Biennial Report of the Director

Overview of NIH Research Portfolio
Harnessing Technology

In today’s world, technological advances move at an unprecedented pace. NIH is tapping into this technological revolution in multiple ways, from fostering new technological advances for rapid data collection and sharing huge amounts of data, to developing new technologies to better detect and treat numerous diseases and disorders, and to ensuring that research results—from scientific publications to patient and consumer health information—are readily available to all.

NIH support of technology development continues to trigger revolutions in the understanding of health and disease. In recent years, biotechnology and nanotechnology have undergone extensive development and expansion. Biotechnology combines disciplines such as genetics, molecular biology, biochemistry, embryology, and cell biology, which in turn are linked to disciplines such as information technology, robotics, and bioengineering to enable the development of new or enhanced tools and devices to further basic scientific research as well as lead to improvements in human health. Nanotechnology research takes advantage of the phenomenon that the properties of some materials change significantly at very small scales, often with surprisingly useful consequences. NIH-supported nanotechnology research exploits this phenomenon in efforts to develop devices with unique features for diagnosing and treating disease. It is a highly multidisciplinary field, drawing from disciplines such as applied physics, materials science, supramolecular chemistry, and mechanical and electrical engineering.

Many of the core challenges in today’s research require technologies, databases, and other scientific resources that are more sensitive, robust, and easily adaptable to unique applications than what currently exists. New technologies are needed, for example, to develop a more detailed understanding of the vast networks of molecules that make up cells and tissues, their interactions, and their regulation; to develop a more precise knowledge of the combined effects of environmental exposures, individual susceptibility, and molecular events at the onset of disease; and to capitalize on the completion of the human genome sequence and recent discoveries in molecular and cell biology. Moreover, widespread access to such tools will be essential for moving these fields forward.

The development, deployment, and utilization of biomedical information systems (i.e., disease registries and other databases) are essential to managing large amounts of data for research, clinical care, and public health. Increasingly, these technologies serve not only as repositories of information but also as research tools in and of themselves, extending, and in some cases, augmenting the laboratory. For example, scientists are able to use molecular databases to study the profiles of individual tumors and conceptualize small-molecule anticancer agents to target them. However, new analytical tools are needed to explore increasingly complex questions, such as how the expression patterns of multiple genes are associated with a particular trait or response. Tools such as this are most effective when these databases are interoperable and capable of communicating with each other and make use of similar software applications. NIH is also keenly attuned to the importance and challenges associated with preserving, protecting, and ensuring the validity and security of information stored in biomedical databases.

NIH supports technology development through several complementary approaches, including:

The research pipeline is replete with examples of NIH’s commitment to technology development, its foresight in identifying emerging needs and promising areas of investigation, and its ability to foster the development of technology that links basic research with clinical applications.

Harnessing the power of the Internet creates unprecedented access to health care information in patient files as well as to raw research data from clinical trials. For health science researchers, shared virtual libraries provide access to data and images from hundreds of studies in various fields. Devising the infrastructure to support a seamless end-user environment requires the collaboration of a host of professionals in computer science, medicine, records management, and other related fields.

NIH-supported efforts are affecting how healthcare providers, patients, and researchers will use information technology in the future. One such endeavor allows patients to access their own health information. Complete access to diagnostic results and treatment details will permit patients to play an active role in their own healthcare decision-making by asking more informed questions about their care. Patients will be able to provide this information to any healthcare provider regardless of where they are located. NIH supports research to ensure that the data are secure during storage and transmission and to address compliance with the Health Insurance Portability and Accountability Act (HIPAA). Benefits of this approach include a reduction in medical errors and elimination of duplicative diagnostic procedures.

Next-generation healthcare will offer consumers ultrasensitive technologies and techniques to assess normal and diseased states of the body coupled with quick access to vast amounts of health-related data. New modes of collecting patient information, such as the Patient-Reported Outcomes Measurement Information System (PROMIS), may improve how patients provide information on their conditions and how doctors use that information in treatment decisions. An online computer-adaptive testing system, PROMIS records patient reports of symptoms such as pain, fatigue, and emotional distress related to a wide variety of chronic diseases and conditions.

Because of the growing importance of information and its management in biomedical science, clinical care, and public health, virtually every NIH IC is engaged in the development, deployment, and use of biomedical information systems that support its mission. NIH databases and information systems have become indispensable national and international resources for biomedical research and public health. Several trans-NIH activities feature the development of significant biomedical information resources, including the tools, infrastructure, and associated research needed to make databases and registries more valuable.

