Translational Biomedical Research Research Articles

Consortium sandbox: building and sharing resources.

Some common challenges of biomedical product translation-scientific, regulatory, adoption, and reimbursement-can best be addressed by the broad sharing of resources or tools. But, such aids remain undeveloped because the undertaking requires expertise from multiple research sectors as well as validation across organizations. Biomedical resource development can benefit from directed consortia-a partnership framework that provides neutral and temporary collaborative environments for several, oftentimes competing, organizations and leverages the aggregated intellect and resources of stakeholders so as to create versatile solutions. By analyzing 369 biomedical research consortia, we tracked consortia growth around the world and gained insight into how this partnership model advances biomedical research. Our analyses suggest that research-by-consortium provides benefit to biomedical science, but the model needs further optimization before it can be fully integrated into the biomedical research pipeline.

Reengineering Biomedical Translational Research with Engineering Ethics.

It is widely accepted that translational research practitioners need to acquire special skills and knowledge that will enable them to anticipate, analyze, and manage a range of ethical issues. While there is a small but growing literature that addresses the ethics of translational research, there is a dearth of scholarship regarding how this might apply to engineers. In this paper we examine engineers as key translators and argue that they are well positioned to ask transformative ethical questions. Asking engineers to both broaden and deepen their consideration of ethics in their work, however, requires a shift in the way ethics is often portrayed and perceived in science and engineering communities. Rather than interpreting ethics as a roadblock to the success of translational research, we suggest that engineers should be encouraged to ask questions about the socio-ethical dimensions of their work. This requires expanding the conceptual framework of engineering beyond its traditional focus on "how" and "what" questions to also include "why" and "who" questions to facilitate the gathering of normative, socially-situated information. Empowering engineers to ask "why" and "who" questions should spur the development of technologies and practices that contribute to improving health outcomes.

Birth of healthy offspring following ICSI in in vitro-matured common marmoset (Callithrix jacchus) oocytes.

Intracytoplasmic sperm injection (ICSI), an important method used to treat male subfertility, is applied in the transgenic technology of sperm-mediated gene transfer. However, no study has described successful generation of offspring using ICSI in the common marmoset, a small non-human primate used as a model for biomedical translational research. In this study, we investigated blastocyst development and the subsequent live offspring stages of marmoset oocytes matured in vitro and fertilized by ICSI. To investigate the optimal timing of performing ICSI, corrected immature oocytes were matured in vitro and ICSI was performed at various time points (1–2 h, 2–4 h, 4–6 h, 6–8 h, and 8–10 h after extrusion of the first polar body (PB)). Matured oocytes were then divided randomly into two groups: one was used for in vitro fertilization (IVF) and the other for ICSI. To investigate in vivo development of embryos followed by ICSI, 6-cell- to 8-cell-stage embryos and blastocysts were nonsurgically transferred into recipient marmosets. Although no significant differences were observed in the fertilization rate of blastocysts among ICSI timing after the first PB extrusion, the blastocyst rate at 1–2 h was lowest among groups at 2–4 h, 4–6 h, 6–8 h, and 8–10 h. Comparing ICSI to IVF, the fertilization rates obtained in ICSI were higher than in IVF (p>0.05). No significant difference was noted in the cleaved blastocyst rate between ICSI and IVF. Following the transfer of 37 ICSI blastocysts, 4 of 20 recipients became pregnant, while with the transfer of 21 6-cell- to 8-cell-stage ICSI embryos, 3 of 8 recipients became pregnant. Four healthy offspring were produced and grew normally. These are the first marmoset offspring produced by ICSI, making it an effective fertilization method for marmosets.

Development of an open source software module for enhanced visualization during MR-guided interstitial gynecologic brachytherapy.

