Revolutionizing medicine in the 21(st) century through systems approaches

Personalized medicine is a term for a revolution in medicine that envisions the individual patient as the central focus of healthcare in the future. The term "personalized medicine", however, fails to reflect the enormous dimensionality of this new medicine that will be predictive, preventive, personalized, and participatory-a vision of medicine we have termed P4 medicine. This reflects a paradigm change in how medicine will be practiced that is revolutionary rather than evolutionary. P4 medicine arises from the confluence of a systems approach to medicine and from the digitalization of medicine that creates the large data sets necessary to deal with the complexities of disease. We predict that systems approaches will empower the transition from conventional reactive medical practice to a more proactive P4 medicine focused on wellness, and will reverse the escalating costs of drug development an will have enormous social and economic benefits. Our vision for P4 medicine in 10 years is that each patient will be associated with a virtual data cloud of billions of data points and that we will have the information technology for healthcare to reduce this enormous data dimensionality to simple hypotheses about health and/or disease for each individual. These data will be multi-scale across all levels of biological organization and extremely heterogeneous in type - this enormous amount of data represents a striking signal-to-noise (S/N) challenge. The key to dealing with this S/N challenge is to take a "holistic systems approach" to disease as we will discuss in this article.     

Systems Approaches to Biology and Disease Enable Translational Systems Medicine

The development and application of systems strategies to biology and disease are transforming medical research and clinical practice in an unprecedented rate.In the foreseeable future,clinicians,medical researchers,and ultimately the consumers and patients will be increasingly equipped with a deluge of personal health information,e.g.,whole genome sequences,molecular profiling of diseased tissues,and periodic multi-analyte blood testing of biomarker panels for disease and wellness.The convergence of these practices will enable accurate prediction of disease susceptibility and early diagnosis for actionable preventive schema and personalized treatment regimes tailored to each individual.It will also entail proactive participation from all major stakeholders in the health care system.We are at the dawn of predictive,preventive,personalized,and participatory(P4) medicine,the fully implementation of which requires marrying basic and clinical researches through advanced systems thinking and the employment of high-throughput technologies in genomics,proteomics,nanofluidics,single-cell analysis,and computation strategies in a highly-orchestrated discipline we termed translational systems medicine.     

Circular causality in integrative multi-scale systems biology and its interaction with traditional medicine

This paper discusses the concept of circular causality in “biological relativity” (Noble, Interface Focus. 2, 56-64, 2012) in the context of integrative and multi-scale systems approaches to biology. It also discusses the relationship between systems biology and traditional medicine (sometimes called scholarly medical traditions) mainly from East Asia and India. Systems biology helps illuminate circular processes identified in traditional medicine, while the systems concept of attractors in complex systems will also be important in analysing dynamic balance in the body processes that traditional medicine is concerned with. Ways of nudging disordered processes towards good attractors through the use of traditional medicines can lead to the development of new ways not only of curing disease but also of its prevention. Examples are given of cost-effective multi-component remedies that use integrative ideas derived from traditional medicine.     

Systems healthcare: a holistic paradigm for tomorrow

Systems healthcare is a holistic approach to health premised on systems biology and medicine. The approach integrates data from molecules, cells, organs, the individual, families, communities, and the natural and man-made environment. Both extrinsic and intrinsic influences constantly challenge the biological networks associated with wellness. Such influences may dysregulate networks and allow pathobiology to evolve, resulting in early clinical presentation that requires astute assessment and timely intervention for successful mitigation. Herein, we describe the components of relevant biological systems and the nature of progression from at-risk to manifest disease. We illustrate the systems approach by examining two relevant clinical examples: Alzheimer’s and cardiovascular diseases. The implications of systems healthcare management are examined through the lens of economics, ethics, policy and the law. Finally, we propose the need to develop new educational paradigms to enhance the training of the health professional in an era of systems medicine.     

