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Biennial Report of the Director
National Institutes of Health Fiscal Years 2006 & 2007



Summary of Research Activities by Key Approach and Resource

Molecular Biology and Basic Research

Over 30 years ago, the introduction of recombinant DNA technology as a tool for basic biological research revolutionized the study of life. Molecular cloning allowed the study of individual genes of living organisms; however, this technique was dependent on obtaining relatively large quantities of pure DNA. This problem was solved by the development of the polymerase chain reaction (PCR), which produced large quantities of a specific DNA sequence from a complex DNA mixture. Because of its simplicity and elegance, PCR transformed the way in which almost all studies requiring the manipulation of DNA fragments were performed. As described by Kary Mullis, who was awarded the Nobel Prize for Chemistry in 1993 for inventing PCR, the technique “lets you pick the piece of DNA you're interested in and have as much as you want.” Because of its simplicity and ability to create hundreds of thousands of copies of a specific DNA sequence of interest, PCR allows for the routine yet highly efficient performance of most major molecular biology techniques including sequencing, cloning, and identifying variations in genes, including gene mutations that cause disease.8

Introduction
Basic research is a major force driving progress across the biomedical and behavioral sciences, making it possible to understand the causes and progression of disease, intervene to prevent disease from occurring, develop better and more precise diagnostic devices and tests, and discover new treatments and cures. Basic research leads to fundamental insights that, on the surface, might not have an immediate or apparent application to human health, but are essential to understanding basic human biology and behavior in their normal and diseased states. It provides the foundation for responding to unexpected health crises. Whether the new insights come from blockbuster discoveries or an accumulation of incremental advances, history shows that over time, basic research yields inestimable rewards. Thus, it is a critical component of the Nation's public investment in research and is a central feature of each IC's research program. The importance of basic research to new interventions cannot be overestimated.

Basic research involves and relies on many scientific disciplines, including genomics, proteomics, endocrinology, immunology, genetics, epidemiology, neuroscience, behavioral, and social science, and cell, developmental, and vascular biology—to name a few. Importantly, basic scientists and clinical researchers frequently work together to translate research findings from bench to bedside and back.

As an influential component of basic research, molecular biology focuses on the formation, structure, and function of macromolecules—very large molecules that consist of many smaller structural units linked together. Macromolecules including proteins and nucleic acids—such as DNA and RNA—are involved in critical biological functions such as cell replication and storing and transmitting genetic information. The study of macromolecules provides information about structures that are essential to life. Such study yields knowledge of the molecular components of the cells of all types of organisms and the complex ways in which these molecules are organized, regulated, and interact, and provides essential insights for understanding and eventually controlling a wide range of human diseases.

Some researchers focus on individual or a few proteins, whose functions or structures, particularly if disrupted, may play key roles in specific diseases. Meanwhile, other researchers are engaged in “proteomics,” which entails integrating analytic technologies to identify and measure levels of large sets of (instead of individual) proteins. Scientists then study their interactions and how their levels fluctuate under various conditions. These basic efforts are helping to determine how such sets of proteins might change with the onset and progression of specific diseases, often providing insights about ways to intervene in the patient.

Molecular biology, like other areas of basic biological research, depends on harnessing the expertise and skills of allied disciplines such as physics, chemistry, mathematics, computer science, and engineering.

Every IC embraces basic research as essential to furthering the NIH mission—improving health. Although many ICs, such as NIAID and NCI, focus on research fundamental to specific diseases and organ systems, others, such as NIEHS and NIGMS, have missions that mandate they support basic research across a wide range of specialized disciplines. Still other ICs, such as NIBIB and NHGRI pursue basic research in more targeted areas.

For example, basic research in infectious disease examines the mechanisms that pathogens use to invade and infect the body, the interactions between pathogens and the bodies they infect, the mechanisms bodies naturally use to fight pathogens, and the environmental and genetic influences on the spread and evolution of pathogens. Insights from such investigations provide the targets for candidate vaccines, diagnostics, and treatments.

Because cancers affect various cells, organs, and tissues throughout the body, basic research in cancer is aimed, for instance, at understanding immune and inflammatory responses, stem cells, DNA repair mechanisms, and the microenvironment enveloping tumors. Discoveries in these areas are leading to medical advances that help patients with particular types of cancer. Not long ago, for example, experts disputed the validity of immunotherapy as a way of treating cancer. (Immunotherapy stimulates or restores the ability of the immune system to fight cancer, infections, and other diseases.) Now, this approach is being used as one standard of care for treating several specific types of cancer, including leukemia, lymphoma, and melanoma. Similarly, efforts to understand basic molecular mechanisms for repairing DNA could help cancer patients recuperate more quickly after receiving radio- and chemotherapy, both of which damage healthy as well as cancer cells.

Efforts to understand the microenvironment of cancer cells complement efforts to learn more about how the broader environment and associated toxic agents can affect human health and contribute to diseases other than cancer. One emergent area of research sponsored by NIEHS involves studying how toxic substances in the environment can impinge on signaling pathways within our cells, sometimes disrupting biochemical pathways and leading to subtle stresses or outright disease.

As part of fulfilling its mission to support a wide spectrum of basic research, NIGMS funded Andrew Fire and Craig Mello, who shared the 2006 Nobel Prize in Physiology or Medicine. In studying the roundworm C. elegans, they discovered a type of double-stranded RNA molecule that silences genes in that organism. Other researchers soon learned that similar RNA molecules silence genes in other organisms, including humans. Now these molecules are being studied as potential treatments for specific diseases. Thus, basic research on a roundworm, of no obvious direct medical interest itself, furnished insights that soon could lead to novel treatments for a diverse array of diseases, including Huntington's disease, hepatitis B, and cancer, among others.

The 2007 Nobel Prize in Physiology or Medicine was awarded to two long-time NIH grantees whose work underscores the power of basic research to stimulate progress in the treatment and cure of disease. NIGMS began supporting Mario Capecchi and Oliver Smithies in 1968 and 1973, respectively. Later, other ICs also provided support. Working independently, Capecchi and Smithies created an elegant and powerful gene-targeting method in mice that has become an indispensable tool for biomedical research. The method enables scientists to create “transgenic” mice, which contain specific insertions of extra genes from mice or other organisms. When transferred genes involve human diseases, the transgenic mice can serve as model organisms for studying those human disorders. Researchers also can use the gene-targeting technique to insert defective genes that “knock out” the normal versions. Once these are “knocked out,” scientists can understand the importance of these genes to normal function or disease. Mice developed with this technology are used for a wide range of medical research from basic studies of biological processes to investigations of, for example, cancer, heart disease, and cystic fibrosis.

Basic research often relies on studies in “model organisms” such as bacteria, fruit flies, or mice. Because human cells contain the same molecular building blocks and pathways as those of most other living things, researchers can learn much about the way our cells work by studying these simpler organisms. Although seemingly removed from human health, historically, many productive routes to medical discoveries involve organisms that typically are far simpler to study than are humans.

In addition, because candidate diagnostics and therapeutics typically need to be validated in model systems—for example, by studying animals that are susceptible to the same or similar microbial pathogens that cause diseases in humans or that develop diseases similar to humans, the development of animal models of disease is an important element of basic research. NIH-supported researchers have developed animal models for corneal disease, cleft palate, hearing loss, blindness, and even mental retardation. Animal models can lead to the development of promising interventions that then are subject to further refinement and testing before being evaluated in clinical trials. Conversely, fundamental research focused on improving human health also can provide veterinary benefits. For example, basic studies of the role of immune factors in controlling herpes led to a vaccine for a deadly disease in chickens.

The long-term implications of basic research in bioengineering and imaging also are profound. NIBIB is pursuing the tools that will enable tissue engineering and regenerative medicine to become standard medical realities. Basic research in imaging techniques is fueling a wide array of new means of diagnosis and making a quantum leap in structure-based design of drugs, a method that cuts through the cumbersome and expensive screening processes.

Basic science can yield unanticipated benefits, as scientists make so-called serendipitous discoveries. For example, while creating compounds to clog proteasomes—cellular garbage disposal-like structures implicated in muscle wasting—scientists noticed that one of the substances had anticancer properties; this drug (Velcade™) is now used to treat multiple myeloma, the second most common blood cancer. As another example, while studying the structures of complex sugars, scientists developed prototypes of new drugs to help control blood clots, which can cause heart attacks and strokes during surgery. This unpredictability is intrinsic to the interconnectedness of biological systems and the rudimentary stage of our knowledge. And rather than randomness or caprice—serendipity is the beauty of biology. However, as stewards of the Nation's investment in health science, NIH does not count on the serendipity—that is, NIH never funds or justifies a project based on expectations for serendipity. Rather, serendipitous findings are an added bonus from research projects already deemed meritorious for their intended purposes.

Basic biomedical research also benefits other sectors of the economy. Many nonbiomedical industries have emerged as a result of or been enhanced by biomedical discoveries. For example, freeze-drying, which was developed to concentrate and preserve laboratory samples, is now widely used in the food industry. As another example, basic studies of digestive enzymes led to food industry improvements including meat tenderizers, bread dough conditioners, milk coagulants for cheese production, and preservatives for juices.

