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

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Biennial Report of the Director

Summary of Research Activities by Key Approach and Resource
Molecular Biology and Basic Research








Who would have predicted that curiosity about a naturally glowing protein in the luminescent jellyfish Aequorea victoria would lead to the development of a tool that has transformed molecular and cellular biology? The 2008 Nobel Prize in Chemistry was awarded to Drs. Osamu Shimomura, Martin Chalfie, and Roger Tsien for the discovery and development of the green fluorescent protein (GFP).When attached to cellular molecules, GFP allows scientists to peer into living cells and observe molecular processes and cellular development. As is often the case with basic research studies, the yield on the initial research investment was not fully realized for many years. Dr. Shimomura first isolated GFP in 1962, yet it was not until more than 30 years later that Dr. Chalfie demonstrated that GFP could be used as a tag to observe biological processes in the bacteria E. coli and the simple roundworm C. elegans. Dr. Tsien, who studied the chemical basis of green fluorescence, has created a colorful palette of fluorescent proteins that have been used in exquisitely detailed cell biology studies. With GFP-based studies continuing to generate advances in biomedical research, the discovery and development of GFP have made a significant contribution to our understanding of fundamental biological processes underlying health and disease.


Introduction

Basic research is a major force driving progress across the biomedical and behavioral sciences and is paramount in uncovering the fundamental principles of biology, wellness, disease, and public health. Investments in basic biomedical and behavioral research make it possible to understand the causes of disease onset and progression, design preventive interventions, develop better diagnostic tests, and discover new treatments and cures. From the incremental advances in our understanding of a given disease to the groundbreaking discoveries that revolutionize our approaches for treating or preventing it, investments in basic research have and will continue to yield inestimable rewards and benefits to public health. As such, fostering a broad basic research portfolio is a critical component of fulfilling the NIH mission.


Uncovering Fundamental Aspects of Biology and Behavior through Basic Research

Biological function occurs over a huge span of spatial dimensions that ranges from organisms to cells to molecules. Despite the range in size, from meters to one-billionth of a meter—which is like comparing the diameter of the earth to the diameter of a marble—similar principles of structure, interaction, and dynamics govern biological function at the molecular, cellular, and organismal levels. These principles have been finely tuned to allow biological processes to play out in concerted harmony; however, disharmony can occur in molecular and cellular structures, interactions, and dynamics that often form the underlying basis of disease.

As examples of fundamental aspects of biology at the molecular level, scientists are interested in understanding how biological macromolecules—proteins, nucleic acids, sugars, and lipids—carry out cellular processes. What molecules are involved and what are their functions? How do their shapes define their functions? How do particular molecules interact to turn their functions on and off? And, how are innumerable molecular events properly coordinated to turn genes on and off, initiate cell growth and division, determine cell type, metabolize nutrients, and, when necessary, instruct a cell to die? Understanding how these events occur in wellness provides a framework for pinpointing molecular causes of disease.

At the cellular level, similar molecular questions are focused on understanding how cells sense and respond to their environment. How do cells interact and communicate with each other to form tissues and the organ structures of our body? How do cells process and distribute nutrients to disparate parts of the body? How do cells orchestrate a response to protect our body from invasion by foreign molecules? What is the molecular program that develops an initial ball of unspecialized cells into a fully functioning human being?

Similar to basic molecular and cellular biomedical research, basic behavioral research does not focus specifically on disease outcomes per se. Rather, it is designed primarily to elucidate knowledge about underlying mechanisms and processes, knowledge that is fundamental to improving the understanding, explanation, observation, prediction, prevention, and management of illnesses, as well as the promotion of optimal health and well-being. Basic behavioral and social sciences research involves both human and animal studies, as well as many non-animal model systems, and spans the full range of scientific inquiry, from processes involved in the behavior of individuals, as individuals, to those involved in the interactions between and among individuals that explain inter-individual, group, organizational, community, population, macroeconomic, and other systems-level patterns of collective behavior. The domains and units of analysis can include intra-organismic as well as inter-organismic factors ("cells to society"), over varying units of time from nanoseconds to centuries, and lifespan developmental phases and phenomena that may occur within and across generations.


Basic Research Questions are Addressed through an Interdisciplinary Approach

The breadth of basic research questions spans all aspects of human development, physiology, behavior, and disease. Thus, basic research is encompassed in the missions of all NIH ICs. Progress in the basic sciences often requires interdisciplinary approaches. Expertise from multiple disciplines often is needed to develop new technologies, improve methods of data analysis, and provide insight on a fundamental disease pathway. NIH fosters collaborations that span all of the traditional and emerging disciplines of the life, physical, engineering, computer, behavioral, and social sciences.

The breadth of basic research questions spans all aspects of human development, physiology, behavior, and disease. Thus, basic research is encompassed in the missions of all NIH Institutes and Centers.

Although basic research is concerned with advancing our understanding of human health and disease, there are a number of reasons—both ethical and practical—that make humans poor subjects for exploring the fundamental aspects of biology. Therefore, scientists often carry out their basic research investigations in "model systems" that are simpler to work with in a precisely defined and controlled setting.

In the simplest experimental setting, researchers often remove the context of the organism and cell altogether and study individual molecules. By isolating a single type of protein, for instance, scientists can study its physical properties, functional activity, and three-dimensional structure. Understanding the structure and function of a protein allows researchers to design molecules that can selectively turn it "off" or "on" and forms the basis for the development of many pharmaceutical agents. In addition, these types of studies allow researchers to uncover how particular mutations alter molecular structure and function to cause disease.

An understanding of how molecules behave in isolation, however, must always be connected back to how they behave in a cellular setting. Scientists can study the function and interaction of molecules in cells grown in culture dishes in the laboratory. With the power of modern molecular biology, scientists can introduce virtually any gene of interest into a cell line to understand how it affects cellular outcomes, visualize how it interacts with different cellular components, and query how cellular processes are affected by particular disease-causing mutations. In addition to studying individual molecules in a cellular setting, researchers are more recently turning to "-omics" technologies to generate a systemwide picture of all of the molecules in a cell. This includes determining the sequences of all the genes in a certain cellular context (genomics), generating a profile of all the genes that are turned on or off in response to particular stimuli (transcriptomics), mapping out all of the protein-protein interactions and how they are modulated in different disease states (proteomics), following the path of all compounds generated by metabolism (metabolomics), and decoding the chemical markers that regulate gene expression (epigenomics). By amassing enormous data sets of gene sequences, protein-protein interactions, and gene expression profiles, systems biology researchers work to develop computational models to describe how all of these molecular components are integrated in normal health and disease.

With the power of modern molecular biology, scientists can introduce virtually any gene of interest into a cell line to understand how it affects cellular outcomes, visualize how it interacts with different cellular components, and query how cellular processes are affected by particular disease-causing mutations.

Finally, to provide the context of an organism, researchers will study biological processes in model organisms, including bacteria, yeast, plants, worms, fruit flies, fish, rodents, non-human primates, and many other organisms. Because human cells contain essentially the same molecular building blocks and pathways as these other organisms, model organisms can serve as powerful surrogates in the quest for understanding human biology and behavior. For example, certain biological processes, such as DNA replication, have been studied in detail in the single-celled organisms such as bacteria and yeast. In addition, the ability to manipulate particular genes of interest in relatively short developmental periods make worms and fruit flies powerful systems for studying normal and impaired developmental processes. Finally, as a mammalian relative, mice have served as an important system for generating animal models of human diseases and behavior. Researchers can introduce or alternatively "knock out" particular genes or cells to generate a physiological, behavioral, or disease "phenotype" of interest and examine the molecular basis for disease onset, progression, and treatment.


Advances in Basic Research Form the Building Blocks for Clinical Discovery and Improvements in Public Health

Progress in basic research does not necessarily follow a linear path from test tubes to cell culture to animal models as outlined above. Instead, basic research advances result from a continuum of collaborative interactions between research groups across multiple disciplines. The discovery of a gene that causes a diseased state in mice may spark the creation of research programs aimed at understanding the structural basis for how that gene’s protein product interacts with a partner molecule as well as cellular studies to elucidate a novel molecular pathway that they regulate to generate a biological response. Conversely, the visualization of a previously unknown protein structure may provide remarkable insight on the protein’s function and generate a hypothesis for how a particular mutation may generate a relevant disease model in mice. Regardless of the path taken to arrive at an incremental advance or a groundbreaking discovery, basic research lays the foundation for clinical advances that improve public health. At the heart of every clinical discovery is a body of fundamental basic knowledge that provides the impetus for setting forth a clinical hypothesis and generating the information required to safely and ethically proceed to testing in humans.

As an example of how advances in basic research build the foundation for clinical discovery and improvements in public health, NIH-supported investigators have recently discovered a novel approach for targeting the infectious bacterium Staphylococcus aureus; this is an important public health concern given the increasing resistance of S. aureus to conventional antibiotics. In 2005, a team of researchers discovered that the pigment molecule that gives S. aureus its golden color also serves to protect the bacteria from being killed by the human immune system following an infection.31 Having seen this result, another NIH-funded scientist, who studies how the human body makes cholesterol, observed that the protein and molecular machinery used to make the bacterial pigment molecule is very similar to that used to make cholesterol in humans; in fact, the first steps are nearly identical.32 Based on this observation, the two research teams, working together, went on in 2008 to demonstrate that cholesterol-lowering drugs that target a protein in humans also can be used to block S. aureus pigment synthesis.33 Moreover, when these drugs are administered to mice infected with S. aureus, the mice are better able to kill the bacteria and overcome the infection than mice that did not receive the drug. With basic, fundamental knowledge of the proteins and pathway used to make this bacterial "virulence factor," this group of scientists has gone on to design new molecules that are more effective at blocking pigment production and reducing S. aureus virulence.34 Having shown promising results in animal models, the years of collective, and initially unconnected, basic research that led to the development of this novel antimicrobial approach may offer a new strategy for reducing the public health burden of antibiotic-resistant S. aureus infection in humans.


