for precise measurements and hard numbers.

One aspect is simply the time you need to spend in the lab: some microbes can grow remarkably fast; remember the “rule of thumb” for Escherichia coli, that under nutrient-rich condititions, the doubling time of E. coli can be as short as 20 minutes. In the eukaryotic realm, the maximal doubling time of many yeasts - ~75 minutes (specific growth rate of 0.55/h) - is a slow-down, yet still enables to produce a lot of offspring in a short time period. Now try to compare that with a typical human stem cell, which divides every 24 hours at best - a downgrade by some 20-fold, compared to yeasts!

Another consideration is the nutritional requirements: many lab microbes can grow on minimal media, meaning they can produce all the molecules which they need to make two cells out of one. Natural microbial isolates often exhibit a small number of auxotrophies, i.e. they have lost the ability to produce certain compounds. But the wild microbes almost exclusively form communities, and these relationships between different microbes covers the need for the missing biochemical capacity.

Back to the lab, where we cultivate microbes mostly in monocultures, two practical consequences arise out of use of minimal media: it (i) makes cultivation of the organism easier (and cheaper), and (ii) enables accurate bookkeping of consumption vs. production of metabolites. The latter is especially relevant given the currently used analytical methods (high-performance liquid chromatography, HPLC, for instance), where different analytes can interfer with the measurements and thus complicates the analysis of growth in rich media.

Even with the hurdles named (and even a longer list not named), we are still curious about the life strategies of higher eukaroytes. Yes, the cells divide slowly, yes, their growth depends on dozens of different nutritional compounds and signaling molecules being present in the growth medium, yes, they are sensitive even to being looked at in a strange way or you being hungover, aargh! Naturally, human cells are in the spotlight here due to potential translational value of the research, especially in the biomedical field: investigating disease mechanisms, searching for drug targets and testing their action, production of bioactive compounds in cell cultures, etc. But if we cannot draw straightforward conclusions from our experiments, as we do with microbes (“Oh, glucose is below detectable levels in the bioreactor effluent, the growth must be carbon-limited!”), how good are we at really understanding the growth strategies of higher eukaryotes?

I am delighted to have an opportunity to stand on the shoulders of giants, and to benefit from my colleagues - for instance, Jurgen Haanstra - pushing the boundaries of quantitative cell physiology for, e.g., mammalian cells. As an example, Jurgen has been working on methods to quantify extracellular fluxes in cancer cell cultures. These “simple experiments” we have been doing for decades in microbes can truly shed light on mammalian biology and biochemistry. Together with Jurgen and others, one of the subtopics of my work is investigating the growth strategies in cells beyond microbes: what do they need for growth? How their auxotrophies (“essential” amino- and fatty acids) shape their lifestyles? These are only a couple of broad questions we have in our field of vision.