This work leverages cutting-edge genomic and shape analysis methods to study the evolution of mammalian cooperative societies. Current approaches to studying vertebrate cooperative behavior work in the classical, but mechanism-free, frameworks of behavioral ecology and life history theory. Thus, while cooperation itself is of long-standing interest, we know little about how animals that occupy distinct roles in cooperative societies differ at the molecular level.
Here, we propose to integrate new molecular and computational approaches with a 24-year field study of the most cooperative nonhuman mammal yet described, the meerkat. Like cooperative insects, meerkat societies are characterized by a division of social roles: adults are dominant breeders or morphologically and physiologically distinct helpers, who feed and guard the breeders’ young. However, all helpers retain the capacity to transition to breeder throughout life. Meerkats thus present an exceptional opportunity to study alternative phenotypes in cooperative societies. We will first investigate how helpers and breeders are differentiated at the gene regulatory level, including whether steroid hormone signaling generates these differences. Second, we will test social role-driven differences in growth and immune defense. We will track growth by developing computational geometry-based approaches to perform 3D skeletal reconstructions from X-ray data and immune defense using experimental pathogen challenges. Finally, we will test the hypothesis that the competing demands of growth, reproduction, and immune defense create “competition” at the transcriptional level, which is resolved differently by helpers and breeders. Our experiments will not only quantify phenotypic transition-associated trade-offs, but also identify the genes and pathways that mediate them.
The methods required for these analyses either do not exist or will need to be generalized to field studies for the first time. Thus, this study requires collaboration across behavioral ecology, genomics, immunology, and computational image analysis. Together, it will contribute a powerful model for applying modern tools to long-standing puzzles in evolution and behavior. It will also yield new insight into the molecular changes involved in the evolution of cooperative societies—a subject of fascination and controversy for almost two centuries.

Pre-implantation development in mammals involves complex processes at the level of genomic organization, DNA methylation and transcriptional activity, leading to embryonic genome activation. How different epigenetic markers interact in single mouse blastomeres at early stages of development to influence the transcription of genes, and to what extent these processes vary from cell to cell and between embryos, is not fully understood. Although, in recent years a number of methods that enable single-cell omics measurement have been described, their integration to measure more than one entity in a single cell has remained challenging. Here, I propose a novel strategy for the integrated measurement of different epigenetic markers in combination with the measurement of nascent transcripts in single cells. The strategy relies on the use of a combination of specific restriction enzymes, for the measurement of 5-methylcytosine (MspJI), 5-hydroxymethylcytosine (AbaSI) and accessible chromatin (MseI and/or NlaIII), as well as 2’-fluoro GTP analogues in combination with specific RNases for the measurement of nascent transcripts. The application of these technologies to pre-implantation mouse embryos will shed light into the relationships of different epigenetic markers and their influence on transcription at the single cell level, and how these processes result in cell differentiation during early development. I further propose to use new deep-learning libraries, such as TensorFlow or Caffe, to quantitatively model and gain understanding of these dynamic processes in single blastomere cells.

The poor regenerative capacity of central nervous system (CNS) neurons leads to devastating and irreversible outcomes after injury or disease. The CNS is an immune privileged site, which maintains specialized crosstalk with the immune system. While the immune response to acute injury in the CNS is very similar to the wound healing process in other parts of the body, this response is oftentimes insufficient to achieve significant repair and restoration of neuronal function. One of the key challenges in analyzing this response is the diversity of the types of cells that participate in the process, which change with time and some of which may be unknown. Cutting-edge advances in massively parallel single-cell genomics, many pioneered by the Regev lab, will now enable me to analyze the entire injured tissue, at high, single-cell resolution, that takes on its complexity, heterogeneity, and temporal variation. Using this approach and comparing low- and high-regeneration states could help identify junctions where the immune response is insufficient to support regeneration, new cell types involved in the process, and targets for therapeutic intervention. Emerging cellular and molecular candidates will be perturbed experimentally in vitro and in vivo, using CRISPR/Cas9 technology and cell augmentation and depletion experiments, to validate their significance for neuronal regeneration. Human samples will be incorporated to establish validity in the clinical setting. The findings could be relevant for different types of CNS trauma, inflicted though mechanical or biochemical injury, autoimmune, neurodegenerative or vascular disease, at the brain, eye and spinal cord.

