The physiology of transport in cells and embryos

From Alan Turing, we know that rates of biochemical reactions (in units of seconds) need to be coupled to physical processes to account for the generation of spatial structure (in units of meters). Suggested morphogenetic driving forces include: passive or active diffusion, directed motor-driven fluxes, and the enigma of cytoplasmic streaming.  Since Turing, a great deal of causal insight into the biochemical basis of cellular organization and morphogenesis has been attained by genetic perturbations. In stark contrast to this, the functional role of physical transport in morphogenesis and homeostasis remains very poorly understood. Specifically, we lack the ability to test the functional role of these physical processes inside cells by appropriate perturbations, i.e.: how would one change direction, velocity or temporal persistence of flows within the cytoplasm of a developing embryo? This is clearly not possible by genetics. As a result of this methodological shortcoming to test competing hypothesizes, there is hardly one accepted proof of a reaction-transport system in biology.

Recently, we succeeded to optically generate hydrodynamic flows in cells and developing embryos via thermo-viscous expansion phenomena (see figure, Mittasch et al., Nat Cell Biol 2018, find video summary here: tinyurl.com/yaa9lh8c ).  As a new paradigm of interactive microscopy in biology, we refer to this approach as Focused-Light-Induced Cytoplasmic- Streaming (FLUCS). FLUCS is localized, directed, dynamic, physically tractable, and strictly non-invasive. Using FLUCS in early embryos of the nematode worm C. elegans, we revealed that i) cytoplasmic streaming enhances zygote polarization, ii) we gained control over cortical flows, and iii) proved sufficiency of cortical flows to transport the polarization defining PAR proteins, a key hypothesis in the field on developmental biology (Munro et al, 2004). iv) Guided by FEM simulations of intracellular flows, we managed to invert polarity of embryos. Most strikingly, these experiments revealed that body axis formation in the C. elegans zygote is a bi-stable process.

More generally our results show: FLUCS opens the door to a new era of microscopy, in which biologists are able to guide central developmental programs, rather than to watch them hands tied. FLUCS will be commercially available. The ability to physically interfere with cells and embryos in a physiological manner will allow us to test a multitude of candidates for Turing type reaction-transport systems in biology, i.e. germline establishment by asymmetric distribution of p-granules in C. elegans embryos, segmentation of the Drosophila embryo, but also mechanical phenotyping of the cytoplasm and subcellular compartments (i.e. the nucleus).

Also read the Nature Cell Biology Commentary about FLUCS by Aurélien Roux et al. 2018.

Optical constraints on retinal architecture

The first part of our research addresses one of the vertebrate retina's most surprising, but least investigated characteristics, its optical architecture: since the sensitive portions of the photoreceptor cells are found on the back of the retina, light needs to travel through several layers of living neuronal tissue before being detected. What is usually regarded as being a problem of neuronal activity is complemented from the perspective of optics, focusing on one key question: how does the retina deal with incident light?

When looking through a piece of freshly excised retinal tissue, in front of a dark background, it appears slightly opaque and silky (Fig.1, left). Any attempt to see through this retina is only successful as long as the object behind it is in the closest proximity to this tissue, clearly indicating strong interaction of light with the tissue, that would not occur in a truly transparent medium, such as the homogeneous and isotropic vitreous humor (Fig. 1, right). Quantitative measurements on the inner retina reveal that despite being scattering in the far-field, retinal tissue possesses a high ability to transfer an image from its inner surface to the back of the outer nuclear layer.

Using custom design microscopes we are aiming to gain a detailed understanding of optical constrains on retinal development that have previously been shown to be present down to the level of the chromatin organization. Apart from its importance for the initiation of the visual process, light propagation in neuronal tissues is also key to the optical observation of brain activity over large scales. Our experimental research is accompanied by theoretical and computer modeling of light tissue interaction.

The origin of life

The most remarkable aspect of life is its mysterious origin.

Although chemists are now able to create the building blocks of life in the lab, the magic spark that makes these molecules self-assemble into something living could not be observed yet. And indeed, a basic law of physics dictates that man made constructs are prone to decay when left to themselves. Our new insights reveal that first replicating entities on our planet were not entirely alone though, but taken care of by heat driven micro-reactors inside submarine volcanic rocks. In these little compartments genetic molecules get trapped and find optimal conditions for replication. Additionally they are selected towards ever increasing complexity, reversing the usual one-way route from living organisms to dead matter.

Reference: Moritz Kreysing, Lorenz Keil, Simon Lanzmich, and Dieter Braun
Nature Chemistry (2015) doi:10.1038/nchem.2155

www.nature.com/nchem/journal/vaop/ncurrent/full/nchem.2155.html (see 'publications' for PDF version of this paper)

More recently, we found that also phase separated protocells can be assembled in this setting, and we are looking forward to study the implications of this finding supported by a 5-year collaborative grant that we received from the Volkswagen Foundation (see jobs section in case of interest).