Harald H.H.W. Schmidt

Maastricht University | UM · Department of Pharmacology & Personalised Medicine

For complex diseases, most drugs are highly ineffective, and the success rate of drug discovery is in constant decline. While low quality, reproducibility issues, and translational irrelevance of most basic and preclinical research have contributed to this, the current organ-centricity of medicine and the ‘one disease–one target–one drug’ dogma obs...

Noncommunicable diseases (NCDs) have become globally abundant, yet the therapeutics we use for them are imprecise. In parallel, identifying new treatments has become more costly than ever due to the ever-aggravating efficacy crisis drug discovery faces. What unites these failures is our ontological classification of diseases, primarily based on des...

Nitric oxide (NO) is a widely distributed gasotransmitter binding to the heme of soluble guanylate cyclase (sGC) to stimulate the formation of the second messenger cyclic GMP. In disease, two pathomechanisms can occur, scavenging of NO by reactive oxygen species so that sGC is insufficiently stimulated, and oxidative damage of sGC resulting in heme...

Genomic profiling has shown that not all cancer patients who share similar macro- and microscopical features harbour the same underlying molecular mechanism. This suggests the urge for matching patients to mechanism-based cancer therapies, independent of their primary tumour location and histology (Bashraheel et al. 2020). Currently, precision onco...

Traditional drug discovery faces a severe efficacy crisis. Repurposing of registered drugs provides an alternative with lower costs, reduced risk, and faster clinical application. The underlying mechanisms of complex diseases are best described by disease modules. These modules represent disease-relevant pathways and contain potential drug targets...

Soluble guanylate cyclase (sGC) - cyclic guanosine monophosphate (cGMP) signalling is important for healthy memory function and a healthy vascular system. Targeting sGC-cGMP signalling can therefore be a potential strategy to enhance memory processes. sGC can be targeted by using agonists, such as sGC stimulator riociguat. Therefore, this study aim...

We hardly understand any disease mechanistically and low precision drug interventions are the norm in the clinics [1,2]. Current disease definitions are also organ- and symptom-based which runs the risk that different mechanisms that cause a similar symptom are subsumed under one umbrella term. They are thus converted into one common and complex di...

Stroke is currently the third cause of death and first of disability in industrialized countries. However, translational stroke research has yielded only one thrombolytic and no neuroprotective therapy over the last decades. In fact, only single-drug targets were hitherto pursued leading to no patient benefit and thus obstructing innovation in the...

Cancer is a heterogeneous disease characterized by unregulated cell growth and promoted by mutations in cancerdriver genes some of which encode suitable drug targets. Since the distinct set of cancer driver genes can varybetween and within cancer types, evidence-based selection of drugs is crucial for targeted therapy following theprecision medicin...

Differential gene expression normalised to a single housekeeping (HK) is used to identify disease mechanisms and therapeutic targets. HK gene selection is often arbitrary, potentially introducing systematic error and discordant results. Here we examine these risks in a disease model of brain hypoxia. We first identified the eight most frequently us...

Atherosclerosis and its complications are major causes of cardiovascular morbidity and death. Apart from risk factors such as hypercholesterolemia and inflammation, the causal molecular mechanisms are unknown. One proposed causal mechanism involves elevated levels of reactive oxygen species (ROS). Indeed, early expression of the ROS forming NADPH o...

Cancer is a heterogeneous disease characterized by unregulated cell growth and promoted by mutations in cancer driver genes some of which encode suitable drug targets. Since the distinct set of cancer driver genes can vary between and within cancer types, evidence-based selection of drugs is crucial for targeted therapy following the precision medi...

So far, it’s always been about genes. And most likely you have been considering only the cells of your body and their genes. However, you may have heard that there are microbes in and on us. This refers primarily to bacteria, viruses, and fungi, which in their entirety are referred to as our microbiome. “But it can’t be that important”, you might t...

Sooner or later—depending on whether and how well and quickly biomedical research reforms—all genes and their importance in maintaining health and curing disease will be elucidated. However, you, dear reader, will personally only be able to benefit from this if you also know your own genes and variants. But what exactly does that look like and how...