31 Liu GY, et al. J Exp Med 2005:202(2):209-15. PMID: 16009720. PMCID: PMC2213009.
32 For more information, see http://www.nih.gov/news/health/feb2008/nigms-14.htm.
33 Liu CI, et al. Science 2008;319(5868):1391-4. PMID: 18276850. PMCID: PMC2747771.
34 Song Y, et al. J Med Chem 2009:52:3869-80. PMID: 19456099. PMCID: PMC2753857.


Summary of NIH Activities

NIH supports a comprehensive portfolio of molecular biology and basic research aimed at understanding fundamental life processes. The results of such studies provide insights on fundamental aspects of biology and lay the foundation for other studies that will lead to ways to extend healthy life and reduce the burdens of illness and disability. In fact, each new finding serves as a building block for establishing a deeper understanding of human health and disease.

NIH supports general basic research, as well as basic research focused within a specific area or context. For example, NIH supports studies aimed at understanding the immune system in general, such as a program to better define human immune responses to infection or vaccination,35 and also studies focused on understanding a particular aspect of the immune system, such as the immune response to specific pathogens (e.g., HIV, influenza virus, Mycobacterium tuberculosis) and immune-mediated diseases (e.g., allergies, type 1 diabetes, lupus, rheumatoid arthritis, primary immunodeficiency disorders).


35 For more information, see http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-09-040.html.


Model Organisms and Systems

Basic research using model systems and organisms has provided the foundation of knowledge on which much of what is known about human growth and development, behavior, and the maintenance of wellness and development of disease has been learned. Research on bacteria, yeast, insects, worms, fish, rodents, primates, and even plants has shown that the basic operating principles are nearly the same in all living organisms; therefore, a finding made in fruit flies or mice may shed light on a biological process in humans. The fundamental knowledge created through studies of model systems and organisms has led to new methods for maintaining health and diagnosing and treating disease. (Also see the section on Technology Development in Chapter 3).

When scientists discover that a particular gene is associated with a disease in humans, one of the first things they typically do is find out what that gene does in a model organism. This often provides important clues for understanding the cause of a disease and for developing potential treatments. NIH supports the development and distribution of collections of animal systems with defects in known genes. These can be used to investigate how a particular gene found to be associated with a particular disease affects development overall and disease susceptibility and progression. For example, the NIH-sponsored National Resource for Zebrafish, Drosophila Stock Center, and Caenorhabditis Genetics Center provide the research community with well-characterized wild-type (normal) and mutant zebrafish, fruit flies, and roundworms, respectively.

NIH supports the development and distribution of collections of animal systems with defects in known genes. These can be used to investigate how a gene that is associated with a particular disease affects disease susceptibility and progression.

Model organisms often are especially useful for clarifying medical problems that have similar molecular causes. For example, protein clumping defects are common to several neurological disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. Scientists can recreate these cellular defects in yeast, worms, and fruit flies, and then the findings can be translated into knowledge to benefit people with those diseases.

In addition to supporting studies of model organisms, NIH supports the development of a wide range of research models, particularly marine invertebrates and lower vertebrates, and the identification and development of new and improved animal models for the study of human diseases. For example, in 2008, NIH-funded researchers reported the development of a new mouse model for food allergy that mimics symptoms generated during a human allergic reaction to peanuts.36 The animal model provides a new research tool that will be invaluable in furthering the understanding of the causes of peanut and other food allergies and in finding new ways to treat and prevent their occurrence.

In 2008 NIH-funded researchers reported the development of a new mouse model for food allergy that mimics symptoms generated during a human allergic reaction to peanuts.

36 Ganeshan K, et al. J Allergy Clin Immunol 2009;123(1):231-238.e4. PMID: 19022495. PMCID: PMC2787105.


Molecular Mechanisms, Pathways, and Networks

In the human body, all biological components—from individual genes to entire organs—work together to promote normal development and sustain health. This amazing feat of biological teamwork is made possible by an array of intricate and interconnected pathways that facilitate communication among genes, molecules, and cells. While some of these biological pathways already have been discovered, many more remain to be found. Further research also is needed to understand how these pathways are integrated in humans and other complex organisms, as well as to determine how disturbances in these pathways may lead to disease and what might be done to restore disturbed pathways to their normal functions.

NIH supports a broad spectrum of research aimed at improving the molecular-level understanding of fundamental biological processes and discovering approaches to their control. In 2008, for example, NIH-supported researchers discovered that the activation of a novel set of proteins plays an important role in the development and persistence of chronic neuropathic pain conditions.37 This discovery points scientists toward new targets for possible interventions that block the development of chronic pain. In another advance supported by NIH during FYs 2008 and 2009, scientists discovered two molecules that are important for tumor formation in head and neck cancers.38 By uncovering how these molecules function in a key signaling pathway, scientists may be able to develop therapies that target them for the treatment of these devastating cancers. As in these studies, the goals of research supported by NIH in this area include an improved understanding of drug action; pharmacogenetics and mechanisms underlying individual responses to drugs; new methods and targets for drug discovery; advances in natural products synthesis; an enhanced understanding of biological catalysis; a greater knowledge of metabolic regulation and fundamental physiological processes; and the integration and application of basic physiological, pharmacological, and biochemical research to clinical issues.

NIH-supported researchers discovered that the activation of a novel set of proteins plays an important role in the development and persistence of chronic neuropathic pain conditions.

37 Kawasaki Y, et al. Nat Med 2008;14:331-6. PMID: 18264108. PMCID: PMC2279180.
38 Li J, Wang C-Y. Nat Cell Biol 2008;10(2):160-9. PMID: 18193033.


Cell and Molecular Biology

Growth and development is a life-long process that has many phases and functions. Much of the research in this area focuses on cellular, molecular, and developmental biology to build understanding of the mechanisms and interactions that guide a single fertilized egg through its development into a multicellular, highly organized adult organism. The eventual goal of these studies is to improve the diagnosis, treatment, cure, and prevention of human genetic and developmental disorders and diseases. (Also see the sections on Life Stage, Human Development, and Rehabilitation in Chapter 2 and Genomics in Chapter 3).

Just like a living creature, an individual cell has life stages. It is "born" (usually when its parent cell divides in two); it carries out its biological functions; it reproduces by dividing, often dozens of times; and it dies. Underlying these milestones are regular cycles, which can last from less than an hour to years or even decades. Progress through each cycle is governed by a precisely choreographed biochemical cascade involving a repertoire of molecules.

For the past several decades, NIH-supported researchers have conducted detailed studies of molecules that guide cells through division and development, methodically unraveling their biochemical identities and properties. The scientists have examined the molecules’ ebb and flow throughout the cell cycle and their eventual demise as they are chemically chewed up when their job is done—until generated again for the next cell cycle. As for most life processes, when the biochemical choreography goes awry, the result can be disastrous.

Glitches in the cell cycle can lead to a host of diseases, most notably cancer, which can be defined simply as uncontrolled cell division and the failure of programmed cell death. Scientists are poised to take advantage of the wealth of basic research on the cell cycle. They are testing scores of potential anticancer drugs that aim to bolster or block cell cycle molecules. For instance, researchers also are harnessing their knowledge of the cyclical fluctuations in cell cycle molecules to predict the aggressiveness of a cancer and to tailor treatments.


Stem Cells

Stem cells have the remarkable potential to develop into many different cell types in the body during early life and growth. In addition, in many tissues they serve as a sort of internal repair system, dividing essentially without limit to replenish other cells as long as the person or animal is still alive. When a stem cell divides, each new cell has the potential either to remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell.

Given their unique regenerative abilities, stem cells offer new potentials for treating diseases such as diabetes, heart disease, Parkinson’s disease, and Alzheimer’s disease. Today, donated organs and tissues often are used to replace ailing or destroyed tissue, but the need for transplantable tissues and organs far outweighs the available supply. Stem cells, directed to differentiate into specific cell types, offer the possibility of a renewable source of replacement cells and tissues to treat diseases. However, much work remains to be done in the laboratory and the clinic to understand how to use these cells for cell-based therapies to treat disease.

One particularly interesting research project on regenerative medicine involves a collaboration between NIH intramural researchers and scientists at Walter Reed Army Medical Center. Working together, in 2008, these scientists discovered that tissue removed from traumatic wounds, either to promote healing of orthopedic injuries or to treat war-related injuries, contain large numbers of progenitor cells that are capable of differentiating into bone, fat, and cartilage cells.39 Those cells could be used as a cell source for regenerative medicine therapies, and thereby avoid additional surgery to harvest stem cells from other sources.

During FYs 2008 and 2009, NIH funded multiple research projects on the basic biology of human embryonic stem cells (hESC) and has developed initiatives to support fundamental research on a new kind of stem cell, called an induced pluripotent stem cell (iPS). iPS cells are reprogrammed from adult cells to a pluripotent state remarkably like hESC. These reprogrammed cells offer a powerful approach to generating patient-specific stem cells that ultimately may be used in the clinic. (Also see the section on Ensuring Responsible Research in Chapter 1 for a summary of NIH activities concerning guidelines for the use of embryonic stem cells).

