Hot Topic: Molecular Therapy Drives Patient‐Centric Health Care Paradigms (2010)

The unmet need for efficacious and inexpensive treatments providing patient-centered solutions to challenges in worldwide distributable health care is accelerating, reflecting global unremitting poverty, aging of populations, and westernization of lifestyles.1,2 During the past century, technology breakthroughs in basic and clinical sciences yielded paradigms addressing global issues in the delivery of care to patients and populations, including vaccination, hormone replacement, and organ transplantation. Despite these advances presaging a golden era of scientific medicine and surgery, the intricacies of health care delivery have restrained the full potential of these innovations. It has been challenging to initiate vaccination programs that eradicate infectious diseases, which is in the global scope.3 Endocrine replacement, while ameliorating symptoms, has not provided cures and in the course of treatment has revealed incipient degenerative diseases. Transplant medicine has become unsustainable as a solution to organ pathology, reflecting the limited access to donors. The burden of disease is accelerating on a macro scale, demanding essential health care solutions emanating from across the continuum of discovery, development, regulation, and utilization. This escalating challenge in international health care delivery is being met by the exponential evolution in scientific innovation. Fueled by emerging technological paradigms, the new biology has advanced knowledge of disease prevention and cure. One example of the ongoing scientific revolution is the development of molecular therapeutics, which leverage integrative network-dependent molecular-scale concepts in pathobiology to identify mechanism-based therapeutic targets, amplify curative efficacy, and eliminate off-target adverse effects.4,5 The revolution in biological insight propelling molecular therapeutics is best exemplified by the mechanistic association between infections by select viruses and the pathophysiology of tumorigenesis that established the framework for developing vaccines for primary cancer prevention.6 Mechanistic insights into links between viral infections and cancer, in turn, have translated into previously unavailable opportunities to eliminate human papilloma virus and hepatitis B virus infections with the goal of universal prevention of cervical and hepatocellular cancer, respectively. Additionally, the growing armamentarium of molecular, genomic, proteomic, metabolomic, and regenerative platforms has produced opportunities to fully personalize pharmacotherapy for individual patients. Indeed, single nucleotide polymorphisms in proteins defining the pharmacokinetics of drugs identify patients who may, or may not, respond to specific hormone-targeted therapies in patients with breast cancer.7–10 Further, this expanding toolbox of molecularly targeted therapies increasingly incorporates biologically based therapies, including natural or engineered stem cell paradigms, promoting self-healing processes to repair injured organs. In turn, regenerative medicine is providing unique solutions to overcome the inherent imbalance between donor organs, which are severely in short supply, and transplant recipients, which are overwhelmingly in excess, a mismatch of resources that has historically constrained the impact of transplant medicine.11,12 Together, the foundation provided by molecular therapeutics extends beyond the palliative algorithms of conventional clinical practice, in which therapies are delivered employing one-size-fits-all paradigms. Rather, molecular therapeutics embraces individualization of curative solutions for patients and populations encompassed by emerging disciplines including preventive, personalized, and regenerative medicine.4,13 The revolution in biomedicine and the associated emergence of molecular therapeutics entrains near-term objectives that translate the product of the discovery pipeline shaped by the new biology and the resultant pathophysiological insights into patient-centered algorithms of health care. Indeed, this goal is highlighted by the sharp contrast between the abundance of treatment opportunities produced by emerging technology platforms, and the paucity of their translation to management of disease across individuals and populations. These considerations are underscored by the breadth and depth of the global burden of infectious diseases, one leader of worldwide morbidity and mortality, which has been incompletely addressed by immunization.6 In addition, there are only a small number of therapies that have addressed diagnostic validation and regulatory milestones important for predicting drug safety, although an abundance of genetic and epigenetic structures defining individual kinetic and dynamic adverse responses have been identified.7–10,14–22 Examples include CYP2C9/VKORC1 and warfarin in anticoagulation, thiopurine methyltransferase and mercaptopurines for leukemia, and UGT1A1 and irinotecan in colon cancer. Further, while regenerative medicine is positioned to be maximally impactful, with indications across the continuum of care, stem cell therapy