In 2010, gynecologic malignancies were the 4th leading cause of death in U.S. women and for patients with extensive primary or recurrent disease, treatment with interstitial brachytherapy may be an option.However, brachytherapy requires precise insertion of hollow catheters with introducers into the tumor in order to eradicate the cancer. In this study, a software solution to assist interstitial gynecologic brachytherapy has been investigated and the software has been realized as an own module under (3D) Slicer, which is a free open source software platform for (translational) biomedical research. The developed research module allows on-time processing of intra-operative magnetic resonance imaging (iMRI) data over a direct DICOM connection to a MR scanner. Afterwards follows a multi-stage registration of CAD models of the medical brachytherapy devices (template, obturator) to the patient’s MR images, enabling the virtual placement of interstitial needles to assist the physician during the intervention.

The Microbe Farms: Microbial Biorepositories in Clinical Microbiology

Biorepositories aim to acquire, authenticate, preserve, develop, and distribute biological specimens, along with information, technology, intellectual property, and standards for the advancement and application of scientific knowledge. Biorepositories are critical components of modern healthcare, as they provide resources to advance translational biomedical research, navigation through the FDA process for in vitro devices, verification and validation of diagnostic methods, and personalized medicine. In order to fully realize the opportunities that biorepositories offer to medicine, laboratories must be able to guarantee high-quality biospecimens, associated information, and a system able to respond to the needs of method verification, quality control, or the requests of scientific colleagues. A biorepository requires funding resources and space, which are often difficult to find within existing health care resources, yet health care may benefit most from the resources biorepositories provide. It is crucial that institutions be able to recognize these issues and start preparing and releasing adequate resources to support the development of biorepositories with a common goal to improve health care by increasing the quality of biomedical research and diagnostic test development. The future of biorepositories depends on the development of more evidence-based practices in both the research and clinical settings. As the field matures, educating a new generation of biospecimen/biobanking scientists will be an important need.

Multiple hereditary exostoses (MHE): elucidating the pathogenesis of a rare skeletal disorder through interdisciplinary research

An interdisciplinary and international group of clinicians and scientists gathered in Philadelphia, PA, to attend the fourth International Research Conference on Multiple Hereditary Exostoses (MHE), a rare and severe skeletal disorder. MHE is largely caused by autosomal dominant mutations in EXT1 or EXT2, genes encoding Golgi-associated glycosyltransferases responsible for heparan sulfate (HS) synthesis. HS chains are key constituents of cell surface- and extracellular matrix-associated proteoglycans, which are known regulators of skeletal development. MHE affected individuals are HS-deficient, can display skeletal growth retardation and deformities, and consistently develop benign, cartilage-capped bony outgrowths (termed exostoses or osteochondromas) near the growth plates of many skeletal elements. Nearly 2% of patients will have their exostoses progress to malignancy, becoming peripheral chondrosarcomas. Current treatments are limited to the surgical removal of symptomatic exostoses. No definitive treatments have been established to inhibit further formation and growth of exostoses, prevent transition to malignancy, or address other medical problems experienced by MHE patients, including chronic pain. Thus, the goals of the Conference were to assess our current understanding of MHE pathogenesis, identify key gaps in information, envision future therapeutic strategies and discuss ways to test and implement them. This report provides an assessment of the exciting and promising findings in MHE and related fields presented at the Conference and a discussion of the future MHE research directions. The Conference underlined the critical usefulness of gathering experts in several research fields to forge new alliances and identify cross-fertilization areas to benefit both basic and translational biomedical research on the skeleton.

Toward Functional Screening of Cardioactive and Cardiotoxic Drugs with Zebrafish in Vivo Using Pseudodynamic Three-Dimensional Imaging

