1. WORKSHOP OVERVIEW & BACKGROUND

The “Synthetic Biology + NHLBI: Teaming Developers and Users” workshop convened virtually on November 4–5 & 8, 2024, bringing together researchers, clinicians, program officers, and industry stakeholders to explore how synthetic biology (SynBio) approaches can be applied to advance heart, lung, blood, and sleep (HLBS) science at the National Heart, Lung, and Blood Institute (NHLBI). For reference, the initial NHLBI Synthetic Biology Workshop in May 2022 defined SynBio as the design of natural or existing biological systems for specific purposes. The event was organized by a cross-division team at NHLBI, in collaboration with participating investigators from multiple academic institutions. The overarching goal was to foster new collaborations between those developing advanced synthetic biology tools and those conducting research or needing novel solutions for HLBS diseases.

NHLBI staff introduced the NIH/NHLBI mission and highlighted the planned “refresh” of the Institute’s strategic vision. They expressed the hope that workshop participants would help identify opportunities for interdisciplinary, next-generation solutions to the most pressing challenges in HLBS-related fields, ranging from organoid development to cell-based therapies and beyond. Over the course of two days, participants shared emerging research highlights, needs, and obstacles. The final day included closed-session discussions focused on matchmaking considerations, peer-review processes, funding mechanisms (including the NHLBI Catalyze program), and strategy-setting for future joint efforts.

2. MAIN THEMES & TOPICS

The workshop was planned to be in harmony with NHLBI’s current strategic plan and focused in the continuing opportunities for synthetic biologists and bioengineers to be synchronized with HLBS scientists and physicians. In particular, attendees explored emerging synthetic biology methods including CRISPR-based genetic circuits and advanced biomaterials and discussed their potential to address clinical and scientific bottlenecks in HLBS research.

Multidisciplinary Collaboration & Teaming
The workshop underscored a strong focus on bridging domain experts in HLBS areas of expertise with synthetic biology developers. The importance of forging partnerships that align fundamental tool creation with explicitly defined clinical needs was a recurring topic.

Application-Specific Opportunities
Discussions centered on how synthetic biology might offer targeted solutions within four primary HLBS domains:
1) Sleep & Circadian Biology
2) Blood Disorders & Therapeutics
3) Lung Development & Disease Modeling
4) Cardiovascular Health, Fibrosis, & Tissue Engineering

From Bench to Bedside: Translation & Scale-Up
Participants highlighted the complexities of manufacturing, regulatory approval, and commercial pathways for cell- and gene-based therapies. They emphasized the critical need for collaborative efforts to develop, share and standardize robust processes that facilitate large-scale or “scale-out” production, especially for cell therapies.

Funding & Infrastructure
The workshop provided details on how researchers can utilize the various NIH funding mechanisms (e.g., R01 mechanisms, NHLBI’s Catalyze Program, and SBIR/STTRs) and resources such as the NIH’s Center for Scientific Review (CSR), NHLBI’s Innovation and Commercialization Office and technology development programs. Discussions also addressed the importance of establishing biomedical manufacturing centers or foundries for automated DNA assembly, high-throughput screening, and advanced analytics.

3. KEY DISCUSSIONS & INSIGHTS

Synthetic Biology as a Unifying Framework
Speakers emphasized that synthetic biology merges ideas from molecular biology, engineering, and computational science. Key examples included the development of programmable promoter systems to drive phase-specific gene expression, potentially enabling chronotherapy interventions for sleep and circadian rhythm disorders; leveraging advanced gene editing tools to produce universal donor cells or to embed genetic circuits controlling cell fate; and delivering more targeted cell-based interventions for HLBS diseases. The presentations and discussions included the following topics:

Sleep & Circadian Biology
Presenters noted that while circadian clock research is well established, knowledge gaps persist in how some aspects of sleep homeostasis can be monitored or manipulated at a molecular level. Examples of synthetic promoters synchronized with the circadian cycle were proposed for gene expression “windows,” enabling time-specific therapies (e.g., administering drugs in synergy with circadian phase) and hold promise for better mechanistic understanding and eventual therapeutic development.

Blood & Hematopoiesis
Participants described efforts to engineer hematopoietic stem cells (HSCs) for universal donor lines, manufacture platelets in vitro, and produce cell-based therapies with minimal immunologic risk. Biosensors for disease monitoring—particularly in rare blood disorders—were discussed, along with the potential for advanced gene regulatory tools to address immunomodulation (e.g., controlling graft-versus-host scenarios).