NIH efforts to develop and deploy disease registries, databases, and biomedical information systems to advance biomedical science, health, and healthcare focus on:

In order to make these and other data systems more useful to researchers, clinicians, and the public, NIH invests in a number of activities, including the following:

Catalog of Disease Registry, Database, and Biomedical Information System Activities

In response to the mandate under SEC. 403 (a)(4)(C)(ii) of the Public Health Service Act to provide catalogs of disease registries and other data systems, Appendix G is included with an inventory of NIH intramural and extramural activities ongoing in FYs 2010 and 2011 to develop or maintain databases, disease registries, and other information resources for the benefit of the larger research community.

NIH Scientific Databases: Enhancing Access to Research Information

Keeping pace with the expanding volume of biomedical knowledge is a continuing challenge for scientists, clinicians, policymakers, and the public; thus, NIH devotes considerable attention and resources to developing, expanding, and maintaining tools and resources for information management. Biomedical databases store and provide access to a wide range of information, from the results of scientific or clinical research studies, to genomic information, to standard reference materials (such as genome sequences or anatomical images), and to published journal articles and citations to the medical literature. They are widely used by biomedical researchers, as well as by a growing number of clinicians, public health officials, and consumers. NIH often undertakes special initiatives to make these resources more accessible to a broader, more diverse set of users.

Among the most widely used of NIH’s databases are those that collect and provide access to scientific literature. These comprehensive resources are used extensively by scientists, health care providers, and consumers who seek trusted, peer-reviewed information on biomedical and health topics of interest. NIH houses the leading source of authoritative biomedical literature for professional and lay audiences. The exhaustive PubMed database comprises more than 21 million citations for biomedical literature from MEDLINE, life science journals, and online books.

In addition, NIH continues to expand PubMed Central (PMC), its digital archive of full-text scientific journal articles. PMC was established to provide online access to a growing number of scientific journal articles deposited by publishers and NIH-funded researchers, and now provides public access to more than 2.5 million research articles. Some of this increase is attributable to an expanding scope of user (not just biomedical researchers, but also clinicians, other practitioners, and consumers) that highlights the importance of this type of resource.

PMC serves as the repository for manuscripts submitted in accordance with the NIH Public Access Policy, which ensures that the public and the scientific community have access to the published results of NIH-funded research by requiring NIH-funded scientists to submit final peer-reviewed journal manuscripts that arise from NIH funds to PMC. PMC software also is used by funding agencies in other countries to establish repositories for their funded research.

NIH also puts effort into developing and maintaining information systems that collect data stemming from biomedical research. These systems organize data, and make it accessible for subsequent research. NIH’s PubChem database, for example, houses the voluminous data on molecular structures and functions that is produced through NIH funding under the Molecular Libraries Initiative of the NIH Common Fund. It provides information about the biological activity of small molecules, organized as three linked databases along with a chemical structure similarity search tool. PubChem now contains more than 35 million unique chemical structures and more than 600,000 bioassays. PubChem is integrated with NIH’s Entrez suite of biomedical information resources, an integrated collection of some 40 databases and more than 570 million records of molecular and genomic data. This integration enables users to retrieve related data from multiple databases and navigate among them with relative ease.

Individual Institutes also support efforts to integrate the enormous data streams for the benefit of catalyzing research in certain diseases and disorders. For example, NIDCR supports the FaceBase Consortium, creating a freely available database compiling the biological and genetic instructions to construct the middle region of the human face. FaceBase will facilitate data production and integration, as well as accelerate translational and clinical application of this knowledge for the prevention, treatment, and management of craniofacial birth defects. FaceBase’s individual scientific projects continue to provide data to the FaceBase data integration and management hub; the hub’s informatics development team is creating new interfaces for displaying and searching those data on the consortium’s Web site, www.facebase.org Exit Disclaimer.

Genomic Information Systems: Understanding the Genetic Basis of Disease

NIH has made great strides in developing information resources to support genetics research. Considerable effort has been aimed at supporting the analysis of data from GWAS, which explore the connection between specific genes (genotype information) and observable diseases or conditions (phenotype information, such as diabetes, high blood pressure, or obesity). NIH’s dbGaP (database of Genotype and Phenotype) houses data from a number of GWAS, including those funded by NIH. NIH’s GWAS policy encourages NIH grantees to submit their GWAS data to dbGaP and establishes procedures for making it available to other researchers to speed up disease gene discovery while at the same time protecting the privacy of research subjects in genomics studies.

