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Biennial Report of the Director
National Institutes of Health Fiscal Years 2008 & 2009

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Biennial Report of the Director

Summary of Research Activities by Key Approach and Resource
Technology Development








By 2030, 72 million Americans will be 65 years old or older. The strain that this population will put on the health care system will be broad-based, but critical care settings in particular—especially intensive care unit (ICUs)—will face significant challenges. ICU care succeeds in part by intensive monitoring of a patient's changing condition. However, keeping track of that level of detail, especially in a busy unit, can slow treatment decisions, and in some cases, lead to errors. A team of NIH-funded researchers sees an opportunity to improve the efficiency, accuracy, and timeliness of clinical decision-making in the intensive care setting. They are developing an ICU patient monitoring system that not only will track vital signs in real time but also will model and predict potential clinical outcomes given various scenarios. Clinicians and researchers also will use this multiparameter intelligent monitoring in intensive care (MIMIC) system as a knowledge base with open access to further develop and test computer models that may improve care.

Introduction

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 technology development. 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 fields such as applied physics, materials science, supramolecular chemistry, and mechanical and electrical engineering.

Examples of FYs 2008 and 2009 NIH-supported technology development research include:

  • A microchip to identify cancer cells circulating throughout the body
  • "Medical GPS" to navigate through the body, find cancer cells within a tumor, destroy them, and deliver chemotherapy
  • Hand and arm prosthesis systems controlled by intact muscle recordings that produce fine finger movements and offer feedback on position and force
  • A lensless microscope that fits into a cell phone and assists with remote bedside monitoring
  • Innovative high-throughput methods for detecting and characterizing disease-causing alterations in genes and proteins
  • A new system of biomaterials that reprograms cells in the body to fight cancer
  • Smart coatings for implants that mimic human tissue

Technology development critical to research on a specific disease, organ system, life stage, or field is supported by the relevant NIH Institute. For example, NCI supports the development of technology necessary to more effectively diagnose and treat cancer. NIEHS supports research on how environmental exposures affect human health and actively develops technology that facilitates understanding of how the environment influences the development and progression of human disease.

In addition, NIBIB and NCRR support broad areas of technology development and application, including infrastructure. They also support interdisciplinary research aimed at developing fundamental platform technologies that can be translated into several biomedical applications. This work sometimes is done in collaboration with a disease-specific Institute as the work moves closer to clinical application.

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 existing technologies. This is especially true in order 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, wide access to such tools is important. In 2002, NIH recognized that a gap existed in the support of crosscutting technology development essential to creating such tools. In response, the NIH Roadmap theme New Pathways to Discovery was initiated to advance understanding of biological systems and build a better "toolbox" for medical research in the 21st century. The NIH Roadmap is supporting the development of these resources through five components of the New Pathways to Discovery theme, including Building Blocks, Biological Pathways, and Networks; Molecular Libraries and Molecular Imaging; Structural Biology; Bioinformatics and Computational Biology; and Nanomedicine.

NIH supports technology development through several complementary approaches, including:

  • High-risk, innovative projects with very little preliminary indication of the likelihood of success but a potentially significant impact. These projects usually have small budgets and short timeframes, aimed at proof-of-principle.
  • Research project grants with a sound basis in preliminary data, directed at development of a particular technology; some projects may take only a few years while others continue for a decade or more.
  • Bioengineering research partnerships, which bring together multiple disciplines such as engineering, cell biology, physics, and neurology to develop solutions to specific biomedical questions or diseases.
  • Specialized centers that represent a critical mass of expertise and technology, in which multidisciplinary development of complex, often unique technologies is pursued, typically in the context of challenging research problems that cannot be approached with existing tools.
  • Small business grants through the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs foster highly innovative projects to bring technological advances into the marketplace for the broadest possible availability and impact. These programs allow NIH to leverage the unique resources and perspectives available in the private sector to complement the work done at universities and the NIH intramural program.

Summary of NIH Activities

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. The following is an overview of technology development activities at NIH.


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, that is, 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.

NIH funds 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.

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, for example in diagnosing malaria. The cost of an individual unit would be about $10.

Another new device has the potential to save eyesight. Born of collaboration between researchers at NIH and 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.

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-supported researchers have created a microchip able to detect circulating tumor cells in whole blood.

E-Health and Biomedical Information Technology

Harnessing the power of the Internet will create 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 health care 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 health care decision-making by asking more informed questions about their care. Patients will be able to provide this information to any health care 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. Benefits of this approach include a reduction in medical errors and elimination of duplicative diagnostic procedures.

Next-generation health care 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), will affect how patients provide information on their conditions and how doctors use that information in treatment decisions. A Web-based computer adaptive testing system, PROMIS will record patient reports on symptoms such as pain, fatigue, and emotional distress related to various chronic diseases. Other programs that take advantage of the Internet include Positive Choice, a program to reduce risky behaviors that lead to the spread of HIV.

Databases and information clearinghouses are vital tools that allow investigators to streamline their research efforts. (Also see the section on Disease Registries, Databases, and Biomedical Information Systems in Chapter 3).The Chemical Effects in Biological Systems (CEBS) Knowledge Base is one such tool that provides data on how different chemicals affect various species. The data, deposited by researchers from industry, government, and academia, assists in understanding how exposures to various substances affect a person’s health.

One of the most popular NIH clearinghouses is the Clearinghouse for Neuroimaging Informatics Tools and Resources (NITRC). In the 2 years since its launch, the NITRC has averaged 7,000 visitors per month, provided 50,000 software downloads, and has nearly 1,000 registered users. In 2009, the project won First Place in the Excellence.gov awards, which recognize the very best in government IT programs.

In the 2 years since its launch, the Clearinghouse for Neuroimaging Informatics Tools and Resources has averaged 7,000 visitors per month, provided 50,000 software downloads, and has nearly 1,000 registered users. In 2009, the project won First Place in the Excellence.gov awards, which recognize the very best in government IT programs.

Another resource for collaborative work is the Cancer Biomedical Informatics Grid® (caBIG®), which offers a wide range of software tools to help basic and clinical scientists translate their findings from laboratory to clinic. The caBIG® approach has been adapted to non-cancer research including the Cardiovascular Research Grid. International partners are assisting in dissemination of the technology worldwide community.

To harness the power of computers, NIH supports the Biowulf cluster, a world-class supercomputer that provides intramural researchers with the ability to conduct large-scale biomedical computational projects. Biowulf comprises more than 6,000 interconnected processors operating cooperatively to solve such diverse problems as identifying genotype patterns of variation across human populations worldwide; validating algorithms used in computer-aided detection of colon polyps in "virtual colonoscopy"; computing the molecular structures of viruses such as HIV using 3-dimensional electron microscopy; facilitating whole-genome assembly and genome-wide association studies resulting from next-generation DNA sequencers; and, as part of the NIH Roadmap Initiative for Molecular Libraries, generating structural information for 25 million chemical structures.

To harness the power of computers, NIH supports the Biowulf cluster, a world-class supercomputer that provides intramural researchers with the ability to conduct large-scale biomedical computational projects.

Gene Sequencing and Beyond

The sequencing of the human genome 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 better 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 health care providers to evaluate individualized outlooks for 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 comorbidities, but also of ways to target treatments based on an individual’s genetic profile. (Also see the section on Genomics in Chapter 3.)


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, computed tomography (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 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 new 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 wipe out residual cancer cells. The center also is 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.

NIH’s new 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.

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.


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, through additional funding provided by the American Recovery and Reinvestment Act, also is supporting the improvement of facilities for basic and clinical research around the United States to meet the research, training, and support needs of colleges, universities, and other institutions. The Extramural Research Facilities Improvement Program awards grants to public and nonprofit private entities to expand, remodel, renovate, or alter existing research facilities or construct new research facilities for biomedical and behavioral research.

Using additional funding provided by the American Recovery and Reinvestment Act, NIH is supporting the improvement of facilities for basic and clinical research around the United States to meet the research, training, and support needs of colleges, universities, and other institutions.

Insights from Animal Models

Another key tool in discovering how a gene or protein malfunctions and causes disease is the use of animal models of disease. Over the last 25 years researchers have bred countless animals with deliberately altered genes that serve as models for studying normal and disease states. These "transgenic" animal models are assisting in fundamental research for a broad range of diseases and conditions. For example, NIH-supported scientists have developed various animal models of human cancer including breast, colon, lung, and others. These models are being used in cancer drug development to answer fundamental questions of drug pharmacology and toxicity. This knowledge is essential to the design of Phase I clinical trials in which the safety, dose level, and response to a new drug are studied in humans.

The models also provide new insights into serious medical conditions such as sepsis, spinal cord injury, and hearing and balance disorders. Sepsis is a serious medical condition caused by a bacterial infection and is a leading cause of illness and death in the United States and worldwide. New treatments for sepsis are on the horizon because of successful studies in animal models. In one study, NIH-supported researchers induced sepsis in an animal model and then infused the blood with bone marrow stromal cells (known to mediate the body’s immune response). The stromal cells weakened the body’s inflammatory response, thereby lessening the negative effects of sepsis. This opens up the possibility of preparing and storing stromal cells for patients at risk of developing sepsis.

New treatments for sepsis are on the horizon because of successful studies in animal models.

NIH-supported researchers also are using mouse models to study how injected peptide amphiphiles (molecules with water-soluble and water-insoluble properties) self-assemble into minute fibers (nanofibers) that inhibit glial scar formation following spinal cord injury and promote regeneration of both motor fibers and sensory fibers.

Mouse models of hereditary hearing impairments have been instrumental in mapping and cloning many of the deafness genes in humans. These animal models offer researchers many opportunities to study deafness, hereditary factors involved in hearing loss, and genes that are critical for the development and maintenance of the human ear. (Also see the section on Molecular Biology and Basic Sciences in Chapter 3.)


Large-Scale Collaborative Activities

The Biomedical Technology Research Centers (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. In FY 2009 there were approximately 70 of these centers located throughout the country that 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.

The Biomedical Technology Research Centers and Biotechnology Resource Centers represent a critical mass of technological and intellectual resources. They develop new technologies and tools in areas including tissue engineering, biomaterials, neural communication technologies, imaging, informatics, synchrotrons, electron microscopy, proteomics and glycomics, optics, and lasers.

The goal of the NIH-funded Biomedical Informatics Research Network (BIRN) is to allow researchers to collaborate by sharing data and tools. The BIRN is developing the informatics infrastructure necessary to allow any group of investigators to share data among themselves or with a broader community (also see the section on Disease Registries and Other Data Systems in Chapter 3). 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.

The goal of the NIH-funded Biomedical Informatics Research Network is to allow researchers to collaborate by sharing data and tools.

The Center for Human Immunology, Autoimmunity, and Inflammation (CHI) is a new trans-NIH intramural initiative designed to study the human immune system. Integrated teams of physicians and basic scientists are organized by CHI to perform research into immune pathophysiologies, the role of inflammation in a wide variety of disorders, and the translation of new knowledge into improvements in diagnosis and treatment of disease. CHI provides unique specific technologies, including flow cytometry to analyze immune cells; high-throughput systems technologies involving the use of new methods for large-scale examination of biological entities ranging from genes to enzymes; and advanced biostatical and computer modeling methods. These technologies often are unavailable to individual laboratories because of cost, complexity, and novelty.

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 and has overtaken the development of reliable analytical methods. Precise, accurate, and rugged 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 the Food and Drug Administration and the National Institute of Standards and Technology to promote the development, validation, and dissemination of analytical methods and reference materials for commonly used dietary supplement ingredients.