For individual genes, the number of transcripts per cell typically increases with cell size, yet how this is achieved is unknown. Recent image-based analysis suggests that both cell volume and surface area contribute to this regulation, with distinct classes of genes showing tighter correlations with either one of these two features. Here, I aim to go beyond these correlations – dissecting the mechanism by which cell geometry shapes the transcriptome. First, using quantitative RNA-sequencing and RNA metabolic labelling in cells with a range of defined shapes and sizes, I will define genome-wide classes of transcripts that scale with cell volume and surface area, and analyze the extent to which regulation of transcription and RNA stability contribute to this scaling. High-resolution mapping of changes in chromatin accessibility and modification state in these constrained cells will also be used to reveal the basis of transcriptional control and to suggest DNA-binding factors involved. Second, high-throughput image-based quantification of specific transcripts in single cells will be combined with genome-wide genetic screening. For each single-gene knockdown, this will generate a multivariate dataset containing the absolute abundance of a panel of selected transcripts in addition to hundreds of single-cell and population-context features. I will specifically identify and pursue genetic perturbations that disrupt the scaling of transcript abundance with either cell volume or area. Following these unbiased approaches with hypothesis-driven experiments and mathematical modeling will provide insight into how single cells precisely adapt genome expression to cell size and shape.

Human mobility is made possible by skeletal muscles, a voluntary tissue under the control of the central nervous system. Upon injury or insult, skeletal muscle regenerates to restore its form and function. Muscle regeneration requires an adult stem cell population termed satellite stem cells (SCs) that reside in a specialized ‘niche’ atop the sarcolemma of multinucleate myofibres and ensheathed by a proteinaceous matrix. Most of the time SCs are quiescent; a state characterized by inactivity. Injury induces SCs to activate and produce committed progenitors called myoblasts that fuse into multinucleate myofibres. In the present state of our knowledge, SC activation is an essential and intriguing process that is not well understood. Although SC activation is tightly controlled in the body, when SCs are removed from the body and studied in two-dimensional culture, activation is the default state. This observation points to the enticing possibility that physical or structural aspects of the three-dimensional tissue microenvironment might contribute to the spatial and temporal control of SC activation. In particular, we hypothesize that injury rapidly alters the SC niche mechanical stress profile and that this serves to engage intracellular mechanisms that tip the balance in favor of SC activation over quiescence by directly altering transcriptional activity in a highly localized manner. The Gilbert (Canada) and Betz (Germany) labs share a common interest in resolving the impact of mechanical stresses on cellular fate, and the Darzacq (USA) is driven by a curiosity as to how the nuclear environment imposes on the fundamental rules of gene regulation. By joining efforts in an international collaboration, we aim to (a) define the mechanical stresses (e.g. compressive, shear) exerted on SCs in resting and regenerating niches and (b) determine the molecular implications of niche mechanics as they relate to the SC transcriptome in the native niche, for the first time. We will integrate our three distinct experimental approaches – SC cell and molecular biology (Gilbert), quantitative biophysics (Betz), and high resolution single molecule imaging of transcription factor binding and nascent transcript activity (Darzacq), to conduct a collaborative study and achieve a holistic understanding of the earliest events that evoke SC activation in the native niche.

