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Translational Neuroscience

Toward New Therapies

Edited by Karoly Nikolich and Steven E. Hyman

Today, translational neuroscience faces significant challenges. Available therapies to treat brain and nervous system disorders are extremely limited and dated, and further development has effectively ceased. Disinvestment by the private sector occurred just as promising new technologies in genomics, stem cell biology, and neuroscience emerged to offer new possibilities. In this volume, experts from both academia and industry discuss how novel technologies and reworked translation concepts can create a more effective translational neuroscience.

The contributors consider such topics as using genomics and neuroscience for better diagnostics and biomarker identification; new approaches to disease based on stem cell technology and more careful use of animal models; and greater attention to human biology and what it will take to make new therapies available for clinical use. They conclude with a conceptual roadmap for an effective and credible translational neuroscience—one informed by a disease-focused knowledge base and clinical experience.

Drug discovery for brain disorders has stalled, much to the detriment of people with conditions such as autism, schizophrenia, and Alzheimer's disease. This book, authored by leading experts in the field, provides compelling new ideas and approaches that could reignite progress.

Eric Nestler, MD, PhD

Nash Family Professor, Director, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai

What is to be done’ to revolutionize the scientific understanding, treatment, and prevention of neurodevelopmental, neurodegenerative, and psychiatric disorders? What has been holding us back? What new scientific tools, technologies, and approaches are now at our disposal to find the treatments that our patients and family caregivers deserve? In this thoughtful and thought-provoking book, leaders from a wide range of disciplines in academia and industry offer their perspectives. They do not provide definitive answers. Rather, they permit us to think about old questions in new ways, they lay out many of the tools needed to navigate what has been most elusive scientific frontier, and they call upon us all to advance the scientific fight against brain and behavioral disorders in the most successful, rapid, and impactful way.

Eric M. Reiman, MD

Executive Director, Banner Alzheimer’s Institute

The decades surrounding the launching of the new millennium witnessed a revolution in fundamental neuroscience research. This elegantly composed volume enunciates a second revolution—applications to clinical relevant problems. Leading authorities explicate with elegant lucidity how basic neuroscience is yielding new understanding and therapy of the major neurologic and psychiatric disabilities. A must-read book for all who care about the brain.

Solomon H. Snyder, MD

Professor of Neuroscience, Johns Hopkins Medical School

A must-read volume, especially for those, like me, hoping that a very new and exciting chapter in translational neuroscience is emerging. As described in this book, it is built on a solid scientific footing—genetics, neurocircuits, disease biology, validated cellular and animal models, and importantly, a rational data-driven nosology—and will unquestionably deliver a new generation of highly effective medicines for some of the most disabling and fatal of human afflictions.

Steve Paul, MD

President and CEO, Voyager Therapeutics; Founder, SAGE Therapeutics and Tal Medical; former President, Lilly Research Laboratories; former Scientific Director, National Institute of Mental Health


Tobias M. Böckers, Thomas Bourgeron, Karl Broich, Nils Brose, Bruce N. Cuthbert, Ilka Diester, Gül Dölen, Guoping Feng, Richard Frackowiak, Raquel E. Gur, Stephan Heckers, Franz Hefti, David M. Holtzman, Steven E. Hyman, Nancy Ip, Cynthia Joyce, Tobias Kaiser, Edward H. Koo, Walter J. Koroshetz, Katja S. Kroker, Robert C. Malenka, Isabelle Mansuy, Eliezer, Masliah, Yuan Mei, Andreas Meyer-Lindenberg, Lennart Mucke, Pierluigi Nicotera, Karoly Nikolich, Michael J. Owen, Menelas N. Pangalos, Alvaro Pascual-Leone, Joel S. Perlmutter, Trevor W. Robbins, Lee L. Rubin, Akira Sawa, Mareike Schnaars, Bernd Sommer, Maria Grazia Spillantini, Laura Spinney, Matthew W. State, Marius Wernig

ISBN: 9780262029865

Photographie: U. Dettmar
Lektorat: BerlinScienceWorks

This Forum is supported by the Deutsche Forschungsgemeinschaft

The German Research Foundation

DFG logo

Diseases of the Nervous System: What Is to Be Done?

Frankfurt am Main, Germany

Karoly Nikolich and Steven Hyman, Chairpersons

Program Advisory Committee

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

Goals of the Forum

  • To explore the commonalities and differences in collaboration as observed in biological, social, and technological systems,
  • To identify core drivers of and constraints on collaboration and the conditions for its emergence, stabilization, and fractionation,
  • To outline putative generic architectures for processes of collaboration, and
  • To model how commons may be created, consumed, and destroyed during collaboration.

Integrating diverse perspectives, the Forum will work to develop a comprehensive framework to support future work.


The stability of social systems depends critically on realizing sustainable methods of “collaboration,” yet how and by which means collaboration is achieved is not clearly understood; neither are the conditions or processes that lead to its breakdown or failure. [For context, collaboration is understood as cooperation between agents toward mutually constructed goals.] Part of the reason for our lack of understanding is that the phenomenon of collaboration is, by nature, a highly multidisciplinary problem, and effective research into its complexities has been difficult to achieve across the broad range of scientific and technical disciplines involved.