NIH has funded multiple research projects on the basic biology of human embryonic stem cells (hESC) and has developed initiatives to support fundamental research on a new kind of stem cell, called an induced pluripotent stem cell (iPS). iPS cells are reprogrammed from adult cells to a pluripotent state remarkably like hESC.

39 Nesti LJ, et al. J Bone Joint Surg Am 2008;90(11):2390-8. PMID: 18978407. PMCID: PMC2657299.


Basic Immunobiology and Inflammation

The human immune system is composed of a network of specialized cells that act together to defend the body against infection by organisms such as bacteria, viruses, and parasites, and also act to prevent cancer. Unfortunately, poorly regulated immune responses can result in the development of immune-mediated diseases that include asthma, allergy, and autoimmune syndromes such as rheumatoid arthritis, multiple sclerosis, type 1 diabetes, and inflammatory bowel disease. Furthermore, it is the immune system that is responsible for the rejection of transplanted organs and tissues, which imposes the need for strong drugs to prevent rejection in transplant patients. The lack of an immune response also can be very deleterious, thus increasing susceptibility to infection. Immunodeficiency disorders can be caused by inherited flaws in the immune system, as is the case with primary immunodeficiency diseases, and by pathogens such as HIV that destroy immune cells.

Although a great deal has been learned about how the immune system operates in both health and disease, there is still more to be learned that will lead to improved and novel methods to prevent or treat human disease. Thus, NIH supports basic science studies in immunobiology (the biology of the immune system) to provide a pipeline of potential new treatments and vaccines. Research in basic immunobiology focuses on the structural and functional properties of cells of the immune system and the proteins they secrete, the interactions of immune components with other physiological systems, and the processes by which appropriate immunoregulation (regulation of the immune system) is achieved to protect the body while still preventing immune attack on self tissues.

Inflammation is triggered by molecules secreted by immune cells. Acute inflammation is triggered by damage to tissue or cells, typically by pathogens or injury. Chronic inflammation has been implicated in the etiology of multiple diseases, including asthma, atherosclerosis, cancer, cardiovascular disorders, and neurodegenerative diseases. Although significant breakthroughs have occurred in our understanding of inflammation, research is needed to further understand inflammatory processes. NIH is funding research to uncover as-yet-unknown immune mechanisms and mediators of inflammation as well as genetic factors, environmental triggers, and the relationship of inflammation to disease.

One of NIH’s newer activities in this arena is the Center for Human Immunology, Autoimmunity, and Inflammation (CHI), a trans-NIH intramural initiative launched in 2008 to study the human immune system. Integrated teams of physicians and basic scientists are organized by CHI to perform research into immune pathophysiologies, the role of inflammation in a wide variety of disorders, and the translation of new knowledge into improvements in diagnosis and treatment of disease.

The Center for Human Immunology, Autoimmunity, and Inflammation is a trans-NIH intramural initiative launched in 2008 to study the human immune system. Integrated teams of physicians and basic scientists are organized to perform research into the role of inflammation in a wide variety of disorders.

"-Omics" Approaches

Technological advances have fundamentally changed the conduct of molecular biology, making it possible to rapidly obtain information on the entire complement of biomolecules within a cell or tissue. For example, it is now possible to measure the expression of all genes (transcriptome) in a cell or tissue in less than a day, something that would have taken months if not years, just a decade ago. These advances have led to the accumulation of large datasets that scientists sift through using statistical methods, or bioinformatics, to understand how networks of cellular components work in concert to produce a state of normal health and to identify the key players that go awry as a cause or result of disease. For example, scientists may now examine the entire genome of an organism to identify genes associated with a particular trait (e.g., susceptibility to disease, developmental stage, physical trait such as height) or to compare the proteome (i.e., the entire complement of proteins) of a specific cell type with those of another (e.g., Alzheimer’s brain cells vs. normal brain cells). This type of research is sometimes referred to as "hypothesis limited" because investigators cast a technological net to obtain information on the entire catalog of biomolecules within a cell or tissue before they set out to prove or disprove a specific hypothesis. (Also see the sections on Genomics; Disease Registries, Databases, and Biomedical Information Systems; and Technology Development in Chapter 3).

NIH has made a significant investment in genomics, transcriptomics, proteomics, and other types of "-omics" that seek to catalog a specific class or type of biomolecule, as well as bioinformatics and computational biology. This investment has led to an explosive growth in biological information, a rich resource that can be mined for clues about fundamental life processes, susceptibility to disease, and disease outcomes. This deluge of genomic information has, in turn, led to an absolute requirement for computerized databases to store, organize, and index the data and for specialized tools to view and analyze the data. NIH’s National Center for Biotechnology Information (NCBI) is charged with creating automated systems for storing and analyzing knowledge about molecular biology, biochemistry, and genetics; facilitating the use of such databases and software by the research and medical community; coordinating efforts to gather biotechnology information both nationally and internationally; and performing research into advanced methods of computer-based information processing for analyzing the structure and function of biologically important molecules. (Also see the section on Disease Registries, Databases, and Biomedical Information Systems in Chapter 3.) The following projects provide a rich array of examples of "-omics" research supported by NIH.


The Blueprint of Life: Genomics

As exemplified by the Human Genome Project, the field of genomics aims to understand how the entire genome, or genetic composition, of a cell or an organism contributes to define development, physiology, and disease. With a map of the human genome in hand, NIH continues to support research to understand how variations in the genetic sequence among individuals contribute to health and disease. Research in the area of pharmacogenomics seeks to understand the inherited variations in genes that dictate drug response and explores the ways these variations can be used to predict whether a patient will have a beneficial response to a drug, a poor or adverse response to a drug, or no response at all. (Also see the section on Genomics in Chapter 3).

Research in the area of pharmacogenomics seeks to understand the inherited variations in genes that dictate drug response and explores the ways these variations can be used to predict whether a patient will have a beneficial response to a drug, a poor or adverse response to a drug, or no response at all.

Genes Don’t Count for Everything: Epigenetics

While the genetic composition of an organism undoubtedly is an important determinant of health and disease, additional mechanisms are involved in interpreting the genome and guiding molecular, cellular, and developmental processes. In the emerging field of epigenetics, scientists are uncovering a complex code of chemical markers that influence whether genes are active or silent, independent of DNA sequence. While epigenetics refers to the study of a single gene or sets of genes, epigenomics refers to more global analyses of epigenetic changes across the entire genome. Epigenetic processes control normal growth and development and this process is disrupted in diseases such as cancer. Diet and exposure to environmental chemicals throughout all stages of human development, among other factors, can cause epigenetic changes that may turn certain genes on or off; research in animal models has revealed that particular parenting behaviors trigger epigenetic changes and alterations in physiological and behavioral function of offspring. Changes in genes that would normally protect against a disease, as a result, could make people more susceptible to developing that disease later in life. Researchers also believe some epigenetic changes can be passed on from generation to generation. NIH-funded scientists have demonstrated that epigenetic changes are associated with the development and growth of many types of tumors and several mental illnesses. In fact, epigenetic marks on a specific gene, the ribosomal RNA gene, have been associated with suicidal behavior. Moreover, in August 2008, NIH scientists uncovered the importance of a mammalian protein called Vezf1 in maintaining genomic integrity by regulating specific epigenetic marks on DNA at widespread sites in the genome.40

The NIH Roadmap Epigenomics Program, which in FYs 2008 and 2009 funded more than 2 dozen projects and consortia under a series of initiatives, aims to stimulate research on understanding the role of epigenetic regulation of gene expression in the origins of health and susceptibility to disease. It is anticipated that this program will transform biomedical research by developing comprehensive reference epigenome maps, identifying novel epigenetic marks, and developing new technologies for comprehensive epigenomic analyses. Ongoing epigenomic projects include studies on cognitive decline, atherosclerosis, and Bispenol A exposure.41


40 Gowher H, et al. Genes Dev 2008;22:2075-84. PMID: 18676812. PMCID: PMC2492749.
41 For more information, see http://nihroadmap.nih.gov/epigenomics/fundedresearch.asp.


We Are Not Alone: The Microbiome

In addition to understanding how human genes contribute to health and disease, NIH also is interested in understanding how bacteria affect human health. The body of a healthy human adult provides a home for an enormous bacterial ecosystem, with bacterial cells outnumbering human cells by a factor of 10 to 1. Despite misconceptions that often associate all bacteria with disease, most of the natural bacterial flora is composed of commensal—or beneficial—species that actually provide necessary cellular functions (such as the digestion of certain nutrients in the intestines). Through the NIH Roadmap, the Human Microbiome Project aims to discover the composition of microbial communities that exist in different parts of the human body and understand how these communities are associated with human health and disease. (Also see the section on Genomics in Chapter 3.)

The Human Microbiome Project aims to discover the composition of microbial communities that exist in different parts of the human body and understand how these communities are associated with human health and disease.

