Network medicine is the application of

network science Network science is an academic field which studies complex networks such as telecommunication networks, computer networks, biological networks, cognitive and semantic networks, and social networks, considering distinct elements or actors rep ...

towards identifying, preventing, and treating diseases. This field focuses on using network topology and

network dynamics Network dynamics is a research field for the study of networks whose status changes in time. The dynamics may refer to the structure of connections of the units of a network, to the collective internal state of the network, or both. The networked ...

towards identifying diseases and developing medical drugs. Biological networks, such as protein-protein interactions and

metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical ...

s, are utilized by network medicine. Disease networks, which map relationships between diseases and biological factors, also play an important role in the field.

Epidemiology Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and determinants of health and disease conditions in a defined population. It is a cornerstone of public health, and shapes policy decisions and evi ...

is extensively studied using network science as well;

social network A social network is a social structure made up of a set of social actors (such as individuals or organizations), sets of dyadic ties, and other social interactions between actors. The social network perspective provides a set of methods fo ...

s and transportation networks are used to model the spreading of disease across populations. Network medicine is a medically focused area of

systems biology Systems biology is the computational and mathematical analysis and modeling of complex biological systems. It is a biology-based interdisciplinary field of study that focuses on complex interactions within biological systems, using a holistic ...

Background

The term "network medicine" was coined and popularized in a scientific article by Albert-László Barabási called "Network Medicine – From Obesity to the "Diseasome", published in The New England Journal of Medicine, in 2007. Barabási states that

biological system A biological system is a complex network which connects several biologically relevant entities. Biological organization spans several scales and are determined based different structures depending on what the system is. Examples of biological syst ...

s, similarly to social and technological systems, contain many components that are connected in complicated relationships but are organized by simple principles. Using the recent development of

network theory Network theory is the study of graphs as a representation of either symmetric relations or asymmetric relations between discrete objects. In computer science and network science, network theory is a part of graph theory: a network can be de ...

,Caldarelli G. (2007). Scale-Free Networks. Oxford University Press. the organizing principles can be comprehensively analyzed by representing systems as

complex network In the context of network theory, a complex network is a graph (network) with non-trivial topological features—features that do not occur in simple networks such as lattices or random graphs but often occur in networks representing real ...

s, which are collections of nodes linked together by a particular relationship. For networks pertaining to medicine, nodes represent biological factors (

biomolecule A biomolecule or biological molecule is a loosely used term for molecules present in organisms that are essential to one or more typically biological processes, such as cell division, morphogenesis, or developmental biology, development. Biom ...

s, diseases, phenotypes, etc.) and links (edges) represent their relationships (physical interactions, shared metabolic pathway, shared gene, shared trait, etc.).Chan, S. Y., & Loscalzo, J. (2012). The emerging paradigm of network medicine in the study of human disease. Circulation research, 111(3), 359–374. Three key networks for understanding human disease are the metabolic network, the disease network, and the social network. The network medicine is based on the idea that understanding complexity of

gene regulation Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products ( protein or RNA). Sophisticated programs of gene expression are w ...

, metabolic reactions, and protein-protein interactions and that representing these as complex networks will shed light on the causes and mechanisms of diseases. It is possible, for example, to infer a

bipartite graph In the mathematical field of graph theory, a bipartite graph (or bigraph) is a graph whose vertices can be divided into two disjoint and independent sets U and V, that is every edge connects a vertex in U to one in V. Vertex sets U and V a ...

representing the connections of diseases to their associated

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

s using the

OMIM Online Mendelian Inheritance in Man (OMIM) is a continuously updated catalog of human genes and genetic disorders and traits, with a particular focus on the gene-phenotype relationship. , approximately 9,000 of the over 25,000 entries in OMIM ...

database.Goh, K. I., Cusick, M. E., Valle, D., Childs, B., Vidal, M., & Barabási, A. L. (2007). The human disease network. Proceedings of the National Academy of Sciences, 104(21), 8685–8690. The projection of the diseases, called the human disease network (HDN), is a network of diseases connected to each other if they share a common gene. Using the HDN, diseases can be classified and analyzed through the genetic relationships between them. Network medicine has proven to be a valuable tool in analyzing big biomedical data.

Research areas

Interactome

The whole set of molecular interactions in the human cell, also known as the interactome, can be used for disease identification and prevention.Barabási, A. L., Gulbahce, N., & Loscalzo, J. (2011). Network medicine: a network-based approach to human disease. Nature Reviews Genetics, 12(1), 56–68. These networks have been technically classified as scale-free, disassortative,

small-world network A small-world network is a type of mathematical graph in which most nodes are not neighbors of one another, but the neighbors of any given node are likely to be neighbors of each other and most nodes can be reached from every other node by a sm ...

s, having a high

betweenness centrality In graph theory, betweenness centrality (or "betweeness centrality") is a measure of centrality in a graph based on shortest paths. For every pair of vertices in a connected graph, there exists at least one shortest path between the vertices suc ...