Lung Biology & Disease Modeling
The complexity of lung architecture, with over 50 cell types and a vast alveolar surface area, poses unique challenges for tissue engineering. Experts highlighted new directions for organoid modeling and high-throughput single-cell omics analysis. Proposed synthetic biology innovations included 3D patterning with morphogen signals, dynamic regulation of organoid spatial organization, and advanced scaffolds to replicate lung biomechanics.

Cardiovascular Opportunities
Cardiovascular disease is multifaceted, requiring interventions targeting myocardium, vasculature, immunological responses, and more. Potential advances include engineering fibroblasts to either limit pathological fibrosis or promote beneficial tissue remodeling, building advanced cell therapies for cardiac repair, and developing sensors or “switches” that modulate immune or inflammatory signals in sync with myocardial regeneration.

Cross-Cutting Themes: Biosensors, Real-Time Monitoring, & Cell Fate Control
Many speakers emphasized real-time biosensors for monitoring cell state and tissue health. Also, building robust synthetic circuits that can track environmental cues, maintain stable expression for months, or respond to physiologic triggers was deemed a game-changer. The need for non-invasive imaging or readouts was frequently mentioned, especially in the context of human studies.

Manufacturing at Scale & Regulatory Considerations
NIH and private sector drug development experts underlined the importance of regulatory compliance at every stage, from concept to post-market surveillance. The panelists urged investigators to incorporate good manufacturing practices (GMP) during early development and to consider cost effectiveness, scalability, and stakeholder acceptance to ensure equitable patient access. There were calls for establishing synthetic biology “foundries” that mirror the manufacturing infrastructure of the pharmaceutical industry, potentially accelerating progress.

Ethical & Social Dimensions
Participants noted that new genetic technologies can face scrutiny and distrust if public engagement is insufficient. They advocated for transparent communication of synthetic biology’s goals, processes, and safety measures, particularly when introducing genetically modified cells into human subjects.

4. CHALLENGES & OPPORTUNITIES

Workshop attendees identified several challenges and opportunities for NHLBI during the course of presentations and open discussion periods.

• Foster Interdisciplinary Collaborations & Networks
  • Encouraging partnerships by hosting regular “matchmaking” events were suggested to bring together basic scientists, clinicians, engineers, and synthetic biologists. These events can materialize as dedicated sessions at scientific conferences, regular networking calls, or themed special interest groups.
  • Exploring cross-agency collaborations with the National Science Foundation (NSF) and the Department of Defense (DoD), were suggested as means to leverage existing synthetic biology and cell manufacturing infrastructure.
• Advance Foundational Tool Development
  • Developing universal donor cell lines will help prioritize initiatives that create off-the-shelf induced pluripotent stem cell (iPSC) or hematopoietic stem cell (HSC) lines engineered to avoid immune rejection, with embedded safety switches for controlled elimination.
  • Improving biosensors and circuit stability will permit Investment in research on stable, multiplexed genetic recorders capable of capturing spatiotemporal cell behavior over long durations (e.g., months).
  • Balancing a translational focus with mechanistic investigations ensures real-time gene circuits function robustly in complex physiological contexts (e.g., dynamic mechanical forces, immune interactions).
• Enhance Training & Workforce Development
  • Support of interdisciplinary programs with a focus on training scientists in both synthetic biology and HLBS fields and thus, will enable new, hybrid skill sets and collaboration readiness.
  • Expansion of mentorship programs will strengthen the next generation of HLBS-SynBio researchers.
• Address Manufacturing & Regulatory Pathways
  • Encouraging early incorporation of good manufacturing practices (GMP) standards, advanced biofabrication methods, and software AI coupled with sensors integrated into QA/QC processes will streamline current scalability issues.
  • Developing methods to “scale out” in modular formats will be particularly useful for personalized therapies.
  • NHLBI’s Catalyze Program was highlighted as a key resource for bridging basic science discoveries and commercial readiness. Investigators should consult program officers early to align proposals with translational milestones.
• Create Focused Grand Challenges
  • Well-defined priorities—such as myocardial infarction, pulmonary fibrosis, or platelet manufacturing— will concentrate research efforts and enable progress.
  • Small seed grants or challenge rounds can incentivize progress toward shared objectives (e.g., iterative gene circuit design contests for HLBS applications).