In addition, several NIH ICs have established genetics repositories to accelerate research and multidisciplinary collaborations in specific disease areas. Programs such as the NEI eyeGENE, NIMH Center for Collaborative Genetic Studies on Mental Disorders, the NIDA Center for Genetic Studies, the NINDS Human Genetics Repository, the NIEHS Chemical Effects in Biological Systems (CEBS) Knowledge Base, and the NIA Genetics of Alzheimer's Disease Data Storage Site give researchers access to vast storehouses of genetic and genomic data, DNA samples, and clinical data, along with informatics tools designed to facilitate their analyses. The wide availability of information linking genotype to phenotype should help researchers better understand gene-based diseases and speed development of effective therapies.

Disease Registries and Surveillance Systems: Tracking and Monitoring Disease

Disease registries collect information about the occurrence of specific diseases, such as cancer and Parkinson’s disease, the kinds of treatment that patients receive, and other information that might be relevant to researchers or public health officials. Increasingly, disease registries also include genomic data from registered patients. Registry information can therefore help identify causal factors of disease, assess the effectiveness of various interventions, and identify questions of concern to researchers, clinical professionals, and policymakers.

Disease registries have been employed for research on autoimmune disorders, including Sjögren’s Syndrome, one of the most prevalent. A significant roadblock for moving discoveries ahead in the field of Sjögren’s Syndrome is a lack of data and biospecimens available for research. Recognizing the problem, NIH spearheaded an effort to establish patient registries at two extramural institutions, as well as through its own intramural program. These groups work together to generate and share genome-wide genotyping data and clinical information from the cohorts enrolled through these efforts with the general research community.

Registries also provide a valuable source of information for tracking the effectiveness of particular treatments or interventions. The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS), for example, is a national registry for patients who are receiving mechanical circulatory support device therapy to treat advanced heart failure. The registry is supported jointly by NIH, FDA, and CMS. Use of standardized terminologies helps ensure that the data collected will facilitate improved patient evaluation and management while aiding in better device development.

NIH continues to invest in tools that can increase the utility of its scientific databases and medical information sources. A key component of such efforts relates to the development and maintenance of standards and vocabularies for use in information systems used for research and clinical care, including electronic health records. Standard vocabularies and ontologies (models of the relationships between concepts) improve information search, retrieval, and exchange by endowing systems with the ability to automatically perceive and retrieve information about related terms. As expansion of scientific frontiers produces new concepts, terms, and relationships, standard vocabularies must be regularly revised so that articles and other data can be properly indexed and search engines can find relevant and related terms.

NIH continues to update the Unified Medical Language System (UMLS), which is used heavily in advanced biomedical research and data mining worldwide. The UMLS Metathesaurus, with more than 8.6 million concept names from 161 source vocabularies, is a distribution mechanism for standard code sets and vocabularies used in health data systems. Many institutions apply UMLS resources in a wide variety of applications including information retrieval, natural language processing, creation of patient and research data, and the development of enterprise-wide vocabulary services for electronic health records.

Data harmonization efforts can similarly boost the impact of individual research by promoting the use of common measures across studies within and across particular research fields. By using common measures, researchers can more easily compare and combine datasets to detect more subtle and complex associations among variables, thereby promoting greater collaboration, efficiency, and return on investment. For example, in 2006, NHGRI initiated the PhenX Toolkit to provide standard measures related to complex diseases, phenotypic traits and environmental exposures. Use of PhenX measures facilitates combining data from a variety of studies, and makes it easy for investigators to expand a study design beyond the primary research focus.

NIH also supports the Neuroimaging Informatics Tools and Resources Clearinghouse42, which finds and compares tools and resources used for analyzing neuroimages such as MRI scans. Tools include software, hardware, and algorithms among others. This resource helps researchers compare and find tools best suited to their research projects. Developers can gain valuable help from the research community to make their tools more usable and accessible.

42 For more information, see https://www.nibib.nih.gov/About/Overview/DDSTFactSheet and https://www.nitrc.org/ Exit Disclaimer.

Large-Scale Informatics Infrastructure

NIH also has embarked on a number of large-scale initiatives to develop and deploy infrastructure and tools for storing, sharing, integrating, and analyzing the large volumes of data routinely generated in research laboratories and in clinical settings. These initiatives tend to produce not only storehouses for data generated by research, but also larger scale networks for sharing data, linking researchers, and conducting further research. NIH supports a number of clinical research networks, for example, which allows for standardized data reporting and sharing of information across clinical studies.

In the area of cancer research, NIH has established the Cancer Biomedical Informatics Grid® (caBIG®), a collaborative information network for all of NCI’s advanced technology and program initiatives that aims to enable collaborative research and personalized, evidence-based care. The network connects scientists, practitioners, and patients, enabling the collection, analysis, and sharing of data and knowledge along the entire research pathway from bench to bedside. Specific biomedical research tools under development by caBIG® include clinical trial management systems, tissue repositories and pathology tools, imaging tools, and a rich collection of integrative cancer research applications.

