Colloquium: Physical approaches to DNA sequencing and detection

With the continued improvement of sequencing technologies, the prospect of genome-based medicine is now at the forefront of scientific research. To realize this potential, however, a revolutionary sequencing method is needed for the cost-effective and rapid interrogation of individual genomes. This capability is likely to be provided by a physical approach to probing DNA at the single-nucleotide level. This is in sharp contrast to current techniques and instruments that probe (through chemical elongation, electrophoresis, and optical detection) length differences and terminating bases of strands of DNA. Several physical approaches to DNA detection have the potential to deliver fast and low-cost sequencing. Central to these approaches is the concept of nanochannels or nanopores, which allow for the spatial confinement of DNA molecules. In addition to their possible impact in medicine and biology, the methods offer ideal test beds to study open scientific issues and challenges in the relatively unexplored area at the interface between solids, liquids, and biomolecules at the nanometer length scale. This Colloquium emphasizes the physics behind these methods and ideas, critically describes their advantages and drawbacks, and discusses future research opportunities in the field

Computational Biomarker Discovery: From Systems Biology to Predictive and Personalized Medicine Applications

poster abstractWith the advent of Genome-based Medicine, there is an escalating need for discovering how the modifications of biological molecules, either individually or as an ensemble, can be uniquely associated with human physiological states. This knowledge could lead to breakthroughs in the development of clinical tests known as "biomarker tests" to assess disease risks, early onset, prognosis, and treatment outcome predictions. Therefore, development of molecular biomarkers is a key agenda in the next 5-10 years to take full advantage of the human genome to improve human well-beings. However, the complexity of human biological systems and imperfect instrumentations of high-throughput biological instruments/results have created significant hurdles in biomarker development. Only recently did computational methods become an important player of the research topic, which has seen conventional molecular biomarkers development both extremely long and cost-ineffective. At Indiana Center for Systems Biology and Personalized Medicine, we are developing several computational systems biology strategies to address these challenges. We will show examples of how we approach the problem using a variety of computational techniques, including data mining, algorithm development to take into account of biological contexts, biological knowledge integration, and information visualization. Finally, we outline how research in this direction to derive more robust molecular biomarkers may lead to predictive and personalized medicine. Indiana Center for Systems Biology and Personalized Medicine (CSBPM) was founded in 2007 as an IUPUI signature center by Dr. Jake Chen and his colleagues in the Indiana University School of Informatics, School of Medicine, and School of Science. CSBPM is the only research center in the State of Indiana with the primary goal of pursuing predictive and personalized medicine. CSBPM currently consists of eleven faculty members from the School of Medicine, School of Science, School of Engineering, School of Informatics, and Indiana University Simon Cancer Center. The primary mission of the center is to foster the development and use of systems biology and computational modeling techniques to address challenges in future genome-based medicine. The ultimate goal of the center is to shorten the discovery-to-practice gap between integrative ―Omics‖ biology studies—including genomics, transcriptomics, proteomics, and metabolomics—and predictive and personalized medicine applications

Use of Embark Database and An Active Learning Protocol in a High School Classroom

With advances in technology, personal genome sequencing has become more affordable than ever before. With this wealth of genetic information come new individualized approaches to medicine and pharmacology, along with moral, legal, and ethical issues to carefully consider. Yet studies suggest that most members of the general public do not have the genetic literacy required to understand the implications of genomic data. It is important that today’s students are able to grasp concepts relating to their own genome to make informed medical decisions in the future. Here I describe an active learning-based activity designed to enhance high school students’ understanding of genetic concepts. This activity is centered around online exploration of canine genomic data using Embark, a direct-to-consumer genetic testing company associated with the Cornell University College of Veterinary Medicine. Progress developing a study protocol to test the effectiveness of this activity in a Lafayette county high school classroom is discussed

