Transformative R01 – Transformative Application

According to the NIH Roadmap Website, the Great Zerhouni (via OER) will be issuing a Funding Opportunity Announcement this summer for the Transformative R01 Program (T-R01) “designed to stimulate disruption of existing paradigms or creation of paradigms where none exists” by supporting “highly creative, ‘out-of-the-box’ projects.” Research priorities (“Special Areas of Highlighted Need”) include:

  • Understanding and Incenting Behavior Change
  • 3-D Tissue Models
  • Functional Variation in Mitochondria
  • Transition from Acute to Chronic Pain
  • Formulation of novel protein capture reagents
  • Evidence for Pharmacogenomics clinical studies
  • “Incenting”? Also note that the “T-R01 Program represents a High Risk/High Reward Demonstration Project in which novel approaches to peer review and program management are to be piloted.” In other words, start thinking in 12-page essays.

    Update: In fact, start thinking in terms of 12-page transformative essays today. The first T-R01 RFA was just released: Epigenomics of Human Health and Disease with a Sept 28 LOI due date and an Oct 28 receipt date. Details below in a separate comment.

    As a reminder, the Enhancing Peer Review recommendations include modifying the rating system to focus less on methodological details and more on potential scientific impact. The 5 specific review criteria comprise: impact, investigator(s), innovation/originality, project plan/feasibility, and environment. So what might this look like in practice?

    The obvious NIH model would be the EUREKA R01, which is due for re-announcement soon and which involves an 8-page essay focused “on the importance of the problem, the novelty of the hypothesis and/or the proposed methodology, and the magnitude of the potential impact, rather than on experimental details,” with reviewers told to evaluate “significance and innovation” and “the PI’s record of overcoming difficult scientific hurdles.” I definitely recall considerable difficulty coaching PIs on this application.

    Then there are the DP1 and DP2 mechanisms. DP1s include the NIH Director’s Pioneer Award Program and the NIDA Avant-Garde Award Program for HIV/AIDS Research. The DP1s involve an essay of 3-5 pages that addresses the PI’s “innovative vision for, and the significance of, the biomedical or behavioral problem to be addressed, and his/her qualifications to engage in groundbreaking research.”

    DP2s include the NIH Director’s New Innovator Award Program (aka “Junior Pioneer Award”) and the Type 1 Diabetes Pathfinder Award. The DP2s request an essay of “no more than 10 pages that addresses (1) the significance of the project, (2) what makes the approaches exceptionally innovative and how the applicant will address risks and challenges, and (3) the applicant’s qualifications.” I’m looking at a funded application, and, um, it reads like a traditional research grant (specific aims and the works), but this was the first year of the competition. The 2008 awards will be announced in September, so we’ll see if these essays are more transformative.

    Outside the NIH model, we have the HHMI Early Career Scientist Competition. For this application, PIs could write up to 3000 words through which they would be “evaluated on their potential for significant research productivity and originality, as judged by their doctoral and postdoctoral work, their research plans, and results from their independent research program.”

    And, of course, we have the 15-page NSF proposal, for which the project description should include “objectives for the period of the proposed work and expected significance; relation to longer-term goals of the PI’s project; and relation to the present state of knowledge in the field, to work in progress by the PI under other support and to work in progress elsewhere” as well as “the general plan of work, including the broad design of activities to be undertaken” and “as an integral part of the narrative, the broader impacts resulting from the proposed activities.” However, the NIH seems to be leaving off the NSF broader impacts for now (i.e., integration of research and education, infrastructure enhancement, dissemination, and potential benefit to society at large).

    So, keeping these models in mind for now, I’d suggest you all start thinking about your work in terms of marketing catch-phrases rather than the staid and traditional scientific report format we all grew up with. Have at it – and have fun.



    1. Neuro-conservative said

      Dissent on incent

    2. BB said

      Agree with Neuro-conservative on the diction.

      Back to point, what are the chances of viewing a successful T-RO1 essay? It would be quite illuminating to see how broadly problems are present, how innovation is highlighted, and what scientific hurdles were presented and hpw they were overcome. Is preliminary data not necessary? Will there be separate study sections? If I say something is innovative, does that make it so?

    3. Odyssey said

      Let’s not forget that with an NSF renewal you also have to squeeze into the 15 pages a description of what you did with the last lot of money. Both the intellectual merit and broader impacts parts. I submitted mine Monday. It ain’t easy (definitely needed some incentivizing). And having reviewed for the NSF I can assure you this is not a section you want to skimp on.