In an effort to support and accelerate research in the prevention, cause, diagnosis, and treatment of research on Autism Spectrum Disorders, NIH created the National Database for Autism Research. This database collects a wide range of data types, including phenotypic, clinical, and genomic, as well as de-identified medical images, derived from individuals who participate in Autism Spectrum Disorders research, regardless of the source of funding. The National Database for Autism Research provides the infrastructure to store, search across, retrieve, and analyze these varied types of data. It also coordinates data access with many other federal databases, such as the NIMH Center for Collaborative Genetic Studies. The center is a national resource for researchers who study the genetics of complex mental and developmental disorders, such as Autism Spectrum Disorders, and stores human DNA, cell cultures, and clinical data. In 2011, the National Database for Autism Research received an HHSinnovates award, recognizing its outstanding innovation efforts within HHS.

Other efforts aim to provide the informatics infrastructure to advance basic research and clinical studies across the spectrum of biomedical sciences. The CardioVascular Research Grid provides infrastructure for sharing cardiovascular data and data analysis tools. The CardioVascular Research Grid builds on and extends tools developed in the caBIG®, and the Biomedical Informatics Research Network projects to support national and international collaborations in cardiovascular science. The National Centers for Biomedical Computing are intended to be part of the national infrastructure in Biomedical Informatics and Computational Biology. There are eight Centers that cover biophysical modeling, biomedical ontologies, information integration, tools for gene-phenotype and disease analysis, systems biology, image analysis, and health information modeling and analysis. The centers create innovative software programs and other tools that enable the biomedical community to integrate, analyze, model, simulate, and share data on human health and disease.

Biomedical Informatics Research and Training

Ensuring continued advances in biomedical informatics resources requires active support of fundamental research that seeds the further development of new tools, resources, and approaches. It is also critical to generate a continuous supply of skilled biomedical informatics researchers, information specialists (such as medical librarians), and life sciences researchers trained in bioinformatics. NIH continues to expand its efforts in bioinformatics research and training in response to the growing importance of informatics in the biomedical and life sciences. NIH also is the principal source of support for research training in biomedical informatics, providing research training grants to 18 institutions that enroll approximately 200 pre- and post-doctoral trainees each year.

Diagnostic and Point-of-Care Technologies

Ideally, patients would have access to high-quality and consistent health care regardless of where they live. Realizing this vision necessitates the development of portable, reliable, and inexpensive equipment. To achieve this also will require the leveraging of technologies developed in other fields, such as telecommunications. Advances in fiber-optic and wireless communications devices allow physicians to engage in telemedicine (the transmission via the Internet of medical information) to deliver health care by communicating with other physicians or pathologists thousands of miles away.

NIH currently funds the Point-of-Care Technologies Research Network, a network of four centers that are developing new point-of-care technologies for early and rapid detection of a wide variety of serious conditions such as neurological emergencies, sexually transmitted diseases, multi-pathogen detection for national disaster preparedness, and diagnosis of infections. These technologies are being designed for use in low-resource settings among underserved populations. The network emphasizes collaboration between front-line health care workers and technology developers so that appropriate tools are created to meet clinical needs.

NIDCR supports initiatives that couple discoveries in the pathophysiology of human diseases, with innovations in engineering and electronics, to develop point-of-care medical diagnostic devices. Driving this change will be the use of saliva, an easy-to-access diagnostic fluid that may be useful in the evaluation of oral and systemic diseases, including the identification of HIV, oral cancer, and cardiovascular disease. As envisioned, a drop of saliva will be collected and loaded onto a small, all-in-one device that rapidly measures biomarkers associated with disease allowing early detection, whether in a clinic or in remote resource-poor settings.

Researchers have also been able to detect the inflammatory biomarker C-reactive protein (CRP), a strong predictor of the development of cardiovascular disease, in microscopic quantities of saliva. NIDCR is currently supporting aggressive efforts to provide clinical validation of these experimental results that could provide a self-contained, portable diagnostic test for cardiovascular disease. In related work, salivary biomarkers are being evaluated to detect myocardial infarction in patients presenting with chest pain at emergency departments, providing a tool that may one day enable Emergency Medical Technicians to assess if a patient being transported by ambulance is having a heart attack.

Researchers have also been able to detect the inflammatory biomarker C-reactive protein (CRP), a strong predictor of the development of cardiovascular disease, in microscopic quantities of saliva. NIDCR is currently supporting aggressive efforts to provide clinical validation of these experimental results that could provide a self-contained, portable diagnostic test for cardiovascular disease. In related work, salivary biomarkers are being evaluated to detect myocardial infarction in patients presenting with chest pain at emergency departments, providing a tool that may one day enable Emergency Medical Technicians to assess if a patient being transported by ambulance is having a heart attack.

