Billions of years of evolution have made enzymes superb catalysts capable of accelerating reactions by several orders of magnitude. The underlying physical principles of their extraordinary catalytic power still remains highly debated, which makes the alteration of natural enzyme activities towards synthetically useful targets a tremendous challenge for modern chemical biology. The routine design of enzymes will, however, have large socio-economic benefits, as because of the enzymatic advantages the production costs of many drugs will be reduced and will allow industries to use environmentally friendly alternatives. The goal of this project is to make the routine design of proficient enzymes possible. Current computational and experimental approaches are able to confer natural enzymes new functionalities but are economically unviable and the catalytic efficiencies lag far behind their natural counterparts. The groundbreaking nature of NetMoDEzyme relies on the application of network models to reduce the complexity of the enzyme design paradigm and completely reformulate previous computational design approaches. The new protocol proposed accurately characterizes the enzyme conformational dynamics and customizes the included mutations by exploiting the correlated movement of the enzyme active site residues with distal regions. The guidelines for mutation are withdrawn from the costly directed evolution experimental technique, and the most proficient enzymes are easily identified via chemoinformatic models. The new strategy will be applied to develop proficient enzymes for the synthesis of enantiomerically pure β-blocker drugs for treating cardiovascular problems at a reduced cost. The experimental assays of our computational predictions will finally elucidate the potential of this genuinely new approach for mimicking Nature’s rules of evolution.
Despite the tremendous progress achieved over the past decade, the study of stellar formation is far from complete. We have not yet measured the minimum mass for star formation, nor the shape of the IMF down to the least massive free-floating planets, or know how universal this shape is. Although clusters are the building blocks of galaxies, little is known about their early dynamical evolution and dispersal into the field. The main culprit for this state of affairs is the high level of contamination and incompleteness in the sub-stellar regime, even for the best photometric and astrometric surveys. COSMIC-DANCE aims at overcoming these drawbacks and revealing the shape of the IMF with a precision and completeness surpassing current and foreseeable surveys of the next 15 years. We will: 1) Measure: using a groundbreaking, proven and so far unique method I designed, we will measure proper motions with an accuracy comparable to Gaia but 5 magnitudes deeper, reaching the planetary mass domain, and, critically, piercing through the dust obscured young clusters inaccessible to Gaia’s optical sensors. 2) Discover: feeding these proper motions and the multi-wavelength photometry to innovative hyper-dimensional data mining techniques, we will securely identify cluster members within the millions of sources of the COSMIC-DANCE database, complemented by Gaia at the bright end, to obtain the final census over the entire mass spectrum for 20 young nearby clusters, the end of a 60-year quest. 3) Understand: by providing conclusive empirical constraints over a broad parameter space unaccessible to current state-of-the-art surveys on the much debated respective contributions of evolutionary effects (dynamics, feedback and competitive accretion) and initial conditions (core properties) to the shape and bottom of the IMF, the most fundamental and informative product of star formation, with essential bearings on many areas of general astrophysics.
Understanding how the mammalian brain network acquires its ability during development to process information and interact with the environment is one of the fundamental challenges in modern biology. The brain originates from a sheet of neural progenitors during embryogenesis but rapidly develops into distinct functional areas such as primary sensory and the highly associative cortices. Although all cortical areas consist of the same main neuronal elements, excitatory and inhibitory cells, their functions are markedly distinct. Unlike others, primary sensory cortical regions receive direct inputs from the environment through the respective thalamic nuclei starting at an early stage in development and are therefore likely to be shaped by incoming activity from sensory modalities. Despite the plethora of data on the arealization of the cortex by early signaling centers and the critical period plasticity mechanisms which take place after the basic elements of the circuit have been laid out, very little is known about the important period in between and how individual elements bind together to construct a functional circuit. This proposal is aimed at bridging this gap in knowledge, by addressing the long-standing question of how genes and activity interact during development to establish the correct wiring of excitatory and inhibitory cells in cortical sensory areas. As the primary role of inhibitory cells is to shape the flow of information transfer in the brain, they are well positioned to contribute significantly to the distinct modes of information processing performed in different cortical areas. Considering that dysfunction of cortical inhibitory circuits has been proposed as a major contributor to the etiology of neuropsychiatric-neurodevelopmental disorders, it is my hope that this approach will not only provide insights into the making of the healthy brain, but also into clinically relevant pathologies.
Partners: Technion – Israel Institute of Technology
Organisms across all kingdoms share several systems that are essential to life, one of the most central being protein synthesis. Living in a continuously changing environment, cells need to constantly respond to various environmental cues and change their protein landscape. In extreme cases, cells globally shut down protein synthesis and upregulate stress-protective proteins. Mechanisms of translational repression or selective enhancement of stress-induced proteins have been characterized, but their effects were demonstrated on an individual mRNA basis. Which target mRNAs are translationally regulated in response to different environmental cues, and what are the cis-regulatory elements involved, largely remain as open questions. Using ribosome footprint profiling, I recently discovered a novel mode of translational control in stress, underscoring the potential of new technologies to uncover novel regulatory mechanisms. But while transcription cis-regulatory elements have been thoroughly mapped in the past decade, and splicing regulatory elements are accumulating, the identification of translation cis-regulatory elements is lagging behind. Here I propose to crack the mammalian translation regulatory code, and close this long-standing gap. I present a novel interdisciplinary framework to comprehensively identify translation cis-regulatory elements, and map their mRNAs targets in a variety of cellular perturbations. Importantly, we plan to explore mechanisms underlying novel cis-regulatory elements, and create the first genome-wide functionally annotated translation regulatory code. The translation regulatory code will map targets of existing mechanisms and shed light on newly identified pathways that play a role in stress-induced translational control. The proposed project is an imperative stepping stone to understanding translational regulation by cis-regulatory elements, opening new avenues in the functional genomics research of translational control.
