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  1. NCTR Publications

NCTR Research Highlights

Periodic report on research activities and special events at NCTR

2023 Research Highlights

 

April 12, 2023

FDA Grand Rounds Presentations — NCTR Research Using Microphysiological Systems as Novel Disease Models and Drug Development Tools

Dayton Petibone, Ph.D. and Qiang Shi, Ph.D.—researchers at NCTR—presented on the topic “Microphysiological Systems as Novel Disease Models and Drug Development Tools” at the virtual FDA Grand Rounds event held on March 9, 2023.

The FDA Grand Rounds is an educational presentation that is webcast monthly to highlight cutting-edge research conducted by the Agency and its impact on protecting and advancing public health. Each session features one or more FDA scientists presenting on a key public health challenge and how FDA is applying science to its regulatory activities.
 
The presentation by Dr. Petibone, which centered around the Zika virus (ZIKV) and the potential for this virus to cause birth defects or fetal loss, described the evaluation of testicular organoids for use as an in vitro model of ZIKV infection. Once developed, this model might be useful for evaluating potential vaccines or treatments for ZIKV infection in the male reproductive system. During the presentation “Evaluation of Testicular Organoids as a Model for Zika Virus Infection,” Dr. Petibone:  

  1. Described the ways ZIKV is transmitted among the human population and the negative outcomes associated with ZIKV infection. 
  2. Discussed how in vitro testicular organoid models can be used as a model of ZIKV infection. 

 
Dr. Petibone, a research biologist in NCTR’s Division of Genetic and Molecular Toxicology, is collaborating with scientists from FDA’s Center for Biologics Evaluation and Research to develop in vitro models of ZIKV infection and transmission. This research was funded through FDA’s Medical Countermeasures Initiative.

Dr. Shi’s presentation focused on the development of liver microphysiological systems. These models aim to maintain in vitro cultured liver cells in a physiologically relevant environment and may evolve into improved tools to study drug metabolism and aid the prediction of drug hepatotoxicity. During his presentation “Liver Microphysiological Systems as Emerging Tools for the Study of Drug Metabolism and Hepatotoxicity,” Dr. Shi:  

  1. Explained the definition of liver microphysiological systems. 
  2. Described how the major commercial liver microphysiological systems work. 
  3. Discussed the expectations for and challenges of using liver microphysiological systems to aid drug discovery and development. 

Dr. Shi completed postdoctoral training at NCTR and currently works as a visiting scientist in NCTR’s Division of Systems Biology. Dr. Shi’s main research focus is on mechanisms, biomarkers, and models for drug-induced liver injury.

View the recorded presentation here.

March 31, 2023

Bioinformatics Conference led by NCTR Scientist with Opening Remarks from FDA’s Chief Scientist

The Arkansas Bioinformatics Consortium (AR-BIC) recently held its 9th Annual Conference in Little Rock, Arkansas, on March 13 and 14, 2023. The theme for this year’s conference was “Bioinformatics, Big Data, AI (Artificial Intelligence), and Public Health: An Integrated World.” Under the leadership of Dr. Weida Tong, Director of NCTR’s Division of Bioinformatics and Biostatistics (DBB), the Scientific Program Committee organized a one-and-a-half-day program that included a wide range of presentations by speakers from diverse fields. In attendance were several researchers from NCTR as well as FDA’s Chief Scientist, Dr. Namandjé Bumpus. Dr. Bumpus provided opening remarks for the conference by highlighting the current research goals of pursuing new alternative methodologies and helping the public to better understand science.

The conference featured keynote speakers, breakout sessions, AI workshops, over 30 platform presentations, and more than 40 poster presentations. The in-person attendance for this year’s conference was the largest in AR-BIC’s nine-year history at over 180 participants. A special issue of the journal Experimental Biology and Medicine has been planned for research performed by this year’s AR-BIC participants. By the end of the conference, over 10 papers had been confirmed for submission to the special issue, which is intended to become an annual tradition. This conference successfully provided a platform to share and discuss current state-of-the-art practices and ongoing efforts to apply AI in healthcare and to enable efficient data mining to promote public health.

March 30, 2023

Papers (Co)Authored by Researchers in NCTR’s Division of Biochemical Toxicology Recognized by Scientific Journals

Three papers, authored or co-authored by researchers from NCTR’s Division of Biochemical Toxicology (DBT), were selected by their respective publishers for awards or other recognition. 

