Director’s $500K Transformative Award

Overview:

The Brigham Research Institute (BRI) has made funds available in FY18 to support projects/activities aligned with the BRI’s mission through the BRI Director’s $500K Transformative Awards.  Funds will be awarded on a competitive basis.  Applications will be evaluated and prioritized on the basis of a strategic and scientific review by an internal faculty Review Committee and BRI leadership. The final selection round will be a live review session with the BWH Scientific Advisory Board. $500,000 is available to this RFA; requests for up to $500K will be considered.

 

Letters of intent (due May 9th, 2018) will be reviewed and a subset of applicants will be invited by June 12th , 2018 to submit full applications due August 7th, 2018; monies are expected to be made available on December 3rd 2018.  The BRI anticipates funding one project, however, there will be no obligation to spend any or all of the funds and projects may be partially funded.

 

Process:

  • This RFA, which has a deadline of 5/1/2018 for letters of intent and 8/7/2018 for full applications, will be open to all scientific themes and will consider a variety of activities – see application criteria (below) for more details.
  • An internal faculty review committee with broad expertise will review letters of intent and full proposals.
  • Based on the outcome of the internal scientific review, up to three finalists will present to the BWH Scientific Advisory Board at the October 2nd meeting; the SAB will make a recommendation on which project should be funded to the BRI EC.
timeline
Feb 2nd, 2018 RFA issued
May 1st, 2018 Letters of Intent due
Jun 12th, 2018 Semi-finalists invited to submit full proposals (Up to 10)
Aug 7th, 2018 Full Proposals due (Partners Innovation notified)
Sept 11th, 2018 Finalists notified and invited to present at Oct 2nd SAB meeting
Oct 2nd, 2018 Up to 3 finalists present at BWH SAB meeting (if you are not able to attend this meeting (9 am-1 pm) please do not apply)
Dec 3rd, 2018 Award date
Application criteria
  • Applications may be submitted to seek funding for:
    • New cross-departmental, interdisciplinary activities that support collaborative projects rather than individual investigator/R01 type projects
    • Current BRI Center/Programs to transform themselves into hubs for facilitating discovery/translation by developing novel programs that will lead to new sources of resources, collaborations with industry, or implementation of a philanthropic strategy as examples. See appendix A for “attributes of a model research center”)\
    • The creation of new BWH/BRI Centers or Programs with similar goals as stated above.

 

  • Applications must be scientifically and strategically meritorious:
    • Scientific merit: Applications that propose a new BWH/BRI Center or Program or those that propose the transformation of an existing BRI Center/Program should have a very well-developed plan for moving such an entity forward with the goal of becoming self-sustaining (see appendix A)
    • Strategic merit: In order to receive funding, all applications should be aligned with the BRI’s and BWH’s strategic goals. If the application is from a current BRI Center/Program, it should also be relevant to that entity’s strategic plan.

 

  • Emerging strategic goals as defined by the BWH SAB are included in Appendix B.

 

  • Allowable expenses include (but are not limited to) salary and equipment purchases (for equipment that would enable research relatively broadly). Collaborations are encouraged; external collaborations are permitted and subcontracts are capped at $50,000 inclusive of 15% indirect costs.
Eligibility
  • All members of the BWH research community with a rank of Assistant Professor and above are invited to apply. Co-Investigators need not rank Assistant professor or above.
  • Individuals may serve as the PI of only one proposal but may be co-Is on multiple proposals. Recipient must remain at BWH for duration of the award, award may otherwise be forfeited.
  • Finalists MUST be able to appear in person at the SAB meeting on 10/2/18 between 9am-1pm
  • Projects that have been presented to the BRI’s Scientific Advisory Board (SAB) in the last three years are ineligible for reapplication.
Reciprocity
  • Recipients will be obligated to provide a one year report of activity to the BRI, an oral presentation to the BRI ROC at the end of the funding period and an update at a BWH Scientific Advisory Board meeting.
  • Grantees will notify the BRI when other grants are received as a result of this funding
  • Grantees will acknowledge the BRI in publications (posters, journal articles and grants) resulting from this support and will notify the BRI when such papers have been submitted.
Application Process