.Loscalzo, J., & Barabasi, A. L. (2011). Systems biology and the future of medicine. Wiley Interdisciplinary Reviews: Systems Biology and Medicine, 3(6), 619–627. Protein-protein interactions have been mapped, using proteins as

node In general, a node is a localized swelling (a " knot") or a point of intersection (a vertex). Node may refer to: In mathematics * Vertex (graph theory), a vertex in a mathematical graph * Vertex (geometry), a point where two or more curves, line ...

s and their interactions between each other as links. These maps utilize databases such as BioGRID and the Human Protein Reference Database. The metabolic network encompasses the biochemical reactions in

s, connecting two

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, ...

s if they are in the same pathway. Researchers have used databases such as KEGG to map these networks. Others networks include

cell signaling In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...

networks, gene regulatory networks, and RNA networks. Using interactome networks, one can discover and classify diseases, as well as develop treatments through knowledge of its associations and their role in the networks. One observation is that diseases can be classified not by their principle

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (biology), morphology or physical form and structure, its Developmental biology, developmental proc ...

s (pathophenotype) but by their ''disease module'', which is a neighborhood or group of components in the interactome that, if disrupted, results in a specific pathophenotype. Disease modules can be used in a variety of ways, such as predicting disease genes that have not been discovered yet. Therefore, network medicine looks to identify the disease

module Module, modular and modularity may refer to the concept of modularity. They may also refer to: Computing and engineering * Modular design, the engineering discipline of designing complex devices using separately designed sub-components * Modul ...

for a specific pathophenotype using clustering algorithms.

Diseasome

Human disease networks, also called the diseasome, are networks in which the nodes are diseases and the links, the strength of correlation between them. This correlation is commonly quantified based on associated cellular components that two diseases share. The first-published human disease network (HDN) looked at genes, finding that many of the disease associated genes are non-essential genes, as these are the genes that do not completely disrupt the network and are able to be passed down generations. Metabolic disease networks (MDN), in which two diseases are connected by a shared

, have also been extensively studied and is especially relevant in the case of

metabolic disorder A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients, such as proteins, fats, and carbohydrates. Metabolic disorders can happen when abnormal chemical reactions in the body alter t ...

s. Three representations of the diseasome are: * ''Shared gene formalism'' states that if a gene is linked to two different disease phenotypes, then the two diseases likely have a common genetic origin (

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

s). * ''Shared metabolic pathway formalism'' states that if a metabolic pathway is linked to two different diseases, then the two diseases likely have a shared metabolic origin (

s). * ''Disease comorbidity formalism'' uses phenotypic disease networks (PDN), where two diseases are linked if the observed

comorbidity In medicine, comorbidity - from Latin morbus ("sickness"), co ("together"), -ity (as if - several sicknesses together) - is the presence of one or more additional conditions often co-occurring (that is, concomitant or concurrent) with a primary ...

between their

s exceeds a predefined threshold. This does not look at the mechanism of action of diseases, but captures disease progression and how highly connected diseases correlate to higher mortality rates. Some disease networks connect diseases to associated factors outside the human cell. Networks of environmental and genetic etiological factors linked with shared diseases, called the "etiome", can be also used to assess the clustering of environmental factors in these networks and understand the role of the environment on the interactome. The human symptom-disease network (HSDN), published in June 2014, showed that the symptoms of disease and disease associated cellular components were strongly correlated and that diseases of the same categories tend to form highly connected communities, with respect to their symptoms.

Pharmacology

Network

pharmacology Pharmacology is a branch of medicine, biology and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemica ...

is a developing field based in

systems pharmacology Systems pharmacology is the application of systems biology principles to the field of pharmacology. It seeks to understand how drugs affect the human body as a single complex biological system. Instead of considering the effect of a drug to be the ...

that looks at the effect of drugs on both the interactome and the diseasome.Hopkins, A. L. (2008). Network pharmacology: the next paradigm in drug discovery. Nature Chemical Biology, 4(11), 682–690. The drug-target network (DTN) can play an important role in understanding the mechanisms of action of approved and experimental drugs. The network theory view of

pharmaceutical A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...

s is based on the effect of the drug in the interactome, especially the region that the drug target occupies.

Combination therapy Combination therapy or polytherapy is therapy that uses more than one medication or modality. Typically, the term refers to using multiple therapies to treat a ''single'' disease, and often all the therapies are pharmaceutical (although it can al ...

for a complex disease (polypharmacology) is suggested in this field since one active pharmaceutical ingredient (API) aimed at one target may not effect the entire disease module. The concept of disease modules can be used to aid in

drug discovery In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or b ...

, drug design, and the development of

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...

s for disease detection. There can be a variety of ways to identifying drugs using network pharmacology; a simple example of this is the "guilt by association" method. This states if two diseases are treated by the same drug, a drug that treats one disease may treat the other.

Drug repurposing Drug repositioning (also called drug repurposing) involves the investigation of existing drugs for new therapeutic purposes. Repurposing achievements A number of successes have been achieved, the foremost including sildenafil (Viagra) for erect ...