    4. writedit said

      Instructions for the first T-R01: Epigenomics of Human Health and Disease

      Research plan: The research plan is limited to 12 pages. It should be self-contained, since appendices and updates are not allowed. Omit the Specific Aims, Background and Significance, and Preliminary Studies sections. In the Research Design and Methods section, the applicant should address the following six points in a single PDF file with a separate subheading for each point. Applications will be evaluated by review panels that represent a diversity of scientific interests and expertise. Therefore, jargon must be avoided. Explain the challenge, the potential impact, and the approach in language that scientists with broad expertise can understand.

      1. The Challenge: What is the disease or condition that will be studied, and what is the hypothesis to be tested concerning epigenomic mechanisms underlying this disease/condition? How will the work disrupt the standard paradigm or create a paradigm where none exists?

      2. The Potential Impact: How will the results transform our understanding of this disease/condition? How broad is the potential impact? Which community will be affected? What is the size of that community?

      3. The Approach (limit, 4 pages): What are the epigenomic marks to be analyzed, and how will they be mapped across the genome and of which cells? Provide enough information that reviewers can determine what, in general, you are proposing to do, but do not include a detailed experimental plan. If your methodology is novel, what is unconventional and exceptionally innovative about your approach? How does your approach differ from what other investigators have attempted to do? If you plan to use mammalian cells, provide strong justification: why can human cells not be used to understand the disease of interest?

      4. The Appropriateness of Roadmap: Why is the proposed research uniquely suited to the stated goals of the NIH Roadmap Epigenomics initiative? How does the proposed research differ from what is being done in your and other laboratories?

      5. The Likelihood of Success: Briefly describe your prior efforts in the area of epigenomic mapping. What were the technologies used in your prior studies, how comprehensive have prior efforts been in determining the epigenomic structure of particular cells, and how do they compare to the current application?

      6. Timeline (limit, half a page): Provide a timeline for the proposed research. To facilitate evaluation of progress reports, describe when you anticipate that essential components of the project (e.g., acquisition of samples, optimization of protocols, critical experiments to verify the hypothesis, validation of novel tools or techniques) will be completed.

      Literature Cited: limited to one page. Note that the 12 page limit for the Research Plan does not include the Literature Cited section (separate Pdf.).

      Appendix: Not allowed

      No updates will be accepted.

    5. Neuro-conservative said

      Does this mean that the whole notion of the 12-page app will be limited to these T-R01’s, and that regular R01s will remain 25 pages?

      I assume this is one of the “pilot” trials of the proposed 12-page R01 format (noted in the Enhancing Peer Review timeline and more specifically by the NIAID) and that the long-term plan is still to transition all R01s to 12 pages or thereabouts, with the page length of other mechanisms adjusted accordingly. – writedit

    6. […] system, and giving applicants more useful feedback.” This month? June??? Yes! in the form of Transformative R01s […]

    7. writedit said

      Roadmap Transformative R01 Program (R01)

      Letters of Intent Receipt Date(s): December 29, 2008
      Application Due Date(s): January 29, 2009

      The NIH common fund intends to commit $25 million dollars in FY 2009 to fund up to 60 applications submitted in response to this FOA.

      For this FOA, the R01 application Research Plan component of the PHS 398 may not exceed 8 pages, including tables, graphs, figures, diagrams and charts. Applicants must clearly articulate (1) the fundamental issue to be addressed and its overarching importance to the biomedical/behavioral research enterprise, (2) how the studies will either establish new or disrupt existing paradigms, and (3) how the proposed rationale and/or approaches significantly differ from state of the art in the field.

      Understanding and Facilitating Human Behavior Change

      Behavior change is critical to the prevention, management, and treatment of many important health conditions. However, the initiation and maintenance of behavior change can be very difficult, and even those interventions that succeed in controlled clinical trials do not always scale well. Transformative advances in the science of behavior change, especially those that can unify disease-specific efforts, are urgently needed. In response to this challenge, the T-R01 program invites proposals from investigators and interdisciplinary teams working to understand basic mechanisms of behavior change at the biological, behavioral and social levels and developing innovative approaches to intervention. Questions of particular interest include how the interaction between neural, biological, behavioral, psychological, and social factors result in initial and sustained behavior change (possibly best understood via transdisciplinary approaches including neuro- and behavioral economics, affective neuroscience, and approaches that focus on “will power” or behavior regulation). Highly responsive applications may also propose the use of new technologies and/or consider the broader context in which individuals live to understand basic mechanisms of behavior change common to multiple health conditions.

