The Human BioMolecular Atlas Program

The goal of the Human BioMolecular Atlas Program (HuBMAP) is to catalyze development of a framework for mapping of the human body with cellular resolution to enhance our understanding of tissue organization and function. This will be achieved by:

• Accelerating the development of the next generation of tools and techniques for constructing high-resolution spatial tissue maps that quantify multiple types of biomolecules; • Generating foundational 3D tissue maps using validated high-content, high-throughput imaging and omics assays;

• Establishing an open data platform that will develop novel approaches to integrating, visualizing and modelling imaging and omics data to build multi-dimensional maps, and making data rapidly findable, accessible, interoperable, and reusable by the global research community;

• Coordinating and collaborating with other funding agencies, programs, and the biomedical research community to build the architecture and tools for mapping the human body with cellular resolution;

• Supporting projects that demonstrate the value of the resources developed by the program to study individual variation and tissue changes across the lifespan and the health-disease continuum.

For additional information about how HuBMAP is structured, see Program Goals and Initiatives.

HuBMAP will scale-up the scope of tissues, technologies, data management and community engagement that are being addressed during the eight-year duration of the program. The program will have four stages: a setup phase in FY18, a scale-up phase FY19-21, a production phase FY22-24 and a transition phase in FY25. The five research initiatives that compose the program are:

• Transformative Technology Development - This set of initiatives, the first of which will be issued FY18, seeks to establish proof of principle and validation of the next generation of tools, techniques and methods that will be foundational for mapping the human body with micron resolution.

• Rapid Technology Integration - This set of initiatives, which will start in FY19, will focus on nimble integration of promising imaging and omics technologies into HuBMAP that have the potential to enhance data collection and validation during the program, and expanding throughput, multiplexing or discrimination of different classes of biomolecules.

• Tissue Mapping Centers - These Centers, which will be initially funded in FY18, will build, benchmark, standardize, validate and generate extensive data from high-content, high-throughput imaging and omics technologies to produce 3D human tissue maps with high spatial resolution. Centers will be expected to integrate and optimize all parts of the data generation pipeline, from tissue collection and preservation through to data integration, analysis and interpretation.

• HIVE - This multi-component collaboratory, which will be funded in FY18, will have responsibility for: 1) managing the data generated by the Consortium, 2) coordinating internal and external Consortium activities, 3) developing novel tools for visualizing, searching and modelling data and 4) building an atlas of tissue maps.

• Demonstration Projects - The goal of this initiative, which will start half way through the program, is to demonstrate how HuBMAP resources, in combination with new or other datasets or biospecimens as needed, can be used to build better statistical and analytic tools and models of cellular organization and communication in tissues.

Pending the availability of funds and dependent on progress, the budget for the program is expected to increase significantly over the first half of the program as the scale and complexity of Consortium activities increase. During the first year of the program, the setup phase, the focus for the Consortium will be on establishing working groups, policies, SOPs, joint activities and the infrastructure to support these activities. Individual projects will be expected to recruit needed staff, carry out calibration and benchmarking experiments and build collaborations with other Consortium members. During years 2-4 of the program, the scale-up phase, the Consortium will move on to develop and begin to populate the data matrix for the Consortium using data generated from validated assays, to carryout joint projects such as cross validation studies or integrated analysis, and to establish collaborations with similar national and international programs. Individual projects will be expected to generate validation and pilot data by the end of the phase to generate publication-quality data from human tissues using their assays, to optimize the resolution, content and throughput of their assays, and rapidly share their research products with the Consortium. During years 5-7 of the program, the production phase, the Consortium will be expected to have regular data releases of publication-quality data, to work with the wider research community to establish data and resource sharing policies, and to create tools and engage in activities that will accelerate awareness and re-use of Consortium data. Individual projects will validate and implement emerging technologies into their data generation pipelines, regularly contribute significant amounts of well annotated, high quality data to the HIVE in standardized formats, and analyze the generated data for new insights into inter-individual variability, changes in tissue organization across the lifespan, and changes across the health-disease continuum. Common Fund programs are designed to be short-term, cross-cutting investments by NIH. The goal of the final stage of the program in year 8, the transition phase, is to achieve long-term sustainability of the high-value resources generated by the Consortium by implementing a pathway that will maintain and curate the resources using other sources of funding.

