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NeuroView Transforming Our Approach to Translational Neuroscience: The Role and Impact of Charitable Nonprofits in Research Cynthia Joyce1,* 1MQ: Transforming Mental Health, 1-5 Clerkenwell Road London, EC1M 5PA, UK *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2014.10.030
From mental health to rare diseases, charitable nonprofits and foundations are bringing energy, perspective, and leadership to the process of translational research. In challenging researchers to become more connected—to each other and to patients—charities are helping neuroscience deliver innovation that is relevant to real people in the real world. Translational aims have been a remarkable engine for driving research investment in the neurosciences. But, as noted by many writers in this issue of Neuron, despite decades of major investment, our therapeutic successes have been few and far between. Could it be that our aims are only wishful thinking? Most certainly not. As this issue makes clear, there is value in taking a critical look at what has been achieved thus far, considering lessons learned, and reconsidering our approaches to treatment development. This period of reflection also creates an opportunity to invite different perspectives to the table and to engage in broader thinking about our challenges. Non-profit and charitable organizations, which already play an important role in the research enterprise, represent one such important and often overlooked perspective. What might we learn from them? And how can we include these organizations more effectively in efforts to transform the translational neuroscience effort? Not All Nonprofits Are Alike It is important to note from the start that nonprofits are as widely variable in character as entities in any other business sector. Most of us learn about nonprofits from the organizations that flood our mailboxes, street corners, and walking paths with fundraising appeals; for the purposes of this article, I will be referring solely to nonprofits supporting health/medical research, particularly in the neurosciences. Even so, this area of nonprofit activity is huge, encompassing small local
fundraising groups and massive philanthropic organizations like the Wellcome Trust or the Bill and Melinda Gates Foundation (see Table 1). For the sake of clarity, I will use the terms ‘‘charity’’ to refer to organizations (of any size) raising money from the public and ‘‘foundation’’ to refer to private philanthropy and endowed foundations. Having worked with organizations in both the US and the UK, I can confirm that while there are some differences in operational style (due to cultural and taxcode differences), these differences pale in comparison to the large strategic issues facing the entire sector. The impact of social media on both fundraising and program development has been enormous: Witness the impact of the ‘‘Ice Bucket Challenge’’ on the ALS community. Fastmoving changes in technology and the push toward personalized medicine are taking place on both sides of the Atlantic. Adapting to these changes is just one of the many challenges facing health research charities, all while keeping an eye on the prize—delivering improvements in diagnosis, treatment, and prevention interventions. The Spectrum of Research Investors Just as there is a spectrum of nonprofits across the US and UK, so is there a spectrum of research strategies and research investment styles employed by charities and foundations. Some organizations focus their energies on basic science and discovery research, while others seek only to support applied or
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translational research; others support a mixed portfolio. Even further along the spectrum are organizations, particularly social services charities, investing in research toward prevention. To get the most benefit from nonprofit relationships, it is important for translational neuroscientists to understand how an organization positions their funding goals with respect to the classic T0-T4 translational pathway and their investment strategy (Figure 1). A large percentage of nonprofit research programs use investigator-driven funding models as established by the NIH and the MRC. In the neurosciences, discussions about funding generally include that most traditional and familiar charity funding strategy—the ‘‘career development award.’’ This resource is more important than ever for early career investigators as government and industry funding for neuroscientists becomes tighter. For charities, these awards are a way to seed a field and develop career paths in emerging areas of research—as has been the case with much beloved funding from the Hereditary Disease Foundation (http://www.hdfoundation.org) or the NARSAD (http://www.bbrfoundation.org) grants from the Brain and Behavior Research Foundation. We are utilizing this time-honored approach to introduce my own organization, MQ: Transforming Mental Health, (http://www.joinmq.org) to research professionals. At the more experimental end of the research spectrum are the organizations working to stimulate meaningful advances in the translational research
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NeuroView path itself. Charities like the Alzheimer’s Association (http://www.alz.org), Michael J. Fox Foundation (MJFF) (http://www. michaeljfox.org), and the Spinal Muscular Atrophy Foundation (SMA Foundation, where I worked for many years; http:// www.smafoundation.org) are directing research investments toward tool development, biomarker initiatives, and therapeutics development itself. Typically, this kind of research strategy requires the ability to invest a million dollars or more in individual projects, which has been a barrier to many smaller charities. However, over the last 20 years, a small group of nonprofits, generally focused on single gene disorders, have formed solely to accelerate therapeutics development. These charities are finding ways to make smaller grants (on the order of $50,000– $500,000) meaningful by supporting timely and important ‘‘derisking’’ investments along the discovery and development pathway. Examples of these kinds of nonprofits include investors like the Parent Project for Muscular Dystrophy (http://www.parentprojectmd.org) (therapeutics development); FARA (http:// www.curefa.org), which leads infrastructure and therapeutics investments in Freidrich’s Ataxia; FRAXA (http://www. fraxa.org) doing the same for Fragile X syndrome; and the Rett Syndrome charities. Each of these organizations has made important contributions to demonstrating that the translational research pathway can indeed advance discovery and/or therapeutics development for brain diseases. At the far end of the spectrum are philanthropic investors such as Paul Allen, James Simon, Eli Broad, the Stanley Family, Lord David Sainsbury and others in the US, UK and abroad who, through their foundations, are making iconic investments in the research process. Their support of major initiatives including the Allen Brain Atlas (http://www.brain-map.org), SFARI (http://sfari.org) and the Simon Simplex Collection (autism), the Broad Institute and Stanley Centers (http:// www.broadinstitute.org) (schizophrenia) for genetic research and the Sainsbury Wellcome Center (http://www.ucl.ac.uk/ swc) for Neural Circuits and Behavior, is giving researchers the standardized tools and resources needed to advance translational pathways across multiple