Multidisciplinary and Interdisciplinary Research

Team research offers one of the best environments to develop new technologies and refine current ones. This approach applies principles and methods from the quantitative sciences and engineering to address problems in the biological sciences and medicine. A team of scientists from different disciplines may identify problems and develop innovative solutions more quickly than a researcher working alone. NIH fosters and cultivates cooperative research so that fundamental discoveries and tools can be developed, even when their specific applications might not be obvious. For example, the laser—originally developed in the physics laboratories studying energy and light—has been adapted to invent microscopes that are critical to many research areas as well as a variety of surgical tools, including systems for laser eye surgery. Continued success in the future will require sustained and strong linkages among engineering, clinical medicine, physical science, computational science, and the biological sciences.

Multidisciplinary teams are essential to solving the complex technological problems that many emerging fields present. NIH-supported investigators studying osteoarthritis are working with imaging researchers to develop new ways of diagnosing and assessing the degeneration of cartilage. Using a relatively new imaging technique, optical coherence tomography, along with MRI, the group hopes to create a new method of visualizing the microstructures found in cartilage. (Optical coherence tomography is a technique for obtaining high-quality, three-dimensional, cross-sectional images of tissues using optical beams.) They are but one of several groups recently awarded grants under the Building Interdisciplinary Research Teams (BIRT) program. The initiative promotes interdisciplinary research backed by strong innovation and high potential benefits to advance study in the areas of arthritis and musculoskeletal and skin diseases.

NIH-supported investigators studying osteoarthritis are working with imaging researchers to develop new ways of diagnosing and assessing the degeneration of cartilage.

Building a better mousetrap often means pooling resources and ideas. 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 damaged or lost limbs as well as civilian amputees and those with spinal cord injuries. A range of electronic and robotic devices will help these individuals stand, move, and step. Especially promising is a new generation of hand and arm prostheses that provide fine finger movement and a sense of touch.

Getting to the moon required input from engineers, physicists, computer scientists, bioscientists, and a host of others. Going back into space for a prolonged stay requires the same collaborative effort. NIH recently paired with NASA to support biomedical experiments that astronauts can perform on the International Space Station (ISS). As a national laboratory, the ISS now provides space to researchers from other Federal agencies, universities, and industry. New experiments on the ISS will examine the effects of microgravity and radiation on biological systems. Molecular and cellular biologists and researchers interested in biomaterials and telemedicine are especially needed to design experiments.

Here on Earth, the interplay of ideas among teams of NIH-supported investigators, including clinicians, biomedical researchers, and electrical and computer engineers, has produced promising techniques to identify mothers at risk for premature delivery. One group used a noninvasive ultrasound approach to assess 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 United States.


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.

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.

NIH’s Alliance for Nanotechnology in Cancer brings together researchers from biology to oncology, 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.

Oversight for nanotechnology research falls to the Trans-NIH Nanotechnology Task Force, a body established to discover new avenues of study at the nexus of nanotechnology, nanomedicine, and nanobiology as well as to examine the human health effects of engineered nanomaterials. NIH has been named the Government’s lead agency for coordination of Federal research on the health implications of nanotechnology under auspices of the National Nanotechnology Initiative’s Nanoscale Science, Engineering, and Technology Subcommittee (NSET) and plays a key role in development of its Environmental, Health, and Safety Strategy.


Probing Proteins

Information resulting from the Human Genome Project is now helping scientists as they begin to study proteins, the tiny powerhouses within cells responsible for cell function. 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.

As a result of the NIH-sponsored Protein Structure Initiative (PSI), investigators now have a more potent set of tools to examine the protein in three dimensions. By the end of October 2009, PSI-supported researchers had identified more than 4,000 protein structures. In 2009, NIH announced plans for a new phase of the program—PSI: Biology. During the PSI: Biology phase, highly organized networks of investigators will apply the new paradigm of high-throughput protein structure determination, which was successfully developed during the earlier phases of the PSI, to study a broad range of important biological and biomedical problems. The initiative will make resources for high-throughput structure determination available to a larger community of scientists than has been engaged to date. The majority of targets for structure determination will be defined through consortium partnership arrangements and an open, ongoing community nomination process. Additional targets will be defined through biological theme projects of the structure determination centers.

As a result of the NIH-sponsored Protein Structure Initiative, investigators now have a more potent set of tools to examine the protein in three dimensions. By the end of October 2009, researchers had identified more than 4,000 protein structures.

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 United States 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

The combination of new tools and techniques developed to improve basic research as well as those aimed at delivering better health care will transform the current medical paradigm in response to 21st century needs. Health care of the future will include innovations such as neural interfaces to help paralyzed individuals; approaches that will enable diagnostic tests and therapeutic treatment to be administered simultaneously (theranostics); and improvements in the health, quality of life, and productivity of older individuals. NIH-supported researchers are leading the way toward a new paradigm in which technology is a central feature of fast and effective health care delivery. NIH funding of technology development provides an environment that enables investigators to think beyond what is conventional, to do so across disciplines, and to take the health care system to a level that will engage scientists, patients, and physicians in a collaborative experience.

Neural interfaces are systems that operate at the intersection of the nervous system and an internal or external device, including neural prosthetics. Neural prosthetic devices restore or supplement nervous system functions that have been lost through disease or injury, allowing people with disabilities to lead fuller and more productive lives. NIH pioneered the development of this technology, beginning more than 35 years ago. The program has, directly or indirectly, catalyzed the development of cochlear implants that help people with hearing impairments, respiratory and hand grasp devices for people with spinal cord injuries, and deep brain stimulation for Parkinson’s disease, among other contributions. Current work aims to restore voluntary bowel and bladder control and standing to spinal cord injured persons, allow paralyzed persons to control devices directly from their brains, improve cochlear implants, and improve deep brain stimulation, which may be applicable to many brain disorders. Through the years, this program has fostered the development of a robust research community, now including private sector companies, and represents a cooperative effort between NIH, the Department of Veterans Affairs, and the Department of Defense.

Neural prosthetic devices restore or supplement nervous system functions that have been lost through disease or injury, allowing people with disabilities to lead fuller and more productive lives. NIH pioneered the development of this technology.

NIH is leading the way in the development of new technologies to provide both 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. A team of chemists and neurosurgeons at the University of Michigan is developing highly specific, dye-loaded nanoparticles capable of delivering targeted photosensitizers to improve the survival of brain tumor patients. These particles also contain imaging contrasting agents to visualize response to therapy. This technique will allow neurosurgeons to visualize the brain tumors for surgical resection of the main tumor mass while eradicating remaining tumor cells through a process known as photodynamic therapy.

A team of chemists and neurosurgeons at the University of Michigan is developing highly specific, dye-loaded nanoparticles capable of delivering targeted photosensitizers to improve the survival of brain tumor patients.

As the baby boomer generation continues to celebrate milestone birthdays, improving the health of older Americans is more important than ever. To that end, NIH supports 13 Edward R. Roybal Centers whose objective is to improve the health, quality of life, and productivity of middle-aged and older people by facilitating translation of basic behavioral and social science to practical outcomes by developing new technologies and stimulating new "use-inspired" basic research in the behavioral and social sciences. Roybal investigators have made several key discoveries. For example, researchers have developed tools and technologies for identifying older adults at risk for automobile crash involvement, and are working with industry partners to develop and disseminate products based on these tools. Additionally, researchers have developed a "living laboratory" model methodology for in-home assessment of activity to facilitate early detection of changes in health or memory. Other companies have used this model to develop related products, and the model has spurred several new grant-funded research projects, including the development of a new medication tracker for older adults.

On many fronts, NIH-supported technology development is making a difference in how we approach both wellness and disease. This knowledge, in turn, will help to improve the quality of life for all.


Notable Examples of NIH Activity
Key
E = Supported through Extramural research
I = Supported through Intramural research
O = Other (e.g., policy, planning, or communication)
COE = Supported through a congressionally mandated Center of Excellence program
GPRA Goal = Concerns progress tracked under the Government Performance and Results Act
ARRA = American Recovery and Reinvestment Act

IC acronyms in bold face indicate lead IC(s)

Diagnostics and Point-of-Care Technology

Point-of-Care Technologies: Testing at the point of initial contact, or point-of-care (POC), rather than at specialized centers or hospitals uses state-of-the-art diagnostics and information systems that can be used in the doctor's office or even at home. Consequently, the use of POC devices also can help patients monitor their wellness in preventive medicine. The POC approach to health care delivery can significantly improve the quality and reduce the cost of health care by: providing earlier diagnosis of disease when treatment is more effective and less costly; making modern medicine available to those who lack access to regular care, such as people in rural settings or developing countries; combining cutting-edge diagnostic and communication technologies to bring patients into more frequent and regular contact with health care providers; and enabling a patient-centered process with home-based monitoring. To address the challenges of health care quality and accessibility, NIH currently funds a network of four Centers that targets the development of new POC technologies for early and rapid detection of strokes, detection of sexually-transmitted diseases, rapid multi-pathogen detection for national disaster readiness, and diagnosis of infections, which can be used in low-resource settings among underserved populations. A major characteristic of the network is to facilitate clinical/technology interactions so that user-specific information can be shared with technology developers who typically lack relevant clinical connections. In 2009, the network funded several collaborative exploratory development projects through clinical need-based solicitations in their respective areas.
Low-Cost, Lens-Free Optical Microscope: The optical microscope is used widely in biological and biomedical research. Since the days of van Leeuwenhoek, the image magnification has been based on lenses. This research explores an innovative design of a lens-free microscope. Images are acquired by direct projection imaging of specimens that flow past the imager in microfluidic channels. Using the innovative design concepts, the microscope device has been fabricated in a package of the size of a dime. Early estimation of the fabrication cost of the optofluidic microscope suggested that such devices can be made very inexpensively at about $10 per unit. This lensless compact microscope can be integrated readily into a point-of-care diagnostic device for applications dealing with rural and global health care challenges. Large numbers of the compact device can be assembled together for massively parallel imaging of large populations of cells and microorganisms.
A New Imaging Device for Early Detection of Cataract: A transparent ocular lens is essential to vision. Cataract (clouding of the lens) remains the primary cause of blindness in the world today. Age-related cataract, the most common type of cataract, is caused by abnormal aggregation of lens proteins that clouds the lens. In the last few years, it has been established that a particular lens protein, alpha crystallin, prevents other lens proteins from aggregating and probably plays a major role in preventing cataract formation. Humans are born with a fixed amount of alpha crystallin, so age-related cataracts occur when the supply is depleted. Researchers at NIH and NASA collaborated to develop a new imaging device that allows clinicians to detect and quantify the amount of unbound alpha crystallin protein in a patient's eye. The device uses dynamic light scattering to measure the amount of alpha crystallin remaining in the lens. This may lead to a better understanding of the early stages of protein aggregation before cataracts form that impinge on vision. Early detection of lens protein disruption may provide clues to preventive treatments that could delay the need for cataract surgery.
Microchip Captures Early Circulating Cancer Cells: Malignant cancers shed cells that enter the circulation, travel to other areas of the body, and often grow into secondary tumors, or metastases. Indeed, metastases are responsible for the great majority of cancer deaths. It is estimated that 70,000 men per year are diagnosed with recurrent prostate cancer after prostatectomy, as shown by rising prostate surface antigens. For these men, the ability to detect and characterize the malignant cells in the blood may enable personalized therapy. Researchers are developing a technology to facilitate quantitative detection of circulating tumor cells (CTCs). They have engineered a microchip with a large surface area of an adhesion molecule that binds CTCs from whole blood, making detection of CTCs more reliable than previous approaches. They are analyzing molecular and genomic information in the CTCs to identify new biomarkers to customize treatments that are personalized for the patients and to predict treatment outcomes. The NIH-supported research has the potential to eliminate or greatly reduce cancer deaths due to metastases.
A Test for Taste: Altered taste function has a tremendous impact on food choice, diet, and overall nutritional status. The loss of taste (and smell) affects the appreciation of food and the desire to eat. This loss exposes an individual to a variety of health risks, including gastrointestinal disorders, heart disease, and diabetes. The true prevalence of taste disorders is not known because scientists lacked a validated taste test that is suitable for large-scale population studies. Such a taste test must be easy to use and can be completed in less than 10 minutes. NIH-supported scientists have adapted a product developed for the food industry (the edible taste strip) to measure human taste capabilities. The precise amount of tastant (sweet, sour, salty, bitter, or savory) can be dissolved in the taste strip, and the strip can be placed in various regions of the mouth (e.g., tongue or palate). The edible taste strip is a sensitive test suitable for the clinic setting to aid the physician during an examination of an individual who is experiencing problems with the sense of taste. The taste strip can be used in epidemiological studies for individuals of different ages to establish normative data on the prevalence of taste problems in the general population. This simple, reliable taste test now provides an invaluable diagnostic tool to assess taste function, and, in combination with a smell test, can evaluate chemosensory function.
  • Smutzer G, et al. Laryngoscope 2008;118(8):1411-6.
  • (E) (NIDCD)

