Evolving From Reductionism to Holism: Title and subTitle BreakIs There a Future for Systems Medicine?

Health reform discussions revolve around how best to achieve the goals of cost containment, increased access to care, and improved quality. However, in the current health reform debate, little attention is paid to how medicine is currently taught and practiced. It has long been understood that the fundamental tenets of health arise from understanding the interaction among genomics, the external environment, and behavior. Modern medicine often neglects this comprehensive model and treats disease in isolation, without taking into account the dynamic, integrative systems in the human body. Proponents of a new approach in medical education and practice look toward “systems medicine,” which incorporates the complex biochemical, physiological, and environmental interactions that sustain living organisms. Although a holistic approach to medicine should benefit patients and society, consideration of the sociolegal, ethical, and economic implications is essential.

Modern Medicine. Modern medical education and practice is rooted in the scientific method¹ premised on fundamental biological discovery, elucidation of underlying mechanisms, and delivered as evidence-based medicine. The logic of this approach remains compelling but has resulted in an increasingly reductionist framework. With this approach, a patient's presenting complaint is parsed by organ system, cellular dysfunction, and molecular defect, often neglecting the dynamic interaction of all elements and how they affect the system as a whole. This differential diagnostic exercise leads to a reduced root cause of illness and a focused, typically organ-based therapeutic plan. Despite the application of evidence-based medicine, the patient often is approached as a collection of visceral organs and a nervous system.

Systems Medicine . The application of engineering precepts to biological systems has spawned the field of systems biology.² Systems biology is based on a network of interacting components—such as the coordination of internal systems (nervous, endocrine, respiratory, etc) with gene and gene product expression and behavioral and environmental factors—and how these components contribute to the course of health and disease. Stemming from systems biology, systems medicine incorporates interactions between all components of health and disease. Care for the whole person—derived from the medical tenets of cura personalis—exemplifies the connectivity and integration at multiple levels of systems medicine, expanding medicine beyond reductionism. Positing this holistic approach requires not only new organizing principles but also retention of medicine's rigorous scientific foundation.

A key feature of systems medicine is that existing networks, through dynamic (time-dependent) interactions, manifest “emergent properties” that define the whole and that these properties are not simply the sum of the features of its component parts. The predictive power (ability to estimate future behaviors or adaptations) of a systems approach has been demonstrated for some microorganisms, subcellular organelles, and plants.³ Phylogenetics—the study of evolutionary relationships among organisms—suggests these predictive results can be scaled to humans. Although systems biology and medicine both involve high-level computing and modeling, the latter incorporates attributes uniquely human, such as human genetics, environment, and behavior.

Nearly all major classes of human disease are genetically complex, with more than a single gene contributing risk for disease development. For example, in type 1 diabetes mellitus, often presenting in the first 2 decades of life, the genes HLA-DQB1, HLA-DRB1, and 21 non-HLA genes are known to be contributory.⁴ Typically, a group of inherited vulnerability genes is insufficient to produce disease; rather, the promotion of disease is affected by other factors. There are several speculated environmental risk factors for type 1 diabetes, including exposure to bovine insulin in infant formulas⁵ and, given the subset of vulnerability genes that type 1 diabetes shares with celiac disease, exposure to gluten.⁶

Three levels of data collection inform a systems approach at the nexus of genetic risk and environmental modulation. First, inherited genetic vulnerability provides a baseline for risk stratification. Second, epigenetic changes caused by endogenous factors, environmental factors, or both alter specific DNA sites within key genes. When expressed at the cellular level, these alterations promote changes in the encoded gene networks and subsequently in their effects on proteins and metabolites. The third level integrates the biomolecular data with conventional clinical, historical, serologic, hematologic, and imaging data.

All 3 levels of data require high-performance computation to reduce complexity and render the outputs useful. If enabled, systems medicine can be transitioned in phases: detection of manifest disease, presymptomatic detection of disease, and identification of individuals at greatest risk. The progressive shift toward prevention mandates a different economic model and a repositioning of individual and clinician responsibility for wellness.