Translating the Genetic Code: Transcriptomics, Proteomics, and Metabolomics

Beyond understanding genes and their regulation, NIH also supports systemwide studies to understand what genes are actually turned on and off and when (transcriptomics). Since genes code for the proteins that carry out almost all cellular functions, understanding which genes are active and, by extension, the catalog of proteins carrying out cellular functions (proteomics) in a given cell type under particular sets of conditions, provides a picture of the molecular players involved in normal and disease states. In one example, NIH supported a comprehensive analysis of the salivary proteome—a catalog of all the proteins present in saliva. This initial description of the salivary proteome, published in 2008, provides a significant first step toward a comprehensive understanding of saliva function and provides a source of potential diagnostic and prognostic biomarkers for oral and systemic conditions.42 In the growing field of metabolomics, researchers are using high-throughput methodologies to characterize the types and amounts of metabolic compounds present in our cells and to map the metabolic pathways and networks through which they are generated and regulated. By studying the network of chemical pathways and their chemical products, these types of studies have the capability of defining normal homeostatic and disease mechanisms. In February 2009, NIH-supported investigators reported using metabolomics to identify metabolic compounds associated with the progression from benign prostate tissue to prostate cancer.43 Having identified pathways and compounds associated with disease progression, researchers can then use hypothesis-driven basic research experiments to further understand how particular proteins and molecules function in these pathways.

In February 2009, NIH-supported investigators reported using metabolomics to identify metabolic compounds associated with the progression from benign prostate tissue to prostate cancer.

42 Denny P, et al. J Proteome Res 2008;7(5):1994-2006. PMID: 18361515. PMCID: PMC2839126.
43 For more information, see http://www.nih.gov/news/research_matters/february2009/02232009cancer.htm.


Shape Matters: Structural Biology of Proteins

In addition to understanding the collective composition of proteins in a cell, researchers also aim to characterize their three-dimensional structures. The Structural Biology Roadmap is a strategic effort to create a "picture" gallery of the molecular shapes of proteins in the body. Of particular interest, NIH is focusing efforts on determining structures of the proteins that reside in the membrane barrier that separates the inside of the cell from the outside. These membrane proteins account for about 30 percent of the proteins in the cell and are major targets for developing therapeutic drugs to treat a particular disease by blocking, inhibiting, or activating the specific molecule. In a noteworthy example of structural advances made during FYs 2008 and 2009, NIH-supported scientists determined the three-dimensional structure of the β2-adrenergic receptor,44,45 an important target of pharmaceutical agents; knowledge of this structure adds to our fundamental understanding of how this class of proteins functions and provides insight on how to design new and improved drugs.


44 Shukla AK, et al. Mol Pharmacol 2008;73(5):1333-8. PMID: 18239031.
45 Rasmussen SG, et al. Nature 2007;450:383-7. PMID: 17952055.


The Sugar Coating: Glycomics

NIH is also interested in mapping out additional molecular compounds associated with cellular function. In one field, NIH is seeking to understand the role of glycans—complex chains of sugar molecules—in various cellular functions. Glycans often are found attached to the surface of cells and to proteins found on the cell surface, and they serve important roles in inflammation, arteriosclerosis, immune defects, neural development, and cancer metastasis. To advance the field of "glycomics," NIH supports programs that develop technologies for the analysis of glycans in complex biological systems and has established the Consortium for Functional Glycomics, which provides access to a technological infrastructure for glycobiology in support of basic research. Recent findings indicate that basic research on glycosylation may lead to the development of a broad spectrum antiviral. Over several years, NIH researchers discovered three antiviral proteins that bind to sugar groups commonly found on the surfaces of many viruses, which prevent the viruses from entering cells and reproducing. In 2009, investigators reported that one particularly potent antiviral protein, known as griffithsin (GRFT), appears to work well against SARS and Ebola viruses, as well as HIV.46 So far, GRFT has only been tested in animals and cell cultures, but results are promising.


46 Service RF. Science 2009;325(5945):1200. PMID: 19729635.


Putting It All Together with Systems Biology

With the increasing application of "-omics" and high-throughput technologies, scientists are generating massive amounts of data on the genetic and molecular basis of biological processes and responses. In an effort to put all of this information together across multiple scales, NIH researchers are turning to and pioneering the emerging field of systems biology. Systems biology draws on the expertise of biology, mathematics, engineering, and the physical sciences to integrate experimental data with computational approaches that generate models to describe complex biological systems. In addition to describing the interactions among genes, proteins, and metabolites, the models are intended to be predictive of physiological behavior in response to natural and artificial perturbations. By monitoring the effects of a perturbation in "virtual" experiments, scientists can generate hypotheses to test in cellular systems or model organisms and gain a better understanding of the molecular contributions to normal health and disease.

To support initiatives in this area, NIH has established National Centers for Systems Biology. At 10 interdisciplinary centers, NIH-funded scientists are using computational modeling and analysis to study the complex dynamics of molecular signaling and regulatory networks involved in cell proliferation, differentiation, and death; developmental pattern formation in organisms; genome organization and evolution; and drug effects on cells, organs, and tissues. The Program in Systems Immunology and Infectious Disease Modeling, a component of NIH’s intramural research program, seeks to apply a systems biology approach to characterize a complex biological system–the human immune system. In this effort, researchers are seeking to develop models that enhance our understanding of the molecular basis for an immune response to infection or vaccination. In another area of systems biology research, NIH supported the construction of a "metabolic network map" for the bacterium that causes severe, chronic periodontal disease.47 This model describes the metabolic properties of the bacterium and can be used to predict the effect of the loss of certain genes or metabolic pathways on bacterial growth rate. As the first model of this type for an oral pathogen, this metabolic network map provides opportunities to discover new antibacterial drug targets. Finally, the NIH Integrative Cancer Biology Program (ICBP) is providing new insights into the development and progression of cancer as a complex biological system. Researchers at ICBP Centers are generating and validating computational models that describe and simulate the complex process of cancer, which should ultimately lead to better cancer prevention, diagnostics, and therapeutics.

The Program in Systems Immunology and Infectious Disease Modeling in NIH’s intramural research program seeks to apply a systems biology approach to characterize a complex biological system–the human immune system.

47 Mazumdar V, et al. J Bacteriol 2008;191(1):74-90. PMID: 18931137. PMCID: PMC2612419.


Environmental Factors that Impinge on Human Health and Disease

Just as cells respond to changes in their microscopic environment, they also are responsible for sensing and responding to environmental factors present in our "macroscopic" human world. As part of its effort to reduce the burden of human illness and disability, NIH supports basic research efforts to understand how environmental factors are detected by our bodies and how, at the molecular and cellular levels, they influence the development and progression of human diseases. The National Toxicology Program (NTP), for example, is developing innovative methods to determine which of the many chemicals that humans are exposed to are toxic, with an aim of understanding how they impart their toxic effects on human cells. In another area, researchers at the Breast Cancer and the Environment Research Centers are using genomics and proteomics approaches to study the impact of chemicals in the environment on mammary gland development and are evaluating how environmental exposures affect important cell-cell interactions. NIH also has established research programs to investigate the relationship between exposure to heavy metals, such as mercury, in the environment and the progression and development of autoimmune disorders; understanding at the molecular level how these agents impart immune system dysfunction could offer potential therapeutic targets for treating these disorders.


Role of Basic Behavioral and Social Science Research

Recognizing the importance of behavioral and social factors in health and disease, NIH supports a broad portfolio of research in the basic behavioral and social sciences. Research in these areas provides fundamental knowledge and approaches that are essential for understanding individual and collective systems of behavior and psychosocial functioning; for predicting, preventing, and controlling illness; for developing more personalized (tailored) interventions; for enhancing adherence to treatment and minimizing the collateral impact of disease; and for promoting optimal health and well-being across the lifespan and over generations. Priority areas in basic behavioral and social sciences research include: gene-environment interactions; systems models and procedures for measurement, analysis, and classification; intergenerational transmission of behavior; biopsychosocial stress markers; and social integration and social capital.

At NIH, the mission of supporting basic behavioral and social science research is shared across ICs and OD Offices. To pursue shared opportunities and address common interests, NIH created the trans-NIH initiative known as the NIH Basic Behavioral and Social Science Opportunity Network (OppNet) in 2009. The purpose of OppNet is to pursue opportunities for strengthening basic behavioral and social sciences research while expanding and innovating beyond existing investments in these areas.

Basic behavioral and social sciences research supported by NIH is comprised of research on behavioral and social processes, biopsychosocial research, and research on methodology and measurement. Within the first category is research on behavior change, including the study of factors that shape health decision-making (e.g., cognitive, social, environmental, and developmental) and the conditions under which knowledge leads to action vs. inaction. Basic behavioral economic and decision research approaches—such as "choice architecture," which describes the way in which decisions are influenced by how the choices are presented, as well as the use of financial incentives to promote behavior change—are yielding findings that may be translated into effective interventions to change behavior and improve health. Basic research on social networks is improving our understanding of how smoking and obesity spread through socially connected individuals and provides insight into how networks might be used as vehicles to spread healthy behaviors.

Biopsychosocial research includes research on gene-environment interactions and other biobehavioral processes. The Exposure Biology Program of the NIH Genes, Environment and Health Initiative supports the development of tools to measure dietary intake, physical activity, psychosocial stress, and addictive substances—aspects of the behavioral and social environment—in addition to tools to measure environmental pollutants, for future use in studies of gene-environment interactions. Biopsychosocial research in humans and rodent models is elucidating how psychosocial stressors influence biological pathways involved in the growth and spread of cancer. Knowledge gained from biopsychosocial research will inform interventions to prevent, manage, and treat a variety of diseases and disorders.

The Exposure Biology Program of the NIH Genes, Environment and Health Initiative supports the development of tools to measure dietary intake, physical activity, psychosocial stress, and addictive substances—aspects of the behavioral and social environment—in addition to tools to measure environmental pollutants, for future use in studies of gene-environment interactions.