areas of interest. In so doing, these philanthropists have raised the level of visibility of the neuroscience among policy makers – and also a certain level of expectation that science is working to deliver tangible human benefit (Broad, 2014). In many ways, research funding from the Howard Hughes Medical Institute and the Wellcome Trust underpin many of our translational efforts in the neurosciences. The projects supported by these endowed foundations are important charitable complements to investments by governmental agencies; their contributions to research methods and policy development cannot be overestimated. While perhaps not as familiar to people in the US, the Wellcome Trust has been a major driver of discovery and translational efforts across many fronts in the UK, from the Sanger Institute for genetics research to psychological research; it also happens to be the leading funder of our grand experiment in mental health research at MQ. While not all nonprofits are alike, there is sophistication, energy, and momentum in this sector. It is wise to think of charities as not only supporters, but also initiators and partners for translational initiatives in our field. Thanks to new tools at our disposal to better understand brain function, there has never been a more important time to work with nonprofits to maximize our translational research opportunities (Deisseroth, 2014). How Can Nonprofits Best Contribute to Translational Neuroscience Research Going Forward? Realistic Expectations for Translation Are Essential Despite our optimism about the translational process, experience has shown us that it can take 20 years or more to realize the clinical benefits of the search for new treatment targets (Wooding et al., 2013). Similarly, our experience in single gene disorders (Huntington’s disease and muscular dystrophy are prime examples) has taught us that gene identification does not directly lead to treatment. If nothing else, our current decade should represent the time when research funders and investigators alike work together to describe translational neuroscience process more realistically for patients and donors. Therefore, an important step
for both sides of a charity relationship is to encourage clarity and feasibility of research goals. Charities and advisers need to be conscious of their respective tolerance for risk and expectations for return on investment. Ultimately, there is a sweet spot for every investor and researcher seeking to make a contribution to translational neuroscience research. Learning from Charitable Investments Thus Far Funders and researchers are sharing lessons learned from translational experience in forums supported by various institutes at the NIH, the Institute of Medicine, and professional associations like the Health Research Alliance (http://www. healthra.org) in the US and the Association of Medical Research Charities (http://www.amrc.org.uk) in the UK. There also exists a delightful commitment to ‘‘pay it forward’’ in the nonprofit community, exemplified by leaders like Robert Beall, the CEO of the Cystic Fibrosis Foundation (http://www.cff.org) and architect of the development of Kalydeco, a true translational success story (for an interesting background profile, see Groopman, 2009). Another is Robi Blumenstein, visionary leader of the CHDI Foundation (http://chdifoundation.org) and coauthor of a recent paper on how funders can contribute to best practices for scientific reproducibility (Munafo` et al., 2014). NIH has taken knowledge sharing a step further with several programs designed to foster translation for charities and investigators alike. Many of these projects have now been consolidated under the new National Center for Advancing Translational Sciences (NCATS; http://www.ncats.nih.gov), including the Rare Diseases Clinical Research Network, some 22 consortia focused on linking researchers and clinicians in therapeutic development and the Clinical and Translational Science Award (CTSA; 60 participating institutions). The Therapeutics for Rare and Neglected Diseases (TRND) program has been used effectively to advance therapeutics development for muscular dystrophy and for Neiman-Pick Disease (see the Ara Parseghian Medical Research Foundation; http://www.parseghian.org). NCATS is also home to specific translational resources from assay development and
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Table 1. Examples of Nonprofit Organizations Supporting Translational Neuroscience Research
Organizationsa
2013 Research Expenditure (unless stated)b
Website
Focus
Examples of Translational Projects
Alzheimer’s Association
http://www.alz.org
Advance understanding of Alzheimer’s, identify new treatment strategies, improve care for people with dementia, optimize services for their families, and further knowledge of brain health and disease prevention.
$15,069,000
World Wide Alzheimer’s Disease Neuroimaging Initiative (WW-ADNI). Global biomarker standardisation consortium.
Autism Speaks
http://www.autismspeaks.org
Fund global biomedical research into the causes, prevention, treatments and a possible cure for autism
$15,790,797
DELSIA (Delivering Scientific Innovation to Autism) to catalyse private investment in product development. AGRE: Autism Genetic Resource Exchange.
Brain and Behaviour Research Foundation
https://bbrfoundation.org
Committed to alleviating the suffering caused by mental illness by awarding grants that will lead to advances and breakthroughs in scientific research.
$13,037,212 (2012)
Supports research into New Technologies, and Next Generation Therapies.
Friedreich’s Ataxia Research Alliance (FARA)
http://www.curefa.org/about.html
Dedicated to the pursuit of scientific research leading to treatments and a cure for Friedreich’s ataxia.
$2,860,246
The Collaborative Clinical Research Network in Friedreich’s Ataxia (CCRN in FA).
FRAXA Research Foundation
http://www.fraxa.org/fraxa
Focus on finding effective treatments and ultimately a cure for Fragile X. Portfolio spans the spectrum of translational, pre-clinical, and clinical research.
$1,443,565
FRAXA Drug Validation Initiative (Chile) tests promising compounds with therapeutic potential in various animal models of fragile X.
Micheal J. Fox Foundation
https://www.michaeljfox.org
To elimate Parkinson’s in our lifetime. Accelerate the best ideas in Parkinson’s disease research toward clinical testing and practical relevance for patients.
$75,341,541
BioFind biomarker discovery program; Parkinson’s Progresson Marker Initiative; drug development pipline projects
MQ : Transforming Mental Health
http://www.joinmq.org
Supports research across disciplines, building diverse portfolio with focus on 1) improving current treatments and 2) new strategies for diagnosis, treatment or prevention of mental illness.
N/A
Psy-IMPACT research towards a better understanding of how psychological treatments work, with whom and why they work, and how they can be improved upon.
One Mind
http://www.onemind.org
Fostering fundamental changes that will radically accelerate the development and implementation of improved diagnostics, treatments and cures for diseases and injuries of the brain.
N/A
Apollo: open science interactive data exchange portal for brain disease and brain injury. Gemini clinical study to accelerate the discovery of diagnostics, treatments, and cures for TBI
Parent Project for Muscular Dystrophy
http://www.parentprojectmd.org/site/ PageServer?pagename=nws_index
Fund the most promising near and long term Duchenne research strategies and cutting-edge therapies.
$3,295,024
Project Catalyst: initiative designed to identify new drugs in collaboration with PTC Therapeutics, Inc. (PTC). Also GIFTED—Global Investment For Therapeutics to End Duchenne.
SMA Foundation
http://www.smafoundation.org
The mission of the SMA Foundation is to accelerate the development of a treatment for Spinal Muscular Atrophy.
Unknown
Invested more than $100 M to move treatments from the laboratory through the clinic.
Charities
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Website
Focus
Examples of Translational Projects
Paul Allen Foundation - Allen Institute for Brain Science
https://www.alleninstitute.org
Accelerate the understanding of how the human brain works in health and disease. Using a big science approach, generate useful public resources, drive technological and analytical advances, and discover fundamental brain properties through integration of experiments modeling and theory.
