The Future of Integrated Systems and Technologies for Modeling Human Response to Biothreats
Overview
The U.S. government has recognized the expansion of the biological threat landscape, as evidenced by the guidance and priority missions outlined in various documents, including the 2023 Department of Defense (DoD) Biodefense Posture Review, the 2022 National Defense Strategy, and the Biomedical Advanced Research and Development Authority Strategic Plan for 2022-2026. There is broad recognition that applying other scientific disciplines, such as artificial intelligence (AI), materials science, chemistry and physics to biology increases the risks of novel biological and chemical threats.
To better predict against novel, engineered threats, significant and purposeful investment is needed over the next 10-20 years. In the national security enterprise, this is driven by the requirements to advance the scientific understanding of disease/injury progression throughout the body’s systems and to accelerate the development of medical countermeasures (MCMs) that treat exposure to high-priority threats, including chemical, bacterial, radiation, viral and toxin agents.
Development of integrated prediction models of the complex cellular and molecular machinery within the human body system will entail committing long-term funding to advance three-dimensional tissue model systems (i.e., organ-on-chip, organoids), in silico modeling methods, wearable systems integration that allows for continuous data collection, multiomics collection and data intelligence, machine learning tools for rapid analysis of complex data sets, and integration across drug candidate libraries.
The realization of these complex models, tissue model systems, data intelligence and integrated lab methods will ultimately enable a disruptive capability that allows full life-cycle test and evaluation of promising MCM treatments and will aid in the discovery of disease mechanisms and biomarkers that are not available through classic discovery methods and animal models.
FDA Modernization Act
In December 2022, President Biden signed the FDA Modernization Act 2.0 into law. Prior to this, the Federal Food, Drug, and Cosmetic Act of 1938 mandated animal testing for all drug development. FDA Act 2.0 fundamentally addresses the “Three R’s” principle around animal use in drug development and preclinical testing: Replacement, Reduction and Refinement.
The FDA Modernization Act 3.0, when eventually signed into law, will require the U.S. Food and Drug Administration to fully implement FDA Act 2.0 and will require the Health and Human Services secretary to establish processes, procedures and methods to qualify nonanimal test methods.
The passing of this law will present an opportunity to the scientific community, drug developers, private investment firms, U.S. government agencies and federal regulators to address critical gaps in the development and testing of safe and effective products while simultaneously addressing the ethical use of animals.
Existing Regulatory and Scientific Challenges
A primary limitation of the established process for the FDA regulatory approval of a new drug or MCM is hampered by biologically simplistic preclinical tools that fail to capture the complexity of human cell and tissue biology. Second, the suite of animal testing models does not always correlate well with human physiology, data collection points may be limited and some sample types cannot be collected from a live animal. Third, human clinical trials typically lack demographic and health diversity. Finally, the accepted preclinical animal models and human clinical trial approaches have embedded time and cost constraints that affect MCM development timelines for critical chemical, biological, radiological, nuclear and explosives threats.
Combined, these challenges are significant when evaluating MCM safety, quality and performance in preclinical and clinical settings. The counterpoint is that integrated model systems have built-in advantages that present a unique opportunity not only to reduce a reliance on animal testing but have the potential to improve all aspects of the MCM/drug development process, ultimately resulting in safer and more effective treatments for the warfighter and the ability to protect the U.S. population during a national emergency.
The Technology and Regulatory Road Map
To accomplish this broad vision, the ecosystem will require coordination and structured business relationships among many stakeholders ranging from academic researchers, nonprofit research and development organizations, large for-profit corporations with structured research and development investment portfolios, specialized start-ups with focused capabilities, federally funded research and development corporations (FFRDCs), and government contractors, all of which will be driven by research and development and regulatory requirements articulated by multiple U.S. government agencies.
A canonical example is the development of structured business relationships that allow for the transfer of emerging technology advancements from academic and other research institutions that would allow licensing of their research into real-world, engineered systems while simultaneously not constraining their ability to capture future work with the U.S. government to advance the state of the art. The sections that follow describe the major technology investments required.
Immune Model Integration. Multiple microphysiological systems providers in the market (from low technology readiness level-research platforms to commercially available systems) have demonstrated some immune-related capability, and several providers have included innate immune components in their systems. However, the long-term goal must be to develop an integrated, adaptive immune system. From a scientific and systems engineering perspective, this is an extraordinarily complex challenge that will result in incremental innovations. The long-term goal is to model the short- and long-term immune response to threats and MCM/vaccine response.
