Applying Systems
Thinking to
Regenerative Medicine

PROCEEDINGS OF A WORKSHOP

Siobhan Addie, Meredith Hackmann, Lydia Teferra,
Anna Nicholson, and Sarah H. Beachy, Rapporteurs

Forum on Regenerative Medicine

Board on Health Sciences Policy

Health and Medicine Division

THE NATIONAL ACADEMIES PRESS
Washington, DC
www.nap.edu

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This activity was supported by contracts between the National Academy of Sciences and Advanced Regenerative Manufacturing Institute; Akron Biotech; Alliance for Regenerative Medicine; American Society of Gene & Cell Therapy; Burroughs Wellcome Fund (Grant No. 1021433); California Institute for Regenerative Medicine; Centre for Commercialization of Regenerative Medicine; Department of Veterans Affairs (Contract No. VA26816C0051P00004); Food and Drug Administration: Office of the Commissioner and Center for Biologics Evaluation and Research (Grant No. 1R13FD006614-02); International Society for Cellular Therapy; International Society for Stem Cell Research; Johnson & Johnson; The Michael J. Fox Foundation for Parkinson’s Research; National Institute of Standards and Technology; National Institutes of Health (Contract No. HHSN263201800029I; Order No. 75N98019F00847): National Center for Advancing Translational Sciences; National Eye Institute; National Heart, Lung, and Blood Institute; National Institute of Biomedical Imaging and Bioengineering; National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Neurological Disorders and Stroke; National Institute on Aging; The New York Stem Cell Foundation; and Sanofi (Contract No. 55630791). Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project.

International Standard Book Number-13: 978-0-309-15182-5
International Standard Book Number-10: 0-309-15182-1
Digital Object Identifier: https://doi.org/10.17226/26025

Additional copies of this publication are available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu.

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Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2021. Applying systems thinking to regenerative medicine: Proceedings of a workshop. Washington, DC: The National Academies Press. https://doi.org/10.17226/26025.

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PLANNING COMMITTEE ON APPLYING SYSTEMS THINKING TO REGENERATIVE MEDICINE¹

ANNE PLANT (Co-Chair), Fellow, National Institute of Standards and Technology

KRISHNENDU ROY (Co-Chair), Robert A. Milton Chair and Professor; Technical Lead, National Cell Manufacturing Consortium, Georgia Institute of Technology

TOM BOLLENBACH, Chief Technology Officer, Advanced Regenerative Manufacturing Institute

JAMIE HAMILTON, (former) Senior Associate Director, Research Programs, The Michael J. Fox Foundation for Parkinson’s Research

DEBORAH HOSHIZAKI, Program Director, Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health

SADIK KASSIM, Chief Technology Officer, Vor Biopharma

MALCOM MOOS, Medical Officer and Senior Investigator, Center for Biologics Evaluation and Research, Food and Drug Administration

PHIL VANEK, Partner, Gamma Biosciences

CLAUDIA ZYLBERBERG, Chief Executive Officer, Akron Biotech

Forum on Regenerative Medicine Staff

SARAH H. BEACHY, Senior Program Officer and Forum Director

SIOBHAN ADDIE, Program Officer

MEREDITH HACKMANN, Associate Program Officer

LYDIA TEFERRA, Research Assistant

Board on Health Sciences Policy Staff

BRIDGET BOREL, Program Coordinator

ANDREW M. POPE, Senior Board Director

___________________

¹ The National Academies of Sciences, Engineering, and Medicine’s planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution.

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FORUM ON REGENERATIVE MEDICINE¹

TIM COETZEE (Co-Chair), Chief Advocacy, Services, and Science Officer, National Multiple Sclerosis Society

KATHERINE TSOKAS (Co-Chair), Vice President, Regulatory, Quality, Risk Management and Drug Safety, Janssen Inc. Canada

SANGEETA BHATIA, John J. and Dorothy Wilson Professor, Institute for Medical Engineering and Science, Electrical Engineering and Computer Science, Massachusetts Institute of Technology

PHILIP JOHN BROOKS, Program Director, Office of Rare Disease Research, National Center for Advancing Translational Sciences, National Institutes of Health

GEORGE Q. DALEY, Director, Stem Cell Transplantation Program, Boston Children’s Hospital and Dana-Farber Cancer Institute; Dean, Harvard Medical School

BRIAN FISKE, Senior Vice President, Research Programs, The Michael J. Fox Foundation for Parkinson’s Research