$44,000,000 estimated. Institute also attracts NIH funding.
Data and tools are all available to anyone—for free—through the Allen Brain Atlas data portal. Involved in White House BRAIN Initiative, and the European Human Brain Project (HBP).
Simons Foundation/Sfari
http://sfari.org
SFARI’s mission is to improve the understanding, diagnosis and treatment of autism spectrum disorders by funding innovative research of the highest quality and relevance.
$60,000,000 estimated
Collection of well-characterized individuals with autism or with specific genetic alterations (the Simons Simplex Collection and the Simons Variation in Individuals Project). Tools that enable researchers to keep track of the genetic landscape (SFARI Gene), to order mouse models (Autism Mouse Models) or to order biospecimens and other types of data from research projects (SFARI Base).
Wellcome Trust
http://www.wellcome.ac.uk/Funding/ Biomedical-science/index.htm
Vision is to achieve extraordinary improvements in human and animal health. Support the brightest minds in biomedical research and the medical humanities. One of 5 key areas is to support research to improve understanding of how the brain functions and to find improved approaches for treating brain and mental health disorders.
£45,000,000 estimated on mental health research.
Discovery and development portfolio. Together with the Gatsby Foundation, founded the Sainsbury Wellcome Research Centre for neural circuits and behavior at Univeristy College London.
Foundations
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This table depicts a representative, but by no means comprehensive, list of charitable organizations with an interest in neuroscience research. ‘‘Charity’’ refers to organizations (of any size) raising money from the public. ‘‘Foundation’’ refers to private philanthropy and endowed foundations that do not raise money from the public. b US-based charities spend was taken from IRS Form 990 (2013) if available. UK based charities spend was taken from the AMRC (http://www.amrc.org.uk/our-members/sector-data/data-faqs#Res_ex_db). For foundations (US and UK), spend was calculated by searching individual websites. N/A denotes newly formed charities. a
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Organizationsa
2013 Research Expenditure (unless stated)b
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Table 1. Continued
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Figure 1. Classic Model of Translational Research Pathway T0–T4 While this linear model suggests finite phases of research, in reality, the iterative process of translational research is far more interactive, with feedback loops within and across translation. Importantly, this model can be applied to any intervention, whether diagnostic, treatment, or prevention oriented. Taken with permission from (IOM, 2013).
high throughput screening to toxicity profiling resources; MJFF recently announced a partnership to explore mitochondrial dysfunction targets. Similar infrastructures now exist at many universities in the US and UK (see the Target Discovery Institute at Oxford University; http://www.tdi.ox.ac.uk/home). It is also important to note that the Foundation for the National Institutes of Health (http://www.fnih.org) is home to several public/private partnerships in translational research including the groundbreaking Alzheimer’s Disease Neuroimaging Initiative (ADNI; http:// www.adni-info.org), which helped define parameters for successful collaboration among diverse partners including charitable organizations. The Alzheimer’s Association has been a leader in this regard and has extended its learning to partnerships around the world to advance therapeutics research. The European Union has taken these collaborations to a new level with the Innovative Medicines Initiative (http://www.imi.europa.eu) described elsewhere in this issue. There are, of course, common themes that run across these examples of nonprofit investment: 1. Charities bring a sense of urgency, focus, and mission to research that can transcend obstacles to discovery and development. The urgent need for treatments of any kind can free up remarkable energies to
address obstacles to research. For example, charitable organizations have tackled intellectual property concerns by helping the research community make practical distinctions between precompetitive and competitive areas of research. Such distinctions seem commonplace now but were an innovation 12 years ago when the SMA Foundation and others were looking to create access to research tools like mouse models and antibodies. It was that simple act of identifying aligned goals between academia, industry, and charities that proved to be a key step in advancing IP discussions and removing blockades in the research process. When time is of the essence, in fatal disorders like SMA or ALS, nothing is more important than keeping programs moving smoothly along the translational pathway toward the clinic. Hence, translational investigators are sure to meet families and charities that know the drug development process well and are focused on transferring discovery from academia to industry as rapidly as possible so that business timelines can be invoked. This transfer process is not a one-way street: The best translational programs involve academia and industry in iterative work to more fully understand disease and treatment pathways. 2. Charities are effective facilitators of translational opportunities in neuroscience.
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Charities are teaching us how to forge connections across disciplines (and continents) to further our understanding of brain disorders. Using the SMA experience as an example again, one of the strengths of the business case for SMA research was the potential for learnings that might be applicable to other neurodegenerative disorders. Interestingly enough, not only does SMA research inform ALS programs (D’Ambrosi et al., 2014) and other neurodegenerative disorders (Vanderweyde et al., 2013), it has also had implications for known and emerging disorders of transcription and RNA processing. Similar examples include the intersections between Down’s syndrome and dementia and 22q deletion syndrome and risk for schizophrenia (Karayiorgou et al., 2012). Charity-sponsored research programs are also helping us to use translational concepts to greater effectiveness. The pipeline for SMA therapeutics comprises novel treatment modalities (antisense oligos and gene therapy) as well as classic drug discovery approaches to treatment development (Naryshkin et al., 2014 and Cherry et al., 2014). Experimental medicine paradigms have been important to the advancement of the nucleotide-based treatments. Demonstrating the feasibility of these studies in infant patient populations has been an important development in pediatric research. In areas where treatments do exist such as epilepsy, multiple sclerosis, Alzheimer’s disease, or mental illness, the quest for better and more precise therapies is still underway. Charities also support research to improve treatment outcomes, utilizing diverse methodologies from behavioral medicine, health implementation, and/or public health research. The National MS Society (http://www. nationalmssociety.org), for example, is supporting programs under the headings ‘‘Stop disease progression’’ and ‘‘Restore what has been lost’’ that cross research boundaries to include rehabilitation and psychological treatments. Charities can be important partners in the dissemination, adoption, and practice of innovation; the support of research targeting healthcare processes that take place after regulatory approval has high public value and should be taken seriously (Lloyd and White, 2011).
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NeuroView 3. Charities are critical to the development of patient resources needed in translational research. Publicly supported charities have long served as resources for people with an interest in participating in research. Now, translationally savvy charities are taking an activist role in supporting the development of resources needed for better characterization of disorders and more efficient clinical studies. Examples include the following: d
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Natural history studies to benchmark care and outcomes, such as the Pediatric Neuromuscular Clinical Research Network study for SMA (Kaufmann et al., 2012); Biomarker projects—see MJFF for a discussion of Parkinson’s disease biomarker development and ADNI for more on neuroimaging biomarkers; Registries for clinical trial recruitment. See the European Huntington’s Disease Network (http://www. euro-hd.net) supported by CHDI or FARA for examples of successful patient registry projects. A recent publication from the Agency for Healthcare Quality and Research (Workman, 2013) provides important perspective on the pros and cons of such projects.
