A long time has passed since Leeuwenhoek used a handmade microscope to describe the existence of microorganisms in the XVIIth century and since then, our knowledge about these tiny creatures has massively increased. He provided the foundations of modern microbiology, but it wasn’t until over two centuries later that the first evidences of microbial genetics were provided. The discovery of DNA and the birth of genetic engineering later in the XXth century allowed us to unravel the secrets and the potential encoded within these microorganisms.

Learning about microbes in such detail has enabled us not only to understand but also to exploit organisms paving the way for younger disciplines such as biotechnology to design organisms that can meet our industrial needs. A lot of progress has been made but the main challenge remains: “How do we convince a microbe to do something? We are trying to change a machine that we don’t fully understand” explains Uwe Sauer, R4B partner and systems biology professor at ETHZ.

Aiming to bring us a step further, synthetic biology recently joined this history allowing us to design microorganisms as if they were programmable machines with standardise pieces and elements,” The strength of synthetic biology is its ability to focus on one circuit and to understand that circuit in detail “, comments Sauer. The problem comes when we try to put the individual circuits or pieces together and really work like an engineer would do constructing complex microorganisms that have to reach high production levels and competitive prices when we work in industrial settings, “We are good at doing this for small circuits but not for a whole cell yet”, highlights the professor.

To help us overcome this limitation and better understand how microbes really work globally, we need to step back a little and gain perspective. In this context -omics technologies allow us to get the broader picture. These approaches produce great amounts of valuable data shedding light on the different regulatory levels of the microbial cells from genes and transcripts to proteins and metabolites. The latter field is precisely the expertise area from Sauer and his team, “we aim at understanding how microorganisms coordinate their metabolism – a large network of around 1000 different metabolic reactions and how metabolism is feeding back into different regulation systems” explains Sauer.

The microbial metabolism is complex and thus it can be studied at different levels. From the precise quantification of a small set of metabolites to the analysis of the complete metabolome of a given cell, metabolomics can produce different sets of data that vary in regard to the precision of the quantification and the number of components detected. All these approaches pose however a common challenge, how to evaluate and make sense out of this information, a question that Sauer and his team aim at answering.

To do so they develop and apply computational approaches that allow them to combine their large metabolic datasets with proteomics and transcriptomics data to generate and validate hypothesis. “To understand a whole cell will take a long long time,” recognises Sauer, “We need different computational tools and methods to generate hypothesis and make predictions that we can test and to learn why the predictions fail, that is where the future has to go”, he adds.

While we get there and work to develop the tools capable of monitoring the cells in a comprehensive and dynamic way, every little piece and circuit will bring us a step closer to fully understanding the whole picture and continuing the path that Leeuwenhoek started more than 300 year ago with a modest microscope.