Point-of-care technologies for use in pathology laboratories, emergency rooms, doctors’ offices, and homes will be a key component of the evolving health care system. Current devices, developed largely with NIH support, range from handheld glucose monitoring systems used by diabetics to monitor their blood sugar levels to laptop-sized ultrasound scanners. Among the technologies on the horizon is a lens-free optical microscope about the size of a dime. The device could be inserted into a cell phone and used as a diagnostic device in rural settings or developing countries in diagnosing malaria.

Two ultrasound technologies developed with support from NIH are now being used in clinical practice, often outside the hospital or health clinic. The V-Scan is a hand-held ultrasound imaging system the size of a cell phone that is now commercially available through General Electric at a fraction of the cost of traditional ultrasound systems. The device produces high quality images of internal organs in real time and is being used world-wide. Color-coded images enable physicians to quickly identify problems in blood flow or in organs such as the heart. The size and portability of the V-Scan allows diagnosis and treatment to occur at the point of care, whether that is at a patient’s bedside or in a remote area.

The second ultrasound technology will be used to treat patients. The High-Intensity Focused Ultrasound is a non-invasive tool that uses a concentrated, highly intense ultrasound beam that can be targeted at a specific area in the body to remove tissue, destroy tumors or repair injured organs or blood vessels. This technique has been approved by the FDA for treatment of uterine fibroids. Studies on other uses such treating brain tumors or for drug delivery to specific organs are continuing.

Another new device has the potential to save eyesight. Developed in collaboration between researchers at NIH and the National Aeronautics and Space Administration (NASA), a dynamic light-scattering probe detects and quantifies a protein in the eye that is critical to keeping the eye’s lens clear. Age-related cataracts develop because too little of the protein, alpha crystallin, is present in the eye. The new probe will be used to monitor the effects of cosmic radiation on astronauts’ eyes as well as to study the effects of aging on earth-bound eyes. Early detection of alpha crystallin depletion could lead to treatments that could delay or eliminate the need for cataract surgery.

NIH has also partnered with the Department of Biotechnology of the Ministry of Science and Technology in India to support the development of low-cost diagnostic and therapeutic medical technologies that will be used in underserved communities worldwide. One such diagnostic tool under development through NIH support of a small business is a low-cost, simple, and rapid point-of-care test for tuberculosis that will enable rapid diagnosis and ensure that appropriate treatment can be given to all affected individuals, thereby reducing the public health impact of this contagious disease.

Although treatment outcomes for primary cancers have improved in the last decade, many deaths occur as a result of the cancer spreading. Body scans can detect distant cancers but often only after the cancer has begun its destructive work. NIH-supported researchers have created a microchip able to detect circulating tumor cells (CTC) in whole blood. This means that from a sample of a patient’s blood the microchip identifies specific cancer cells that are spreading through the body via the circulatory system. Clinicians can then make treatment decisions for specific patients based on the molecular and genomic information provided by the CTC analysis.

NIH also supported two critical phases of the development of a novel “lab-on-a-chip” device for rapidly detecting HIV. The technique has proved highly successful, and the research team has gone on to refine and clinically test this microfluid-based lab-on-a-chip—or mCHIP—in real life settings, with studies demonstrating that the mCHIP can accurately, rapidly, and cost-effectively detect clinically relevant infectious diseases in resource-limited settings.43

Another example of “micro” technology improving health care is the portable micro-NMR (nuclear magnetic resonance) device.44 This device, operated by a smart-phone, is capable of diagnosing tumors from a small sample of cells with greater accuracy than traditional biopsy. The need for a small sample allows the tissue to be obtained using a very thin needle, resulting in reduced pain and recovery time for patients.

43 Chin CD, et al. Nat Med. 2011;17(8): 1015–9. PMID: 21804541.
44 Haun JB, et al. Sci Transl Med. 2011;3(71):71ra16. PMID: 21346169.

Gene Sequencing and Beyond

The sequencing of the human genome in 2003 generated excitement in the scientific community. It gave researchers a new way to analyze the function of cells, tissues, and systems in the body to understand the causes of disease. As more is learned about the genetic contributions to disease, DNA sequence information will become an important tool for individuals and healthcare providers to evaluate individualized disease risk and to improve the prevention, diagnosis, and treatment of disease. However, to deliver genetic information to individuals on a much wider basis, significant decreases must be made in the cost and time needed to sequence an entire human genome. Rapid gains have been made on this front since the start of the Human Genome Project, and costs continue to fall dramatically. NIH supports technology development to make genome sequencing more affordable and genomic information a routine part of health care. For example, NIH-supported researchers are conducting studies to discover the molecular mechanisms underlying complex diseases like addiction, which is strongly influenced by genetics. Investigators studying various neurological and psychiatric illnesses already have linked certain genes with specific diseases using custom screening tools known as “gene chips.”Applying these tools to addiction and other brain disorders advances understanding of not only vulnerability to addiction and its co-morbidities, but also of ways to target treatments based on an individual’s genetic profile.