Individualised medicine and health care system. Summary

There is already a medical need for increasing patient involvement in health care, and this is likely to increase in the future. Visions of technology suggest that an "individualised health care" could emerge from the combination of this trend with findings from the life sciences in about twenty years: Medical services that can be more specifically adapted to the individual than in the past are seen as having the potential to achieve more ambitious quality and cost targets in health care. Such individualised medicine could permeate all stages of service provision - from prevention and (early) diagnosis to therapy and follow-up monitoring. It is based on such diverse scientific and technological developments as genome analyses, nanomedicine, autologous cell therapies, molecular imaging, nutrigenomics or the determination of patient-specific protein expression patterns. Subject and objective of the project The Committee on Education, Research and Technology Assessment commissioned a report on the future of this topic, which is still predominantly in the research and development stage. Already in the early phase of the research and health policy discussion on the future option, the aim was to analyse > which lines of development in the life sciences can contribute to individualised medicine, > how the current state of science and technology and possible future developments are to be assessed, > what implications arise for technology development and the embedding of these technologies in the future health care system if they are to contribute to individualised medicine, and > what implications could arise from individualised medicine for medical care, for companies and health insurance

From metabonomics to pharmacometabonomics: The role of metabolic profiling in personalized medicine

Variable patient responses to drugs are a key issue for medicine and for drug discovery and development. Personalised medicine, that is the selection of medicines for subgroups of patients so as to maximise drug efficacy and minimise toxicity, is a key goal of 21st century healthcare. Currently, most personalised medicine paradigms rely on clinical judgement based on the patient’s history, and on the analysis of the patients’ genome to predict drug effects i.e. pharmacogenomics. However, variability in patient responses to drugs is dependent upon many environmental factors to which human genomics is essentially blind. A new paradigm for predicting drug responses based on individual pre-dose metabolite profiles has emerged in the past decade: pharmacometabonomics, which is defined as ‘the prediction of the outcome (for example, efficacy or toxicity) of a drug or xenobiotic intervention in an individual based on a mathematical model of pre-intervention metabolite signatures’. The new pharmacometabonomics paradigm is complementary to pharmacogenomics but has the advantage of being sensitive to environmental as well as genomic factors. This review will chart the discovery and development of pharmacometabonomics, and provide examples of its current utility and possible future developments

Racially-Tailored Medicine Unraveled

In June 2005, the FDA approved BiDil, a heart failure medication that is labeled for use only by African-Americans and thus is the first treatment of its kind. The drug likely portends a future of growing interest in race-based medicine. This phenomenon is emerging at the same time that scientists, in light of the Human Genome Project, are reaching an understanding that race has no biological meaning, and consequently, racially-tailored medicine is both puzzling and troubling. This Article explores the reasons for the new focus on racial-profiling in medicine. It analyzes the risks and dangers of this approach, including medical mistakes, stigmatizations, discrimination, exacerbation of health disparities, and violation of anti-discrimination mandates. The author does not argue against the pursuit of attribute-based therapies, but cautions that the attribute or attributes at issue must be carefully determined and will not be equivalent to what is conventionally thought of as race. The article develops recommendations for safeguards that should be implemented by scientific review boards, IRBs, researchers, health care providers, and journalists involved with attribute-based research and therapeutic practices to ensure that this new approach promotes rather than diminishes public health and welfare

Guidelines for Genome-Scale Analysis of Biological Rhythms

Genome biology approaches have made enormous contributions to our understanding of biological rhythms, particularly in identifying outputs of the clock, including RNAs, proteins, and metabolites, whose abundance oscillates throughout the day. These methods hold significant promise for future discovery, particularly when combined with computational modeling. However, genome-scale experiments are costly and laborious, yielding “big data” that are conceptually and statistically difficult to analyze. There is no obvious consensus regarding design or analysis. Here we discuss the relevant technical considerations to generate reproducible, statistically sound, and broadly useful genome-scale data. Rather than suggest a set of rigid rules, we aim to codify principles by which investigators, reviewers, and readers of the primary literature can evaluate the suitability of different experimental designs for measuring different aspects of biological rhythms. We introduce CircaInSilico, a web-based application for generating synthetic genome biology data to benchmark statistical methods for studying biological rhythms. Finally, we discuss several unmet analytical needs, including applications to clinical medicine, and suggest productive avenues to address them

CRISPR/Cas9‐mediated genome editing: from basic research to translational medicine