Letters of Intent (due May 1, 2018, 10:59pm) should be submitted electronically online here

and must include the following:

  1. Basic information, including:
  • Title of project
  • Applicant’s Name, Degree, Department and Division, BWH and HMS professional appointments, telephone number and e-mail address
  • 1-page scientific abstract or proposal summary in PDF format. NOTE: Emphasize how exactly your proposal will be transformative in the short (2-5 years) and long term (10-20 years). Examples of a transformative proposal include but are not limited to those that will result in a significant leap for research in the specific field, those that could have significant commercial impact, result in increased cost savings for BWH, have an extraordinary effect on patient care at BWH or uniquely position BWH to achieve one or more of these. Also, as you prepare the LOI, please keep in mind the list of terms below that reviewers used to critique past proposals.

 

Full Applications (due August 7, 2018, 11:59pm) should be submitted electronically (Link will be sent to invited applicants via email) and must include the following:

  1. Basic information, including:
  • Title of project
  • Applicant’s Name, Department and Division, BWH and HMS professional appointments, telephone number and e-mail address
  • Scientific Abstract or proposal summary – limit 300 words

 

  1. Proposal (5-page limit, excluding references):
A.Introduction (state problem or challenge)
B. Specific Aims. IF the proposal is for the creation of a new BWH/BRI Center/Program or transformation of an existing one, please describe a clear plan for how the funds will be used towards developing a “model research center’’ – see Appendix A. Also, include a clear plan for how this functional platform will serve the larger BRI community
C.Background, significance i.e., potential impact of this work in the short-term (2-5 year) or long-term (10-20 years) and, if available, preliminary data (not required)
D.Approach (include experimental details, approximate timeline, contributions of each team member)
E.Durability/sustainability, i.e., how will this project leverage funding beyond this grant including plans for development and collaboration with industry

 

  1. Biosketches of Principal Investigator, co-investigators and significant key personnel in NIH format.
  2. Detailed budget for two years year for a maximum of $500,000 (direct costs) and 15% indirect costs. Subcontracts (external collaborations) are capped at $50,000 inclusive of 15% indirect costs.

 

Compilation of Reviewer Critique Terms from Past Proposals:

Summary of positive review terms

  • Builds on the Brigham’s strengths
  • Has potential for future funding
  • Transformative
  • Useful for the community
  • Has broad applicability
  • Powerful for prospective patients

Summary of negative review terms

  • Sustainability in question
  • Not transformative science
  • Proposal already ready to be submitted as R01
  • Clinical applications not strong
  • Doesn’t seem scalable

Attributes of a Model Research Center (excerpted from BRI Leadership Retreat, April 8, 2008, Center Strategic Assessment & Planning Workshop and modified)

 

Interdisciplinary – in terms of members, science, projects and funding

  • Must bring people together in new ways to achieve objectives that would not be achieved via the traditional department and division structure
  • Focus on translational activities
    • Integration of research and patient care
    • Translation of innovation into commercialization

 

Clear vision/mission

  • Encompassing a logical reason for the center beyond the interest of the founding members

 

Develop and provide value added core resources or research infrastructure to the research community (can be either a specific research community or the entire BWH research community).

  • Clear understanding of why and how the center benefits each member.

 

Provide a voice for the research community and bring greater visibility BWH research

  • Represent the research community to BWH senior management
  • Represent BWH to the Harvard wide community

 

Sustainable

  • Funding for Center versus specific projects – might include philanthropic support or collaborations with industry
  • Strong leadership with appropriate governance
  • Strong administrative management structure

 

Educational activities – both for internal purposes and for outreach

The BWH SAB initially defined three priorities:

  1. Training the next generation of physician-scientists and translational research scientists.
  2. Developing an entrepreneurial environment
  3. Science initiatives. BWH should consider creating larger interdisciplinary initiatives that the BRI can guide and support in areas that distinguish BWH from competitors globally. What are the next “grand ideas” or “grand challenges” in science?

Question posed by SAB: Can we define opportunistic areas of research that warrant new initiatives or program enrichments that will engender greater successes at BWH?

