This page contains information on and links to recordings of Plenary and Medical Research Council lectures delivered at the SOT Annual Meeting and ToxExpo, as well as recordings from other SOT meetings and activities.
Chairperson(s): Donna L. Mendrick, US FDA, Division of Systems Biology, Jefferson, AR, and William B. Mattes, PharmPoint Consulting, Poolesville, MD.
With the recent focus on (a) cellular pathways involved in toxicity sequelae and (b) translational biomarkers that may link animal and in vitro model observations with clinical reality, there is a need to broaden the understanding of how experimental models may replicate human toxicity and disease processes. Multicellular organisms may have large numbers of genes and proteins, but a relatively limited repertoire in terms of pathophysiology in response to disease or toxicant exposure. This fact allows research to improve and protect human health to be founded on the use of model systems that allow for tractable experimentation. Animal models and, more recently, in vitro systems have served as a means of both exploring mechanisms and identifying hazards in terms of disease and adverse events. However, the interconnections between disease and toxicity are rarely explored leaving the information in silos. This symposium will examine organ-based toxicity and disease processes, and compare lessons learned in biomarker identification and use across toxicity, disease, and species.
- Introduction, Donna L. Mendrick
- Use of Biomarkers in Hepatology, Liver Disease, and Liver Toxicity, Arie Regev
- Fibrinogen: A New Kid on the Block of Translational Biomarkers for Kidney Damage, Vishal S. Vaidya
- Cardiac Disease, Cardiotoxicity, and Translational Biomarker, James R. Turk
- Links Between Neurological Disease and Toxicity, David Gerhold
Lecturer: Samuel M. Cohen, University of Nebraska Medical Center, Omaha, NE.
Cancer develops because of multiple permanent genetic errors arising in a single stem cell, a clonal disease. Every time DNA replicates, spontaneous mistakes can occur. Thus, the risk of cancer can be increased by either directly damaging DNA each time it replicates (DNA reactive) or increasing the number of DNA replications (cell proliferation), or both. Some have indicated that the “spontaneous” errors that occur during DNA replication are the basis for cancer being due to “bad luck,” and are the cause of most cancers. However, it is well-known that numerous environmental factors can increase the risk of cancer. This dilemma is readily resolved by realizing that the number of stem cells and the rate of their proliferation can be markedly influenced by the environment. Over the course of more than a 50-year career in carcinogenesis research, I have been actively involved in research on DNA reactive carcinogens (nitrofurans, aromatic amines, nitrosamines) and non-DNA reactive carcinogens (saccharin, PPARγ agonists, arsenicals, others). Based on the fundamentals of carcinogenesis, a mode of action (MOA) approach, and the accumulated knowledge of carcinogenesis in animals and humans, carcinogenic risk can be readily evaluated today without utilizing the two-year bioassay.
This SOT Merit Award Lecture was delivered during the SOT 56th Annual Meeting and EUROTOX 2018.
Lecturer: Stephen P. Jackson, The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
Inherited or acquired defects in detecting, signalling or repairing DNA damage are associated with various human pathologies, including immuno-deficiencies, neurodegenerative diseases and various forms of cancer. Our increasing knowledge of cellular DNA-damage responses (DDR) is therefore providing new insights into the aetiology of such diseases and, moreover, is presenting opportunities for novel diagnostic and therapeutic strategies. Work in Dr. Jackson’s laboratory aims to decipher the mechanisms by which cells detect DNA damage and signal its presence to the DNA-repair and cell-cycle machineries. In particular, much of the work focuses on DNA double-strand breaks (DSBs) that are generated by ionizing radiation and radiomimetic chemicals, and which can also arise when the DNA replication apparatus encounters other DNA lesions.
In this talk, Dr. Jackson will first provide an overview of how cells respond to DNA damage and will describe the key protein players in these events. Next, he will discuss some of our recent work that has identified new proteins that mediate DSB responses, control DSB processing or modulate chromatin structure at DNA damage sites. He will then explain how this type of work identified therapeutic opportunities that led to me founding KuDOS Pharmaceuticals Ltd, whose mission was to develop DDR inhibitors for cancer therapy. Finally, He will use the example of the KuDOS drug olaparib (now owned by and being developed by AstraZeneca) to highlight the exciting potential for DDR inhibitors in treating many cancers.
Specifically, Dr. Jackson will explain the molecular basis for how olaparib is exquisitely cytotoxic to cancer cells bearing DSB repair defects because of inherited mutations in BRCA1 or BRCA2 but is well tolerated by normal cells of cancer patients. In closing, he will explain how this and related mechanisms of “synthetic lethality” might be applied to a wider range of cancers that bear DDR defects.
Lecturer: Michael H Hastings Neurobiology Division, Medical Research Council Laboratory of Molecular Biology, Cambridge, U.K.
Circadian (approximately one day) rhythms dominate our lives, most obviously via the sleep/wake cycle. Driven by internal clocks, they adapt us to the world by preparing tissues to perform appropriate, but very different, functions in anticipated day and anticipated night. The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal circadian clock of the mammalian brain. It is entrained to solar time by direct retinal innervation, and in turn, it co-ordinates innumerable cellular clocks distributed in all major organs across the body. At a cellular level, circadian timekeeping in SCN and other cells pivots around self-sustaining transcriptional/translational feedback loops (TTFLs) in which the positive regulators CLOCK and BMAL1 drive expression of the negative regulators PERIOD (PER) and CRYPTOCHROME (CRY) via E-box DNA regulatory sequences. Delayed negative feedback by PER and CRY at E-boxes, followed by degradation of PER and CRY, establishes a spontaneous oscillation with a period of approximately 24 hours. This mechanism orchestrates local cell type-specific circadian transcriptomes, synchronized by SCN-dependent behavioral, neuroendocrine, and autonomic cues. These programs in turn sustain the coherent 24-hour cycles of local gene expression that underpin circadian behavior, metabolism, and physiology. This presentation will review recent advances in understanding of the molecular genetic basis of the cell-autonomous clock mechanism of the SCN. It will then consider how circuit-level cellular interactions establish the SCN as a powerful self-sustained clock. Finally, it will consider how the SCN directs circadian behavior and physiology. Where appropriate, it will illustrate how developments in real-time imaging of neuronal function and genetic code expansion have been useful in elucidating the clock’s inner mechanism. The overarching message from the circadian neurobiology field is that our bodies are extremely sophisticated 24-hour machines, an observation with significant implications for health and disease.