      Complex 3-Dimensional Tissue Models

      Although tissues and organs are 3-dimensional structures, their physiology and pathophysiology are currently studied in vitro with 2-dimensional techniques, in which key phenotypic and functional characteristics are often lost. Development of complex 3-dimensional tissue models would revolutionize the study of human responses by bridging the knowledge gap between describing basic cellular processes and understanding the aggregate, intricate responses of intact organisms. Human tissue models to be supported under the T-R01 program should integrate features such as multiple cell types, cell-instructive scaffolds with appropriate spatial organization, vascularization/microchannels for tissue perfusion and maintenance, components of the immune system, innervation, tunable microenvironments, and real time monitoring. The resultant platforms should yield quantitative, biologically relevant information while driving rapid and iterative design flexibility. It is anticipated that these human tissue models might ultimately be adapted to high throughput screening platforms to conduct studies of environmental stressors or for pre-clinical drug discovery.

      Functional Variation in Mitochondria in Disease

      Mitochondria are one of the most complex and important organelles found in eukaryotic cells. In addition to their central role in energy metabolism, mitochondria are involved in many key cellular processes such as the formation of reactive oxygen species and apoptosis. Mutations in mitochondrial DNA lead to a diverse collection of diseases that are challenging to diagnose and treat, and where precise mechanisms of disease pathogenesis remain elusive. Mitochondrial dysfunction has also been implicated in aging and in many chronic disease states including cancer, Parkinson’s, diabetes mellitus, Alzheimer’s, hepatic and cardiovascular diseases. Given the central importance of mitochondrial function in human biology, the ability to identify, measure and track the structural and functional basis of mitochondrial heterogeneity in human cells and tissues over the lifespan would transform our understanding of the role of this critical organelle in human health and disease. For this reason, the T-R01 program is soliciting proposals that propose innovative approaches to overcoming major roadblocks in human mitochondrial research. Significant challenges to be addressed under the T-R01 program include defining variability in human mitochondrial structure and function within and between cells and tissues in health and disease, developing tools and technologies to identify, study and manipulate human mitochondrial function in vivo at an organelle level, and elucidating the complexity of human mitochondrial function through the use of integrative, systems-biology based approaches.

      Transitions from Acute to Chronic Pain

      More than 30 million Americans suffer from unrelieved chronic pain. Management strategies often fail, in part because an individual’s susceptibility to chronic pain is highly variable, the identification of those destined to transition from acute to chronic pain is difficult, and, once pain has become chronic, changes may have occurred that cannot be easily reversed. The lack of well defined phenotypes that reflect the cellular, molecular, genetic, psychological, cognitive, and behavioral changes that occur as individuals transition to chronic pain has been a major barrier to development of personalized approaches to pain intervention. For these reasons, T-R01 proposals are sought that will transform how we view the pain state of individuals and that will revolutionize the current empirically-based analgesic treatment approaches to ones based upon objective and predictive measures of an individual’s pain phenotype. It is anticipated that responsive studies will involve formation of innovative partnerships including interdisciplinary and multidisciplinary teams to adequately address the topic and experimental aims.

      Formulation of Novel Protein Capture Reagents

      A comprehensive analysis of the human proteome will be essential for gaining deeper insights into the biological basis of human health and disease. Reaching this goal depends upon the development of protein capture tools that will reliably detect over a broad range of concentrations and that can characterize the structure, function and interactions of multiple proteins in human samples. The limited availability of suitable capture reagents and immobilization chemistries is a major bottleneck to high throughput analysis of the human proteome. In response to this challenge, a number of technologies are emerging that involve the insertion of combinatorial binding sites in alternate (non-antibody) protein scaffolds, synthesis of oligomers (RNA and DNA aptamers, oligo- and polypeptides of either natural or unnatural amino acids, and hybrids of these forms), and small organic molecules whether natural (biotin, tetrodotoxin, resiniferatoxin, lectin binding carbohydrate side chains) or entirely synthetic (substrate-based enzyme inhibitors). These novel technologies and the new and validated reagent sets that result will have the potential to transform methods and paradigms in both basic and clinical research. Given this transformative potential, T-R01 proposals are sought that will develop innovative approaches and enabling technologies for providing diverse libraries of protein capture reagents that are adaptable to high throughput platforms. Particularly needed are comprehensive reagent sets that can specifically or selectively recognize, bind and “capture” a broad universe of human proteins, or that can distinguish among the natural variants of a single protein such as splice variants, co- and post-translational modifications including but not limited to glycosylation, phosphorylation, acylation, and oxidation. Inherent in the development of this technology would be the development of array-based and other high throughput technologies for the validation and analysis of these reagent sets.