 

The SAB further elaborated:

 

Our vision for the future of the BWH is to be a global leader in this new era of healthcare innovation—capitalizing on novel basic scientific discoveries by BWH researchers that are translated into the next generation of diagnostics and therapeutics, to establish global centers of clinical and research excellence for difficult-to-treat diseases and to train the next generation of leaders for this new era of molecular-based, precision medicine.

 

  1. Areas of Scientific and Clinical Focus

BWH would create larger focused interdisciplinary initiatives that would allow us to clearly distinguish ourselves both from other scientifically-sophisticated AMCs as well as from community-based healthcare delivery systems.   In determining these areas of focus, each area should at a minimum conform to three principles (i) leverage the existing scientific and clinical strengths of the institution and its faculty, (ii) allow for the BHW to be a global leader and be difficult for others, particularly community-based health systems or companies to replicate, (iii) address significant diseases with large unmet clinical need and clear scientific opportunity.  Several interesting examples that fulfill these principles were discussed including:

  1. A Global Clinical Informatics Initiative
  2. Initiative(s) built around novel shared disease mechanisms rather than traditional disease entities
  3. Initiative(s) built around novel technologies
  4. A BWH Translational Accelerator

 

  1. Re-thinking how we are organized

It is now clear that in the future, both research and clinical treatments for many diseases will require extensive cross-functional collaborations between basic scientists, radiologists, medical doctors, surgeons and informaticians as well as others.  The group discussed a novel hub and spoke model in which we might create internal centers of excellence focused around a disease and/or technology.  These centers might be geographically co-located, aligning laboratories with operating rooms and basic scientists with clinicians and informaticians.  The spokes radiating from these hubs could include corporate and venture partnerships as well as integrated scientific and training programs and patient advocacy, foundations, and fund-raising efforts.  The existing BRI structures associated with several of the potential disease areas would be conducive to the expansions necessary to achieve these goals.

 

  1. A culture of Entrepreneurship and Risk Taking

 

Summary

The Brigham is uniquely positioned to create “the next paradigm for research and clinical care in an AMC”.  As described above, success will require at least three important changes in structure and culture:

  • A focus on specific “Centers of Scientific and Clinical Excellence” in which the Brigham is uniquely positioned to be a global leader.
  • A significant internal reorganization around these Centers of Excellence to facilitate cross-functional interactions between many different research scientists, clinicians from different departments, and trainees as well as corporate partners, venture capitalists and patient advocacy groups and foundations.
  • A cultural realignment that encourages both long-term high-risk research and entrepreneurial translation of that research into novel diagnostics and therapeutics, the training necessary and the organizational models that bring the internal (academic) and external (commercial and philanthropic) entities together.

PAST AWARDEES

2017
Michael Brenner, MD, Professor, Dept. of Medicine

Disease Deconstruction by Single Cell Transcriptomics: Onsite Single Cell RNA-seq Core

 

Abstract:

A next step in understanding tissue pathology across diseases is the identification of abnormal infiltrating cells and pathologic changes in the tissue parenchymal cells and stroma at the single cell level. Molecular studies on whole tissues and enriched cell types provide a global picture of pathological processes, while single cell analyses provide a new look at the nature of cell types, cell states, cellular interactions, and molecular pathways that may be obscured in bulk populations. Inflammation is one type of pathologic process that underlies a broad range of medical conditions. The BWH Human Immunology Center and the Evergrande Center for Immunologic Diseases both emphasize inflammation and the power single cell and high- dimensional analyses, including flow cytometry, mass cytometry (CyTOF) and RNA sequencing (RNA-seq), to reveal critical cell types and pathways active in blood, fluids and end organs in many diseases. The advent of droplet-based single cell transcriptomics analyses, led by the 10X Genomics platform, now offers the ability to assess single cells from patient samples (or animal models) in dramatic transcriptomic detail and has the potential to identify new pathologic cell subsets and phenotypes that may be targeted therapeutically. When abnormal tissues are disaggregated and analyzed by single cell transcriptomics, an integrated picture of the inflammatory pathways present and changes in the transcriptomes of the tissue parenchymal cells and stroma provide an unprecedented detailed and composite picture of organ pathology and inflammation. Here, we propose to implement the 10X genomics technology at BWH, with an integrated platform that includes technical expertise in processing and analyzing samples, bioinformatics support for data analysis, and pilot funding to help facilitate adoption by investigators new to the technology. We expect that this platform will empower single-cell transcriptomic studies across hospital departments, disease centers, laboratories and clinical divisions. Single cell disease deconstruction studies have the potential to reveal new pathologic cell states in both the immune compartment and in organ tissue cells. Defining pathologic processes at the state of the art level is now possible with single cell transcriptomics and is highly sought by academic investigators and the pharmaceutical industry.