Systems Approaches to Drug Efficacy and Toxicity in an Era of Big Data
Lecturer: Peter Sorger, Harvard Medical School, Boston, MA
The development of new therapeutic drugs is fundamental to improving human health, but the process is challenged by rising costs and a high rate of failure. New and better technology and big data are often put forward as the solutions to these problems. However, I will discuss laboratory and clinical studies showing that some of the fundamental concepts in pharmacology and toxicology are ripe for reinvention. Increasing data on the impact of cell-to-cell variability and temporal variation in cellular physiology motivates new ways of thinking about seemingly simple concepts such as drug dose-response. Better understanding of sources of variation in laboratory and clinical data should also improve our ability to identify robust biomarkers of therapeutic and adverse effects.
I will argue that big data and data science are essential but insufficient: correct interpretation of empirical data in biomedicine hinges on theories about mechanism. I will discuss these theories, with reference to cytotoxic and targeted anti-cancer therapies, and studies of drug response in cell culture, animal models, and human clinical trials. New pharmacological principles derived from such studies are being developed into practical algorithms and open-source software as a means to improve target qualification, lead molecule optimization, and early phase clinical trials. The hoped for outcome: better drugs at a cost society can afford.
Open Ecosystems for Understanding Toxicities and Adverse Events
Lecturer: Lara Mangravite, Sage Bionetworks, Seattle, WA
The presentation will address the use of collaborative approaches for the gathering, sharing and interpretation of health data. This will include the use of remote sensor-based data collection approaches to capture fluctuations in health relative to medication and disease—and the consideration of how these could be used to track adverse events.
Lecturer: Matthew H. Porteus, Stanford University, Stanford, CA.
Genome editing provides a mechanism to precisely alter the DNA sequence of a cell. The most efficient mechanism to achieve genome editing is to induce a site-specific DNA double-strand break at the genomic target site to be modified, thereby activating the cell’s own repair machinery. The CRISPR-Cas9-gRNA system has accelerated the field of genome editing because of its ease of use, its high on-target activity, and its high specificity compared to other nuclease platforms. If a donor template is provided along with the nuclease, the cell will use that donor template to repair the break by homologous recombination and precise sequence changes can be introduced into the target gene. We have focused our efforts on developing a clinically compatible method of engineering human primary blood cells, including hematopoietic stem cells, by homologous recombination. Using this system, we now achieve gene editing by homologous recombination frequencies of 40–80% in CD34+ hematopoietic stem and progenitor cells and 20–50% in primary human T cells. I will discuss our translation of this process to the clinic for genetic diseases of the blood and immune system, including sickle cell disease, and our ability to use homologous recombination to engineer complex phenotypes in primary human T cells. As genome-edited primary human cells are a novel therapeutic, a careful assessment of the safety and toxicology of such products is critical. Traditional methods of evaluating such toxicology using the paradigms of small molecules or biologics may not be appropriate for this different class of therapeutics. Genetically engineered cell based therapeutics have a different PK/PD profile, for example, that needs to be considered. I will discuss some of the approaches we have taken to evaluate safety and toxicology in our genome-edited cell based products.
Lecturer: Brigitta Stockinger, MRC National Institute for Medical Research, London, United Kingdom.
The aryl hydrocarbon receptor (AhR), well known in the pharmacology/toxicology field for its role in mediating the toxicity of xenobiotics, has more recently attracted the attention of immunologists. The evolutionary conservation of this transcription factor and its widespread expression in the immune system point to important physiological functions that are slowly being unravelled. In particular, the emphasis is now shifting from the role of AhR in the xenobiotic pathway toward its mode of action in response to physiological ligands. The current focus in the field is on understanding the molecular interactions and functions of AhR in the immune system in steady state and in presence of infection and inflammation, particularly in barrier organs such as the skin, the gut, and the lung.
Dr. Stockinger obtained her PhD in biology at the University of Mainz, and did postdoctoral training in London, Cambridge (UK), and at the Cancer Research Institute in Heidelberg. In 1985 she became a member of the Basel Institute for Immunology. In 1991 she became a group leader in the Division of Molecular Immunology of the National Institute for Medical Research in Mill Hill. Her research initially focused on immune tolerance using T cell receptor transgenic mouse models. The current research focus of her laboratory is on T cell biology, understanding the development, differentiation and function of peripheral CD4 T cell subsets, as well as the physiological functions of the aryl hydrocarbon receptor in the immune system. Dr. Stockinger obtained an ERC Advanced Investigator grant in 2009 to study physiological functions of AhR and in 2013 was awarded a Wellcome Senior Investigator Grant that will continue and expand the investigation of AhR in innate and adaptive immune cells. She became a Fellow of the Academy of Medical Sciences in 2005, an EMBO fellow in 2008, and a Fellow of the Royal Society in 2013.