Methodological development in the behavioral and social sciences includes a new emphasis on systems science approaches. Much like the systems approaches to biology described above, systems science examines the multilevel, complex interrelationships among the many determinants of health—biological, behavioral, and social—to provide a way to address complex problems within the framework of the "big picture." Systems science involves developing computational models to examine the dynamic interrelationships of variables at multiple levels of analysis (e.g., from cells to society) simultaneously (often through causal feedback processes), while also studying impact on the behavior of the system as a whole over time. For instance, systems science methodologies are beginning to be employed for planning and preparing against acute threats to public health such as global spread of a pandemic influenza. The Models of Infectious Disease Agent Study (MIDAS) is a collaboration of seven multi-institutional research and informatics groups focused on developing computational models of the interactions between infectious agents and their hosts, disease spread, prediction systems, and response strategies. The models will be useful to policymakers, public health workers, and other researchers who want to better understand and respond to emerging infectious diseases. Chronic diseases and risk factors for which systems science approaches would enhance our understanding and decision-making capacity include heart disease, diabetes, obesity, high blood pressure, eating behavior, physical activity, smoking, and drug and alcohol use.


Research Resources, Infrastructure, and Technology Development

In building the foundation for its broad portfolio of basic research programs, NIH also makes significant investments in the development of research resources, infrastructure, and state-of-the-art technologies that facilitate the next discoveries in biomedical and behavioral research. In line with its interest to ensure that research resources developed with NIH funding are made readily available to the research community for further research, NIH supports multiple repositories for the collection and dissemination of animal models, cell lines, and other vital biomedical research reagents. Repositories are updated continuously as resources become available and include the Mutant Mouse Regional Resource Centers, which stores, maintains, and distributes selected lines of genetically engineered mice; the National Stem Cell Bank, which makes human embryonic stem cell lines readily available; and the Beta Cell Biology Consortium, which generates animal models and antibodies that are available to the scientific community for research on type 1 and type 2 diabetes.

In addition to animal models and research reagents, NIH also supports the distribution of massive amounts of genome sequence, transcriptional profiling, and cellular structure function data for use and analysis by the research community at large. NIH continues to serve as a leading global resource for building, curating, and providing sophisticated access to molecular biology and genomic information. This includes databases such as Genbank, a collection of nearly all known DNA sequences that also provides access to the assembled Human Genome Project data. In addition to databases, NIH also provides resources for retrieving, visualizing, and analyzing molecular biology and genome sequence data online. Other examples of data sharing resources include the Biomedical Informatics Research Network, which supports the integration of data, expertise, and unique technologies to advance research on Alzheimer’s disease, autism, and other areas of neuroscience; and the Influenza Virus Resource,which provides a database of influenza virus genome sequences that may help researchers identify potential therapeutic, diagnostic, and vaccine targets. Together, it is expected that the timely sharing of research resources and data housed in these and other databases will further the research enterprise for the betterment of public health. (Also see the section on Disease Registries, Databases, and Biomedical Information Systems in Chapter 3).

NIH continues to support the Shared Instrumentation and High End Instrumentation Grant Programs to ensure that NIH-supported investigators have access to state-of-the-art technologies necessary to fulfill their research goals.

NIH continues to support the development and maintenance of our Nation’s research infrastructure. Since many areas of biomedical research require the use of sophisticated instrumentation, NIH continues to support the Shared Instrumentation and High End Instrumentation Grant Programs to ensure that NIH-supported investigators have access to state-of-the-art technologies necessary to fulfill their research goals. Critical to this infrastructure is support for biocontainment laboratories that allow scientists to study highly contagious, life-threatening pathogens in a safe and secure setting. NIH also continuously seeks to improve the current "state-of-the-art" in different technology areas. This is highlighted by the NIH-supported Biomedical Technology Research Centers that develop innovative technologies to aid researchers who are studying virtually every human disease. (Also see the section on Technology Development in Chapter 3.)


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

IC acronyms in bold face indicate lead IC(s)

Model Organisms and Systems

Zebrafish Help Scientists Identify Susceptibility Genes for Hearing and Balance Loss, and Drugs that May Prevent It: The sensory hair cells in the inner ear are topped with tiny, hair-like projections that detect sound or head position and movement (important for maintaining balance). Individuals demonstrate varying susceptibility to hair cell damage, which can be due to exposure to certain antibiotics, chemotherapy, other chemical agents; prolonged exposure to loud sounds; and in aging. Hair cell damage leads to hearing and balance disorders. Scientists working to understand the reason for this variability in susceptibility have used the zebrafish lateral line to model human hair cell damage. The lateral line on the fish's side contains sensory cells that detect the fish's position and motion in water. Hair cells in the lateral line function similarly to the hair cells in the human inner ear, and NIH-supported scientists exploited this to develop an important screening system. After generating fish with random mutations, the scientists subjected the mutant fish's exposed sensory cells to a potentially damaging antibiotic drug. By identifying the specific genetic mutations present in the fish and noting how the lateral line was affected by the antibiotic insult, the scientists are beginning to understand which genetic variations may be important for hearing and balance damage susceptibility. They also used the zebrafish model to study the effects of antibiotic insult combined with treatment using potentially protective substances to identify substances that seem to protect the sensory cells from damage—thus preventing potential hearing and balance disorders. The insight gained may help scientists develop personalized treatments based upon an individual's genetic makeup, and may enable prevention of some hearing and balance disorders via careful administration of protective drugs. These approaches increasingly will become important as the Nation's health care system faces the challenge of treating the aging Baby Boomer generation, many of whom already have hearing and balance problems.
  • Owens KN, et al. PLoS Genet 2008;4(2):e1000020. PMID: 18454195. PMCID: PMC2265478.
  • (E) (NIDCD)
Researchers Discover Why Mammalian Teeth Form in a Single Row: Why do mammals develop a single row of teeth whereas other vertebrates, such as sharks, can develop multiple rows of teeth? Researchers studying mutations in the genes of mice that develop teeth serving no apparent function may have solved the mystery. Most of the mutations under study caused the mice to develop the extra teeth within the space between the normal incisor and the normal first molar. Since tooth buds normally develop within this part of the developmental field but later regress, these genetic alterations did not alter the normal plane within which teeth developed. However, one particular mutation had a different result. The researchers found that a knockout mutation (i.e., elimination) of a gene known as Odd-skipped related 2 (Osr2) also resulted in the production of extra teeth, but strikingly, these teeth developed outside the usual plane, on the tongue side of the normal molars, suggesting that the mutation results in an expansion of this developmental field in the affected mice. Supporting this theory, the knockout mice (i.e., mice lacking Osr2) have spatially expanded expression of other genes involved in tooth development. That suggests that normal Osr2 acts to restrict tooth development to within its usual, single-row plane. Previous work from this group discovered the Osr2 gene and demonstrated that it is a novel regulator of palate formation. The current study demonstrates that Osr2 function also is critical to the patterning of tooth formation and sheds light on the restriction of teeth to a single row in mammals. Osr2 function may be an important consideration for researchers seeking to grow replacements eventually for lost teeth in adults.

Molecular Mechanisms, Pathways and Networks

New Method to Synthesize Molecules: During the past year, NIH-supported researchers discovered a new method for the preparation of a small heterocyclic molecule containing three rings that was completely unprecedented in the literature. The discovery of a ready access to novel heterocyclic scaffolds is a key contribution to innovative pharmaceutical research. Seventy analogs of this new molecule were made, and biological studies revealed potent and selective activities at G-protein coupled receptors, a biological target that accounts currently for approximately 50 percent of all new drugs.
  • Walczak MA, Wipf P. J Am Chem Soc 2008;130 (22):6924-5. PMID: 18461936. PMCID: PMC2754197.
  • (E) (NIGMS) (GPRA)
Evolutionary Analysis of Protein Domains: A group of investigators at NIH employ the latest techniques in the field of computational biology to study fundamental biological problems such as molecular evolution. Elucidating the biochemical and biological functions of protein domains is central to understanding basic life processes. (A "protein domain" is a discrete section of a protein that has its own function and can evolve independently.) Computer simulations, based on evolutionary principles, are used for the discovery, classification, evolutionary analysis, and biochemical predictions of protein domains and domain architectures. An important dimension in this type of research is discovery of "new" domains that are shared by many diverse proteins but have not been defined previously. An example of this research is the prediction of the function of the DBC1 gene, which is deleted in a prevalent form of breast cancer. Analysis of the complex domain architectures of the members of the DBC1 family suggest that they are likely to function as integrators of distinct regulatory signals, and the findings also suggest the possibility for developing new therapeutics based on soluble small molecules.
  • Anantharaman V, Aravind L. Cell Cycle 2008;7(10):1467-72. PMID: 18418069. PMCID: PMC2423810.
  • (I) (NLM)
New Targets Identified for Intervention in the Development of Head and Neck Cancers: Over the last decade, cancer researchers have made significant progress in defining the molecular pathways involved in the development of head and neck squamous cell cancer. Studies that identify and characterize "key players" hold tremendous promise for the future treatment of these devastating cancers and ultimately improve the overall survival and quality-of-life for afflicted patients. One such key player is a family of proteins known as Wnt. Aberrant activation of the Wnt pathway has been found to be associated with cancer development and progression. Wnt promotes initiation of cancer by increasing the nuclear accumulation of ß-catenin, an integral component of Wnt signaling, to activate target genes downstream. However, the mechanism of ß-catenin recruitment to the Wnt target gene promoter largely is unknown. In an elegant study, the researchers discovered that ß-catenin interacted with two other molecules (commonly called TBL1 and TBLR1), leading to the recruitment of ß-catenin to the promoter of Wnt target genes. Decreasing TBL1 or TBLR1 via genetic knock-down did not affect the nuclear accumulation of ß-catenin, but it did inhibit ß-catenin significantly from binding to Wnt target gene promoter and the expression of Wnt target genes associated with tumor development. Moreover, depletion of TBL1 or TBLR1 inhibited invasive growth of tumor cells. These results provide fundamental knowledge about tumor genesis by revealing two new components required for nuclear ß-catenin function. Targeting these molecules can have important therapeutic implications for head and neck cancer.
  • Li J, Wang C-Y. Nat Cell Biol 2008;10(2):160-9. PMID: 18193033.
  • This example also appears in Chapter 2: Cancer and Chapter 3: Technology Development
  • (E) (NIDCR)
New Model Reveals Novel Molecular Strategies in the Fight to Overcome Oral Cancer: Oral and pharyngeal carcinomas are the ninth most common cancer worldwide, with more than 35,000 new patients and more than 7,500 deaths each year in the United States alone. The 5-year survival rate has improved only marginally over the past 40 years. There is an urgent need for new options for these patients. Emerging information on the deregulation of normal molecular mechanisms that result in the cancer's progression provides the possibility of new mechanisms-based therapeutic approaches for these aggressive oral malignancies. NIH scientists recently used a two-step chemical carcinogenesis model and found that the drug rapamycin exerted a remarkable anticancer activity. It decreased the tumor burden of mice having early and advanced tumors, and even brought about the regression of recurrent squamous cell skin cancers. The scientists reported that the persistent activation of mTOR, the mammalian Target of Rapamycin, occurs frequently in head and neck cancer patients and that its inhibition by rapamycin causes regression of human oral cancer tumors implanted in mice. Because chemically induced animal cancer models often better reflect the complexity of the clinical setting, the scientists developed an oral-specific chemical carcinogenesis mouse model. In this model, activation of mTOR is an early event in precancerous lesions; rapamycin treatment can halt the malignant conversion of precancerous lesions and promote the regression of advanced carcinogen-induced oral squamous cell carcinomas (SSCs). Significance: The development of this SCC carcinogenesis model demonstrates that the use of mTOR inhibitors may provide a novel molecular-targeted strategy for chemoprevention and treatment of oral squamous cell cancer.
  • Amornphimoltham A, et al. Clin Cancer Res 2008;14(24):8094-101. PMID: 19073969.
    Czerninski R, et al. Cancer Prevention Res 2009;2(1):27-36. PMID: 19139015.
  • For more information, see  http://www.nidcr.nih.gov/DataStatistics/FindDataByTopic/OralCancer/
  • This example also appears in Chapter 2: Cancer and Chapter 3: Technology Development
  • (I) (NIDCR)
Tumor Biology, Microenvironment, and Metastasis: The Tumor Biology and Metastasis Program supports research delineating the molecular mechanisms and signaling pathways involved in tumor progression, cell migration and invasion, angiogenesis (growth of blood vessels), lymphangiogenesis (formation of lymphatic vessels), and metastasis. Novel areas of research include the contributions of bone marrow-derived cells to tumor formation, progression, and metastasis; the role of dormant cells and their microenvironment; the role of host tissue microenvironment in organ-specific metastasis; characterization of the heterogeneity within the tumor microenvironment; and the characterization of cancer as a systemic disease. The Tumor Microenvironment Network (TMEN) investigates mechanisms of tumor-stroma interactions in human cancer. (Stroma is the connective tissue that supports or surrounds other tissues and organs.) In addition to delineating the role of host stroma in carcinogenesis, TMEN investigators are generating novel reagents that can be shared with the research community. The Cancer Immunology/Hematology Program supports research on the cellular and molecular characterization of tumor stem cells, which are minor populations of tumor cells that may be responsible for recapitulating all the cell types in a given tumor and causing metastasis due to their unique self-renewal properties. In FY 2008, NIH sponsored two RFAs on tumor stem cells aimed at enhancing synergistic research between basic scientists and translational scientists working on tumor stem cells. In addition, a program announcement for Stem Cells and Cancer was released to stimulate efforts to isolate and characterize tumor stem cells from a large spectrum of tumors to understand better the progression of malignant disease.
Glucosamine and Chondroitin Fare No Better Than Placebo in Slowing Structural Damage of Knee Osteoarthritis: Osteoarthritis affects an estimated 27 million Americans, and researchers are seeking ways not only to treat pain, but also to address the loss of cartilage—a hallmark of the condition. The two-part Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), funded by NIH, investigated whether this dietary supplement can treat pain and diminish structural damage associated with knee osteoarthritis. In the primary study (GAIT I), combined glucosamine/chondroitin sulfate did not provide significant relief among study participants overall, although a smaller subgroup with moderate to severe pain did show significant relief. The 18-month GAIT II ancillary study followed cartilage loss in GAIT participants with moderate or severe osteoarthritis in one or both knees, comparing the effects of glucosamine and/or chondroitin sulfate with placebo. In GAIT II, glucosamine and chondroitin—together or alone—appeared to fare no better than a placebo in slowing loss of cartilage in osteoarthritis of the knee, measured by joint space width as seen on x-rays. Interpreting the study results is complicated, however, because participants taking placebo had a smaller loss of cartilage than predicted. In addition to its findings on the effects of dietary supplements taken by many Americans for osteoarthritis, GAIT II provided new insights on osteoarthritis progression, techniques for measuring loss of joint space width, and characteristics of osteoarthritis patients who may respond best to glucosamine/chondroitin.
  • Sawitzke AD, et al. Arthritis Rheum 2008;58(10):3183-91. PMID: 18821708.
  • For more information, see  http://nccam.nih.gov/news/2008/092908.htm
  • This example also appears in Chapter 2: Chronic Diseases and Organ Systems
  • (E) (NCCAM, NIAMS)
Promising Approaches to Treating Chronic Pain: Opioid analgesics are the most powerful pain medications currently available; unfortunately, they can result in addiction, tolerance, and physical dependence, all of which may undercut their value in some patients. Thus, an area of enormous need is the development of potent analgesics with diminished abuse liability for treating chronic pain. In response, NIH has implemented an aggressive and multidisciplinary research program that is yielding tangible results, which stand to revolutionize the field of pain management. At the molecular level, cannabinoid (CB) research has shown that it is possible to activate the CB system selectively to provide analgesia with minimal or no effects on mental function, and no abuse liability. New findings in basic pharmacology reveal previously unrecognized complexity emerging from the natural mixing of different (heteromeric) receptors. Targeting them could provide a vastly expanded range of pharmacotherapeutics. 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 non-neuronal brain cells 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 other 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.
  • Varga EV, et al. Curr Mol Pharmacol 2008;1(3):273-84. PMID: 20021440.
    Ferre S, et al. Trends Neurosci 2007;30(9):440-6. PMID: 17692396.
    Daniels DJ, et al. Proc Natl Acad Sci U S A 2005;102(52):19208-13. PMID: 16365317. PMCID: PMC1323165.
    Ledeboer A, et al. Expert Opin Investig Drugs 2007;16(7):935-50. PMID: 17594181.
    deCharms RC. Trends Cogn Sci 2007;11(11):473-81. PMID: 17988931.
  • This example also appears in Chapter 2: Neuroscience and Disorders of the Nervous System and Chapter 2: Chronic Diseases and Organ Systems
  • (E) (NIDA, NINDS)
Peripheral Neuropathies: NIH funds studies focused on understanding the genetic basis and molecular and cellular mechanisms of many peripheral neuropathies, including diabetic neuropathy, HIV/AIDS-related and other infectious neuropathies, inherited neuropathies such as Charcot-Marie-Tooth, inflammatory neuropathies such as chronic inflammatory demyelinating polyneuropathy, and rare forms of peripheral neuropathy. Other notable projects include a natural history study of diabetic neuropathy, projects to improve the efficiency and effectiveness of diagnosis for various peripheral neuropathies, and a Phase III clinical trial to treat Familial Amyloidotic Polyneuropathy. In August 2008, a pair of program announcements was released to promote translational research in neuromuscular disease. Diseases included in these program announcements are those that affect the motor unit—the motoneuron, its process (axon), and the skeletal muscle fiber that is innervated by the neuron—such as peripheral neuropathy, amyotrophic lateral sclerosis, and muscular dystrophy. This unique structure-function framework provides a coordinated approach for therapeutic development in a subset of neurological diseases that share many common features, including the peripheral neuropathies.