Biobanks are a critically important source of materials for genetic, molecular, and pathology studies; with the advent of cost-effective whole genome sequencing, more and more charities are supporting these fundamental studies to better describe disease. Classic examples of nonprofit supported endeavors include the previously mentioned Simons Simplex repository at SFARI or the Autism Genetic Resource Exchange (AGRE) supported by Autism Speaks (http://www. autismspeaks.org). The Genetic Alliance (http://www. geneticalliance.org), Faster Cures (http:// www.fastercures.org), and other nonprofits are leading discussions on the ethical use of biosamples, patient data, and other sensitive information that people may wish to control. Data privacy concerns continue to evolve with technological advances such as the use of mobile device apps for personalized
care. Translational neuroscience benefits from greater public knowledge, understanding, and dialogue on these important topics. 4. Charities help bring the patient voice to the research table. Patient input in the therapeutic development process, often coordinated by research charities, is critical to the future of translational neuroscience. Patient input has been used to help shape tolerability profiles and understand risk/benefit assessment for novel treatments. Consultations during the trial design process have led to improvements in recruitment efficiency and participant satisfaction (Ennis and Wykes, 2013). Investigators and regulators recognize patient-reported outcome measures as important assessments in clinical trials—so much so that the NIH has devoted enormous resources to measure development through the PROMIS initiative (http://commonfund. nih.gov/promis/index). The movement to incorporate patient input into research priority setting is receiving greater attention: In the UK, the National Institute for Health Research (NIHR) has utilized charity-driven patient and public surveys to inform funding calls (Lloyd et al., 2012); the Patient-Centered Outcomes Research Institute (PCORI; http://www.pcori.org) (Frank et al., 2014) in the US has adopted similar methodologies in determining effectiveness research priorities. While ethics provide the rationale underpinning these efforts, it is still too early to tell how these investments are affecting attitudes toward research or research success. Neuroscience would do well to embrace and improve upon methods for patient and public input into research, as participatory research processes become a global standard. MQ, A New Research Charity My own organization, MQ: Transforming Mental Health, is fast becoming a case study on the role of charities in translational neuroscience. Launched in 2013 with a founding grant from the Wellcome Trust, we are building de novo research and fundraising platforms that will fill a major gap in a sector where charity (and public) support for mental health research is virtually nonexistent. There are notable exceptions to this generalization, of
course, like the organizations mentioned previously. A revolution in mental health care is unlikely, however, without a groundswell of public engagement, similar to that seen in cancer or HIV movements, where charity support and investment has been critical to translational successes. MQ is working to identify themes that will engage public support for mental health research, and we look to our colleagues in the sciences to help us accomplish that goal. Not surprisingly, the uncertainty around diagnostic criteria presents a challenge to the development of a new translational research program. With the RDoC experiment well underway, we are exploring alternate ways to contribute to better understanding of the mental illnesses. There is a wealth of resources in the UK—from cohort studies to the major government investment in Improving Access to Psychological Treatments program (IAPT)—which have generated patient and descriptive data that can be tapped to inform research; we hope to work with these resources in the near future. It is also clear that we will need to forge new research paradigms to address the inescapable fact that mental illness can be attributed to biological, psychological, social, and environmental factors, all or most of which can be the subject of intervention. Interdisciplinary approaches to mental health research are desperately needed, as is the leadership to bridge the gaps between disciplines. The recent call for a new interdisciplinary ‘‘mental health science’’ highlights both the opportunity and the challenges involved in forging connections across the sciences (Holmes et al., 2014). Neuroscience should be at the vanguard of these efforts; charities like MQ are poised to help. Here are some ideas we are incorporating in our thinking about new approaches to translational neuroscience: d
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Brain and behavior disorders are global problems for which solutions need to be global, too. Charities can help bridge boundaries between countries, organizations and processes. Research programs need to be relevant to and understandable by patients and their families.
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NeuroView It’s more than neuroscience: A bio/ psycho/social approach is needed for brain and behavior disorders. It’s not just about drug development: Alongside drugs, effective interventions that will benefit from iterative neuroscience studies include psychological treatments; neuromodulation devices; social, environmental, and public health interventions and combinations thereof. Regulatory approval is not the only endpoint: We need behavioral science to help us address important barriers to dissemination, adoption of innovation, treatment acceptance, and adherence among both patients and professionals.
life. Charities can help bridge the gaps between the disciplines needed to reach these goals. Charities can help the neurosciences keep their eye on that prize—research that is relevant to real people in the real world. Indeed, in their work to get the best results from investments in neuroscience, charities may be among the most important players on the field.
Frank, L., Basch, E., and Selby, J.V.; PatientCentered Outcomes Research Institute (2014). JAMA 312, 1513–1514.
ABOUT THE AUTHOR
Karayiorgou, M., Flint, J., Gogos, J.A., and Malenka, R.C.; Genetic and Neural Complexity in Psychiatry 2011 Working Group (2012). Nat. Neurosci. 15, 811–812, http://dx.doi.org/10.1038/ nn.3115.
The call for a paradigm shift in our thinking about translational neuroscience research is essentially about adopting a truly iterative process, rather than paying lip service to it. We can no longer afford a straight-line approach to development, especially for therapies for complex disorders of the brain. In many ways, this community is still engaged in proof-ofprinciple studies to demonstrate that the translational model of therapeutic development, in all its iterative glory, works in neuroscience. At this time, it is simply the best plan on the table. Making this approach work for all types of interventions will be key to reducing the burden of disease, as will the involvement of all stakeholders in the process. The neurosciences are vital to helping us understand how biological, psychological, social, and environmental interventions work and their impact on quality of
Thanks to my many colleagues in the nonprofit sector who have contributed their thoughts and experiences in past years. Special thanks to my colleagues Alison Cranage, Neil Balmer, Sarah Shenow, and Olivia Birkby for research, advice, and editorial assistance. The author has no conflict to declare.