E-Health and Biomedical Information Technology

Multiparameter Intelligent Monitoring in Intensive Care: NIH is funding a team of investigators to develop and evaluate an advanced intensive care unit (ICU) patient monitoring system. The system is designed to substantially improve the efficiency, accuracy, and timeliness of clinical decision-making in intensive care. The investigators are gathering data from ICU medical information systems, hospital medical information systems, and bedside ICU monitors. The project has collected approximately 30,000 patient records for the clinical database as well as ICU monitor data for about 5,000 of these patients for the waveform database. The databases have implemented sophisticated de-identification methods, which they developed, so that the data they collect can be reused by others. For example, they have replaced all dates in the records with surrogate dates. Future work will include the development of innovative algorithms and clinician interfaces based on the need for information extracted from this extensive data set.
Health Information Technology: Health information technology research that enables the integration of clinical data and medical image diagnostic and treatment data with the patient's medical history in a comprehensive electronic medical record will improve clinical decision-making. The ability to connect and exchange diagnostic information and medical images between health care providers, clinics, and hospitals will help provide the timely information that is needed for effective health care and will help reduce unnecessary, excessive, and duplicative procedures. A patient-centered approach to comprehensive electronic health records will allow patients access to their health information. This will enable patients to play an active role in their own wellness by enabling them to ask knowledgeable questions about treatment options. Additionally, patients also are empowered to provide this information to any and all health care providers as needed, independent of their location or where the medical data was created or stored. NIH supports research in new methods and technologies to address issues such as: interoperability of data systems, compatibility of computer software across medical institutions, security of data during transmission, HIPAA compliance, availability of affordable data systems for patient care providers, and integration of medical decision-support information in medical data systems.
  • This example also appears in Chapter 3: Disease Registries, Databases, and Biomedical Information Systems
  • (E) (NIBIB, NLM)
Health IT Standards and Electronic Health Records: NIH researchers are engaged in developing Next Generation electronic health records (EHRs) with advanced decision-support capabilities to facilitate patient-centered care, clinical research, and public health. As the central coordinating body for clinical terminology standards within HHS, NIH works closely with the Office of the National Coordinator for Health Information Technology (ONC) to support nationwide implementation of an interoperable health information technology infrastructure. NIH develops or licenses key clinical terminologies that are designated as standards for U.S. health information exchange. The Unified Medical Language System Metathesaurus, with more than 8.1 million concept names from more than 125 vocabularies, is a distribution mechanism for standard code sets and vocabularies used in health data systems. NIH also produces RxNorm, a standard clinical drug vocabulary; supports the LOINC nomenclature for laboratory tests and patient observations; and collaborates with the International Health Terminology Standards Development Organisation to promote international adoption of the SNOMED CT clinical terminology. In FY 2009, NIH released the first version of the CORE Problem List Subset of SNOMED CT, designed to facilitate coding of problem list data in EHRs by mapping frequently used terms from seven large-scale health care institutions to corresponding SNOMED CT concepts. The Newborn Screening Codes and Terminology Guide, a Web portal to support more effective use of newborn screening laboratory test information, was created in FY 2009 in collaboration with ONC, the Health Resources and Services Administration, and newborn screening organizations.
Patient-Reported Outcomes Measurement Information System (PROMIS): The PROMIS initiative is developing new ways to measure patient-reported outcomes (PROs) for clinical research, such as pain, fatigue, physical functioning, emotional distress, and social role participation, which have a major impact on quality of life across a wide variety of chronic diseases. The first phase of PROMIS successfully has addressed its initial broad objectives of developing and testing a large item (survey question) bank for measuring PROs, along with translation of certain items into Spanish; creating a computer adaptive testing (CAT) system that allows for efficient, scientifically robust assessment of PROs in patients with a spectrum of chronic diseases; and producing a publicly available, Web-based system that continues to be updated and modified, to allow clinical researchers access to PROMIS resources, such as a common repository of validated items, a CAT system, and hard copy surveys. Preliminary results demonstrate that a short, 10-item PROMIS survey, administered by CAT, outperforms the most commonly used, paper-based, self-reporting assessment tool for arthritis disability (the Health Assessment Questionnaire). These results are indicative of the anticipated advantages of the PROMIS tool: better answers with fewer patients. The success of the project has garnered 4 more years of NIH funding for PROMIS. Prioritized tasks for PROMIS include validating and evaluating usability in future NIH-supported clinical trials, including Spanish translations; developing additional modes of administration; facilitating adoption of PROMIS by the clinical research community; and building partnerships to secure long-term sustainability for the PROMIS tools.
Using the Web to Broaden the Delivery of Effective Treatments: NIH is testing the efficacy of delivering evidence-based psychosocial interventions for drug abuse and HIV prevention via the Web or other computer-based media, while assessing their relative cost and efficacy compared to more traditional delivery formats. Variables of interest include abstinence, treatment retention, health risk, quality of life, and social outcomes. New research shows that computer-based training for cognitive behavioral therapy appears to have both short-term and enduring effects on drug use—that is, fewer days of drug use for many months following treatment compared to controls. Another computer-based intervention, called Positive Choice, was tested in HIV-positive patients as a means of reducing risky behaviors that lead to HIV spread. Five San Francisco clinics participated, exposing patients to a "video doctor" to conduct a risk assessment and risk reduction counseling program. Patients waiting to see the provider use a laptop computer to watch video clips and respond by means of a color-coded keyboard. That, too, was successful, and sharply reduced sexual and drug risk behaviors in HIV-positive patients. These delivery methods stand not only to greatly increase cost effectiveness of interventions, but to provide a means for broader dissemination, including to those in remote locations where therapists may not be available. Our research will continue to investigate how such interactive technology can be integrated to improve the addiction treatment system and bring about more widespread adoption of evidence-based approaches.
A Clearinghouse for Neuroimaging Informatics Tools and Resources: Many neuroimaging tools and databases are underutilized because they cannot be found easily, are not user-friendly, or are not easily adoptable or adaptable. In an effort to promote the enhancement, adoption, distribution, and evolution of neuroimaging informatics tools and resources, the NIH Blueprint for Neuroscience Research has launched the Neuroimaging Informatics Tools and Resources Clearinghouse (NITRC). Examples of included tools are: image segmentation, image registration, image processing pipelines, statistical analysis packages, spatial alignment and normalization algorithms, and data format translators. Resources include: well-characterized test datasets, data formats, and ontologies. Since the first release in October 2007, the clearinghouse website, or NITRC, has become host to 180 tools and resources, with a community of 13,602 unique visitors who downloaded NITRC tools and resources, and 7,000 unique visitors per month, more than 954 of which are registered users (11 percent non-English speaking). The hits to the site have reached 15,635,019/month. Since its inception, more than 50,000 software files have been downloaded. More than 53 percent of the tools on NITRC had not been shared online previously but now are available to the community. In 2009, the NITRC project won the first place of Excellence.gov awards, the largest Federal government award program to recognize the very best in government IT programs, among 61 competitors. Through the initiative, nearly 40 awards have been made to neuroimaging tools and resource developers to enhance the accessibility, interoperability, and adoptability of their existing tools and resources.
  • Ardekani BA, Bachman AH. Neuroimage 2009;46(3):677-82. PMID: 19264138. PMCID: PMC2674131.
  • For more information, see  http://www.nitrc.org/
  • For more information, see  http://neuroscienceblueprint.nih.gov/
  • This example also appears in Chapter 2: Neuroscience and Disorders of the Nervous System and Chapter 3: Disease Registries, Databases, and Biomedical Information Systems
  • (E) (NIH Blueprint, NCCAM, NCRR, NEI, NIA, NIAAA, NIBIB, NICHD, NIDA, NIDCD, NIDCR, NIEHS, NIGMS, NIMH, NINDS, NINR, OBSSR)
The Cancer Biomedical Informatics Grid® (caBIG®): The caBIG® initiative connects researchers and institutions to enable collaborative research and personalized, evidence-based care. More than 1,500 individuals representing more than 450 government, academic, advocacy, and commercial organizations have collaborated to develop a standards-based grid infrastructure (caGrid) and a diverse collection of interoperable software tools, enabling basic and clinical researchers to speed the translation of information from bench to bedside. Forty-nine of the 65 NCI-designated Cancer Centers and 8 of 10 organizations of the NCI Community Cancer Centers Program are actively deploying caBIG® tools and infrastructure in support of their research efforts. Additionally, caBIG® technology is adapted to power noncancer research initiatives such as the CardioVascular Research Grid. Ongoing collaborations with research and bioinformation organizations in the United Kingdom, China, and India are driving international adoption of caBIG® resources. The caBIG® infrastructure also supports a new health care ecosystem, BIG Health™, in collaboration with various stakeholders in biomedicine (e.g., government, academia, industry, nonprofits, and consumers) in a novel organizational framework to demonstrate the feasibility and benefits of personalized medicine. BIG Health™ will provide the foundation for a new approach in which clinical care, clinical research, and scientific discovery are linked.
NIH Biowulf Cluster Enables Large-Scale Biomedical Research: The Biowulf cluster provides NIH researchers with a world-class supercomputer that enables the conduct of large-scale biomedical computational projects, allowing scientific research that otherwise would not be possible. Biowulf comprises more than 6,000 interconnected processors operating cooperatively to solve such diverse problems as: identifying genotype patterns of variation across worldwide human populations; validating algorithms used in computer-aided detection of colon polyps ("Virtual Colonoscopy"); computing the molecular structures of viruses such as HIV using 3D electron microscopy; facilitating whole-genome assembly and genome-wide association studies resulting from next-generation DNA-sequencers; and, as part of the NIH Roadmap Initiative for Molecular Libraries, generating conformation ensembles for 25 million chemical structures. In 2008-2009, more than 105 scientific papers published by NIH intramural scientists cited the use of Biowulf as a computational resource.
  • This example also appears in Chapter 3: Disease Registries, Databases, and Biomedical Information Systems
  • (I) (CIT)
Informatics Training for Global Health: As biomedical information has increased exponentially in recent years, computer-based tools have been developed to access and analyze this information and to aid the process of research design, data management, and data analysis. The sheer volume of data generated in many biomedical and behavioral research projects and in clinical trials can no longer be managed effectively without electronic help. Further, access to computers and the Internet is becoming commonplace in research institutions throughout the developing world. To take advantage of these tools, individuals with the advanced skills to use them are critically needed. However, despite the central role informatics plays in global health, many low and middle income country (LMIC) institutions have very few informatics experts and a very weak information technology infrastructure. There is a critical need to train local experts who are able to develop local research applications or modify existing platforms to provide tools that are appropriate for the needs, culture, and infrastructure of their institutions and countries. In response, NIH’s Informatics Training for Global Health program aims to develop human capital to meet global health challenges, to support the development of research hubs in LMICs, and to bolster the development of expertise in the use of information and communication technologies in support of research and research training.
Children and Clinical Studies: Medical research in children has saved lives and improved health and well-being, yet parents often are reluctant or uncertain about allowing their child to participate in a clinical study. The Children and Clinical Studies campaign helps parents and others to learn more about how clinical research is conducted in children, so that they can make well-informed decisions about whether to participate. Its website, which is available in English and Spanish, combines practical information with award-winning video footage of parents, health care providers, and children themselves discussing the rewards and challenges of participating in research. Educational materials for parents and health care providers can be requested through the site, as well.