Understanding the Roles of Non-Neuronal Cells in Neuropathic Pain Provides New Targets for Intervention: Chronic pain caused by nerve injury, called neuropathic pain, is difficult to treat because we do not yet fully understand the biological mechanisms underlying its development and persistence. Most pain-relieving medications for chronic pain target nerve cells, yet it is becoming clear that non-nerve (non-conducting) cells also play an important role in some chronic pain conditions. Matrix metalloproteases (MMPs) are enzymes that break down the medium surrounding tissue cells. MMPs also activate several pro-inflammatory proteins that stimulate the non-nerve conducting function of of the supportive glial cell. Scientists are wondering if neuropathic pain and inflammation are linked by a common mechanism involving MMP activation. Researchers found that a specific matrix metalloprotease, MMP9, showed increased activity soon after nerve injury, which stimulated the glial cells in the spinal cord, but this increased activity declined after several days. A different enzyme, MMP2, also was increased, but at later times after injury; this increase led to activation of another nerve-supportive cell in the spinal cord. The research showed that the pain response of nerve-injured animals were blocked early by inhibitors of MMP9 or later by inhibitors of MMP2. These findings suggest an important role for MMP9 in the onset of chronic neuropathic pain conditions, and for MMP2 in the persistence of those conditions. The results also demonstrate the complex interplay between nerve cells and several non-nerve cells. This research describes a novel set of molecules involved in neuropathic pain, and points scientists toward new targets for possible interventions to short-circuit the onset and persistence of chronic pain conditions.
  • Kawasaki Y, et al. Nat Med 2008;14(3):331-6. PMID: 18264108. PMCID: PMC2279180.
  • This example also appears in Chapter 2: Neuroscience and Disorders of the Nervous System and Chapter 2: Chronic Diseases and Organ Systems
  • (E) (NIDCR)
From Genes to Therapy in Neurogenetic Disorders: Neurofibromatosis (NF) and tuberous sclerosis complex (TSC) are neurogenetic disorders that cause tumors on nerves, in the brain, and on other organs. Although the tumors are benign, consequences of their size and location can be serious. Clinical manifestations can include seizures, autism, and cognitive disability. NIH support led to identification of the genes underlying these disorders, and recently has enabled investigators to uncover disease mechanisms that point to strategies for therapeutic development. One NF study revealed that an NF1 gene mutation in bone marrow cells (which infiltrate peripheral nerves prior to NF tumor development) is necessary for tumor growth. Activation of c-kit, a molecule implicated in some cancers and targeted by the cancer drug Gleevec, enables release of the cells from bone marrow to stimulate neurofibroma growth. In this study, Gleevec treatment prevented formation and reduced neurofibroma size and activity. If clinical trials prove successful, Gleevec could become the first approved NF treatment. In TSC, genetic mutations cause deregulation of an anti-tumor molecule, mTOR, which is a known target of rapamycin (a drug currently used to treat organ transplant rejection). In previous studies, rapamycin reduced the size of brain and kidney tumors in TSC patients. Recent NIH-supported research in mice revealed that rapamycin, via the mTOR pathway, inhibited TSC-induced brain enlargement and mortality, prevented seizures, and improved cognitive ability in mice, results which have led to clinical trials now in Phase III. Rapamycin also alleviated seizures in a rat model of epilepsy, which may shed light on TSC-associated neurological diseases, including autism and epilepsy.
  • Ehninger D, et al. Nat Med 2008;14(8):843-8. PMID: 18568033. PMCID: PMC2664098.
    Meikle L, et al. J Neurosci 2008;28(21):5422-32. PMID: 18495876. PMCID: PMC2633923.
    Yang FC, et al. Cell 2008;135(3):437-48. PMID: 18984156. PMCID: PMC2788814. 
    Zeng LH, et al. J Neurosci 2009;29(21):6964-72. PMID: 19474323. PMCID: PMC2727061.
    Zeng LH, et al. Ann Neurol 2008;63(4): 444-53. PMID: 18389497.
  • This example also appears in Chapter 2: Neuroscience and Disorders of the Nervous System
  • (E) (NINDS, NCI, NICHD, NIMH)
Insights into the Molecular Interplay Governing Formation of Cranial Sensory Ganglia: The developmental biology underlying sensory nerve development is fascinatingly intriguing. Take the trigeminal ganglion, which is responsible for touch, pain, and temperature sensation for most of the face. How do precursor cells self-organize in the embryo to produce an anatomically correct sensory network connecting to the central nervous system? Many of the answers are wired into the molecular circuitry of two transient embryonic cell types called neural crest cells and ectodermal placodes. They interact during embryonic development to differentiate into the nerve cells that form the trigeminal ganglion. But virtually nothing is known about the molecular interplay that mediates this interaction. It is a biological puzzle with no known pieces. Now NIH grantees have introduced the first two pieces of the puzzle. They demonstrated in animal studies that the cranial subtype of neural crest cells express the protein Slit1 on their surface during their programmed migration to the trigeminal-forming ectodermal placodes. Meanwhile, as the trigeminal placode cells follow their developmental program, they express on their surface the Robo2 protein, which is the receptor for the Slit1 protein. The Robo2-Slit1 connection, like fitting a hand in a glove, mediates the interaction of neural crest and trigeminal placode cells during the formation of sensory ganglia. When the scientists disrupted one or both molecular signals, the resulting sensory ganglia were abnormal. The teams' findings are important to understanding the mechanisms that regulate formation of the sensory nervous system and thus provide potential targets for identifying the causes of congenital sensory disorders involving the neural crest cell population.
Neurobiology of Appetite Control: NIH supports research to elucidate the complex biologic pathways that converge in the brain to regulate appetite. For example, the sight of food has been found to induce different responses in the brains of patients following weight loss; these differences are due to changes in levels of the hormone leptin. Researchers also discovered that rats susceptible to becoming obese from a high-calorie diet have fewer neural connections in the brain in the hypothalamus (the part of the brain that has a key role in weight regulation) compared to normal rats. Additionally, a factor secreted by the small intestine in response to dietary fat intake has been found to enter the brain and suppress appetite in rats. More recently, six new genetic regions associated with obesity were identified and found to be in or near genes expressed in the brain. To highlight further the connection between brain function and obesity, a trans-NIH workshop on neuroimaging in obesity research was held to share data and experiences with functional neuroimaging approaches to study brain involvement in various aspects of obesity such as weight gain and loss, and the neurotransmitters and brain structures associated with energy balance, hunger, and decision-making. A recent funding opportunity announcement was issued to foster new research using neuroimaging approaches to enhance understanding of food intake and energy expenditure in the context of obesity. This research has implications for new therapies for obesity.
  • Rosenbaum M, et al. J Clin Invest 2008;118(7):2583-91. PMID: 18568078. PMCID: PMC2430499.
    Bouret SG, et al. Cell Metab 2008;7:7(2):179-85.PMID: 18249177. PMCID: PMC2442478.
    Gillum MP, et al. Cell 2008;135(5):813-24.PMID: 19041747. PMCID: PMC2643061.
    Willer CJ, et al. Nat Genet 2009;41(1):25-34. PMID: 19079261. PMCID: PMC2695662.
  • For more information, see  http://www3.niddk.nih.gov/fund/other/neuroimaging2008/
  • For more information, see  http://grants.nih.gov/grants/guide/rfa-files/rfa-dk-08-009.html
  • This example also appears in Chapter 2: Neuroscience and Disorders of the Nervous System and Chapter 2: Chronic Diseases and Organ Systems
  • (E) (NIDDK)
Not Only In Your Mouth—Your Gut Can Taste, Too: Sugars consumed in food affect blood sugar levels differently than sugars given intravenously. Scientists have been examining sugar-binding molecules in the gut lining to determine why this happens. While the tongue has been known as the taste organ of the body, NIH-funded scientists recently have identified taste receptors in the human gut. Their data suggest that the human gut detects sugars in food through these taste receptors, and uses this information to turn up the production of blood sugar-regulation hormones, including the hormone that regulates insulin release. Individuals that have difficulty detecting and regulating sugar can gain weight more easily and/or develop other metabolic problems, including diabetes. The discovery of taste receptors in the lining of the gut may help scientists develop drugs that are specific to the gut taste receptors to treat weight problems and diabetes, two very significant public health issues.
  • Jang HJ, et al. Natl Acad Sci USA 2007;104(38):15069-74. PMID: 17724330. PMCID: PMC1986614.
    Margolskee RF, et al. Proc Natl Acad Sci USA 2007;104(38):15075-80. PMID: 17724332. PMCID: PMC1986615.
  • (E/I) (NIDCD, NIA)
Grape Seed Extract May Help Neurodegenerative Diseases: Tauopathies—a group of neurodegenerative conditions such as Alzheimer's disease—have been linked to the build-up of "misfolded" tau proteins in the brain. (Tau proteins are associated with microtubules, which help to regulate important cellular processes.) In light of previous studies indicating that grape-derived polyphenols may inhibit protein misfolding, an NIH-funded research center examined the potential role of a particular grape seed polyphenol extract (GSPE) in preventing and treating tau-associated neurodegenerative disorders. In one study, the researchers found that this GSPE reduced Alzheimer's-type neuropathology and cognitive decline in a mouse model of Alzheimer's disease and inhibited an Alzheimer's-linked process called cerebral amyloid deposition. In another study, the researchers used a variety of analytical techniques to clarify further how the GSPE produces its effects. The results of their preclinical study showed that GSPE interferes with the generation of tau protein aggregates and also disassociates preformed aggregates. Thus, GSPE may affect processes critical to the onset and progression of neurodegeneration and cognitive dysfunctions in tauopathies. The studies' findings, together with indications that this GSPE is likely to be safe and well-tolerated in people, support further exploration and development of GSPE as a therapy for Alzheimer's disease.
  • Ho L, et al. J Alzheimers Dis 2009;16(2):433-9. PMID: 19221432. PMCID: PMC2800939.
    Ono K, et al. J Biol Chem 2008;283(47):32176-87. PMID: 18815129. PMCID: PMC2583320.
    Wang J, et al. J Neurosci 2008 Jun 18;28(25):6388-92. PMID: 18562609. PMCID: PMC2806059.
  • For more information, see  http://nccam.nih.gov/research/results/spotlight/031209.htm
  • This example also appears in Chapter 2: Neuroscience and Disorders of the Nervous System
  • (E) (NCCAM)

