Thomas Caulfield, Ph.D., has a research background in biochemistry, medicinal chemistry, biophysics, computational modeling and in silico drug studies. His long-term focus is on areas related to protein modeling and new drugs, such as structural studies of biomolecular targets, assessment of druggability, drug discovery (hit to lead through optimization) and de novo design.
Dr. Caulfield's laboratory is focused on investigating structure-function behavior of neurological disease targets, cancer biology targets and other metabolic targets using algorithmic strategies to study dynamics behaviors, protein-protein interactions and other complexes. The integrated interplay among molecular targets, cofactors and ligands is central to cellular pathways and can be examined at the level of gene, message transcript, protein or other macroscopic readouts. However, Dr. Caulfield's laboratory is primarily interested in studying the atomic level of detail that governs the interactions of the cellular components and integrating (data fusion) biological data to improve machine learning data sets for better predictions.
Dr. Caulfield collaborates with Mayo Clinic's Center for Individualized Medicine (CIM) on variant of uncertain significance (VUS) research and the Precision Cancer Therapeutics (PCT) Program pipeline. A VUS is the result of a random genetic single nucleotide polymorphism (SNIP) and requires categorization as a pathogenic or benign polymorphism, which is a common outcome with genetic counseling. PCT is working on developing novel drug therapeutics to address important cancer therapies that are precision driven and complement other work within CIM.
Dr. Caulfield collaborates with several labs across multiple departments on Mayo Clinic's campuses in Jacksonville, Florida; Rochester, Minnesota; and Scottsdale, Arizona. Dr. Caulfield also has numerous collaborators at labs around the world that help foster discoveries in biochemistry, clinical genomics, computational biology, cancer biology and neuroscience.
- Ribosomopathies, frameshifting and quality control mechanisms. Dr. Caulfield leads a research group studying ribosomopathies and their influence in disease role processes that can have effects on the proper reading of mRNA during translation. These quality control mechanisms can have broad implications in many diseases from cancer to neurodegeneration.
- VUS categorizations. Dr. Caulfield is leading an effort to build large scale data sets for protein informatics to use machine learning coupled with biological readouts (organ-on-a-chip and HT animal models such as C. elegans and zebrafish) for improved in silico prediction using 3D dynamic protein structural modeling.
- SARS-CoV2 multidrug targeting. Dr. Caulfield is leading a national team of investigators from Harvard, University of California, In Vivo Biosystems and Mayo Clinic to perform large-scale in silico and in vivo experiments on de novo drugs to better understand COVID-19 and halt its progression. University of California hosts a live virus BSL3 facility for rapidly screening novel compounds that Dr. Caulfield's lab designs in silico and refines with feedback using machine learning techniques and data layering.
- Method, drug and technology development (quantum-based adaptive docking). Dr. Caulfield also serves as a principal investigator for studies on ribosome modeling and design of next-generation de novo drug compounds using computational methods development to improve on existing cutting-edge technologies within such areas as docking, simulations and complex data analyses.
- Collaborative studies. Dr. Caulfield has expertise in molecular simulations, virtual screening of large libraries of compounds for targets, in silico modeling of proteins and nucleic acids, de novo drug design for inhibitors and activators, and complex structural data analyses for molecular partners. His collaborative research includes work with dozens of Mayo Clinic laboratories. Other ongoing collaborations include colleagues at University of California, Riverside; Ichan School of Medicine at Mount Sinai; and both Karolinska Institutet and Uppsala University. The principal aim of these collaborations is to accelerate drug discovery and focus experimental design for improved efficiency.
- Neurodegeneration. Dr. Caulfield receives National Institutes of Health R01 funding for Parkinson's disease research. Specifically, he studies Parkin and PINK1 dynamics and structure-function behavior roles in mitophagy. In collaboration with Wolfdieter Springer, Ph.D., Dr. Caulfield continues to develop a drug program for Parkin and PINK1 interplay with mitochondria.
- Dual inhibitors and heterofunctional drugs. These drugs have multifunctional purpose in drug therapeutics in which complicated pathways may need multiple targets stimulated. Dr. Caulfield uses these drugs successfully to slow tumorigenesis in resistant strains of blood cancer. His research team is focused on delivering dual inhibitors that may be used in conjunction with the standard of care to prevent onset of aggressive resistant relapse.
- Cancer collaborations. Dr. Caulfield has extensively been researching mesotrypsins, trypsins and metalloproteases within cancer pathways in collaboration with Evette S. Radisky, Ph.D. and her Proteases in Cancer Laboratory, which has studied both complex interactions and is currently examining drug screenings. Dr. Caulfield is investigating the effect of the enzyme SCD1 on the endoplasmic reticulum stress-signaling pathway as well as studying the correlation between inhibition of SCD1 and inhibition of tumor development in associated cancers. In collaboration with John A. Copland III, Ph.D, and colleagues in the Cancer Biology and Translational Research Laboratory, Dr. Caulfield has developed new SCD1 inhibitors with novel (and patentable) compound structures (in silico) and synthesized and tested them for activity.
- Brain cancers. Other cancer projects include investigation of CNS-specific compounds, such as agelastatin A analogs, neurological tumors and osteopontin-related cancers in collaboration with Dr. Copland and Han W. Tun, M.D. Other brain cancer research includes the work of Hugo Guerrero Cazares, M.D., Ph.D., and Alfredo Quinones-Hinojosa, M.D.
Significance to patient care
Dr. Caulfield anticipates that through his accelerated drug discovery and research platform, small-molecule modulators for selected targets can be devised to help study the cellular pathways related to these targets. This in turn allows a better understanding of important protein targets. The ultimate goal of his research is to develop novel pharmacological interventions that can prevent and treat diseases with clearly identified macromolecular targets.
- Co-investigator, Molecular Mechanisms of Parkin-Directed Mitochondrial Quality Control, research project grant, National Institutes of Health, 2014-2019
- Co-investigator, Identification of Parkin Activators Through Structure-Function Analyses, The Michael J. Fox Foundation Award, 2014-2015
- Journal reviewer, Nature Structural & Molecular Biology (2014-present); PLOS Computational Biology (2014-present); Molecular BioSystems, Royal Society of Chemistry (RSC) (2013-present); Computational and Structural Biotechnology Journal (2013-present); MedChemComm, RSC (2012-present); BioMed Central online publisher (2012-present)