Gene Sequencing and Beyond

Medical Sequencing: As more is learned about the genetic contributions to disease, DNA sequence information will become even more important for providing medically relevant information to individuals and their health care providers. When it becomes practical to sequence each patient's genome, genetic information will be used to provide more individualized outlooks of disease risk and improve the prevention, diagnosis, and treatment of disease. NHGRI's medical sequencing program, initiated in 2006, aims to drive continued improvement in DNA sequencing technologies and to produce data important to biomedical research. Seven studies currently are underway to identify the genes responsible for several relatively rare disorders and to survey the range of gene variants that contribute to certain common diseases.
Genome Technology and the $100,000 and $1,000 Genome Initiatives: Taking the discoveries made in genetic research initiatives and delivering them to patients on a much wider basis will require significant decreases 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. However, it still remains prohibitively expensive to sequence the genomes of individual patients in the clinic. Developing technology to make genome sequencing more affordable is essential for making genomic information part of routine medical care. NIH's Genome Technology program supports research to develop rapid, low-cost methods, technologies, and instruments that will:
  • Read DNA sequences
  • Check sequences for genetic variations (SNP genotyping)
  • Aid research to understand the effects of genetic variations on genomic function.

In 2004, NIH began funding research to develop technologies specifically intended to lower the cost of sequencing the amount of DNA in a human genome, about 3 billion base pairs. These efforts include:

  • "Near-Term Development for Genome Sequencing" Grants. These awards support research to enable the sequencing of a human-sized genome for about $100,000.
  • Revolutionary Genome Sequencing Technologies Grants. These awards aim to develop breakthrough technologies that will enable an individual's genome to be sequenced for $1,000 or less.
    New Genetics/Epigenetic Tools Shed Light on Addiction: NIH-supported research is taking full advantage of expanding databases and fast technologies to identify links between genetic variations and disease, health, and behavior. Such genetic studies are critical to teasing apart the molecular mechanisms underlying complex diseases like addiction, which genes strongly influence. Investigators studying various neurological and psychiatric illnesses have already linked certain genes with specific diseases using custom screening tools known as "gene chips" (e.g., the neurexin gene has been found to play a role in drug addiction). Applying these tools to addiction and other brain disorders advances our understanding not only of vulnerability to addiction and its frequent comorbidities, but also of ways to target treatments based on a patient's genetic profile. To complement these efforts, NIH is investing in the equally important field of epigenetics, which focuses on the lasting modifications to the DNA structure and function that result from exposure to various stimuli. Attention to epigenetic phenomena is crucial to understanding the interactions between genes and the environment, including the deleterious long-term changes to brain circuits from drug abuse. For example, using a powerful new technique known as ChIP-on-chip to monitor epigenetic changes correlated with gene activity, investigators recently have mapped the genomic effects of chronic cocaine use in the reward center of the mouse brain. Such analyses provide needed information about which genes are altered by cocaine and can point to new targets for medications development. Epigenetic discoveries also can inform ways to smartly alter environmental factors so as to decrease the risk for drug abuse and addiction.

    Image-Guided Interventions

    Development of Image-Guided Interventions: Image-guided interventions (IGI) provide therapy that can minimize trauma and improve patient outcomes. They are applicable in procedures such as biopsy, surgery, radiation treatment, vascular interventions, and guidance during delivery of devices, drugs, cells, or genes. These improved capabilities particularly are important in light of the shifting trend in medicine toward a model of early, presymptomatic detection of disease. Representative of ongoing research is an effort to improve image-guided surgical removal of tissue using optical coherence tomography (OCT). Recent studies suggest that OCT optical imaging techniques may have a significant impact on breast cancer biopsy and treatment. High-resolution OCT image guidance could help ensure complete surgical removal of tumors and adequate diagnostic biopsy sampling. As other biomedical imaging modalities, such as MRI, improve the ability to detect small suspicious lesions, OCT can be used to guide a biopsy needle precisely to tumor tissue and cells and enable sampling of these smaller nonpalpable lesions. In preliminary studies, surgically removed lumpectomy specimens from more than 65 patients have been imaged with OCT in the operating room. When compared to post-operative histopathology, OCT yielded a sensitivity of 100 percent and a specificity of 82 percent and demonstrates the potential of OCT as a real-time method for the intraoperative margin assessment in breast-conserving surgeries.
    • Nguyen FT, et al. Meeting Abstract: Optical coherence tomography (OCT) as a diagnostic tool for the real-time intraoperative assessment of breast cancer surgical margins. Cancer Res 2009;69: 802.
    • This example also appears in Chapter 2: Cancer
    • (E) (NIBIB) (GPRA)
    Image-Guided, Minimally Invasive Interventions: Image guidance offers a cost-effective, safe, and less invasive approach to many common diseases. From treating a uterine fibroid, a brain aneurysm, or cancer, image-guided minimally invasive interventions are ushering in an era of personalized and cost-effective alternatives to open surgery. Diagnosis and therapy often are poorly integrated, creating a gap in health care delivery. NIH support of technology development has enabled physicians to better use medical imaging during minimally invasive procedures, not solely for pre- or post-procedure diagnosis. The unique translational environment of the NIH CC has enabled interdisciplinary and trans-agency development and dissemination of novel cost-effective approaches. This includes navigation with "Medical GPS" for tumor ablation, whereby a "smart" needle is inserted with image guidance into a tumor to heat and kill cancer cells. The heat also deploys nanoparticles at the site of the tumors that are engineered specially to deploy their chemotherapy cargo where needed to avoid systemic toxicities. Such drug + device + imaging combination therapies were pioneered by NIH as part of an inter-agency, multi-IC, and industry-academic partnership. Using prior images during later invasive procedures makes the procedures targeted and personalized, without requiring the expensive imaging equipment to be brought physically to the procedure room. Imaging also has been used to guide energy (high-intensity focused ultrasound) through the skin, to the level of the inner disease process to kill tissue or to deposit drugs in a targeted fashion.

    Imaging Biological Systems

    High Resolution Anatomical and Functional Imaging of the Human Brain: NINDS and NIMH Intramural Research Programs are partnering to push the frontiers of MRI (magnetic resonance imaging) of the human brain and to make these developments available to researchers. The NINDS Laboratory of Functional and Molecular Imaging has led development of the next generation MRI device that uses a powerful 7T (Tesla) magnet, compared to the usual 1.5T magnetic strength. Overcoming the many technical challenges of imaging at 7T has yielded extraordinarily detailed images, which have contrast and spatial resolution as much as 100 times better than previous methods. These images reveal structures never before seen in the living human brain that may be critical in detecting early stages of disease. The NIMH functional MRI core facility serves more than 30 principal investigators on the NIH Bethesda campus and leads development of functional brain imaging. The facility has played a major role in making 3T MRI widely available for routine use. Together NINDS and NIMH investigators have pioneered imaging methods that increase the detail of structural and functional changes that investigators can detect in the brain, while improving time resolution and shortening duration for brain scans. A two-step strategy to continue this successful program will first translate 7T MRI from its present prototype design to routine use and then develop one of the world's first 11.7T MRI devices for imaging the human brain. Increased MRI resolution will improve diagnosis and monitoring of neurological and psychiatric disorders and open new opportunities for understanding brain function.
    Feeling Organs with Imaging: MRI is known for providing exquisite anatomical images of internal organs. Using a new technique that involves imaging while pushing on an organ with sound waves, researchers are able to feel the stiffness of internal organs. Because tumors often are more stiff than normal tissue (think, for example, of feeling for a "lump" of stiffer tissue in the breast), this technique may provide important diagnostic information about disease. Initially, this technique is being used to examine the stiffness of liver and potentially provide an alternative to liver biopsy for the 170 million individuals worldwide who live with chronic hepatitis C, a major cause of liver disease.
    • Venkatesh SK, et al. AJR Am J Roentgenol 2008;190:1534-40. PMID: 18492904.
      Yin M, et al. Magn Reson Med 2007;58:346-53. PMID: 17654577.
      Yin M, et al. Clin Gastroenterol Hepatol 2007;5:1207-13. PMID: 17916548. PMCID: PMC2276978.
      Kruse SA, et al. Neuroimage 2008;39:231-7. PMID: 17913514. PMCID: PMC2387120.
    • For more information, see  http://www.nibib.nih.gov/HealthEdu/eAdvances/28Aug08
    • This example also appears in Chapter 2: Chronic Diseases and Organ Systems
    • (E) (NIBIB)
    NCI Imaging Programs: In addition to their applications in basic scientific discovery, imaging technologies contribute to cancer care through contributions to screening, diagnosis, disease staging, treatment guidance, treatment monitoring, and detection of cancer recurrence. NCI's imaging programs include the extramural Cancer Imaging Program (CIP), whose mission is to promote and support basic, translational, and clinical research in imaging sciences, and several intramural efforts within the Center for Cancer Research (CCR), such as the Molecular Imaging Program, Radiation Biology Branch, Radiation Oncology Branch, Center for Interventional Oncology, and NCI-Frederick Small Animal Imaging Program. The National Lung Screening Trial (NLST) is comparing two ways of detecting lung cancer: spiral computed tomography (CT) and standard chest X-ray. Both chest X-rays and spiral CT scans have been used to find lung cancer early. So far, neither chest X-rays nor spiral CT scans has been shown to reduce a person's chance of dying from lung cancer. This study will aim to show if either test is better at reducing deaths from this disease.
    Simulating and Analyzing Musculoskeletal Dynamics: NIH-funded investigators have introduced OpenSim, a freely available open-source simulation platform to accelerate the development and sharing of simulation technology and to integrate dynamic simulations into the field of movement science, in particular animal and human neuromusculoskeletal systems. OpenSim tools allow one to edit muscles, analyze dynamic simulations, and track motions, a process that enables accurate muscle-driven simulations to be generated that represent the dynamics of individual subjects. OpenSim is being developed and maintained on Simtk.org, which is a software development environment that is being developed under the parent Roadmap Simbios National Center for Biomedical Computing.
    • Liu MQ, et al. J Biomech 2008;41(15):3243-52. PMID: 18822415.
    • (E) (NIGMS)
    Molecular Imaging Probe Development Program Review: An emerging biomedical technology with great potential for improving disease diagnosis and treatment is molecular imaging. However, molecular imaging techniques still are used primarily for preclinical applications. The transfer of these preclinical tools into clinical tools remains a demanding problem and requires the development of novel molecular imaging probes that have increased sensitivity and specificity, and are nontoxic. Approaches to developing more sensitive and specific nontoxic probes were discussed and developed at a Molecular Imaging Program Progress Review that was held on May 19, 2008, in Bethesda, MD. The panel identified high-priority areas that would advance future research in the molecular imaging field, and, in particular, would be capable of translation to clinical applications. The report of this panel discussion was posted on the NIBIB website and provided to the National Advisory Council for Biomedical Imaging and Bioengineering for further strategic planning in this area.