系统生物学对医学的影响

系统生物学是21世纪最前沿的科学之一,它是随着生命科学飞速发展而产生的一门新兴生物学分支[1],它综合数学、信息科学和生物学的各种工具来阐明和理解大量的数据所包含的生物医学意义,从而使人们能够从整体上理解生物医学系统并精确、量化地预测生物医学系统的行为。随着系统生物学的发展及其理论的突破,将在疾病诊治、新药开发、预防医学方面发挥重要的作用,有助于弥补传统医学缺陷并促进其发展。     

Emerging issues in traditional Chinese medicine

Traditional Chinese medicine (TCM) has many beneficial effects and has been practiced for several thousand years. It is known to treat the cause of a disease rather than to alleviate its symptoms. Based on a belief that TCM is natural, safe, and of lower cost, consumers worldwide are spending more out-of-pocket money on this form of therapy. This increased spending, and reports of adverse reactions, has drawn the attention of many regulatory agencies. Scientists have called for more evidence-based and scientific research on the risks and benefits of TCM. In Canada, the Natural Health Product Regulations came into effect January 2004. TCM herbal product manufacturers will need to provide products of reputable quality to the market. Many will apply modern technology and good science to support their products. The issues facing producers, scientists, and consumers alike are quality control and assessment, standardization of bioactive components, mechanisms of actions, and integration of the evolved modern Chinese medicine into the healthcare system. Solid science, better regulation of the final product, and better education of consumers are necessary to extract the best of TCM to complement existing conventional medicine to deliver the best healthcare.     

Editorial: Systems biology and personalized medicine - the future is now

This special issue on "Systems biology and personalized medicine" includes five complementary articles that highlight how functional genomics and computational physiology can contribute to the development of predictive, preventive, personalized and participatory (P4) medicine. Edited by Prof. Leroy Hood and Prof. Charles Auffray.     

Systems Biology,Systems Medicine,Systems Pharmacology: The What and The Why

Systems biology is today such a widespread discipline that it becomes difficult to propose a clear definition of what it really is. For some, it remains restricted to the genomic field. For many, it designates the integrated approach or the corpus of computational methods employed to handle the vast amount of biological or medical data and investigate the complexity of the living. Although defining systems biology might be difficult, on the other hand its purpose is clear: systems biology, with its emerging subfields systems medicine and systems pharmacology, clearly aims at making sense of complex observations/experimental and clinical datasets to improve our understanding of diseases and their treatments without putting aside the context in which they appear and develop. In this short review, we aim to specifically focus on these new subfields with the new theoretical tools and approaches that were developed in the context of cancer. Systems pharmacology and medicine now give hope for major improvements in cancer therapy, making personalized medicine closer to reality. As we will see, the current challenge is to be able to improve the clinical practice according to the paradigm shift of systems sciences.     

An economic perspective on personalized medicine

The concept of personalized medicine not only promises to enhance the life of patients and increase the quality of clinical practice and targeted care pathways, but also to lower overall healthcare costs through early-detection, prevention, accurate risk assessments and efficiencies in care delivery. Current inefficiencies are widely regarded as substantial enough to have a significant impact on the economies of major nations like the US and China, and, therefore the world economy. A recent OECD report estimates healthcare expenditure for some of the developed western and eastern nations to be anywhere from 10% to 18%, and growing (with the US at the highest). Personalized medicine aims to use state-of-the-art genomic technologies, rich medical record data, tissue and blood banks and clinical knowledge that will allow clinicians and payors to tailor treatments to individuals, thereby greatly reducing the costs of ineffective therapies incurred through the current trial and error clinical paradigm. Pivotal to the field are drugs that have been designed to target a specific molecular pathway that has gone wrong and results in a diseased condition and the diagnostic tests that allow clinicians to separate responders from non-responders. However, the truly personalized approach in medicine faces two major problems: complex biology and complex economics; the pathways involved in diseases are quite often not well understood, and most targeted drugs are very expensive. As a result of all current efforts to translate the concepts of personalized healthcare into the clinic, personalized medicine becomes participatory and this implies patient decisions about their own health. Such a new paradigm requires powerful tools to handle significant amounts of personal information with the approach to be known as “P4 medicine”, that is predictive, preventive, personalized and participatory. P4 medicine promises to increase the quality of clinical care and treatments and will ultimately save costs. The greatest challenges are economic, not scientific.     

Infection systems biology: from reactive to proactive (P4) medicine

This short review establishes the conceptual bases and discusses the principal aspects of P4-shorthand for predictive, preventive, personalized and participatory medicine-medicine, in the framework of infectious diseases. P4 medicine is a new way to approach medical care; instead of acting when the patient is sick, physicians will be able to detect early warnings of disease to take early action. Furthermore, people might even be able to adjust their lifestyles to prevent disease. P4 medicine is fuelled by systems approaches to disease, including methods for personalized genome sequencing and new computational techniques for building dynamic disease predictive networks from massive amounts of data from a variety of OMICs. An excellent example of the effectiveness of the P4 medicine approach is the change in cancer treatments. Emphasis is placed on early detection, followed by genotyping of the patient to use the most adequate treatment according to the genetic background. Cardiovascular diseases and perhaps even neurodegenerative disorders will be the next targets for P4 medicine. The application of P4 medicine to infectious diseases is still in its infancy, but is a promising field that will provide much benefit to both the patients and the health-care system.     

