ERC FUNDED PROJECTS

Large protein complexes carry out some of the most complex functions in biology. Such structures are often assembled spontaneously from individual components through the process of self-assembly. If self-assembled protein complexes could be engineered from first principle it would enable a wide range of applications in biomedicine, nanotechnology and materials science. Recently, approaches to rationally design proteins to self-assembly into predefined structures have emerged. The highlight of this work is the design of protein cages that may be engineered into protein containers. However, current approaches for self-assembly design does not result in the assemblies with the required structural complexity to encode many of the sophisticated functions found in nature. To move forward, we have to learn how to engineer protein subunits with more than one designed interface that can assemble into tightly interacting complexes. In this proposal we propose a new protein design paradigm, shape directed protein design, in order to address shortcomings of the current methodology. The proposed method combines geometric shape matching and computational protein design. Using this approach we will de novo design assemblies with a wide variety of structural states, including protein complexes with cyclic and dihedral symmetry as well as icosahedral protein capsids built from novel protein building blocks. To enable these two design challenges we also develop a high-throughput assay to measure assembly stability in vivo that builds on a three-color fluorescent assay. This method will not only facilitate the screening of orders of magnitude more design constructs, but also enable the application of directed evolution to experimentally improve stable and assembly properties of designed containers as well as other designed assemblies.

2 325 292 €

Start date: 2018-06-01, End date: 2023-05-31

The centriole is the largest evolutionary conserved macromolecular structure responsible for building centrosomes and cilia or flagella in many eukaryotes. Centrioles are critical for the proper execution of important biological processes ranging from cell division to cell signaling. Moreover, centriolar defects have been associated to several human pathologies including ciliopathies and cancer. This state of facts emphasizes the importance of understanding centriole biogenesis. The study of centriole formation is a deep-rooted question, however our current knowledge on its molecular organization at high resolution remains fragmented and limited. In particular, exquisite details of the overall molecular architecture of the human centriole and in particular of its central core region are lacking to understand the basis of centriole organization and function. Resolving this important question represents a challenge that needs to be undertaken and will undoubtedly lead to groundbreaking advances. Another important question to tackle next is to develop innovative methods to enable the nanometric molecular mapping of centriolar proteins within distinct architectural elements of the centriole. This missing information will be key to unravel the molecular mechanisms behind centriolar organization. This research proposal aims at building a cartography of the human centriole by elucidating its molecular composition and architecture. To this end, we will combine the use of innovative and multidisciplinary techniques encompassing spatial proteomics, cryo-electron tomography, state-of-the-art microscopy and in vitro assays and to achieve a comprehensive molecular and structural view of the human centriole. All together, we expect that these advances will help understand basic principles underlying centriole and cilia formation as well as might have further relevance for human health.

1 498 965 €

Start date: 2017-01-01, End date: 2021-12-31

The spread of farming practices in various parts of the world had a marked influence on how humans live today and how we are distributed around the globe. Around 10,000 years ago, warmer conditions lead to population increases, coinciding with the invention of farming in several places around the world. Archaeological evidence attest to the spread of these practices to neighboring regions. In many cases this lead to whole continents being converted from hunter-gatherer to farming societies. It is however difficult to see from archaeological records if only the farming culture spread to other places or whether the farming people themselves migrated. Investigating patterns of genetic variation for farming populations and for remaining hunter-gatherer groups can help to resolve questions on population movements co-occurring with the spread of farming practices. It can further shed light on the routes of migration and dates when migrants arrived. The spread of farming to Europe has been thoroughly investigated in the fields of archaeology, linguistics and genetics, while on other continents these events have been less investigated. In Africa, mainly linguistic and archaeological studies have attempted to elucidate the spread of farming and herding practices. I propose to investigate the movement of farmer and pastoral groups in Africa, by typing densely spaced genome-wide variant positions in a large number of African populations. The data will be used to infer how farming and pastoralism was introduced to various regions, where the incoming people originated from and when these (potential) population movements occurred. Through this study, the Holocene history of Africa will be revealed and placed into a global context of migration, mobility and cultural transitions. Additionally the study will give due credence to one of the largest Neolithic expansion events, the Bantu-expansion, which caused a pronounced change in the demographic landscape of the African continent

1 500 000 €

Start date: 2017-11-01, End date: 2022-10-31

Drones are disrupting industries, such as agriculture, package delivery, inspection, and search and rescue. However, they are still either controlled by a human pilot or heavily rely on GPS for navigating autonomously. The alternative to GPS are onboard sensors, such as cameras: from the raw data, a local 3D map of the environment is built, which is then used to plan a safe trajectory to the goal. While the underlying algorithms are well understood, we are still far from having autonomous drones that can navigate through complex environments as good as human pilots. State-of-the-art perception and control algorithms are mature but not robust: coping with unreliable state estimation, low-latency perception, real-time planning in dynamic environments, and tight coupling of perception and action under severe resource constraints are all still unsolved research problems. Another issue is that, because battery energy density is increasing at a very slow rate, drones need to navigate faster in order to accomplish more within their limited flight time. To obtain more agile robots, we need faster sensors and low-latency processing. The goal of this project is to develop novel scientific methods that would allow me to demonstrate autonomous, vision-based, agile quadrotor navigation in unknown, GPS-denied, and cluttered environments with possibly moving obstacles, which can be as effective in terms of maneuverability and agility as those of professional drone pilots. The outcome would not only be beneficial for disaster response scenarios, but also for other scenarios, such as aerial delivery or inspection. To achieve this ambitious goal, I will first develop robust, low-latency, multimodal perception algorithms that combine the advantages of standard cameras with event cameras. Then, I will develop novel methods that unify perception and state estimation together with planning and control to enable agile maneuvers through cluttered, unknown, and dynamic environments.

2 000 000 €

Start date: 2020-09-01, End date: 2025-08-31