    Investments in Infrastructure

    Shared Instrumentation Grant and High-End Instrumentation Programs: The goal of the NIH instrumentation programs is to provide new-generation technologies to groups of NIH-supported 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. The Shared Instrumentation Grant (SIG) program funds equipment in the $100,000-$500,000 range, while the High-End Instrumentation (HEI) program funds instrumentation in the $750,000-$2 million range. New research technologies supported by these programs enable novel modes of inquiry, which in turn lead to increases in knowledge, and ultimately have the potential for improving human health. To increase cost-effectiveness, the instruments are located at core facilities with trained technical staff to assist in protocol development and to facilitate integration of new technologies into basic and translational research. In FY 2008, the SIG program funded a total of 82 grants for $30,623,406; the HEI funded a total of 20 awards for $33,309,434. In FY 2009, NIH received $300 million in ARRA funding to provide shared instrumentation to extramural researchers through the SIG and HEI programs. To best serve the needs of NIH-supported investigators, the range of HEI awards funded by ARRA was expanded and now is $600,000 to $8 million.
    Extramural Construction Program Expands Research Capacity: The American Recovery and Reinvestment Act (ARRA) provided $1 billion to NIH for the Extramural Construction program. The program will build capacity to conduct biomedical and behavioral research by supporting the costs of improving non-Federal basic research, clinical research, and animal facilities to meet the research, research training, or research support needs of institutions. One component of the program, the Extramural Research Improvement Program, awards grants to public and nonprofit private entities to expand, remodel, renovate, or alter existing research facilities or construct new research facilities for biomedical and behavioral research. Another component of the program, the Core Facility Renovation, Repair, and Improvement activity, awards grants to public and nonprofit private entities to renovate, repair, or improve core facilities. A core facility is a centralized shared resource that provides access to instruments or technologies or services, as well as expert consultation to investigators supported by the core. Institutions apply for construction grants by submitting applications, which are selected using NIH's standard, competitive, peer-reviewed process. Funding decisions are based on the scientific and technical merit of the application as determined by first and second level of peer review, the availability of funds, the relevance of the application to NIH program priorities, the national geographic distribution of awards, and the priorities specified in the ARRA, such as energy efficiency and job creation. The objective of the ARRA Extramural Construction program aligns with the objective of the existing Research Facilities Improvement Program, which is also administered by NIH.
    ARRA-Funding Expands Research Capabilities: NCRR is using its ARRA funds designated for scientific research to accelerate the Center's research priorities and support research, resources, tools, and training to help researchers funded by NIH transform basic discoveries into improved human health. In contrast to most of the NIH ICs that fund primarily Research Project Grants (i.e., R01s), NCRR primarily supports large Center programs that build research capacity and offer training and career development. Consistent with NCRR's research portfolio, a few previously reviewed Research Project Grants (R01s and R21s) are being awarded with ARRA funds. Through competitive revision awards, NCRR is encouraging NIH-funded researchers (primarily supported by other NIH ICs) to leverage the resources, expertise, and infrastructure of NCRR centers and Center-like programs. To further advance the scientific progress of NCRR programs, administrative supplements are being awarded to: advance translational (pre- and post-clinical) research, achieve CTSA consortium strategic goals, enhance NCRR pilot project mechanisms, promote collaborative community engagement research, improve research workforce development, and strengthen science education and dissemination. A new ARRA-supported initiative will develop infrastructure to connect people and resources across the Nation and promote interdisciplinary collaborations and scientific exchange. Additional ARRA funding is supporting NIH-led activities such as the Challenge Grants and the Summer Research Experiences for Students and Science Educators. From the beginning of the ARRA-funding strategy development, NCRR leadership decided to align its ARRA activities broadly with the goals and objectives of the NCRR 2009-2013 Strategic Plan.
    Electronic Scientific Portfolio Assistant: Demand for information about program performance and results, as well as accountability and transparency, continues to increase across the Federal government. The Electronic Scientific Portfolio Assistant (e-SPA) offers a comprehensive means by which to conduct statistically meaningful portfolio analyses of program performance. The development of e-SPA grew out of program needs to ensure accountability and transparency of information about program performance and results. Though e-SPA was developed initially for NIAID program managers, it quickly has become a valuable analysis tool across NIH. e-SPA provides extramural program directors with the capability to monitor, analyze, and compare the performance of their research portfolios and individual investigators. The tool generates user-defined portfolios of research projects and links the projects to outcome indicators including funding, publications, citations, impact factors, inventions, and patents. e-SPA uses information available from multiple databases to enhance synthesis and analysis of relevant data, and provides data visualization capability through a dashboard and graphs.
    • (O) (NIAID)

    Insights from Animal Models

    New Biomaterials System Programs Cells in situ to Fight Cancer: In the body's immune response to foreign invaders, dendritic cells signal and activate other cells to initiate a generalized inflammatory response. Cell-based cancer vaccinations build on this natural tendency by isolating and activating a patient's dendritic cells using tumor antigens, and then injecting the reprogrammed cells back into the patient. The activated dendritic cells travel home to the lymph nodes and promote an antitumor response. Unfortunately, most transplanted dendritic cells die. Additionally, reprogrammed cells partially lose their effectiveness after injection back into the body. Thus, multiple rounds of injections are required to achieve significant effect. To address these limitations, investigators developed a multifunctional in situ dendritic cell reprogramming system composed of polymeric biomaterials that release cytokines to attract dendritic cells already within the lymph nodes into the biomaterials. The dendritic cells are then activated by the biomaterials. The biomaterials reduce their cytokine release at a controlled rate so that after activation, the dendritic cells will migrate away from the biomaterials back home to the lymph nodes and present tumor antigens to T cells found there. In a mouse model this sophisticated system provided protection from tumor development equal or superior to that provided by traditional cancer vaccines without the complications and costs of ex vivo cell manipulation and transplantation. The new system also provided much better control over the number of dendritic cells than traditionally generated cancer vaccines. This study demonstrates a powerful new application for polymeric biomaterials that could be used in the future against cancers and other diseases.
    • Ali OA, et al. Nature Materials 2009;8(2):151-8. PMID: 19136947. PMCID: PMC2684978.
    • This example also appears in Chapter 2: Cancer
    • (E) (NIDCR)
    New Model Reveals Novel Molecular Strategies in the Fight to Overcome Oral Cancer: Oral and pharyngeal carcinomas are the ninth most common cancer worldwide, with more than 35,000 new patients and more than 7,500 deaths each year in the United States alone. The 5-year survival rate has improved only marginally over the past 40 years. There is an urgent need for new options for these patients. Emerging information on the deregulation of normal molecular mechanisms that result in the cancer's progression provides the possibility of new mechanisms-based therapeutic approaches for these aggressive oral malignancies. NIH scientists recently used a two-step chemical carcinogenesis model and found that the drug rapamycin exerted a remarkable anticancer activity. It decreased the tumor burden of mice having early and advanced tumors, and even brought about the regression of recurrent squamous cell skin cancers. The scientists reported that the persistent activation of mTOR, the mammalian Target of Rapamycin, occurs frequently in head and neck cancer patients and that its inhibition by rapamycin causes regression of human oral cancer tumors implanted in mice. Because chemically induced animal cancer models often better reflect the complexity of the clinical setting, the scientists developed an oral-specific chemical carcinogenesis mouse model. In this model, activation of mTOR is an early event in precancerous lesions; rapamycin treatment can halt the malignant conversion of precancerous lesions and promote the regression of advanced carcinogen-induced oral squamous cell carcinomas (SSCs). Significance: The development of this SCC carcinogenesis model demonstrates that the use of mTOR inhibitors may provide a novel molecular-targeted strategy for chemoprevention and treatment of oral squamous cell cancer.
    • Amornphimoltham A, et al. Clin Cancer Res 2008;14(24):8094-101. PMID: 19073969.
      Czerninski R, et al. Cancer Prevention Res 2009;2(1):27-36. PMID: 19139015.
    • For more information, see  http://www.nidcr.nih.gov/DataStatistics/FindDataByTopic/OralCancer/
    • This example also appears in Chapter 2: Cancer and Chapter 3: Molecular Biology and Basic Research
    • (I) (NIDCR)
    Bone Marrow Stromal Cells Help Fight Sepsis: Sepsis is a serious medical condition that affects 18 million people per year worldwide, and is characterized by a generalized inflammatory state caused by bacterial infection. Widespread activation of inflammation and blood clotting pathways leads to multiple organ failure, collapse of the circulatory system (septic shock), and death. In the last few years, it has been discovered that bone marrow stromal cells (BMSCs, also known as mesenchymal stem cells) are potent modulators of immune responses. In this study, BMSCs were administered before or shortly after inducing sepsis by puncturing the intestine to determine whether BMSCs injected into the circulation would have a beneficial effect in preventing or attenuating septic shock. Infusion of BMSCs significantly decreased sepsis-induced mortality and increased organ function in an animal model. The effects appear to be mediated by the production of Prostaglandin E2 when BMSCs are activated during the early stages of sepsis. Prostaglandin E2 subsequently induces the recipient's macrophages to produce substantially more IL-10, a factor that dampens the inflammatory response, which if left unabated, leads to death. This is the first determination of a mechanism by which BMSCs modulate the immune response in an animal model of sepsis. As many people die of sepsis annually as die from heart attacks. A new treatment or preventative regimen desperately is needed. Since the animal model suggests that the BMSCs need not be isolated from the same individual as will receive them, it is possible that cells isolated from nonrelated donors could be prepared and stored for use in patients with high risk for sepsis.
    • Nemeth K, et al. Nat Med 2009;15(1):42-9, PMID: 19098906. PMCID: PMC2706487.
    • For more information, see  http://www.nature.com/nm/journal/v15/n1/abs/nm.1905.html
    • This example also appears in Chapter 2: Infectious Diseases and Biodefense and Chapter 3: Molecular Biology and Basic Research
    • (I) (NIDCR)
    Bioactive Nanostructures for Neural Regeneration: Spinal cord injury (SCI) often leads to permanent paralysis and loss of sensation below the site of injury because of the inability of damaged axons to regrow across the injury site in adults. Nanomaterials built from a family of self-assembling molecules may offer hope for treating serious injuries, such as spinal cord injury according to new results from NIH research. Recently, an NIH-supported research group developed peptide amphiphile (PA) molecules that self-assemble in vivo into supramolecular nanofibers and tested them on mouse models of spinal cord injury. In this work, in vivo treatment with the PA nanofibers, after SCI, reduced cell death and promoted regeneration of both motor fibers and sensory fibers through the lesion site. Treatment with the PA also resulted in significant behavioral improvement. These observations demonstrate that it is possible to inhibit glial scar formation and to facilitate regeneration after SCI using bioactive three-dimensional nanostructures displaying high densities of neuroactive epitopes on their surfaces.
    • Tysseling-Mattiace VM, et al. J Neurosci 2008;28(14):3814-23. PMID: 18385339. PMCID: PMC2752951.
    • This example also appears in Chapter 2: Neuroscience and Disorders of the Nervous System and Chapter 2: Life Stages, Human Development, and Rehabilitation
    • (E) (NIBIB)
    Using Mice to Examine Hearing and Balance Disorders: Mouse models of hereditary hearing impairment have been instrumental in mapping and cloning many deafness genes in humans. These animal models offer researchers many opportunities to study deafness, hereditary factors involved in hearing loss, and genes that are critical for the development and maintenance of the human ear. For example, the varitint-waddler mouse exhibits hearing loss due to a mutation in the Trpml3 gene that encodes the protein, TRPML3, which is responsible for mechanosensory conduction within the inner ear. Mutations in the Trpml3 gene cause disorganization of the stereocilia bundle of sensory hair cells in the inner ear, which ultimately leads to hearing loss. The senses of hearing and balance are highly dependent on the structure of the stereocilia bundles. In this study, NIH intramural scientists, in collaboration with scientists in the United Kingdom, used immunofluorescence to locate the Trpml3 protein in the base of developing and growing auditory hair cell stereocilia. This study identifies Trpml3 as a critical channel in maintaining the base of the bundle during stereocilia maturation, which appears to be necessary to establish a functioning stereociliary hair bundle. Mouse models of hearing impairment are important tools to unravel the molecular basis of hearing. They also, in many instances, faithfully mimic the pathophysiology and genetics of human hearing impairment, thus providing animal models to explore the mechanism of action.
    • van Anken AF, et al. J Physiol 2008;586(Pt 22):5403-18. PMID: 18801844. PMCID: PMC2655368.
    • (I) (NIDCD)
    Researchers Discover Why Mammalian Teeth Form in a Single Row: Why do mammals develop a single row of teeth whereas other vertebrates, such as sharks, can develop multiple rows of teeth? Researchers studying mutations in the genes of mice that develop teeth serving no apparent function may have solved the mystery. Most of the mutations under study caused the mice to develop the extra teeth within the space between the normal incisor and the normal first molar. Since tooth buds normally develop within this part of the developmental field but later regress, these genetic alterations did not alter the normal plane within which teeth developed. However, one particular mutation had a different result. The researchers found that a knockout mutation (i.e., elimination) of a gene known as Odd-skipped related 2 (Osr2) also resulted in the production of extra teeth, but strikingly, these teeth developed outside the usual plane, on the tongue side of the normal molars, suggesting that the mutation results in an expansion of this developmental field in the affected mice. Supporting this theory, the knockout mice (i.e., mice lacking Osr2) have spatially expanded expression of other genes involved in tooth development. That suggests that normal Osr2 acts to restrict tooth development to within its usual, single-row plane. Previous work from this group discovered the Osr2 gene and demonstrated that it is a novel regulator of palate formation. The current study demonstrates that Osr2 function also is critical to the patterning of tooth formation and sheds light on the restriction of teeth to a single row in mammals. Osr2 function may be an important consideration for researchers seeking to grow replacements eventually for lost teeth in adults.