Summary of NIH Activites
As noted above, the impact of any single basic research discovery may be quite wide, bearing on multiple other fields. Research on neuronal receptors is perfectly likely to inform understanding of viral receptors. The inherent unpredictability to basic research means that it is not easily compartmentalized. The examples below reflect the breadth and diversity of the basic research pursued by NIH-research that touches on the mission of every IC, and every disease, condition, and effort to improve health.

One critical area of basic research that aims to understand how genes turn off or on or malfunction is epigenetics. In epigenetics research, investigators focus on factors that affect genes at the molecular level but do not change the sequence of the basic building blocks of DNA. Because epigenetics is concerned with factors unrelated to DNA sequence, these efforts differ from conventional genomics and genetics. Factors that cause epigenetic changes can come from the environment or may be in the diet, or related to other influences. Moreover, they are linked to a broad range of illnesses. A recently developed NIH program, the Genes, Environment and Health Initiative, supports research to understand how environmental exposures might induce epigenetic changes, particularly in critical periods such as during pregnancy, early life, and puberty. Related NIH-supported research aims at understanding how epigenetic changes and variations occur at the molecular level. (Also see Chapter 1 for description of the Roadmap 1.5 Epigenetics/Epigenomics initiative, in the section titled “Roadmap 1.5 and the Common Fund Strategic Initiative Process.”)

Another example of NIH-supported basic molecular research is the Molecular Libraries Roadmap Initiative. This program, established in 2006, offers public-sector researchers access to tens of thousands of small (that is, low in molecular weight) chemical compounds to probe the functions of genes, cells, and biological pathways and their impact on health and disease. Already investigators have used this resource to explore a wide variety of biological activities specifically related to normal processes and disease, including inflammatory pathways, previously unknown signaling proteins, and changes in cellular phenotypes associated with disease. Other investigators are gaining leads for drug discovery through access to these compounds.

The recently established Nanomedicine Development Centers, another component of the NIH Roadmap, takes advantage of technology developments at the nanoscale (on the level of biological molecules and structures inside living cells). The goal of this 10-year program, now involving more than 120 scientists from 30 institutions working at 8 centers, is to understand and control the nanomachinery of life in order to diagnose or treat and prevent diseases and repair injured tissues.

Some molecular-level research focuses on how pain signals are transmitted. For instance, NIH scientists recently learned that a particular protein, cyclin-dependent kinase 5, plays a regulatory role in pain signaling affecting sensory nerves. Their findings suggest that new analgesic drugs that alter this protein's activity could prove beneficial in relieving pain. Separate research on cannabinoids is guiding the design of molecules that block pain more selectively and safely, with minimal side effects and low potential for abuse.

NIH is supporting several molecular-level research programs studying complex carbohydrates, or polysaccharides, which consist of many linked sugars that are attached to the surfaces of proteins and lipids that form the surface of cells. These sugar-containing molecules are involved in diverse cellular activities, including signaling, recognition, adherence, and motility. They also play a role in inflammation, arteriosclerosis, immune defects, neural development, and cancer metastasis. The detection and analysis of such carbohydrates are considered critical for basic and clinical research but are widely regarded as a very difficult challenge.

Some NIH-sponsored molecular-level research explores fundamental physiological processes. For instance, NIH-supported scientists recently identified a protein, PKD1L3, in sensory cells that plays a key role in forming channels specifically for detecting sour tastes. This advance may help scientists treat taste impairments and could lead to the development of better salt and sugar substitutes for the millions of Americans on restricted diets that help to control high blood pressure, diabetes, and obesity.

Other NIH-supported scientists recently found that patients with chronic periodontitis, or gum disease, overproduce a signaling protein known as SHIP, which plays an important regulatory role in immune cells, inducing them to tolerate instead of react against an endotoxin, whose presence is associated with chronic periodontitis and tooth loss. Yet other NIH-supported scientists are studying a molecular byproduct, called resolvin E1 (RvE1), that derives from omega-3 fatty acids. RvE1 dramatically alters the progress of microorganism-initiated periodontitis and other diseases that arise through overly active inflammatory responses.

Some basic molecular-level research entails studying changes in molecules that disrupt cells and thus lead to specific diseases. For instance, misfolded proteins in brain cells are implicated in several neurodegenerative diseases, including Huntington's, Alzheimer's, and Parkinson's. Misfolded proteins can, in turn, disrupt other normal proteins in brain cells, leading to their death. NIH-supported scientists now surmise that learning how to bolster cell-repair mechanisms could provide an approach for treating some of these degenerative diseases.

In addition to proteins, damage also can occur to DNA molecules in cells when they are exposed to factors such as ultraviolet light or environmental toxins, sometimes leading to cancer or other serious clinical problems. NIH-supported scientists recently identified a protein that triggers a “lock-down” response to double-stranded DNA breaks, and helps to explain how cells ordinarily maintain their genetic material but sometimes lose that control in the case of cancer. More broadly, the NIH Tumor Biology and Metastasis Program supports research to delineate molecular mechanisms and signaling pathways involved in tumor progression, cell migration and invasion, angiogenesis (the process by which new blood vessels are formed), and metastasis.

NIH supports a range of basic research projects exploring cells, which are the basic membrane-bound units that make up organisms, and investigating biological systems, meaning the interactions among several or many biological components within organisms that lead to complex effects and integrated behaviors, including at the metabolic, cellular, and organ levels.

For example, many basic research projects focus on embryonic and adult stem cells, with some emphasizing genetic approaches and others analyzing critical events in early human development. NIH-funded researchers recently discovered a genetic switch that enables embryonic stem cells to develop into recognizable cell types; this and similar critical insights are expected to advance research on regenerative medicine and may lead to new treatments for many conditions, including, potentially, Parkinson's disease and spinal cord injuries.

Another example of an NIH-supported effort focused on cellular development is the Beta Cell Biology Consortium, which is conducting research relevant to the development of therapies for type 1 and type 2 diabetes. The consortium is studying how insulin-producing beta cells are made, exploring the potential of stem cells as a source for making insulin-producing islet cells, and determining the mechanisms underlying beta cell regeneration.

Some cell-based research focuses on the thousands of different microbial species that naturally associate with particular anatomic sites within or outside the human body, including in the intestinal tract and on the skin. These studies will help differentiate microorganisms that help to maintain health from others that can cause disease. The studies also are advancing understanding of how environmental factors affect such microorganisms and whether environmental factors affect host susceptibility to or severity of diseases that occur at those and other anatomic sites.

Of course, some microorganisms such as the influenza virus are well known to be pathogenic. The threat of the H5N1 influenza virus, which has been circulating in Asia and elsewhere, is of particular concern because this strain of virus, while not readily transmissible between humans, is highly lethal to those who become infected. As part of a broad-based effort to track and analyze this emerging viral threat, NIH established the Influenza Virus Resource, which includes a database containing sequence information for more than 40,000 influenza sequences including the sequences of more than 2,500 whole influenza genomes. Moreover, in 2007 NIH established six Centers of Excellence for Influenza Research and Surveillance to conduct research on both animal and human influenza viruses. These efforts will assist investigators in understanding the basic mechanisms by which influenza virus replicates and spreads, which ultimately could lead to better treatments or vaccines.

Research on the activity of influenza viruses is one among several basic science efforts that address the complexities of the human immune system. Another example is the Immune Tolerance Network, a consortium of more than 80 investigators who share the long-term goal of learning how to eliminate harmful immune responses, such as graft rejection, while preserving protective immunity against infectious agents and other disease threats. Similarly, the NIH Consortium of Food Allergy Research is using a mouse model to study how modified forms of peanut allergens protect against peanut-induced anaphylaxis and is conducting an observational study to examine immune mechanisms, genetic factors, and environmental factors associated with the development of new food allergy to peanut and the loss of egg allergy in high-risk young children. In addition, the six centers of the Cooperative Study Group for Autoimmune Disease Prevention are devoted to understanding immune homeostasis (physiological balance or equilibrium), a concept fundamental to preventing autoimmune diseases, with one emphasis being type 1 diabetes. In yet another effort that began in FY 2005, NIH supports research to better understand the underlying biological and physiological factors involved in asthma exacerbations. These insights ultimately could lead to the development of more effective treatments for this immune system-related condition.

Beyond the immune system, NIH is supporting systems biology research that is driven by both basic experimental and computational approaches. For instance, NIH sponsors efforts at seven interdisciplinary centers to develop predictive computer models for use in analyzing drug metabolism, host-pathogen interactions, organism development, and cell signaling. Similarly, the Integrative Cancer Biology Program is focusing on networks and systems genetic research to develop a more basic understanding of cancer through multidisciplinary research.

Genetics provides yet another systems approach to studying particular diseases or wider physiological systems. For instance, the Gene Expression Nervous System Atlas, or GENSAT, is a comprehensive effort to analyze where and when during development genes are active within the mouse nervous system. In addition, the genetically engineered mice used to generate the atlas are also proving to be a valuable resource. For example, researchers recently used mice from the GENSAT project to study mechanisms that kill nerve cells in patients with Parkinson's disease. Meanwhile, other genetics efforts in basic research are aimed at uncovering the cause of hereditary hearing loss and stuttering, identifying the genes involved in regulating sensitivity to alcohol, and analyzing the 400 or more genes involved in vision loss.

NIH supports the development or identification of many different animal models for use in studying a broad range of diseases and conditions. In mice alone, this ranges from the development of a genetically engineered mouse for studying several diseases affecting the surface of the eye to the use of aged and obese mice in studying the mechanisms controlling the lifespan.