5. CONCLUSION & SUMMARY

Across the workshop, a clear theme emerged: synthetic biology will advance HLBS most effectively when tool development is anchored to concrete clinical and research needs. Participants acknowledged substantial overlap with tissue engineering, cell therapy, and CRISPR-based editing, but emphasized that synthetic biology is more than the sum of these parts. Synthetic biology is best thought of as a unifying engineering framework that integrates molecular biology, computational modeling, and systems design to create programmable, modular, and scalable functions not found in nature. Combining precise gene editing with the complexities of cardiovascular, pulmonary, hematologic, and sleep biology opens rich opportunities. Examples include programmable promoters for phase‑specific expression, genetic circuits that control cell fate, and strategies to engineer universal donor cells that go beyond current therapeutic paradigms. Realizing this potential will require systematic, methodical, and collaborative work; panel discussions, Q&A sessions, and fireside chats with regulatory and industry experts underscored the need to pair scientific innovation with patient‑centered design, robust manufacturing pipelines, and early regulatory planning.

Within NHLBI’s HLBS mission, the group outlined application-focused opportunities in sleep & circadian biology, blood disorders & therapeutics, lung development & disease modeling, and cardiovascular health/fibrosis/tissue engineering. The common thread was aligning advanced tools (e.g., gene circuits, smart biomaterials) with clearly defined biological and clinical needs to accelerate translation. This complements the workshop’s original synthesis that marrying precise gene-editing with the complexity of cardiovascular, pulmonary, hematologic, and sleep biology reveals exciting but methodical routes to impact.

Participants identified several challenges and opportunities unique to synthetic biology. Chief among them were maintaining circuit stability and robustness over clinically relevant timescales and linking molecular-level designs to tissue- and organ-level complexity, including the biomechanical and immune contexts in which circuits must function. The group prioritized developing long-duration, multiplexed recorders and biosensors, ensuring circuits remain stable in dynamic physiological environments, and creating noninvasive readouts suitable for human studies. The lung’s complex architecture was highlighted as a demanding yet informative testbed for multiscale design.

For clinical translation, participants emphasized integrating manufacturing and regulatory planning from the outset. They recommended incorporating Good Manufacturing Practice (GMP) into discovery‑stage workflows, developing scale‑out processes for personalized therapies, and using foundry‑like infrastructure for automated DNA assembly, high‑throughput screening, and analytics to shorten the path from proof‑of‑concept to equitable patient access.

Ultimately, progress will depend not only technical advances but also strong multi‑PI collaborations. The community expressed enthusiasm for concrete next steps. Specifically, participants called for pilot studies and grant applications that embed synthetic biology in high‑priority HLBS problems and continued development of robust human-based model systems, manufacturing pipelines, and early regulatory strategies. Together, these efforts and the momentum from the inaugural “Synthetic Biology + NHLBI” workshop establish a strong foundation for subsequent demonstrations and scale‑up toward novel diagnostics and therapeutics.

The findings, knowledge gaps, and opportunities described here represent a summary of individual opinions and ideas expressed during the workshop. The summary does not represent a consensus opinion or directive made to or by NHLBI or NIH.

PUBLICATION

Integrating synthetic biology to understand and engineer the heart, lung, blood, and sleep systems.
Elliot L. Chaikof, Jichao Chen, Martha U. Gillette, Laurie A. Boyer, Tara L. Deans, Pulin Li, Isaac B. Hilton, Kyle Daniels, Yogesh Goyal, Ying Mei, Changyang Linghu, Theresa B. Loveless, David M. Truong, Michael R. Blatchley, Mingxia Gu, Caleb J. Bashor, Jason H. Yang, Ritu Raman, Akhilesh B. Reddy, Krishanu Saha, Jennifer Davis, Kalpna Gupta, Xiaojing J. Gao, Kate E. Galloway
Cell Systems, Volume 16, Issue 12, 2025, 101446, ISSN 2405-4712, https://doi.org/10.1016/j.cels.2025.101446

Workshop Roster in Order Listed in Workshop Agenda
Workshop Co-Chairs
Katie Galloway, Ph.D., MS
W.M. Keck Career Development Professor in Biomedical Engineering and Chemical Engineering at Massachusetts Institute of Technology

Xiaojing Gao, Ph.D.
Assistant Professor of Chemical Engineering, Terman Faculty Fellow, Faculty Fellow Stanford ChEM-H, Stanford University

Workshop Speakers
Michelle Olive, PhD
NHLBI Division of Cardiovascular Sciences, Basic and Early Translational Research Program, Associate Director

Martha Gillette, PhD, MS
Chan-Zuckerberg Biohub, Investigator; University of Illinois Urbana-Champaign, Alumni Professor

