Network Medicine in Pathobiology Application of Systems Biology to Complex Diseases

Human diseases are exceptionally complex. Consider various forms of cancer, heart disease, diabetes, atherosclerosis, diseases of immunity, genetic diseases, infectious diseases, and many others. The causes of these disease processes are equally complex and almost always multifactorial, with contributions from the host/patient (related to genetics or physiology), various exposures to disease agents, factors from the environment, and many more. The patients themselves are complex and so the presentation, consequences, and severity of disease have a tendency to vary tremendously among an affected cohort. Despite recognition of these complexities associated with human disease, researchers have historically taken reductionists approaches to their study. Hence, our knowledge of many diseases reflect the combination of results (and inferences) from ex vivo approaches, in vitro cell culture, model systems, and examination of limited numbers of molecular mediators of disease. It has been recognized for many years that the complete understanding of any disease process will require the ability to examine the condition in the context of the patient, without elimination of the complexities of the in vivo condition. Welcome to the world of systems biology and network science!

Laurel Lee, MD, DPhil and Joseph Loscalzo, MD, PhD

In the July issue of The American Journal of Pathology, Lee and Loscalzo review emerging concepts and approaches associated with the application of systems biology and network science to pathobiology and the study of complex diseases. (LY-H Lee, J Loscalzo. Network medicine in pathobiology. Am J Pathol 2019;189:1311-1326)

"...The past decade has witnessed exponential growth in the generation of high-throughput human data across almost all known dimensions of biological systems. The discipline of network medicine has rapidly evolved in parallel, providing an unbiased, comprehensive biological framework through which to interrogate and integrate systematically these large-scale, multi-omic data to enhance our under­standing of disease mechanisms and to design drugs that reflect a deep knowledge of molecular pathobiology..."

Laurel Yong-Hwa Lee, MD, DPhil, is a Cardiovascular Medicine Fellow at the Brigham and Women’s Hospital and postdoctoral research fellow in the laboratory of Dr. Loscalzo. Joseph Loscalzo, MD, PhD is the Hersey Professor of Theory and Practice of Medicine at Harvard Medical School and Head of the Department of Medicine at the Brigham and Women’s Hospital. Dr. Loscalzo is recognized as an outstanding cardiovascular scientist, clinician, teacher, and well-funded researcher.

Lee and Loscalzo introduce basic concepts, principles, and components of network medicine, prior to describing how interactomes and disease networks are constructed.

"...Networks can be used to represent a broad range of bio­logical systems. A biological network consists of multiple nodes that represent distinct individual biological entities, such as genes, proteins, or metabolites. Relationships among nodes are depicted by connecting lines and denoted edges, which may represent a wide variety of molecular in­teractions, such as gene regulation, physical protein-protein interaction, or substrate metabolism..."
"...An interactome represents a comprehensive, unbiased mapping of all known biologically relevant human molec­ular interactions...A disease network module is defined as a subgroup of inter­active nodes whose altered states (eg, gene deletions, muta­tions, copy number variations, or differential expressions) are associated with specific disease phenotypes..."

Following an introduction to the basic principles of systems biology and network science, Lee and Loscalzo provide descriptions of major biological networks that accommodate systems-level omics studies and how current approaches enable integrative, multidimensional assessment of complex human disease. Their treatment of this subject covers genetic studies, transcriptomics and gene regulatory networks, single-cell RNA sequencing, epigenetics, and metabolomics.

"...Given the high degree of cross-talk among multiple bio­logical systems, a perturbation in one domain inevitably leads to a change(s) in others. Our increasing ability to integrate large-scale, multidimensional biological data to unravel complex human (patho)biology and connect geno­types and (patho)phenotypes promises to provide unprece­dented insight into disease mechanisms..."

Lee and Loscalzo point out that despite the increasing capability to identify molecular changes associated with disease states, there remains tremendous discordance between the molecular findings and the observed heterogeneity of the clinical phenotype (including responses to treatment). Assessment of patients using approaches informed by systems biology and network medicine will transform precision medicine and personalized therapy for management of complex diseases.

"...Network approaches provide unique abilities with which to perform in silica predictions of drug action in a complex biological context. Drugs can be mapped to the human interactome through their (known) targets as part of a bio­logical network with their effect on a node(s) (target) rep­resented with edges ..."

In their review, Lee and Loscalzo show us not only the future of pathology research, but the current state-of-the-art in systems pathobiology, the power of systems and network approaches, and the potential impact of this new biology on the advancement of our understanding of complex human diseases.

"...Network medicine represents a unique integrative path to accelerate our understanding of complex human diseases and to improve therapeutics with unprecedented breadth and pre­cision. The future of the discipline and its consequences for diagnostics, prognosis, and therapeutics has great potential..."

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