Title of proposed idea: Regulatory Science Initiative  

Nominator: NIH Institutes/Centers

 Major obstacle/challenge to overcome: The rapid pace of scientific discovery coupled with development of new technologies presents a challenge to researchers, clinical investigators, and regulators as they work to translate basic scientific advances into approved medical products.  Basic and preclinical research has been performed in large part independent of regulatory issues. In addition, it is clear that novel technologies and approaches to medical research are outpacing the ability of our regulatory system to incorporate them into current review practices and guidelines. To overcome these obstacles, NIH should support strategic initiatives that are essential to the translation of NIH funded discoveries into diagnostic and therapeutics.

Emerging scientific opportunity ripe for Common Fund investment:   An investment in Regulatory Science will benefit all stakeholders by helping to advance and incorporate cutting-edge science into regulatory decision making and helping to develop improved tools, standards and approaches for assessing the safety, efficacy, quality and performance of medical products. Major advances in genomics and genomics-based medicine are also creating potential scenarios in the clinical setting that are relatively new to the FDA regulatory process. Moreover, the unprecedented partnership between the NIH and FDA through the Joint Leadership Council provides an extraordinary opportunity to coordinate therapy development efforts, including regulatory decision-making guidelines, between the two agencies. 

Common Fund investment that could accelerate scientific progress in this field: A number of scientific opportunities are ripe for investment in the area of Regulatory science and across the therapeutics development pipeline. For instance:

• Advances stemming from next generation sequencing technologies to help set the stage for personalized medicine, and other novel, genomics-based approaches to drug development, and treatments, such gene-editing, regulatory RNAs, gene –silencing or transcriptional activation
• Nanotechnology, microfluidics, and stem cell technologies to alter the way experimental agents are tested for safety and efficacy, and ultimately delivered to patients as therapies
• New approaches to predictive toxicology including high-throughput screening strategies/models, new in-silico approaches and computer-simulation models
• Development of bioinformatics tools and approaches for data mining and meta-analyses on safety and efficacy that capitalizes on the increasing volumes of clinical and medical product-related information in data repositories,
• Novel approaches of conducting clinical trials for rare and neglected diseases

Potential impact of Common Fund investment: Pre-clinical and clinical investigators, and other researchers who are engaged in the diagnostics and therapeutics development industries will benefit from having a more rapid integration of evidence-based knowledge into a regulatory framework, thereby quickening the pace at which basic science advances can move into the therapy development realm. For instance, in the area of stem-cell technologies, the NIH and FDA are working together to identify and define markers and characteristics of “stemness”, thus providing standards that the entire field can use for purposes of comparing studies and preparing for regulatory considerations.  The possibility of individualized, autologous utility of stem cell-derived therapeutics, organs, tissues, and other biomedical products are fast becoming a reality. Other emerging areas in regulatory science will advance, such as nanomedicine, personalized medicine, efficient and expeditious clinical trial designs, predictive toxicology, and biomimetic models that are able to simulate human conditions and better predict safety and efficacy.  The NIH-FDA joint efforts in these areas would help to pave a clearer and more transparent scientific and regulatory path for the scientific community that will impact therapeutics product development and clinical practice.

Title of proposed idea Chronic Pain Conditions: A Transformative Classification for Stimulating Research, Improving Diagnosis, and Personalizing Treatment

Nominator: NIH Institutes/Centers

Major obstacle/challenge to overcome: Chronic pain conditions afflict as many as one-third of the US population and incur $560-635 billion per year in incremental healthcare costs and lost productivity (IOM Report June 29, 2011). The long term clinical goal in alleviating chronic pain is to develop targeted therapies and identify patients responsive to these therapies, both of which are supported by etiological- and mechanism-based case definitions and diagnostic criteria of disease. A major challenge in the field is the lack of a mechanism-based case definition and diagnostic criteria for multiple chronic pain conditions. Common Fund investments could facilitate the development of a new objective, biopsychosocial classification system for chronic pain disorders to overcome this major obstacle. This new system will accelerate research by standardizing research diagnoses used across laboratories, enhance clinical diagnoses by developing more objective, mechanism-based measures of disease, and identify subjects responsive to new therapies by developing novel biomarkers of disease and clinical outcomes.

Emerging scientific opportunity ripe for Common Fund investment:    We propose a research program to develop a new, comprehensive, mechanism-based, biopsychosocial classification of chronic pain conditions. Three opportunities are ready for Common fund investment. This proposal endorses the ideas and sharpens the focus of “Molecular Classification of Disease”, a topic that emerged from the Innovation Brainstorm meeting, and takes on sophisticated data management and analysis elements of the topics on “Beyond GWAS” and “Cross-Cutting Issues in Computation and Informatics”.