Given the high mortality in patients with cardiovascular diseases and the life-threatening consequences of drugs with unforeseen adverse effects on hearts, a critical evaluation of the pharmacological response of cardiovascular function on model animals is important especially in the early stages of drug development. We report a proof-of-principle study to demonstrate the utility of zebrafish as an analytical platform to predict the cardiac response of new drugs or chemicals on human beings. With pseudodynamic 3D imaging, we derive individual parameters that are central to the cardiac function of zebrafish, including the ventricular stroke volume, ejection fraction, cardiac output, heart rate, diastolic filling function, and ventricular mass. We evaluate both inotropic and chronotropic responses of the heart of zebrafish treated with drugs that are commonly prescribed and possess varied known cardiac activities. We reveal deranged cardiac function of a zebrafish model of cardiomyopathy induced with a cardiotoxic drug. The cardiac function of zebrafish exhibits a pharmacological response similar to that of human beings. We compare also cardiac parameters obtained in this work with those derived with conventional 2D approximation and show that the latter tends to overestimate the cardiac parameters and produces results of greater variation. In view of the growing interest of using zebrafish in both fundamental and translational biomedical research, we envisage that our approach should benefit not only contemporary pharmaceutical development but also exploratory research such as gene, stem cell, or regenerative therapies targeting congenital or acquired heart diseases.

Effective gene targeting in rabbits using RNA-guided Cas9 nucleases

Effective gene targeting in rabbits using RNA-guided Cas9 nucleases

Genomic research perspectives in Kazakhstan.

IntroductionTechnological advancements rapidly propel the field of genome research. Advances in genetics and genomics such as the sequence of the human genome, the human haplotype map, open access databases, cheaper genotyping and chemical genomics, have transformed basic and translational biomedical research. Several projects in the field of genomic and personalized medicine have been conducted at the Center for Life Sciences in Nazarbayev University. The prioritized areas of research include: genomics of multifactorial diseases, cancer genomics, bioinformatics, genetics of infectious diseases and population genomics. At present, DNA-based risk assessment for common complex diseases, application of molecular signatures for cancer diagnosis and prognosis, genome-guided therapy, and dose selection of therapeutic drugs are the important issues in personalized medicine.ResultsTo further develop genomic and biomedical projects at Center for Life Sciences, the development of bioinformatics research and infrastructure and the establishment of new collaborations in the field are essential.Widespread use of genetic tools will allow the identification of diseases before the onset of clinical symptoms, the individualization of drug treatment, and could induce individual behavioral changes on the basis of calculated disease risk. However, many challenges remain for the successful translation of genomic knowledge and technologies into health advances, such as medicines and diagnostics.It is important to integrate research and education in the fields of genomics, personalized medicine, and bioinformatics, which will be possible with opening of the new Medical Faculty at Nazarbayev University. People in practice and training need to be educated about the key concepts of genomics and engaged so they can effectively apply their knowledge in a matter that will bring the era of genomic medicine to patient care. This requires the development of well-equipped laboratories, bioinformatics, as well as qualified trained physicians and laboratory staff.

Translational research combining orthologous genes and human diseases with the OGOLOD dataset

OGOLOD is a Linked Open Data dataset derived from different biomedical resources by an automated pipeline, using a tailored ontology as a scaffold. The key contribution of OGOLOD is that it links, in new RDF triples, genetic human diseases and orthologous genes, paving the way for a more efficient translational biomedical research exploiting the Linked Open Data cloud.

Digital pathology and image analysis augment biospecimen annotation and biobank quality assurance harmonization

Standardization of biorepository best practices will enhance the quality of translational biomedical research utilizing patient-derived biobank specimens. Harmonization of pathology quality assurance procedures for biobank accessions has lagged behind other avenues of biospecimen research and biobank development. Comprehension of the cellular content of biorepository specimens is important for discovery of tissue-specific clinically relevant biomarkers for diagnosis and treatment. While rapidly emerging technologies in molecular analyses and data mining create focus on appropriate measures for minimizing pre-analytic artifact-inducing variables, less attention gets paid to annotating the constituent makeup of biospecimens for more effective specimen selection by biobank clients. Both pre-analytic tissue processing and specimen composition influence acquisition of relevant macromolecules for downstream assays. Pathologist review of biorepository submissions, particularly tissues as part of quality assurance procedures, helps to ensure that the intended target cells are present and in sufficient quantity in accessioned specimens. This manual procedure can be tedious and subjective. Incorporating digital pathology into biobank quality assurance procedures, using automated pattern recognition morphometric image analysis to quantify tissue feature areas in digital whole slide images of tissue sections, can minimize variability and subjectivity associated with routine pathologic evaluations in biorepositories. Whole-slide images and pathologist-reviewed morphometric analyses can be provided to researchers to guide specimen selection. Harmonization of pathology quality assurance methods that minimize subjectivity and improve reproducibility among collections would facilitate research-relevant specimen selection by investigators and could facilitate information sharing in an integrated network approach to biobanking.