Specialized Organ/Tissue Models. The future of microphysiological systems/organoid models will continue to expand as the threat landscape will continue to evolve over time. Clearly, we can see the long-term requirements to advance integrated brain models, neural system models, microbiome models, nasal passage (route of entry) models, cardiac models, thymus models and spleen models, among others.
Multi-Organ Integrated Systems. The development of specific threat models (and testing of candidate MCM solutions to counter those threats) will require advancing far more complex multi-organ systems than are currently available. Ultimately, a long-term strategy could be to develop integrated “human-on-a-chip” system architectures that allow researchers and regulators the ability to more effectively study the effects of disease across the body while allowing government regulators the ability to predict the safety and efficacy of candidate MCM solutions before moving into a human clinical trial.
In Silico Models. Continuing investment and strategies for the next generation of in silico models (or digital twins) are of critical importance. The advantages of in silico models are quite apparent—the capability to simulate the complex biochemistry processes of the body’s cellular and molecular machinery using advanced machine learning and evolving AI capabilities are at the forefront of these applications. The creation of virtual tissue models, including multiple tissue types that link together toxicology models that offer the ability to evaluate large, complex toxicology data sets to discover unknown safety issues, and characterization of data from these virtual models with data from animal and microphysiological systems-based technologies are core implementation strategies.
Next Generation Omics-based Data Intelligence. Long-term, sustained funding in this area is required to understand the complexities and interactions of genomics, epigenomics, transcriptomics, proteomics and metabolomics, collectively referred to as multiomics data. The use of multiomics data analyses is critical to a holistic understanding of the intricacies of biomolecules and their interactions with each other.
Wearables Data Integration and Biomarker Discovery. Continuing investment and funding in this area is an important element of the overall strategy. The DoD appears to have a long-term strategy to continue investments in this area. The Defense Threat Reduction Agency/Joint Science and Technology Office is one such example.
High-Containment Laboratory Facilities. Continued access to and collaboration with the nation’s biocontainment research facilities must be a priority. They provide a unique platform for safe and secure work with biologicals and toxins at Biological Safety Level 3 and 4. This is a critical resource to maintain technology and provide surge capabilities for U.S. government programs as the threat landscape changes. Historically, the National Institutes of Allergies and Infectious Disease provided grants to 15 academic institutions to build 13 regional biocontainment laboratories and two national biocontainment laboratories across the United States to support biodefense research in the aftermath of the terrorist and anthrax bioterrorism attacks in 2001.
Regulatory Partnerships and Data Standardization. Exploring and developing relationships with the regulatory offices and the Food and Drug Administration is another critical aspect of this road map. While microphysiological systems and related platforms hold significant promise in addressing the limitations of traditional systems, data from these are not routinely accepted by the FDA for inclusion in investigational new drug applications.
Cell Sourcing. Continued and long-term research and development funding is required to address the lack of adequate cell sources. This issue is fairly straightforward. There is a lack of commercial sources of donor-derived primary cell types required to conduct broader studies across diverse populations with differing health and genetics backgrounds, including co-morbidities like asthma, heart disease, kidney disease, etc. Induced pluripotent stem cells (iPSCs) are adult stem cells that are reprogrammed and differentiated into new cell types. While iPSC-derived cells hold some promise, long-term research and development is required to improve the methods and technologies to take advantage of this capability.
Summary
Various elements within the DoD and other U.S. government agencies have mission sets that will accelerate the development and evaluation of “safe and effective” medical countermeasures that are required to protect the warfighter and the broader U.S. population in a national emergency that results from exposure to chemical, radiation, bacterial, viral and toxin agents. This multidimensional and multifaceted road map will require long-term funding and experts from leading universities, industry partners, national labs, FFRDCs and contract research organizations to execute all elements of the vision.
Roger Odegard is a senior program manager at The Charles Stark Draper Laboratory (Draper). Odegard leads Draper’s Biodefense/Accelerating Medical Countermeasure Development Portfolio. This portfolio of programs and projects is focused on biothreats and biodefense problems that include chemical, biological, radiological and nuclear threats, emerging infectious disease threats, microphysiological systems, human physiology, data intelligence and sensor systems and instrumentation.