Sleep takes approximately one third of our lives yet its functions remain elusive. Extensive efforts have been made and hypotheses raised to link sleep with synaptic plasticity and memory consolidation. The sleep/wake pattern and sleep architecture evolve as development proceeds, and so does cortical connectivity, as featured by spinogenesis in early postnatal life and spine pruning during later adolescence. Several subcortical neuromodulators, including hypocretin, norepinephrine and dopamine, play critical roles in promoting arousal and thus control the sleep/wake cycle. We hypothesize that these arousal circuits help to shape the synaptic connections in cortex during development and the disruption of coherent sleep/wake cycle at certain developmental stages may cause defects in brain functions in adulthood. Mechanistically, synapses “tagged” by the arousal inputs during the previous wake phase may be selectively strengthened while other “untagged” synapses weakened in the following sleep. We will combine a series of state-of-art techniques including optogenetic and/or chemogenetic manipulations, viral tracing, two-photon live imaging as well as fiber photometry to interrogate these hypotheses, which will broaden and deepen our understanding towards sleep and brain plasticity in a developmental point of view and provide potential clinical insights on sleep and arousal disorders.

Living cells organize their interior in a non-random, polarized manner to carry out specialized biological functions. Cell polarity arises from a complex interplay between the plasma membrane, associated proteins and cytoplasmic molecules. In eukaryotic cells, symmetry is in most cases initially broken at the level of membrane-bound molecules such as phosphatidylinositol lipids and Rho-type GTPases. These conserved signaling hubs synergistically control cell morphogenesis and movement through the actin cytoskeleton. While many of the components of these intimately linked systems have been defined, very little is known about the biochemical mechanisms underlying cell polarity and shape changes. Instead of studying intracellular pattern formation and actin assembly in the complex cellular environment, I want to establish the minimal requirements for these processes by re-building them from purified components. To this aim, I will combine multiprotein reconstitution on artificial membranes with advanced fluorescence imaging techniques and employ synthetic biology methods. Specifically, I aim to understand (i) how membrane-associated signaling systems self-organize into macroscopic spatial patterns and (ii) how membrane polarity can be harnessed by the actin cytoskeleton to construct distinct structures at opposing ends of the cell. As a whole, this work has the potential to advance our understanding of the mechanistic foundations of cell polarity and morphogenesis at the systems biochemistry level.

The current Zika virus epidemic attracted public attention to the problem of mosquito-borne viral infections. Vector control is an essential element to prevent disease transmission due to the absence of arbovirus-specific drugs and limited availability of vaccines. Historical vector control methods such as the use of insecticides and environmental control are facing challenges due to the wide spread of insecticide resistance throughout natural mosquito populations and the complexity of breeding site elimination in the modern urban environment. Novel genetics-based strategies are emerging as promising complement to historical mosquito control methods. One idea is to genetically-manipulate the vectors so that they become unable to support pathogen infection, replication or transmission. The development of these novel transmission-blocking interventions requires in-depth insights into how mosquito vectors interact with and transmit arboviruses. It is thought that the immune system influences the efficiency by which mosquitoes transmit specific viruses. Recently, a novel immune response was identified that recognizes viral RNA and breaks it down into small fragments. In this project, the investigators will study whether mosquitoes from different locations across the globe differ in this immune response. Moreover, they will analyze how these differences influence transmission of the epidemic Dengue and Zika viruses. The multi-disciplinary research team includes experts in mosquito evolution and genomics, entomology, and virology, allowing a complementary approach to address the research aims. The proposed project will have immediate and profound implications for public health and may lead to novel mosquito control strategies.

The nucleolus is a large, complex, and dynamic nuclear body, whose structure is directly related to its role in producing ribosomes. It consists of three morphologically and compositionally distinct sublayers with liquid like properties, which hierarchically self-organize around transcriptionally active rRNA genes in a process that is poorly understood. Moreover, despite the significance of ribosome biogenesis, little is known about the order and loci of ribosome assembly, and the role ribosomal intermediates play in shaping nucleolar organization. A major difficulty in studying these processes lays in the absence of stable physical boundaries in between the sublayers, which facilitate a continuous flow of pre-ribosomal intermediates and hampers single layer isolation for in vitro analysis. Here I propose to recapitulate immiscible liquid phases of purified nucleolar components onto core particles with tethered rRNA in order to seed nuclei with isolated nucleolar sublayers. I will monitor the recruitment of sublayer specific components from the nucleoplasm into the synthetic layers and study ribosome biogenesis using the immobilized rRNA. The ability to seed nucleolar sublayers will be used to study nucleolar self-organization and to probe compositional changes in each sublayer separately, and to link them to concomitantly occurring ribosome production steps. Furthermore, it offers a means for studying ribosome biogenesis in vivo while restricting ribosome production steps only to those occurring within a specific sublayer, synchronizing the initial rRNA level of assembly, and sequestering ribosomal intermediates.