Despite the potential for improved preventive and personalized care, a shift to systems medicine raises critical legal, ethical, and policy issues. By encompassing concerns expressed in genomics, pharmacogenomics, and personalized medicine, systems medicine adds new dimensions of concern based on the multidimensional information collected.

Cost. Systems medicine offers the prospect of more cost-effective treatment by preventing and reducing the burden of chronic disease and by providing better-targeted therapies, yet it requires gathering and analyzing vast amounts of data, with significant upfront costs. The economic savings, therefore, may not be realized until well after implementation of this model. At the same time, the development and use of new therapeutic interventions, together with increased life span, could increase costs. If treatment begins before symptoms start, what determines whether symptoms will emerge in a person's lifetime and be worth treating?

Privacy. Systems medicine requires complex electronic databases and high-powered computing and modeling, which hospitals and physicians have been slow to adopt. Personalized information would include treatment and responses, lifestyle (eg, sexual habits, diet, smoking, and drug use), genetic profiles, environmental factors, and family history. Personally identifiable data would be needed because anonymous information could negate the purposes of individualized medicine, but enhanced privacy and security measures would have to be implemented because of the heightened sensitivity of the information collected. Privacy safeguards rely heavily on informed consent, although in practice many patients are not fully informed of what may or may not be done with their information.⁷ Systems medicine would require more complex and potentially confusing consent forms, with the potential to dramatically increase existing knowledge gaps. Moreover, genetic information has profound implications for the patient's family, resulting in difficult ethical issues of whether they should be informed of genetic predispositions.⁸

Discrimination. The collection and use of sensitive health information raises ethical and legal concerns about discrimination in health insurance, employment, and education.³ The Genetic Information Non-Discrimination Act (GINA) prohibits discrimination based on genetic information for health insurance and employment. Additionally, the Americans with Disabilities Act proscribes discrimination against persons with disabilities but has significant gaps in coverage. Individualized treatments could incorporate predictors specific to ethnic group (eg, predictors for sickle cell anemia among African Americans and for Tay-Sachs disease among Ashkenazi Jews). However, ethnic group profiling can result in stigma and adverse treatment of minorities.

Justice. History teaches that the poor and minorities often have unequal access to new technologies, particularly when interventions are novel or expensive. It may be unreasonable, moreover, to expect that already disadvantaged patients will be able to navigate the new terrain of systems medicine and dedicate more time to their own health. Multiple barriers (eg, language, education, remote location, and socioeconomic status) to equal access of systems medicine could quickly become apparent. These barriers could exacerbate existing disparities in access to quality care, raising serious questions of distributive and social justice.

Introducing systems medicine into medical curricula and practice is anticipated to result in more comprehensive and systematic patient care in an economically sustainable fashion. However, current technology and knowledge may not be prepared for the shift. Although recent genome-wide association studies have been able to identify common gene variants, they account for only a fraction of the genetic variation known to exist and explain only a small proportion of underlying genetic contributions to common diseases. Genes identified by these studies provide useful information about the biological pathways underlying polygenic diseases and traits⁹ but do not necessarily contribute to the prediction of the risk of disease. Thus, the claims of companies purporting to offer accurate risk predictions of future health and disease should be viewed with caution, because the genetic variants resulting in the highest relative risks are likely to be overestimated. Furthermore, while systems medicine purports to account for a multitude of complex factors in the prediction of disease, quantification of multiple factors—such as environmental influences—remains a challenge.¹⁰

Systems medicine seems targeted toward an educated, aware, and health-conscious consumer. It promises greater precision in diagnosis, opportunity for earlier intervention, risk-based prevention, individualization of care, and optimization of the patient-clinician interface. This suggests greater orchestration of research teams, patients, and physicians, as well as an even greater demand for fully informed consent. Resources are required for physician, student, and consumer education to implement this new model. More important, systems medicine raises fundamental sociolegal considerations of cost-effectiveness, privacy, consent, discrimination, and attainment of social justice. Therefore, a shift to systems medicine must take these critical factors into account.