ERC FUNDED PROJECTS

We propose to elucidate the structural design principles of naturally occurring antibody complementarity-determining regions (CDRs) and to computationally design novel antibody functions. Antibodies represent the most versatile known system for molecular recognition. Research has yielded many insights into antibody design principles and promising biotechnological and pharmaceutical applications. Still, our understanding of how CDRs encode specific loop conformations lags far behind our understanding of structure-function relationships in non-immunological scaffolds. Thus, design of antibodies from first principles has not been demonstrated. We propose a computational-experimental strategy to address this challenge. We will: (a) characterize the design principles and sequence elements that rigidify antibody CDRs. Natural antibody loops will be subjected to computational modeling, crystallography, and a combined in vitro evolution and deep-sequencing approach to isolate sequence features that rigidify loop backbones; (b) develop a novel computational-design strategy, which uses the >1000 solved structures of antibodies deposited in structure databases to realistically model CDRs and design them to recognize proteins that have not been co-crystallized with antibodies. For example, we will design novel antibodies targeting insulin, for which clinically useful diagnostics are needed. By accessing much larger sequence/structure spaces than are available to natural immune-system repertoires and experimental methods, computational antibody design could produce higher-specificity and higher-affinity binders, even to challenging targets; and (c) develop new strategies to program conformational change in CDRs, generating, e.g., the first allosteric antibodies. These will allow targeting, in principle, of any molecule, potentially revolutionizing how antibodies are generated for research and medicine, providing new insights on the design principles of protein functional sites.

1 499 930 €

Start date: 2013-09-01, End date: 2018-08-31

One of the greatest challenges in exploiting the electron spin for information processing is that it is not a conserved quantity like the electron charge. In addition, spin lifetimes are rather short and correspondingly coherence is quickly lost. This challenge culminates in the coherent manipulation and detection of information from a single spin. Except in a few special systems, so far, single spins cannot be manipulated coherently on the atomic scale, while spin coherence times can only be measured on spin ensembles. A new concept is needed for coherence measurements on arbitrary single spins. Here, the principal investigator (PI) will combine a novel time- and spin-resolved low-temperature scanning tunneling microscope (STM) with the concept of pulsed electron paramagnetic resonance. With this unique and innovative setup, he will be able to address long-standing problems, such as relaxation and coherence times of arbitrary single spin systems on the atomic scale as well as individual spin interactions with the immediate surroundings. Spin readout will be realized through the detection of the absolute spin polarization in the tunneling current by a superconducting tip based on the Meservey-Tedrow-Fulde effect, which the PI has recently demonstrated for the first time in STM. For the coherent excitation, a specially designed pulsed GHz light source will be implemented. The goal is to better understand the spin dynamics and coherence times of single spin systems as well as the spin interactions involved in the decay mechanisms. This will have direct impact on the feasibility of quantum spin information processing with single spin systems on different decoupling surfaces and their scalability at the atomic level. A successful demonstration will enhance the detection limit of spins by several orders of magnitude and fill important missing links in the understanding of spin dynamics and quantum computing with single spins.

2 469 136 €

Start date: 2016-07-01, End date: 2021-06-30

Mammalian organisms possess the remarkable ability to maintain internal body temperature (Tcore) within a narrow range close to 37°C despite wide environmental temperature variations. The brain’s neural “thermostat” is made up by central circuits in the hypothalamic preoptic area (POA), which orchestrate peripheral thermoregulatory responses to maintain Tcore. Thermogenesis requires metabolic fuel, suggesting intricate connections between the thermoregulatory centre and hypothalamic circuits controlling energy balance. How the POA detects and integrates temperature and metabolic information to achieve thermal balance is largely unknown. A major question is whether this circuitry could be harnessed therapeutically to treat obesity. We have recently identified the first known molecular temperature sensor in thermoregulatory neurons of the POA, transient receptor potential melastatin 2 (TRPM2), a thermo-sensitive ion channel. I aim to use TRPM2 as a molecular marker to gain access to and probe the function of thermoregulatory neurons in vivo. I propose a multidisciplinary approach, combining local, in vivo POA temperature stimulation with optogenetic circuit-mapping to uncover the molecular and cellular logic of the hypothalamic thermoregulatory centre and to assess its medical potential to counteract metabolic syndrome. Acclimation is a beneficial adaptive process that fortifies thermal responses upon environmental temperature challenges. Thermoregulatory neuron plasticity is thought to mediate acclimation. Conversely, maladaptive thermoregulatory changes affect obesity. The cell-type-specific neuronal plasticity mechanisms underlying these changes within the POA, however, are unknown. Using ex-vivo slice electrophysiology and in vivo imaging, I propose to characterize acclimation- and obesity-induced plasticity of thermoregulatory neurons. Ultimately, I aim to manipulate thermoregulatory neuron plasticity to test its potential counter-balancing effect on obesity.

1 902 500 €

Start date: 2018-09-01, End date: 2023-08-31

Formation of the Earth and the other terrestrial planets of our Solar System (Mercury, Venus and Mars) commenced 4.568 billion years ago and occurred on a time scale of about 100 million years. These planets grew by the process of accretion, which involved numerous collisions with smaller (Moon- to Mars-size) bodies. Impacts with such bodies released sufficient energy to cause large-scale melting and the formation of deep “magma oceans”. Such magma oceans enabled liquid metal to separate from liquid silicate, sink and accumulate to form the metallic cores of the planets. Thus core formation in terrestrial planets was a multistage process, intimately related to the major impacts during accretion, that determined the chemistry of planetary mantles. However, until now, accretion, as modelled by astrophysicists, and core formation, as modelled by geochemists, have been treated as completely independent processes. The fundamental and crucial aim of this ambitious interdisciplinary proposal is to integrate astrophysical models of planetary accretion with geochemical models of planetary differentiation together with cosmochemical constraints obtained from meteorites. The research will involve integrating new models of planetary accretion with core formation models based on the partitioning of a large number of elements between liquid metal and liquid silicate that we will determine experimentally at pressures up to about 100 gigapascals (equivalent to 2400 km deep in the Earth). By comparing our results with the known physical and chemical characteristics of the terrestrial planets, we will obtain a comprehensive understanding of how these planets formed, grew and evolved, both physically and chemically, with time. The integration of chemistry and planetary differentiation with accretion models is a new ground-breaking concept that will lead, through synergies and feedback, to major new advances in the Earth and planetary sciences.

1 826 200 €

Start date: 2012-05-01, End date: 2018-04-30