In the temple of Amsterdam’s music, Bimhuis and Muziekgebouw, Bas and his AIMMS team organized a two-day festival celebrating how multidisciplinary molecular sciences can create societal impact. The music of life is made by orchestra of molecules, and so the venue was a perfect fit. With workshops, keynotes, discussions and poster sessions, the place was bubbling. As one of the invited external speakers said it: “I have not before seen so much energy at a science event with such a broad audience”.

Not the least because our own Yves blew us away with his band Freaky Fish. Evelina freaked out of course and with her the SysBioLab danced the night away. See the full program and a recap that will appear soon: www.aimmsfestival.nl

Jurgen and Christoff contributed a kinetic modelling analysis to a publication that came out last month in Nucleic Acid Research. The paper describes improved measurements of globally quantify RNA processing rates and half-lives for mRNAs in the sleeping sickness parasite Trypanosoma brucei.

Christoff plugged those values into a kinetic model of gene expression. The modelling shows that RNA half-life is a stronger predictor of total mRNA levels than the RNA processing rates. However, none of the two processes alone was sufficient to fully predict total RNA levels. Instead, both processes exert control, and it is the combination of them that determines RNA total levels.

The paper is linked to other papers that our group published in collaboration with other groups: A previous model that Jurgen made in 2008, has now been used again to interpret improved datasets. For the modelling this is a follow up to analysis with versions of the model in 2014 and 2016.

How can you measure something that cannot be measured directly? Think of a rate: this must always be inferred from some other measurements. In the 6^th of Jan issue of Nature Metabolism the Springer lab describes a new mechanism by which cells can measure metabolic rates – in this case rates of the conversion of the sugar galactose in Baker’s yeast. They found that the key enzyme of the galactose pathway, galactose kinase, not only sets the metabolic rate, but also directly regulates the enzyme levels of the pathway. Bas Teusink, Bob Planqué and Frank Bruggeman wrote a News & Views piece about the relevance of the finding. The VU-AIMMS researchers propose that this mechanism provides a missing link in our understanding how cells can optimally distribute cellular resources to maximize fitness. Read about it here:

https://rdcu.be/d5q7Y

A new collaborative paper with Greg Bokinsky has just came out in Nature Communications! You find it here: paper link.

When temperature changes, the kinetics of enzymes change (think of the Arrhenius law) as well as their diffusive properties (the diffusion coefficient depends linearly on temperature, at constant viscosity). The change in the diffusion coefficient of cytosolic and membrane proteins is different since membrane proteins are dependent on the change in membrane fluidity (via, the membrane viscosity change). Some of those changes are large, whereas others are small. Their magnitudes depend on the precise biochemistry of the associated molecules, which is outside of the realm of control by the microbe, and all molecular changes to temperature propagate in a nonlinear way to the phenotype. The only measure a microbe has — to somehow control this — is by adjusting protein expression and hereby change its molecular composition, including the lipid composition of its membrane. To achieve this, the microbe needs mechanisms akin to thermometers and homeostatic controls — similarly to the thermostats in your house!

Dr Greg Bokinsky, from the nanoscience department of the TU Delft, developed a mass spectrometry based method for the measurement of the most important intermediates and enzymes of fatty acid and lipid metabolism in Escherichia coli. He used this method to monitor the temperature response of this metabolic system as function of time. Since this bacterium does not measure membrane fluidity, like other organisms do, he was interested in figuring out how fluxes in lipid metabolism are repartitioned in response to temperature to adjust the membrane lipid composition such that membrane fluidity remains (almost) independent of temperature.

We got involved in this because Greg found that several adaptive mechanisms act concertedly and on different time scales. Metabolic regulation on a time scale of second to minutes, and gene expression adaptation on a time scale of tens of minutes. Also, it remained unclear which enzymes were likely temperature sensitive — this is hard to determine in vitro because of the complexity of the substrates and the cell-free extract assays. We helped Greg to figure these things out, together with his students. The model we eventually ended up with was remarkably simple and powerful in describing the data, giving us confidence in our understanding of this complex adaptive mechanism.

What I enjoyed most of this study, in addition to solving this puzzle with Greg, is the experiment that addresses the consequences of temperature maladaptation. It turns that the diffusion of one of the components of the respiratory chain can become rate-limiting when the temperature drops, the membrane fluidity is increased which effectively removes this rate limitation and restores fast growth. This is shown in Figure 5 of the paper, when E. coli grows on succinate.

We hope you enjoy this work!

