Program

The circadian clock, our endogenous time-generating system, regulates behavioral, physiological, and cellular processes. Disruptions to this clock, such as those caused by shift work, jet lag, or genetic alterations, are associated with an increased risk of various diseases, including obesity, diabetes, cardiovascular diseases, and cancer. Circadian medicine, the study of how time affects health and disease, has emerged as a promising approach to enhance health and performance and to optimize treatment timing. However, the potential of circadian medicine is limited by the lack of non-invasive tools for characterizing the circadian clock.
 To address this challenge, we developed TimeTeller, a non-invasive methodology to analyze circadian rhythms. Currently employed in various clinical studies, TimeTeller profiles circadian rhythms based on gene expression measurements. Through mathematical modeling and bioinformatics analysis, we derive predictions regarding optimal time windows for performance and treatment administration.
 By aligning an individual's circadian clock with optimal times for daily routines and incorporating personal health information across lifestyle, care, and research settings, we can improve physical and mental performance and enhance the effectiveness of certain therapies.

The mammalian intestine contains trillions of microbes, a community that is dominated by members of the domain Bacteria but also includes members of Archaea, Eukarya, and viruses. The vast repertoire of this microbiome functions in ways that benefit the host. The mucosal immune system co-evolves with the microbiota beginning at birth, acquiring the capacity to tolerate components of the community while maintaining the capacity to respond to invading pathogens. The gut microbiota is shaped and regulated by multiple factors including our genomic composition, the local intestinal niche and multiple environmental factors including our nutritional repertoire and bio-geographical location. Moreover, it has been recently highlighted that dysregulation of these genetic or environmental factors leads to aberrant host-microbiome interactions, ultimately predisposing to pathologies ranging from chronic inflammation, obesity, the metabolic syndrome and even cancer. We have identified various possible mechanisms participating in the reciprocal regulation between the host and the intestinal microbial ecosystem, and demonstrate that disruption of these factors, in mice and humans, lead to dysbiosis and susceptibility to common multi-factorial disease. Understanding the molecular basis of host-microbiome interactions may lead to development of new microbiome-targeting treatments.

This seminar will highlight groundbreaking findings from four recent Randomized Controlled Trials (RCTs) – DIRECT, CASCADE, CENTRAL, and DIRECT PLUS – exploring the significant impacts of lifestyle and dietary interventions on aging. The  2-year Dietary Intervention Randomized Controlled Trial (DIRECT) and  a 4-year follow-up (A Dietary Intervention- Randomized Controlled Trial (DIRECT) Study), compared the effects of dietary strategies on cardiometabolic risk and plaque regression. The 2-year CASCADE trial(The CArdiovasCulAr Diabetes & Ethanol (CASCADE) Trial), addressed the effect of moderate alcohol in type 2 diabetes. The  CENTRAL (Diet and Body Composition (CENTRAL)) whole-body MRI trial focused on dynamic of human-specific fat depots and fuel metabolism across dietary strategies. The DIRECT PLUS trial (Effects of Green-MED Diet Via the Gut-fat-brain Axis (DIRECT-PLUS)) explored the effect of the diet and specific high- polyphenols foods as Mankai on the gut-fat-brain axis. In this trial, new horizons were explored related to Autologous Fecal Microbiota Transplantation, brain atrophy attenuation, and epigenetics. The talk will discuss transformative effects of various dietary interventions to significantly reduce age-related health decline. The seminar will cover reductions in vascular stiffness, carotid atherosclerosis, and brain atrophy, emphasizing the role of diet and exercise in promoting cardiovascular and cognitive longevity. The lecture will discuss the crucial role of the gut microbiome in aging and how dietary patterns optimize its composition and will gain insights into epigenetic changes and their influence on biological aging, showcasing how interventions can attenuate the aging process beyond weight loss.