Announcements and regularly updates will be posted on the program website: https://commonfund.nih.gov/hubmap. The program also maintains a mailing list. Further information about the FY18 RFAs will also be available during a webinar scheduled for January 11th. There will also be a webinar specifically to discuss the HIVE Initiative and Other Transaction awards. We will post recordings of these webinars after they occur. More information can be found at: https://commonfund.nih.gov/HuBMAP/meetings.

For HuBMAP, a 3D tissue map is a high resolution, representation of the quantitative distribution of intrinsic biomolecules found in human tissue. These biomolecules fall into many classes including but not limited to DNA, RNA, proteins and metabolites. A biomolecular atlas is a collection of related biomolecular maps. Applicants are strongly encouraged to propose assays that can be easily multiplexed to produce comprehensive maps of the 3D spatial distribution of multiple classes of biomolecules across a tissue, including both intracellular and extracellular compartments.

Tissue Mapping Centers are responsible for, among other things, generating individual maps in cartesian space. The HIVE is responsible for, among other things, integrating these maps together body-wide using a Common Coordinate Framework, generating maps in non-cartesian space, and providing a framework for generating atlases of functional, structural and biomolecular data that enable studies of inter-individual variability, changes across the lifespan and across the health-disease continuum.

Projects that propose studying non-human, diseased or dysfunctional tissues are not within the scope of the program. Projects that propose studying bodily fluids are not within the scope of the program. Motile human cells in the context of a tissue, such as tissue resident macrophages, are within the scope of the program. Projects may generate information from bodily fluids, or about microbiome interactions, the virome or exogenous compounds to enhance their understanding of tissue organization and function, though they should not be the focus of the project. There are no preferences or limitations to the tissues that will be analyzed as HuBMAP beyond each project being expected to work with non-diseased human tissue. Given (1) technology limitations, (2) availability of high quality tissue, and (3) tools, data and analysis available from similar programs, applicants are strongly encouraged to consider: (1) how their choice of tissues provides a unique and synergistic opportunity for HuBMAP, (2) the rationale and synergy between the technologies, tissues and analysis tissues and organs proposed, and (3) the significance of the biological insights that will be gained from the data generated and analyzed. Additional details can be found in each RFA. There are no specific requirements for the collection, preservation and processing of tissue. However, it is expected that high quality tissue will be used and degradation will be characterized and minimized particularly if existing tissue specimens will be used, that specimens are of a sufficient size and there is sufficient information about the location and orientation of tissue blocks can be accurately positioned in the human body using anatomical landmarks, and that donor consent does not inhibit the sharing and re-use of information within the Consortium. Although there are no specific requirements for preservation and pre-analytical processing (e.g. fixation and sectioning), these steps should minimize perturbation of the tissue, maximize compatibility with multiple downstream assays, and make sharing with other Consortium members practical. Projects are encouraged to develop, compare and optimize preservation and pre-analytical techniques for each of the tissues they propose studying.

HuBMAP supports the development and application of high-content, high-throughput, cost-effective assays that generate high quality quantitative data for characterizing cells and the extracellular structures at high resolution. The focus of the program is on in-situ analysis of the biomolecular composition and morphology of tissue, using unbiased, qualitative assays that can be readily multiplexed with other assays and used for analyzing multiple human tissues. Technologies that only assay a small number of biomolecules, have low sensitivity or specificity, are not generally applicable to all tissues or require significant optimization for each tissue, do not provide a reproducible quantitative readout, are not capable of high throughput analysis, do not preserve information about spatial organization and have high resolution, do not identify specific biomolecules, or are not cost-effective will be considered as low priority. Tools and technologies which require significant pre-processing of the tissue that results in significant biomolecular degradation, or that work with dissociated or fragmented cells and do not accurately recover spatial organization with high resolution will also be considered a low priority.

