Karoly Nikolich, Department of Psychiatry, Stanford University, Palo Alto; and Circuit Therapeutics, Menlo Park, CA, U.S.A.
Steven Hyman, Broad Institute of MIT and Harvard, Cambridge, MA, U.S.A.
Robert Malenka, Department of Psychiatry and Behavioral Sciences, Stanford University Medical Center, Palo Alto, CA, U.S.A.
Menelas N. Pangalos, Innovative Medicines, AstraZeneca, Mereside, Alderley Park, U.K.
Bernd Sommer, CNS Diseases Research, Boehringer IngelheimPharma GmbH & Co. KG, 88937 Biberach an der Riss, Germany
Translational neuroscience is at a critical juncture and could take us down two paths: extinction or revolution. The unique challenges and numerous failures to treat complex and often slowly developing diseases of pathological neural circuits have been disheartening. Yet, profound progress is unfolding through discoveries and techniques to understand the underlying pathophysiological mechanisms of nervous system diseases.
What is to be done? The goal of this Forum is to envision a conceptual roadmap that will create an effective, credible, and productive path that will take us from the bedside to the lab and back again. Over the past decade, breakthrough approaches and technologies have emerged that allow unprecedented insights into central and peripheral nerve function and, consequently, are expected to enable the discovery and development of new drugs, as well as therapeutic devices. The combined progress in genetics, biomarkers, live imaging, circuit analysis and modulation, stem cell technologies, neurostimulation devices are promising to revolutionize novel therapies.
We envision that the synergistic discussions between the leading minds in the neurosciences and neuropsychiatry communities will constitute a landmark and serve academic research for decades to come as well as yield new therapies for humanity.Top of page
According to the World Health Organization,1 brain and nervous system disorders are the leading cause of disability worldwide and the leading overall cause of disease burden in established market economies. With changing global demographics, specifically an increasing proportion of the world’s population living past 60 years of age, the relative burden of brain disorders is projected to increase markedly within the next 2–3 decades. The potent influence of these disorders on disability stems from the fact that the brain is the organ of thought, emotion, and behavioral control. To varying degrees, brain disorders result from the interaction of genetic risks factors and developmental and environmental factors, ranging from early malnutrition to severe stress (exacerbated globally by prolonged, serious conflict in many regions). The effects of these disorders on individuals, families, and society are enormous. Early onset disorders, such as autism, epilepsy, schizophrenia, and mood and anxiety disorders, disrupt personal development and are potent causes of disability. Neurodegenerative diseases impact an increasingly large segment of the world’s population and, like early onset disorders, affect not only the sufferer, but also their families (e.g., caregivers must often devote their entire time to care). Finally, disorders such as depression are well documented to exert a malign effect on the course of other chronic diseases, such as heart disease and diabetes.
Despite the impact of diseases of the nervous system on individuals and society as a whole, our current arsenal of therapies to treat CNS diseases effectively is extremely limited and dated. The efficacy of major classes of drugs to treat depression, anxiety, schizophrenia, and bipolar disorder reached a plateau nearly a half century ago, and despite promising research, disease-modifying treatments for neurodegenerative disorders have not yet materialized. In spite of the dire need, the complexities of such diseases and the challenges of successfully developing new therapies have prompted many large pharmaceutical companies to abandon further efforts. Among their reasons were: (a) the heterogeneity of many brain disorders and the need in many cases to rely on descriptive diagnoses, (b) the lack of knowledge of the fundamental causes and mechanisms of most diseases, (c) a lack of animal models that translate to human and predict treatment efficacy, and (d) a lack of objective human biological markers with which to conduct clinical trials.
Concurrent with the exit of industry, however, neuroscientists, geneticists, chemists, bioengineers, and clinical investigators including psychiatrists, neurologists, and neurosurgeons are finally at the threshold of discovering pathobiological mechanisms and identifying molecular, cellular, and neural circuits that can be addressed using specific and targeted therapies. Over the past decade, several breakthrough technologies have emerged, and new approaches continue to arise that allow unprecedented insights into brain function and, consequently, would enable the discovery and development of new drugs, as well as therapeutic devices. For example:
To address the global burden of CNS disease, collaboration is essential. Oncology has set a most impressive example of how discoveries have been translated into a wide range of effective treatments, including small molecules, antibodies, and biological agents, over a timeframe of 20–25 years, starting with the discovery of oncogenes, kinase receptors, angiogenesis, patient stratification and personalization based on genetics and genomics. Solid science has led to effective therapies. A similar transformation is needed for CNS diseases and can be anticipated based on recent scientific breakthroughs. What is exceedingly important at this stage is to envision and define a roadmap that will guide future discovery and development efforts. The time is ripe to bring together the leading minds in the field to define a roadmap for future discovery and development efforts in this vitally important area.
1 The Global Burden of Disease: 2004 Update. WHO 2008: ISBN 978 92 4 156371 0Top of page
To radically transform the status quo, we need to identify: