2023 Research Highlights
NCTR Scientist Showcases Organ-on-a-Chip Research at “American Possibilities: A White House Demo Day”
In a concerted effort with FDA’s Office of the Chief Scientist, Dr. Qiang Shi of NCTR and Dr. David Strauss of the Center for Drug Evaluation and Research presented FDA research on organ-on-a-chip technology at American Possibilities: A White House Demo Day on November 7, 2023. This invitation-only event was hosted by the White House Office of Science and Technology Policy to showcase what federal research and development can accomplish. President Biden toured the more than 40 demonstrations during the event. The invited audience included White House staff, members of Congress and staff, Biden-Harris Administration leaders, and others. Organ-on-a-chip is an emerging technology that aims to grow mini-organs in a test-tube-like environment mimicking whole-body conditions for biomedical research. NCTR scientists are using liver-on-a-chip and brain-on-a-chip technology to study drug-induced liver injury and Alzheimer's disease, respectively. The incorporation of organ-on-a-chip technologies in new drug development programs holds the promise to significantly reduce the cost and time needed in clinical trials and animal tests, as exemplified by the fact that a single donor’s liver will provide enough cells for over one million tests using liver-on-a-chip technology. FDA research on organ-on-a-chip technologies is expected to provide guidance to industry facilitating the discovery and development of safe and effective medications to promote and protect public health.
President Biden stopped by @WHOSTP’s “American Possibilities: A White House Demo Day” to see innovations in science and technology that are being made possible by federal investment. pic.twitter.com/dsR03ZM5fQ— The White House (@WhiteHouse) November 8, 2023
October 16, 2023
Jyotshna Kanungo, Ph.D.—research biologist and principal investigator (PI) in NCTR’s Division of Neurotoxicology—and scientists in NCTR’s Division of Biochemical Toxicology collaborated with scientists from FDA’s Center for Food Safety and Applied Nutrition—including Co-PI Dr. Suzanne Fitzpatrick—and the Center for Veterinary Medicine to augment traditional developmental toxicity testing with emerging research models, such as zebrafish, to assess the risk of human developmental problems from exposure to inorganic arsenic. Inorganic arsenic is a contaminant frequently found in rice and rice-based products, including foods commonly eaten by infants and children (e.g., rice cereal), as well as canine feed. Inorganic arsenic is also found in groundwater, soils, and sediments. Scientists exposed zebrafish to inorganic arsenic within the first 72 hours of development and described the effects on specific types of neurons. Zebrafish are ideal for testing developmental toxicants because they have transparent bodies, allowing researchers the ability to assess internal organs in real time and see if they are negatively impacted. A paper describing the study was published in the journal Neuroscience Letters.
The study showed that inorganic arsenic affects the development of neurons in zebrafish larvae and that motor neurons are affected through a specific pathway (Sonic hedgehog pathway). Results from this study may help explain why arsenic-exposed populations suffer from psychiatric disorders and motor neuron disease (i.e., progressive neurological disorders that destroy the nerve cells that control functions such as moving, breathing, swallowing, and speaking).
Researchers performed gene-expression analyses to further examine the effects of sodium arsenite - an inorganic arsenic compound—on signaling pathways, including apoptosis (normal cell death). After analyzing specific genes in the p53 pathway, data suggested that sodium-arsenite likely induced apoptosis. These findings were published in the Journal of Applied Toxicology earlier this year. The data from this study highlights potential mechanisms for arsenic toxicity and will strengthen the risk assessment of inorganic arsenic levels in human and animal foods. It may also be used as a model for assessing the toxicity of other heavy metals found in food.
NCTR’s Dr. Igor Pogribny Inducted into the Arkansas Research Alliance Academy of Scholars and Fellows
Igor Pogribny, M.D., Ph.D., a research biologist in NCTR’s Division of Biochemical Toxicology, was formally inducted as a new fellow of the Arkansas Research Alliance (ARA) Academy of Scholars and Fellows on August 10, 2023. Highlighted by a special welcome and recognition from Arkansas Governor Sarah Huckabee Sanders, he was one of seven new members welcomed during the ceremony at the Arkansas State Capitol.
Dr. Pogribny is a renowned scientist in the field of molecular toxicology and carcinogenesis. He earned an M.D. with honors from Ivano-Frankivsk National Medical University in Ukraine in 1982, and a Ph.D. in biochemistry/oncology from Kyiv National Medical University in 1986. He has worked at NCTR since 2003 and in 2021 was certified for credentialing and appointment in the FDA’s Senior Biomedical Research and Biomedical Product Assessment Service. His ARA Fellow nomination, put forward by Tucker Patterson, Ph.D., NCTR Center Director, was approved unanimously by the ARA Board of Trustees. Dr. Pogribny was selected to join the ARA Fellows program that recognizes research leaders with an established history of impact. The award summary described Dr. Pogribny’s impact as:
…your strong record of research and innovation along with your exceptional mentorship of the next generation of scientists. This distinction recognizes your research leadership and underscores your value to continue advancements and breakthroughs that support ARA’s mission to invest in strategic research talent that supports statewide economic development. It enrolls you as a “lifetime” member of the ARA Academy of Scholars and Fellows.