Bioelectromagnetic medicine: The role of resonance signaling

Only recently has the critical importance of electromagnetic (EM) field interactions in biology and medicine been recognized. We review the phenomenon of resonance signaling, discussing how specific frequencies modulate cellular function to restore or maintain health. The application of EM-tuned signals represents more than merely a new tool in information medicine. It can also be viewed in the larger context of EM medicine, the all-encompassing view that elevates the EM over the biochemical. The discovery by Zhadin that ultrasmall magnetic intensities are biologically significant suggests that EM signaling is endogenous to cell regulation, and consequently that the remarkable effectiveness of EM resonance treatments reflects a fundamental aspect of biological systems. The concept that organisms contain mechanisms for generating biologically useful electric signals is not new, dating back to the nineteenth century discovery of currents of injury by Matteucci. The corresponding modern-day version is that ion cyclotron resonance magnetic field combinations help regulate biological information. The next advance in medicine will be to discern and apply those EM signaling parameters acting to promote wellness, with decreasing reliance on marginal biochemical remediation and pharmaceuticals.     

Systems biology, proteomics, and the future of health care: toward predictive, preventative, and personalized medicine

The emergence of systems biology is bringing forth a new set of challenges for advancing science and technology. Defining ways of studying biological systems on a global level, integrating large and disparate data types, and dealing with the infrastructural changes necessary to carry out systems biology, are just a few of the extraordinary tasks of this growing discipline. Despite these challenges, the impact of systems biology will be far-reaching, and significant progress has already been made. Moving forward, the issue of how to use systems biology to improve the health of individuals must be a priority. It is becoming increasingly apparent that the field of systems biology and one of its important disciplines, proteomics, will have a major role in creating a predictive, preventative, and personalized approach to medicine. In this review, we define systems biology, discuss the current capabilities of proteomics and highlight some of the necessary milestones for moving systems biology and proteomics into mainstream health care.     

传统中国医药与现代系统生物学研究理论的殊途同归

系统生物学是研究一个生物系统中所有组成成分(基因、mRNA、蛋白质等)的构成与组分之间相互关系的学科,近年来,系统生物学作为后基因组学时代研究的一个重要内容,已广泛深入到生命科学和医药学的各个领域。而作为中国传统医学而言,似乎与之相去甚远,然而当我们对这两个新老学科基础理论进行比较时,我们发现:传统中国医药与现代系统生物学研究理论的殊途同归。有鉴于此,本文论述了系统生物学和中医学的思想起源、相互联系,基于系统生物学的发展、研究思路和方法,阐述了生物学由还原论的研究方法过渡到系统论的研究方法,强调对生命现象从系统和整体的层次进行研究和把握,对传统中医学研究方法的变革起到了推动作用,最后对系统生物学在中医药学未来发展进行了评价。     

Systems biology,emergence and antireductionism

This study explores the conceptual history of systems biology and its impact on philosophical and scientific conceptions of reductionism, antireductionism and emergence. Development of systems biology at the beginning of 21st century transformed biological science. Systems biology is a new holistic approach or strategy how to research biological organisms, developed through three phases. The first phase was completed when molecular biology transformed into systems molecular biology. Prior to the second phase, convergence between applied general systems theory and nonlinear dynamics took place, hence allowing the formation of systems mathematical biology. The second phase happened when systems molecular biology and systems mathematical biology, together, were applied for analysis of biological data. Finally, after successful application in science, medicine and biotechnology, the process of the formation of modern systems biology was completed.Systems and molecular reductionist views on organisms were completely opposed to each other. Implications of systems and molecular biology on reductionist–antireductionist debate were quite different. The analysis of reductionism, antireductionism and emergence issues, in the era of systems biology, revealed the hierarchy between methodological, epistemological and ontological antireductionism. Primarily, methodological antireductionism followed from the systems biology. Only after, epistemological and ontological antireductionism could be supported.     