Lecturer: Paul Elliott, Imperial College, London, United Kingdom
National and international variations in disease rates, and temporal trends—for example, the remarkable and rapid declines in coronary heart disease mortality in many countries over recent years, point to the overwhelming importance of environmental factors in risk of chronic diseases. The new developments in ’omics technologies, new sensor technologies and exposure assessment methods, provide an unprecedented opportunity to make real advances in understanding the links between environmental stressors, health and disease. Recently the exposome concept has been proposed as a means to gain greater understanding of the interaction between the environment and the host. The exposome captures the totality of internal (biochemical) and external exposures (and their biological imprints) from a variety of sources including chemical and biological agents, gut microbial and lifestyle/psychosocial factors, over the life course. The idea is that these factors interact at a cellular and systems level to generate molecular signatures of health or disease, providing new insights into disease etiopathogenesis that can inform both preventive strategies and new treatments. The metabolic signature can be assessed through ’omic technologies and biomarkers, encompassing a wide range of molecules, including small molecule metabolites in blood or urine (metabolomics), and downstream changes in gene expression levels and regulation (transcriptomics, epigenomics, proteomics). Metabolomics in particular is a powerful and innovative approach that captures in high-resolution direct signatures of the end products of metabolic pathways associated with a wide range of physiological and pathophysiological processes. This lecture will present some recent applications of the exposome approach, including use of the Metabolome-Wide Association Study (MWAS) concept, and discuss how these ideas may be taken forward in the future.
Chairperson(s): Marie C. Fortin, Environmental and Occupational Health Sciences Institute, Piscataway, NJ, and Anne Loccisano, The Hamner Institutes for Health Sciences, Research Triangle Park, NC.
Want to learn how to write effective grants and publications, or sharpen your scientific writing skills to communicate better? As toxicologists, it is essential that we be able to articulate new ideas in the form of grants and to disseminate the results of research in the form of scientific publications. Thus effective communication through writing is fundamental therefore it is crucial for early career scientists to learn effective writing skills. Publishing is imperative in academic or non-profit sectors and obtaining sufficient funding is a necessity when establishing a career and reputation. However, most scientists do not receive any formal training in writing and these skills are usually learned by following the style of a mentor or other authors. This issue is particularly important for graduate students, postdoctoral fellows, and other early career scientists who would like to enhance their critical writing skills which are needed for good communication. Our panel of experts will provide the audience with tactics to write promising NIH grant applications, general approaches that enhance the publication success of scientific papers, as well as concrete scientific writing strategies from an author’s and reader’s standpoint. Attendees will be provided with tips to enhance their skills that will enable more effective communication of both their ideas and their science, from grant proposals to publication.
- Introduction, Marie Fortin
- Communicating Ideas Efficiently: An Essential Skill for All Researchers, Deborah A. Cory-Slechta
- Grantsmanship at NIH: How to Swim with the Sharks, Jerrold J. Heindel
- Writing for Success, Angela K. Eggleston
Lecturer: Dr. Bruce A. Beutler, University of Texas Southwestern Medical Center, Dallas, TX.
Microbes were known to be the causative agents of infectious diseases since the mid-nineteenth century, and infections were known since antiquity for their inflammatory character. However, the molecular interactions through which microbes were recognized, and through which they triggered an inflammatory response on the part of the host, remained unknown until much more recently. A genetic approach was required to elucidate them. Applying a positional cloning approach to mice that were refractory to lipopolysaccharide (LPS), we identified the LPS receptor, and with it, a family of receptors responsible for sensing diverse molecules of microbial origin. These, the Toll-like receptors, signal by way of a system of adaptors, protein kinases, and transcription factors to induce the biosynthesis of hundreds of cytokines that orchestrate inflammation. Subsequently RIG-I-like helicases, NOD-like receptors, and C-type lectin receptors also were found to respond to infection. A number of common inflammatory diseases appear to depend upon these molecular pathways, which evolved to check the spread of micro-organisms prior to the advent of adaptive immunity.
Bruce A. Beutler is a Regental Professor and Director of the Center for the Genetics of Host Defense at University of Texas Southwestern Medical Center. He received his MD from the University of Chicago in 1981. As a postdoctoral associate at Rockefeller University (1983–1986), he isolated mouse tumor necrosis factor (TNF) and discovered its importance as a mediator of inflammation. Subsequently at UT Southwestern he analyzed mammalian responses to bacterial lipopolysaccharide. This work culminated in the discovery of Toll-like receptors as key sensors of the innate immune system, capable of detecting infection within minutes of the time the host is inoculated with microbes. In further studies, Beutler has used a forward genetic strategy to elucidate many aspects of mammalian immunity. He received numerous awards for his work, among them the Balzan Prize (2007), the Albany Medical Center Prize (2009), the Shaw Prize (2011), and election to the US National Academy of Sciences (2008), the Institute of Medicine (2008), and EMBO. In 2011, he shared the Nobel Prize in Physiology or Medicine for “discoveries concerning the activation of innate immunity.”
The US Environmental Protection Agency estimates that the US generated 2.4 million tons of e-waste (used electronics) in 2010 compared to the 2.3 million tons that China produced that year. Combined, the two countries are the generators of the largest amount of used electronics, according to a 2010 United Nations Environment Programme report. The current production of e-waste overwhelms recycling sites and e-waste is sometimes exported to reclaim valuable metals and ideally manage the release of hazardous materials. Efforts to quantify the hazardous components of e-waste are underway in California where high levels of brominated flame retardants have been found in residents and wildlife. Each day, from 50 to 80 percent of the e-waste that is collected is shipped overseas for dismantling in developing countries where workers often lack training and technology to dispose safely of e-waste. Informal recycling like this releases heavy metals and persistent organic pollutants into the soil, water, and air. Distinguished panelists will explore the scope of the problem, talk about the contaminants that are regulated and unregulated in California waste streams, and discuss the impacts of its disposal and the dangers of informal or careless recycling. Finally, panelists will also talk about preliminary findings from ongoing epidemiological studies that are showing adverse health effects in the workers dismantling the electronic waste and their families.
- Introduction, Eric Dahl
- The Scope of the Problem—International Regulation and the Basel Treaty, Sanmi Areola
- Regulated and Unregulated Contaminants in California Waste Streams, Myrto Petreas
- Mechanisms of III–IV Semiconductor Toxicity—Prospects for the Future of E-Waste Disease Prevention, Bruce A. Fowler
- E-Waste Recycling in Developing Countries: Concerns of Developmental Toxicity, Aimin Chen
Lecturer: John D. Scott, Howard Hughes Medical Institute, Department of Pharmacology, University of Washington, Seattle, WA.
Intracellular signal transduction events are precisely regulated in space and time. This is achieved in part by A-Kinase Anchoring Proteins (AKAPs) that tether signaling enzymes such as protein kinases and phosphatases in proximity to selected substrates. AKAP targeting provides an efficient means to reversibly control the phosphorylation status of key substrates and contributes to the dynamic regulation of sophisticated cellular events. Using a variety of genetic, electrophysiological, and live-cell imaging techniques, we show that AKAPs, which enhance the precision of signaling events, are up-regulated under certain pathophysiological states. This leads to aberrant regulation of certain physiological processes and disorders such as diabetes and heart disease. In this talk Dr. Scott will present some recent data on the role of anchored signaling complexes that modulate various extra-pancreatic complications of diabetes, including hypertension and cataract formation.
Dr. Scott is the Edwin G. Krebs—Hilma Speights Professor in the Department of Pharmacology at the University of Washington School of Medicine, Seattle. He received his BSc (Hons) degree in biochemistry from Herriot-Watt University, Edinburgh, and his PhD degree from the University of Aberdeen. He did postdoctoral research on protein kinase inhibitors in the laboratory of Edwin Krebs at the University of Washington and then joined the faculty of the University of California, Irvine. Dr. Scott continued his research at the Vollum Institute at the Oregon Health & Sciences University, Portland, Oregon, until 2008, when he moved to the University of Washington, Seattle. Dr. Scott is a fellow of the Royal Society, London, and the Royal Society of Edinburgh.
Lecturer: Margaret Hamburg, US Food and Drug Administration, Washington, DC
Described as, “an inspiring public health leader with broad experience in infectious disease, bioterrorism, and health policy,” by HHS Secretary Kathleen Sebelius we are delighted to have Dr. Margaret A. Hamburg, the 21st US FDA Commissioner present a keynote plenary lecture at the Society’s 50th Anniversary Annual Meeting. Dr. Hamburg is exceptionally qualified by her training and experience as a medical doctor, scientist, and public health executive.
Dr. Hamburg graduated from Harvard Medical School, and completed her residency in internal medicine at what is now New York Presbyterian Hospital-Weill Cornell Medical Center, one of the top-ten hospitals in the nation. She conducted research on neuroscience at Rockefeller University in New York, studied neuro-pharmacology at the National Institute of Mental Health on the National Institutes of Health campus in Bethesda, Maryland, and later focused on AIDS research as Assistant Director of the National Institute of Allergy and Infectious Diseases.
During her career she has been widely praised for her initiatives, decisive leadership, and significant public health measures. As a public health official she is credited with improving services for women and children, a needle-exchange program to reduce the spread of HIV (the AIDS virus), and the initiation the first public health bio-terrorism defense program in the nation. Her most celebrated achievement, however, was curbing the spread of tuberculosis in the 1990s.
In 1994, Dr. Hamburg was elected to the membership in the Institute of Medicine, one of the youngest persons to be so honored. Three years later, at the request of President Clinton, she accepted the position of Assistant Secretary for Policy and Evaluation in the US Department of Health and Human Services.
Mast Cells and Glia: Two Tracks on the Road to Neuroinflammation
Lecturer: Stephen Skaper, University of Padua, Padua, Italy.
One of the more important recent advances in neuroscience research is the understanding that there is extensive communication between the immune system and the central nervous system (CNS). Proinflammatory cytokines play a key role in this communication. The emerging realization is that glia and microglia, in particular, (which are the brain’s resident macrophages), constitute an important source of inflammatory mediators and may have fundamental roles in CNS disorders from neuropathic pain and epilepsy to neurodegenerative diseases. Microglia respond also to proinflammatory signals released from other non-neuronal cells, principally those of immune origin. Mast cells are of particular relevance in this context. These immune-related cells, while resident in the CNS, are capable of migrating across the blood-spinal cord and blood-brain barriers in situations where the barrier is compromised as a result of CNS pathology. Emerging evidence suggests the possibility of mast cell-glia communication and opens exciting new perspectives for designing therapies to target neuroinflammation by differentially modulating the activation of non-neuronal cells normally controlling neuronal sensitization, both peripherally and centrally. This presentation will provide an overview of recent progress relating to the pathobiology of neuroinflammation, the role of microglia, neuroimmune interactions involving mast cells, in particular, and the possibility that mast cell-microglia crosstalk may contribute to the exacerbation of acute symptoms of chronic neurodegenerative disease and accelerate disease progression, as well as promote pain transmission pathways.
Inflammation and Neurodegeneration in CNS Injury: Evolving Concepts and New Therapeutic Targets
Lecturer: Alan I. Faden, University of Maryland School of Medicine, Baltimore, MD.
It has long been claimed that prior traumatic brain injury (TBI) increases the subsequent incidence of Alzheimer’s disease (AD). However, recent larger epidemiological studies indicate a relationship to subsequent dementia but not to AD. There is also a well-recognized association between repeated mild TBI and progressive cognitive decline or other neuropsychiatric abnormalities. The latter was first described in boxers as dementia pugilistica, and has received widespread attention in relationship to high contact sports. The term chronic traumatic encephalopathy (CTE) has been used to define a “specific” entity marked by neurobehavioral changes and deposition of phosphorylated tau protein. Less well appreciated with regard to post-traumatic neurodegeneration is the role of sustained neuroinflammation, even though this association has been recognized pathologically for decades. More recent experimental work, as well as clinical neuroimaging studies, has underscored the relationship between chronic neuroinflammation and progressive brain neurodegeneration in a number of disorders including TBI, while providing mechanistic support. Manifested by extensive microglial and astroglial activation, chronic traumatic brain inflammation (CTBI), or perhaps better termed chronic traumatic inflammatory encephalopathy (CTIE), appears likely to be the most important cause of post-traumatic neurodegeneration and related cognitive decline in terms of prevalence. Perhaps even more critically, emerging preclinical studies indicate that persistent neuroinflammation and associated neurodegeneration may be treatable weeks to months after the initiating insult(s).
Lecturer: J. Craig Venter, J. Craig Venter Institute, San Diego, CA
J. Craig Venter is a biologist renowned for his contributions in sequencing the first draft human genome in 2001, the first complete diploid human genome in 2007 and construction of the first synthetic bacterial cell in 2010. He is founder, chairman, and CEO of the J. Craig Venter Institute (JCVI), founder and CEO of the company, Synthetic Genomics Inc (SGI), and a co-founder and CEO of Human Longevity Inc (HLI). He and his teams are focused on a variety of projects and programs including: synthetic genomic research and the application of these advances to develop new biofuels, vaccines, and food and nutritional products; continued analysis of the human genome including the human microbiome, and discovering and understanding genetic diversity in the world’s oceans. Dr. Venter is a recipient of the 2008 National Medal of Science and is a member of the National Academy of Sciences. He is the author of Life at the Speed of Light: From the Double Helix to the Dawn of Digital Life (Viking, 2013) and A Life Decoded: My Genome: My Life (Viking, 2007).
Lecturer: Lawrence Tabak, Principal Deputy Director, National Institutes of Health
Lecturer: Sir John B. Gurdon, Wellcome Trust/Cancer Research UK, Institute of Cancer and Developmental Biology, University of Cambridge, Cambridge, United Kingdom
The different cell types that compose our bodies are remarkably stable. Hardly ever do we find skin cells in the brain or liver cells in the heart. In those very special cases where some regeneration can take place in vertebrates, there is little if any evidence for a switch in cell type. Nevertheless, nuclear transfer, cell fusion, and induced pluripotency can result in pluripotent embryo cells being derived from specialized adult cells. The mechanisms by which nuclear reprogramming can occur in these cases is beginning to be understood. It may become possible for new, regenerated cell types to be derived from adult cells and given back to a patient so that they receive new cells of their own genetic constitution, thereby avoiding the need for immunosuppression. The history of work in this area, and the prospects for cell replacement in the future, will be discussed.
Dr. Gurdon was a zoology undergraduate at Oxford University and returned, after a postdoc year at CalTech, as Lecturer in Embryology. In 1971, he joined the MRC molecular biology lab in Cambridge to continue his work on amphibian developmental biology. In 1983, as John Humphrey Plummer Professor of Cell Biology at the University of Cambridge, he co-founded a research institute of developmental and cancer biology (now named the Gurdon Institute) with Professor Laskey, acting as Chairman until 2002. His career has concentrated on nuclear transplantation in the frog and experiments to discover the value of mRNA microinjection, mechanisms of response to morphogen gradients, and recently, mechanisms of nuclear reprogramming by Xenopus oocytes and eggs. Master of Magdalene College Cambridge from 1995–2002, he has received various recognitions, including the 2009 Lasker Award for Basic Medical Science and the Nobel Prize for Physiology or Medicine in 2012.
Lecturer: Prof. Jeremy K. Nicholson, Imperial College London, United Kingdom.
Systems biology tools can be applied at both individual and population levels to understand integrated biochemical function in relation to disease pathogenesis. Metabolic phenotyping offers an important window on systemic activity and both advanced spectroscopic approaches can be used to characterize disease processes and responses to therapy. There is now wide recognition that the extensive cross-talk and signalling between the host and the symbiotic gut microbiome links to both the responses to therapy and disease risk factors and indeed these also modulate drug toxicity. Such symbiotic supraorganismal interactions greatly increase the degrees of freedom of the metabolic system that poses significant challenges to fundamental notions on the nature of the human diseased state, the aetiopathogenesis of common diseases, and current systems modelling requirements for personalized medicine. We have developed scalable and translatable strategies for phenotyping the hospital patient journey using top-down systems biology tools that capitalize on the use of both metabolic modelling and pharmaco-metabonomics for diagnostic and prognostic biomarker generation to aid clinical decision making at point-of-care. Such diagnostics (including those for near real-time applications, as in surgery and critical care) can be extremely sensitive for the detection of diagnostic and prognostic biomarkers in a variety of conditions and are a powerful adjunct to conventional procedures for disease assessment that are required for future developments in precision medicine including understanding of the symbiotic influences on patient state. Many biomarkers also have deeper mechanistic significance and may also generate new therapeutic leads or metrics of efficacy for clinical trial deployment. Furthermore, the complex and subtle gene-environment interactions that generate disease risks in the general human population also express themselves in the metabolic phenotype, and, as such, the Metabolome Wide Association Study approach gives us a powerful new tool to generate disease risk biomarkers from epidemiological sample collections and for assessing the health of whole populations. Such population risk models and biomarkers can also feedback to individual patient healthcare models thus closing the personal and public healthcare modelling triangle.
Jeremy K. Nicholson has won many accolades and international prizes for his work, which spans three decades, and is the author of over 500 peer-reviewed scientific papers and many other articles/patents on the development and application of novel spectroscopic and systems biology approaches to the investigation of disturbed metabolic processes in complex organisms. He was elected as a Fellow of the Academy of Medical Sciences in 2010 and currently holds honorary professorships at eight overseas universities and the Chinese Academy of Sciences, and is on the editorial board of eight international scientific journals. He is head of Department of Surgery and Cancer at Imperial College London. He is also a consultant for many pharmaceutical/healthcare companies in the United Kingdom, Europe, and the United States, and is a founder director of Metabometrix, an Imperial College spin-off company specializing in molecular phenotyping, clinical diagnostics, and toxicological screening via metabonomics and metabolomics.
