Eleven New HuBMAP Centers Begin Operations
Eleven New HuBMAP Centers Begin Operations
Projects Will Map the Cells in a Number of Human Organ Systems at High 3D Resolution and Create New Mapping Technologies.
October 1, 2020
Tissue Mapping Centers for the Human Biomolecular Atlas Program
NIH created the Tissue Mapping Centers for the Human Biomolecular Atlas Program to enable scientists across the U.S. and their colleagues to establish state-of-the-art Tissue Mapping Centers (TMCs) that generate high-resolution, high-content, multiscale maps of healthy human organs and systems. These centers work closely with other HuBMAP programs to help build a framework for mapping the human body in 3D at high resolution. Six new projects were established in 2020 under this program.
Multi-Omic 3D Tissue Maps for a Human Biomolecular Atlas
PI: Wei-Jun Qian, Battelle Pacific Northwest Laboratories
Grant #: 1U54DK127823-01
One limitation of many state-of-the-art tissue visualization technologies is that they are based on matching known gene sequences or antibodies engineered to target known proteins. Because of this, they can’t show us the locations of biomolecules we don’t already know about. In this project, a group from Battelle will use a technology called mass spectroscopy, which creates a kind of molecular fingerprint of all biomolecules in a sample, to probe unknown molecules in high-resolution, 3D maps of human pancreatic tissue. Combined with protein and RNA probes of known biomolecules, the method could have a significant impact in understanding the pancreas in health and diseases such as diabetes and cancer.
Penn Center for Multi-Scale Molecular Mapping of the Female Reproductive System
PI: Junhyong Kim, University of Pennsylvania
Grant #: 1U54HD104392-01
Today we know that, in addition to carrying out the crucial role of reproduction, the reproductive system in both men and women plays important roles in general health. While scientists have studied the female reproductive system’s elements in isolation, no one has yet mapped the entire system for the high-resolution location of critical biomolecules. This study will use samples from the 3,500 surgical procedures performed by the Penn Department of Obstetrics and Gynecology to obtain samples that chart out the detailed anatomy of the system using six different probes for RNA, DNA and proteins. The resulting 3D map, integrated into the Common Coordinate Framework, will uncover the complex interactions of cells that determine reproductive health and help identify new therapeutic strategies.
Female Reproductive Tissue Mapping Center
PI: Louise Chang Laurent, University of California, San Diego
Grant #: 1U54HD104393-01
The elements of women’s reproductive system develop and change through life—and through pregnancy. This UCSD project will generate and integrate data from both medical image scans and laboratory analysis of tissues to understand how the reproductive organs communicate and coordinate through healthy development, collecting valuable understanding for a follow-on study of how disturbances in these systems lead to organ dysfunction and disease. In close coordination with other HuBMAP projects focused other organ systems, this project will integrate data from MRI and ultrasound scans, biomechanical tests, and protein and nucleic acid probes to develop 3D multiscale maps of the placenta, uterus, ovaries and fallopian tubes to shed light on common but poorly understood conditions like preeclampsia, endometriosis, female infertility and gynecologic cancers.
High-Resolution 3D Mapping of Cellular Heterogeneity within Multiple Types of Mineralized Tissues
PI: David W. Rowe, University of Connecticut Schools of Dental Medicine
Grant #: 1U54AR078664-01
The mineralized tissues of the body—bones, cartilage, and teeth—have many roles in health and disease beyond providing a physical frame that other tissues hang onto. But their detailed anatomy has been hard to study because the tissues themselves are hard. This meant that, before now, scientists could not study them with many of the tools needed for HuBMAP projects. A UConn team is overcoming these limitations with a new protocol capable of performing the same kind of repeated probing of microscopic samples seen in other HuBMAP centers. The group will develop this technology to study three very different mineralized tissues: teeth, trabecular bone and cartilage. The project will leverage the experience of scientists elsewhere in HuBMAP and at UConn who are experts in high-resolution confocal microscopy to integrate micro-CT scans and nucleic-acid based probes of these tissues at high resolution. The end result will be 3D cellular maps that shed light on how communication between neighboring cells in mineralized tissues coordinate their activities in response to mechanical forces and signals from elsewhere in the body. The work will for the first time bring the skeletal biology community into the 3D mapping word, and solve major genetic and therapeutic challenges affecting skeletal health.
Biomolecular Multimodal Imaging Center: 3-Dimensional Tissue Mapping of the Human Pancreas and Eye
PI: Jeffrey M. Spraggins, Vanderbilt University
Grant #: 1U54EY032442-01
Though very different in their tissues and functions, the eyes and the pancreas share an important connection in the disease process of diabetes. This Vanderbilt Tissue Mapping Center will employ a range of technologies including whole-organ imaging, molecular fingerprinting via imaging mass spectroscopy, classic stains that image tissue types, and autofluorescence microscopy to associate and align different types of molecular and anatomical information in a 3D atlas spanning from whole organs to single cells. The effort will combine technical expertise at Vanderbilt’s Data Analysis Core and the Delft University of Technology, Netherlands with medical expertise at Vanderbilt University Medical Center and the University of Alabama at Birmingham to understand the molecules of human tissues in the eye and pancreas, their locations and their functions at unrivaled resolution.
Center for Developmental Mapping of Heart and Bone Tissues
PI: Kai Tan, Children’s Hospital of Philadelphia
Grant #: 1U54HL156090-01
Bone and heart tissues communicate with each other to play a critical role in normal development and in diseases of both organs. This Children’s Hospital project will explore the anatomical, cellular and functional differences between tissues within each organ to discover how the microenvironment organization of the tissues affects signaling pathways underlying inter-organ communication. The team will map molecular and cellular changes in these tissues in three dimensions, over the course of human lifespan using single-cell and imaging technologies. The effort will produce organ atlases at cellular resolution, annotated with clinical and epidemiological data, new computational methods that may help advance other scientific studies and a bank of specimens available to other researchers. The ultimate goal will be to help guide studies of improved treatments to improve outcomes in diseases that involve these organs.