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Cynthia Joyce is currently Chief Executive, MQ: Transforming Mental Health. She served as Executive Director of the SMA Foundation from 2003– 2011. ACKNOWLEDGMENTS
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NeuroView Transforming Our Approach to Translational Neuroscience: The Role and Impact of Charitable Nonprofits in Research Cynthia Joyce1,* 1MQ: Transforming Mental Health, 1-5 Clerkenwell Road London, EC1M 5PA, UK *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2014.10.030
From mental health to rare diseases, charitable nonprofits and foundations are bringing energy, perspective, and leadership to the process of translational research. In challenging researchers to become more connected—to each other and to patients—charities are helping neuroscience deliver innovation that is relevant to real people in the real world. Translational aims have been a remarkable engine for driving research investment in the neurosciences. But, as noted by many writers in this issue of Neuron, despite decades of major investment, our therapeutic successes have been few and far between. Could it be that our aims are only wishful thinking? Most certainly not. As this issue makes clear, there is value in taking a critical look at what has been achieved thus far, considering lessons learned, and reconsidering our approaches to treatment development. This period of reflection also creates an opportunity to invite different perspectives to the table and to engage in broader thinking about our challenges. Non-profit and charitable organizations, which already play an important role in the research enterprise, represent one such important and often overlooked perspective. What might we learn from them? And how can we include these organizations more effectively in efforts to transform the translational neuroscience effort? Not All Nonprofits Are Alike It is important to note from the start that nonprofits are as widely variable in character as entities in any other business sector. Most of us learn about nonprofits from the organizations that flood our mailboxes, street corners, and walking paths with fundraising appeals; for the purposes of this article, I will be referring solely to nonprofits supporting health/medical research, particularly in the neurosciences. Even so, this area of nonprofit activity is huge, encompassing small local
fundraising groups and massive philanthropic organizations like the Wellcome Trust or the Bill and Melinda Gates Foundation (see Table 1). For the sake of clarity, I will use the terms ‘‘charity’’ to refer to organizations (of any size) raising money from the public and ‘‘foundation’’ to refer to private philanthropy and endowed foundations. Having worked with organizations in both the US and the UK, I can confirm that while there are some differences in operational style (due to cultural and taxcode differences), these differences pale in comparison to the large strategic issues facing the entire sector. The impact of social media on both fundraising and program development has been enormous: Witness the impact of the ‘‘Ice Bucket Challenge’’ on the ALS community. Fastmoving changes in technology and the push toward personalized medicine are taking place on both sides of the Atlantic. Adapting to these changes is just one of the many challenges facing health research charities, all while keeping an eye on the prize—delivering improvements in diagnosis, treatment, and prevention interventions. The Spectrum of Research Investors Just as there is a spectrum of nonprofits across the US and UK, so is there a spectrum of research strategies and research investment styles employed by charities and foundations. Some organizations focus their energies on basic science and discovery research, while others seek only to support applied or
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translational research; others support a mixed portfolio. Even further along the spectrum are organizations, particularly social services charities, investing in research toward prevention. To get the most benefit from nonprofit relationships, it is important for translational neuroscientists to understand how an organization positions their funding goals with respect to the classic T0-T4 translational pathway and their investment strategy (Figure 1). A large percentage of nonprofit research programs use investigator-driven funding models as established by the NIH and the MRC. In the neurosciences, discussions about funding generally include that most traditional and familiar charity funding strategy—the ‘‘career development award.’’ This resource is more important than ever for early career investigators as government and industry funding for neuroscientists becomes tighter. For charities, these awards are a way to seed a field and develop career paths in emerging areas of research—as has been the case with much beloved funding from the Hereditary Disease Foundation (http://www.hdfoundation.org) or the NARSAD (http://www.bbrfoundation.org) grants from the Brain and Behavior Research Foundation. We are utilizing this time-honored approach to introduce my own organization, MQ: Transforming Mental Health, (http://www.joinmq.org) to research professionals. At the more experimental end of the research spectrum are the organizations working to stimulate meaningful advances in the translational research
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NeuroView path itself. Charities like the Alzheimer’s Association (http://www.alz.org), Michael J. Fox Foundation (MJFF) (http://www. michaeljfox.org), and the Spinal Muscular Atrophy Foundation (SMA Foundation, where I worked for many years; http:// www.smafoundation.org) are directing research investments toward tool development, biomarker initiatives, and therapeutics development itself. Typically, this kind of research strategy requires the ability to invest a million dollars or more in individual projects, which has been a barrier to many smaller charities. However, over the last 20 years, a small group of nonprofits, generally focused on single gene disorders, have formed solely to accelerate therapeutics development. These charities are finding ways to make smaller grants (on the order of $50,000– $500,000) meaningful by supporting timely and important ‘‘derisking’’ investments along the discovery and development pathway. Examples of these kinds of nonprofits include investors like the Parent Project for Muscular Dystrophy (http://www.parentprojectmd.org) (therapeutics development); FARA (http:// www.curefa.org), which leads infrastructure and therapeutics investments in Freidrich’s Ataxia; FRAXA (http://www. fraxa.org) doing the same for Fragile X syndrome; and the Rett Syndrome charities. Each of these organizations has made important contributions to demonstrating that the translational research pathway can indeed advance discovery and/or therapeutics development for brain diseases. At the far end of the spectrum are philanthropic investors such as Paul Allen, James Simon, Eli Broad, the Stanley Family, Lord David Sainsbury and others in the US, UK and abroad who, through their foundations, are making iconic investments in the research process. Their support of major initiatives including the Allen Brain Atlas (http://www.brain-map.org), SFARI (http://sfari.org) and the Simon Simplex Collection (autism), the Broad Institute and Stanley Centers (http:// www.broadinstitute.org) (schizophrenia) for genetic research and the Sainsbury Wellcome Center (http://www.ucl.ac.uk/ swc) for Neural Circuits and Behavior, is giving researchers the standardized tools and resources needed to advance translational pathways across multiple