Pharmacogenomics of Drug Toxicity in Cancer: Making the Case for Precision Medicine
Lecturer: Jun J. Yang, St. Jude Children's Research Hospital, Memphis, TN
Elucidation of the genetic basis for inter-patient variability in drug toxicity not only reveals important biology of a drug' s mechanism of action but also provides critical knowledge that enables risk-adapted treatment individualization. This is particularly relevant in cancer where chemotherapy is often associated with severe acute toxicities and debilitating long-term side effects. Therefore, the narrow therapeutic index of anti-leukemic drugs provides a compelling rationale for improvements in evidence-based precision medicine approaches. Focusing on acute lymphoblastic leukemia as a model disease, our pharmacogenomics research identifies genetic factors associated with response and toxicity of a wide range of common anti-cancer drugs, from which we then develop genetics-guided individualized therapy. For example, inherited deficiency in detoxification enzymes TPMT and NUDT15 predisposes children with leukemia to severe thiopurine-induced myelosuppression and preemptive dose adjustment based on gene genotype effectively minimizes host toxicity without compromising anti-cancer efficacy of this class of drugs. In fact, there is a rapidly-growing number of medications for which pharmacogenomic variants can directly guide treatment choice and/or dosing strategy. At the forefront of precision medicine, pharmacogenomics hold particularly great promise to transform medical practice with more efficacious and safer therapies across diseases.
The Role of Precision Medicine in Closing the Innovation Gap
Lecturer: Richard Barker, University of Oxford, Oxford, United Kingdom
The tremendous recent advances in basic bioscience are not translating as effectively and affordably as they should into health benefit for patients and positive change in healthcare delivery. The presentation will analyze and illustrate this phenomenon and the threat it represents to the long-term sustainability of biomedical innovation. It will also propose changes to both the innovation process and the environment in which it operates, highlighting the golden thread of precision medicine—vital to the potential to make major changes in innovation productivity. The talk will draw on the speaker›s recent experience launching the UK’s Precision Medicine Catapult.
Moderator: Daniel Krewski, PhD, MHA, McLaughlin Centre for Population Health Risk Assessment, University of Ottawa
On October 1, 2014, the Scientific Liaison Coalition (SLC) hosted a webinar, Progress Made on Tox21: A Framework for the Next Generation of Risk Science, presented by Daniel Krewski. The Society of Toxicology (SOT) is a participating member of the SLC. Dr. Krewski is currently Professor of Epidemiology and Community Medicine and Scientific Director of the McLaughlin Centre for Population Health Risk Assessment at the University of Ottawa. He served as Chair of the National Research Council’s Committee on Toxicity Testing and Assessment of Environmental Agents, which published its influential report, “Toxicity Testing in the 21st Century: A Vision and a Strategy,” published in June of 2007.
The mission of the SLC is “improving the ability of societies to partner with other domestic and international organizations that have objectives consistent with the goal of increasing the impact of the science of toxicology to improve public health“ by:
- Strengthening partnerships among scientific- and health-based organizations to increase awareness of the impact of toxicology and related subjects on human health, and
- Functioning as a means to enhance cooperation among societies as equals with the goal of accomplishing tasks benefiting human health and disease prevention through joint and several shared activities.
The participating societies in the SLC include the American Association for Cancer Research (AACR), American Academy of Clinical Toxicology (AACT), American Chemical Society (ACS), American College of Medical Toxicology (ACMT), American College of Toxicology (ACT), The Endocrine Society (ENDO), Environmental Mutagenesis and Genomics Society (EMGS), International Society for the Study of Xenobiotics (ISSX), Safety Pharmacology Society (SPS), Society for Risk Analysis (SRA), Society for the Study of Reproduction (SSR), Society of Environmental Toxicology and Chemistry (SETAC), Society of Toxicologic Pathology (STP), SOT, and Teratology Society (Teratology).
*Note to Mac users: Due to software incompatibilities, it is advisable that you view this recording on a PC.
Lecturer: Robin J.M. Franklin, Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.
Remyelination, the process by which new myelin sheaths are restored to demyelinated axons, represents one of the most compelling examples of adult multipotent stem cells contributing to regeneration of the injured CNS. This process can occur with remarkable efficiency in multiple sclerosis (MS), and in experimental models, revealing an impressive ability of the adult CNS to repair itself. However, the inconsistency of remyelination in MS, and the loss of axonal integrity that results from its failure, makes enhancement of remyelination an important therapeutic objective. There is now compelling evidence that ageing is the major contributor to the declining efficiency of remyelination and that this is largely due to a failure of stem cell differentiation. This talk will review recent studies we have undertaken aimed at obtaining a detailed understanding of the mechanisms of regulating differentiation during remyelination and hence identifying novel therapeutic targets.
Building a Heart: From Cells to Tissues to Organs
Lecturer: Doris Taylor, Texas Heart Institute, Houston, TX.
Cardiovascular disease (CVD) is the number one cause of death in the United States. However, few treatments for CVD provide a means to regain full cardiac function with no long-term side effects. Novel tissue-engineered products may provide a way to overcome the limitations of current CVD therapies by replacing injured myocardium with functioning tissue or by inducing more constructive forms of endogenous repair. Dr. Taylor will discuss some of the factors that must be considered in the development of tissue-engineered products and review the methods currently being investigated to generate more.
From 3D Microchip to Human Organ Culture Models: Trachea, Bronchi/Bronchiole and Lung Biomimetic Models for Disease Modeling, Drug Discovery and Toxicology Evaluation
Lecturer: Joan Nichols, University of Texas Medical Branch, Galveston, TX.
