Division of Systems Biology
Major Functions and Responsibilities
The Division of Systems Biology focuses on the development and evaluation of new technologies and the identification of new biomarkers (disease indicators) to support the FDA mission.
Division Director: William B. Mattes, Ph.D., DABT
The Division is divided into three branches:
Biomarkers and Alternative Models Branch — Finds new translational biomarkers to a) improve detection of safety concerns with drugs and other FDA-regulated products and b) improve the identification of disease onset and its progression to enable better medical intervention.
Innovative Safety and Technologies Branch — Develop and evaluate innovative in vivo and in vitro methods to evaluate drug toxicity, develop analytical methodologies to advance the identification of foodborne pathogens and chemical adulteration, and develop models to enhance diagnostic procedures.
Personalized Medicine Branch — Determines the impact of differences in the responses of species and human sub-populations on current assessments of drug safety and efficacy.
2018 Select Accomplishments
Biomarkers of Doxorubicin-Induced Heart Injury
The use of a potent chemotherapeutic drug, doxorubicin (DOX), is restricted because of the risk of heart damage in cancer patients and survivors. In one study, a mouse model of DOX-induced heart injury developed at NCTR was utilized and transcriptomics analyses identified two proteins (NOTCH1 and vWF) that were elevated in plasma prior to the release of cardiac-specific injury marker, troponin T, and development of pathology in the heart. Increased level of both proteins was mitigated when toxic effects of DOX were diminished in the heart in mice that received a cardioprotective drug, dexrazoxane, suggesting these proteins as candidate early markers of DOX cardiotoxicity. These early protein markers of DOX-induced heart injury with potential applications in the clinic for monitoring and/or predicting cardiotoxicity induced by DOX will help design more effective treatment regimens. These results have been published in Toxicology and Applied Pharmacology (Desai et al. Toxicol. Appl. Pharmacol. 2019; 363:164).
Inter-Individual Heterogeneity Among hiPSC-CMs Reponses to Kinase Inhibitors
While human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide unprecedented opportunities for examining the cardiac effects of drugs on heart cells in vitro, commercially-available hiPSC-CMs are typically derived from single donors. A team of scientists from NCTR, the Arkansas College of Osteopathic Medicine, and the Medical College of Wisconsin hypothesized that hiPSC-CMs derived from different individuals would display heterogeneous sensitivities to kinase inhibitors, drugs used in cancer therapy that also can cause heart problems. The team reported at the annual meeting of the American Heart Association that following drug exposure, they observed cell-line and drug- dependent differences in cell beating rate and toxicity. Their results strongly suggest that inter-individual differences impact hiPSC-CM cardiotoxicity assessments and support the need to test multiple cell lines during in vitro toxicity screens. The results of the study were presented at the 2018 annual meeting of the American Heart Association (White el al. Circulation. 2018; 138:A17363).
Effect of Diet on Drug Prevention of Mammary Cancer
Efforts have been underway to explore if various drug treatments might prevent breast cancer. In one of these studies, using rats as a model, the effect of diet on these treatments was examined. Scientists from NCTR collaborated with those from the National Cancer Institute to analyze the metabolic changes induced by a standard diet and a high fat diet (HFD) with and without treatments. The HFD significantly increased the number and size of tumors and had significant impact on the serum metabolites. These results have been published in Cancer Prevention Research (Lubet et al. Cancer Prev. Res. (Phila). 2018; 11:831).
Development of a Mouse Testis Organ System
The potential for medicines to have adverse effects on male reproductive capacity remains a concern in drug development. While animal tests have been useful in assessing the risk new drugs might have, faster methods would be desirable. At the meeting titled FutureTox IV Progress to Maturity: Predictive Developmental and Reproductive Toxicology for Healthy Children, scientists from NCTR and CDER presented results of a new, in vitro assay where a mouse testis organ system is used to examine the toxicity of chemicals. Further work is planned to refine this system.
2019 Select Research Projects
- Sex Differences in Drug-Induced QT Prolongation and Torsade De Pointes: Establishing an In Vitro Model for High-Throughput Screening and Risk Assessment of Torsadogenic Drugs
- Investigation of the Mechanistic Aspects of Sex-Based Differences in Susceptibility to Doxorubicin-Induced Cardiac Toxicity in Mice
- A Comprehensive Characterization of iPSC-CMs Models for Drug-Induced Arrhythmia Using High-Throughput Screening
- Evaluation of an In Vitro Testis Organ System as an Alternative Model for Male Reproductive Toxicology
- Systems Biology Approach to Discover Biomarkers in Biofluids for Drug-Induced Liver Injury to Determine Individual Susceptibility, Severity, Adaptation and Regeneration: Using Acetaminophen as a Proof-Of-Concept
- An In Vitro Assay to Identify New Early Diagnostic Biomarkers of Prostate Diseases (Benign Hyperplasia and Cancer)
- Predict Tyrosine Kinase Inhibitor (TKI) -Induced Cardiotoxicity Using Induced Pluripotent Stem Cell-Derived Cardiomyocytes
- Development of A Mouse Model for Doxorubicin-Induced Delayed Cardiotoxicity
- Investigating Changes in Metabolome and Cefoperazone Metabolism in MAIT Knockout Mice
- In Vitro Toxicity Assessment of Opioids on Neural Precursor Cell Specification, Proliferation and Differentiation
Resources for You
- National Center for Toxicological Research
Food and Drug Administration
3900 NCTR Rd
Jefferson, AR 72079
- (870) 543-7391