LAWRENCE GOLDSTEIN, Distinguished Professor, Department of Cellular and Molecular Medicine, Department of Neurosciences; Director, University of California, San Diego, Stem Cell Program; Scientific Director, Sanford Consortium for Regenerative Medicine; Director, Sanford Stem Cell Clinical Center, University of California, San Diego, School of Medicine

CANDACE KERR, Program Officer, Stem Cell Program, Aging Physiology Branch Division of Aging Biology, National Institute on Aging, National Institutes of Health

ROBERT S. LANGER, David H. Koch Institute Professor, Massachusetts Institute of Technology

CATO T. LAURENCIN, University Professor, Albert and Wilda Van Dusen Distinguished Professor of Orthopaedic Surgery, Professor of Chemical, Materials Science, and Biomedical Engineering; Director, The Raymond and Beverly Sackler Center for Biomedical, Biological, Physical, and Engineering Sciences; Chief Executive Officer, Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut

TERRY MAGNUSON, Sarah Graham Kenan Professor, Vice Chancellor for Research, University of North Carolina at Chapel Hill

MICHAEL MAY, President and Chief Executive Officer, Centre for Commercialization of Regenerative Medicine

___________________

¹ The National Academies of Sciences, Engineering, and Medicine’s forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution.

RICHARD McFARLAND, Chief Regulatory Officer, Advanced Regenerative Manufacturing Institute

JACK MOSHER, Senior Manager, Scientific Affairs, International Society for Stem Cell Research

DAVID OWENS, Acting Deputy Director, Division of Extramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health

AMY PATTERSON, Chief Science Advisor and Director of Scientific Research Programs, National Heart, Lung, and Blood Institute, National Institutes of Health

DUANQING PEI, Director General, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences

ANNE PLANT, Chief of the Biosystems and Biomaterials Division, National Institute of Standards and Technology

KIMBERLEE POTTER, Scientific Program Manager, Biomedical Laboratory R&D Service, Office of Research and Development, Department of Veterans Affairs

DAVID RAMPULLA, Director, Division of Discovery Science and Technology (Bioengineering), Delivery Systems and Devices for Drugs and Biologics Synthetic Biological Systems, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health

DEREK ROBERTSON, Co-Founder and President, Maryland Sickle Cell Disease Association

KELLY ROSE, Program Officer, Burroughs Wellcome Fund

KRISHNENDU ROY, Robert A. Milton Chair and Professor in Biomedical Engineering; Technical Lead, National Cell Manufacturing Consortium; Director, Marcus Center for Therapeutic Cell Characterization and Manufacturing, Georgia Institute of Technology

KRISHANU SAHA, Associate Professor and Retina Research Foundation Kathryn and Latimer Murfee Chair, Department of Biomedical Engineering, University of Wisconsin–Madison

RACHEL SALZMAN, Society Officer, American Society of Gene & Cell Therapy

IVONNE SCHULMAN, Program Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health

JAY P. SIEGEL, (retired) Chief Biotechnology Officer and Head, Scientific Strategy and Policy, Johnson & Johnson

LANA SKIRBOLL, Vice President, Science Policy, Sanofi

SUSAN L. SOLOMAN, Founder and Chief Executive Officer, The New York Stem Cell Foundation

MARTHA SOMERMAN, (former) Director, National Institute of Dental and Craniofacial Research, National Institutes of Health

MICHAEL STEINMETZ, Director, Division of Extramural Science Programs, National Eye Institute, National Institutes of Health

SOHEL TALIB, Associate Director of Therapeutics and Industry Alliance, California Institute for Regenerative Medicine

DANIEL WEISS, Chief Scientific Officer, International Society for Cellular Therapy

MICHAEL WERNER, Co-Founder and Senior Policy Counsel, Alliance for Regenerative Medicine

CELIA WITTEN, Deputy Director, Center for Biologics Evaluation and Research, Food and Drug Administration

CLAUDIA ZYLBERBERG, Founder and Chief Executive Officer, Akron Biotech

Forum on Regenerative Medicine Staff

SARAH H. BEACHY, Senior Program Officer and Forum Director

SIOBHAN ADDIE, Program Officer

MEREDITH HACKMANN, Associate Program Officer

LYDIA TEFERRA, Research Assistant

Board on Health Sciences Policy Staff

BRIDGET BOREL, Program Coordinator

ANDREW M. POPE, Senior Board Director

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Reviewers

This Proceedings of a Workshop was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published proceedings as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the charge. The review comments and draft manuscript remain confidential to protect the integrity of the process.