areas of interest. In so doing, these philanthropists have raised the level of visibility of the neuroscience among policy makers – and also a certain level of expectation that science is working to deliver tangible human benefit (Broad, 2014). In many ways, research funding from the Howard Hughes Medical Institute and the Wellcome Trust underpin many of our translational efforts in the neurosciences. The projects supported by these endowed foundations are important charitable complements to investments by governmental agencies; their contributions to research methods and policy development cannot be overestimated. While perhaps not as familiar to people in the US, the Wellcome Trust has been a major driver of discovery and translational efforts across many fronts in the UK, from the Sanger Institute for genetics research to psychological research; it also happens to be the leading funder of our grand experiment in mental health research at MQ. While not all nonprofits are alike, there is sophistication, energy, and momentum in this sector. It is wise to think of charities as not only supporters, but also initiators and partners for translational initiatives in our field. Thanks to new tools at our disposal to better understand brain function, there has never been a more important time to work with nonprofits to maximize our translational research opportunities (Deisseroth, 2014). How Can Nonprofits Best Contribute to Translational Neuroscience Research Going Forward? Realistic Expectations for Translation Are Essential Despite our optimism about the translational process, experience has shown us that it can take 20 years or more to realize the clinical benefits of the search for new treatment targets (Wooding et al., 2013). Similarly, our experience in single gene disorders (Huntington’s disease and muscular dystrophy are prime examples) has taught us that gene identification does not directly lead to treatment. If nothing else, our current decade should represent the time when research funders and investigators alike work together to describe translational neuroscience process more realistically for patients and donors. Therefore, an important step
for both sides of a charity relationship is to encourage clarity and feasibility of research goals. Charities and advisers need to be conscious of their respective tolerance for risk and expectations for return on investment. Ultimately, there is a sweet spot for every investor and researcher seeking to make a contribution to translational neuroscience research. Learning from Charitable Investments Thus Far Funders and researchers are sharing lessons learned from translational experience in forums supported by various institutes at the NIH, the Institute of Medicine, and professional associations like the Health Research Alliance (http://www. healthra.org) in the US and the Association of Medical Research Charities (http://www.amrc.org.uk) in the UK. There also exists a delightful commitment to ‘‘pay it forward’’ in the nonprofit community, exemplified by leaders like Robert Beall, the CEO of the Cystic Fibrosis Foundation (http://www.cff.org) and architect of the development of Kalydeco, a true translational success story (for an interesting background profile, see Groopman, 2009). Another is Robi Blumenstein, visionary leader of the CHDI Foundation (http://chdifoundation.org) and coauthor of a recent paper on how funders can contribute to best practices for scientific reproducibility (Munafo` et al., 2014). NIH has taken knowledge sharing a step further with several programs designed to foster translation for charities and investigators alike. Many of these projects have now been consolidated under the new National Center for Advancing Translational Sciences (NCATS; http://www.ncats.nih.gov), including the Rare Diseases Clinical Research Network, some 22 consortia focused on linking researchers and clinicians in therapeutic development and the Clinical and Translational Science Award (CTSA; 60 participating institutions). The Therapeutics for Rare and Neglected Diseases (TRND) program has been used effectively to advance therapeutics development for muscular dystrophy and for Neiman-Pick Disease (see the Ara Parseghian Medical Research Foundation; http://www.parseghian.org). NCATS is also home to specific translational resources from assay development and
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Table 1. Examples of Nonprofit Organizations Supporting Translational Neuroscience Research
Organizationsa
2013 Research Expenditure (unless stated)b
Website
Focus
Examples of Translational Projects
Alzheimer’s Association
http://www.alz.org
Advance understanding of Alzheimer’s, identify new treatment strategies, improve care for people with dementia, optimize services for their families, and further knowledge of brain health and disease prevention.
$15,069,000
World Wide Alzheimer’s Disease Neuroimaging Initiative (WW-ADNI). Global biomarker standardisation consortium.
Autism Speaks
http://www.autismspeaks.org
Fund global biomedical research into the causes, prevention, treatments and a possible cure for autism
$15,790,797
DELSIA (Delivering Scientific Innovation to Autism) to catalyse private investment in product development. AGRE: Autism Genetic Resource Exchange.
Brain and Behaviour Research Foundation
https://bbrfoundation.org
Committed to alleviating the suffering caused by mental illness by awarding grants that will lead to advances and breakthroughs in scientific research.
$13,037,212 (2012)
Supports research into New Technologies, and Next Generation Therapies.
Friedreich’s Ataxia Research Alliance (FARA)
http://www.curefa.org/about.html
Dedicated to the pursuit of scientific research leading to treatments and a cure for Friedreich’s ataxia.
$2,860,246
The Collaborative Clinical Research Network in Friedreich’s Ataxia (CCRN in FA).
FRAXA Research Foundation
http://www.fraxa.org/fraxa
Focus on finding effective treatments and ultimately a cure for Fragile X. Portfolio spans the spectrum of translational, pre-clinical, and clinical research.
$1,443,565
FRAXA Drug Validation Initiative (Chile) tests promising compounds with therapeutic potential in various animal models of fragile X.
Micheal J. Fox Foundation
https://www.michaeljfox.org
To elimate Parkinson’s in our lifetime. Accelerate the best ideas in Parkinson’s disease research toward clinical testing and practical relevance for patients.
$75,341,541
BioFind biomarker discovery program; Parkinson’s Progresson Marker Initiative; drug development pipline projects
MQ : Transforming Mental Health
http://www.joinmq.org
Supports research across disciplines, building diverse portfolio with focus on 1) improving current treatments and 2) new strategies for diagnosis, treatment or prevention of mental illness.
N/A
Psy-IMPACT research towards a better understanding of how psychological treatments work, with whom and why they work, and how they can be improved upon.
One Mind
http://www.onemind.org
Fostering fundamental changes that will radically accelerate the development and implementation of improved diagnostics, treatments and cures for diseases and injuries of the brain.
N/A
Apollo: open science interactive data exchange portal for brain disease and brain injury. Gemini clinical study to accelerate the discovery of diagnostics, treatments, and cures for TBI
Parent Project for Muscular Dystrophy
http://www.parentprojectmd.org/site/ PageServer?pagename=nws_index
Fund the most promising near and long term Duchenne research strategies and cutting-edge therapies.
$3,295,024
Project Catalyst: initiative designed to identify new drugs in collaboration with PTC Therapeutics, Inc. (PTC). Also GIFTED—Global Investment For Therapeutics to End Duchenne.
SMA Foundation
http://www.smafoundation.org
The mission of the SMA Foundation is to accelerate the development of a treatment for Spinal Muscular Atrophy.
Unknown
Invested more than $100 M to move treatments from the laboratory through the clinic.
Charities
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Website
Focus
Examples of Translational Projects
Paul Allen Foundation - Allen Institute for Brain Science
https://www.alleninstitute.org
Accelerate the understanding of how the human brain works in health and disease. Using a big science approach, generate useful public resources, drive technological and analytical advances, and discover fundamental brain properties through integration of experiments modeling and theory.