      Providing an Evidence Base for Pharmacogenomics

      In the future, prescribing decisions will be increasingly guided by genetic tests that can predict risk and effectiveness of treatments for individual patients. However, few evidence-based guidelines have been established linking individual genetic variations to medication response profiles. Proposals are sought under this T-R01 initiative that will establish and validate the predictive value of genetic profiling for creating clinical practice guidelines. Pilot studies that will broaden the pharmacogenomics evidence base in unique populations through the use of innovative clinical study designs, methods, and algorithms for use in clinical decision making are of primary interest. It is anticipated that responsive studies may involve formation of innovative partnerships including interdisciplinary and multidisciplinary teams to adequately address the topic and experimental aims.

      Scientific/Research Contact(s):

      Kristin M. Abraham, Ph.D.
      Division of Strategic Coordination -OPASI
      Office of the Director, NIH
      Telephone: (301) 594-8190

    8. writedit said

      Stodgy NIH Announces New Program for Risky, Far-Out Reseach

      The Chronicle of Higher Education’s Dan Greenberg opines that the “NIH is too big and too encrusted with old-boy alliances and obligations, customs and traditions. Congress should break it up into several granting agencies, including a virtual NIH that would do its reviewing and granting on line.”

      On the T-R01 program, he believes …

      The new program is worth a try, but doesn’t come close to the problems that inspire NIH to proclaim a turnaround in favor of bold ideas, scientific risk, important breakthroughs, high-impact research, and all the other techniques and values that should dominate the workings of an effective philanthropic organization.

      The political reality behind the inspirational words is a struggle between two sectors in the biomedical-research world. On the one hand, there’s the traditional biomedical research community, which regards NIH as a bank for investigator-initiated basic in academe, particularly in medical schools. On the other, there’s a broader research and health-care community that wants NIH to focus its vast resources on health rather than science. Director Zerhouni has fought a long battle on behalf of greater emphasis on health-related research, most notably in establishing the NIH Roadmap for Medical Research. Designed to “accelerate the translation of research to improvements in public health,” the Roadmap is regarded by NIH’s old timers as a diversion from the true path. On paper, it’s supposed to take up 5 percent of the NIH budget, someday. But so far, it has received less than 2 percent, along with continuous sniping.

      I’d love to see a PhysioProffed response in the comments section.

      The type in the title above, BTW, is a direct quote from what’s online at The Chronicle.

    9. writedit said

      FYI, for those considering the T-R01 initiative. I suspect the first part of this session will address strategies for applications in response to any of the RFA priorities. I’m sure more meetings like this will be scheduled around the other program topics.

      Transformative R01 Round Table Discussion: 3-D Tissue Models

      The NIH has issued a Roadmap initiative calling for “Transformative R01” applications. Since this will be a new program, we anticipate that the research community will have many questions. NIH will host a meeting to help establish a dialog and begin to address some of these questions for one of the “areas of highlighted need that have been identified through an NIH strategic planning process” in this initiative, specifically the generation of complex, 3-dimensional tissue models.

      The meeting will be a “Round Table Discussion” hosted by Dr. Alan Krensky (Director, NIH Office of Portfolio Analysis and Strategic Initiatives) and will include about a dozen discussants with experience in the area of in vitro engineered tissues. The discussion will be held on the NIH campus, Building 31/Conference Room 10 on Friday, October 24, 2008, 8:30 AM – 12:30 PM. The broad objective will be to illuminate potential transformative research for the field—to distinguish between incremental progress and work that will truly disrupt current paradigms, or create new ones where none exist. This will be an open meeting and will also be broadcast live from the NIH Videocast Website with additional questions collected via e-mail ( There is also a link to the meeting from the NIH Roadmap Website.

      Invited Discussants
      Linda Griffith (Massachusetts Institute of Technology)
      Jonathan Garlick (Tufts University)
      Anna-Katerina Hadjantonakis (Sloan-Kettering Institute)
      Christy Haynes (University of Minnesota)
      Meenhard Herlyn (Wistar Institute)
      Karen Hirschi (Baylor College of Medicine)
      Michelle LaPlaca (Georgia Institute of Technology)
      Milan Mrksich (University of Chicago)
      David Mooney (Harvard University)
      Cheryl Nickerson (Arizona State University)
      Shuichi Takayama (University of Michigan)
      Herman Vandenburgh (Brown University)
      Gordana Vunjak-Novakovic (Columbia University)

    10. writedit said

      As an FYI, details on the timeline for implementing broader changes in grant application submission and review can be found here.

    11. writedit said

      New Notice on the T-R01 Epigenomics of Human Health and Disease related to the involvement of Reference Epigenome Mapping Centers (REMCs).

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