We have learned a great deal about respiratory tract and lung physiology or pathophysiology of disease from the study of animal disease models, tissues from patients isolated at autopsy or growth of monoclonal human cell populations in two dimensional (2D) cultures. Animal models, mainly mice, have been widely used in research and although animal models can simulate human disease they never fully mirror all aspects of human immune response or pathophysiology of disease. Because of this many drug treatments and vaccines developed solely using animal models have been ineffective when used in patient care. Recent advances in microfabrication technology, microfluidics, and tissue engineering have provided a new approach to the development of human 3D tissue culture models which enable production of robust long-lived human tissue analogs. Use of these models along with more complex 3D human organ culture models, containing multiple cell phenotypes, provides a more reasonable approximation of what occurs in the dynamic in vivo microenvironment of human tissues. Microfluidic supported 3D respiratory tract and lung models are currently being used as advanced human testing platforms for evaluating drug response or drug toxicity, hopefully reducing the cost of drug development. Human tissue models may also provide a mechanism for development of personalized medical care based on testing of drugs on a patient’s own cells or engineered tissues in the future.
Lecturer: William L. Murphy, University of Wisconsin-Madison, Madison, WI.
The need for human, organotypic culture models coupled with the requirements of contemporary drug discovery and toxin screening (i.e. reproducibility, high throughput, transferability of data, clear mechanisms of action) frame an opportunity for a paradigm shift. The next generation of high throughput cell-based assay formats will require a broadly applicable set of tools for human tissue assembly and analysis. Toward that end, we have recently focused on (1) generating iPS-derived cells that properly represent the diverse phenotypic characteristics of developing or mature human somatic cells, (2) assembling organotypic cell culture systems that are robust and reproducible, (3) translating organotypic cell culture models to microscale systems for high-throughput screening, and (4) combining genomic analyses with bioinformatics to gain insights into organotypic model assembly and the pathways influenced by drugs and toxins. This lecture will emphasize recent studies in which we have explored assembly of organotypic vascular, liver, and brain tissues. These tissues mimic critical aspects of human organ structure and can be used for reproducible identification of drug candidates and toxic compounds. Our work particularly emphasizes reproducibility and data transferability, which we view as vital to the widespread use of organotypic human models in toxicity testing. The lecture will also introduce the use of our assembled human tissues to develop models of rare developmental disorders and degenerative diseases of the brain.
Lecturer: Witold Filipowicz, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
MicroRNAs (miRNAs) are a novel class ~20-nt-long regulatory RNAs expressed in eukaryotes. MiRNAs regulate gene expression post-transcriptionally, by imperfectly base-pairing to 3’UTR of mRNAs, what results in translational repression or mRNA deadenylation and degradation. The number of different miRNAs in humans reaches ~1,000, and ~50% of all human genes are predicted to be subject to miRNA regulation. Although specific functions and target mRNAs have been assigned to only a fraction of identified miRNAs, much evidence exists that miRNAs participate in the regulation of nearly all cellular and developmental processes. Expression of many miRNAs is tissue or development specific and major changes in miRNA expression are observed in human pathologies, including cancer. Clearly, discovery of miRNAs added a new dimension to the complexity and regulation of eukaryotic genomes.
This lecture will provide current knowledge about the mechanism of miRNA-mediated repression of gene expression, procedures to identify miRNA targets, as well as a role of miRNAs in selected human pathologies and the use of miRNA profiling as a diagnostic tool in human diseases and in tissue and cell injuries. MiRNAs has been found to be secreted from cells via exosomes and their profiling in human serum and other body fluids appears to be a promising diagnostic tool in different pathologies. MiRNAs may also play important roles in cellular responses to xenobiotic stresses and in control of drug-metabolizing enzymes. In addition, miRNAs or compounds blocking their function represent promising therapeutic agents.
Chairperson(s): Lyle Burgoon, US EPA, Durham, NC, and Sneha Bhatia, Research Institute for Fragrance Materials Inc., Woodcliff Lake, NJ.
How many times a day do we use Google or a search engine? Its use has become so intuitive that we have coined this term as a verb and simply cannot imagine functioning without it. Information that was once confined to libraries and various periodicals is now free and easily accessible since the advent of Internet technology. Furthermore, it has broken cultural and language barriers and enabled one to communicate and collaborate with people all over the world. The combination of social media, open source programs, and bioinformatics has transformed the role of the computer in the modern scientist’s life. Video journals, blogging, open access journals, social network websites, and podcasts have become the new channels of communication—enabling first hand transfer of free knowledge and an ease by which to carry out many collaborative efforts. A familiarity with simple Internet searching, word processing, and expansive spreadsheets is simply not an adequate preparation. Furthermore, the software tools used to deal with data arising from in silico models, toxicogenomics, or high-throughput screens require an understanding of basic concepts in computer science, database design, bioinformatics, and statistics. To bridge the gap between these two worlds our panel of experts will provide toxicologists with the basic knowledge of the informatics and various open source tools available. In closing, we’ll discuss innovative strategies including the use of social media as a communication, collaboration, networking, and a career advancement tool.
- The Cloud, Open Source, and Data Democratization: Innovating Computational Toxicology and Bioinformatics, Lyle D. Burgoon
- Hazard Communication in the 21st Century: Use of Social Media and Internet Technologies to Communicate Hazard, Phil Wexler
- Social Media Essentials for Toxicologists, Matthew Price
- Social Media As a Career Advancement Tool: Your Virtual Resume, Sneha Bhatia
Chairperson(s): Kelly J. Chandler, US EPA, Research Triangle Park, NC, and Bethany R. Hannas, US EPA, Research Triangle Park, NC.