Restricting restriction

Systems biology is a new, fashionable and well-funded discipline, which to quote from a recent review aims to 'examine the structure and dynamics of cellular and organismal function, rather than the characteristics of isolated parts of a cell or organism em leader ' (Kitano, H. (2002) Science 295:1662-1664). Systems biology will do this by profiting from the vast amounts of biological information that are available in the genomics era and make extensive use of computer modelling. But: 'many breakthroughs in experimental devices, advanced software and analytical methods are required before the achievements of system biology can live up to their much-touted potential'. This edition of Molecular Microbiology contains a paper that is the product of traditional experimental biology but which could serve as a test case for systems biology. The paper shows how bacteria integrate such disparate subsystems as DNA restriction, homologous recombination and regulated proteolysis to protect their chromosomes from degradation. When systems biology can predict this level of choreography, it will be a mature discipline.     

Advocacy and community: the social roles of physicians in the last 1000 years. Part I

Over the last 1000 years, the practice of medicine in the Western world has been shaped by extraordinary transformations -- in the organizational structures of healthcare delivery, the changing concepts of disease and illness, and the ethical and social issues posed to a growing and diversified profession. Some critical aspects that characterize contemporary Western medicine -- as professionally defined, highly organized and regulated, and scientifically and technologically based -- have emerged only within the last 200 years. For most of its history, medicine was practiced without these distinctions -- but precursors to many current tensions can be traced back to Hippocratic times. In the last millennium, medicine developed in tandem with emerging political ideologies and social structures, and the roles of physicians evolved to respond to the needs of individual patients, the profession, and society at large. As medicine became increasingly effective, it was harnessed into the political objectives of promoting social cohesion and productivity. Professional regulation and social mechanisms for the equitable distribution of healthcare became significant considerations for the profession and society. In this brief 3-part history, we will trace the major organizational, conceptual, and political changes that, together, by the year 2000, created a profession with responsibilities of advocacy for individual patients in concert with attention to the needs and demands of all the individuals in the larger community.     

Application of proteomics in the mechanistic study of traditional Chinese medicine

Systems biology is considered to be the possible technology that could bring breakthroughs in the study of TCM (traditional Chinese medicine). Proteomics, as one of the major components of systems biology, has been used in the mechanistic study of TCM, providing some interesting results. In the present paper, we review the current application of proteomics in the mechanistic study of TCM. Proteomics technologies and strategies that might be used in the future to improve study of TCM are also discussed.     

Individualized medicine 2010

Molecular and cell biology have revolutionized not only diagnosis, therapy and prevention of human diseases but also greatly contributed to the understanding of their pathogenesis. Based on modern molecular and biochemical methods it is possible to identify on the one hand point mutations and single nucleotide polymorphisms. On the other hand, using high throughput array technologies, it is possible to analyse thousands of genes or gene products simultaneously, resulting in an individual gene or gene expression profile (signature). These data increasingly allow to define the individual risk for a given disease and to predict the individual prognosis of a disease as well as the efficacy of therapeutic strategies (individualized medicine). In the following sections some of the recent advances of predictive medicine and their clinical relevance will be addressed.     

Stem cells, regenerative medicine, and animal models of disease

The field of stem cell biology and regenerative medicine is rapidly moving toward translation to clinical practice, and in doing so has become even more dependent on animal donors and hosts for generating cellular reagents and assaying their potential therapeutic efficacy in models of human disease. Advances in cell culture technologies have revealed a remarkable plasticity of stem cells from embryonic and adult tissues, and transplantation models are now needed to test the ability of these cells to protect at-risk cells and replace cells lost to injury or disease. With such a mandate, issues related to acceptable sources and controversial (e.g., chimeric) models have challenged the field to provide justification of their potential efficacy before the passage of new restrictions that may curb anticipated breakthroughs. Progress from the use of both in vitro and in vivo regenerative medicine models already offers hope both for the facilitation of stem cell phenotyping in recursive gene expression profile models and for the use of stem cells as powerful new therapeutic reagents for cancer, stroke, Parkinson's, and other challenging human diseases that result in movement disorders. This article describes research in support of the following three objectives: (1) To discover the best stem or progenitor cell in vitro protocols for isolating, expanding, and priming these cells to facilitate their massive propagation into just the right type of neuronal precursor cell for protection or replacement protocols for brain injury or disease, including those that affect movement such as Parkinson's disease and stroke; (2) To discover biogenic factors--compounds that affect stem/progenitor cells (e.g., from high-throughput screening and other bioassay approaches)--that will encourage reactive cell genesis, survival, selected differentiation, and restoration of connectivity in central nervous system movement and other disorders; and (3) To establish the best animal models of human disease and injury, using both small and large animals, for testing new regenerative medicine therapeutics.