Image-Guided Interventions

To detect disease in its earliest stages, and thereby preempt it before symptoms appear, clinicians will need to examine smaller, more localized areas of the body. Image-guided interventions (IGI)—treatments or procedures that precisely target areas within the body with the aid of imaging techniques such as MRI, CT, or ultrasound—enable clinicians to look beneath the surface anatomy to visualize underlying pathology. As a result, images can be used to navigate the anatomy for biopsy and treatment of disease. In addition to diagnosing at-risk individuals, IGI may offer a safer, less-invasive, and often less costly approach to many surgical procedures. Compared with traditional open surgery, minimally invasive procedures result in less tissue trauma, less scarring, and faster postoperative recovery time, which translates into shorter hospital stays and a more rapid return to family and work.

NIH’s Center for Interventional Oncology is leading the way in developing and disseminating innovative cost-effective alternatives to open surgery. Physicians can navigate through the body using “medical GPS”—real-time imaging such as magnetic resonance, computed tomography, or ultrasound. Once at the desired location, the physician can insert a needle into a tumor, deliver heat to destroy it, and then deposit a drug to eliminate residual cancer cells. The Center is also pioneering new image-guided approaches to track personalized responses to new drug therapies over time. These endeavors are contributing to the future of personalized medicine.

Imaging Biological Systems

Better tools and techniques to understand activities within cells, tissues, and organ systems enable researchers to probe deeper to gain an understanding of the biological systems and networks that control both normal function and diseased states. For example, two NIH intramural research groups are collaborating to develop a next-generation MRI system to examine the human brain. The system uses a 7-tesla magnet to produce highly detailed images that reveal structures not visible using conventional MRI.

More detailed information about the body’s internal organs is critical to detecting early stages of disease. Finding new ways of using current MRI systems can advance safer diagnostic methods. In the case of liver disease, biopsies may cause pain, result in missed work, and also carry a risk of bleeding. NIH-supported researchers have developed a non-invasive way to assess the liver using MRI and shear waves, a special type of sound wave. With MRI, the researchers capture snapshots of the shear waves as they propagate through liver tissue. A computer program translates the waves into a map of the liver that displays the stiffness of the organ. Stiffness indicates disease while suppleness indicates healthy tissue. This could provide a safer alternative not only for liver biopsy but also for diagnosis of cancer in the breast, prostate, and kidney.

Harnessing the power of imaging and molecular biology enables us to probe disease mechanisms and image the affected pathways. For example, hyperpolarized C-13 compounds injected into prostate cancer patients can be observed with magnetic resonance spectroscopy as these compounds are metabolized in cancer cells.45 These metabolic changes serve as biomarkers for prostate cancer as disease progresses. Decisions on therapeutic management can thus be closely monitored by magnetic resonance spectroscopy.

Recent advances in imaging technology also present opportunities to develop qualified quantitative imaging biomarkers. NIBIB is supporting a public-private consortium called the Quantitative Imaging Biomarkers Alliance (QIBA). This effort aims to improve the value and practicality of quantitative imaging biomarkers by reducing variability across devices, patients, and time. QIBA has selected several candidates and has made advances in establishing standards, methods, and processes aimed at accelerating translation of these biomarkers from bench to bedside by engaging researchers, healthcare professionals and industry.

45 For more information, see https://www.radiology.ucsf.edu/research/labs/hyperpolarized-mri-tech Exit Disclaimer.

Investments in Infrastructure

Advances in the development of new technology cannot come without supporting the infrastructure that undergirds the research endeavor. To that end, NIH supports a Shared Instrumentation Grant and High-End Instrumentation Program, which provides new generation technologies to groups of NIH-supported extramural investigators for a broad array of basic, translational, and clinical research. These programs provide essential instruments that are too expensive to be obtained through regular research grants. NIH also continuously seeks to improve the current “state-of-the-art” in different technology areas. This is highlighted by the NIH-supported Biomedical Technology Research Centers that develop innovative technologies to aid researchers who are studying virtually every human disease.