What underlies the ability to count and where did it come from? This project tests the broad hypothesis that the ability to represent the number of objects in a set (numerosity) has an evolutionarily conserved neural basis, and identifies the cell and molecular processes involved using multidisciplinary analysis in zebrafish. Although a wide range of species are able to estimate numerosities, only in primates has a neural mechanism homologous to humans’ been demonstrated and the underlying cellular processes are unknown. Using automated operant conditioning we train zebrafish to perform numerical tasks and identify lines of fish with differential abilities (e.g. mutants in candidate genes identified from human studies generated using CRISPR). We use 2 photon light sheet imaging of neural activity as wildtype and mutant larvae discriminate numerosities to identify circuits involved. Behavioural analysis will establish the ontogeny and extent of zebrafish’ numerosity. Genetic analysis tests the hypothesis that numerosity has an evolutionarily conserved basis. Neural imaging will test the hypothesis that “number neurons” exist in fish as in primates and indicate the circuits involved.

Our proposal is aimed at discovering the molecular mechanisms underlying the remarkable force-sensing and responsive properties of cellular attachment to the extracellular matrix. Many proteins contribute to the intracellular machinery that links the cytoplasmic domains of the transmembrane integrin adhesion receptors to the actomyosin contractile apparatus within the cell. These integrin adhesion complexes (IACs) provide a paradigm for a distinctive class of subcellular protein complex. Rather than assembling a structure of fixed stoichiometry (e.g. ribosome, centriole) via exclusive interactions, evidence is emerging that IACs engage a dynamic set of heterogeneous interactions that evolve from IAC initiation through maturation to achieve their signaling and mechanical functions.
Thus, we hypothesize that a key feature of IACs is their ability to exchange multivalent interactions between components, so changing their composition in response to diverse inputs, including force, developmental history and location within the organism. We have selected a few pivotal components of the IACs as the focus for our project: namely talin, kindlins, the IPP sub-complex (integrin-linked-kinase (ILK), PINCH, parvin), and vinculin.
To test this hypothesis we will combine Giannone's expertise in live single protein tracking and super-resolution microscopy with Brown's expertise in Drosophila developmental genetics. First we will advance existing methods to achieve the challenging task of quantitative super-resolution imaging within IACs in living tissues. Second, we will develop new tools to image interacting proteins, study their dynamic behavior and alter the interactions. Discovering the regulation of IAC rearrangement will greatly improve our understanding not only of mechanisms mediating Integrin adhesion but also of dynamic macromolecular protein complexes.
By bringing together the contrasting approaches of the two applicants we will gain an exceptional view of how the molecular machinery at integrin adhesion sites has evolved to be able to respond diverse environments and activities within the organism. We anticipate that this will lead to an understanding of general principles directing the progressive formation of macromolecular complexes.

