CAAT’s research activities are (or were) funded by ARDF, Colgate Palmolive, DoD, European Commission, FDA, NCATS, NIH, and LUSH.
The main purpose of the research program is to practice what we advocate—the paradigm shift in toxicology. Our vision is to move away from current animal-based tests to pathway-based cell assays. Our projects combine 3D organotypic cell models with high-content and high-throughput approaches. This includes metabolomics, proteomics, transcriptomics, miRNA profiling, and imaging techniques. By combining different methods using bioinformatics tools we are aiming to identify pathways of toxicity (PoT) and defense (PoD) and mechanisms of xenobiotics.
In the recent years, the research group has developed three 3D brain models based on rat primary cells, a human dopaminergic cell line, and human induced pluripotent stem cells (iPSCs). The models have been used for numerous different applications, including developmental neurotoxicity, neurotoxicity, Parkinson’s disease, resilience, blood-brain barrier, autism, Down’s syndrome, inflammation, Zika, and other virus infections. Several papers have been published, submitted, or are in preparation. The iPSCs model, in particular, has received widespread press coverage, leading to extensive new collaborations both within and outside Johns Hopkins.
In the NIH-funded project “Mapping the Human Toxome by Systems Toxicology” the workflow using omics technologies has been established using endocrine disruption as a proof of concept. Emerging tools such as pathways analysis software and network databases have been used to analyze and integrate data from the multi-omics approach. Several core and associate articles have recently been submitted and/or published.
In addition, a computational toxicology program has been established to make use of high amount of data, both from our own studies but also from large toxicology databases such as REACH. This group is consistently submitting new grants to expand and continue the research activities.
Organoid Intelligence
CAAT’s Organoid Intelligence (OI) initiative aims to revolutionize our understanding of brain function and cognitive processes by integrating cutting-edge Artificial Intelligence (AI) with advancements in bioengineering, particularly in the field of brain microphysiological systems (MPS). This ambitious venture is driven by the development of 3D organ equivalents using induced pluripotent stem cells (iPSC) since 2009, which has dramatically advanced biomedical research, offering increasingly human-relevant model systems of the brain.
Evidence-Based Toxicology Collaborative
The Evidence-Based Toxicology Collaboration (EBTC) is sponsored by a collection of leading organizations including The Johns Hopkins Center for Alternatives to Animal Testing (CAAT), Society of Toxicology, American Chemistry Council, American Cleaning Institute, and CropLife America. A diverse team of expert toxicologists, hailing from industry, academia, government oversight, and animal welfare sectors, formed the founding board of this unique initiative. Since then, this project has transitioned away from being board-directed and moved into a membership-led model. This transition marks a new and exciting phase for this coalition.
ToxAIcology and Green Toxicology
Toxicology has transformed from an observational discipline into a data-rich field, ideal for the integration of AI techniques like machine learning and deep learning. This shift has been driven by the exponential growth in computing power and the accumulation of large toxicological datasets, enabling the enhancement of chemical hazard assessment. AI in toxicology encompasses various domains, including predictive toxicology, data analysis, and risk assessment. The integration of AI offers significant advantages such as the ability to analyze large volumes of heterogeneous data and enhance precision and speed in toxicological evaluation.
Green Toxicology is an approach which seeks to work with green chemistry to enable the rapid development of new chemicals which reduce hazard and are more sustainable. In practice, this means the development of methods – ranging from computational modeling to in vitro testing – which can quickly assess toxicity before a chemical is brought to market and can consider the broader environmental and ecological implications of chemical exposure.
Microphysiological Systems (MPS)
These are cell culture systems replicating (patho-) physiology through engineered organ architecture and functionality. This includes especially 3D-(co-)cultures such as organoids, organ-on-chip models, and multi-organ models, as well as the technologies to engineer and analyze these systems. Microphysiological systems (MPS) comprise a number of bioengineering breakthroughs that reproduce organ architecture and function in vitro. Fueled by stem cell technologies, a broad variety of especially human models and test systems have emerged, which make relevant experimental tools broadly available through international and multi-disciplinary collaborations. In 2021, CAAT received a three-years R13 grant from NIH NCATS to support this effort. The inaugural MPS World Summit took place in New Orleans, followed by a Summit in Berlin, Germany, and most recently in Seattle, US. The MPS World Summit is now managed by the International Microphysiological Systems Society (iMPSS) a society co-created by CAAT.
The Exposome
Through its involvement with the JHU Exposome Collaborative, CAAT aims to develop a useful framework to study the totality of environmental exposures over a lifetime and their impacts on human health, complementing the genome. The results from genome-wide association studies, classical heritability twin studies, and migrant studies, demonstrate that disease risks and health disparities are largely driven by unknown environmental factors. As most studies of environmental risk focus on single factors, there have been few attempts to integrate the impact of multiple environmental exposures over time on disease initiation, progression, and severity; the exposome addresses this fundamental gap in knowledge.
The Human Exposome, which encompasses the integrated compilation of all physical, chemical, biological, and psychosocial influences that impact biology, requires a comprehensive characterization to translate its potential into medicine and public health practice. Hence CAAT joins the call for The Human Exposome Project to complement the Human Genome Project.
Achieving this ambitious goal demands an international, coordinated effort involving governments, organizations, scientists, funders, the technology sector and the public, — a “moonshot” approach. CAAT co-organized the inaugural Exposome Moonshot Forum, which gathered these diverse stakeholders to collaboratively translate the exposome from concept to utility. The event will now take place annually at new international and domestic locations each session.