Large-Scale Collaborative Activities

NIH creates critical, often unique technology and methods and applies them to a broad range of basic, translational, and clinical research through the Biomedical Technology Research Centers (BTRCs). Supported by NIGMS and NIBIB, there are currently 65 BTRCs nationwide. The technologies developed in the centers involve over 7,000 investigators that are funded by 22 ICs in FY 2010. BTRCs and Biotechnology Resource Centers supported by NIH serve a unique purpose in the broad context of NIH-funded research. They represent a critical mass of technological and intellectual resources with a strong focus on service and training for outside investigators. They develop new technologies and tools in areas including tissue engineering, biomaterials, neural communication technologies, imaging, informatics, synchrotrons, electron microscopy, proteomics and glycomics, optics, lasers, and BioMEMS (microelectromechanical systems—technology just above nano-size—that manipulate, analyze, and measure biological or chemical materials). Access to these technologies is critical to enabling research, yet they are frequently too advanced or expensive to be widely available. These centers disseminate and promote the application of such cutting-edge technologies. These technologies are developed across the full spectrum from bench to bedside. These centers are multidisciplinary and collaborative and serve as catalysts for integrating the diverse efforts of NIH-supported researchers, and providing technological infrastructure, experimental and computational resources, and expertise.

NIH’s Biomedical Informatics Research Network is a virtual community of shared informatics resources. The network’s grid computing technology makes digital research data freely available for sharing and exchange among communities of researchers; its data integration tools allow searching across distributed databases; and it provides tools for data analysis, management, and collaborative research. The resulting collaborative environment extends beyond the boundaries of individual laboratories to enable collaborations that cross geographic and disciplinary boundaries. Basic and clinical investigators are able to share disparate data as well as powerful new analytical tools and software across animal models and among multiple sites. This major initiative was developed to allow neuroimagers to share data and tools, but the infrastructure is generic and therefore applicable to other disciplines.

Another technology-intensive collaborative endeavor has developed due to the rapid expansion of the dietary supplement marketplace. This expansion has resulted in a proliferation of ingredients and products. Precise, accurate, and rigorous analytical methods and reference materials are essential for verification of ingredient identity and measuring the amounts of declared ingredients in raw materials and finished products. Also, dietary supplement labels are required to list certain facts about product identity and content and to be truthful and not misleading. That this is not always the case is due, in part, to the lack of proven and agreed-upon methods to precisely assess the quantity of constituents of many supplements and supplement ingredients. NIH’s congressionally mandated Analytical Methods and Reference Materials program is intended to assist in providing these critical tools for quality assurance. NIH is partnering with FDA and the National Institute of Standards and Technology (NIST) to promote the development, validation, and dissemination of analytical methods and reference materials for commonly used dietary supplement ingredients.

Bringing a Multitude of Scientific Disciplines Together

NIH fosters and cultivates cooperative research between health scientists and quantitative scientists so that fundamental discoveries and tools can be developed, even when their specific applications might not be obvious. For example, the laser, which was originally developed in physics laboratories studying energy and light, has been adapted for microscopes that are critical to many research areas as well as a variety of surgical tools, including systems for laser eye surgery.

Partnerships among engineers, clinicians, scientists, and industrial technologists provide a reservoir of information for NIH investigators. One such partnership is creating innovative technologies to assist war veterans who have suffered limb damage or loss as well as civilian amputees and those with spinal cord injuries. A range of electronic and robotic devices will help these individuals stand and move. A new generation of hand and arm prostheses that provide fine finger movement, and a sense of touch is especially promising.

NIH and NASA have a strong history of collaboration and share many interests in the life and health sciences. In 2010, NIH awarded the first new grants under the Biomedical Research on the International Space Station (BioMed-ISS) initiative, a collaborative effort between NIH and NASA. Using a special microgravity environment that Earth-based laboratories cannot replicate, researchers will explore fundamental questions about important health issues, such as how bones and the immune system get weak.

The interplay of ideas among teams of NIH-supported investigators has produced promising techniques to identify mothers at risk for premature delivery. One group used a noninvasive ultrasound approach to assess uterine cervical changes in an animal model weeks before the due date. Another group has developed novel computational tools to analyze uterine biomagnetic signals of term and preterm patients to predict the onset of labor. With an early warning of potential preterm delivery, clinicians may have new tools to fight one of the leading causes of infant death in the U.S.

Nanotechnology

A sheet of paper is about 100,000 nanometers thick. The field of nanotechnology deals with matter approximately 1 to 100 nanometers in dimension. At these scales, matter exhibits unusual biological, chemical, and physical properties. By bringing together researchers from physics, material science, and engineering, NIH is developing a powerful cadre of investigators who will use nanotechnology to significantly change how we diagnose and treat disease. One such group has used electrical forces generated at the molecular level to suspend a microscopic object in mid-air. This finding could contribute to the design of tiny machines to perform surgery. Nanotechnology is also informing new ways of delivering medicine. For example, NIDA-funded researchers have used nanotechnology to successfully demonstrate a prototype programmable skin patch that will let physicians dynamically schedule transdermal medication doses to match a patient’s fluctuating needs.