The proposed project will investigate the origin of animal cell contractility through both comparative and experimental evolution approaches in the choanoflagellate Salpingoeca rosetta. The project will address three scales of biological organization: (1) Gene expression. The differential transcriptomic profile of contractile and non-contractile S. rosetta cell types will be determined by single-cell RNAseq. In parallel, I will investigate the function in S. rosetta of the three key myogenic transcription factors of animals (Mef2, SRF and Myocardin) by ChIP-seq and CRISPR/Cas9-based genome editing, and I will determine their interaction partners by pulldown/mass spectrometry. (2) Cellular phenotype. Choanoflagellates show an intense contractile activity during settlement. I will test whether this contractility is controlled by membrane depolarization and calcium influx by live imaging of choanoflagellates expressing calcium/voltage sensors, pharmacological assays, and microelectrode voltage measurements. (3) Multicellular phenotype. S. rosetta develops into spherical colonies of up to 50 cells. In an experimental evolution approach, I will assess whether simple (actomyosin-mediated) departures from this spherical shape can be brought about by consistently applying, over hundreds of generations, selection pressures thought to have favored the early evolution of animal morphogenesis: selection for larger colonies or for benthic feeding from bacterial biofilms.

Due to its high prevalence among birds and high human fatality rate, avian influenza represents a serious and continuing pandemic threat, in particular via mutations that facilitate human infection, resulting in pathogenic strains. Mutations associated with human infection are concentrated in the PB2 subunit of influenza polymerase. This subunit is imported into the nucleus, where viral replication and transcription occurs, via a selective interaction with importin-alpha. Once in the nucleus, interaction of PB2 with protein ANP32A has been proposed to play an essential species-specific regulatory role.

The behavior of PB2 in solution reveals a high level of conformational flexibility that is essential to function. In addition intrinsically disordered domains of both ANP32A and importin-alpha are thought to play important roles in the interaction with PB2. This uncommonly high level of disorder presents particular challenges for structural studies, requiring development of state-of-the-art NMR-based technology.

My aim is to investigate the molecular basis of avian influenza adaptation to nuclear import and replication in human host. I will characterize structurally and dynamically key interactions between human-adapted avian influenza polymerase and human host proteins to contribute to a deeper understanding of viral replication, providing the basic information to facilitate design of innovative drugs.

Viruses of the positive-sense RNA ((+)ssRNA) type are a major class of pathogens. In humans they cause diseases ranging from hepatitis C to viral myocarditis, Zika, Dengue fever and Chikungunya. The extracellular stage of these pathogens, the virus particles, have been studied in great detail often resulting in 3D structures at atomic resolution. Here, we propose to study an intracellular stage of (+)ssRNA viruses which has been more elusive to structural and mechanistic studies. Upon entering a target cell, (+)ssRNA viruses create dedicated organelles called replication complexes (RCs) , in which the viral genome is copied and hidden from detection until it is packaged into new virus particles. Since RCs form on cellular membranes as inseparable parts of the infected cell, they have largely resisted detailed characterisation by established methods of structural and molecular biology.

To overcome this challenge, we will study (+)ssRNA virus RCs using cryo-electron tomography (cET). cET can create 3D images (tomograms) of the interior of cells with a resolution high enough to identify individual macromolecular complexes. These tomograms will reveal in unprecedented detail how replication complexes are constructed from virus proteins and membranes inside the infected cell.

In parallel, we will create synthetic replication complexes from their individual protein-, RNA- and lipid components. The formation and subsequent RNA synthesis by such in vitro reconstituted replication complexes will be monitored by fluorescence microscopy, allowing us to make detailed observations about their molecular mechanisms.

The intestinal epithelium has the complex task of transporting water, ions and nutrients, while providing an efficient barrier to microbes and other potentially harmful luminal constituents. This delicate balance is notably altered in chronic inflammatory conditions of the gut, such as Crohn’s disease.
Luminal nutrients such as glucose have long been recognized as regulators of epithelial permeability. Recently, a role of the enteric nervous system in the control of barrier function has been proposed. Indeed, alterations to either enteric neurons or enteric glial cells leads to dysregulation of epithelial permeability. The structural basis for an interaction between the epithelium, glial cells and nerves has recently been provided, but neither the detailed nature nor the integration of this communication have been examined.
My project aims to investigate how nutrient-sensitive epithelial cells called enteroendocrine cells communicate with enteric glia and nerves in the mucosa to regulate epithelial permeability.
My approach will be to evaluate the signal integration, from the luminal stimulus to the epithelial response. We will use a combination of live cell imaging techniques and fluorescent reporters to visualize the propagation of the signals in living tissues. We will selectively block or release enteroendocrine cell mediators, inhibit enteric glial cells and/or block or stimulate enteric nerves to dissect the various components of this crosstalk.
My project will lead to a comprehensive understanding of signal integration in the intestine between the epithelium and the enteric nervous system, extending the concept of neural control of intestinal barrier function.