    Large-Scale Collaborative Activities

    Biomedical Technology Research Centers (BTRCs): The BTRCs develop versatile new technologies and methods that help researchers who are studying virtually every human disease, each creating innovative technologies in one of five broad areas: informatics and computation, optics and spectroscopy, imaging, structural biology, and systems biology. This is accomplished through a synergistic interaction of technical and biomedical expertise, both within the Centers and through intensive collaborations with other leading laboratories. The BTRCs are used annually by nearly 5,000 scientists from across the United States and beyond, representing more than $700 million of NIH funding from 22 ICs. As an example, optical technologies enable researchers to:
    • Harness the power of light to "see" biological objects, from single molecules to cells and tissues, which are otherwise invisible. New technologies using fluorescence and infrared spectroscopies revealed exquisite details of how proteins fold and interact.
    • Detect and assess malignancy in a rapid, noninvasive manner. Optical technologies have been used successfully to measure responses of breast tumors to chemotherapy and define the margin of tumors so that surgeons can more precisely remove cancerous tissue during surgery.
    Biomedical Informatics Research Network (BIRN): Modern biomedical research generates vast amounts of diverse and complex data. Increasingly, these data are acquired in digital form, allowing sophisticated and powerful computational and informatics tools to help scientists organize, store, query, mine, analyze, view, and, in general, make better use and sense of their data. Moreover, the digital form of these data and tools makes it possible for them to be shared easily and widely across the research community at large. NIH has supported development of the BIRN infrastructure to share data and tools by federating new software tools or using the infrastructure to federate significant datasets. BIRN fosters large-scale collaborations by using the capabilities of the emerging national cyberinfrastructure. In FY 2009, the BIRN Coordinating Center transitioned to a new home at the University of Southern California. The new BIRN Coordinating Center uses grid computing technology to create a virtual organization for basic and clinical science investigators across the network. In addition, a new BIRN Community Service (U24) grant was awarded to help expand the BIRN user community to researchers and clinicians beyond the neuroscience and imaging fields.
    Center for Human Immunology, Autoimmunity, and Inflammation: The Center for Human Immunology, Autoimmunity, and Inflammation (CHI) is a new trans-NIH intramural initiative designed to study the human immune system. Integrated teams of physicians and basic scientists are organized by CHI to perform research into immune pathophysiologies, the role of inflammation in a wide variety of disorders, and the translation of new knowledge into improvements in diagnosis and treatment of disease. The Center provides unique specific technologies often unavailable to individual laboratories because of cost, complexity, and novelty. The core of CHI is made up of three technology centers. The first center features assays of immune cells and their products, based mainly on a technique known as flow cytometry and similar emerging techniques. The second center contains high-throughput systems technologies, involving the use of new methods for large-scale examination of genes, proteins, enzymes, and/or lipids. It also features advanced biostatical and computer modeling methods for mining these diverse data sets, thereby providing for a deeper understanding of immune function and pathology. The third center is based in protocol development, with staff dedicated to producing methods that efficiently translate to the clinic while considering all of the ethical and regulatory requirements for human research.
    Analytical Methods and Reference Materials (AMRM) Program: The rapid expansion of the dietary supplement marketplace has resulted in a proliferation of ingredients and products and overtaken the pace of development of reliable analytical methods. Precise, accurate, and rugged 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 AMRM program is intended to assist in providing these critical tools for quality assurance. The program promotes development, validation, and dissemination of analytical methods and reference materials for commonly used dietary supplement ingredients. Responding to concerns about the quality and accuracy of standards and methods used by testing laboratories to measure vitamin D in the body, NIH, in collaboration with the National Institute of Standards and Technology, has developed a new Standard Reference Material (SRM) for vitamin D in blood serum to help laboratories evaluate their analytical methods. This SRM represents a first step toward standardization of vitamin D testing.
    National Centers for Biomedical Computing: There are seven NIH Roadmap National Centers for Biomedical Computing (NCBC). Funded as cooperative agreements, these centers collectively cover broad areas of neuroinformatics, functional genomics, image post processing, multiscale modeling, cellular pathways, semantic data integration and ontologies, information networks, cellular networks and pathways, clinical informatics, disease-gene-environment analysis, and clinical decisions support.
    • For more information, see  http://ncbcs.org/
    • This example also appears in Chapter 3: Molecular Biology and Basic Research and Chapter 3: Disease Registries, Databases, and Biomedical Information Systems
    • (E) (NIGMS, Common Fund - all ICs participate)
    Glycomics Technology Development, Basic Research, and Translation into the Clinic: Glycans are ubiquitous complex carbohydrates found on the surfaces of cells and secreted proteins. Glycan binding proteins mediate cell signaling, recognition, adherence, and motility, and play a role in inflammation, arteriosclerosis, immune defects, neural development, and cancer metastasis. Detection and analysis of carbohydrate molecules is thus critical for basic and clinical research across the spectrum of health and disease, but widely is regarded as one of the most difficult challenges in biochemistry. Four NIH programs are striving to make this easier by working together across the domains of technology development and basic and translational research.
    • Biomedical Technology Research Centers develop and share cutting-edge technologies for analysis of carbohydrates in complex biological systems.
    • Consortium for Functional Glycomics creates and provides access to technological infrastructure for carbohydrate biology and analysis in support of basic research.
    • Alliance of Glycobiologists for Detection of Cancer and Cancer Risk leverages the technology and expertise developed in NIH programs for translational research in cancer biomarker discovery.
    • A Small Business Innovation Research (SBIR)/Small Business Technology Transfer (STTR) program funds the commercial development of innovative technologies for carbohydrate analysis.