$44,000,000 estimated. Institute also attracts NIH funding.
Data and tools are all available to anyone—for free—through the Allen Brain Atlas data portal. Involved in White House BRAIN Initiative, and the European Human Brain Project (HBP).
Simons Foundation/Sfari
http://sfari.org
SFARI’s mission is to improve the understanding, diagnosis and treatment of autism spectrum disorders by funding innovative research of the highest quality and relevance.
$60,000,000 estimated
Collection of well-characterized individuals with autism or with specific genetic alterations (the Simons Simplex Collection and the Simons Variation in Individuals Project). Tools that enable researchers to keep track of the genetic landscape (SFARI Gene), to order mouse models (Autism Mouse Models) or to order biospecimens and other types of data from research projects (SFARI Base).
Wellcome Trust
http://www.wellcome.ac.uk/Funding/ Biomedical-science/index.htm
Vision is to achieve extraordinary improvements in human and animal health. Support the brightest minds in biomedical research and the medical humanities. One of 5 key areas is to support research to improve understanding of how the brain functions and to find improved approaches for treating brain and mental health disorders.
£45,000,000 estimated on mental health research.
Discovery and development portfolio. Together with the Gatsby Foundation, founded the Sainsbury Wellcome Research Centre for neural circuits and behavior at Univeristy College London.
Foundations
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This table depicts a representative, but by no means comprehensive, list of charitable organizations with an interest in neuroscience research. ‘‘Charity’’ refers to organizations (of any size) raising money from the public. ‘‘Foundation’’ refers to private philanthropy and endowed foundations that do not raise money from the public. b US-based charities spend was taken from IRS Form 990 (2013) if available. UK based charities spend was taken from the AMRC (http://www.amrc.org.uk/our-members/sector-data/data-faqs#Res_ex_db). For foundations (US and UK), spend was calculated by searching individual websites. N/A denotes newly formed charities. a
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Organizationsa
2013 Research Expenditure (unless stated)b
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Table 1. Continued
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Figure 1. Classic Model of Translational Research Pathway T0–T4 While this linear model suggests finite phases of research, in reality, the iterative process of translational research is far more interactive, with feedback loops within and across translation. Importantly, this model can be applied to any intervention, whether diagnostic, treatment, or prevention oriented. Taken with permission from (IOM, 2013).
high throughput screening to toxicity profiling resources; MJFF recently announced a partnership to explore mitochondrial dysfunction targets. Similar infrastructures now exist at many universities in the US and UK (see the Target Discovery Institute at Oxford University; http://www.tdi.ox.ac.uk/home). It is also important to note that the Foundation for the National Institutes of Health (http://www.fnih.org) is home to several public/private partnerships in translational research including the groundbreaking Alzheimer’s Disease Neuroimaging Initiative (ADNI; http:// www.adni-info.org), which helped define parameters for successful collaboration among diverse partners including charitable organizations. The Alzheimer’s Association has been a leader in this regard and has extended its learning to partnerships around the world to advance therapeutics research. The European Union has taken these collaborations to a new level with the Innovative Medicines Initiative (http://www.imi.europa.eu) described elsewhere in this issue. There are, of course, common themes that run across these examples of nonprofit investment: 1. Charities bring a sense of urgency, focus, and mission to research that can transcend obstacles to discovery and development. The urgent need for treatments of any kind can free up remarkable energies to
address obstacles to research. For example, charitable organizations have tackled intellectual property concerns by helping the research community make practical distinctions between precompetitive and competitive areas of research. Such distinctions seem commonplace now but were an innovation 12 years ago when the SMA Foundation and others were looking to create access to research tools like mouse models and antibodies. It was that simple act of identifying aligned goals between academia, industry, and charities that proved to be a key step in advancing IP discussions and removing blockades in the research process. When time is of the essence, in fatal disorders like SMA or ALS, nothing is more important than keeping programs moving smoothly along the translational pathway toward the clinic. Hence, translational investigators are sure to meet families and charities that know the drug development process well and are focused on transferring discovery from academia to industry as rapidly as possible so that business timelines can be invoked. This transfer process is not a one-way street: The best translational programs involve academia and industry in iterative work to more fully understand disease and treatment pathways. 2. Charities are effective facilitators of translational opportunities in neuroscience.
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Charities are teaching us how to forge connections across disciplines (and continents) to further our understanding of brain disorders. Using the SMA experience as an example again, one of the strengths of the business case for SMA research was the potential for learnings that might be applicable to other neurodegenerative disorders. Interestingly enough, not only does SMA research inform ALS programs (D’Ambrosi et al., 2014) and other neurodegenerative disorders (Vanderweyde et al., 2013), it has also had implications for known and emerging disorders of transcription and RNA processing. Similar examples include the intersections between Down’s syndrome and dementia and 22q deletion syndrome and risk for schizophrenia (Karayiorgou et al., 2012). Charity-sponsored research programs are also helping us to use translational concepts to greater effectiveness. The pipeline for SMA therapeutics comprises novel treatment modalities (antisense oligos and gene therapy) as well as classic drug discovery approaches to treatment development (Naryshkin et al., 2014 and Cherry et al., 2014). Experimental medicine paradigms have been important to the advancement of the nucleotide-based treatments. Demonstrating the feasibility of these studies in infant patient populations has been an important development in pediatric research. In areas where treatments do exist such as epilepsy, multiple sclerosis, Alzheimer’s disease, or mental illness, the quest for better and more precise therapies is still underway. Charities also support research to improve treatment outcomes, utilizing diverse methodologies from behavioral medicine, health implementation, and/or public health research. The National MS Society (http://www. nationalmssociety.org), for example, is supporting programs under the headings ‘‘Stop disease progression’’ and ‘‘Restore what has been lost’’ that cross research boundaries to include rehabilitation and psychological treatments. Charities can be important partners in the dissemination, adoption, and practice of innovation; the support of research targeting healthcare processes that take place after regulatory approval has high public value and should be taken seriously (Lloyd and White, 2011).
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NeuroView 3. Charities are critical to the development of patient resources needed in translational research. Publicly supported charities have long served as resources for people with an interest in participating in research. Now, translationally savvy charities are taking an activist role in supporting the development of resources needed for better characterization of disorders and more efficient clinical studies. Examples include the following: d
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Natural history studies to benchmark care and outcomes, such as the Pediatric Neuromuscular Clinical Research Network study for SMA (Kaufmann et al., 2012); Biomarker projects—see MJFF for a discussion of Parkinson’s disease biomarker development and ADNI for more on neuroimaging biomarkers; Registries for clinical trial recruitment. See the European Huntington’s Disease Network (http://www. euro-hd.net) supported by CHDI or FARA for examples of successful patient registry projects. A recent publication from the Agency for Healthcare Quality and Research (Workman, 2013) provides important perspective on the pros and cons of such projects.