Several basic research programs focus on angiogenesis, the process whereby new vessels form to supply specific tissues and organs with blood, as well as other disorders affecting blood vessels. For example, NIH-supported research in animal models showed that dietary omega-3 polyunsaturated fatty acids reduce harmful angiogenesis in the retina. In a separate effort, investigators are using mouse models to study the biological and chemical properties of the drug losartan, which is widely used to control hypertension, to determine whether it might also be useful for preventing life-threatening aortic aneurysms, which occur often among individuals with Marfan syndrome. Yet other NIH-sponsored basic research aims at developing novel synthetic replacements for damaged or diseased blood vessels. Further, NIH is sponsoring basic research into the lymphatic system and its function in health and disease; such research might lead to the development of new diagnostic methods and treatment interventions.

The NIH also supports basic research in neuroscience at the molecular, cellular, systems, and cognitive and behavioral levels to understand the development and function of the nervous system (also see the section on Neuroscience and Disorders of the Nervous System in Chapter 2). This research in people and in animal models includes studies of the neurobiological mechanisms underlying pain, sensory perception, learning, and addiction, among other nervous system functions. One project in the neurosciences is developing a set of standardized measures of cognitive, emotional, sensory, and motor function that will help researchers compare and integrate data collected across different studies. Basic research in the neurosciences also includes efforts to develop tools to monitor or probe discrete brain systems. For example, NIH-supported investigators recently genetically engineered neurons in mice and worms to express light-sensitive genes from algae and bacteria, allowing for rapid and precise control over neuronal circuit activity with pulses of light. NIH also invests in research in the behavioral and social sciences, with a goal to better understand social and cultural factors affecting health and illness.

Complementing these efforts, NIH supports a substantial portfolio of multidisciplinary research on mind-body interventions, such as meditation and Tai Chi Chuan, including basic research to understand the biological response to such interventions. Other projects involving complementary and alternative medicine focus on Alzheimer's disease and dementia, and include evaluations of the biological and biochemical consequences of the use of natural products such as an omega-3 fatty acid, Ginkgo biloba, and a component of pine trees. Still other projects are elucidating the fundamental mechanisms of turmeric extracts and green tea, used for treating conditions such as rheumatoid arthritis and obesity-associated insulin resistance, respectively. These basic research studies in animal models provide the foundation for future translational and clinical research.

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

Basic Research at the Molecular Level

Promising Approaches to Treating Chronic Pain: Opioid analgesics are the most powerful pain medications currently available; unfortunately they can produce drug dependence. Thus, an area of enormous need is the development of potent non-opioid analgesics. In recognition of this, NIH has implemented an aggressive and multidisciplinary research program. Many of these initiatives are yielding tangible results that stand to revolutionize the field of pain management. At the molecular level, cannabinoid (CB) research has shown that it is possible to selectively activate the CB system to provide analgesia with minimal or no psychotropic side effects or abuse liability. New findings in basic pharmacology reveal previously unrecognized complexity emerging from the natural mixing of different receptors, the targeting of which could provide a vastly expanded range of pharmacotherapeutic effects. This approach has already ushered in the development of promising designer molecules that can block pain more selectively and safely. At the cellular level, active research on a non-neuronal brain cell type, glia, has led to the realization that glia activation can amplify pain. This discovery suggests that targeting glia and their proinflammatory products may provide a novel and effective therapy for controlling clinical pain syndromes and increasing the utility of analgesic drugs. At the brain circuit level, a new approach has been developed to harness the brain's intrinsic capacity to train itself through a strategy in which subjects “learn” how to regulate pain by viewing and then controlling images of their own brains in real time. Environmental Influences on Epigenetic Regulation: The field of epigenetics (gene expression and heritability unrelated to DNA sequence) is uniquely related to environmental health sciences. Almost all known factors causing epigenetic change are from the environment, diet, or supplements. Epigenetic mechanisms are being linked to multiple illnesses, including cancer, cognitive dysfunction, and respiratory, cardiovascular, reproductive, autoimmune, and neurobehavioral diseases. Recently, NIH developed a program in epigenetics that supports research to understand how the epigenome is affected by environmental exposures and how this affects human health. This field promises to shed light on how early life exposures can lead to disease later in life. One purpose of this program is to identify critical windows of susceptibility to epigenetic changes, particularly during pregnancy, early life, and puberty; this will help us develop biomarkers of early exposure, as well as identify possible therapeutic strategies to prevent later disease. Projects currently being supported by this program include epigenetic modulation of DNA repair during breast carcinogenesis and progression, gene silencing in mammalian cells induced by environmental exposure, impact of nongenetic factors on breast cancer susceptibility gene functions, and epigenetics of human cancer from chronic radiation exposure. The Tumor Biology and Metastasis Program: This program supports research to delineate the molecular mechanisms and signaling pathways involved in tumor progression, cell migration and invasion, angiogenesis, lymphangiogenesis, and metastasis. Research indicates that the progression of cancer depends on the co-evolution of carcinoma cells in their immediate microenvironment. In 2006, NIH launched the Tumor Microenvironment Network (TMEN), to investigate the composition of the stroma in normal tissues, with the goal of delineating the mechanisms of tumor-stromal interactions in human cancer. Glycomics Technology Development, Basic Research, and Translation into the Clinic: Complex carbohydrates are ubiquitous, 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 is widely 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 Resources are developing and sharing 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.
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 on 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 2006 and 2007 the SIG program funded a total of 264 grants for $95.2 million; the HEI funded a total of 39 awards for $55.9 million.