Let’s go back to my earlier car-in-the-workshop example. What was it again, back in the day? Suddenly, your car’s engine wasn’t pulling right. Once you even stalled on a hill. And now you were at your regular little garage. They had fixed something, replaced a few parts, but tell you when you pick it up that you’ll have to come back every 3 months...

Go digital! Create your digital twin! Have your genome sequenced now, determine your microbiome (or its metabolites), and use an electronic health record. The term electronic “health” record is more attractive and important than the more commonly used term electronic “patient” record. The latter suggests that this tool only becomes relevant to you...

Dear reader, I am delighted that you are taking the time to join me on a journey. I promise you it will be worth it. It’s about medicine and health, but it’s about much more than that. It’s about the world’s next great social and economic revolution, which we are now at the beginning of. And that revolution has even begun is directly relevant to yo...

To clarify the causes of diseases and to develop new therapies is not only the task of the pharmaceutical industry, which we dealt with in the previous chapter, but above all basic biomedical research. Pharmaceutical companies also draw their ideas for drug development from the findings of all biomedical scientists worldwide.

The core problem of both medicine and all biomedical research, which would also exist if all research had become reproducible, statistically correct, and exclusively patient-oriented, is the division of the human body organ by organ. Apart from you GP, for each organ, there is a specialist in charge (Fig. 9.1) and a clinical department. This is sim...

Most of our genetically defined disease risks will involve so many genes that it will be unrealistic to erase them from our body by gene therapy. They will thus remain a chronic risk or weakness. However, whether they materialize into symptoms will often be preventable by a lifestyle adapted to your personal risk profile. At least the severity of s...

Check-up success at the GP, check-up success at the dentist, less diabetes, healthier diet, less alcohol consumption, more exercise, better sleep, less stress, and life expectancy all correlate somehow with better education and higher socio-economic status and virtually not at all with the healthcare systems in place in each country. Some of the mo...

No two countries are alike when it comes to organizing and delivering healthcare for their people. When the Prussian government sent Rudolf Virchow to Upper Silesia in 1848 to investigate the epidemic of typhus there, he identified hunger, poverty, and poor hygiene as the main causes. Virchow saw the state and the church as responsible. And his pre...

Every minute of the day, approximately 3 petabytes (in bytes, that would be a number with 15 zeros!) of internet data are generated. Considering the exposome, many of them can be declared as health-related data in a narrower or broader sense. Only computers provide a solution for the analysis of these gigantic amounts of data for the purpose of ind...

Let’s do a little research into the causes of the many chronic diseases and why they threaten to shorten our life expectancy, as they are already doing in the USA and Great Britain. Of all chronic diseases, 80% are caused by 15 symptoms and complaints:

Before we take off into the new medicine and move from Part I to Part II, I would like to pause with you for a moment and reflect on two aspects that the German physician and psychiatrist Klaus Dörner and the philosopher Byung-Chul Han have thrown into the spokes, so to speak, like a little stick. Dörner writes: “One can do an infinite amount for o...

I don’t want to end this book with a futuristic outlook into a wonderful new world of health, so that you can then put the book down—better prepared for what’s coming, of course—but still just waiting for what may come. I would like You to:

The innovations required to eliminate the undesirable developments described in the first part of this book are tantamount to a revolution. It is no longer a matter of optimizing a candle, but of inventing something completely new with an electric light bulb. It is not a matter of somehow improving sailboats, making them bigger or faster, but of re...

There is no uniform definition for being “chronically ill” or even “chronic”; not even the duration is defined. Is one chronically ill from 1 year of suffering? Or already from 6 months or only from 2 years? For sure, chronically ill patients are under lifelong medical control and treatment.

Before we get started on the new health care system, let’s pause for a moment to consider all that we have and need: How far have we come since Part I of the book? Diseases were recognized too late. When symptoms appeared, their cause was not known, and only the symptom could be treated. Since diseases could neither be prevented nor cured, many dis...

Most likely it’s not working for you. When you are prescribed a medicine and take it, you do so in the hope that you will have a benefit from it. Why else would you take it? But, unfortunately, in far too many cases, that hope is deceptive. Because every day, millions of people take medications that won’t benefit them.