An Interview with Teruo Okano, PhD

An Interview with Teruo Okano, PhD

The National Institutes of Health’s Biomedical Translational Research Information System (BTRIS): Design, contents, functionality and experience to date

The US National Institutes of Health (NIH) has developed the Biomedical Translational Research Information System (BTRIS) to support researchers’ access to translational and clinical data. BTRIS includes a data repository, a set of programs for loading data from NIH electronic health records and research data management systems, an ontology for coding the disparate data with a single terminology, and a set of user interface tools that provide access to identified data from individual research studies and data across all studies from which individually identifiable data have been removed. This paper reports on unique design elements of the system, progress to date and user experience after five years of development and operation.

Therapeutic Hydroxyurea Dosing Is Associated With Decreased Organ Damage and Longer Survival In Adults With Sickle Cell Anemia

▪ IntroductionHydroxyurea (HU) is the only FDA-approved medication to treat adults with sickle cell anemia (hemoglobin SS disease, SCA). Two studies showed improved survival with long term HU therapy. Conversely, subsequent studies reported most patients continue to die by the fifth decade of life despite long term treatment. Further, no studies have shown that HU prevents organ dysfunction. In this work, we sought to assess the effect of HU dosing on survival and organ function in SCA in a cohort of patients at a single referral institution. MethodsAdults with SCA enrolled on the Bethesda Sickle Cell Cohort Study between January 2001 and October 2012 were included in this retrospective analysis. The NIH Biomedical Translational Research Information System was used to electronically retrieve clinical notes, administration records, and medication orders. Computer-assisted review facilitated the extraction of HU dose histories. Survival, laboratory, and cardiopulmonary parameters were compared between enrollment and most recent follow-up based on HU status and fetal hemoglobin (HbF) response. ResultsOf 388 subjects with SCA, 254 (65%) were treated with HU at a median dose of 19.4 mg/kg/day. Mean follow-up was 3.58±3.53 years. Of subjects prescribed HU, 166 (65%) were on a therapeutic dose. Subjects taking HU had a significantly higher HbF (9.2 versus 6.8%, p=0.0003) and mean corpuscular volume (MCV, 96.2 versus 88.3fL, p<0.001) at their initial visit compared to those not taking HU. A similar pattern was seen at the last visit for HbF (12.0 versus 6.5%, p<0.0001) and MCV (99.2 versus 87.4fL, p<0.0001), suggesting that HU was administered for a prolonged period of time. Total hemoglobin was not different between groups at either visit (8.9 versus 9.0g/dL at initial visit, p=0.41 and 8.9 versus 8.8g/dL at most recent visit, p=0.66 in HU versus no HU patients, respectively).There was no difference in overall survival based solely on HU treatment (p=0.11). However, subjects prescribed therapeutic HU doses (15-35 mg/kg/day, N=166) were more likely to be alive than subjects who never took HU (N=131, p=0.04). Survival was similar when comparing sub-therapeutic HU (N=46) to no HU (p=0.52) groups, and survival was also similar between subjects prescribed sub-therapeutic HU versus therapeutic HU (p=0.46). Multivariate analysis confirmed HU dose is independently associated with prolonged survival (p=0.006).At enrollment, creatinine was lower (1.2 versus 0.8mg/dL, p=0.0016), total bilirubin was greater (3.3 versus 2.8mg/dL, p=0.02), and tricuspid regurgitant velocity was higher (2.6 versus 2.5m/s, p=0.03) in patients on HU. There were no significant differences in ejection fraction, brain natriuretic peptide, transaminases, alkaline phosphatase, or direct bilirubin. Further, there were no differences for any markers of organ function at the most recent follow-up.To determine if the best HU responses were associated with improved organ function, subjects were divided into groups based on whether their maximum HbF was within the lowest or the highest quartile. The HU dosages were 24.1 versus 4.8mg/kg/day in the high versus low HbF groups, respectively (p<0.0001). Maximum HbF was 26.1% as compared to 1.5% in the low HbF group. Ejection fraction was higher and transaminases and creatinine were lower at both visits in subjects with the highest HbF levels (see Table). After adjusting for age, only creatinine remained lower in the high HbF group at enrollment (p=0.007).First VisitLast VisitVariableLow HbFHigh HbFP-valueLow HbFHigh HbFP-valueEjection Fraction (%)56.259.90.00457.560.20.04Alanine Aminotransferase (U/L)34.625.70.0138.928.50.03Aspartate Aminotransferase (U/L)52.041.40.0454.733.7<0.0001Creatinine1.70.70.0022.00.90.004 ConclusionsHU therapy correlates with prolonged survival and preservation of organ function, but only when given in therapeutic dosages. These HU associations are not observed for sub-therapeutic doses less than 15 mg/kg/day. Patients should be treated with a maximum tolerated HU dose to achieve the highest possible HbF response, ideally before organ damage occurs. Additional studies are indicated to further confirm these findings. Disclosures:No relevant conflicts of interest to declare.