Common Fund investment that could accelerate scientific progress in this field:   This program would create a centralized data bank/repository containing information from a large chronic pain cohort to include study subjects with Temporomandibular Joint Disorders, Fibromyalgia, Chronic Fatigue Syndrome, Vulvodynia, Endometriosis, Irritable Bowel Syndrome, Interstitial Cystitis, Headache, Low Back Pain, Arthritis, etc., recruited and identified using today’s best diagnostic criteria.  Many of these subjects will have multiple, comorbid chronic pain conditions. This cohort would be genotyped as well as phenotyped extensively using molecular, imaging and psychosocial methodologies.  All data would be agnostically analyzed via pathway analyses and new algorithms for lumping and splitting in order to subtype and re-classify these chronic pain patients.  Results emerging from the Common Fund incubator space would lead to a breakdown in the current “walls” separating these disorders (and researchers) and a transformation of diagnostic criteria based on a completely new classification of chronic pain conditions. After an intense 5 year effort, the data bank/repository and analytical tool set would become self sustaining with support from Pharma, the genotyping industry, and the NIH Pain Consortium.

Potential impact of Common Fund investment: The outcome of this project will be a completely new way of discovery and management of chronic pain conditions: researchers currently housed in different laboratories collaborating in multidisciplinary teams to study pain, rapid discovery of therapeutic targets, development of novel analgesic therapies based on common mechanisms of disease, introduction of individualized medical treatments and identification of those likely to respond to therapy. Ultimately, results from this project will lead to an overall reduction in the burden of chronic pain, currently $560-$635 billion/year in the US in incremental healthcare costs and lost productivity.

Chronic pain should be thought of as a disease unto itself like other chronic conditions such as diabetes and heart disease, and not merely a symptom of disease.  Research approaches to and management of chronic pain conditions must consider that, like other chronic conditions, disease progression and complexity, early identification and intervention, and effective therapies, all influence patient burden and economic costs of disease. A transformative classification of chronic pain conditions will ultimately reduce long-term morbidity and decrease the economic impact of these wide-spread conditions.

Title of proposed idea: Artificial Organs: From Lab Bench to the Body (see “Artificial Organs as Tools for Translation” in Innovation Brainstorm ideas)

Nominator: NIH Institutes/Centers

 Major obstacle/challenge to overcome:The long-term clinical objective of this Program is to make available artificial organs for in vivo replacement or in situ regeneration of non-functional ones due to aging, tissue degeneration, birth defects, and injury.  Common Fund investments could facilitate accomplishing this goal by supporting a research Program in developing powerful in vitro tissue platforms for drug screening, toxicology testing, disease modeling, and diagnostics, as well as for in vivo strategies for organ replacement, by leveraging recent breakthroughs in cellular reprogramming, bioengineering, high-throughput technologies and pharmacogenomics.

Successful building of new organs will require overcoming a number of challenges.  The nature of these challenges will depend on the intended application; whether, for example, the organ will be used for the development of simple or sophisticated in vitro platforms, or if it will be used for replacing diseased organs in vivo. The utility of the iPS cells for organ building is primarily related to their pluripotent nature, because pluripotency permits virtually unlimited expansion of patient-specific genetically matched undifferentiated cells. However, obtaining fully functional and homogeneous populations of stably -differentiated non-tumorigenic cells from iPS cells is notoriously difficult, and this limitation is considered to be a significant impediment to translational applications of these cells. Therefore, additional approaches are needed for obtaining abundant cell sources that do not posses limitations of the iPS cells.

Emerging scientific opportunity ripe for Common Fund investment:  The proposed Program endorses and expands the idea of “Artificial Organs as Tools for Translation” that was derived from the Innovation Brainstorm meeting.  However, we believe that building the CF Program solely on fully reprogrammed iPS cells, as currently planned will significantly limit the overall success of the effort. We also argue that the results of in vitro and in vivo work should and will synergistically benefit each other. Therefore, separating them, and focusing primarily on in vitro screening technologies with only minor emphasis on in vivo organ replacement, as currently proposed, will diminish the long-term translational impact of this CF investment. 

We propose to initiate a Program to create unprecedented opportunities for basic research, and translational and clinical applications by anchoring on the rapidly-developing direct lineage reprogramming technologies that are widely recognized as paradigm shift approaches for creating artificial organs for in vitro assays and for organ replacement in vivo.  Direct reprogramming can overcome limitations of iPS cell technologies, because it involves only partial reversal of terminal differentiation state (as opposed to full, as with iPS cells) thus leading to formation of patient-specific lineage-committed embryonic or adult progenitors. Such cells can be expanded and are amenable to robust differentiation into functional somatic cells. Moreover, with the help of advanced bioengineering tools, it will be possible to achieve safe direct reprogramming in vivo making in situ organ regeneration into a reality. The drawback of directly reprogrammed cells is in their relatively limited expansion capacity which is similar to that of adult stem cells or embryonic progenitors, and this complicates the task of obtaining sufficient cell numbers for building human-size organs. Therefore, the intent of the proposed expansion of the “Artificial Organs as Tools of Translation” Program is to enhance the Program by taking advantage of full and direct reprogramming to benefit translational application of these breakthrough technologies.

Common Fund investment that could accelerate scientific progress in this field:    Recommended CF investments in this area (in addition to those proposed in original Program) include: (i) Developing strategies for induction of full and direct reprogramming using novel gene delivery and small molecule approaches that will eliminate the need for  genetic modification; (ii) Developing platforms to study epigenetic, proteomic and transcriptomic changes for improved efficiency of reprogramming;  (iii) Advancing science and technology for expansion and differentiation of reprogrammed cell; and (iv) Developing strategies for direct reprogramming in vivo.