Terrie Inder, MD, MBChB, Professor, Dept. of Newborn Medicine

Healthy Starts to Life – Transformative Award in Newborn Research

 

Abstract:

The health of the pregnant woman, fetus, and newborn infant forms the foundation for health throughout the life course. As conceptualized by the Developmental Origins of Health and Disease paradigm, adverse experiences early in development have a profound impact on one’s risk for chronic diseases later in life, including asthma, hypertension, diabetes, neuropsychiatric and neurodegenerative disorders. With this BRI Transformative Award, we propose to build a new neonatal and childhood research platform, that will both expand on the existing LIFECODES platform alongside more in depth pipelines for targeted populations of high-risk infants. LIFECODES is one of the nation’s largest pregnancy (n>4,000) cohort studies with an extensive biobank of samples (blood, urine, and placenta) collected during pregnancy to research biomarkers of pregnancy complications including preterm birth and preeclampsia. To date, limited neonatal and no childhood data has been collected for these pregnancies. In part one of the platform, we will engage prospectively enrolling LIFECODES mothers to facilitate collection of more extensive neonatal data and specimens with opportunity for later childhood outcomes. This research platform will be established in collaboration with LIFECODES investigators (Maternal-Fetal Medicine), Precision Medicine (Pathology), Bioinformatics (HMS and Partners). In part two of the platform, we will develop a more in-depth investigational pipeline for pilot data characterization of several high-risk populations of infants (approx. 20-30 mother-infant pairs per group) that are the focus of multiple investigators within BWH. The first patient group will be a control group of uncomplicated term pregnancies and healthy infants. For the at-risk infant groups, we will focus on a) infants born very preterm (<32 weeks’ gestation); b) term born infants exposed in-utero to maternal selective serotonin reuptake inhibitors; c) infants with hypoxic-ischemic brain injury; and finally, d) infants with Down Syndrome.

2016
Oliver Jonas, PhD, Assistant Professor, Dept. of Radiology

Lab-in-a-patient Microdevices for NextGeneration Precision Medicine

 

Abstract:

Despite technological advances in experimental biology and genomics, our understanding of disease pathophysiology and our therapeutic decision making often rely upon inferences based on incomplete snapshots of data rather than the intricate variations across space, time, and cellular components that characterize living tissues. In lung cancer, for instance, there is currently no functional characterization of suspected lesions to aid clinical decision making among various surgical or systemic treatment options. This project will develop a novel microscale “lab-in-a-patient”technology that allows for the first time in a single system – monitoring and probing the disease microenvironment in real time within human tissue. Using implantable microdevices that are inserted directly into tissue, we provide phenotypic readouts for up to 100 distinct therapies or molecular sensors from a single tumor in real time using integrated optical microsensors, in a minimally invasive manner and without systemic toxicities. We envision that such comprehensive functional profiling of the tumor will be integrated with existing interventional and surgical procedures, and enable superior therapeutic decision making in lung cancer and beyond. Support from the BRI for this project will unite efforts in the Biomedical Imaging Program, Cancer Research Center and Center for Surgical Innovation to advance the technology into near term use in first in man clinical studies to be conducted at BWH.

