The National Heart, Lung, and Blood Institute (NHLBI) convened a group of multidisciplinary experts for a workshop, “Single-Cell Omics ꟷA New Frontier in the Research of Heart, Lung, and Blood Diseases and Sleep Disorders.” Experts in heart, lung, blood, and sleep diseases (HLBS) research and those in the areas of single-cell omics biology, technology, computational biology and national/international single-cell omics consortiums participated to identify research gaps and opportunities in cardiovascular, pulmonary, hematologic and sleep research.
Review the current state of the art knowledge, analytic tools and technologies in the field of single cell biology and discuss the needs for developing and utilizing these resources for better understanding basic biology and pathology of Heart, Lung, and Blood Diseases and Sleep Disorders.
Specific abnormalities in individual cells for most HLBS are either unknown or not well characterized at the molecular level, which is a major obstacle preventing a better understanding of the pathology at the cellular level resulting in tissue damage. The recent advances in technologies for single-cell omics make it feasible to identify the abnormalities of individual cells in HLBS research.
The workshop identified areas of scientific opportunity that would benefit from the use of single-cell omics approaches. The panel discussed these opportunities in four key areas: 1) the cellular origins of HLBS diseases, 2) cell-to-cell interactions during disease progression, 3) cellular phenotypes that define subtypes or endotypes of HLBS diseases and 4) discovery of novel therapeutic targets/approaches that can stop cellular transition to diseased cell types. In addition, the discussion also covered technological advances in the field, such as the best practices for utilizing single-cell technologies, 3D tissue mapping and image mapping. The expert panel made recommendations on the short-term needs and for long-term projections in HLBS research in the area of single cell biology.
Scientific Gaps and Opportunities
- Using single-cell biology to understand HLBS disease pathology will require the establishment of single-cell omics resource of “normal, non-diseased” cells for the research community. With rapid advances in technologies for single-cell biology, there is no single technology or institution being able to build a normal cell reference resource. The expert panel agreed that the best way to build this normal reference is to collect and integrate single-cell omics data generated by many high quality studies using multiple technologies with the following recommendations:
- Use of a standard naming and ontology system.
- Use of a common coordinated system for 3D mapping.
- Establishment of standard/commonly used data models, formats, quality standards, workflow and processing steps.
- The panel strongly recommended the support of single-cell biology analysis on a large number of samples representing the demographics in the USA.
- There is a need for a consolidated community tissue resource, which can be a virtual center to collect human tissues from both healthy and diseased subjects.
- Similar to the approaches of the TOPMed, generation single-cell omics data by centralized sequencing centers might be a cost effective way to analyze a large number of subjects, while the tissue and library preparations can be performed at individual study sites.
- Computational methods and analytic tools for single-cell biology are rapidly advancing and no single method will perfectly fit the diverse needs of HLBS research community. The panel identified an unmet need for supporting computational biologists to develop/refine tools needed by HLBS community. Training should be a major focus going forward to build these experts within the HLBS research community.
- The cost of high-end GPUs and infrastructure required for maintaining computing hardware is an impediment to progress in HLBS research, especially for performing 3D spatial analysis and utilization of machine learning tools. Most academic institutions do not have the necessary infrastructure, therefore solely depend on large companies to provide it such as Google and Amazon, which is cost prohibitive. This panel agreed that the development of this infrastructure will need investment by academic institutions and NIH.
- Technology development should target specific diseases and is not to expected to be one size fits all. Even the best and commonly used technologies still needs to be customized for specific disease areas—a major difference from DNA sequencing technologies. Model systems such as animals, organoids, ex vivo and in vitro system are required for testing hypothesis and validating data obtained from single-cell analyses.
- To support advancements in single-cell biology, NHLBI needs to harmonize with the research community in order to leverage existing/on-going efforts initiated by other programs and resources including NIH (HuBMAP), the international community (HCA) and individual investigators. The goal for harmonization is to collect and integrated data generated elsewhere for use by HLBS research community.
- The use of single-cell omics will help us understand the functions of individual cells in normal and diseased states. However, use of single-cell biology/techniques is not a standalone effort and should be a part of methods used to advance biomedical research in other areas. Specifically, single-cell omics should be integrated into on-going GWAS/WGS programs such as the TOPMed, so genomic variants can be associated with cell types and cellular features—which is currently missing from any large scale GWAS data. Integration of single-cell omics data need to link cell type specific information to the genomic variants associated with known disease physiology, pathology and clinical measurements.
The meeting participants will develop a workshop report, highlighting the meeting’s main objectives and scientific opportunities identified. The report will be published in a peer-reviewed journal.
