The long-term consequences of exposure to excess stress on the initiation and progression of many age-related diseases are well established. The period of intrauterine life represents among the most sensitive developmental windows, at which time the effects of stress may be transmitted inter-generationally from a mother to her as-yet-unborn child. The elucidation of mechanisms underlying such effects is an area of intense interest and investigation. Aging, by definition, occurs with advancing age, and age-related disorders result from exposures over the life span of factors that produce and accumulate damage. The novel concept advanced in this proposal is that the establishment of the integrity of key cellular aging-related processes that determine variation across individuals in the onset and progression of age-related disorders may originate very early in life (in utero) and may be plastic and influenced by developmental conditions. We propose that telomere biology and the epigenetic DNA methylation-based aging profile (DNAmAGE) represent candidate outcomes of particular interest in this context. A prospective, longitudinal cohort study of 350 mother-child dyads will be conducted from early pregnancy through birth till one year of age. Specific hypotheses about the effects of maternal stress and maternal-placental-fetal stress biology on newborn and infant telomere length, telomerase expression capacity, and DNAmAGE will be addressed. Serial measures of maternal psychological, behavioral and physiological characteristics will be collected across gestation using an innovative ecological momentary assessment (EMA) based real-time, ambulatory sampling protocol. The proposed study will help identify new strategies for risk identification and primary and secondary interventions to augment current efforts to prevent, delay and ameliorate age-related disorders.

Demographic change includes population ageing, and incidence rates begin to increase for many types of cancer in middle-aged and elderly people. Traditional cancer treatment includes surgery, chemotherapy, and radiation therapy, while tumour immunotherapy by T cell receptor (TCR) gene transfer represents an alternative form of treatment. The transfer of tumour-specific TCR genes into patient’s peripheral blood lymphocytes targets cancer specifically and effectively. But while patient-derived low-affinity TCRs do not show therapeutic activity, optimal-affinity TCRs, as isolated from newly-generated antigen-negative humanized mice with a diverse human TCR repertoire, can effectively delay tumour regression. X-ray crystallography is a powerful tool of structural biology, which helps researchers to identify the three-dimensional (3D) structures of biological macromolecules such as TCRs complexed to their cognate peptide-loaded major histocompatibility complex (pMHC) molecules. Recent research uncovered the docking topologies of naturally selected TCRs, but therapeutically efficient optimal-affinity TCRs recognizing tumour-associated self-antigens, have not been analysed to date. The exceptional specificity of TCRs is determined by three complementarity-determining regions (CDRs) of the TCR alpha- and beta-chains. Biomedical research on TCR gene therapy and design of future clinical trials will hugely benefit from the identification of CDR-mediated contact points made between therapeutic TCRs and the pMHC on their target cells. TCRabX is an interdisciplinary research project investigating the 3D structures of 13 TCRs complexed to MHC-I or MHC-II, respectively. It connects innovative clinical immunology research in Berlin/Germany and world-class structural biology research in Melbourne/Australia. The proposed research will enhance the health and well-being of citizens in Europe and worldwide by supporting the advancement of cancer immunotherapy approaches.

Cellular interactions are of fundamental importance in life, orchestrating organismal development, tissue homeostasis and immunity. In the immune system, cell-cell interactions act as central hubs for information processing and decision making that collectively determine the outcome of complex immune responses. In leukemias, a cancer originating from immature immune cells, a multilayered network of cellular interactions between immune and leukemic cells underlies effective immune control of the cancer, immune evasion and response to immunotherapies. However, technical limitations in studying cell-cell interactions restrict our understanding into these highly complex and dynamic processes. In order to overcome this limitation, I propose to develop a novel ‘interact-omics’ approach, capable of characterizing millions of cellular interactions across complex organ systems, entire organisms and patient cohorts. Applying the ‘interact-omics’ approach to sophisticated leukemia mouse models will enable us to dissect the dynamic cellular interaction networks between antigen-specific T cells, bystander immune cells and leukemic cells that drive anti-leukemia immunity and immune evasion. In combination with the in vivo perturbation of cellular interactions, this will allow us to systematically decode the cellular logic of how the complex leukemia-immune interplay determines the disease course. Additionally, by making use of leukemia patient cohorts which are either responsive or non-responsive to immunotherapy treatment, we will unravel previously unknown therapy resistance mechanisms and predict therapy response. Together, our approach will set the basis for a comprehensive understanding of the leukemia-immune cell crosstalk underlying immune control, immune escape and therapy response, and may serve as a blueprint to fundamentally expand our insights into other biological processes driven by cellular interactions.

The most pressing global health challenges of our time require strong partnerships for multi-stakeholder exchange and appropriate policy responses. Against this background, the World Health Summit would like to strengthen its collaboration with expert organizations such as Wellcome Trust, to make a greater contribution to policy-making in the field of global health research and strengthen scientific and political activity in Berlin and beyond in the spirit of the sustainable development goals.

Five out of ten diseases leading to long term-disability are related to the brain, including stroke, depression or dementia. Despite tremendous progress in neurotechnology, there is still no effective treatment option available for many brain-related disorders. A very promising approach to treat brain disorders uses transcranial electric or magnetic stimulation (TES/TMS) to directly influence brain activity related to specific symptoms. However, these methods are limited in their spatial resolution, specificity and ability to reach deep brain areas. The aim of the proposed project is to develop a technical and experimental proof-of-concept for a new non-invasive tool that allows for millimeter- and millisecond-precise modulation of neural activity in superficial and deep areas of the human brain. Capitalizing on temporal interference effects, the device will apply high carrier frequency magnetic fields through a pair of coils. By modulating their relative phase, the combined fields will induce a locally amplitude-modulated electric field in the brain. As neural tissue is insensitive to unmodulated high-frequency fields (>1kHz), but responds to low-frequency amplitude-modulated fields, only brain regions will be stimulated where the combined field is amplitude-modulated. Building on the resulting versatility of stimulation frequencies and waveforms, we aim at providing proof for cell-type specificity of such temporal interference magnetic stimulation (TIMS). Moreover, we aim at providing proof for the feasibility of targeting neural activity at millisecond-to-millisecond precision. Availability of such device offering high spatial resolution, depth selectivity, steerability, as well as closed-loop-compatibility and cell-type specificity would mark a major break-through for clinical neuroscience. Together with two partners from industry and a partner for technology transfer, we strive for fast translation of expected research results into innovative products.