The recent development of the CRISPR/Cas9 system as an efficient and accessible programmable genome-editing tool has revolutionized basic science research. CRISPR/Cas9 system-based technologies have armed researchers with new powerful tools to unveil the impact of genetics on disease development by enabling the creation of precise cellular and animal models of human diseases. The therapeutic potential of these technologies is tremendous, particularly in gene therapy, in which a patient-specific mutation is genetically corrected in order to treat human diseases that are untreatable with conventional therapies. However, the translation of CRISPR/Cas9 into the clinics will be challenging, since we still need to improve the efficiency, specificity and delivery of this technology. In this review, we focus on several in vitro, in vivo and ex vivo applications of the CRISPR/Cas9 system in human disease-focused research, explore the potential of this technology in translational medicine and discuss some of the major challenges for its future use in patients.Portuguese Foundation for Science and Technology: UID/BIM/04773/2013 1334 Spanish Ministry of Science, Innovation and Universities RTI2018-094629-B-I00 Portuguese Foundation for Science and Technology SFRH/BPD/100434/2014 European Union (EU) 748585 LPCC-NRS/Terry Fox grantsinfo:eu-repo/semantics/publishedVersio

Development of Protacs to Target Cancer-promoting Proteins for Ubiquitination and Degradation

The proteome contains hundreds of proteins that in theory could be excellent therapeutic targets for the treatment of human diseases. However, many of these proteins are from functional classes that have never been validated as viable candidates for the development of small molecule inhibitors. Thus, to exploit fully the potential of the Human Genome Project to advance human medicine, there is a need to develop generic methods of inhibiting protein activity that do not rely on the target protein’s function. We previously demonstrated that a normally stable protein, methionine aminopeptidase-2 or MetAP-2, could be artificially targeted to an Skp1-Cullin-F-box (SCF) ubiquitin ligase complex for ubiquitination and degradation through a chimeric bridging molecule or Protac (proteolysis targeting chimeric molecule). This Protac consisted of an SCFß-TRCP-binding phosphopeptide derived from I{kappa}B{alpha} linked to ovalicin, which covalently binds MetAP-2. In this study, we employed this approach to target two different proteins, the estrogen (ER) and androgen (AR) receptors, which have been implicated in the progression of breast and prostate cancer, respectively. We show here that an estradiol-based Protac can enforce the ubiquitination and degradation of the {alpha} isoform of ER in vitro, and a dihydroxytestosterone-based Protac introduced into cells promotes the rapid disappearance of AR in a proteasome-dependent manner. Future improvements to this technology may yield a general approach to treat a number of human diseases, including cancer

iCOD : an integrated clinical omics database based on the systems-pathology view of disease

<p>Abstract</p> <p>Background</p> <p>Variety of information relating between genome and the pathological findings in disease will yield a wealth of clues to discover new function, the role of genes and pathways, and future medicine. In addition to molecular information such as gene expression and genome copy number, detailed clinical information is essential for such systematic omics analysis.</p> <p>Results</p> <p>In order to provide a basic platform to realize a future medicine based on the integration of molecular and clinico-pathological information of disease, we have developed an integrated clinical omics database (iCOD) in which comprehensive disease information of the patients is collected, including not only molecular omics data such as CGH (Comparative Genomic Hybridization) and gene expression profiles but also comprehensive clinical information such as clinical manifestations, medical images (CT, X-ray, ultrasounds, etc), laboratory tests, drug histories, pathological findings and even life-style/environmental information. The iCOD is developed to combine the molecular and clinico-pathological information of the patients to provide the holistic understanding of the disease. Furthermore, we developed several kinds of integrated view maps of disease in the iCOD, which summarize the comprehensive patient data to provide the information for the interrelation between the molecular omics data and clinico-pathological findings as well as estimation for the disease pathways, such as three layer-linked disease map, disease pathway map, and pathome-genome map.</p> <p>Conclusions</p> <p>With these utilities, our iCOD aims to contribute to provide the omics basis of the disease as well as to promote the pathway-directed disease view. The iCOD database is available online, containing 140 patient cases of hepatocellular carcinoma, with raw data of each case as supplemental data set to download. The iCOD and supplemental data can be accessed at</p> <p><url>http://omics.tmd.ac.jp/icod_pub_eng</url></p