Synthetic Biology and New Directions for HLBS Application Virtual Workshop

Synthetic biology (or engineering biology) is the designing and construction of new biological processes and systems and the redesigning of existing and natural biological systems for a specific purpose. To improve the reach and impact of synthetic biology on human health, the National Heart, Lung, and Blood Institute (NHLBI) convened a virtual workshop on May 10–11, 2022. The workshop aimed to evaluate the promise of the emerging field of synthetic biology in advancing HLBS research and clinical applications. Workshop experts—who included synthetic biologists, computational scientists, cell biologists, engineers, geneticists, developmental biologists, and physician-scientists—discussed research findings, challenges, gaps, and opportunities. Plenary sessions covered research in four areas: (1) network and systems biology, (2) cellular tools and applications, (3) bioengineered circuits, and (4) regenerative medicine. Bioethical considerations related to synthetic biology were presented, with an emphasis on the need to assess potential harms and benefits to individuals participating in research. In a roundtable discussion on translation, synthetic biologists with industry experience discussed the tools and capabilities that might advance the field, possible goals not currently addressed, and intersections with HLBS applications. Workshop experts also participated in breakout groups focused on identifying potential HLBS research areas where synthetic biology could have the largest impact. Several discussion themes emerged from the workshop.

Synthetic Biology Tools and Technologies with Potential HLBS Applications

• Engineered tissues and organoids—quantitative tools for comparing microscopy-based data to models, agent-based modeling platforms, molecular and computational-aided design tools, and artificial genetic multicellular circuits.

• Therapeutic platform technologies—chimeric antigen receptor T cells (CAR T cells) equipped with gene circuits to enhance their safety and efficacy (e.g., split, universal, and programmable [SUPRA] CAR cells; CAR T cells targeting cardiac fibrosis; drug-regulatable CAR T cells; and an mRNA/lipid nanoparticle platform for CAR T cells).

• Cell identity, cell fate, and reprogramming—computational approaches (e.g., Capybara) to measure cell identity in bulk; CellTag–ATAC–RNA, a multi-omic method that allows parallel capture of chromatin accessibility, transcriptome and cell lineage information; and cell fate engineering systems.

• Optogenetic and molecular imaging tools—a new probe that is light- and temperature-sensitive (with separate tuning); chemical exchange saturation transfer magnetic resonance imaging (CEST MRI); and molecular contrast agents that can be used to image reporter genes and to measure the outcomes of cell therapy in small animals.

• Biosensors—electronic sensors made of two-dimensional materials (substances with a thickness of only a few nanometers or less) for wearable or implantable devices; engineered cell-sensing devices; new approaches for sensing RNA in living cells; and new approaches to characterizing kinome architecture.  

• Bioengineered gene circuits—engineered humanized transcription regulators based on genome-orthogonal zinc fingers (synZiFTRs), transcriptional factors, and logic gates; cell-based devices with a sensor, processor, and actuator; harnessing the process of transcription via supercoiling-mediated feedback; and epigenomic editing with CRISPR/Cas9 to change gene regulation with high precision.

Challenges and Research Opportunities

• A better understanding of basic biology is needed in key areas—such as developmental biology (particularly how the body exerts molecular control and the factors that influence differentiation into specific cell types) and immunology and immune cells.

• Tools, technology, and measurement require improvement. For example, engineered gene circuits should have built-in tools to reduce the metabolic burden on chassis cells. Other areas for improvement include methods for storing in vitro assays and designing genetic circuits and predicting outcomes with high throughput. Noninvasive and quantitative measures of the results of gene editing are needed.

• Scaling up and improving the manufacturing of DNA, proteins, and other biological products is a significant challenge that must be addressed. An overarching issue is that currently such efforts are left to industry (methods are proprietary) with no federal support to academic investigators for such efforts.

• The field is also impeded by limited access to HLBS-relevant human tissues and publicly available large data sets. Additionally, disease models are limited (e.g., for use at scale), and there is a gap between human data and animal systems.

• Experts emphasized that the field would benefit from formal mechanisms that support partnerships and links among synthetic biologists, basic scientists, and clinical experts in disease models. A common pedagogy among academic institutions for training the next generation of synthetic biologists would be helpful.

Bioethical Considerations

When defining the risk–benefit ratio of studies, researchers need to consult diverse stakeholders—including underrepresented and underserved populations—and interdisciplinary experts. To eliminate mistrust of genetic research among underrepresented and underserved communities, investigators need to engage them in developing research questions and designing studies in a way that addresses benefits. Researchers should work with offices of community engagement in clinical research and seek research ethics consultation services to receive assistance with the broader interdisciplinary review of a study at the stage of research design.

Opportunities to Advance the Field

Although the tools, approaches, and concepts of synthetic biology are not unique to NHLBI, they are currently underutilized in HLBS disease research and their potential to advance HLBS research remains largely unexplored.

Research opportunities: To advance the field, it is important to support two distinct but synergistic opportunities: (1) promoting the application of synthetic biology tools and approaches to understand fundamental biology, and (2) applying synthetic biology to generate therapeutics, diagnostics, and their combination: theragnostics. Synthetic biology tools have the potential to accelerate the development of many other tools and more accurate in vitro and in vivo models. In the area of advancing basic biology research, it will be important to focus on the application of synthetic biology to cell engineering (e.g., in the heart and blood) and understanding disease mechanisms by enabling the incorporation of detailed information learned about cells. Synthetic biology tools and approaches allow hypothesis-free exploration of biological systems which has the potential to lead to new discoveries.