Although the focus is on technologies that provide quantitative readout of the spatial organization of specific biomolecules, such as proteins, RNA, DNA and metabolites, projects can propose generating data from technologies that will enhance scientific understanding, including from but not limited to MRI, micro-CT, photoacoustic imaging, Raman spectroscopy, histology, and mechanical imaging.

For HuBMAP, a high-resolution assay is one that can reliably and reproducibly assign detected biomolecules to individual cells or extracellular compartments of a tissue. This is typically understood to be at a length scale of around a micron, though projects may propose techniques within an order of magnitude depending on the biomolecules and tissues being studied. A high content approach is one that maximizes identification of tissues features through a combination of biomolecular depth, spatial resolution and multiplexing of complementary, multi-parameter assays. A high throughput pipeline is one that maximizes the bandwidth of data production to result in any or all of the following: 1) accelerated speed of analysis, so that hundreds or thousands of samples can be analyzed at once, 2) greater depth of analysis, so that hundreds or thousands of molecules can be analyzed in a single sample, or 3) enhanced capacity for volume, so that a given set of molecules can be analyzed in all the cells within a larger tissue sample. Approaches that maximize the volume of tissue that will be analyzed while maintaining cellular resolution and high biomolecular content are strongly encouraged.

The focus of the program is to understand the spatial distribution of identifiable biomolecules in non-diseased human tissue, including both intracellular and extracellular space. Therefore, projects proposing to study cell lines, organoids, diseased or non-human tissues will be considered unresponsive (the exception is for the UG3 phase of TTD projects where mammalian tissues can be used). Projects proposing to use a combination of assays that do not generate high spatial resolution, high content and high throughput data on a diverse range of biomolecules will be considered unresponsive. Likewise, projects that use a preponderance of assays that do not generate maps of identifiable biomolecules (e.g. anatomical or morphological imaging or functional or physiological assays) will be considered unresponsive.

Projects that propose to use only dissociative techniques that do not capture spatial information or only examine intracellular compartments will be considered unresponsive. Projects can use dissociative techniques in combination with complementary imaging approaches, or propose dissociation assays where the spatial organization of the tissue can be inferred and the conditions varied to analyze intracellular and extracellular regions. Projects can propose starting with intracellular transcript-only assays, though will be expected to broaden their range of assays during the project to include other biomolecules and extracellular compartments. Investigators are strongly encouraged to use multiple assays that can be cross-validated, to minimize perturbation and degradation of tissue during pre-analytical process and to optimize and standardize their assays.

The Transformative Technology Development (TTD) initiative will begin in FY18, while the Rapid Technology Implementation (RTI) initiative will begin in FY19 pending the availability of funds. Applicants are strongly encouraged to only apply for the initiative that best describes their stage of readiness. TTD applications with significant preliminary results that demonstrate proof of concept or validation in mammalian tissue will be considered a low programmatic priority. While TTD projects are encouraged to motivated by an unaddressed biological challenge, the focus of these projects should be on development of novel, high-impact technologies that significantly expand our capabilities.Likewise, This expansion may involve improving the sensitivity, specificity or throughput of an assay by at least an order of magnitude over any similar technology in the peer-reviewed literature at time of submission, or developing the capability to assay specific biomolecules of interest at the single cell level that currently cannot be assayed. hConversely, high-risk technologies that have not generated publication-quality data from at least one human tissue will be considered a low-priority for the RTI initiative. RFAs for the RTI initiative are expected to focus on specific technological needs of the Consortium.