We thank the following individuals for their review of this proceedings:

Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the content of the proceedings nor did they see the final draft before its release. The review of this proceedings was overseen by LINDA DEGUTIS, Henry M. Jackson Foundation for the Advancement of Military Medicine. She was responsible for making certain that an independent examination of this proceedings was carried out in accordance with standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the rapporteurs and the National Academies.

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Acknowledgments

The support of the sponsors of the Forum on Regenerative Medicine was crucial to the planning and conduct of the workshop Applying Systems Thinking to Regenerative Medicine and for the development of this Proceedings of a Workshop. Federal sponsors were the Department of Veterans Affairs; Food and Drug Administration: Office of the Commissioner and Center for Biologics Evaluation and Research; National Institute of Standards and Technology; and National Institutes of Health: National Center for Advancing Translational Sciences; National Eye Institute; National Heart, Lung, and Blood Institute; National Institute of Biomedical Imaging and Bioengineering; National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Neurological Disorders and Stroke; and National Institute on Aging. Nonfederal sponsorship was provided by Advanced Regenerative Manufacturing Institute; Akron Biotech; Alliance for Regenerative Medicine; American Society of Gene & Cell Therapy; Burroughs Wellcome Fund; California Institute for Regenerative Medicine; Centre for Commercialization of Regenerative Medicine; International Society for Cellular Therapy; International Society for Stem Cell Research; Johnson & Johnson; The Michael J. Fox Foundation for Parkinson’s Research; The New York Stem Cell Foundation; and Sanofi.

The Forum on Regenerative Medicine wishes to express gratitude to the expert speakers who explored how cross-disciplinary systems thinking

approaches can support the development of safe and effective regenerative medicine therapies. The forum also wishes to thank the members of the planning committee for their work in developing an excellent workshop agenda. The project director would like to thank the project staff who worked diligently to develop both the workshop and the resulting Proceedings of a Workshop.

Contents

ACRONYMS AND ABBREVIATIONS

1 INTRODUCTION

Organization of the Proceedings

2 INTRODUCTION TO SYSTEMS THINKING CONCEPTS

An Introduction to Systems Thinking

Applying Systems Thinking to the Development of Regenerative Medicines

Systems Dynamics of Cell-State Transitions: Relevance for Regenerative Medicine

Discussion

3 EXPLORING THE CHALLENGES OF CRITICAL QUALITY ATTRIBUTES: THE ROLE OF SYSTEMS THINKING

Systems Thinking and the Regulation of Regenerative Medicine Products

Using Systems Thinking Approaches for Cell Therapy Product Development

Discussion

4 CHALLENGES ASSOCIATED WITH DATA COLLECTION, AGGREGATION, AND SHARING

Toward Open Science in Omics Analysis and Disease Modeling

Using Big Data for Clinical Stratification of Patients

Discussion

5 CHALLENGES AND OPPORTUNITIES ASSOCIATED WITH SYSTEMS-LEVEL ANALYSIS AND MODELING

Developing Algorithms for Single-Cell Genomics

Modeling Dynamic Data to Identify a Latent Space

Adopting Metabolic Modeling Tools in Biopharmaceutical Drug Development

Discussion

6 ADDRESSING REGENERATIVE MEDICINE MANUFACTURING AND SUPPLY CHAIN CHALLENGES WITH SYSTEMS-LEVEL APPROACHES

Artificial Intelligence in Cell and Gene Therapies

Modeling the Manufacturing Process in Regenerative Medicine

Novel Supply Chain and Cost Modeling for Cell Therapies

Discussion

7 EXPLORING ISSUES OF WORKFORCE DEVELOPMENT RELATED TO SYSTEMS THINKING

Education and Workforce Development to Advance Systems Thinking

Reflections on the Workshop

Final Words on Models and Data

REFERENCES

APPENDIXES

A WORKSHOP AGENDA

B SPEAKER BIOGRAPHICAL SKETCHES

C STATEMENT OF TASK

Boxes, Figures, and Tables

BOXES

1-1 Workshop Statement of Task

6-1 Grand Challenges in Cell Manufacturing

6-2 Questions to Consider in Determining Analysis Objectives

FIGURES

1-1 Cell therapy: interaction of multi-scale dynamic complex systems

1-2 A systems approach to inform the regenerative medicine field

2-1 Fruit fly early development: from maternal inputs to larva

3-1 Process of cell therapy development as a system

6-1 Complexity of regenerative medicine supply chain ecosystem

TABLES

4-1 Use Cases for Real-World Data

6-1 Factors Influencing Each Stage in the Development of Autologous Cell Therapies

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Acronyms and Abbreviations