, drug-drug interactions and drug side-effects have also been studied in this field.

Network epidemics

Network epidemics has been built by applying network science to existing epidemic models, as many transportation networks and social networks play a role in the spread of disease. Social networks have been used to assess the role of social ties in the spread of

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...

in populations. Epidemic models and concepts, such as spreading and

contact tracing In public health, contact tracing is the process of identifying persons who may have been exposed to an infected person ("contacts") and subsequent collection of further data to assess transmission. By tracing the contacts of infected individua ...

, have been adapted to be used in network analysis. These models can be used in

public health Public health is "the science and art of preventing disease, prolonging life and promoting health through the organized efforts and informed choices of society, organizations, public and private, communities and individuals". Analyzing the det ...

policies, in order to implement strategies such as targeted immunization and has been recently used to model the spread of the

Ebola virus epidemic in West Africa The 2013–2016 epidemic of Ebola virus disease, centered in Western Africa, was the most widespread outbreak of the disease in history. It caused major loss of life and socioeconomic disruption in the region, mainly in Guinea, Liberia and S ...

across countries and continents.

Drug Prescription Networks (DPNs)

Recently, some researchers tended to represent medication use in form of networks. The nodes in these networks represent medications and the edges represent some sort of relationship between these medications. Cavallo et al. (2013) described the topology of a co-prescription network to demonstrate which drug classes are most co-prescribed. Bazzoni et al. (2015) concluded that the DPNs of co-prescribed medications are dense, highly clustered, modular and assortative. Askar et al. (2021) created a network of the severe drug-drug interactions (DDIs) showing that it consisted of many clusters.

Other Networks

The development of organs P. Auconi, G. Caldarelli, A. Scala, G. Ierardo, A. Polimeni (2011). A network approach to orthodontic diagnosis, Orthodontics and Craniofacial Research 14, 189-197 . and other biological systems can be modelled as network structures where the clinical (e.g., radiographic, functional) characteristics can be represented as nodes and the relationships between these characteristics are represented as the links among such nodes.Scala,A. Auconi,P., Scazzocchio,M., Caldarelli,G., McNamara,J., Franchi,L. (2014). Complex networks for data-driven medicine: the case of Class III dentoskeletal disharmony, New J. Phys. 16 115017 Therefore, it is possible to use networks to model how organ systems dynamically interact.

Educational and Clinical Implementation

The Channing Division of Network Medicine at

Brigham and Women's Hospital Brigham and Women's Hospital (BWH) is the second largest teaching hospital of Harvard Medical School and the largest hospital in the Longwood Medical Area in Boston, Massachusetts. Along with Massachusetts General Hospital, it is one of the two ...

was created in 2012 to study, reclassify, and develop treatments for complex diseases using network science and

. It focuses on three areas: * ''Chronic Disease Epidemiology'' uses

genomics Genomics is an interdisciplinary field of biology focusing on the structure, function, evolution, mapping, and editing of genomes. A genome is an organism's complete set of DNA, including all of its genes as well as its hierarchical, three-dim ...

and

metabolomics Metabolomics is the scientific study of chemical processes involving metabolites, the small molecule substrates, intermediates, and products of cell metabolism. Specifically, metabolomics is the "systematic study of the unique chemical fingerprin ...

in large, long-term epidemiology studies, such as the Nurses' Health Study. * ''Systems Genetics & Genomics'' focuses on complex respiratory diseases, specifically

COPD Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce ...

and

asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...

, in smaller population studies. * ''Systems Pathology'' uses multidisciplinary approaches, including as

control theory Control theory is a field of mathematics that deals with the control system, control of dynamical systems in engineered processes and machines. The objective is to develop a model or algorithm governing the application of system inputs to drive ...

dynamical systems In mathematics, a dynamical system is a system in which a function describes the time dependence of a point in an ambient space. Examples include the mathematical models that describe the swinging of a clock pendulum, the flow of water in a ...

, and

combinatorial optimization Combinatorial optimization is a subfield of mathematical optimization that consists of finding an optimal object from a finite set of objects, where the set of feasible solutions is discrete or can be reduced to a discrete set. Typical combi ...

, to understand complex diseases and guide

design.

Massachusetts Institute of Technology The Massachusetts Institute of Technology (MIT) is a private land-grant research university in Cambridge, Massachusetts. Established in 1861, MIT has played a key role in the development of modern technology and science, and is one of th ...

offers an undergraduate course called "Network Medicine: Using Systems Biology and Signaling Networks to Create Novel Cancer Therapeutics". Also,

Harvard Harvard University is a private Ivy League research university in Cambridge, Massachusetts. Founded in 1636 as Harvard College and named for its first benefactor, the Puritan clergyman John Harvard, it is the oldest institution of higher le ...

Catalyst (The Harvard Clinical and Translational Science Center) offers a three-day course entitled "Introduction to Network Medicine", open to clinical and science professionals with doctorate degrees.

References

{{reflist Network theory