Major Depression (MD) is often chronic and characterized by frequent recurrences of symptoms and burden. The need to better understand how and when relevant transitions in symptoms occur is urgent. A seemingly unsolvable scientific problem is the enormous etiological complexity of mental disorders such as MD, involving continuously ongoing gene-environment interactions that act in highly person-specific ways. This hampers accurate assessment of personalized risk. I will use an out-of-the-box and interdisciplinary approach to tackle this problem. MD is not the only phenomenon that is influenced by many factors, is unpredictable and makes sudden transitions. This is also the case for other so-called complex dynamical systems such as climate or water quality of lakes. For the latter systems generic early warning signals (EWS) have been found that indicate the approach of a transition. I hypothesize that transitions in mood can be anticipated using the same generic EWS as reported for other complex dynamical systems. Finding direct evidence for this hypothesis requires a completely novel approach in the field of psychiatry, which would involve (i) a design that captures data of the complete dynamic process within a single individual in order to detect the timing of EWS and sudden transitions in symptoms, prospectively and intra-individually, and (ii) frequent replications of these individual experiments. With help of recent technology and my acquired expertise I will use precisely this novel approach to search for personalized EWS that anticipate critical transitions in depression. This is the aim of my project. Evidence that transitions in mood behave according to principles of complex dynamical systems would change the field majorly. First, it would lead to a new understanding of mental disorders and the way we study them. Second, it would yield a sophisticated novel way of obtaining personalized and clinically relevant information on risk for transitions.

My goal is to optically detect the magnetic resonance of free radicals/ROS inside cells. Radicals are suspected to play a crucial role in numerous pathogenic conditions including diseases responsible for most deaths worldwide (as arteriosclerosis, cancer, immune responses to pathogens). They are also involved in many processes in healthy cells as mitochondrial metabolism or aging of cells and part of the working mechanism of many drugs. Despite their relevance relatively little is known about where and when radicals are built, how they work or which ones play a role. Their short lifetime and reactivity poses a problem for many state of the art methods. Thus they are often a bottleneck in understanding stress responses. My goal is to develop a method, which can detect their magnetic resonance in the nanoscale. The method is based on a fluorescent defect in diamond, which changes its optical properties based on its magnetic surrounding. While this technique has been able to detect even the faint signal of a single electron spin, this technique is entirely new to biological fields. We can localize where, when and how much of a certain radical is generated with nm resolution. This is impossible with the current state of the art. Furthermore, since we obtain spectra we can also differentiate radicals to some extent. I am proposing to investigate two systems: 1) the involvement of radicals in the aging of yeast cells 2) the response of macrophages to stress. In the first project I will test the so-called free radical theory, which states that organisms age because cells accumulate free radical damage over time. In the second project I will answer the question how a macrophage reacts to the impact of a pathogen or a drug. Outcomes of this project would enable us to increase our understanding on how stress responses work on a molecular level. This will open up new possibilities to assess if and how drugs are working or how and why certain pathogens are worse than others.

Melanoma is the most aggressive type of skin cancer, and its spread to distal tissues is often a death sentence. Immunotherapies have led to increased survival rates but they are extremely expensive and efficient for approximately only 25% of patients. Therefore research into new methods to prevent or arrest the progression of melanoma is urgently needed. Nevi are pigmented lesions on skin which consist of a clonal mass of melanocytes in a state of proliferative arrest termed ‘senescent’. This state prevents further hyperplasia, but if mutations occur in proteins required to maintain senescence, cells can re-proliferate and progress into melanoma. Selectively clearing senescent melanocytes may therefore be an effective strategy to improve current preventative measures against melanoma. This project will use a combination of interdisciplinary techniques to identify and target molecular components that confer survival to senescent melanocytes. First, I will use whole-transcriptome analysis to identify novel genes associated to cell survival. Second, genes of interest will be validated via siRNA mediated gene silencing in vitro using techniques in molecular biology to assess viability and apoptosis. Third, selected targets will be validated in vivo using a unique novel mouse model established in the host laboratory where nevi can be induced and senescent cells can be quantified by luminescence. Successful identification of these targets may lead to future development of new therapies which help reduce the health and economic impacts of malignant melanoma.

Amyotrophic lateral sclerosis (ALS) is a fatal disease that progressively causes loss of neuronal and muscle function, for which there is no known cure. Although the genetic causes of ALS vary, the cytoplasmic accumulation of the TDP-43 protein in neurons is highly consistent among patients. Thus, TDP-43 is believed to be a point of convergence in the pathway responsible for ALS progression. However, while many genetic and cellular mechanisms have been linked to ALS, there is still a lack of understanding of the neuro-muscular interactions in ALS. In this project, we will identify neuronal or muscle cell-specific suppressors of motor impairment using an ALS model in the nematode worm Caenorhabditis elegans. In this model, transgenic C. elegans overexpress TDP-43 in the neurons, resulting in severe motility defects. We will use optogenetic tools to excite neurons and muscle cells separately in the C. elegans ALS model, contributing to our understanding of how TDP-43 accumulation affects tissue function. In addition, live in vivo microscopy of C. elegans will help us to elucidate the impact of TDP-43 on neuro-muscular interactions over time. Furthermore, novel automated tracking of the nematode worms enables high-throughput analysis of C. elegans mobility. Thus, we can efficiently analyse mobility when TDP-43 is overexpressed, and use this tracking for high-throughput screening of mutants that rescue the ALS phenotype. Once we have identified the mutants that Rescue Motility Defects (RescueMoDe), we will characterize their impact on neuronal and muscular function. Therefore, it will be possible to analyse the tissue-specific role of these candidates, and how they fit into the progression of TDP-43 toxicity in this system. Overall, we aim to further the understanding of ALS progression, which will allow a highly informed continuation of studies in mammalian cell culture or in murine model systems, which may lead to therapeutic research opportunities.