A novel thermophilic histone with promising gene transfection efficiency

concerns with respect to stimulus selection to trigger shape recovery and the integrated functions. Direct heating has been themost common stimulus to use, however it is not always practical for in vivo applications. High-intensity focused ultrasound has been a subject of interest for decades in biomedical research [2]. It may also have a prominent selective heating effect on a particular locationwithminimal effect on surrounding tissue, whichmakes on-demanddelivery of drugs possible. This work aims to evaluate the feasibility of using an SMP carrier based on chitosan modified poly(lactic-co-glycolic acid) (CTSPLGA) microspheres for controlled drug release upon exposure to ultrasound. Fluorescein isothiocyanate labeled lysozyme (FITC-Lyz) is entrapped within the microspheres by the emulsion evaporation method (Fig. 1a). A cylindrical rodwas subsequently fabricated through hot-pressing the microspheres into a mold (Fig. 1b). Results from release assays (Fig. 1c) indicate that the released amount of Lyz increases with the duration and applied power of ultrasound irradiation. The shape recovery process of the drug loaded SMP rod can be controlled simultaneously. Our current demonstration will pave the way for developing even more sophisticated and multifunctional ultrasound-responsive scaffolds and implants for translational biomedical research and applications.

Startle response memory and hippocampal changes in adult zebrafish pharmacologically-induced to exhibit anxiety/depression-like behaviors

Zebrafish (Danio rerio) are rapidly becoming a popular animal model for neurobehavioral and psychopharmacological research. While startle testing is a well-established assay to investigate anxiety-like behaviors in different species, screening of the startle response and its habituation in zebrafish is a new direction of translational biomedical research. This study focuses on a novel behavioral protocol to assess a tapping-induced startle response and its habituation in adult zebrafish that have been pharmacologically-induced to exhibit anxiety/depression-like behaviors. We demonstrated that zebrafish exhibit robust learning performance in a task adapted from the mammalian literature, a modified plus maze, and showed that ethanol and fluoxetine impair memory performance in this maze when administered after training at a dose that does not impair motor function, however, leads to significant upregulation of hippocampal serotoninergic neurons. These results suggest that the maze associative learning paradigm has face and construct validity and that zebrafish may become a translationally relevant study species for the analysis of the mechanisms of learning and memory changes associated with psychopharmacological treatment of anxiety/depression.

Anti-inflammatory therapy in chronic disease: challenges and opportunities.