Elliot Chaikof, MD, PhD
Beth Israel Deaconess Medical Center, Surgeon-in-Chief; Harvard Medical School, Professor

Jichao Chen, PhD, MHS
University of Cincinnati, Professor; UC Division of Pulmonary Biology, Director

Laurie Boyer, PhD
Massachusetts Institute of Technology (MIT), Professor

Isaac Hilton, PhD
Rice University, Associate Professor

Mingxia Gu, MD, PhD, FAHA
Cincinnati Children’s Hospital Medical Center, Assistant Professor

Kalpna Gupta, PhD
University of California, Professor

Akhilesh Reddy, PhD, MA, MB BChir
University of Pennsylvania, Associate Professor

Michael Blatchley, PhD
Syracuse University, Assistant Professor

Changyan Linghu, PhD
University of Michigan Neuroscience Institute, Assistant Professor

Kareen Coulombe, PhD
Brown University, Associate Professor

Ying Mei, PhD
Clemson University, McQueen Quattlebaum Professor of Bioengineering

Caleb Bashor, PhD
Rice University, Assistant Professor

Pranam Chatterjee, PhD, MS
Duke University, Assistant Professor

Anja Karlstaedt, MD, PhD
Smidt Heart Institute at Cedars-Sinai Medical Center, Assistant Professor

Timothy McKinsey, PhD
University of Colorado Anschutz Medical Campus, Professor; University of Colorado Consortium for Fibrosis Research and Translation, Associate Division Head

Tara Deans, PhD
Emory University and Georgia Institute of Technology, Associate Professor

Jared Toettcher, PhD
Princeton University, Associate Professor

Pulin Li, PhD
Massachusetts Institute of Technology, Professor; Whitehead Institute for Biomedical Research, Researcher

Wilson W. Wong, PhD
Boston University, Associate Professor

Leonardo Morsut, PhD
University of Southern California, Assistant Professor

Theresa Berens Loveless, PhD
Rice University, Assistant Professor

Yogesh Goyal, PhD
Northwestern University, Assistant Professor

Rogelio Hernández-López, PhD
Stanford University, Assistant Professor

David Truong, PhD
NYU Tandon School of Engineering, Assistant Professor

Kris Saha, PhD, MPhil, BS
University of Wisconsin-Madison, Associate Professor

Jermont Chen, PhD, MS
National Institute of Biomedical Imaging and Bioengineering, Program Officer

Sita Somara, PhD, MBA
Qura Therapeutics and Atelerix Life Science, Director

Leah Miller, PhD, MBA
NHLBI Office of Workforce Development and Support, Director

Ritu Raman, PhD
Massachusetts Institute of Technology, Eugene Bell Assistant Professor

Jason Yang, PhD
Rutgers New Jersey Medical School, Assistant Professor and Chancellor Scholar

Manu Platt, PhD
NIH Biomedical Engineering Technology Acceleration (BETA) Center, Director

Tatiana Cohen, PhD
NIH Center for Scientific Review

Jennifer Davis, PhD, MA
University of Washington, Assistant Professor; UW Center for Cardiovascular Biology, Director; UW Institute for Stem Cell and Regenerative Medicine (ISCRM), Interim Director

Charles Joyce, PhD
NHLBI Division of Extramural Research Activities-Office of Scientific Review, Director

NHLBI Planning Committee:
Bishow Adhikari, Ph.D.
Program Director, Heart Failure and Arrhythmias Branch, Division of Cardiovascular Sciences

Nitin Agrawal, Ph.D.
Program Director, Molecular Cellular and Systems Blood Science, Division of Blood Diseases and Resources

Shilpy Dixit, Ph.D.
Program Director, Prevention and Sleep Health, National Center on Sleep Disorders Research

Allison Gillaspy, Ph.D.
Branch Chief, Molecular Cellular and Systems Blood Science, Division of Blood Diseases and Resources

Marrah Lachowicz-Scroggins, MFS, GCCP, Ph.D.
Branch Chief, Lung Development and Pediatric Diseases Branch, Division of Lung Diseases

Sara Lin, Ph.D.
Program Director, Lung Development and Pediatric Diseases Branch, Division of Lung Diseases

Charlene Schramm, Ph.D.
Program Director, Heart Development and Structural Diseases Branch, Division of Cardiovascular Sciences

Sidd Shenoy, Ph.D.
Program Director, Digital Health and Informatics Technologies Program, Division of Lung Diseases

Rahul Thakar, Ph.D.
Program Director, Advanced Technologies and Surgery Branch, Division of Cardiovascular Sciences (Planning Committee Lead)