ERC FUNDED PROJECTS

Abrupt shifts occasionally reshape complex systems in nature ranging in scale from lakes and reefs to regional climate systems. Such shifts sometimes represent critical transitions in the sense that they happen at tipping points where runaway change propels the system towards an alterative contrasting state. Although the mechanism of critical transitions can often be reconstructed in the hindsight, we are virtually unable to predict when they will happen in advance. Simulation models for complex environmental systems are simply not good enough to predict tipping points, and there is little hope that this will change over the coming decades. The proposed project is aimed at developing an alternative way to predict critical transitions. We aim at finding early warning signals for such transitions that are generic in the sense that they work irrespective of the (often poorly known) mechanisms responsible for the tipping points. Mathematical theory indicates that this might be possible. However, although excitement about these ideas is emerging, we are far from having a cohesive theory, let alone practical approaches for predicting critical transitions in large complex systems like lakes, coral reefs or the climate. I will work towards this goal with my team along three lines: 1) Develop a comprehensive theory of early warning signals using analytical mathematical techniques as well as models ranging in character from simple and transparent to elaborate and realistic; 2) Test the theory on experimental plankton systems kept in controlled microcosms; and 3) Analyze data from real systems that go through catastrophic transitions. The anticipated results would imply a major breakthrough in a field of research that is exiting as well as highly relevant to society. If we are successful, it would allow us to anticipate critical transitions even in large complex systems where we have little hope of predicting tipping points on the basis of mechanistic models.

2 299 171 €

Start date: 2011-06-01, End date: 2016-05-31

This application addresses mechanisms linking the activity of single neurons with network events by defining the function of identified cell types in the cerebral cortex. The key hypotheses emerged from our experiments and propose that neurogliaform cells and axo-axonic cells achieve their function in the cortex through extreme forms of unspecificity and specificity, respectively. The project capitalizes on our discovery that neurogliaform cells reach GABAA and GABAB receptors on target cells through unitary volume transmission going beyond the classical theory which states that single cortical neurons act in or around synaptic junctions. We propose that the spatial unspecificity of neurotransmitter action leads to unprecedented functional capabilities for a single neuron simultaneously acting on neuronal, glial and vascular components of the surrounding area allowing neurogliaform cells to synchronize metabolic demand and supply in microcircuits. In contrast, axo-axonic cells represent extreme spatial specificity in the brain: terminals of axo-axonic cells exclusively target the axon initial segment of pyramidal neurons. Axo-axonic cells were considered as the most potent inhibitory neurons of the cortex. However, our experiments suggested that axo-axonic cells can be the most powerful excitatory neurons known to date by triggering complex network events. Our unprecedented recordings in the human cortex show that axo-axonic cells are crucial in activating functional assemblies which were implicated in higher order cognitive representations. We aim to define interactions between active cortical networks and axo-axonic cell triggered assemblies with an emphasis on mechanisms modulated by neurogliaform cells and commonly prescribed drugs.

2 391 695 €

Start date: 2011-06-01, End date: 2017-05-31

Current state-of-the-art drug carrier systems deliver new ‘biological drugs’ (like proteins and nucleic acids) poorly to the target site. This is something I daily experience in my research on delivery of small interfering RNA. The in vivo challenges are threefold: • Biological drugs are fragile molecules (subject to degradation and denaturation) • They need to gain access to the target site • They need delivery to a specific cell type and even to a specific subcellular location to be active. Recent research points out an endogenous communication system transporting proteins and nucleic acids between cells, outperforming current synthetic drug delivery systems. These carriers, known as microvesicles, appear Nature’s choice for delivery of biologicals and have created excitement in the research community. Microvesicles encompass a variety of submicron vesicular structures that include exosomes, shedding vesicles, and microparticles. The lipids, proteins, mRNA and microRNA delivered by these microvesicles change the phenotype of the receiving cells. Microvesicles appear to play an important role in many disease processes, most notably inflammation and cancer, where their efficient functional delivery of biological cargo contributes to the disease progress. Up to now, most research addresses the role of microvesicles in cell biology. At the same time, surprisingly little is known about their in vivo kinetics, targeting behavior and tissue distribution from a drug carrier standpoint. The aim of my proposal is to design and develop microvesicle-inspired drug delivery systems to improve targeting and delivery of biological drugs. The work plan is divided into two approaches: 1-A synthetic approach based on liposomes or isolated microvesicle constituents 2-A biological approach based on biotechnologically-engineered and cell-produced microvesicles. The results of this research are expected to improve insights into in vivo behavior of microvesicles and the critical molecules that trigger their delivery and targeting success. It should also be clear which of the two approaches is best suited for the production of pharmaceutically acceptable microvesicle-mimics. Finally, the research should result in a prototype microvesicle-inspired carrier. These results can form the basis for an attractive new generation of microvesicle mimicking drug delivery systems.

1 338 000 €

Start date: 2010-12-01, End date: 2015-11-30

I propose to unravel parts of the mechanochemistry of two key genome transactions: replication and transcription using an array of single-molecule techniques. To this end, I propose to study the minimal genomic machinery of mitochondria. Mitochondria are organelles in eukaryotic cells that contain their own DNA (mtDNA). Significant understanding of the biochemistry of DNA transactions in mitochondria is obtained from the in vitro reconstitution of mitochondrial replication and transcription. However, elucidating the physics of these molecular mechanisms has only just started. A major challenge of the coming decades will be dissecting and quantifying biological systems to such an extent that it makes predictive modeling possible. Single-molecule tools play a major role in this development. Hence, I plan within the scope of this proposal, to combine optical manipulation with powerful fluorescent techniques. This combination of single-molecule manipulation and fluorescence has much more potential than has been explored, so far. With the development of such tools complex biological systems can not only be controlled and measured but also visualized at the same time. The human mitochondrial genetic machinery is an ideal system for such an approach, because replication and transcription can be re-created in vitro with only seven proteins. Hence, this proposal represents a unique opportunity to quantitatively dissect a genetic machine that is actually accessible by biophysical tools. Finally, about 1 in 5000 humans suffers from a disease caused by mutations of in the mtDNA. The research proposed here will permit direct observation of proteins in action. Normal and dysfunctional proteins can thus be compared, permitting insight in the mechanistic basis of a disorder.

1 497 868 €

Start date: 2011-01-01, End date: 2015-12-31