Extracellular interactome networks consisting of secreted and cell surface proteins coordinate complex biological processes, including embryonic development, homeostatic regulation and cancer progression. Identification of extracellular protein-protein interactions (PPIs) is central to biomedical science and therapeutics. For example, multiple cell surface and secreted proteins are targets for FDA-approved drugs. However, a description of extracellular PPIs for many of these proteins remains either unknown or incompletely known. We are particularly interested in Wnt signaling that controls the central nervous system (CNS) vascular development and blood-brain-barrier (BBB) formation and maintenance. The CNS vascular dysfunction including BBB breakdown is associated with brain trauma, stroke, multiple sclerosis and neurodegenerative disorders. So far information of extracellular PPIs of Wnt signaling for the development and regulation of CNS vasculature is limited. Here, we aim to utilize and improve an innovative technology for systematic and unbiased methods to identify novel extracellular PPIs related to Wnt signaling for the CNS vascularization and the BBB integrity. We expect to validate novel candidate PPIs using biochemical and biophysical assays. Additional experiments will assess these PPIs and their significance for CNS vascularization using cell culture systems and mouse genetic models. The information obtained from these studies will expand our knowledge of CNS vascular biology and bring a new approach to the study of extracellular interactomes.

The X-ray free-electron laser (XFEL) promises the study of systems that cannot be crystallized and the ability to follow the evolution of structures undergoing reactions or other dynamic processes, overcoming limitations of crystallography (which requires crystals) and cryo-electron microscopy (which requires cooled samples). Both of those methods are fundamentally constrained by the problem of radiation damage, which sets a limit to the exposure that can be tolerated by the sample. The XFEL breaks this limit with very intense and brief X-ray pulses that are shorter than the time atoms can move on the atomic scale, even though the sample is ultimately vaporized. This enhanced dose tolerance has been well demonstrated by high-intensity experiments using protein nanocrystals, where diffraction patterns are collected at many thousands of times higher exposures than is possible otherwise. However, even at these extreme intensities, the diffraction signal of non-crystalline objects is low, comparable to the achievable signals of biological molecules in cryo-electron microscopy (cryo-EM).
We propose to develop radically new methods to image single uncrystallized biological molecules at atomic resolution by XFEL diffraction of nano-engineered samples. By attaching DNA origami structures to the sample we obtain stronger signal than from the molecule alone. The structural information of the sample is built up from millions of diffraction patterns from such samples, collected one at a time at the repetition rate of the XFEL. These patterns can only be fully interpreted to give a three-dimensional (3D) structure of the molecule if they are individually registered to each other in all three orientations (similar to cryo-EM). The flexibility of DNA nanotechnology will be exploited to build structures that align in a flowing jet or orient on a membrane substrate such as graphene. The unknown rotation of the object about the alignment axis will be obtained from signatures based on the designed DNA structure. In addition to boosting the diffraction signal and orienting the molecule, the known DNA origami structure provides a holographic reference to phase the aggregated diffraction intensities and give the 3D electron density map. Our general-purpose technique will be applied to obtain atomic resolution imaging of biological molecules that do not readily crystallize.