Woody Tolleson, Ph.D., retired research chemist, was the lead scientist on a paper selected as an Editor's Choice Article in the journal Toxins. The paper, titled “Microcalorimetric Investigations of Reversible Staphylococcal Enterotoxin Unfolding,” discusses how toxins found in certain isoforms of Staphylococcus aureus bacteria are considered “Category B Select Agents of Bioterrorism” by the Department of Health and Human Services.  While heat treatment inactivates the bacteria, preformed toxins can persist, causing Staphylococcal Food Poisoning. Due to the lack of a thorough thermodynamic study, the thermal stability and reversibility of inactivation of two classical protein isoforms, Staphylococcal Enterotoxin A (SEA) and SEB—both listed as “select agents,” and the novel isoform recombinant SEH, were investigated using differential scanning calorimetry.

Annie Lumen, Ph.D. and Un Jung Lee, Ph.D. — former NCTR fellows — were co-authors on a paper titled, “Quantitative In Vitro to In Vivo Extrapolation for Developmental Toxicity Potency of Valproic Acid Analogues.” This paper was selected by the Society for Birth Defects Research and Prevention for the “2023 James G. Wilson Publication Award,” which recognizes the best published paper in Birth Defects Research. The paper highlights the importance of pharmacokinetic considerations surrounding in vitro assays and demonstrates the utility of the devTOXqP human stem cell-based platform to assess the toxicity of chemicals.

Dr.  Lumen also co-authored another paper that was selected by Toxics as one of their 10 “Annual Recommended Reviews in 2022.” The paper, titled “IVIVE: Facilitating the Use of In Vitro Toxicity Data in Risk Assessment and Decision Making,” is a review of in-vivo to in-vitro extrapolation (IVIVE), a new methodology in development to reduce, refine, or replace animal testing. In the paper, the researchers promote the use of IVIVE to facilitate the replacement of animal models through continued evolution and development of IVIVE methods and developing a strategic plan for regulatory acceptance of these methods.

March 6, 2023

Dr. Jessica Hawes Presents NCTR Research at FDA’s Rare Disease Day Public Meeting

NCTR participated in the virtual FDA Rare Disease Day 2023 public meeting on February 27, 2023, in global observance of Rare Disease Week. The purpose of this meeting, titled “Intersections with Rare Diseases — A patient-focused event” was to promote awareness of rare diseases, their burdens, and how best to collaborate and support the development and regulation of medical products for rare diseases.

Jessica Hawes, Ph.D., Deputy Director of the Division of Systems Biology, presented on the significance of promoting research and awareness of rare diseases. This topic is important to her both professionally and personally. Dr. Hawes shared a personal story of her son Jaden’s battle with cholesteatoma, a rare disease that causes tumors in the inner ear. She recalled how difficult it was to find anyone that specialized in this rare disease to help her and her family during this struggle, but that eventually she was able to connect with a doctor at Johns Hopkins Medicine. After many surgeries, Jaden’s hearing was almost fully restored. He is tumor-free and on his way to living a full and healthy life. Dr. Hawes expressed how lucky she and Jaden were that research had been conducted on cholesteatoma but acknowledged that research has not been conducted on many other rare diseases and the need for such efforts.

Dr. Hawes also spoke about her support for securing funding of regulatory science research on rare diseases at FDA. She explained NCTR’s research capabilities and expertise and the current work that is being done at NCTR to support such research. She provided an overview of three categories of research currently conducted at NCTR on rare diseases — 1) treatment modality safety in the areas of nucleotide drug safety, gene therapy, and cell therapy; 2) biomarkers for detection of blood and bone marrow cancers (myelodysplastic syndromes and acute myeloid leukemia) and the neurodegenerative Creutzfeldt-Jakob disease; and 3) predictive toxicology approaches to evaluate therapeutics for rare pancreatic cancers and Zika-related neurodevelopmental defects. Dr. Hawes acknowledged the accomplishments and contributions of multiple researchers from NCTR and the work they are doing to support awareness of rare diseases and their potential treatments.

A recording of Dr. Hawes’s presentation at the FDA Rare Disease Day meeting is available on YouTube.