Modeling offers opportunities to expand predictive power. For example, agent-based modeling platforms can be used to design new multicellular systems (e.g., organoids) or interrogate special features of naturally occurring ones (e.g., tumor architecture). This allows researchers to control the emergence of spatial behaviors in a desired time and study how sequences of patterns emerge. Additionally, datasets with temporal data offer researchers the opportunity to study systems dynamics at scale.

Synthetic biology approaches have the potential to lead to significant advances in our understanding of basic biological processes in several key areas. These include the immune system (particularly how it senses disease and how it can be manipulated to affect therapeutics), engineering the human vasculature, the role of the microbiome in HLBS-related health and diseases, pathways affected by sleep deprivation and possible links with HLBS conditions, and transcription factors that maintain cell type. Blood may be used as a model to study diverse systems (e.g., differentiation, plasticity, and distributed functions) and engineer novel cell-based therapies.

Opportunities to improve communication among synthetic biologists and other experts: NHLBI has an opportunity to spur communication and possible collaboration among synthetic biologists, basic scientists, and clinical experts to match bioengineering design objectives and platform and tool development with specific HLBS applications. By connecting these communities, NHLBI has an opportunity to advance the development of cell therapies and the identification of the knowledge needed to improve therapeutic outcomes. Possible opportunities to accomplish this aim might include forums for exploratory work, program project grants, leveraging existing intra-NIH and interagency efforts and current partnerships,  a Gordon Research Conference prior to the grant writing stage, innovation laboratories, and grand challenges.

Workshop Speakers/Panelists in Order Listed in Workshop Agenda

James Collins, Ph.D., Co-Chair, Termeer Professor of Medical Engineering and Science, Massachusetts Institute of Technology
Krishanu Saha, Ph.D., Co-Chair, Associate Professor, Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin–Madison
Akhilesh Reddy, Ph.D., Associate Professor of Pharmacology, University of Pennsylvania
Melissa Kemp, Ph.D., Carol Ann and David D. Flanagan Professor, Wallace H. Coulter Department of Bioengineering, Georgia Institute of Technology and Emory University
Wilson Wong, Ph.D., Associate Professor, Department of Biomedical Engineering, Boston University
Shawn Gomez, Ph.D., Professor, Departments of Pharmacology and Biomedical Engineering, University of North Carolina at Chapel Hill
Samantha Morris, Ph.D., Associate Professor of Genetics and Developmental Biology, Washington University School of Medicine
Arjun Raj, Ph.D., Professor of Genetics, Perelman School of Medicine, University of Pennsylvania
Lukasz Bugaj, Ph.D., Assistant Professor of Bioengineering, University of Pennsylvania
Moriel Vandsburger, Ph.D.; Assistant Professor of Bioengineering; University of California, Berkeley
Katie Galloway, Ph.D., Charles and Hilda Roddey Career Development Professor in Chemical Engineering, Massachusetts Institute of Technology
Deblina Sarkar, Ph.D., Assistant Professor, Massachusetts Institute of Technology
Corey Wilson, Ph.D., King-Chávez-Parks Professor of Chemical and Biomolecular Engineering, Georgia Institute of Technology
Joshua Leonard, Ph.D., Associate Professor of Chemical and Biological Engineering, Northwestern University
Michael Elowitz, Ph.D.; Professor of Biology, Bioengineering, and Applied Physics; California Institute of Technology
Ahmad (Mo) Khalil, Ph.D., Associate Professor, Department of Biomedical Engineering, Boston University
Jonathan Epstein, M.D., Professor of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania
Xiaojing Gao, Ph.D., Assistant Professor of Chemical Engineering, Stanford University
Leonardo Morsut, Ph.D., Assistant Professor of Stem Cell Biology and Regenerative Medicine and Assistant Professor of Biomedical Engineering, University of Southern California
Charles Gersbach, Ph.D., John W. Strohbehn Distinguished Professor of Biomedical Engineering, Duke University
Mildred Cho, Ph.D., Professor of Pediatrics and Medicine, Stanford University
Michael Jewett, Ph.D., Walter P. Murphy Professor of Chemical and Biological Engineering, Northwestern University
Peyton Greenside, Ph.D., Founder and Chief Scientific Officer, BigHat Biosciences
Tim Lu, M.D., Ph.D., Co-Founder and CEO, Senti Bio
David Hava, Ph.D., Chief Scientific Officer, Synlogic

NHLBI Workshop Planning Committee

Bishow Adhikari, Ph.D., Program Director, Heart Failure and Arrhythmias Branch, Division of Cardiovascular Sciences
Shilpy Dixit, Ph.D., Program Director, Prevention and Sleep Health, National Center on Sleep Disorders Research
Allison Gillaspy, Ph.D., Program Director, Translational Blood Science and Resources Branch, Division of Blood Diseases and Resources
Marrah Lachowicz-Scroggins, Ph.D., Program Director, Airway Biology and Disease Branch, Division of Lung Diseases
Charlene Schramm, Ph.D., Program Director, Heart Development and Structural Diseases Branch, Division of Cardiovascular Sciences
Rahul Thakar, Ph.D., Program Director, Advanced Technologies and Surgery Branch, Division of Cardiovascular Sciences (Planning Committee Lead)

Agenda