Its Academy of Scholars and Fellows program serves as the cornerstone for ARA and plays a pivotal role in bridging university research and economic development. According to Governor Sanders, ARA is “an amazing organization that brings together not just the research, but what that research can be turned into, what it can mean for our state long-term, the businesses that it will bring in, the talent that it will help us keep right here in our own back yard.” Founded in 2008, ARA is governed by a board of trustees comprised of chancellors from Arkansas research universities and chief executives from companies across the state. ARA is dedicated to elevating the fundamental belief that research matters. Operating as a public-private partnership, ARA invests in research that stimulates innovation, encourages collaboration, and strengthens economic opportunity in areas in which Arkansas possesses core competencies.
FDA Grand Rounds, July 2023: The Plasmid Puzzle—Finding Solutions in Salmonella
Kristina Feye, Ph.D., research microbiologist in NCTR’s Division of Microbiology (DM), presented at the virtual FDA Grand Rounds event on July 13, 2023. Her presentation—“The Plasmid Puzzle: Finding Solutions in Salmonella”—was shared with the public and discussed new sequencing technologies, their current limitations, and ways to overcome some of those limitations to improve their use. The goals of her presentation were to:
- help attendees understand the strengths and limitations of different next-generation sequencing (NGS) platforms and how new knowledge can help all sequencing methods,
- explain the importance of plasmids in public health and across the One Health Spectrum, and
- communicate different ways that plasmids can impact the microbiome and why being able to track all the plasmids in a system is important.
Dr. Feye began her presentation by explaining the important role NCTR plays in FDA’s mission by conducting research to provide reliable data to assist FDA’s decision-making capabilities and to provide cutting-edge tools and approaches. She discussed DM’s role within NCTR to “…evaluate the impact that antimicrobial agents, food contaminants with additives, nano materials, and FDA-regulated products have on the microbiome,” among other research goals critical to the NCTR and FDA.
She described how the use of NGS technology has revolutionized our understanding of the microbial world. However, because not all NGS technology provides the same level of precision, work is needed to ensure that researchers’ chosen method to analyze sequencing data tells the whole story. Dr. Feye discussed the history of sequencing and how different sequencing technologies impact the ability to detect plasmids of all sizes. The sequencing results did not align with what was expected for small plasmids based on laboratory results. Plasmids are important for both characterizing foodborne pathogens and for understanding how plasmids interact with the microbiome. Without fully understanding the impact that each sequencing technology and bioinformatics approach has on the data, it is hard to determine if the data is accurate. This is especially true if benchtop research is no longer pursued to support bioinformatics data.
Dr. Feye hopes that her FDA Grand Rounds presentation leads to conversations about how sequencing technologies are applied to problems. While multiple sequencing technologies are available to researchers and their use in the lab is made more accessible with easy-to-use, pre-determined bioinformatics tools available online, those sites may not provide the most up-to-date or detailed approach. One benefit of learning coding languages like Python or R is that they are used to run new bioinformatics programs that use those languages. Because of the flexibility that using languages provides us, we can adapt to emerging research and enhance the precision of our analytical approach. Using less canned approaches also allows us to stay up to date with the literature and provide the best analysis possible for our data. The research presented during Dr. Feye’s FDA Grand Rounds presentation highlights why benchwork is still very important to complement bioinformatics approaches.
NCTR works closely with the Center for Veterinary Medicine on plasmid research and shares their research data with other government agency through scientific work groups.
FDA Grand Rounds, May 2023: Electron Microscopy—Still a Powerful Research Tool
Angel Paredes, Ph.D., director of NCTR’s Electron Microscopy Core Facility, presented at the virtual FDA Grand Rounds event on May 11, 2023. He spoke on the topic of electron microscopy, a technique for obtaining high-resolution images of biological and non-biological specimens, during his presentation entitled “Electron Microscopy—Still a Powerful Research Tool.”
Dr. Paredes described NCTR’s Core Facility capabilities and the services it provides to scientists across the FDA. During his presentation, Dr. Paredes discussed how:
- The resolution provided by electron microscopes and the techniques that make them a powerful resource for biological investigation.
- Microscopes can be used to identify elements in samples such as gold, silver, copper, and iron.
- Cryo-electron microscopy (cryoEM) as a powerful imaging tool to image materials such as viruses and liposomes and determine their ultrastructures.
- His knowledge and expertise enabled NCTR to develop the center’s first published standard on cryoEM of liposomes entitled “Standard Practice for Performing Cryo-Transmission Electron Microscopy of Liposomes” published in 2018.
- Serial Block Face Scanning Electron Microscopy (SBFSEM) – a relatively new and powerful technology is being used at NCTR to examine the sub-cellular structures and experimental tissues of interest in 3D (the quality of being three dimensional). Images are acquired and analyzed after sequential sectioning through a microtome and imaging by SEM, producing image stacks that are analyzed by a computer software, and 3D reconstruction.
Lastly, he shared how the data produced by SBFSEM was challenging, due to inherent artifacts produced by the technology. Dr. Paredes now uses AI and computer learning to develop models that can be used to extract the valuable 3D information from these data to answer the questions posed by the experiments. He explained that what would take years to accomplish now takes AI a few weeks to perform.
Dr. Paredes started his training in electron microscopy at the University of Texas at Austin as a graduate student. Later, during his doctoral studies, he conducted electron cryomicroscopy to determine the structure of the Sindbis virus, a prototype alphavirus.
FDA Grand Rounds, March 2023: 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:
- Described the ways ZIKV is transmitted among the human population and the negative outcomes associated with ZIKV infection.
- 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:
- Explained the definition of liver microphysiological systems.
- Described how the major commercial liver microphysiological systems work.
- 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.
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.
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.
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.
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.
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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