A cooperative agreement funding mechanism supports discrete, specified, circumscribed projects to be performed by investigators in an area representing their specific interest and competencies and is used when substantial NIH programmatic involvement is anticipated. In addition to a Program Officer from the administering Institute, each award will be assigned a Project Scientist(s) from NIH who will participate with the Principal Investigators on a Steering Committee. NIH staff will not direct the research but will assist in aligning progress with the goals of the program and promote interaction with other members of the Consortium. There are several key expectations described in each RFA such as:

• Attendance at Consortium meetings, workshops, and conference calls

• All investigators are under a confidential disclosure agreement regarding all private information within the Consortium

• Participate in cross-validation of your own and others’ tools/technologies

Other Transactions (OTs) are funding mechanisms, which are not grants, cooperative agreements, or contracts, under section 402(b)(7) or 402(b)(12) of the Public Health Service Act. OTs are used by components within the NIH, including the Common Fund, which have been authorized by Congress to use them. They allow the NIH to:

• Seek participation by non-traditional research partners

• Foster innovation and nimbleness to quickly develop and engage in programmatic activities

• Alter the course of the project in real-time to meet the overarching goal

• Conduct objective review

• Expand, modify, partner, not support, or discontinue awarded activities based on performance and programmatic need.

For additional information, please see the HuBMAP Other Transactions Policy Guide.

Investigators funded as part of the program will be expected to participate in a range of Consortium activities. The Consortium will have a range of regular teleconferences, including Steering Committee and working group calls. In addition, investigators will be expected to attend the annual investigator meeting in person and other appropriate face-to-face meetings and workshops organized by the Consortium and should budget accordingly. Funded projects will be expected to participate in Consortium projects, that may include development of SOPs and metadata standards, cross-site validation studies using the same tissue specimens, joint analysis projects, multi-site training programs, or coordinated outreach initiatives and applicants are strongly encouraged to propose and budget for these activities as part of their applications.

NIH intends that the products of the HuBMAP be broadly available to the research community to establish the foundations for a human body map that other programs and the international community to build upon; this includes methods, tools, reagents, biospecimens, datasets, and software. All funded investigators must facilitate the public release and dissemination of results, data, reagents, technologies, and other products generated through their HuBMAP awards in a timely manner and abide by Consortium and NIH policies. Awardees will be expected to develop policies for public access; data sharing; protocol, tool, and reagent sharing; intellectual property; and software sharing to work collectively with the NIH to harmonize and implement these policies across the Consortium. Applicants are expected to be conversant with the NIH Genomic Data Sharing Policy and will be expected to share data, protocols and analytical tools rapidly with Consortium members, disclose publications before submission for review, regularly submit data to the HIVE (e.g. quarterly), and are strongly encouraged to make advances rapidly known through preprint servers.

Awardees will be expected to develop policies for public access; data sharing; protocol, tool, and reagent sharing; intellectual property; and software sharing to work collectively with the NIH to harmonize and implement these policies across the Consortium.

NIH takes data security and privacy very seriously. Although applicants are not expected to be compliant with FISMA and FEDRAMP requirements, they are encouraged to propose working with infrastructures that have experience and credentials for handling detailed human sequencing data, and to propose a data management plan that includes security assurance and testingassessment, access control with appropriate user verification, and appropriate approaches for de-identifying data.

No, a milestone is a defined event, achievement, or important stage that is used to indicate the progress of a project. Milestones are expected to be:

• Major steps or events (e.g., activities or outcomes) with a clearly defined purpose.

• Specific targets that depict progress toward project goals.

• Descriptive of what will be done and when it will be completed.

• Collectively organized in a logical order (e.g. sequentially, simultaneously, or iteratively).

• Associated with a timeframe (e.g., end of the fiscal year).

Common Fund initiative milestones are not specifics aims or broadly aspirational statements of what a project is expected to achieve.

TMCs are strongly encouraged to develop, optimize and validate their data generation pipeline with a single OSP during the setup phase of the program, and to expand their repertoire of OSPs during the scale-up phase. By the production phase, Centers will be expected to be generating and sharing publication-quality data from multiple organs. The generation of 3D maps and analysis of this data by the Data Analysis Core is expected to increase rapidly in sophistication during the scale-up phase and for the significant majority of the data generated by the TMCs during the production phase to be both analyzed in-house and shared with the HIVE, contributing to a data release for the Consortium. The Data Analysis Core of each TMC is expected to at least generate a cartesian map of biomolecules for each dataset it submits to the HIVE and it is hoped that in the process it can share its organ-specific expertise with the HIVE and work with the HIVE to develop new mapping techniques.