Liquid Biopsy has been defined as the analysis of tumor cells or products released from primary or metastatic tumor tissues into the blood or other body fluids. Over the past ten years, CTCs, ctDNA and extracellular vesicles have received enormous attention as new biomarkers and subject of translational research. In particular, CTC and ctDNA research has opened new avenues for a better understanding of tumor biology in cancer patients, including intra-patient heterogeneity and evolution towards resistance to therapy. Although both biomarkers are already used in numerous clinical trials, their clinical utility is still under investigation with first promising results. Clinical applications include early cancer detection, improved cancer staging, early detection of relapse, real-time monitoring of therapeutic efficacy and detection of therapeutic targets and resistance mechanisms. In particular, interventional clinical studies are required to demonstrate clinical utility of liquid biopsy as an important prerequisite for the introduction of this new diagnostic approach into clinical practice. Moreover, assay harmonization and standardization as conducted by international consortia like the European Liquid Biopsy Society (ELBS; www.elbs.eu) is essential. Here, I will discuss the potential and current challenges of liquid biopsy research for understanding human cancer biology and the implementation of this new diagnostic approach into clinical studies with emphasis on solid tumors.

Over the past decade, technological and computational advancements have dramatically improved our ability to collect high-dimensional, medically relevant data across nearly all molecular levels, including the genome, transcriptome, proteome, and metabolome. While the rapid analysis of such data has become feasible, it is currently integrated into clinical practice only for a few conditions, such as cancer and certain monogenic diseases, including rare immune deficiencies. 
I will use chronic inflammatory diseases (CIDs) as an example to highlight the challenges and opportunities in translating systems medicine into routine clinical care. CIDs are emerging diseases associated with our industrialized, urban lifestyle, affecting various organ systems such as the skin, joints, or gut. These diseases account for the highest medication costs across Europe and the US. I will summarize recent systems-based approaches from e:Med projects that address unmet clinical needs in CIDs, particularly focusing on the issue of inadequate therapy response. In CIDs, multiple targeted therapies that neutralize specific immune system factors have been approved. However, these therapies are expensive and face high rates of primary and secondary non-response. Currently, no molecular rationale or biomarker exists to guide the selection of a specific therapy for individual patients. Our recent work aims to understand the immunological network states and dynamic shifts associated with response and non-response to different biologics, such as inhibitors of TNF or adhesion molecules. We employ multimodal clinical diagnostics and multi-omics approaches (including transcriptome, DNA methylome, and microbiome analyses) in longitudinal studies. The goal is to develop a systems-based decision support tool that helps select the right therapy at the right time and to establish new molecular definitions of optimal disease control, similar to the concept of minimal residual disease in cancer, for these incurable conditions.
 

The field of systems medicine is transforming our understanding of cardiovascular diseases by integrating large-scale population data from cohort studies with innovative translational approaches. This interdisciplinary strategy enables the identification of novel biomarkers and molecular mechanisms underlying CVD development and progression, providing the basis for translation into clinical applications.
This lecture will provide an overview of our translational systems medicine approaches, ranging from the molecular identification of target molecules and their experimental characterization to digital strategies for clinical diagnostics. The talk will present the results of the e:Med Junior Research Group symAtrial on the biomarker long-chain acyl-carnitine, which has demonstrated arrhythmogenic potential and involvement in the development of atrial fibrillation. Moreover, data will be shared on the newest digital strategies for the diagnosis of myocardial infarction and the steps toward exploitation and clinical application. These translational approaches are examples of how innovative research can bridge the gap between molecular discoveries and clinical practice, paving the way for more personalized diagnostics and treatments.
 