A number of widespread and devastating chronic diseases, including atherosclerosis, type 2 diabetes, and Alzheimer's disease, have a pathophysiologically important inflammatory component. In these diseases, the precise identity of the inflammatory stimulus is often unknown and, if known, is difficult to remove. Thus, there is interest in therapeutically targeting the inflammatory response. Although there has been success with anti-inflammatory therapy in chronic diseases triggered by primary inflammation dysregulation or autoimmunity, there are considerable limitations. In particular, the inflammatory response is critical for survival. As a result, redundancy, compensatory pathways, and necessity narrow the risk:benefit ratio of anti-inflammatory drugs. However, new advances in understanding inflammatory signaling and its links to resolution pathways, together with new drug development, offer promise in this area of translational biomedical research.

Translational Developmental Toxicology: Prospects for Protective Therapeutic Obstetrical and Neonatal Interventions

Contemporary translational biomedical research strives to move from discoveries in models (in silico, in vitro and in vivo) into human clinical trials to expeditiously develop specific therapeutics. Translational toxicology must similarly strive to identify applicable therapeutics that can safely and effectively mitigate potential harm from exposures. Since human exposures to chemicals, physical agents and social factors are inevitable, the human fetus is subject to effects that can have lifelong consequences. In order to apply the translational concept to developmental toxicology, we are guided by the modest number of established and accepted obstetrical therapeutics used primarily for fetal benefit. These established or potential therapeutic obstetrical interventions suggest that early steps into testing or implementing developmental translational toxicology therapies during the in utero and early neonatal period will likely derive from Generally-Recognized-As-Safe (GRAS) options. If we are to translate environmental health discoveries into safe and effective interventions, we must assert and characterize valid, applicable therapies such as GRAS treatments and eventually “ethical pharmaceuticals” for the protective care of these highly vulnerable young patients. We can create a safe and efficacious environmental health portfolio of interventional options to improve human health that include both reduction/avoidance of exposure and specific preventative/mitigative/restorative therapeutics.

Translational Biomedical Informatics and Computational Systems Medicine

Translational Biomedical Informatics and Computational Systems Medicine

Characterizing biobank organizations in the U.S.: results from a national survey

BackgroundEffective translational biomedical research hinges on the operation of 'biobanks,' repositories that assemble, store, and manage collections of human specimens and related data. Some are established intentionally to address particular research needs; many, however, have arisen opportunistically, in a variety of settings and with a variety of expectations regarding their functions and longevity. Despite their rising prominence, little is known about how biobanks are organized and function beyond simple classification systems (government, academia, industry).MethodsIn 2012, we conducted the first national survey of biobanks in the U.S., collecting information on their origins, specimen collections, organizational structures, and market contexts and sustainability. From a list of 636 biobanks assembled through a multi-faceted search strategy, representatives from 456 U.S. biobanks were successfully recruited for a 30-minute online survey (72% response rate). Both closed and open-ended responses were analyzed using descriptive statistics.ResultsWhile nearly two-thirds of biobanks were established within the last decade, 17% have been in existence for over 20 years. Fifty-three percent listed research on a particular disease as the most important reason for establishment; 29% listed research generally. Other reasons included response to a grant or gift, and intent to centralize, integrate, or harmonize existing research structures. Biobank collections are extraordinarily diverse in number and types of specimens and in sources (often multiple) from which they are obtained, including from individuals, clinics or hospitals, public health programs, and research studies. Forty-four percent of biobanks store pediatric specimens, and 36% include postmortem specimens. Most biobanks are affiliated in one or multiple ways with other entities: 88% are part of at least one or more larger organizations (67% of these are academic, 23% hospitals, 13% research institutes). The majority of biobanks seem to fill a particular 'niche' within a larger organization or research area; a minority are concerned about competition for services, although many are worried about underutilization of specimens and long-term funding.ConclusionsEffective utilization of biobank collections and effective policies to govern their use will require understanding of the immense diversity found in organizational features, including the very different history and primary goals that many biobanks have.