Ecem Yuksel, Remco Kort, and colleagues wrote a new review about the different bacteria in our intestines that can degrade a certain kind of dietary fiber called pectin, and how this can benefit our gut health. Check out the review here! (Picture from here)

The human gastrointestinal microbiota, densely populated with a diverse array of microorganisms primarily from the bacterial phyla Bacteroidota, Bacillota, and Actinomycetota, is crucial for maintaining health and physiological functions. Dietary fibers, particularly pectin, significantly influence the composition and metabolic activity of the gut microbiome. Pectin is fermented by gut bacteria using carbohydrate-active enzymes (CAZymes), resulting in the production of short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate, which provide various health benefits. The gastrointestinal microbiota has evolved to produce CAZymes that target different pectin components, facilitating cross-feeding within the microbial community. This review explores the fermentation of pectin by various gut bacteria, focusing on the involved transport systems, CAZyme families, SCFA synthesis capacity, and effects on microbial ecology in the gut. It addresses the complexities of the gut microbiome’s response to pectin and highlights the importance of microbial cross-feeding in maintaining a balanced and diverse gut ecosystem. Through a systematic analysis of pectinolytic CAZyme production, this review provides insights into the enzymatic mechanisms underlying pectin degradation and their broader implications for human health, paving the way for more targeted and personalized dietary strategies.

The new academic year kicked off on 2 September 2024 with the Opening Academic Year. This year’s theme was ‘Reasons for Hope’. Bas was interviewed as part of the panel and spoke as the Director of AIMMS about how we are committed to making a positive impact on life and the environment by accelerating breakthroughs in molecular science. He also highlighted our initiatives to unite a new generation of thinkers to address complex societal challenges, including organizing hackathons.

C2W:Mens & Molecule is a Dutch publication platform (including a magazine) for independent science journalism for chemistry and life sciences. Our current research on usage of alternative cofactors (e.g. replacing the NADH/NAD couple) in novel metabolic engineering strategies for microbial biotechnology has recently feature in this magazine. We carry out this research in collaboration with labs from the universities in Wageningen and Delft, all working on different aspects. At the VU, four of us are working on the project Lies, Maaike, Bas and myself.

You find the article here: https://www.sciencelink.net/verdieping/meer-grip-op-het-metabolisme-van-microben/22138.article.

Maaike and Pranas participated in the third summer school on Economic Principles in Cell Biology that took place on the 8-11th July, 2024, in Paris and online. Lab PhD students Francesco and Luis also attended the lectures online. Maaike was one of some 30 participants selected for in-person attendance, and Pranas gave one of the introductory lectures, “An inventory of cell components” (together with Diana Széliová, University of Vienna). A small size of this course came to our advantage for the social part: we enjoyed both the science and the beers at the Seine (and watching EURO2024!) with colleagues coming from different parts of the continent and beyond.

The scientific part of the summer school was accompanied by two more soft-skills oriented activities: first, the workshop on the creative process in science, Night Science by Martin Lercher. You might have heard of the editorials- and podcast series of Martin and Itai Yanai under the same name – give it a listen if you haven’t! The last day was dedicated for the Atelier SEnS, a workshop on exploring the relationship between one’s personal values and the research they conduct.

The summer school is an activity that emerged from the community initiative of the same name that aimed to bring the colleagues working under similar philosophy together. It all started as a monthly seminar via Zoom in early 2020, organized by a handful of professors (including our own Frank!), and the community expanded over time. Eventually, an idea to write an open-source textbook started gaining momentum. The book project is led by Wolfram Liebermeister at INRAE (France), and Pranas is one of the coordinators of the initiative since recently. The summer school is one of the ways to promote the textbook project, and to test its didactical value in practice.

Overall, it was a very nice experience, and quite a relaxed one (in both best and worst ways of it). The 2025 summer school, if all things turn as planned, will be held in Vienna, with a lot of improvements/changes planned, so we are quite excited to join it if it materializes!

Since cells have finite biosynthetic resources for protein synthesis, a rise in one protein concentration is generally at the expense of that of others. A logical consequence is then that phenotypic traits trade-off: cells cannot excel at everything. They cannot grow fast and be very stress tolerant and adaptive to new conditions at the same time. Another consequence is that protein under- and over-expression without a long-term fitness benefit is likely selected against. 

How do cells then decide on the expression level of proteins? Can they even tune protein concentrations optimally — to prevent wasteful over-expression and suboptimal under-expression? What do cells try to achieve by changing protein concentrations? How can they decide that tuning is finished and that protein concentrations are optimal?

In this new paper (https://doi.org/10.1042/EBC20230045), we can gave an overview of how cell can achieve growth-rate-maximising tuning of metabolic protein concentrations, via optimal gene expression of metabolic genes. We pioneered this method in Berkhout et al.(https://doi.org/10.1038/srep01417) and generalised it in Planqué et al. (https://doi.org/10.1371/journal.pcbi.1006412), and applied its way of thinking to understand the regulation of ribosomal gene expression in E. coli in Bosdriesz et al. (https://doi.org/10.1111/febs.13258). Here we give an elementary overview of this theoretical method. We apply it to understand the gene-regulatory feedback regulation of amino-acid metabolism. 

Some more background information on this way of thinking can also be found in some teaching material I wrote for a course on enzyme kinetics (https://teusinkbruggemanlab.nl/course-information-from-enzyme-kinetics-to-models-of-metabolism/).

We hope that we have inspired you to think also about how cellular objectives can be achieved by gene-regulatory circuits.