      Multidisciplinary and Interdisciplinary Research

      Building Interdisciplinary Research Teams (BIRT) Awards: The scale and complexity of biomedical research demands that scientists move beyond the confines of their individual disciplines and explore new organizational models for team science. Integrating different disciplines holds the promise of opening scientific avenues of inquiry and, in the process, potentially forms new disciplines for addressing increasingly complex questions. The BIRT award was created by NIH to promote interdisciplinary research by supplementing collaborations with high innovation and potentially high impact in general areas of arthritis, musculoskeletal, and skin biology and diseases. In 2008, 11 grants were awarded for the following areas of collaboration: developmental biology—systems biology, soft tissue biology—imaging technologies, tissue engineering—immunology, and tissue engineering—developmental biology.
      Prostheses to Restore Lost Function: Many veterans return home with significant injuries to their extremities, including loss of limbs. Through multidisciplinary partnerships between engineers, clinicians, scientists, and industrial partners, NIH investigators are developing new and novel technology for assistive rehabilitation, such as electrodes for neural and muscular recordings, networked implantable systems for functional electrical stimulation, robotics for rehabilitation, and brain computer interface systems for communication and control. For example, next-generation hand and arm prosthesis systems controlled by intact muscle recordings will be able to produce fine finger movements and provide to the user the sensation of position and force applied to an artificial hand. Other examples include multifunctional stimulation systems that allow spinal cord-injured subjects to change posture, stand, step, and control hand and arm function.
      • Weir RF, et al. IEEE Trans Biomed Eng 2009;56(1):159-71. PMID: 19224729.
      • This example also appears in Chapter 2: Life Stages, Human Development, and Rehabilitation
      • (E) (NIBIB)
      Stem Cells and Regenerative Medicine: Stem cells are able to renew themselves and generate progeny that differentiate into more specialized cells. They play critical roles in organism development, and some are essential for normal homeostasis and tissue repair. NIH has made a significant investment in stem cell research. One NIH-supported study showed that the sex of cells in a subpopulation of muscle-generating stem cells in adult mice can influence their capacity to repair tissue considerably. This finding could lead to future therapies for various diseases, including muscular dystrophy. A collaboration between NIH Intramural researchers and those at Walter Reed Army Medical Center discovered that waste tissues from surgery, removed to promote healing of orthopaedic injuries and war-traumatized muscle, contain large numbers of progenitor cells that are capable of differentiating into bone, fat, and cartilage cells. They could be used as a cell source for regenerative medicine therapies, and thereby avoid additional surgery to harvest cells. NIH has partnered with the Department of Defense on an initiative to speed treatments to wounded soldiers abroad, and civilian trauma victims and burn patients in the United States. This collaboration has resulted in the establishment of the new Armed Forces Institute of Regenerative Medicine (AFIRM). The AFIRM-led program will focus on regrowing fingers, repairing shattered bones, and restoring skin to burn victims with genetically matched skin, to pave the way for commercial products in the near future. Hair follicles are useful models for organ regeneration. Recent discoveries have been made in the molecular processes that govern the growth of hair follicle stem cells, which are a source for newly formed hair follicles.
      Cooperation in Space-Related Health Research: In FY 2009, NIH and the National Aeronautics and Space Administration (NASA) issued a funding opportunity announcement to support biomedical experiments that astronauts could perform on the International Space Station (ISS). The ISS provides a special microgravity and radiological environment that Earth-based laboratories cannot replicate. Congress, recognizing the immense promise the facility holds for American-led science and technology efforts, opened the U.S. portion of the ISS to other Federal agencies and university and private sector researchers when it designated the U.S. resources as a National Laboratory in 2005. Recently published ISS experiments from investigators supported by NIH and NASA have offered new insights into how bacteria cause infectious disease. The FY 2009 solicitation is the next step in a partnership to apply the National Laboratory to research that complements NASA's space exploration efforts. The program encourages a new cadre of health researchers from a variety of disciplines to incorporate the space environment into their experiments, and will support them as they prepare their experiments for launch and analyze their data following a mission. Applications particularly are encouraged from researchers who are interested in molecular or cellular biology, biomaterials, or telemedicine. NIH expects to fund applications in FY 2010, FY 2011, and FY 2012, and to send experiments into space by 2011.
      Researchers Developing a Noninvasive Ultrasound Technique to Detect Early Signs of Premature Delivery: Premature delivery is one of the leading causes of infant mortality in the United States, according to CDC. Currently, clinicians only can attempt to delay delivery once the extensive uterine contractions of labor have been initiated in the final stages of the delivery process. However, because the cervix prepares for delivery weeks to months before labor in a process termed "preterm cervical ripening," an NIH-supported scientist, together with a team of electrical and computer engineers, theorized that a noninvasive ultrasound technique might be used to detect this early warning sign well in advance of premature delivery. The research team developed and tested such a technique using computer simulations in rat tissue samples, followed by studies with live rats. The results were promising in that cervical changes clearly were identifiable using this technique in the tissue samples. With further development, this innovative technique could prove powerful in identifying mothers at risk for premature delivery, thereby reducing or preventing the associated morbidity and mortality.
      • Bigelow TA, et al. J Acoust Soc Am 2008;123(3):1794-800. PMID: 18345867. PMCID: PMC2637349.
      • For more information, see  http://www.ncbi.nlm.nih.gov/pubmed/18345867
      • This example also appears in Chapter 2: Life Stages, Human Development, and Rehabilitation
      • (E) (NINR)
      Facilitating Interdisciplinary Research via Innovation in the Behavioral and Social Sciences: An NIH Roadmap Funding Opportunity Announcement (FOA), Facilitating Interdisciplinary Research via Methodological and Technological Innovation in the Behavioral and Social Sciences, was released. Using a modified Exploratory/Developmental (R21) mechanism, this FOA solicits applications to develop new and innovative measures, methods, and technologies that support the integration of human social and/or behavioral science with other disciplines across varying levels of analysis. Supported projects have included: creation of tools to measure sun exposure and vitamin D, models of spinal cord injury, and an Internet-based system for providing feedback to teachers and consultants on the school readiness and mental health of children. Several national conferences have been planned in relation to this initiative, including Facilitating Interdisciplinary Research: Methodological and Technological Innovation in the Behavioral and Social Sciences (October 2009).
      Interdisciplinary Research Consortia Funded by the NIH Roadmap: One of the four main initiatives established by the NIH Roadmap's Interdisciplinary Research Work Group was a grant program to fund large-scale consortia to support interdisciplinary research. In total, NIH funded nine collaborative teams located across the United States. Each focuses on a particular health problem or process, including substance abuse and stress; obesity; developmental disorders; the process of aging; providing fertility options for cancer survivors; engineering healthy tissue to treat diabetes, heart disease and oral/craniofacial disorders; psychiatric disorders; drug/medications development; and genome engineering. The initial results suggest ways in which this team science approach helps to increase cooperation within and between academic institutions, as well as advancing the individual missions of NIH ICs.
      Exposure Biology Program: The Genes, Environment, and Health Initiative (GEI) aims to accelerate the understanding of genetic and environmental contributions to health and disease. It has two components: the genetic component that focuses on identifying major genetic susceptibility factors, and the environmental component that focuses on development of innovative techniques to measure environmental exposures, diet, physical activity, psychosocial stress, and addictive substances that may contribute to development of disease. This program addresses the second effort, the Exposure Biology Program (EBP), which will create new ways to assess exposures that may be used in studies that capture information about susceptibility across the entire genome. Optimally, using new bioengineering approaches, exposures that an individual comes in contact with will be measured more accurately during critical time points. This program also will develop ways to measure an individual's response to these exposures using new molecular technologies. It is envisioned that these methods will provide measures of personal exposure that are quantitative, precise, reliable, reproducible, and that can be scaled up to implement in large population studies in the near future.
      • Lai M, et al. Nanotechnology 2009;20(18):185602. PMID: 19420618.
        Schwartz DE, et al. Biosens Bioelectron 2008;24(3):383-90. PMID: 18515059. PMCID: PMC2572081.
        Bang JH, et al. Langmuir 2008;24(22):13168-72. PMID: 18950204. PMCID: PMC2647855.
        Lin YY, et al. Anal Chim Acta 2008;612(1):23-8. PMID: 18331854.
        Wang J, et al. Small 2008;4(1):82-6. PMID: 18081131.
        Funk WE, et al. Cancer Epidemiol Biomarkers Prev 2008;17(8):1896-901. PMID: 18708378. PMCID: PMC2821034.
        Kumaresan P, et al. Anal Chem 2008;80(10):3522-9. PMID: 18410131.
        Hahn CG, et al. PLoS One 2009;4(4):e5251. PMID: 19370153. PMCID: PMC2666803.
        Mesaros C, et al. J Chromatogr B Analyt Technol Biomed Life Sci 2009;877(26):2736-45. PMID: 19345647. PMCID: PMC2745066.
        Mangal T, et al. Chem Res Toxicol 2009 May;22(5):788-97. PMID: 19309085. PMCID: PMC2684441.
        Hsu PY, et al. Cancer Res 2009;69(14):5936-45. PMID: 19549897. PMCID: PMC2855843.
        Fleming JL, et al. Cancer Res 2008 Nov 15;68(22):9116-21. PMID: 19010880.
        Cheng AS, et al. Cancer Res 2008;68(6):1786-96. PMID: 18339859.
        Emeny RT, et al. Chem Biol Interact 2009;181(2):243-53. PMID: 19576872.
        Steiling K, et al. PLoS One 2009;4(4):e5043. PMID: 19357784. PMCID: PMC2664466.
        Schembri F, et al. Proc Natl Acad Sci U S A 2009;106(7):2319-24. PMID: 19168627. PMCID: PMC2650144.
        Sridhar S, et al. BMC Genomics 2008;9:259. PMID: 18513428. PMCID: PMC2435556.
        Bharate SB, et al. Bioorg Med Chem Lett 2009;19(17):5101-4. PMID: 19640713. PMCID: PMC2728166.
        Li B, et al. Toxicol Sci 2009;107(1):144-55. PMID: 18930948. PMCID: PMC2638647.
        Nagy JO, et al. Bioorg Med Chem Lett 2008;18(2):700-3. PMID: 18086524. PMCID: PMC2839895.
      • For more information, see  http://www.gei.nih.gov/exposurebiology/index.asp
      • (E) (NIEHS, NIDDK) (GPRA)

      Nanotechnology

      Researchers Levitate Object at a Microscopic Scale: Technique May Assist With Development of Nanotechnology: Similar to the way that like poles of magnets repel each other, certain combinations of molecules generate electrical forces that will prevent them from coming in contact with each other under certain conditions. Building on these concepts, researchers actually have levitated an object, suspending it without the need for external support. Working at the molecular level, the researchers relied on the tendency of certain combinations of molecules to repel each other at close contact, effectively suspending one surface above another by a microscopic distance. In their study, the researchers brought a tiny gold-plated sphere in contact with a flat glass surface, separating them with a liquid known as bromobenzene. At close distances, the molecular forces of the two surfaces, when in the presence of bromobenzene, repelled each other, so that the molecules of gold and glass never came in direct contact with each other and were separated by a few nanometers. The new technique may prove useful to the emerging field of nanomechanics—the development of microscopic machinery and even robots. By altering and combining molecules, tiny machines and even robots could be devised to perform surgery, manufacture food and fuel, and boost computing speed, operating free of friction.
      Nanotechnology in Cancer: Nanotechnology innovation has been driven predominantly by physicists, engineers, and chemists; progress in cancer research comes primarily from discoveries of biologists and oncologists. The NIH Alliance for Nanotechnology in Cancer has set a goal of creating a community of cancer nanotechnologists who work together to develop nanotechnology approaches; apply them to the prevention, diagnosis, and treatment of cancer; and educate the medical community about opportunities enabled by cancer nanotechnology. The Alliance organized a session at 2009 American Association for Cancer Research meeting on Cancer Diagnostics Using Nanotechnology Platforms. Participants included high-profile investigators who work on the development of new nanodevices for in vitro diagnosis and in vivo imaging and clinicians who define oncology applications of those devices. Examples of this work include: PRINT, a technique allowing for controllable fabrication of nanoparticles; researching novel diagnostic techniques for proteins and DNA; developing implantable nanosensors; researching novel nanoparticle-based imaging agents and nanosensors; and developing nanotechnology-based cancer screening tools.
      • For more information, see  http://nano.cancer.gov/
      • This example also appears in Chapter 2: Cancer and Chapter 3: Clinical and Translational Research
      • (E/I) (NCI)
      Nanotechnology Task Force: Nanotechnology deals with the understanding and control of matter at dimensions of approximately 1 to 100 nanometers, where unique phenomena enable novel applications. By applying cross-disciplinary methods from physics, material science, and engineering, NIH is shaping a new paradigm with vast implications for revolutionizing diagnostics, therapeutics, and personalized medicine. NIH initiated the Trans-NIH Nanotechnology Task Force for the purpose of (a) identifying scientific opportunities at the interface of nanotechnology, nanomedicine, and nanobiology; and (b) enhancing understanding of the health implications of engineered nanomaterials (ENMs) for biological systems. The Task Force tracks NIH investments in basic and applied nanoscale research, organizes national and international meetings, develops reports, participates in congressional hearings, and plays a key collaborative role in interagency activities. NIH has been named the Federal government's lead agency for coordination of Federal research on the health implications of nanotechnology under auspices of the National Nanotechnology Initiative's Nanoscale Science, Engineering, and Technology Subcommittee (NSET) and plays a key role in development of its Environmental, Health, and Safety Strategy.
      • For more information, see  http://dpcpsi.nih.gov/collaboration/
      • (O) (OSP/OSPA, FIC, NCI, NCMHD, NCRR, NEI, NHGRI, NHLBI, NIA, NIAAA, NIAID, NIAMS, NIBIB, NICHD, NIDA, NIDCD, NIDCR, NIDDK, NIEHS, NIGMS, NIMH, NINDS, NINR, NLM)
      Tracking Stem Cell Mobility Within Cardiovascular Tissues: Current cellular therapies suffer from low rates of cell engraftment due to the early destruction of cells. In 2007, in response to a program announcement, Innovative Application of Nanotechnology to Heart, Lung, Blood, and Sleep Disorders, NIH funded a grant to formulate a biocompatible cell encapsulation agent designed to protect and track mesenchymal stem cells for administration to patients. (Mesenchymal stem cells are the progenitors of all connective tissue cells). The investigators have demonstrated that encapsulation of mesenchymal stem cells improves long-term cell viability in cultures, and also have shown that the encapsulated cells can be detected using computed tomography or magnetic resonance imaging following in vivo injection. NIH is assessing the progress of the grant through an ongoing GPRA goal—by 2012, develop and apply clinically one new imaging technique to enable tracking the mobility of stem cells within cardiovascular tissues.
      • (E) (NHLBI)