Weiniu Gan, Ph.D
Division of Lung Diseases
National Heart, Lung, and Blood Institute, NIH
WORKING GROUP PARTICIPANTS
- *G.R. Scott Budinger, MD, Northwestern University
- Thomas Croxton, MD PhD, NHLBI
- Weiniu Gan, PhD, NHLBI
- *Naftali Kaminski, MD, Yale
- Marrah Lachowicz-Scroggins, PhD, NHLBI
- Sara Lin, PhD, NHLBI
- Jining Lu, PhD, NHLBI
- Alexander Misharin, MD PhD, Northwestern University
- *Dana Pe’er, PhD, Memorial Sloane Kettering Cancer Center
- Pothur R. Srinivas, PhD, NHLBI
- Pankaj Qasba, PhD, NHLBI
- * Co-Chair
Presenters and Moderators, and Discussants
- Bruce J. Aronow, PhD, Cincinnati Children's Hospital
- Panagiotis (Takis) Benos, PhD, University of Pittsburgh Medical Center
- Mallar Bhattacharya, MD, University of California, San Francisco
- Jahar Bhattacharya MD, D. Phil., Columbia University
- Sunita Bhattacharya MD, Columbia University
- David M. Bodine, PhD, NHGRI
- G.R. Scott Budinger, MD, Northwestern University
- Zhen Chen, PhD, City of Hope
- Tushar Desai, MD, Stanford University
- Elizabeth Duong, MD, University of California San Diego
- Donna L. Farber, PhD, Columbia University
- Toren Finkel, MD, PhD, University of Pittsburgh Medical Center
- John Hogenesch, PhD, Cincinnati Children's Hospital
- Zhenqiu Huang, PhD, Albert Einstein College of Medicine
- Mohammad N. Islam, PhD, Columbia University
- Naftali Kaminski, MD, Yale School of Medicine
- Peter V. Kharchenko, PhD, Harvard University
- Robert Lafyatis, MD, University of Pittsburgh Medical Center
- Linas Mazutis, PhD, Memorial Sloane Kettering Cancer Center
- Alexander Misharin, MD, PhD, Northwestern University
- Ana L. Mora, MD, University of Pittsburgh Medical Center
- Martijn Nawijn, PhD, University of Groningen, Netherlands
- Dana Pe’er, PhD, Memorial Sloane Kettering Cancer Center
- Jayaraj Rajagopal, MD, Harvard Medical School
- Michael Rehman, PhD, Weill Cornell Medical College
- Mauricio Rojas, MD, University of Pittsburgh Medical Center
- Orit Rozenblatt-Rosen, PhD, Broad Institute
- Samir Rustam, MSc, Weill Cornell Medical College
- Vijay G. Sankaran, MD, PhD, Harvard University
- Rahul Satija, PhD, New York Genome Center
- Jonathan Seidman, PhD, Harvard Medical School
- Jonas Schupp, MD, Yale School of Medicine
- Renat Shaykhiev, MD, PhD, Weill Cornell Medical College
- Nikolai Slavov, PhD, Northeastern University
- David F. Smith, MD, PhD, Cincinnati Children's Hospital
- Simon D. Spivack, MD, MPH, Albert Einstein College of Medicine
- Thomas Stoeger, PhD, Northwestern University
- Xin Sun, PhD, University of California San Diego
- Jeff Whitsett, MD, Cincinnati Children's Hospital
- Yan Xu, PhD, Cincinnati Children's Hospital
- Peng Yin, PhD, Harvard University
NIH Staff Attendees
- Neil Aggarwal, MD, Division of Lung Diseases, NHLBI
- Richard Conroy, PhD, Common Fund Program, NIH
- Thomas Croxton, MD, PhD, Division of Lung Disease, NHLBI
- Rebecca Fuldner, PhD, Division of Aging Biology, NIA,
- Zorina Galis, PhD, Division of Cardiovascular Sciences, NHLBI
- Weiniu Gan, PhD, Division of Lung Disease, NHLBI
- Daniel Gossett, PhD, Division of Kidney, Urologic, and Hematologic Diseases, NIDDK
- Candace Kerr, PhD, Division of Aging Biology, NIA
- James Kiley, PhD, Division of Lung Diseases, NHLBI
- Marrah Lachowicz-Scroggins, PhD, Division of Lung Disease, NHLBI
- Sara Lin, PhD, Division of Lung Disease, NHLBI
- Jining Lu, PhD, Division of Lung Disease, NHLBI
- Pothur R. Srinivas, PhD, Division of Cardiovascular Sciences, NHLBI
- Pankaj Qasba, PhD, Division of Blood Diseases and Resources, NHLBI