Liver disease is on the rise, particularly in developed countries, driven by unhealthy diets, alcohol consumption, and sedentary lifestyles. For almost 20 years, a dedicated community of clinicians, experimentalists, and modelers has been intensively working on advancing systems medicine approaches to gain insights into functionalities in the liver and to establish mathematical models for the prediction of disease development. Based on these developments in 2021, the LiSyM-Cancer network now focusses on harnessing this knowledge to improve prevention and early detection of hepatocellular carcinoma (HCC).
The main objectives of the LiSyM-Cancer network are the development of mechanism-based clinical support tools that provide clinicians with insights into a patient’s condition without requiring invasive procedures. In addition, these findings are to be translated into risk prediction models that estimate the HCC risk of individual patients on the basis of clinically applicable scores and thus enable early clinical intervention.
To achieve these goals, the network is organized around three main pillars, each with a specific focus: SMART-NAFLD aims to explore how metabolic alterations in the context of fatty liver disease change proliferation control in liver cells and thereby foster HCC development in the absence of cirrhosis. CTIP-HCC focuses on describing the transition of cirrhotic livers into HCC, and DEEP-HCC is dedicated to an in-depth characterization of HCC. 
Together, we hope to enhance patient care by supporting clinical decisions and optimizing the use of available resources.

Chronic inflammatory disease (e.g. Inflammatory Bowel Disease, rheumatoid Arthritis, etc.) are characterized by a systemic disease behavior requiring long-life pharmacological intervention. Despite the introduction of targeted therapies (e.g. anti-TNF, anti-IL12/23, etc.) the overall long-term remission rate is low and leads to frequent changes in drug therapy. Although several strategies are pursued to develop biomarker for individual therapy stratification, the path towards clinical implementation of molecular biomarker into routine medicine is still unclear. Within the “Molecular Inflammation Board on stage” we will discuss and exemplify in real-world IBD cases, how implementation of molecular medicine can be translated into patient care.

Large-scale, unbiased proteomics studies are constrained by the complexity of e.g. the plasma proteome. The Proteograph™ technology is a highly parallel protein quantitation platform integrating nanoparticle (NP) protein coronas with liquid chromatography-mass spectrometry for efficient proteomic profiling.
Its performance in different biological or clinical studies has been demonstrated, e.g. oncology, neurology, ageing research or metabolomic disease. Low input material as well as other starting samples, like Cerebrospinal fluid (CSF), cell media (for secretome analysis) or tissue homogenate showed its wide applicability and the species agnostic approach makes it adaptable for other model organisms like mouse, rat, cat, pig, monkey and many more.
The streamlined workflow combines depth of coverage and throughput with precise quantification based on unique interactions between proteins and NPs engineered for deep and scalable quantitative proteomic studies.
 

Olink Proteomics for systems medicine: Predict the future of patients – prevent complex diseases
Olink Proteomics combines the specificity of antibodies with the sensitivity and scalability of qPCR and NGS, the patented method is called PEA or Proximity Extension Assay. 
PEA can be used to identify protein signatures in large scale projects as shown with UK Biobank PPP (Pharma Protein Project) and more than 54 thousand participants sampled over the course of 10 years, just using few µl of blood with large Olink Explore panels, up to 5400 protein assays with NGS read out. The same biomarkers once identified as part of a signature can be used again with a smaller and clinical focussed panel for applied use and our Q100 Signature qPCR instrument.
More than 2100 peer reviewed publications show the future clinical utility already clearly. Two examples will be used:
1.    Proteomic signatures improve risk prediction for common and rare diseases, Carrasco-Zanini J, Pietzner M, Davitte J et al., 2024. Nature Medicine, 218 diseases could be studied (with more than 80 cases in the UK biobank PPP cohort), with 67 mainly complex diseases a signature of 5-20 proteins was superior for early detection compared with the standard of care today!
2.    Proteomic aging clock predicts mortality and risk of common age-related diseases in diverse populations, Argentieri MA, Xiao S, Bennett D, et al., 2024, Nature Medicine, from 204 proteins and their expression an aging clock could be generated, useful to improve the early detection of many age-related diseases. This aging clock could be validated also in two independent cohorts from China and Finland to demonstrate its robustness.