ENCODE: The ENCyclopedia Of DNA Elements (ENCODE) is an international research consortium organized by NIH that seeks to identify all functional elements in the human genome. The initial 4-year pilot phase has just been completed, and the consortium has published a series of papers describing an intricate network in which genes and other regulatory mechanisms interact in complex ways. Other insights include the discovery that the majority of DNA in the human genome is transcribed into functional molecules, called RNA, and that these transcripts extensively overlap one another. These findings challenge long-held beliefs that the genome has small sets of genes and vast amounts of “junk” or untranscribed DNA. Until now, most studies have concentrated on the functional elements of specific genes, and have not provided information about functional elements in the vast majority of the genome that does not contain genes. ENCODE's exciting discoveries may well reshape the way scientists think about the genome and pave the way for more effective approaches to both understanding and improving human health. Large-Scale Sequencing Program: NIH's Large-scale Sequencing Program funds three major research centers in the United States to conduct genetic sequencing. During and since the completion of the Human Genome Project, NIH-funded centers have used their industrial-scale enterprises to improve DNA sequencing methods, thereby substantially decreasing costs and increasing capacity. For many years, the Program has achieved twofold decreases in cost approximately every 20 months. One of the main projects now under way is the sequencing of the genomes of other primates, such as orangutan, baboon, gibbon, and marmoset (in addition to chimpanzee and macaque, which are complete). By comparing the human genome to that of other primates, researchers can find important information about both health and abilities that are uniquely human and those shared with other species. The Program also supports the genomic sequencing of human pathogens (organisms that cause disease in humans) and their vectors, the organisms that carry those pathogens. For other relevant NIH programs, see previous section, Microbial Genomics. Also, many mammals are being sequenced to identify elements that are functionally important to human biology. These studies will undoubtedly unveil new biological insights to increase our understanding of how the human genome works. Nanomedicine Development Centers (NDC): The structures inside living cells operate at the nanoscale (about 1/10,000 the thickness of human hair). Recent advances in nanotechnology, which refers to the understanding and control of materials at the nanoscale, have yielded new tools to probe and manipulate objects at the nanoscale. These tools, as well as a variety of newly engineered nanostructures, are starting to be used in biomedical research. Nanomedicine, an offshoot of nanotechnology, is a rapidly emerging, multidisciplinary field that was identified as one of the nine initial NIH Roadmap initiatives. In late 2006, NIH completed the establishment of a national network of eight NDCs after an intensive 2-year planning and application process that involved extramural stakeholders from scientifically and medically diverse fields. The overarching goal of these centers is to understand and control the nanomachinery inside living cells in order to diagnose or treat disease and repair tissue. The work at these centers, which involve over 120 biomedical researchers located in 30 institutions, 12 States, and 6 countries, is geared toward understanding the fundamental properties of intracellular structures with great precision so that highly specific treatment or possibly even replacement of these structures can be achieved with few or no side effects. Unlike traditional, translational research targeting a specific medical problem, these centers are beginning with basic science studies and, over a 10-year period, will apply their tools, technologies, and newly developed structures to a variety of disease or wound conditions that will be identified in parallel with, and as a consequence of, the technological developments. It is expected that this novel approach will stimulate the emergence of nanomedicine as a major contributor to improving human health in a variety of medical specialties. Developmental Epigenetics: This rapidly evolving area of research examines how nonstructural changes in gene expression during normal developmental processes can influence health outcomes across the generations. NIH is expanding its research in this area to help scientists learn how typical epigenetic changes and variations occur at the molecular level, starting well before birth. Understanding these epigenetic changes—how they are inherited and passed onto subsequent generations and what factors influence them—could hold the scientific key to understanding and modifying certain factors that lead to a number of diseases or conditions, from obesity to heart disease.
  • This example also appears in Chapter 2: Life Stages, Human Development, and Rehabilitation.
  • (I) (NICHD)
Researchers Report Chemical Rescue of Cleft Palate in Mice: A growing understanding of the multiple roles played by the enzyme GSK3 has enabled scientists to realize that this protein molecule has a role in determining the developmental fates of certain undifferentiated cells in the embryo. A few years ago, this realization led a team of scientists to develop a technique that prompts small molecules directly to turn GSK3 on and/or off with a high degree of precision at different stages of fetal development. In the March 1 issue of the journal Nature, NIH-supported scientists and their colleagues reported using this on-off technique to determine, in mice, the critical developmental period of the palate, or roof of the mouth. Remarkably, the researchers showed that by turning GSK3 back on in pregnant mice during this key developmental window, their embryos in most cases corrected their developing cleft palates. As they reported, five of nine mouse pups had complete reversal of the developing cleft, while another newborn had a partial rescue of the cleft. As the authors noted: “New approaches to rescuing selected developmental defects require detailed knowledge of timing and levels of protein expression; our studies provide an improved method for defining these experimental conditions in vivo.” Study on Forefronts of Science at the Interface of Physical and Life Sciences: In FY 2006, NIH cofunded a study by the National Academies to identify research Forefronts of Science at the Interface of Physical and Life Sciences. This study, to be completed in 2008, will identify and prioritize well-defined, large-scale, complex problems or grand challenges at the interface of the life and physical sciences and engineering that will drive research and nucleate the broad scientific community. It will also examine appropriate mechanisms for long-term high-risk research as well as approaches to catalyze greater cross-disciplinary collaborations. This study builds upon prior studies and conferences in this area led by Federal agencies and other National Academies efforts.
  • (E) (NIBIB, NIGMS)
How We Detect Taste at the Molecular Level: Taste is critical for discriminating between nutritious and spoiled foods. Taste disorders can lead to reduced appetite and poor nutrition. Scientists are trying to increase their understanding by identifying proteins that we produce to help detect taste. Taste cells are clustered in taste buds on the tongue and palate. NIH-supported scientists have identified a new protein, PKD1L3, found specifically in taste cells. The PKD1L3 protein forms a channel that allows tastants, such as sodium ions or protons, to enter through taste cell membranes so that tastes can be detected. Another group of NIH-supported scientists determined that the protein is located in taste pores and is activated by acids (sour) but not other tastants. A third group of NIH-supported scientists reports that mice lacking PKD2L1-expressing cells cannot detect sour tastants but can detect all others. Together, these three reports suggest that PKD1L3 channels detect sour tastants in food. Scientists can now explain how humans detect the flavors sweet, sour, bitter, and umami, or savory, at the cellular level. This advance in understanding taste may help scientists treat taste impairments, and could also lead to the development of better salt and sugar substitutes for the millions of Americans on restricted diets to control high blood pressure, diabetes, and obesity. Anti-inflammation/Resolution Regulator May Be Involved in a Wide Range of Human Diseases: Resolvin E1 (RvE1) is a new family of bioactive products of omega-3 fatty acid. Using periodontitis as a model disease, a team of NIH-funded researchers recently reported that RvE1 can dramatically alter the progression of microbe-initiated local inflammatory disease. RvE1 therapy demonstrates greater efficacy without the side effects of chronic antibiotic usage. The results of their study provide new directions for treatment of localized aggressive periodontitis and other inflammation-related bone disorders. In many chronic disorders similar to periodontitis, prolonged and unresolved inflammation contributes to pathogenesis. It is now clear that several endogenous biochemical pathways activated in the host during defense reactions can counterregulate inflammation. This study provides evidence for the role of RvE1 as an endogenous anti-inflammation/resolution regulator that may be involved in the pathogenesis of a wide range of human diseases. Discovering the Molecular Mechanisms of Pain: Nociception, the sensory component of pain, depends in part on the intricate network of sensory transmission within our bodies, stretching from our extremities to the spinal cord and onward to the brain. But on its most fundamental level, nociception involves molecules and chemical mechanisms. NIH scientists have reported progress in understanding precisely how individual molecules in our nerve cells generate, transmit, and sustain sensory signals. They discovered that a much-studied protein called cyclin-dependent kinase 5 (Cdk5) plays a regulatory role in pain signaling between sensory nerves in the spinal cord and nerve ganglia. Their paper offers the first direct evidence of this regulatory role for Cdk5. The authors also reported the first evidence from animal studies of the importance of Cdk5 activity in inflammation. These findings point the way for additional research, suggesting that new analgesic drugs that alter Cdk5 activity one day may be beneficial in treating pain. New Molecular Targets to Halt Periodontal Bone Loss: Around 80 percent of American adults have some form of periodontal disease. Chronic periodontitis erodes supporting structures of the tooth, leading to tooth loss. The risk of periodontal diseases is higher in smokers and individuals with diabetes; 20.8 million Americans suffer from diabetes and related complications, including increased incidence and severity of periodontitis: (1) This higher incidence and severity are associated with increased cell death in bone and tissue-forming cells called osteoblasts and fibroblasts. The loss of these cells results in decreased capacity to repair tissue and bone. NIH-supported investigators published two separate papers describing the mechanisms by which the diabetic state enhances cell death. The papers suggest that diabetes-induced cell death and compromised tissue repair are mediated by the TNF-a pro-apoptotic pathway, with the major effector being caspase-3. Inhibition of TNF-a or caspase-3 activity rescues cell death and restores repair capacity. (2) Discrimination between harmful microbes and commensal species is a critical property of the mucosal immune system, essential for maintaining health. Host immune cells have surface receptors that recognize bacterial species such as those known to be associated with periodontitis. Host immune cells can selectively learn to respond strongly or to tolerate endotoxin produced by recognized bacteria. NIH-supported scientists found that patients with chronic periodontitis overproduce a molecule known as SHIP, which plays an important regulatory role in signaling immune cells to tolerate endotoxin. Implication: data from these studies suggest possible targets for developing new ways to treat or prevent chronic periodontitis. Regulating Tumor Formation: Cells contain tiny pieces of RNA, DNA's chemical cousin, that were once thought to be no more than cellular junk. It is now clear that these microRNAs are important in regulating the activity of many genes in the cell. Two groups of NIH-funded scientists have found correlations between specific microRNAs and the ability of cells to form tumors. One group found that a specific family of microRNAs seems to help prevent cellular problems that can lead to cancer. The other group of researchers discovered that a particular chromosomal change—one that is found in human tumors—can disrupt the function of a certain microRNA. Specifically, the genetic change prevents the microRNA from keeping tight control over the activity of a tumor-promoting gene. This suggests that the loss of control is probably a critical step in tumor formation. A better understanding of the role that microRNAs play with respect to cancer may lead to new ways to prevent the development or spread of the disease. Responding to Damaged DNA: Many factors can damage DNA, including ultraviolet light, environmental toxins, and cellular mistakes. When they divide, damaged cells can pass their faulty DNA to new cells. If the process continues, damaged DNA can build up inside the body, potentially causing cancer or other serious problems. To prevent this, the body uses powerful controls that lock down damaged cells, preventing them from dividing until their DNA is repaired. Recently, NIH-supported scientists identified a protein that triggers this lock-down in response to a specific type of DNA damage (double-stranded DNA breaks). These studies provide crucial insights into how cells maintain the accuracy of their genetic material and how they lose this control in cancer cells. Understanding How Protein Aggregation Causes Cell Death: Several neurodegenerative diseases—Huntington's, Alzheimer's, and Parkinson's—are characterized by clumps of misfolded proteins in the brain cells of patients. Normally, the body is very good at repairing or eliminating misfolded proteins, so it is not clear what goes wrong in these diseases. By studying the problem in roundworms, NIH-supported researchers learned that the abnormal protein found in Huntington's disease effectively jams the repair system. As a result, normal cellular proteins that misfold are not repaired. These misfolded, nonfunctional proteins accumulate, which triggers the aggregation of the disease protein. It is likely that the loss of these normal proteins, rather than the clumping of disease protein, is responsible for the death of brain cells. This research suggests that bolstering cellular repair mechanisms could be a promising therapeutic approach to these diseases. The Molecular Libraries Roadmap Initiative: The Molecular Libraries Roadmap Initiative, part of the NIH Roadmap, offers public-sector researchers access to high-throughput screening of libraries of small organic compounds that can be used as chemical probes to study the functions of genes, cells, and biological pathways. This powerful technology provides novel approaches to explore the functions of major cellular components in health and disease. The initiative is composed of several major components: The establishment of the Molecular Libraries Screening Centers Network (MLSCN), the Molecular Libraries Small Molecule Repository (MLSMR), a public Cheminformatics database (PubChem), and a series of technology development initiatives. In its second year, investigators within the Screening Center Network published several new screening approaches, including several that allow the chemical dissection of inflammatory pathways, one that has successfully identified multiple families of previously unknown signaling proteins, one that examines changes in cellular phenotype associated with disease using automated microscopy, and one that allows a range of compound doses to be screened at once. Each of these is expected to facilitate identification of compounds to probe biological activities and disease processes and identify leads for drug discovery. By December 2007, the 10 centers in the Molecular Libraries Screening Centers Network have entered screening data from more than 400 assays in the PubChem database at the National Library of Medicine.