Guillermo Garcia-Cardena, PhD, Associate Professor, Dept. of Pathology

Program in Human Rare (Orphan) Disease Modeling and Therapeutics

 

Abstract:

BWH is a tertiary referral center for high-risk pregnancies nationwide. Each year, over 10,000 babies are born at BWH, and over 1,000 babies are cared in our NICU. Undiagnosed (rare and hard-to-diagnose) diseases can be extremely difficult to patients, their families and physicians. To meet the challenge to care for these patients, in this project, we propose to apply integrated approaches to elucidate the diagnosis, and offer potential therapeutic strategies. Our goal is to expand our Regenerative Medicine Center to establish induced pluripotent stem cells (iPSC)-based models of rare and undiagnosed diseases to mechanistically dissect their pathobiology, and to explore the potential therapeutic strategies for their treatment. To this end, we have assembled a team of physicians and scientists from several departments to collaboratively build on recent developments in genetics, genomics, iPS cell biology, developmental biology, and drug discovery. We will focus our efforts in the following areas: 1) iPS cells will be generated and differentiated in various cells compartments including neuronal, hematopoietic, musculo-skeletal and vascular lineages; 2) Functional assays for each cell type will be used to define the specific defects in a tissue-relevant manner; 3) screening of small molecules will be performed to reverse the dysfunctional cell phenotypes.

Richard Maas, MD, PhD, Professor, Dept. of Medicine

Brigham Genomic Medicine (BGM): An Integrated BWH-wide Genomics Pipeline for Disease Gene Discovery

 

Collaborators:

Andrew Bjonnes MSc; Stephen Joseph Elledge, PhD; Wolfram Goessling, MD, PhD; Robert C. Green, MD, MPH; Elizabeth W. Karlson, MD; Elizabeth Krieg, MS; Joel Brett Krier, MD; Calum A. MacRae, MD, PhD; Melanie C. O’Leary, MS; Soumya Raychaudhuri, MD, PhD; Heidi L. Rehm, PhD; Shamil Sunyaev, PhD; Dana Vuzman, PhD

 

Abstract: 

An Integrated Institution Wide Genomics Pipeline for Disease Gene Discovery; Richard Maas, M.D., Ph.D., on behalf of the BWH BRI Genomics Center The application of genomic sequencing to clinical medicine will transform disease diagnosis and treatment. As part of a programmatic effort to build genomic medicine at BWH, we are now using genome sequence to solve undiagnosed cases. This includes a clinical genetics service focused on monogenic case referrals from multiple BWH departments, a state-of-the-art computational pipeline, and an integrated inter-disciplinary team for causal variant identification and disease gene discovery. BWH patients with monogenic diseases of unknown cause are not uncommon. Discovering the genetic causes of these disorders can help these patients, advance BWH’s standing in genomic medicine, and facilitate discovery of therapeutic targets for these conditions and for more common disorders with similar phenotypes. We propose two integrated aims to accomplish these goals. In Aim 1, we will leverage BWH computational and functional pipelines to identify causal variants within genome sequences obtained via BWH Pathology and the Broad Institute, thus identifying new disease-causing genes. In Aim 2, we will establish the burden of pathologic variants in the same genes in phenotypically related common diseases using genomic sequence repositories and the Partners BioBank. Together, our efforts will transform patient-centered gene discovery, uncover therapeutic targets, and provide commercially valuable knowledge about disease pathways.

Elazer Edelman, MD, PhD and Bodan Pomahac, MD, Dept. of Medicine & Surgery

Controlled Artificial Perfusion of Tissues using Organ Function Markers

 

Collaborators:

Bohdan Pomahac, MD; Ericka M. Bueno, PhD; Brian Yale Chang, PhD; Nicco Krezdorn, MD; Muayyad Alhefzi, MD, PhD

 

Abstract:

Our Partners-based center will support organ resuscitation in organ failure and preservation of harvested organs in transplantation. Leveraging our learning ventricular assist devices (VAD), we will create forum for all users. Our VAD provides constant flow based on embedded sensors that determine how much work the heart can sustain, titrating support AND defining heart state. Our systems operate like modern ventilators, allowing for maximal control or minimal enabling support and intensive quantitative function monitoring. We will extend this to solid organs for support and even limbs for harvest – guiding recovery by varying support based on physiological response measured through some organ function markers (chemical or physical). We will work on a modular basis – general features and resources would be available to all. We will building on the commonality of assets and needs, but be expansive and deep enough to enable individualized support. These resources will include full understanding of perfusion systems from a technical and mechanical perspective, burgeoning insight into the science and physiology of organ preservation, use and fabrication of microsensors for a full range of biomarkers and computational modeling at multiple scales. We will become a patient and organ-specific domain and a nidus for all interested in learning machines and dynamic support.

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