January 31, 2023

Retired NCTR Research Chemist Presented Distinguished Scientist Award by The Toxicology Forum

Daniel R. Doerge, Ph.D., retired research chemist from FDA’s National Center for Toxicological Research (NCTR), was presented the Philippe Shubik Distinguished Scientist Award at the Toxicology Forum Winter Meeting held January 24, 2023. He was nominated for the award by NCTR leadership for his role in the development of toxicology concepts that significantly impacted the field of regulatory science research.

The Philippe Shubik Distinguished Scientist Award is named in honor of The Toxicology Forum's founding president. According to the Tox Forum website, this annual award recognizes an individual who has led a long and productive career in toxicology and has made significant and noteworthy contributions to the field, including all aspects of traditional and regulatory toxicology. 

Dr. Doerge’s areas of research specialization included chemical and biochemical mechanisms of toxicity, thyroid toxicology, toxicology of soy isoflavones, acrylamide, bisphenol A (BPA), and inorganic arsenic. Dr. Doerge played a leading role in the development of novel highly sensitive and specific mass spectral-based analytical methodologies to quantify DNA damage induced by chemical carcinogens. Dr. Doerge was also responsible for the design and implementation of several comprehensive pharmacokinetic assays to address regulatory data gaps for the FDA, including on BPA, an industrial chemical found in some plastics. This work enabled the development of a physiologically-based pharmacokinetic model for BPA, which was the object of the prestigious FDA Chief Scientist Publication Award in 2017. Dr. Doerge served on chemical risk-assessment advisory committees for the European Food Safety Authority, World Health Organization, and U.S. Environmental Protection Agency. He also served as editor-in-chief for Archives of Environmental Contamination and Toxicology. His research publications are highly cited—one of the top 10 most-cited FDA scientists—based on statistics available through Google Scholar.

During his 50-year career, Dr. Doerge mentored and developed future generations of toxicologists, contributing positively to the research community. He provided leadership, guidance, and training to countless research fellows and junior staff members—mentoring postdoctoral fellows, supervising researchers, and informally advising many NCTR colleagues.

Dr. Doerge retired from NCTR in December 2020 after a long, distinguished career developing and adapting important toxicology concepts while also serving as a leader of and role model for future scientists.

January 18, 2023

NCTR Artificial Intelligence Initiatives Selected as Winners in the 2022 EMGS Bioinformatics Challenge

NCTR Artificial Intelligence Initiatives Selected as Winners in the 2022 EMGS Bioinformatics Challenge

Two NCTR scientists—Drs. Ting Li and Xi Chen—have been selected the first- and second-place winners, respectively, for the annual 2022 Environmental Mutagenesis and Genomics Society’s (EMGS) Bioinformatics Challenge! This EMGS Challenge encourages participants to develop novel tools and approaches that use publicly available data to identify signatures of genotoxic hazards or provide insight into their mechanisms of action.

Drs. Li and Chen are working on two of the NCTR-developed AI4TOX four initiatives, SafetAI and AnimalGAN. AI4TOX is an FDA artificial intelligence (AI) program for toxicology under the leadership of Dr. Weida Tong, Director of NCTR’s Division of Bioinformatics and Biostatistics (DBB). The program aims to apply the most advanced AI methods to develop new tools to support FDA regulatory science and strengthen the safety review of FDA-regulated products. 

Dr. Li presented her work on drug-induced liver injury (DILI) “DeepDILI: Deep Learning-Powered Drug-Induced Liver Injury Prediction Using Model-Level Representation” for the EMGS Challenge. Developed by Dr. Li, DeepDILI is an AI drug-safety model within the SafetAI suite that uses a deep learning-powered prediction model designed to use chemical structure information to identify drugs with the potential to cause DILI in humans. The SafetAI initiative aims to develop AI models for toxicological endpoints that are critical to assessing drug safety and may add value to the review of drug candidates prior to human testing.

Dr. Chen presented “AnimalGAN: A Generative AI Alternative to Animal Clinical Pathology Testing” for the EMGS Challenge. Developed by Dr. Chen, AnimalGAN is an AI-based suite that generates specific animal-study datasets for new and untested chemicals by learning from legacy animal-study data. The successful implementation of this AI-based suite is the first example of a generative adversarial network (GAN)-specific application’s use in a virtual animal model. 

Watch the final round of the Bioinformatics Challengeand learn about the other two AI4TOX initiatives, BERTox and PathologAI. For additional information, please contact Dr. Weida Tong.
 

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