Synthetic biology is an emerging discipline that offers powerful tools to control and manipulate fundamental processes in living matter. We propose to develop and apply such tools to modify the genetic code of cultured mammalian cells and bacteria with the aim to study the role of lysine acetylation in the regulation of metabolism and in cancer development. Thousands of lysine acetylation sites were recently discovered on non-histone proteins, suggesting that acetylation is a widespread and evolutionarily conserved post translational modification, similar in scope to phosphorylation and ubiquitination. Specifically, it has been found that most of the enzymes of metabolic processes—including glycolysis—are acetylated, implying that acetylation is key regulator of cellular metabolism in general and in glycolysis in particular. The regulation of metabolic pathways is of particular importance to cancer research, as misregulation of metabolic pathways, especially upregulation of glycolysis, is common to most transformed cells and is now considered a new hallmark of cancer. These data raise an immediate question: what is the role of acetylation in the regulation of glycolysis and in the metabolic reprogramming of cancer cells? While current methods rely on mutational analyses, we will genetically encode the incorporation of acetylated lysine and directly measure the functional role of each acetylation site in cancerous and non-cancerous cell lines. Using this methodology, we will study the structural and functional implications of all the acetylation sites in glycolytic enzymes. We will also decipher the mechanism by which acetylation is regulated by deacetylases and answer a long standing question – how 18 deacetylases recognise their substrates among thousands of acetylated proteins? The developed methodologies can be applied to a wide range of protein families known to be acetylated, thereby making this study relevant to diverse research fields.
Partners: University of Sheffield, Cardiff University, University of St Andrews, Heriot-Watt University, Hitachi Cambridge Laboratory, Swiss Federal Insitute of Technology, TREL
We seek to exploit the highly advantageous properties of III-V semiconductors to achieve agenda setting advances in the quantum science and technology of solid state materials. We work in the regime of next generation quantum effects such as superposition and entanglement, where III-V systems have many favourable attributes, including strong interaction with light, picosecond control times, and microsecond coherence times before the electron wavefunction is disturbed by the environment. We employ the principles of nano-photonic design to access new regimes of physics and potential long term applications. Many of these opportunities have only opened up in the last few years, due to conceptual and fabrication advances. The conceptual advances include the realisation that quantum emitters emit only in one direction if precisely positioned in an optical field, that wavepackets which propagate without scattering may be achieved by specific design of lattices, and that non-linearities are achievable at the level of one photon and that quantum blockade can be realised where one particle blocks the passage of a second. The time is now right to exploit these conceptual advances. We combine this with fabrication advances which allow for example reconfigurable devices to be realised, with on-chip control of electronic and photonic properties. We take advantage of the highly developed III-V fabrication technology, which underpins most present day solid-state light emitters, to achieve a variety of chip-based quantum physics and device demonstrations. Our headline goals include reconfigurable devices at the single photon level, a single photon logic gate based on the fully confined states in quantum dots positioned precisely in nano-photonic structures, and coupling of states by designed optical fields, taking advantage of the reconfigurable capability, to enhance or suppress optical processes. Quantum dots also have favourable spin (magnetic moments associated with electrons) properties. We plan to achieve spins connected together by photons in an on-chip geometry, a route towards a quantum network, and long term quantum computer applications. As well as quantum dots, III-V quantum wells interact strongly with light to form new particles termed polaritons. We propose to open the new field of topological polaritonics, where the nano-photonic design of lattices leads to states which are protected from scattering and where artificial magnetic fields are generated. This opens the way to new coupled states of matter which mimic the quantised Hall effects, but in a system with fundamentally different wavefunctions from electrons. Finally our programme also depends on excellent crystal growth. We target one of the main issues limiting long term scale up of quantum dot technologies, namely site control. We will employ two approaches, which involve a combination of patterning, cleaning and crystal growth to define precisely the quantum dot location, both based around the formation of pits to seed growth in predetermined locations. Success here will be a major step in bringing semiconductor quantum optics into line with the position enjoyed by the majority of established semiconductor technologies where scalable lithographic processes have been a defining feature of their impact.
In the last several decades, it has been extensively studied how strategic behavior of economic agents could affect the outcomes of various institutions. Game theory and mechanism design theory play key roles in understanding economic agents' possible behavior in those institutions, its welfare consequences, and how we should design economic institutions to achieve desired social objectives even if the agents behave strategically for their own interests. However, existing studies mostly focus on somewhat narrow classes of economic environments by imposing restrictive assumptions. The proposed projects aim at providing novel theoretical frameworks which enable us to study agents' behavior and desirable institutions under much less assumptions. I believe that the projects have significant relevance in policy recommendation in practice and empirical studies, even though the proposed projects are primarily theoretical. In mechanism design, most papers in the literature focus on environments with independently distributed private information. We propose two novel (robustness-based) approaches to analyze mechanism design in correlated environments, motivated by their practical and empirical relevance. The robustness brought by my approach can be useful to mitigate certain types of misspecifications in mechanism design in practice. Moreover, the desirable robust mechanisms I obtain appear to be more sensible, and hence, can be useful for empirical studies of auction and other mechanism design problems. In game theory, it is often assumed that the game to be played is common knowledge, or even with uncertainty, uncertain variables are assumed to follow a common-knowledge prior .However, in many situations in reality, those do not seem to be satisfied. Our goal is to provide a novel theoretical framework to predict players' behavior in such incompletely specified games, and to identify conditions for (monotone) comparative statics. Both could be useful in empirical studies.