The insight into the far-reaching unsuccessfulness of our current biomedical research approach—at least as far as its relevance for you as a (potential) patient is concerned—must lead to a radical rethinking if we do not want to continue to waste a large part of the resources and lead bright minds on wrong tracks with false incentives (publications...

Excessive production of renal reactive oxygen species (ROS) play a major role in diabetic kidney disease (DKD). Here, we provide key novel findings demonstrating the predominant pathological role of the prooxidant enzyme NADPH oxidase-NOX5 in DKD, independent of the previously characterised NOX4 pathway. In diabetic patients, we found increased exp...

Complex disease definitions often represent descriptive umbrella terms of symptoms rather than mechanistic entities. A new study shows how network-based approaches can help identify the mechanisms that link genes, cells, tissues and organs in cardiovascular diseases.

With all my euphoria about a new desirable epoch—or sixth wave—for medicine or better health, and before I give you some very concrete tips on how you can become part of the future right now, it is worth pausing for a moment and taking a bird’s eye view, moving away from the details a little, gaining more of an overview. Maybe we will discover new...

Not only are the costs of medicines high, which is why prescription medicines alone account for the third largest cost factor in the healthcare system, but the costs and risks for the pharmaceutical industry have also exploded. At the same time, the industry seems to be running out of ideas, which I see as one of the key symptoms of the crisis in m...

Supposing you knew all your personal “omes”, i.e. your genome, transcriptome, proteome, metabolome, and microbiome, would that be enough to predict your health risks, to carry out effective prevention or to intervene curatively? No, this self-referential approach is unfortunately not yet sufficient, because you are more than the sum of your “omes”.

Aggregates of the microtubule-associated protein tau are a common marker of neurodegenerative diseases collectively termed as tauopathies, such as Alzheimer's disease (AD) and frontotemporal lobar dementia. Therapeutic strategies based on tau have failed in late stage clinical trials, suggesting that tauopathy may be the consequence of upstream cau...

Traditional drug discovery faces a severe efficacy crisis. Repurposing of registered drugs provides an alternative with lower costs and faster drug development timelines. However, the data necessary for the identification of disease modules, i.e. pathways and sub-networks describing the mechanisms of complex diseases which contain potential drug ta...

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targe...

The mammalian genome encodes seven guanylyl cyclases, GC-A to GC-G, that are homodimeric transmembrane receptors activated by a diverse range of endogenous ligands. These enzymes convert guanosine-5'-triphosphate to the intracellular second messenger cyclic guanosine-3',5'-monophosphate (cyclic GMP). GC-A, GC-B and GC-C are expressed predominantly...

Mechanism-based therapy centred on the molecular understanding of disease-causing pathways in a given patient is still the exception rather than the rule in medicine, even in cardiology. However, recent successful drug developments centred around the second messenger cyclic guanosine-3'-5'-monophosphate (cGMP), which is regulating a number of cardi...

Machine Learning (ML) and Artificial Intelligence (AI) have shown promising results in many areas and are driven by the increasing amount of available data. However, this data is often distributed across different institutions and cannot be shared due to privacy concerns. Privacy-preserving methods, such as Federated Learning (FL), allow for traini...

Die jetzige Medizin ist krank. Sie ist ungenau und teuer, auch wenn alle im System ihr Bestes geben. Die meisten Daten aus biomedizinischer Forschung sind nicht reproduzierbar und verschwenden öffentliche Fördermittel. Die meisten Erkrankungen verstehen wir nicht und behandeln daher nur Symptome, aber nicht die Ursachen. Wir sind überversorgt an zu...

Reactive oxygen species (ROS) have been implicated in almost every human disease phenotype, without much, if any, therapeutic consequence foremost exemplified by the failure of the so-called anti-oxidants. This book is a game changer for the field and many clinical areas such as cardiology and neurology. The term ‘oxidative stress’ is abandoned and...

Despite the international guide-lines on the containment of the coronavirus disease 2019 (COVID-19) pandemic, the European scientific community was not sufficiently prepared to coordinate scientific efforts. To improve preparedness for future pandemics, we have initiated a network of nine European-funded Cooperation in Science and Technology (COST)...