      Probing Proteins

      Protein Structure Initiative (PSI): Scientists learn a lot by studying the detailed, three-dimensional structures of proteins. This knowledge helps them better understand the biochemical processes involved in health and disease. It also can greatly advance the design of medicines to treat a wide range of diseases. Recognizing this, NIH established PSI in 2000 to determine the structures of hundreds of novel proteins by means of high-throughput structure determination. In 2009, NIH announced plans for a new direction of the Protein Structure Initiative to be named PSI:Biology. The new program will support research partnerships between groups of biologists and high-throughput structure determination centers to solve problems of biomedical importance. In addition to benefiting the PSI team, this work will continue to accelerate research in other fields.
      New Targets Identified for Intervention in the Development of Head and Neck Cancers: Over the last decade, cancer researchers have made significant progress in defining the molecular pathways involved in the development of head and neck squamous cell cancer. Studies that identify and characterize "key players" hold tremendous promise for the future treatment of these devastating cancers and ultimately improve the overall survival and quality-of-life for afflicted patients. One such key player is a family of proteins known as Wnt. Aberrant activation of the Wnt pathway has been found to be associated with cancer development and progression. Wnt promotes initiation of cancer by increasing the nuclear accumulation of ß-catenin, an integral component of Wnt signaling, to activate target genes downstream. However, the mechanism of ß-catenin recruitment to the Wnt target gene promoter largely is unknown. In an elegant study, the researchers discovered that ß-catenin interacted with two other molecules (commonly called TBL1 and TBLR1), leading to the recruitment of ß-catenin to the promoter of Wnt target genes. Decreasing TBL1 or TBLR1 via genetic knock-down did not affect the nuclear accumulation of ß-catenin, but it did inhibit ß-catenin significantly from binding to Wnt target gene promoter and the expression of Wnt target genes associated with tumor development. Moreover, depletion of TBL1 or TBLR1 inhibited invasive growth of tumor cells. These results provide fundamental knowledge about tumor genesis by revealing two new components required for nuclear ß-catenin function. Targeting these molecules can have important therapeutic implications for head and neck cancer.
      • Li J, Wang C-Y. Nat Cell Biol 2008;10(2):160-9. PMID: 18193033.
      • This example also appears in Chapter 2: Cancer and Chapter 3: Molecular Biology and Basic Research
      • (E) (NIDCR)
      NIGMS/NCI Collaborative Access Team (GM/CA-CAT): 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. Two NIH institutes (NIGMS and NCI) 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 United States to determine the detailed, three-dimensional structures of molecules. Two of these beamlines provide world-leading capabilities for X-ray diffraction data from very small protein crystals only a few microns in dimension. This research capability is important to understand basic biological processes and for drug design. The facility now is in full operation.
      • For more information, see  http://www.gmca.anl.gov
      • This example also appears in Chapter 3: Molecular Biology and Basic Research
      • (E) (NIGMS, NCI)
      Scientists Accomplish Initial Catalogue of the Human Salivary Proteome: Secretions from the major salivary glands (parotid, submandibular, and sublingual) contain many peptides and proteins. They contribute to saliva's important roles in maintaining oral health, including antimicrobial, lubricating, buffering, and digestive properties. Salivary gland disorders, which result in severe dry mouth, compromise quality of life because they often lead to decay and periodontal diseases, mucosal infections, halitosis, taste impairment, and difficulties in swallowing and speaking. Saliva is a complex fluid; over the years, a number of salivary proteins have been reported but a systematic approach to catalogue all the proteins present in saliva was only initiated in 2004. NIH supported three teams of investigators to conduct the first comprehensive analysis of the salivary proteome. After samples were collected and analyzed, the data were standardized and integrated, yielding a salivary proteome that comprises 1,166 proteins. Of these proteins, 152 parotid and 139 submandibular/sublingual proteins were identified by all 3 research groups; these proteins form the core proteome. Most proteins identified were extracellular or secretory proteins, and involved in numerous molecular and cellular processes. A significant number of proteins represented in the salivary proteome also have been found to exist in the plasma or tear proteomes. This initial catalogue of the salivary proteome is a significant first step toward a comprehensive understanding of what the functions of saliva are, and how salivary composition is dependent on physiological variations, including on health and disease. This proteome could be the source of potential diagnostic and prognostic biomarkers for oral and systemic conditions.
      • Denny P, et al. J Proteome Res 2008;7:1994-2006. PMID: 18361515.
      • This example also appears in Chapter 3: Genomics and Chapter 3: Molecular Biology and Basic Research
      • (E) (NIDCR)
      Metabolic Network Model of a Human Oral Pathogen: The bacterium Porphyromonas gingivalis causes severe, chronic periodontal disease. Recently NIH-supported researchers constructed a complex metabolic network map for P. gingivalis with which to model the metabolic properties of all genomically identified components of the system. The scientists used a technique known as flux-balance analysis (FBA) to construct the model, which consisted of 679 metabolic reactions involving 564 metabolites. There was significant correlation between the model's predictions and the bacterium's experimentally observed metabolism. The true power of this model became apparent when "virtual knockouts" were employed to predict the effect of the loss of certain genes or metabolic pathways on growth rate, and the model very effectively predicted disturbances affecting biosynthesis of large molecules known as lipopolysaccharides. This is the first description of a model of this type for an oral periodontal pathogen. Still in their infancy, metabolic network models are a logical extension of genome sequence data. They can provide the ability to perform virtual metabolic modeling of organisms with limited or no in vivo experimental histories. These models also could be applied to highly interdependent mixed microbial communities, including the oral microbiome, ultimately resulting in new biomedical applications. Such modeling greatly increases opportunities to discover new antibacterial drug targets. These studies provide new molecular targets for therapeutic drugs; they also can suggest the molecular mechanisms for virulence, intracellular persistence and survival, and ability of the bacteria to survive stresses from the (in this case, human) host defense mechanisms.
      • Mazumdar V, et al. J Bacteriol 2009;191(1):74-90. PMID: 18931137. PMCID: PMC2612419.
      • This example also appears in Chapter 2: Infectious Diseases and Biodefense, Chapter 2: Chronic Diseases and Organ Systems and Chapter 3: Molecular Biology and Basic Research
      • (E) (NIDCR)
      New Biomaterials System Programs Cells in situ to Fight Cancer: In the body's immune response to foreign invaders, dendritic cells signal and activate other cells to initiate a generalized inflammatory response. Cell-based cancer vaccinations build on this natural tendency by isolating and activating a patient's dendritic cells using tumor antigens, and then injecting the reprogrammed cells back into the patient. The activated dendritic cells travel home to the lymph nodes and promote an antitumor response. Unfortunately, most transplanted dendritic cells die. Additionally, reprogrammed cells partially lose their effectiveness after injection back into the body. Thus, multiple rounds of injections are required to achieve significant effect. To address these limitations, investigators developed a multifunctional in situ dendritic cell reprogramming system composed of polymeric biomaterials that release cytokines to attract dendritic cells already within the lymph nodes into the biomaterials. The dendritic cells are then activated by the biomaterials. The biomaterials reduce their cytokine release at a controlled rate so that after activation, the dendritic cells will migrate away from the biomaterials back home to the lymph nodes and present tumor antigens to T cells found there. In a mouse model this sophisticated system provided protection from tumor development equal or superior to that provided by traditional cancer vaccines without the complications and costs of ex vivo cell manipulation and transplantation. The new system also provided much better control over the number of dendritic cells than traditionally generated cancer vaccines. This study demonstrates a powerful new application for polymeric biomaterials that could be used in the future against cancers and other diseases.
      • Ali OA, et al. Nature Materials 2009;8(2):151-8. PMID: 19136947. PMCID: PMC2684978.
      • This example also appears in Chapter 2: Cancer
      • (E) (NIDCR)
      Clinical Proteomic Technologies for Cancer: The Interagency Oncology Task Force (IOTF) held a workshop in October 2008, bringing together almost 60 participants representing NIH, FDA, industry, academia, and standards organizations. These key stakeholders in the proteomics community gathered to explore the regulatory requirements that will be needed to validate protein-based marker panels and any new technologies (hardware) for their intended use. Because there is a lack of guidance for multiplex proteomic assays, the workshop was an opportunity to engage CPTC scientists currently working through the issues that FDA will need to address when reviewing 510(k) submissions for proteomic technologies such as mass spectrometry and affinity arrays. FDA and the proteomic community posed relevant questions to each other with the goal of understanding the challenges and needs of each group. Outputs will include a publication on analytical validation issues that specific proteomic technologies should address when seeking FDA approval and mock 510(k) regulatory submissions for two technologies—mass spectrometry and affinity platforms. Together, these documents will help orient FDA to proteomic technologies in novel diagnostics and serve as a springboard for guidance to the proteomics community.
      Unique Compounds Added to Chemical Libraries: Potent, drug-like molecules that selectively bind to the kappa opioid receptor have potential utility in the treatment of drug addiction, depression, psychosis and dementia, pain, and even HIV infection. Well more than 100 unique, new molecules constructed independently by two NIH-supported groups have been found to provide entirely new classes of kappa opioid binders. These molecules are potent and display a diversity of pharmacological activities that are under intensive active investigation.

      Transforming Health Care

      Neural Interfaces Program: Neural interfaces are systems that operate at the intersection of the nervous system and an internal or external device, including neural prosthetics. Neural prosthetic devices restore or supplement nervous system functions that have been lost through disease or injury, allowing people with disabilities to lead fuller and more productive lives. NIH pioneered the development of this technology, beginning more than 35 years ago. The program has, directly or indirectly, catalyzed the development of cochlear implants, which help people with hearing impairments; respiratory and hand grasp devices for people with spinal cord injuries; and deep brain stimulation for Parkinson's disease, among other contributions. Current work aims to restore voluntary bowel and bladder control and standing to spinal cord-injured persons, allow paralyzed persons to control devices directly from their brains, improve cochlear implants, and improve deep brain stimulation, which may be applicable to many brain disorders. Through the years, the program has fostered the development of a robust research community, now including private sector companies, and represents a cooperative effort among several ICs, which also coordinate their efforts with programs that now are underway in the Department of Veterans Affairs and Department of Defense.
      Molecular Theranostics: New Technologies for the Diagnosis and Treatment of Diseases: The concept of combining a therapeutic with a diagnostic agent rapidly is evolving and goes beyond traditional diagnostic tests that screen or confirm the presence of a disease. With specialized molecular imaging techniques and biomarkers, theranostics might 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 novel theranostics and approaches that can be applied in clinical studies of human patients. A team of chemists and neurosurgeons at the University of Michigan is developing highly specific, dye-loaded nanoparticles capable of delivering targeted photosensitizers to improve the survival of brain tumor patients. This technique will allow neurosurgeons to visualize the brain tumors for surgical resection of the main tumor mass while eradicating remaining tumor cells through a process known as photodynamic therapy. These particles also contain imaging contrasting agents to visualize response to therapy.
      • This example also appears in Chapter 2: Cancer
      • (E) (NIBIB)
      Edward R. Roybal Centers for Translation Research in the Behavioral and Social Sciences in Aging: NIH supports 13 Roybal Centers whose objective is to improve the health, quality of life, and productivity of middle-aged and older people by facilitating translation of basic behavioral and social science to practical outcomes by developing new technologies and stimulating new "use-inspired" basic research in the behavioral and social sciences. Roybal investigators have made several key discoveries. For example: One Center has developed tools and technologies for identifying older adults at risk for automobile crash involvement, and is working with industry partners to develop and disseminate products based on these tools. Another Center has developed two evidence-based interventions from its in-depth work on physical activity for older adults. One program, Fit and Strong!, is targeted to older adults with lower extremity osteoarthritis, and one is targeted to older adults with developmental/intellectual disabilities (primarily Down syndrome). A Roybal investigator has developed instruments for self-efficacy appropriate for use with older adults with developmental/intellectual disabilities; these have been adopted internationally. Finally, a Center has developed a "living laboratory" model methodology for in-home assessment of activity to facilitate early detection of changes in health or memory. Other companies have used this model to develop related products, and the model has spurred several new grant-funded research projects, including the development of a new medication tracker for older adults.
      Smart Coatings for Implanted Biomaterials: A major limitation on the longevity of vascular grafts and implanted materials stems, not from failure of the graft or material itself, but typically, from the body's rejection in the form of blood clots or refusal to integrate with surrounding tissue. Recently, new classes of polymer-based biomimetics that resemble the cell surfaces of healthy blood vessels have demonstrated excellent resistance to platelet adhesion, a major problem for implanted materials in contact with blood. These biomimetic polymers have undergone successful preliminary clinical testing, and the same approach now is being used to develop biomimetic coatings resembling other types of human tissue. This technology recently was acquired by a major medical implant manufacturer.
      • Kumar AM, et al. J Am Chem Soc 2008;130(4):1466-76.PMID: 18177047. PMCID: PMC2536642.
        Larsen CC, et al. Biomaterials 2007;28(24):3537-48. PMID: 17507089. PMCID: PMC2034336.
      • This example also appears in Chapter 3: Molecular Biology and Basic Research
      • (E) (NIBIB)
      Medical Technologies that Reduce Health Disparities: Appropriate medical technologies should be effective, affordable, culturally acceptable, and deliverable to those who need them. NIH is funding a research initiative to support the development of appropriate medical technologies for underserved settings. To ensure that the technology is appropriate, applications must involve interactions with underserved populations and/or collaborations with clinics in an underserved community.