The Hsp90 molecular chaperone helps fold and activate 10% of the proteome and 60% of the human kinome. Together with the kinase specific co-chaperone Cdc37 it facilitates the folding and regulation of its client-kinases. This is accompanied by transitions between open and closed Hsp90 conformations triggered by ATP hydrolysis. Recently the closed Hsp90ß:Cdc37:Cdk4 complex was solved by the Agard lab using cryoEM. It reveals that Hsp90ß inactivates Cdk4, through clamping an unfolded ß-sheet and thereby separating the two kinase lobes. I aim to elucidate the biochemical and structural basis for kinase capture and refolding by the chaperone machinery. This might either occur directly by kinase binding to a very different “open” Hsp90ß:Cdc37 complex or involve unfolding by Hsp70 and subsequent transfer to Hsp90ß via a “transfer complex” of Hsp70, Hop, Hsp90ß, Cdc37 and the kinase. I will reconstitute the chaperone system in-vitro to identify key steps and necessary protein components. The kinase folding state will be monitored using ligand/inhibitor binding as well as FRET between the lobes. Using this system, I will also study the role of several co-chaperones including FKBP51, Aha1 and PP5. To allow structural characterization of the important dynamic intermediates by cryoEM, I will trap these states using a variety of strategies and determine their structures to atomic resolution by state-of-the-art cryoEM. In vivo relevance will be assessed by disrupting the underlying interactions in cancer cell lines. This will offer the future perspective to pharmacologically target the identified structural states relevant in many human cancers.

Cardiac hypertrophy from different causes represents a major culprit for premature sudden cardiac death in humans. The infrequently feeding Burmese python exhibits a dramatic change in metabolism after a large meal that requires organs to grow, including physiologic cardiac hypertrophy much as is seen in athletes after exercise. Most interestingly, such growth is reversible and cyclically occurs at every meal. This could be clinically important since regression is not seen in most pathological hypertrophy. With this project, we aim to define the mechanisms that allow the python heart to revert hypertrophy, in the attempt to provide novel insights for regression of cardiac growth in mammals. We hypothesize the presence of one or more factors promoting regression in the python plasma after the peak of digestion. We will test this hypothesis by treating hypertrophied neonatal rat myocytes with python plasma and evaluate cellular dimension as a marker for regression of growth. The sponsor’s laboratory has established this protocol. Once we have defined the trigger responsible for regression of hypertrophy, we will study the mechanisms employed by the python to reduce cardiac mass. We envision the involvement of complex signalling cascades leading to apoptosis and autophagy that are needed to reduce cardiac mass in a controlled manner. Moreover, we will extend our research on established mammalian pathological models of cardiac hypertrophy. We will attempt to activate the same signalling pathways in mammalian models in order to reduce cardiac mass. The results of this project are expected to unveil novel pathways that may lead to therapeutics for cardiovascular diseases.

When plants and animals grow they often develop patterns, such as the spiral arrangement of leaves around a stem or the overlapping pattern of scales on a snake. Some of these patterns are controlled by genes acting to shape the cells, and these patterns have been well studied. However, many biological patterns arise simply from physical forces. These patterns depend on the chemistry of the materials that plants and animals are made of, and on the forces that arise as these materials grow. We hypothesise that a single set of rules governs this mechanical pattern formation, and that these rules will relate to how tissues grow, what they are built of, and how stiff they are. By defining and understanding these rules we will be able to explain a great deal of the diversity of living organisms.
We have chosen to study the formation of a particular type of pattern – buckling, or wrinkling, of layers of the skin. Our team comprises a plant biologist, who will study buckling of the petal surface of Hibiscus trionum, an animal biologist, who will study buckling of the skin of corn snakes, and a polymer engineer, who will model buckling in artificial systems and generate rules and predictions. The two biologists will test these predictions in their different models, and the team will work iteratively to refine the models. The two biologists will also share tools and techniques to enable them to measure the same properties of their different systems.
Our findings are poised to provide new understanding of the universal principles that apply to life, and specifically growth processes in both plants and animals. They will help evolutionary biologists to explain the great diversity of plant and animal form, and will underpin many future applications in which engineers use bioinspiration to generate new materials and structures.