Transformative Technology Development for the Human BioMolecular Atlas Program
NIH has funded the Transformative Technology Development for the Human BioMolecular Atlas Program to solicit new technologies that will fundamentally expand scientists’ ability to analyze multiple biomolecules in human tissues quickly and in parallel. The funding will accelerate the development of proof-of-principle demonstration and validation of new tools and techniques to visualize important biomolecules and the chemical modifications they undergo at all levels of anatomy from the organ to the single cell. The projects will proceed in two phases, and the technologies they develop will be available to other HuBMAP centers through close collaboration. Five new projects were begun this year under this program.
High-Spatial-Resolution ECM-Inclusive Multi-omics Sequencing of Human PFA and FFPE Tissue Slides
PI: Rong Fan, Yale University
Grant #: 1UG3CA257393-01
This project will develop a fundamentally new technology for attaching molecular barcodes to important biomolecules while still in their tissues and in a way that preserves their locations in the cells and tissues. The resulting tissue samples will have a 3D pattern of pixels corresponding to the molecules of interest. These pixels will be as small as 5 to 10 micrometers, about the size of a single cell. A major advantage of the new method over current technologies will be significantly faster and less labor-intensive sample processing that should allow much faster collection of data and pace of discovery. The initial phase of the project will develop means of co-analyzing the micro-anatomy of about 500 proteins at once from human heart or aortic tissue. The final phase will see an increase in sample throughput to as many as 100 samples per day and an increase in the area scientists can map in one go, up to about 1.2 by 1.2 centimeters, as well as a way to retain the sample intact for other analysis methods, in the human heart, aorta, skin and kidney.
Spatially Resolved Characterization of Proteoforms for Functional Proteomics
PI: Ljiljana Pasa-Tolic, Battelle Pacific Northwest Laboratories
Grant #: 1UG3CA256959-01
A Battelle Pacific team will develop a new technology to mark epigenetic changes in the histone proteins that package the DNA. Such changes, which can be passed down as if they were mutations even though there is no change in the genes, underlie puzzling aspects of a number of medical conditions as different as cancer, diabetic wound healing, and psychiatric illness. The scientists will use a new form of mass spectroscopy (MS) that, unlike traditional MS, creates a fingerprint of biomolecules in a sample by working on the whole protein rather than first cutting it up into pieces. This innovation will preserve epigenetic changes to the chemistry of the histone proteins that would be altered in traditional MS. The first phase of the work will focus on histones in the kidney to improve the resolution of the method from thousands of cells to a single cell. The second will build comprehensive maps of epigenetic changes in multiple tissues, to completely characterize the full spectrum of these changes in tissues and cells.
A Streamlined Platform for Phosphoproteome Mapping of Human Tissues
PI: Tujin Shi, Battelle Pacific Northwest Laboratories
Grant #: 1UG3CA256967-01
This project will study the location of proteins that have been phosphorylated, down to the level of individual cells. A critical component of signaling within cells, phosphorylation changes the behavior of proteins in ways that modify normal growth, metabolism, hormonal response and numerous other life functions, as well as abnormal states in cancer, diabetes and other diseases. The team promises to add an important new capability to HuBMAP: the ability to trace how phosphorylation signals move through cells at a fine scale to change tissue behavior. In its initial phase, the scientists will develop a streamlined platform that improves sensitivity and speed, allowing for precise measurement of about 1,000 sites of phosphorylation in a single cell or about 7,000 in 10 cells at once, at more than 1,000 samples per day. The second phase will automate the process in human tissue dissected microscopically, using a laser, validating the method for high-resolution 3D mapping in human breast, uterine and other tissues.
Multimodal Mass Spectroscopy of Mouse and Human Liver
PI: Brent R. Stockwell, Columbia University in the City of New York, Morningside Heights
Grant #: 1UG3CA256962-01
This Columbia University group will employ the molecular fingerprinting of mass spectroscopy (MS) in a pipeline that enables rapid and simultaneous mapping of biomolecules in 3D at scales smaller than a single human cell. The method should reveal detail about cellular and tissue organization beyond what is currently possible. The team’s new technology will accomplish this by improving sensitivity of the MS method without complicated sample preparation and with minimal disruption of the structures of the molecules being studied. An automated pipeline of sample preparation, data collection, integration and analysis will allow scientists to study differences in individual cells within a cell to learn how subcellular structure drives normal cell function and disease processes.
Spatial In Situ Mapping of RNA-Chromatin Interactions at Transcriptome-and-Genome Scale in Human Tissues
PI: Shen Zhong, University of California, San Diego
Grant #: 1UG3CA256960-01
The little understood interaction of RNA messengers carrying instructions from the DNA to the rest of the cell with the chromatin protein packaging that surrounds the DNA will be the focus of this UCSD project. The transcriptome—which consists of the population of RNA molecules copied from the DNA genetic code—determines cell behavior by only passing along information from active genes, which the chromatin has exposed to the cell machinery that copies RNA. By simultaneously increasing the spatial resolution, ability to detect both rare and common RNAs at the same time, and the size of samples that can be studied, the team will deliver high-density and high-fidelity maps of how the transcriptome and interactions between the RNA and chromatin varies throughout a given tissue. The team plans to create maps of RNA interaction with 96 proteins from the mesenteric arteries and veins, as well as the microscopic blood vessels in the pancreas, liver and brain.