Basic Research at the Cellular and Systems Levels

Innovative Technologies for Engineering Small Blood Vessels: NIH has initiated a program of basic research studies to enlighten future development of replacements for damaged or diseased small blood vessels. Thousands of patients each year could benefit from small blood vessel substitutes (e.g., to bypass coronary artery or peripheral vascular occlusions or to establish arteriovenous shunts for hemodialysis), but currently available replacement grafts have a high failure rate. Recent advances in materials science, bioengineering, and tissue engineering, as well as the availability of better computational tools, are providing opportunities for the development of replacement blood vessels with properties that closely match those of natural blood vessels.
  • This example also appears in Chapter 2: Chronic Diseases and Organ Systems and Chapter 3: Technology Development.
  • (E) (NHLBI)
The Immune Tolerance Network: In 2007, NIH renewed support for the Immune Tolerance Network (ITN), a consortium of over 80 investigators in the United States, Canada, Europe, and Australia. The ITN studies and tests new drugs and therapies for autoimmune diseases, asthma and allergies, and rejection of transplanted organs, tissues, and cells. ITN studies are based on stimulating immunological tolerance, the mechanism by which the immune system naturally avoids damage to self. Immune tolerance approaches aim to “reeducate” the immune system to eliminate harmful immune responses and graft rejection while preserving protective immunity against infectious agents. The ITN has established state-of-the art core laboratory facilities to study the underlying mechanisms of candidate therapies and to monitor tolerance. In 2006, the ITN reported that a novel DNA-based ragweed allergy therapy could achieve long-lasting symptom reduction after only 6 weeks of therapy, compared to current methods that require years of biweekly injections. Current ITN studies include pancreatic islet transplantation for type 1 diabetes; approaches to slow or reverse progression of autoimmune diseases; approaches to treat and prevent asthma and allergic disorders such as food allergy; and therapies to prevent liver and kidney transplant rejection without causing harmful suppression of immunity. Craniofacial Birth Defects or Syndromes: Craniofacial defects are among the most common of all birth defects. Birth defects and developmental disorders can be isolated or may be part of complex hereditary diseases or syndromes. Cleft lip and cleft palate are among the more common birth defects in the United States, occurring in about 1 to 2 of 1,000 births. Numerous other disorders with oral and craniofacial manifestations such as ectodermal dysplasias, Treacher Collins syndrome, and Apert's syndrome, while considerably more rare than cleft lip/cleft palate, also have serious lifetime functional, esthetic, and social consequences. These disorders are often devastating to parents and children alike. Surgery, dental care, psychological counseling, and rehabilitation may help ameliorate the problems, but often at a great cost and over many years. In fact, the lifetime cost of treating the children born each year with cleft lip or cleft palate is estimated to be $697 million. NIH is actively pursuing knowledge to prevent future defects as well as treat those currently affected. Exciting advances in genetic studies are shedding light on genes that are important in forming the head and face, how these genes function and how they interact with environmental, nutritional, and behavioral factors. Such information may ultimately provide the information necessary for prenatal diagnosis, the development of methods to prevent craniofacial birth defects, and the basis for developing better treatments. The development of biocompatible naturally derived materials and biodegradable scaffolds offer new hope for the treatment of defects resulting from craniofacial birth defects or syndromes. Engineering Stem Cells to Repair or Replace Damaged Tissues: Guiding a person's own stem cells to repair or replace damaged tissues with healthy tissue is the goal of multiple NIH-supported tissue engineering projects. For example, one team previously reported success creating three-dimensional mandibular (jaw) joints using rodent tissue; their continuing work on the project addresses pragmatic questions that must be answered in order to create functional human joints. Other teams are working on regeneration of the temporomandibular disk, which acts as a “cushion” between the bony components of the jaw joint and on the tissue engineering of skeletal muscle. Tissue engineering holds great promise for regeneration or replacement of dental, oral, and craniofacial structures lost due to trauma, disease, or congenital anomalies. The progress seen in this area will also inform tissue engineering solutions for degeneration in other articular surfaces such as knee, hip, and shoulder joints.
  • Mao JJ, et al. J Dent Res 2006; 85:966-79, PMID: 17062735
  • This example also appears in Chapter 3: Clinical and Translational Research and Chapter 2: Life Stages, Human Development, and Rehabilitation.
  • (E) (NIDCR)
GENSAT—Gene Expression Nervous System Atlas: Knowing where and when genes are active is a key to understanding how the nervous system develops, how the normal brain works, and what goes wrong in disease. More than half of all genes are active at some point in the brain, yet only a small fraction of these have been well characterized. To systematically address this issue, NIH initiated the GENSAT project. The project prescreens the activity of many genes at four developmental timepoints in several parts of the brain and spinal cord and, for genes of high interest, generates strains of mice in which a visible marker is turned on wherever and whenever the gene of interest is active. In addition to the value of the publicly accessible GENSAT database, the mice are useful for research on normal development and function and diseases. For example, researchers used GENSAT mice to discover that one of two previously indistinguishable types of nerve cells is selectively vulnerable in Parkinson's disease. By revealing the molecular mechanism that kills the cells, these experiments also identified a new potential drug target. GENSAT is now a resource within the NIH Neuroscience Blueprint and will expand to include nerve cells in the eye, ear, and pain pathways. The Dog Genome and Human Cancer: Cancer is the number one killer of dogs, and studying the major cancers in dogs provides a remarkably valuable approach for developing a better understanding of the development of cancer in humans. The clinical presentation, histology, and biology of many canine cancers very closely parallel those of human malignancies, so comparative studies of canine and human cancer genetics should be of significant clinical benefit to both. Furthermore, information gained from studying the genetic variant involved in dog size can provide important information for studying cell growth in humans and has the potential to be a useful tool in cancer research. A 2007 article by NIH's Dr. Elaine Ostrander et al. reported a genetic variant that is a major contributor to small size in dogs. In the following month, Dr. Ostrander and colleagues published a study reporting that a mutation in a gene that codes for a muscle protein can increase muscle mass and enhance racing performance in dogs. Asthma Exacerbations—Biology and Disease Progression: In FY 2005, NIH began a basic and clinical research initiative to improve understanding of the causes of asthma exacerbations and to facilitate the development of more effective treatments to control symptoms. Twelve projects have been funded under this initiative. As part of NIH GPRA reporting activity, NIH is assessing the progress of the initiative through an ongoing GPRA goal, “to identify and characterize two molecular pathways of potential clinical significance that may serve as the basis for discovering new medications for preventing and treating exacerbations, by 2014. ” Interventions Testing Program: In a recent study, scientists demonstrated in aged obese mice that resveratrol, an activator of a family of enzymes called sirtuins, had better health and survival than untreated aged overweight mice. Future research will assess the safety and effectiveness of resveratrol-related drugs in humans. To further these and other investigations, NIH has undertaken a multi-institutional study to investigate a variety of agents with the potential to extend lifespan and delay disease and dysfunction in mouse models. This program is the centerpiece for a new NIH GPRA goal to “identify, by 2012, at least one candidate intervention that extends median lifespan in an animal model.” The Collaborative Study on the Genetics of Alcoholism (COGA): In its 18th year, COGA is a multisite, multidisciplinary family study with the overall goal of identifying and characterizing genes that contribute to the risk for alcohol dependence and related phenotypes. COGA investigators have collected data from more than 300 extended families (consisting of more than 3,000 individuals) who are densely affected by alcoholism. Several genes have been identified including GABRA2, ADH4, ADH5, and CHRM2, which influence the risk for alcoholism and related behaviors such as anxiety, depression, and other drug dependence. In addition to genetic data, extensive clinical neuropsychological, electrophysiological, and biochemical data have been collected and a repository of immortalized cell lines from these individuals has been established to serve as a permanent source of DNA for genetic studies. These data and biomaterials are distributed to qualified investigators in the greater scientific community to accelerate the identification of genes influencing vulnerability to alcoholism. COGA will continue to identify genes and variations within the genes that are associated with an increased risk for alcohol dependence and will perform functional studies of the identified genes to examine the mechanisms by which the identified genetic variations influence risk.
  • For more information, see https://zork.wustl.edu/niaaa/
  • This example also appears in Chapter 2: Chronic Diseases and Organ Systems, Chapter 3: Genomics, and Chapter 2: Neuroscience and Disorders of the Nervous System.
  • (E) (NIAAA) (GPRA Goal)
Systems Biology and Systems Genetics: NIH launched the Integrative Cancer Biology Program to focus on networks that can be measured, modeled, and manipulated rather than individual components. Multi-disciplinary teams are critical to integrating the disciplines of biology, medicine, engineering, mathematics, and computer science (e.g., computational biology). Equally important to our understanding of cancer is systems genetic research (systems biology + genetics). Networks of genes can be found and their associations tested and quantified, with parallel association studies on relevant human populations.
  • For more information, visit https://icbp.nci.nih.gov/
  • This example also appears in Chapter 2: Cancer and Chapter 3: Technology Development.
  • (E) (NCI)
Biomedical Technology Research Resources (BTRRs): The BTRRs 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 Resources and through intensive collaborations with other leading laboratories. The BTRRs are used annually by nearly 5,000 scientists from across the United States and beyond, representing over $700 million of NIH funding for 22 institutes and centers. 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.
  • For more information, see www.ncrr.nih.gov/biomedical_technology
  • This example also appears in Chapter 3: Clinical and Translational Research and Chapter 3: Technology Development.
  • (E) (NCRR)