is presently restricted to bone marrow transplantation.11,12 These considerations highlight the growing chasm in molecular therapeutics between products of the discovery engine supported by emerging technology platforms, and the constraints inherent in established paradigms for validation, early adoption, and translation into clinical care. This inconsistency, wherein discoveries arising from the new biology are limited in their extension to patient-centric algorithms, reflects the incompatibility of conventional mechanisms for technology translation and paradigms of global health care distribution.5,9,18,23,24 Beyond restrictions in technology transfer from laboratory to clinic, disparities in the distribution of health care resources amplify limitations on applying emerging technology platforms to patient care. One particularly illustrative example is the striking disproportion between cervical cancer incidence in vulnerable populations and immunization against human papilloma virus, reflecting socioeconomic status rather than considering populations at risk. In that context, one priority of health care reform in the United States is to eliminate racial and socioeconomic disparities in health care delivery, including access to emerging technology platforms and individualized molecular therapeutics. These considerations highlight the essential mismatch between the output of the discovery engines driving evolution of available treatments and conventional mechanisms translating them into patient-centered models of health care. This discordance between innovation and translation underscores the unsustainability, at the level of society, of these paradigms in the context of the rapid evolution of biology and technology. Indeed, this imbalance threatens the eventual collapse of the mechanisms translating innovation into optimum therapies that benefit the greatest populations. Evolution of these dysfunctional models of innovation and translation inherent to established health care structures are required to produce the best outcomes for our patients. In turn, this evolution will require the novel integration of systems engineering into these mechanisms, to innovate novel paradigms that realize the full power of discovery, invention, and innovation and their translation to health care, while amplifying the quality and value of molecular therapeutics. As technology platforms evolve from traditional therapeutic approaches modifying incompletely appreciated pathophysiology, to molecular therapeutics modulating information flowing across specific signaling pathways, an essential limitation to their application will remain economics.5,15,22–24 Comparative effectiveness has emerged as an essential element of solutions required to define the value of molecular therapies within the framework of existing socioeconomic structures. In that context, systems engineering will demand coordination across the continuum of discovery-innovation-application to orchestrate optimum integration of products of emerging technology platforms into economically considered strategies that make health care structures responsive to patients with chronic multisystem diseases.25 Moreover, beyond individualization of therapy, personalization of entire health care systems will rely on models engaging patient participation to prevent, rather than interrupt, disease. These new models of patient-centric health care, optimizing the translation of the new biology into individualized molecular therapies, will rely on electronic medical records integrating clinical, demographic, and molecular data to optimize management decisions. Health care structures that design and deploy systems that translate scientific innovation into novel paradigms of clinical care will be at the advancing front of industry standards. Importantly, beyond health care systems in industrialized countries, global health initiatives must capture the innovation inherent in molecular therapeutics to engineer cost-effective distributable solutions to the most vulnerable populations at risk. In that context, fundamental issues beyond basic health care continue to limit the translation of scientific innovation into improved patient lives. Social and political unrest, hygiene, hunger and malnutrition, and poverty constrain deployment of basic health care resources to the neediest populations. Harnessing the value of scientific discovery to advance global standards of health care incorporating the inherent power of molecular therapies will depend on finding novel solutions to existing problems. In that context, the two ends of the health care continuum, encompassing the mutually synergistic disciplines of laboratory-based discovery and delivery of clinical care, are inextricably intertwined. The power inherent in their integration will generate universal personalized solutions to improve the lives of individuals and, more broadly, populations around the world. The authors have no relevant disclosures. Dr. Waldman is the Samuel M.V. Hamilton Endowed Professor of Thomas Jefferson University. Dr. Terzic is the Marriott Family Professor of Cardiovascular Research at the Mayo Clinic. The authors are supported by grants from the NIH.