Sharing information across disciplines is critical to nanotechnology research. NIH’s Alliance for Nanotechnology in Cancer brings together researchers from biology to oncology. The alliance is building a community of cancer nanotechnologists who develop novel approaches to preventing, diagnosing, and treating cancer and sharing that knowledge with the larger medical community. New nanodevices that quickly and accurately assess proteins and DNA structures implicated in cancer, nanoparticle imaging agents to clearly visualize cancer, and implantable nanosensors to monitor cancer progression will reshape the toolkit clinicians use to fight cancer.

Nanotechnology research is also exploring ways to treat disease. Nanoparticle therapy is a method to deliver the correct amount of a drug to a precise location resulting in more of the drug reaching its target, fewer side effects to healthy tissue and less toxicity to other parts of the body.46 Natural nanoparticles are also being cultivated from plant viruses as an alternative to manmade nanoparticles for imaging, drug delivery, vaccination, and design of electronic devices. Plant-based particles have advantages over synthetic materials in that they are biodegradable and harmless to humans, have a defined structure so that dyes and targeting tags can be modified and production is inexpensive.47, 48

46 Kolishetti N, et al. Proc Natl Acad Sci U S A. 2010;107(42):17939–44. PMID: 20921363.
47 Steinmetz NF, et al. Small. 2011;7(12):1664–72. PMID: 21520408.
48 Pokorski JK, Steinmetz NF. Mol Pharm. 2011;8(1):29–43. PMID: 21047140.

Probing Proteins

Information resulting from the Human Genome Project is now helping scientists as they begin to study more closely the structure of proteins. By visualizing protein structures, researchers gain a better understanding of many of the biochemical processes related to health and disease. This information also can be used to design drugs that target specific parts of a bacteria, virus, or tumor.

Structural biology is a field in which scientists learn about molecules by determining their 3-D structures in atom-by-atom detail. Large user facilities called synchrotrons allow researchers to use X-rays to determine molecular structures more easily, quickly, and cheaply than ever before. NIH funded the development of a new experimental station at the Advanced Photon Source at Argonne National Laboratory. The new station includes three X-ray beamlines for use by scientists from across the U.S. to determine the detailed, three-dimensional structures of molecules, which will lead to improved understanding of basic biological processes and for drug design.

Transforming Health Care

Brain-Computer Interface (BCI) devices are medical devices that operate by exchanging information with nearby portions of brain tissue, which could be placed on the surface of the scalp, near the surface of brain, or penetrate into just the top 2mm layer of tissue. All of these approaches are under consideration as candidate designs for a brain computer interface that could be used to provide a means of “speaking” through a computer. Current development efforts are focused on using the brain signals to support communication through basic, brain-controlled movements. One experimental device has allowed patients to “imagine” movement of fingers to control computer cursor movement across a virtual keyboard and type out messages.49 Even at this early stage of development, a similar approach might be used to help someone that has been “locked-in” and unable to speak or move limbs as a result of a brainstem stroke, a medical condition that was described in the book, “The Diving Bell and the Butterfly” by Jean-Dominique Bauby.

BCIs are one example of medical implants called neural prosthesis, which are designed to ameliorate the loss of nervous system function resulting from disease or injury. NIH pioneered the development of this technology through more than 35 years of research and development with the goal of helping people with disabilities lead fuller and more productive lives. The program has catalyzed the development of cochlear implants for people with hearing impairments, experimental control of artificial limbs for people with spinal cord injuries, retinal implants that help people regain sight, and deep brain stimulation for Parkinson’s disease, among other contributions. Through the years, this program has fostered the development of a robust research community, which now includes private sector companies. The cochlear implant has received the most widespread use, with more than 220,000 users worldwide.

NIH is leading the way in the development of new technologies to provide disease diagnosis and treatment simultaneously. The concept of combining a therapeutic with a diagnostic agent is rapidly evolving and goes beyond traditional diagnostic tests that screen or confirm the presence of a disease. With specialized molecular imaging techniques and biomarkers, tailored and personalized medicine approaches could predict risks of disease, diagnose disease, and monitor therapeutic response leading to real-time, cost-effective treatment. NIH supports a number of teams that are developing theranostics that can be applied in clinical studies of human patients.

49 Kuiken TA, et al. JAMA. 2009;301(6):619–28. PMID: 19211469.