National Ophthalmic Disease Genotyping Network (eyeGENE™): More than 400 genes are known to contribute to vision loss. New understanding of disease-related genes is leading to the next generation of vision care. With the remarkable opportunity afforded by gene therapy and other new treatment advances comes the challenge of identifying individuals who could benefit from these treatments. However, DNA testing remains expensive, time-consuming, and not widely available. To address this need, NEI created a partnership of laboratories across the vision research community and established eyeGENE to broaden accessibility of diagnostic genetic testing. These laboratories will facilitate research on genetic causes of eye disease; provide genotyping for patients in a centralized, secure, and certified process; and will provide a research repository of genetic material and diagnostic information. Currently, eyeGENE provides diagnostic testing for over 40 disease genes. Lymphatic System in Health and Disease: NIH recently announced two funding opportunities for research to increase understanding about the lymphatic system and its function in health and disease. The lymphatic system plays a critical role in the well-being of many other systems in the body. When it is not working properly, a broad array of diseases and disorders can result, including lymphedema (characterized by accumulation of lymph fluid that often results in swelling of the arms or legs), inflammation and infections, cancer, and metabolic disorders. In July 2007, NIH issued the program announcement (PA) entitled Lymphatic Biology in Health and Disease to encourage research on the biology of the lymphatic system and potential new therapeutic approaches. In addition, in December 2006, NIH re-issued the PA entitled Pathogenesis and Treatment of Lymphedema and Lymphatic Diseases to stimulate research on the lymphatic system and lymphatic dysfunction and related diseases, as well as to develop new diagnostic methods and treatment interventions. Understanding the Mechanisms of Alcohol-Induced Tissue Injury: Virtually every organ system of the body is impacted by heavy alcohol use (the most vulnerable being the brain and liver) and the resulting pathological conditions contribute to increased mortality and morbidity among all age and racial/ethnic groups and genders. NIH is especially interested in elucidating mechanisms of injury common to multiple body and organ systems. A number of PAs and RFAs have been issued to support research to increase our understanding of the underlying cellular and molecular mechanisms of tissue injury caused by alcohol consumption, including alcohol's genetic, epigenetic and metabolic effects. Long-term goals of these initiatives are to identify biomarkers for alcohol exposure and for the early detection of alcohol-induced tissue injury, and to develop new therapeutics that control or modify outcomes of chronic alcohol use. Centers of Excellence for Influenza Research and Surveillance: Six Centers of Excellence for Influenza Research and Surveillance, established in 2007, significantly expand the ability of NIH to conduct research on different strains of animal and human influenza viruses, collected internationally or in the United States. The centers will lay the groundwork for the development of new and improved control measures for emerging and reemerging influenza viruses, help determine the prevalence of avian influenza viruses in animals in close contact with humans, and extend understanding of how influenza viruses evolve, adapt, and are transmitted. The centers will also bolster research on questions such as how influenza viruses cause disease and how the human immune system responds to infection and will inform public health strategies to control and minimize the impact of seasonal and pandemic influenza. Developing New Adjuvants to Boost Vaccine Effectiveness: The NIH Innate Immune Receptors and Adjuvant Discovery initiative encourages the discovery of novel adjuvants to meet the growing need to boost the effectiveness of vaccines against potential agents of bioterrorism and emerging infectious diseases. Adjuvants activate the body's innate immune system—microbe-engulfing phagocytes and soluble immune stimulators—leading to effective adaptive immune responses by B cells, which produce antibodies, and T cells, which can directly kill infected cells. Using high-throughput screening, several groups of researchers have identified, optimized, and developed adjuvants now in preclinical development.
  • This example also appears in Chapter 2: Infectious Diseases and Biodefense.
  • (E) (NIAID)
The Cooperative Study Group for Autoimmune Disease Prevention: In 2006, NIH renewed the Cooperative Study Group for Autoimmune Disease Prevention, which was established in 2001. This collaborative network is devoted to understanding immune homeostasis in both health and autoimmune diseases and to developing interventions to prevent autoimmune disease. The six participating centers support preclinical research, innovative pilot projects, and non-interventional clinical studies, with an emphasis on type 1 diabetes. By the end of 2006, grantees had published 109 original research papers, and 5 of 48 pilot projects had matured into investigator-initiated grants. Of note, the centers are collaborating on the “Roadmap to Inflammation in the NOD (non-obese diabetic) Mouse” project, which will identify and characterize genes and proteins involved in the development of diabetes, and study the mechanisms by which diabetes develops. NIH Stem Cell Task Force: In 2002, NIH established a Stem Cell Task Force to continually monitor the state of this rapidly evolving area of science. The purpose of the Task Force is to enable and accelerate the pace of stem cell research by identifying rate-limiting resources and developing initiatives to overcome these barriers to progress. The Task Force seeks the advice of scientific leaders in stem cell research about moving the stem cell research agenda forward and exploring strategies to address the needs of the scientific community. Over the past 5 years, under the leadership of the Task Force, NIH has supported a wide array of scientific programs designed to foster research on all types of stem cells, including human embryonic stem cells (hESCs), and is actively working to fund research in this blossoming field. For example, the Task Force has stimulated NIH-supported research by initiating Infrastructure grants to scale up and characterize hESCs eligible for Federal funding, developed training courses to teach stem cell culture techniques, established a National Stem Cell Bank to make hESC lines that are eligible for Federal funding readily available, and encouraged new investigator-initiated research through various means. The Task Force is also responsible for implementing Executive Order 13435, which encourages research on the isolation, derivation, production, and testing of stem cells that are capable of producing all or almost all of the cell types of the developing body and may result in improved understanding of or treatments for diseases or other adverse health conditions, but are derived without creating a human embryo for research purposes or destroying, discarding, or subjecting to harm a human embryo or fetus. Beta Cell Biology Consortium (BCBC): The BCBC is collaboratively pursuing key challenges relevant to the development of therapies for type 1 and type 2 diabetes, including studying pancreatic development to understand how insulin-producing beta cells are made, exploring the potential of stem cells as a source for making islets, and determining the mechanisms underlying beta cell regeneration. The BCBC has generated key research resources, such as animal models, microarrays, and antibodies, which are available to the scientific community.
  • For more information, see https://www.betacell.org
  • This example also appears in Chapter 2: Autoimmune Diseases and Chapter 2: Chronic Diseases and Organ Systems.
  • (E) (NIDDK)
Basic Research on Human Embryonic Stem Cells: Research on human embryonic stem cells (hESC) promises to illuminate critical events in early human development and, in the future, may revolutionize regenerative medicine. In FY 2003, NIH funded the first of six Exploratory Centers for hESC research involving stem cell lines listed on the Human Embryonic Stem Cell Registry. Meetings at NIH in 2005 and 2007 highlighted the significant progress being made in this area by NIH-funded researchers. In FY 2007, NIH continued its support of research into the fundamental properties of hESC by funding two Program Project grants. National Centers for Systems Biology: Systems biology is a new research field that integrates approaches from experimental and computational biology. Currently, NIH-funded researchers at seven interdisciplinary centers are developing predictive computer models to study areas such as drug metabolism, host-pathogen interactions, organism development, and cell signaling. These centers are both advancing their research fields and training the next generation of scientists. Influenza Virus Resource: This database of more than 40,000 influenza virus sequences allows researchers around the world to compare different virus strains, identify genetic factors that determine the virulence of virus strains, and look for new therapeutic, diagnostic, and vaccine targets. The resource was developed by NCBI using data obtained from NCBI's Influenza Virus Sequence Database and from NIAID's Influenza Genome Sequencing Project, which has contributed sequences of the complete genomes from over 2,500 influenza samples. In FY 2006 more than 11,000 influenza virus sequences were entered into the database, and new search and annotation tools were added to assist researchers in their analyses. The Biomarkers Consortium: Launched through the NIH Program on Public-Private Partnerships in October 2006, the Biomarkers Consortium (BC) is a public-private partnership including NIH; the U.S. Food and Drug Administration; the Centers for Medicare & Medicaid Services; the pharmaceutical, biotechnology, diagnostics, and medical device industries; nonprofit organizations and associations; and advocacy groups. The BC is managed by the Foundation for the NIH. The BC will search for and validate new biological markers—biomarkers—in order to accelerate the delivery of successful new technologies, medicines, and therapies for prevention, early detection, diagnosis, and treatment of disease. Biomarkers are objective measures of risk, disease status, and/or health outcomes and include, for example, cholesterol and blood pressure as well known biomarkers of cardiovascular health. The BC structure will accommodate a number of discrete projects, each devoted to biomarker discovery, qualification, or use in targeted areas of disease-related biomedical and clinical science, with the ultimate aim to improve the public health. Projects will be proposed by members of the BC, academics, patient advocates, and the public, and will be developed and implemented according to their scientific merit, public health need and opportunity, and availability of support and funding. Animal Model for Corneal Diseases: NIH scientists have developed a genetically engineered mouse model for studying a number of eye diseases. In this mouse, the Klf4 gene was deleted in the cornea, the conjunctiva, the eyelids, or the lens, to study the role of this gene in normal development and maintenance of the ocular surface. Deletion of the Klf4 gene resulted in a reduced number of epithelial cell layers, irregular, defective cells and an absence of certain cell types. These mouse models will be used to study eye diseases and disorders that affect the surface of the eye, including dry eye, Meesmann's dystrophy, and Stevens-Johnson syndrome. Dietary Control of Angiogenesis in the Eye: The growth of new blood vessels, angiogenesis, can be a double-edged sword: while necessary for the normal development of tissues, uncontrolled angiogenesis can cause blindness in retinopathy of prematurity or diabetic retinopathy, or promote tumor growth in cancer. NIH-supported research in animal models showed that increased dietary intake of omega-3 polyunsaturated fatty acids reduces harmful angiogenesis in the retina. These findings suggest diet may provide a cost-effective method to prevent or ameliorate retinal vascular diseases. Losartan Offers Promise for the Treatment of Marfan Syndrome: New research offers hope that losartan, a drug commonly prescribed to treat hypertension, might also be used to treat Marfan syndrome, a genetic disorder that often causes life-threatening aortic aneurysms. After discovering that Marfan syndrome is associated with a mutation in the gene encoding fibrillin-1, researchers tried for many years, without success, to develop treatment strategies that involved repair or replacement of fibrillin-1. A major breakthrough occurred when NIH-funded researchers discovered that one of the functions of fibrillin-1 is to bind to another protein, TGF-beta, and regulate its effects. After careful analyses revealed aberrant TGF-beta activity in patients with Marfan syndrome, researchers began to concentrate on treating the disease by normalizing the activity of TGF-beta. Losartan, which is known to affect TGF-beta activity, was tested in a mouse model of Marfan syndrome. The results showed that the drug blocked the development of aortic aneurysms as well as lung defects associated with the disease. Based on the promising results, the NHLBI Pediatric Heart Network, in partnership with the National Marfan Foundation, began a clinical trial in 2007 to assess losartan therapy in patients with Marfan syndrome. Genes Involved in the Regulation of Sensitivity to Alcohol: Low doses of alcohol are stimulating in both humans and animals while higher doses have sedating effects. Sensitivity to alcohol, however, varies across individuals and low sensitivity to alcohol is a risk factor for the development of alcohol dependence in humans. Recent animal studies have identified several genes that alter sensitivity to alcohol and may provide targets for medications development.