The need for a fundamental understanding of collaboration, however, has become increasingly important. Not only does humankind demand answers as it attempts to address critical challenges at multiple scales (e.g., climate change, migration, enhanced automation, social and economic inequality), but ever-increasing technological and economical means of interconnecting people and societies are disrupting long-established, familiar patterns of how we interact. Radical technological changes that are ongoing have the potential to reshape collaboration in ways that are currently hard to predict or influence (e.g., by altering configurations in interaction, information creation, and modes of communication). On one hand, such changes could disrupt hitherto stable forms of collaboration by affecting critical communication channels and traditional roles, as can be observed in the rapidly changing patterns in governance, commerce, and social interaction. On the other, technology could lead to the emergence of novel, successful forms of collaboration that deviate from traditional “hierarchical” architectures. Evidence of this can be seen in areas as diverse as highly automated manufacturing plants, the open science movement, collaborative software repositories, user-centered services, and the sharing of economy-based modes of organization. Without a fundamental understanding of the mechanisms, processes, and boundary conditions of collaboration, it is not possible to evaluate or predict which of these possible scenarios are sustainable or even plausible.

To remedy this knowledge gap requires a comprehensive research program. At its core, a theoretical framework must link pertinent aspects of collaboration across spatiotemporal scales and contexts. This task is a tall order, yet given current pressures on human–human, human–machine, and future machine–machine collaboration, we believe that an attempt must be made for a first survey.

This Forum is supported by the Deutsche Forschungsgemeinschaft

The German Research Foundation

DFG logo

Background and Rationale of the Forum

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:

  • Imaging: Unlike peripheral diseases, we typically do not have the ability to sample brain tissue. Therefore, a variety of high-resolution imaging modalities have become vital tools.
  • Biomarkers: Development of disease-specific biomarkers is being used to test drug engagement with the target and/or to serve as surrogate markers of efficacy in human studies.
  • Personalized Healthcare: Relevant criteria for patient stratification are needed in this area, similar to other successful examples seen in other difficult therapy areas (e.g., in oncology).
  • Circuit Analysis: New, minimally invasive techniques have emerged over the past five years that enable the delineation of normal and abnormal neural circuitry. Optical control of neural circuits has allowed us to map synaptic networks involved in specific symptoms in live animals.
  • Genomics and Genetics: The human genome project has prompted the development of powerful new technologies. With modern genomic tools, the first replicable results have appeared for schizophrenia, autism, bipolar disorder, and common late onset forms of Alzheimer’s disease.
  • Gene Silencing and Regulation: shRNA, RNAi, and microRNA technologies offer large-scale screening opportunities for functional characterization of genes that may become drug targets.
  • Stem Cell Technologies willpermit, for the first time, a supply of human neurons that can be studied to understand disease pathways and screened for new agents.
  • Drug Screening Technologies: Cell-free and cell-based micro- and nano-screening technologies that probe targets of neural significance, such as GPCRs, ion channels, synaptic and even intraneuronal targets, have been developed and are being applied with success.
  • Blood-Brain Barrier Penetration Technologies: Several high-capacity transporter molecules have been identified that can carry therapeutically active molecules across the blood-brain barrier.
  • Neurostimulation Devices: Implanted, transcranial, and other electrical and magnetic technologies have been developed that offer increasingly precise control of specific nerves.
  • Simulation-based research: Brain simulation has the potential to provide new insights into the basic causes of neuropsychiatric diseases and new ways to test therapies and understand the way they work by providing a test platform that can directly target the causes of disease.

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 0

This Forum is supported by the Deutsche Forschungsgemeinschaft

The German Research Foundation

DFG logo

To radically transform the status quo, we need to identify:

  • Tools to stratify patient populations
  • The critical “driver” pathways and circuits causing disease in these stratified patient populations
  • Tools to map and modulate critical “driver” pathways and circuits
  • Markers that can reliably and quickly demonstrate target engagement and/or pathway modulation in vivo to know that you can test and refine the hypothesis (and thus motivate a return to basic science)
  • Efficacy endpoints that do not require prohibitively long clinical trials

Group 1: Neurodegenerative Diseases: What Is to Be Done?

  • Does current disease classification impede progress?
  • How do we integrate disease classification with neurobiology and genetics?
  • How do current biases influence research?
  • How do current systems (e.g., grant-making, publications) reinforce/perpetuate existing models?
  • How do we change the culture?
  • Will single-agent therapies ever be sufficient to treat these complex diseases?

Group 2: Neurodevelopmental Disorders: What Is to Be Done?

  • Does current disease classification impede progress?
  • How do we integrate disease classification with neurobiology and genetics?
  • How do current biases influence research?
  • How do current systems (e.g., grant-making, publications) reinforce/perpetuate existing models?
  • How do we change the culture?
  • Will single-agent therapies ever be sufficient to treat these complex diseases?

Group 3: Living Systems: From Models to Patients

  • Are there important issues that can be addressed by humanized animal models (rodent and primate) or only in humans?
  • How do we jump between levels of complexity in these model systems in a way that will apply to patients?
  • How do you go about using engineered cells?
  • Reliability / replicability
  • How can we target specific cells/circuits/regions in the brain?
  • Which particular parameters can be modeled in which particular systems in a meaningful way?
  • Which symptom domains can be modeled and which will require humans?
  • How do we manipulate circuits in the human brain?

Group 4: Pathophysiological Toolkit: Genes to Circuits, Flies to Humans

  • How do we define circuits in animals that are relevant to the human brain?
  • How do we manipulate circuits in the human brain?
  • How do we go from genetic/pathways to circuit dysfunction?
  • How do we use this information for defining patient stratification and biomarkers?
  • What tools do we need to develop?

    This Forum is supported by the Deutsche Forschungsgemeinschaft

    The German Research Foundation

    DFG logo