Potential impact of Common Fund investment:  The specific outcomes from this Program will include novel tools and standardized protocols for cellular reprogramming, expansion, controlled differentiation and repository of functional and well- characterized multipotential cell populations for a variety of applications, including functional assays, diagnostics and organ building in vivo and in vitro.

Since many general questions still need to be answered and new technologies, tools and platforms to be developed, this field will greatly benefit from the “incubator space” of the CF mechanisms.  Once the original goals of the Program are achieved, the need for the CF involvement will decrease and it will become more appropriate for the individual ICs to carry on with their own Programs to build artificial organs for applications in their respective mission areas. 

NIDCR is in excellent position to lead this CF effort because of its trans-NIH and multi-agency shared interests and collaborations through Armed Forces Institute for Regenerative Medicine (AFIRM), Nano Task Force and National Nanotechnology Initiative through the Office of Science and Technology Policy, Multi-Agency Tissue Engineering Science (MATES) Interagency Working Group, and the newly established Intramural National Center for Regenerative Medicine.

Title of proposed idea: Single Cell Analysis

Nominator: Innovation Brainstorm participants

Major obstacle/challenge to overcome: Population heterogeneity among cells in a given tissue is a critical issue whose importance bridges many areas of biomedicine: cancer, infectious disease, developmental processes, organs, and immune responses. However, it is well-known that current approaches are quite limited in that they can only achieve approximate ensemble analyses of cell populations. Roadblocks to progress in this area are biological and technological: Molecular and systems level description (and quantitation) of cells, organs, and disease processes requires a greater understanding of the behaviors of individual cells and the overall composition of the population.

Emerging scientific opportunity ripe for Common Fund investment: Advances in engineering and nanotechnology provide the opportunity for transformative methods in single-cell and population-based analyses. The need for ultra-sensitive analytical methods and sophisticated computational tools calls for expertise from physicists, engineers, and computer scientists. It is possible that existing theorems on organizational behavior could be re-purposed for single-cell studies.

Common Fund investment that could accelerate scientific progress in this field: Potential Common Fund (CF) investments in this area would go beyond most of the current emphasis on microscopic and imaging techniques (although those approaches are also useful and necessary). Potential new investments could be in mapping a single cell’s epigenome, proteome, and metabolome. In addition, CF investment is needed to extend recent proof-of-principle work in single-cell genome sequencing and transcriptomics that is highly innovative, but low-throughput and far from practice. CF investments should emphasize approaches that capture living (or recently living) cells in vivo without need for overexpression or artificial constructs.

Potential impact of Common Fund investment: The ultimate motivation for more research in single-cell analysis is the potential for in vivo application to disease. Developing a robust set of tools to assess (and ultimately manipulate) single cells in situ is a key step toward achieving that goal. This achievement would have broad applicability across biomedicine: both for basic studies and for clinical use.

Title of proposed idea: Molecular Classification of Disease

Nominator: Innovation Brainstorm participants

Major obstacle/challenge to overcome: Currently, “clinical syndromes” are often used to classify disease. The problem with this approach is that a given patient syndrome may contain significant heterogeneity with regard to molecular mechanisms of pathogenesis. As a result, the ability to identify pathogenic mechanisms in population studies is limited, as is the ability to quickly and efficiently identify who will benefit from therapeutic interventions. Thus, new approaches are needed for classifying patients and disease states that are more tied to the molecular basis of disease. Intermediate markers or “endophenotypes” may be helpful in this regard.

Another obstacle to translation is a general lack of willingness to challenge dogma, which can perpetuate stale thinking and practice.

Emerging scientific opportunity ripe for Common Fund investment:  Progress in this area promises to fill gaps between molecular characterization and patient disease states, as well as to identify heterogeneity in classical clinical syndrome classifications. Recent advances in technologies that allow comprehensive profiling of patients at the molecular level and association of these profiles with clinical data provide an opportunity to completely redefine the way we think about and understand disease. However, these capabilities need to be developed further and expanded for regular use in the clinic.

Common Fund investment that could accelerate scientific progress in this field:  Innovation is needed in the way in which we classify patients. Examples include:

The NIH could establish a well-characterized, central sample database to encourage data sharing and integration. New approaches to finding “lenses” to view complex biomedical problems could include funding coherent, high risk programs, as well as considering the relevance and ability of existing networks to pursue this work [e.g., Clinical and Translational Science Awards (CTSAs)].

Potential impact of Common Fund investment: Molecular characterization of disease has obvious benefit across the board for diagnosis and treatment of all diseases. In addition, progress in this area would catalyze the transition from one-size-fits-all medicine to personalized medicine. Clinical trials could be done more quickly and efficiently, and the resources harbored by population studies may be better utilized.

Finally, encouraging a mandate to challenge dogma would likely introduce broader thinking that will undoubtedly open new avenues for exploration.