Background: Systems Medicine is a novel approach to medicine, i.e. an interdisciplinary field that considers the human body as a system, composed of multiple parts and of complex relationships at multiple levels, and further integrated into an environment. Exploring Systems Medicine implies understanding and combining concepts coming from diametral...

Approximately 44 million people worldwide live with Alzheimer’s disease (AD) or a related form of dementia. Aggregates of the microtubule-associated protein tau are a common marker of these neurodegenerative diseases collectively termed as tauopathies. However, all therapeutic attempts based on tau have failed, suggesting that tau may only indicate...

Reactive oxygen species (ROS) have been correlated with almost every human disease. Yet clinical exploitation of these hypotheses by pharmacological modulation of ROS has been scarce to nonexistent. Are ROS, thus, irrelevant for disease? No. One key misconception in the ROS field has been its consideration as a rather detrimental metabolic by-produ...

Open image in new window Nitric oxide synthases (NOS) and their role in health (green) and disease (red). Only neuronal/type 1 NOS (NOS1) has a high degree of clinical validation and is in late stage development for traumatic brain injury, followed by a phase II safety/efficacy trial in ischemic stroke. The pathophysiology of NOS1 (Kleinschnitz et...

Open image in new window The upper panel shows the classical approach to generate hypotheses for a role of ROS in a given disease by focusing on ROS levels and to some degree the ROS type or metabolite. Low levels are considered physiological; higher amounts are thought to cause a redox imbalance, oxidative stress and eventually disease. The source...

Open image in new window Therapeutically relevant NADPH oxidase isoforms type 1, 2, 4, and 5 (NOX1, NOX2, NOX4, NOX5). Of note, NOX5 is not present in mice and rats and thus pre-clinically less studied. NOX2, formerly termed gp91phox, has been correlated with many, too many, diseases and is rather relevant as genetic deficiency in chronic granuloma...

Artificial intelligence (AI) has been successfully applied in numerous scientific domains including biomedicine and healthcare. Here, it has led to several breakthroughs ranging from clinical decision support systems, image analysis to whole genome sequencing. However, training an AI model on sensitive data raises also concerns about the privacy of...

Introduction: Network and systems medicine has rapidly evolved over the past decade, thanks to computational and integrative tools, which stem in part from systems biology. However, major challenges and hurdles are still present regarding validation and translation into clinical application and decision making for precision medicine. Methods: In t...

Rationale: Vascular calcification, the formation of calcium phosphate crystals in the vessel wall, is mediated by vascular smooth muscle cells (VSMCs). However, the underlying molecular mechanisms remain elusive precluding mechanism-based therapies. Objective: Phenotypic switching denotes a loss of contractile proteins and an increase in migration...

Nitric oxide (NO)-cyclic GMP (cGMP) signaling is a vasoprotective pathway therapeutically targeted, for example, in pulmonary hypertension. Its dysregulation in disease is incompletely understood. Here we show in pulmonary artery endothelial cells that feedback inhibition by NO of the NO receptor, the cGMP forming soluble guanylate cyclase (sGC), m...

The mammalian genome encodes seven guanylyl cyclases, GC-A to GC-G, that are homodimeric transmembrane receptors activated by a diverse range of endogenous ligands. These enzymes convert guanosine-5'-triphosphate to the intracellular second messenger cyclic guanosine-3',5'-monophosphate (cyclic GMP). GC-A, GC-B and GC-C are expressed predominantly...

Drug research, therapy development, and other areas of pharmacology and medicine can benefit from simulations and optimization of mathematical models that contain a mathematical description of interactions between systems elements at the cellular, tissue, organ, body, and population level. This approach is the foundation of systems medicine and pre...

Network Medicine applies network science approaches to investigate disease pathogenesis. Many different analytical methods have been used to infer relevant molecular networks, including protein–protein interaction networks, correlation‐based networks, gene regulatory networks, and Bayesian networks. Network Medicine applies these integrated approac...

The First International Conference in Systems and Network Medicine gathered together 200 global thought leaders, scientists, clinicians, academicians, industry and government experts, medical and graduate students, postdoctoral scholars and policymakers. Held at Georgetown University Conference Center in Washington D.C. on September 11-13, 2019, th...