  • Researchers have discovered a genetic mutation that disrupts the function of the fruit fly gene RhoGAP18B, causing the flies to be much more resistant to alcohol sedation. Other variants of the same gene, each of which has a distinctly different effect on the response to alcohol, were subsequently identified.
  • Another fruit fly gene, Homer, has been shown to be required for normal sensitivity and tolerance to alcohol. This study shows that ethanol sensitivity and tolerance co-map to the same population of neurons, suggesting that the neuronal circuits controlling these two behaviors, known to contribute to alcohol dependence, are shared.
Increased Endocannabinoid Signaling Increases Ethanol Consumption and Decreases Acute Ethanol Intoxication: Endocannabinoids, the naturally occurring substances in the brain that act on the same receptors as the active ingredients of marijuana, have been discovered to play a role in regulating appetite for alcohol. NIH-supported scientists discovered that mice lacking expression of fatty acid amidohydrolase (FAAH), the main endocannabinoid-degrading enzyme, showed an increased appetite for ethanol, decreased sensitivity to ethanol-induced sedation and faster recovery from ethanol-induced motor incoordination. These results show that impaired FAAH function leads to increased voluntary alcohol intake and point to a FAAH both as a potential susceptibility factor and as a therapeutic target for excessive alcohol consumption. Hereditary Hearing Loss: NIH recognizes that one of the most rapidly developing areas of research is functional genomics, which involves determining the identity, structure, and function of genes. Hereditary or genetic causes account for approximately 50-60 percent of the severe to profound cases of childhood hearing loss. NIH-supported scientists are working to understand the normal function of these genes and how they are altered in individuals with hereditary hearing loss. At present, over 70 genes causing nonsyndromic hereditary hearing impairment have been mapped to intervals on particular chromosomes; many of these efforts were the result of collaborations involving NIH-supported scientists. In collaborative efforts with scientists in Columbia, India, Indonesia, Israel, Lebanon, Mexico, Newfoundland, Pakistan, Tunisia, Puerto Rico, and the United States, NIH is accelerating this gene discovery effort. These research investments to understand the genetic basis of communication disorders will help scientists develop diagnostic tests and better treatments for the millions of Americans with hereditary hearing impairment. Stuttering: Stuttering is a communication disorder with notable physical and emotional challenges to the speaker and sometimes to the listener. It is estimated that approximately 3 million Americans stutter. Stuttering affects individuals of all ages but occurs most frequently in young children between the ages of 2 and 6 who are developing speech and language. Boys are three times more likely to stutter than girls. Most children, however, outgrow their stuttering. It is estimated that less than 1 percent of adults stutter. NIH-supported scientists identified a specific location for a gene on chromosome 12 that seems to be an important contributor to stuttering in a series of 40 highly inbred families of Pakistani origin. Determining the underlying molecular causes of stuttering may lead to improved diagnosis and treatment of stuttering. Discovering the Causes of Nonsyndromic Cleft Lip and Cleft Palate: For nearly 60 years, NIH has supported scientific investigation of causes and interventions for cleft lip and cleft palate, which are among the most common birth defects. In recent years, advances in technology made it possible for scientists to directly sequence genes they suspected of contributing to cleft lip and/or palate. NIH grantees and their associates have used this approach to identify genetic mutations accounting for up to 13 percent of cleft lip and/or palate cases. One of the most recent advances occurred in March 2007, when the scientists reported sequencing the coding regions of 12 members of the fibroblast growth factor (FGF) and FGF receptor gene families and finding seven mutations that may contribute to as much as 5 percent of nonsyndromic cleft lip and/or palate. The group followed up by generating three-dimensional computer models of the FGF proteins that predicted how the altered amino acids would affect their normal shape and function. In a separate finding, NIH-supported scientists reported that women who carry a fetus whose DNA lacks both copies of a gene involved in detoxifying cigarette smoke substantially increase their baby's chances of being born with a cleft lip and/or palate if they smoke. About a quarter of babies of European ancestry and up to 60 percent of those of Asian ancestry lack both copies of the gene called GSTT1. The scientists calculated that if a pregnant woman smokes 15 cigarettes or more per day, the chances of her GSTT1-lacking fetus developing a cleft increase nearly twentyfold. Globally, about 12 million women each year smoke through their pregnancies. This finding provides additional motivation for expectant mothers to follow existing advice not to smoke. Understanding the Causes and Conceiving New Treatments for Craniosynostosis: Craniosynostosis arises when one or more of the fibrous sutures between the six cranial bones prematurely fuse and lock sections of the skull tightly into place. Because the brain continues to grow during early childhood, if left untreated, craniosynostosis can distort the shape of the skull and portions of the face as well as cause hearing loss, blindness, and/or mental retardation. To better understand the causes of craniosynostosis, a team of NIH-supported researchers study the fusion of cranial sutures in mice. They suspect the premature fusion involves alterations in the normal biochemical interplay between embryonic tissue called mesenchyme, from which the cranial sutures form, and a thin fibrous layer of tissue called the dura mater that lies beneath it. The scientists also have found that different regions of the dura mater send different developmental signals to the overlying mesenchyme. Defining in fine detail the signals between the mesenchyme and dura mater could provide the intellectual basis for discovering and developing noninvasive biological approaches to control craniosynostosis. NIH-supported researchers have made an important step in this direction. They isolated mesenchymal cells derived from cranial sutures in two different areas of the skull, cultured each group of cells separately, and later analyzed their gene expression patterns. The scientists found clear differences in the patterns of genes expressed among the two populations of mesenchymal cells. To their knowledge, this marks the first glimpse of the genetic programs wired into mesenchymal cells derived from cranial sutures. This line of research potentially opens a new chapter in understanding the causes and conceiving new treatments for cranial synostosis. Life on Humans: A large number of microorganisms exist in us and on us, and some are crucial for our survival. Understanding their roles in health and disease is an important goal. Advances in molecular biology have made it possible to obtain a more comprehensive catalogue of the microbes that are present in environments such as the gastrointestinal tract or skin. NIH-supported researchers who examined microbes on the arms of six healthy subjects found that, although some microbes were common to all subjects, there was substantial diversity between individuals. Furthermore, the population of microbes present on a single individual changed over time, indicating that human skin supports a few “resident” microbes and many “transients.” These studies are advancing the understanding of how environmental factors such as humidity, light exposure, and cosmetic use may affect microbes, and whether changes in these factors affect the susceptibility to or severity of skin diseases. Understanding Gene Regulation in Stem Cells: Stem cells are uniquely capable of being maintained indefinitely in an unspecialized state and of growing into specific cell types like muscle, blood, or nerve cells. Scientists hope to coax stem cells into specific cells that can treat diabetes, Parkinson's disease, spinal cord injuries, or other conditions in which specific cell types are not functioning properly. Recently, NIH-funded researchers discovered the genetic switch that enables embryonic stem cells to develop into recognizable cell types. This discovery addresses a fundamental question about the early development of mammals. It also brings researchers a step closer to the goal of using stem cells to treat a host of diseases. Understanding How Prefrontal Cortex Affects Cognitive Function: In FY 2008, NIH will support an RFA to stimulate research on how a brain region called the prefrontal cortex interacts with other parts of the brain to give rise to sophisticated behavior and cognitive function. Abnormal functioning of the prefrontal cortex is associated with mental disorders such as schizophrenia and depression. Visual Processing in Neuroscience Blueprint: Much of the cerebral cortex of the brain is devoted to processing the images that flood our eyes. The visual cortex also connects with many regions of the brain that govern memory, language, movement, and a myriad of other cognitive abilities. NIH's visual processing research portfolio prioritizes understanding of how the brain processes visual information, how brain activity results in visual perception, and how the visual system interacts with other cognitive systems. Link between Eye Movement and Reward: Dopamine is vital to motor behaviors, but neurons that release dopamine carry signals related to rewards, not body movements. As a solution to this puzzle, recent theories propose that the reward-related dopamine signals are used for learning of motor behaviors. However, it is unknown how dopamine neurons acquire the reward-related signals. NIH scientists have shown that a small brain area called the lateral habenula controls dopamine neurons by inhibiting them and thereby suppressing less rewarding eye movements. This discovery opens up new research connecting emotion and motivation to motor behaviors. Powerful New Technique Reveals How Brain Cells Wire Together: In order to understand how the brain processes visual information and performs other tasks, researchers have wanted to construct a “wiring diagram” of the billions of neurons connected in precise, identifiable circuits. A breakthrough technology has helped clear this major hurdle by revealing all the connections made by a single nerve cell. The new tool uses a modified rabies virus, which can spread indefinitely through the nervous system by jumping between communicating nerve cells. However, scientists modified the virus so that it jumps once and then leaves a fluorescent tag in the neurons connected to a single cell. This permits visualization of functional processing circuits in living brains. It can also be used in transgenic mice to deactivate targeted classes of neurons expressing specific genes, revealing changes in brain function, including behavior.

