Single-Cell Omics - A New Frontier in the Research of Heart, Lung, and Blood Diseases and Sleep Disorders

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

1. 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.

2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.

Publication Plans

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.

NHLBI Contact

Weiniu Gan, Ph.D
Division of Lung Diseases
National Heart, Lung, and Blood Institute, NIH

WORKING GROUP PARTICIPANTS

Organizing Committee

• *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

1. Bruce J. Aronow, PhD, Cincinnati Children's Hospital
2. Panagiotis (Takis) Benos, PhD, University of Pittsburgh Medical Center
3. Mallar Bhattacharya, MD, University of California, San Francisco
4. Jahar Bhattacharya MD, D. Phil., Columbia University
5. Sunita Bhattacharya MD, Columbia University
6. David M. Bodine, PhD, NHGRI
7. G.R. Scott Budinger, MD, Northwestern University
8. Zhen Chen, PhD, City of Hope
9. Tushar Desai, MD, Stanford University
10. Elizabeth Duong, MD, University of California San Diego
11. Donna L. Farber, PhD, Columbia University
12. Toren Finkel, MD, PhD, University of Pittsburgh Medical Center
13. John Hogenesch, PhD, Cincinnati Children's Hospital
14. Zhenqiu Huang, PhD, Albert Einstein College of Medicine
15. Mohammad N. Islam, PhD, Columbia University
16. Naftali Kaminski, MD, Yale School of Medicine
17. Peter V. Kharchenko, PhD, Harvard University
18. Robert Lafyatis, MD, University of Pittsburgh Medical Center
19. Linas Mazutis, PhD, Memorial Sloane Kettering Cancer Center
20. Alexander Misharin, MD, PhD, Northwestern University
21. Ana L. Mora, MD, University of Pittsburgh Medical Center
22. Martijn Nawijn, PhD, University of Groningen, Netherlands
23. Dana Pe’er, PhD, Memorial Sloane Kettering Cancer Center
24. Jayaraj Rajagopal, MD, Harvard Medical School
25. Michael Rehman, PhD, Weill Cornell Medical College
26. Mauricio Rojas, MD, University of Pittsburgh Medical Center
27. Orit Rozenblatt-Rosen, PhD, Broad Institute
28. Samir Rustam, MSc, Weill Cornell Medical College
29. Vijay G. Sankaran, MD, PhD, Harvard University
30. Rahul Satija, PhD, New York Genome Center
31. Jonathan Seidman, PhD, Harvard Medical School
32. Jonas Schupp, MD, Yale School of Medicine
33. Renat Shaykhiev, MD, PhD, Weill Cornell Medical College
34. Nikolai Slavov, PhD, Northeastern University
35. David F. Smith, MD, PhD, Cincinnati Children's Hospital
36. Simon D. Spivack, MD, MPH, Albert Einstein College of Medicine
37. Thomas Stoeger, PhD, Northwestern University
38. Xin Sun, PhD, University of California San Diego
39. Jeff Whitsett, MD, Cincinnati Children's Hospital
40. Yan Xu, PhD, Cincinnati Children's Hospital
41. Peng Yin, PhD, Harvard University

NIH Staff Attendees

42. Neil Aggarwal, MD, Division of Lung Diseases, NHLBI
43. Richard Conroy, PhD, Common Fund Program, NIH
44. Thomas Croxton, MD, PhD, Division of Lung Disease, NHLBI
45. Rebecca Fuldner, PhD, Division of Aging Biology, NIA,
46. Zorina Galis, PhD, Division of Cardiovascular Sciences, NHLBI
47. Weiniu Gan, PhD, Division of Lung Disease, NHLBI
48. Daniel Gossett, PhD, Division of Kidney, Urologic, and Hematologic Diseases, NIDDK
49. Candace Kerr, PhD, Division of Aging Biology, NIA
50. James Kiley, PhD, Division of Lung Diseases, NHLBI
51. Marrah Lachowicz-Scroggins, PhD, Division of Lung Disease, NHLBI
52. Sara Lin, PhD, Division of Lung Disease, NHLBI
53. Jining Lu, PhD, Division of Lung Disease, NHLBI
54. Pothur R. Srinivas, PhD, Division of Cardiovascular Sciences, NHLBI
55. Pankaj Qasba, PhD, Division of Blood Diseases and Resources, NHLBI