Background: Systems Medicine is a novel approach to medicine, i.e. an interdisciplinary field that considers the human body as a system, composed of multiple parts and of complex relationships at multiple levels, and further integrated into an environment. Exploring Systems Medicine implies understanding and combining concepts coming from diametral...

Dysfunctional reactive oxygen species (ROS) signaling is considered an important disease mechanism. Therapeutically, non-selective scavenging of ROS by antioxidants, however, has failed in multiple clinical trials to provide patient benefit. Instead, pharmacological modulation of disease-relevant, enzymatic sources of ROS appears to be an alternati...

The mammalian genome encodes transmembrane and soluble receptor guanylyl cyclases, both of which have enzyme activities which convert guanosine-5'-triphosphate to the intracellular second messenger cyclic guanosine-3',5'-monophosphate (cyclic GMP).

Introduction: Drug-resistant infections are becoming increasingly frequent worldwide, causing hundreds of thousands of deaths annually. This is partly due to the very limited set of protein drug targets known for human-infecting viral genomes. The eleven influenza virus proteins, for instance, exploit host cell factors for replication and suppressi...

Significance Current one drug–one target–one disease approaches in drug discovery have become increasingly inefficient. Network pharmacology defines disease mechanisms as networks best targeted by multiple, synergistic drugs. Using the high unmet medical need indication stroke, we here develop an integrative in silico approach based on a primary ta...

Ischemic stroke is a predominant cause of disability worldwide, with thrombolytic or mechanical removal of the occlusion being the only therapeutic option. Reperfusion bears the risk of an acute deleterious calcium-dependent breakdown of the blood-brain barrier. Its mechanism, however, is unknown. Here, we identified type 5 NADPH oxidase (NOX5), a...

Reactive oxygen species (ROS) have been mainly viewed as unwanted by-products of cellular metabolism, oxidative stress, a sign of a cellular redox imbalance, and potential disease mechanisms, such as in diabetes mellitus (DM). Antioxidant therapies, however, have failed to provide clinical benefit. This paradox can be explained by recent discoverie...

Network medicine utilizes common genetic origins, markers and co-morbidities to uncover mechanistic links between diseases. These links can be summarized in the diseasome, a comprehensive network of disease–disease relationships and clusters. The diseasome has been influential during the past decade, although most of its links are not followed up e...

Gene regulatory networks (GRNs) and gene expression data form a core element of systems biology-based phenotyping. Changes in the expression of transcription factors are commonly believed to have a causal effect on the expression of their targets. Here we evaluated in the best researched model organism, Escherichia coli, the consistency between a G...

Endothelial nitric oxide (NO) stimulates the heme protein, soluble guanylyl cyclase (sGC) to form vasoprotective cyclic GMP (cGMP). In different disease states such as pulmonary hypertension, NO-cGMP signaling is pharmacologically augmented, yet the pathomechanisms leading to its dysregulation are incompletely understood. Here we show in pulmonary...

Unphysiological reactive oxygen species (ROS) formation is considered an important pathomechanism for several disease phenotypes with high unmet medical need. Therapeutically, antioxidants have failed multiple times. Instead, focusing on only disease-relevant, enzymatic sources of ROS appears to be a more promising and highly validated approach. He...

Ischemic stroke is a predominant cause of disability worldwide, with thrombolytic or mechanical removal of the occlusion being the only therapeutic options. Reperfusion bears the risk of an acute deleterious calcium-dependent breakdown of the blood-brain-barrier. Its mechanism, however, is unknown. Here we identify type 5 NADPH oxidase (NOX5), a ca...

The past decades have witnessed a paradigm shift from the traditional drug discovery shaped around the idea of “one target, one disease” to polypharmacology (multiple targets, one disease). Given the lack of clear-cut boundaries across disease (endo)phenotypes and genetic heterogeneity across patients, a natural extension to the current polypharmac...

Protein tyrosine nitration, detected as anti-nitrotyrosine immunoreactivity, is considered one of the most relevant disease biomarkers of oxidative stress. The mechanism of nitration, target protein and functional consequences remain often unclear. Here we first extend protein tyrosine nitration from pathology to physiology as additional mechanism...