Biobanks are a critically important source of materials for genetic, molecular, and pathology studies; with the advent of cost-effective whole genome sequencing, more and more charities are supporting these fundamental studies to better describe disease. Classic examples of nonprofit supported endeavors include the previously mentioned Simons Simplex repository at SFARI or the Autism Genetic Resource Exchange (AGRE) supported by Autism Speaks (http://www. autismspeaks.org). The Genetic Alliance (http://www. geneticalliance.org), Faster Cures (http:// www.fastercures.org), and other nonprofits are leading discussions on the ethical use of biosamples, patient data, and other sensitive information that people may wish to control. Data privacy concerns continue to evolve with technological advances such as the use of mobile device apps for personalized
care. Translational neuroscience benefits from greater public knowledge, understanding, and dialogue on these important topics. 4. Charities help bring the patient voice to the research table. Patient input in the therapeutic development process, often coordinated by research charities, is critical to the future of translational neuroscience. Patient input has been used to help shape tolerability profiles and understand risk/benefit assessment for novel treatments. Consultations during the trial design process have led to improvements in recruitment efficiency and participant satisfaction (Ennis and Wykes, 2013). Investigators and regulators recognize patient-reported outcome measures as important assessments in clinical trials—so much so that the NIH has devoted enormous resources to measure development through the PROMIS initiative (http://commonfund. nih.gov/promis/index). The movement to incorporate patient input into research priority setting is receiving greater attention: In the UK, the National Institute for Health Research (NIHR) has utilized charity-driven patient and public surveys to inform funding calls (Lloyd et al., 2012); the Patient-Centered Outcomes Research Institute (PCORI; http://www.pcori.org) (Frank et al., 2014) in the US has adopted similar methodologies in determining effectiveness research priorities. While ethics provide the rationale underpinning these efforts, it is still too early to tell how these investments are affecting attitudes toward research or research success. Neuroscience would do well to embrace and improve upon methods for patient and public input into research, as participatory research processes become a global standard. MQ, A New Research Charity My own organization, MQ: Transforming Mental Health, is fast becoming a case study on the role of charities in translational neuroscience. Launched in 2013 with a founding grant from the Wellcome Trust, we are building de novo research and fundraising platforms that will fill a major gap in a sector where charity (and public) support for mental health research is virtually nonexistent. There are notable exceptions to this generalization, of
course, like the organizations mentioned previously. A revolution in mental health care is unlikely, however, without a groundswell of public engagement, similar to that seen in cancer or HIV movements, where charity support and investment has been critical to translational successes. MQ is working to identify themes that will engage public support for mental health research, and we look to our colleagues in the sciences to help us accomplish that goal. Not surprisingly, the uncertainty around diagnostic criteria presents a challenge to the development of a new translational research program. With the RDoC experiment well underway, we are exploring alternate ways to contribute to better understanding of the mental illnesses. There is a wealth of resources in the UK—from cohort studies to the major government investment in Improving Access to Psychological Treatments program (IAPT)—which have generated patient and descriptive data that can be tapped to inform research; we hope to work with these resources in the near future. It is also clear that we will need to forge new research paradigms to address the inescapable fact that mental illness can be attributed to biological, psychological, social, and environmental factors, all or most of which can be the subject of intervention. Interdisciplinary approaches to mental health research are desperately needed, as is the leadership to bridge the gaps between disciplines. The recent call for a new interdisciplinary ‘‘mental health science’’ highlights both the opportunity and the challenges involved in forging connections across the sciences (Holmes et al., 2014). Neuroscience should be at the vanguard of these efforts; charities like MQ are poised to help. Here are some ideas we are incorporating in our thinking about new approaches to translational neuroscience: d
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Brain and behavior disorders are global problems for which solutions need to be global, too. Charities can help bridge boundaries between countries, organizations and processes. Research programs need to be relevant to and understandable by patients and their families.
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NeuroView It’s more than neuroscience: A bio/ psycho/social approach is needed for brain and behavior disorders. It’s not just about drug development: Alongside drugs, effective interventions that will benefit from iterative neuroscience studies include psychological treatments; neuromodulation devices; social, environmental, and public health interventions and combinations thereof. Regulatory approval is not the only endpoint: We need behavioral science to help us address important barriers to dissemination, adoption of innovation, treatment acceptance, and adherence among both patients and professionals.
life. Charities can help bridge the gaps between the disciplines needed to reach these goals. Charities can help the neurosciences keep their eye on that prize—research that is relevant to real people in the real world. Indeed, in their work to get the best results from investments in neuroscience, charities may be among the most important players on the field.
Frank, L., Basch, E., and Selby, J.V.; PatientCentered Outcomes Research Institute (2014). JAMA 312, 1513–1514.
ABOUT THE AUTHOR
Karayiorgou, M., Flint, J., Gogos, J.A., and Malenka, R.C.; Genetic and Neural Complexity in Psychiatry 2011 Working Group (2012). Nat. Neurosci. 15, 811–812, http://dx.doi.org/10.1038/ nn.3115.
The call for a paradigm shift in our thinking about translational neuroscience research is essentially about adopting a truly iterative process, rather than paying lip service to it. We can no longer afford a straight-line approach to development, especially for therapies for complex disorders of the brain. In many ways, this community is still engaged in proof-ofprinciple studies to demonstrate that the translational model of therapeutic development, in all its iterative glory, works in neuroscience. At this time, it is simply the best plan on the table. Making this approach work for all types of interventions will be key to reducing the burden of disease, as will the involvement of all stakeholders in the process. The neurosciences are vital to helping us understand how biological, psychological, social, and environmental interventions work and their impact on quality of
Thanks to my many colleagues in the nonprofit sector who have contributed their thoughts and experiences in past years. Special thanks to my colleagues Alison Cranage, Neil Balmer, Sarah Shenow, and Olivia Birkby for research, advice, and editorial assistance. The author has no conflict to declare.
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Cynthia Joyce is currently Chief Executive, MQ: Transforming Mental Health. She served as Executive Director of the SMA Foundation from 2003– 2011. ACKNOWLEDGMENTS
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