Research

Equipment in the Paulovich lab

Focus Areas

  • Development of novel approaches to enable the translation of novel biomarkers.
  • Development and dissemination of standardized proteomic assays and reagents to enable harmonization of proteomic results across laboratories, increasing the reproducibility of pre-clinical research.
  • Development of multiplex thematic assay panels (e.g. targeting cell signaling pathways, protein complexes, etc.) to enable high throughput pharmacodynamics studies for biological studies or lead compound characterization
  • Identification of biomarkers of tissue injury, using exposure to ionizing radiation as a model.
  • Characterization of inter- and intra-individual variation in the cellular genotoxic stress response (in both normal and tumor cells), and relation of this variation to clinically relevant endpoints (e.g. risk for malignancy, short and long term toxicity from genotoxic agents, response to genotoxic therapies, etc.).
  • Elucidation of biological responses to exposure to sublethal doses of genotoxic agents.

Overview

As an oncologist, Dr. Amanda Paulovich was struck by the paucity of quantitative assays for measuring clinically relevant phenotypes in her patients, and the limitations that this put on her ability to practice “precision medicine.” Out of these experiences, she became passionate about developing technologies and strategies for translation of novel diagnostics and therapeutics to enable precision medicine.

Humans are wonderfully diverse, and yet most modern medicine treats patients as though they are uniform. Therapies are directed at the “typical” responder. Because individual patients are rarely “typical,” basing treatments on population statistics means that patients are sometimes exposed to potentially toxic therapies that provide less benefit than expected. This not only puts the individual patient at risk, but it often delays effective therapy, may affect outcome, and creates substantial financial burden on our healthcare system. This is particularly true for cancer, where each individual tumor has its own “personality,” manifest as some tumors responding impressively while other tumors from the same organ show no response at all to the same therapy.

A major reason why therapies are directed at the “typical” responder is that we lack critical tools for measuring patient characteristics that could be used to guide therapy. For example, proteins carry out the biological functions of cells and form the basis of diagnostic tests and treatments, yet over 95% of human proteins can’t be studied because we lack reliable laboratory methods (assays) for quantifying their abundances. This lack of reliable assays for quantifying the vast majority of human proteins has left the proteome clinically inaccessible and indeed is the biggest impediment to translating novel protein diagnostics into clinical use, is a major contributor to the irreproducibility of preclinical research, and is a major impediment to systems biology studies needing to interrogate cell signaling networks.

For example, under the current paradigm, the effects of a genetic or compound-based perturbation on cell signaling are assessed using phospho-specific antibodies and conventional technologies, most commonly Western blotting. While this workhorse technology (and related traditional platforms) has been pushed brilliantly to its limit and has formed the basis of many advances in biomedical research for decades, it is wholly inadequate to support the needs of the post-genomic community, where a multitude of phospho-analytes representing multiple signaling pathways need to be precisely quantified in multiplex in an affordable, moderate-to-high throughput manner to characterize an array of biospecimens at several doses and timepoints following perturbation. It is time to create a post-Western blot world.

Over the past 16 years, Dr. Paulovich's research has focused on relieving this roadblock in biomedical research: a lack of validated and standardized tools for quantifying human proteins. The laboratory has been a major developer of multiple reaction monitoring mass spectrometry (MRM)-based proteomic assays (and the lead developer of immuno-MRM), recently selected “Method of the Year” by Nature Methods. Dr. Paulovich's well established team is now pivoting from technology development to turning this technology into transformative tools that will fundamentally change biomedical research and lead to improvements in patient diagnosis and treatment by facilitating precision medicine. Her team is currently developing highly multiplex assays for studying cell signaling networks, with an initial focus on the cellular DNA damage response.

One can imagine a day when any human protein of interest can be reliably quantified (and thus effectively studied) by any researcher in the world. One mission of the next phase of Dr. Paulovich's research program is to foster international public-private partnerships to develop immuno-MRM assays to quantify all human proteins, and to place these assays in the public domain without restriction. This would empower the entire research community, from the basic scientist studying cell biology to the clinical/translational researcher trying to develop new treatments or new diagnostics. Broadly available, standardized tools for quantifying human proteins would fundamentally transform biomedical research and lead to improvements in patient diagnosis and treatment by facilitating precision medicine. This will enable the translation of basic research into tangible medical benefit to patients and society.