Basic Research in the Behavioral Sciences and in Complementary and Alternative Medicine

Tools to Reveal the Mechanisms Governing Behavior: Newly acquired but rapidly evolving tools and techniques that monitor or probe discrete brain systems have allowed NIH-supported researchers to begin filling in the information gap between molecular or cellular events and behavioral outcomes. A notable preclinical example of this trend is the development of a genetically engineered method to turn the electrical impulses of brain cells on and off with pulses of light—in synch with the split-second pace of real-time neuronal activity. The novel technique borrows genes form light-responsive algae and bacteria to unravel the intricate workings of brain circuits with extreme precision. This powerful new tool could be used to assess the role of neuronal activity in regulating normal behavior and disease processes. On the clinical side, an array of brain imaging devices has produced much information on how neural circuits develop and process information under normal conditions, and how they become impaired by a disease like addiction. These advances have led to the fertile concept that the transition from abuse to addiction is not a switch but a gradual degradation of the ability of different circuits to “talk” to each other as they attempt to compensate for their deficiencies. Interestingly, these studies are also showing significant overlap in the circuits involved in drug abuse and the circuits underlying compulsive overeating and obesity. Moreover, in preclinical studies, compounds that interfere with food consumption in animal models of compulsive eating also interfere with drug administration. Centers of Excellence for Research on CAM (CERC), Developmental Centers for Research on CAM (DCRCs), and International Centers for Research on CAM: These Centers bring cutting-edge scientific technology to programs of research on the usefulness, safety, and mechanisms of action of various CAM interventions. Based in collaborations between established biomedical research scientists and experts in CAM or traditional medicine, these programs are also aimed at enhancing the global state of research capacity on CAM. For example, the CERCs are led by scientists with outstanding research records who direct teams of investigators with both CAM and conventional scientific expertise. During the first 3 years of the CERC program, awardees have made sentinel advances in our understanding of the scientific basis for the effects of acupuncture through the use of modern brain imaging, and they have explored innovative approaches to the treatment of asthma with antioxidants and approaches based on traditional Chinese medicine (TCM). Other CERCs are focusing on (1) the study of acupuncture and TCM herbal treatments of arthritis, (2) the effects of mindfulness meditation on the progression of HIV/AIDS, and (3) the mechanisms of action of millimeter wave therapy (use of low-intensity millimeter wavelength electromagnetic waves) for a variety of chronic conditions. NIH will fund additional CERCs in late FY 2007. Basic Research on CAM: In addition to its focus on clinical investigation of complementary and alternative medicine interventions, NIH places a high priority on basic research aimed at filling important gaps in our knowledge about the mechanisms by which they may exert their effects. Recently released initiatives target this area of research. Examples include the following:
  • “Omics and Variable Responses to CAM” utilizes genomic, proteomic, and metabolomic technologies to examine potential causes for variation in individual responses to CAM interventions (PAR-07-377).
  • “Mechanistic Research on CAM Modalities Purported to Enhance Immune Function” examines the scientific basis for a common but generally unsubstantiated claim made on behalf of a number of CAM modalities (RFA-AT-06-004, RFA-AT-06-005).
  • “Research on the Biomechanical, Immunological, Endocrinological, and/or Neurophysiological Mechanisms and Consequences of Manual Therapies” applies state-of-the-art science to investigating the biological basis for CAM interventions, such as spinal manipulation and massage. (PAR-06-312)
  • This example also appears in Chapter 3: Clinical and Translational Research.
  • (E) (NCCAM)
Basic Behavior in Animal Models: This program supports collaboration between behavioral scientists and molecular biologists to study basic mechanisms of behavior using animal models. The program also supports the development and enhancement of animal models to study normal or abnormal human behavior. Methodology and Measurement in the Behavioral and Social Sciences: This program supports basic and applied research to improve the quality and scientific power of data collected in the behavioral and social sciences. Among the FY 2006 and 2007 awards are projects developing improved measures of pain, physical, social, cognitive and neurocognitive functioning, quality of life, coping, and cultural and linguistic competence. Social and Cultural Dimensions of Health: This program supports research that elucidates social and cultural constructs and processes. This knowledge can be used to clarify the role of social and cultural factors in the etiology and consequences of health and illness, to link basic research to practice for improving prevention, treatment, health services, and dissemination, and to explore ethical issues in social and cultural research related to health. The currently funded projects examine multiple racial, ethnic, and other groups, and are investigating basic research topics such as discrimination, neighborhood design, stigma, socioeconomic status, physician decision-making, religiosity/spirituality, risk communication and sleep as they relate to behaviors, quality of life, palliative care, disparities, and other aspects of health. The NIH Toolbox for Assessment of Neurological and Behavioral Function: The NIH Blueprint for Neuroscience Research supports this contract awarded to the Evanston Northwestern Healthcare Research Institute. The project entails development of a set of standardized neurological and behavioral measures of cognition, emotion, sensation, and motor function. The toolbox will foster uniformity among the basic measures used and allow comparisons or data compilations across multiple studies. This innovative approach to measurement will be responsive to the needs of researchers in a variety of settings, with a particular emphasis on measuring outcomes in clinical trials and functional status in large cohort studies, e.g., epidemiological studies and longitudinal studies. Mechanisms of Action of CAM: Important and potentially promising findings from recently reported research aimed at elucidating the fundamental mechanisms of various complementary and alternative medicine interventions include:
  • Extracts of turmeric (a common component of Ayurvedic traditional Indian medicines and ingredient in Indian cuisine) containing compounds known as curcuminoids prevent experimental rheumatoid arthritis in an animal model.
  • Green tea is widely promoted for a variety of health-related benefits. It contains a group of chemicals called catechins, one of which is known as epigallocatechin gallate (EGCG). Investigators recently reported that an EGCG-enriched extract of green tea significantly improves glucose and lipid metabolism in an animal model of obesity/insulin resistance/metabolic syndrome.
Mind-Body Medicine: NIH supports a substantial portfolio of multidisciplinary clinical, translational, and basic research on mind-body interventions, such as meditation and Tai Chi Chuan. This effort is based on (1) promising findings from preliminary controlled clinical investigations and (2) laboratory evidence suggesting that these interventions often involve or invoke well-known biological mechanisms known to play key roles in the cause of and recovery from illness, and in the preservation of health and wellness. For example:
  • Investigators recently demonstrated that patients who practiced Tai Chi Chuan, a form of moving meditation based in traditional Chinese medicine, experienced significant augmentation in levels of immunity to the virus that causes shingles following vaccination against the virus. Other investigators have demonstrated that patients with chronic heart failure show improvements in quality of life, exercise ability, and biomarkers of cardiac health when Tai Chi Chuan is added to conventional medical care.
Preclinical Efficacy of Ginkgo Biloba in Alzheimer's Disease: NIH-supported investigators recently published results showing that Ginkgo biloba, studied in an animal model of Alzheimer's disease, reduces both the formation of the specific brain abnormalities seen in humans, and the resulting paralysis seen in the animals. These experiments lend additional support to the hypothesis that Ginkgo biloba may be useful in slowing the progression of Alzheimer's disease. That hypothesis is being tested in the largest clinical trial to date of Ginkgo biloba for the prevention of dementia, supported by NIH.
8 NIH did not fund Mullis's Nobel Prize-winning research, although it did fund other research by Mullis, and NIH-funded research laid the foundation that made Mullis's invention of PCR possible.