Mentoring is a critical element in the career development of all toxicologists, both in terms of making the most of potential mentors and developing effective mentoring skills. Whether through involvement in academia, or helping to develop the expertise of an early-career scientist, most toxicologists will provide mentoring at some point in their career. The mentor role serves to transfer knowledge, give advice and provide support to a trainee or developing scientist, while the mentee is relied upon by the mentor to provide active participation and input into the relationship. According to national polls, as well as SOT-specific surveys, one of the resounding topics of interest for developing scientists is mentoring from the broad perspectives of choosing the right mentor, down to developing the skills to become a sound mentor. Therefore, this session was designed to complement existing mentor matching opportunities offered through SOT. Speaker presentations will focus on: (1) the fundamentals of mentoring, including the different situations and roles in which the mentee-mentor dynamic may be encountered; (2) an introduction to the most commonly used mentoring techniques; (3) identifying characteristics of a strong mentor-mentee relationship; and (4) mentoring towards the future of science and the challenge to overcome more complex scientific problems. Speaker perspectives will address the mentorship role within academia, government, and industry. Attendees of this session will learn to identify a healthy mentor-mentee relationship and understand the benefits to each member of the collaboration. Mentoring topics discussed in this session will be applicable to scientists at every career stage through highlighting the basics behind a strong, mutually-beneficial mentoring relationship.
- Introduction, Bethany R. Hannas
- Supervisors, Mentors and Yodas: A Perspective on Their Role in Your Career Development, Nigel J. Walker
- Approaches for Mentoring Graduate Students, Stephen H. Safe
- The Two-Way Street of Mentoring: Reflections on Career Development in a Chemical Industry Toxicology Laboratory, Louise Saldutti
- The Future: Mentoring Interdisciplinary Scientists, Ofelia A. Olivero
Lecturer: Leroy Hood, Institute for Systems Biology (ISB) in Seattle, WA
The challenge for biology in the twenty-first century is the need to deal with its incredible complexity. One powerful way to think of biology is to view it as an informational science. This view leads to the conclusion that biological information is captured, mined, integrated by biological networks, and finally passed off to molecular machines for execution. Hence the challenge in understanding biological complexity is that of deciphering the operation of dynamic biological networks across the three time scales of life—evolution, development, and physiological responses. Systems approaches to biology are focused on delineating and deciphering dynamic biological networks and their interactions with simple and complex molecular machines.
Dr. Hood’s focus will be on our strategies for taking a systems approach to disease—looking at prion disease and liver toxicity in mice. We have published a study on prion disease that has taken more than 6 years—that lays out the principles of a systems approach to disease including new insights into pathophysiology, new approaches to diagnosis and therapy as well as dealing with the striking signal to noise problems of high throughput biological measurements and biology itself. We have also studied two types of liver toxicity and these studies have also yielded insights similar to those discussed above. We have made blood a window for assessing health and disease through the use of blood organ-specific markers (for both brain and liver).
Dr. Hood will also discuss the emerging technologies (measurement and visualization) that will transform medicine and the analyses of toxicity over the next 10 years—including next generation DNA sequencing, targeted mass spectrometry, micro-fluidic protein chips, and single-cell analyses.
It appears that systems approaches to disease, together with pioneering changes in technology and the development of powerful new computational and mathematical tools will transform medicine over the next 5–20 years from its currently reactive state to a mode that is predictive, personalized, preventive, and participatory (P4).
In conclusion, Dr. Hood will describe what P4 medicine will do for the individual patient. He will also consider the societal impact of P4 medicine and how ISB has created global strategic partnerships to bring P4 medicine to patients.
Lecturer: Bob Perciasepe, Deputy Administrator, US EPA
Chairperson(s): Maureen R. Gwinn, K–12 Subcommittee Co-Chair, US EPA, Washington, DC, Joanna M. Matheson, K–12 Subcommittee Co-Chair, US Consumer Product Safety Commission, Bethesda, MD, and Toufan Parman, Event Coordinator, SRI International, Menlo Park, CA
Sponsors: Education Committee K–12 Subcommittee Northern California Regional Chapter
The Education Committee K–12 Subcommittee in conjunction with the Northern California Regional Chapter is hosting special activities at the Lawrence Hall of Science on the University of California Berkeley campus to engage visitors in activities related to toxicology and to investigate toxicology careers. Through interactive drama and experiments, families will explore how the dose makes the poison. Toxicologists will share why they think toxicology is a great career. Undergraduate students will assist with the activities.
The Lawrence Hall of Science is a premier science museum for preschoolers on up with fascinating exhibits, ingenuity lab, live science demonstrations, and a planetarium.
In 2011, SOT partnered with The Smithsonian Associates to present a day-long seminar titled “When Good Chemicals Turn Bad.” The seminar featured information on the history of toxicology, as well as new and emerging areas of research.
- The Story of Toxicology by Phil Wexler, MLS, National Library of Medicine
- Toxicology: 1860–2010: 150 Years of the Political Science / Environmental Health Toxicology: The Dose Makes the Poison—What’s Safe by Michael A. Gallo, PhD, DABT, ATS, Rutgers Robert Wood Johnson Medical School, and Marion Ehrich, PhD, DABT, Virginia-Maryland College of Veterinary Medicine (Dr. Ehrich’s presentation begins at approximately 42:40.)
- General Toxicology by Cathleen Clancy, MD, FACMT, FACEP, National Capital Poison Center
- Air Pollutants in Our Environment: From Source to Health Effects by Amir Sapkota, PhD, University of Maryland School of Public Health
- Toxic Trace Elements and the Chesapeake Bay / Human Induced Toxic Effects on Plant Diversity by Gerhardt F. Riedel, PhD, Smithsonian Environmental Research Center, and Kathy Boomer, PhD, Smithsonian Environmental Research Center (Dr. Boomer’s presentation begins at approximately 22:50.)
- Environmental Epigenomics: How Our Environment Early in Life Determines Our Risk of Disease as Adults by Cheryl Lyn Walker, PhD, University of Texas MD Anderson Cancer Center
- Nanomedicines and Nanotechnologies: Opportunities and Challenges by Martin Philbert, PhD, University of Michigan School of Public Health
- From Alternative Methods to a New Toxicology for the 21st Century by Thomas Hartung, MD, PhD, Johns Hopkins University Bloomberg School of Public Health