Cell and Molecular Biology

Basic Research on Human Embryonic Stem Cells: Research on human embryonic stem cells (hESC) promises to elucidate critical events in early human development and may revolutionize customized regenerative medicine. Since FY 2007, NIH has funded five Program Projects on the basic biology of hESC and has developed initiatives to support fundamental research on a new kind of stem cell, called induced pluripotent stem cells (iPS). iPS cells are reprogrammed from adult cells to a pluripotent state remarkably like hESC. These reprogrammed cells offer a powerful approach to generating patient specific stem cells that ultimately may be used in the clinic. NIH sponsored the third in a series of workshops on research and future directions in human embryonic stem cell research in September 2009.
Scientists Demonstrate Hematopoietic Stem Cells' Role in Forming the Stem Cell Niche: Stem cells are important in all multicellular organisms because they have the ability to develop into different kinds of specialized cells. Outside of the organism, researchers can grow stem cells in specific cultures and observe the development of specialized cells. Blood-forming stem cells, known as hematopoietic stem cells (HSCs), are controlled by the hematopoietic stem cell niche, which is located in the bone marrow. Bone-forming cells called osteoblasts are known to play a central role in establishing the HSC niche; however, it is unclear whether HSCs in turn control the differentiation of stem cells that become osteoblasts. Although such interactions in the niche have been proposed, at present there is insufficient direct experimental evidence to define the relationship between HSCs and osteoblast formation. In this work, a group of investigators addressed the role of HSCs in the differentiation of osteoblasts. Using mice, they co-cultured HSCs with stem cells that become osteoblasts, and demonstrated that HSCs can indeed affect the differentiation of cells into osteoblasts. Further, the investigators found that the specialization or differentiation into osteoblasts could be influenced by the age and physical condition of the mice. These findings suggest that HSCs may serve as an important therapeutic target for controlling bone formation and repair. In particular, it should be possible to develop therapeutic agents that specifically target HSCs for treatment of a variety of bone defect such as osteoporosis, nonhealing bone and tooth defects, and congenital bone abnormalities.
  • Jung Y, et al. Stem Cells 2008;26(8):2042-51. PMID: 18499897.
  • This example also appears in Chapter 2: Chronic Diseases and Organ Systems and Chapter 2: Life Stages, Human Development, and Rehabilitation
  • (E) (NIDCR)
Stem Cells and Regenerative Medicine: Stem cells are able to renew themselves and generate progeny that differentiate into more specialized cells. They play critical roles in organism development, and some are essential for normal homeostasis and tissue repair. NIH has made a significant investment in stem cell research. One NIH-supported study showed that the sex of cells in a subpopulation of muscle-generating stem cells in adult mice can influence their capacity to repair tissue considerably. This finding could lead to future therapies for various diseases, including muscular dystrophy. A collaboration between NIH Intramural researchers and those at Walter Reed Army Medical Center discovered that waste tissues from surgery, removed to promote healing of orthopaedic injuries and war-traumatized muscle, contain large numbers of progenitor cells that are capable of differentiating into bone, fat, and cartilage cells. They could be used as a cell source for regenerative medicine therapies, and thereby avoid additional surgery to harvest cells. NIH has partnered with the Department of Defense on an initiative to speed treatments to wounded soldiers abroad, and civilian trauma victims and burn patients in the United States. This collaboration has resulted in the establishment of the new Armed Forces Institute of Regenerative Medicine (AFIRM). The AFIRM-led program will focus on regrowing fingers, repairing shattered bones, and restoring skin to burn victims with genetically matched skin, to pave the way for commercial products in the near future. Hair follicles are useful models for organ regeneration. Recent discoveries have been made in the molecular processes that govern the growth of hair follicle stem cells, which are a source for newly formed hair follicles.
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. Since 2002, 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 actively is 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 the hESCs eligible for Federal funding under prior presidential policy, established a National Stem Cell Bank to make these hESC lines readily available, developed training courses to teach stem cell culture techniques, and encouraged new investigator-initiated research through various means. The Task Force also is responsible for implementing Executive Order (EO) 13505, issued by President Obama on March 9, 2009. EO 13505 authorizes the Secretary of Health and Human Services, through the Director of NIH, to support and conduct responsible, scientifically worthy human stem cell research, including human embryonic stem cell research, to the extent permitted by law. The NIH Guidelines for Human Stem Cell Research were issued on July 7, 2009.
Bone Marrow Stromal Cells Help Fight Sepsis: Sepsis is a serious medical condition that affects 18 million people per year worldwide, and is characterized by a generalized inflammatory state caused by bacterial infection. Widespread activation of inflammation and blood clotting pathways leads to multiple organ failure, collapse of the circulatory system (septic shock), and death. In the last few years, it has been discovered that bone marrow stromal cells (BMSCs, also known as mesenchymal stem cells) are potent modulators of immune responses. In this study, BMSCs were administered before or shortly after inducing sepsis by puncturing the intestine to determine whether BMSCs injected into the circulation would have a beneficial effect in preventing or attenuating septic shock. Infusion of BMSCs significantly decreased sepsis-induced mortality and increased organ function in an animal model. The effects appear to be mediated by the production of Prostaglandin E2 when BMSCs are activated during the early stages of sepsis. Prostaglandin E2 subsequently induces the recipient's macrophages to produce substantially more IL-10, a factor that dampens the inflammatory response, which if left unabated, leads to death. This is the first determination of a mechanism by which BMSCs modulate the immune response in an animal model of sepsis. As many people die of sepsis annually as die from heart attacks. A new treatment or preventative regimen desperately is needed. Since the animal model suggests that the BMSCs need not be isolated from the same individual as will receive them, it is possible that cells isolated from nonrelated donors could be prepared and stored for use in patients with high risk for sepsis.
Effects of Storage on Transfused Red Blood Cells: In 2009, NIH initiated a basic and translational research program to identify the molecular and cellular changes that occur during red blood cell unit preparation and storage and to evaluate the effects of storage lesion elements from red blood cell units on the blood vessel wall, host cells, and tissue oxygenation. Recent data suggest that liberal blood transfusions in certain settings are associated with an increase in morbidity and mortality compared to more restrictive strategies, and that transfusion of blood stored for longer periods of time may not be as beneficial as transfusion of "fresher" blood. This program should provide information for improving red blood cell transfusion therapy and clinical outcomes in transfusion recipients.
  • (E) (NHLBI)
Smart Coatings for Implanted Biomaterials: A major limitation on the longevity of vascular grafts and implanted materials stems, not from failure of the graft or material itself, but typically, from the body's rejection in the form of blood clots or refusal to integrate with surrounding tissue. Recently, new classes of polymer-based biomimetics that resemble the cell surfaces of healthy blood vessels have demonstrated excellent resistance to platelet adhesion, a major problem for implanted materials in contact with blood. These biomimetic polymers have undergone successful preliminary clinical testing, and the same approach now is being used to develop biomimetic coatings resembling other types of human tissue. This technology recently was acquired by a major medical implant manufacturer.
  • Kumar AM, et al. J Am Chem Soc 2008;130(4):1466-76.PMID: 18177047. PMCID: PMC2536642.
    Larsen CC, et al. Biomaterials 2007;28(24):3537-48. PMID: 17507089. PMCID: PMC2034336.
  • This example also appears in Chapter 3: Technology Development
  • (E) (NIBIB)
New Therapeutic Target for Macular Degeneration and Diabetic Retinopathy Discovered: Neovascularization is the term used to describe the growth of abnormal new blood vessels. In some diseases, such as age-related macular degeneration or diabetic retinopathy, neovascularization mistakenly activates and becomes a major pathologic feature. The abnormal vessels leak fluid and serum, which damages the light-sensitive photoreceptor cells in the retina, causing severe and irreversible vision loss. NIH-sponsored research is focused on understanding the pathways that inhibit and promote neovascularization. Previous studies have established that a protein called vascular endothelial growth factor (VEGF) spurs neovascularization, and several therapies have been developed to prevent the abnormal activation of VEGF. A recent NIH-supported study reported the discovery of Roundabout4 (Robo4), a protein that stabilizes the existing vasculature and prevents neovascularization by inhibiting VEGF activity. Robo4 is among a family of Roundabout proteins that previously were found to act as guidance receptors for developing neurons in the nervous system. That Robo4 plays a different and central role in controlling neovascularization represents a breakthrough that may lead to new treatments to prevent or delay the sight-threatening consequences of vascular eye diseases.
Cell Senescence and Aging: Cell senescence is a mechanism prominent in aging processes and widely considered as an anti-cancer preventive or treatment therapy. Studies focus on such topics as senescence induced by the Ras gene and its potential to halt or slow tumor progression, the role of the retinoblastoma protein pRb in cellular senescence and the development of a wide range of cell types and associated tumors, telomere attrition, the role of oxidative stress, epigenetic regulation, and DNA damage and repair. NIA-supported studies on Werner syndrome (a condition characterized by accelerated aging in children) and the role of the WRN protein in telomere metabolism are improving our understanding of basic cellular mechanisms that act to suppress development of specific aging characteristics and cancer.
  • This example also appears in Chapter 2: Cancer and Chapter 2: Life Stages, Human Development, and Rehabilitation
  • (E/I) (NIA)
Cooperative Study Group for Autoimmune Disease Prevention: The Cooperative Study Group for Autoimmune Disease Prevention was established in 2001 by NIH and its cosponsor the Juvenile Diabetes Research Foundation International as a collaborative network of investigators who focus on understanding immune system dysfunctions that contribute to the development of autoimmune disease, with an emphasis on type 1 diabetes. NIH renewed the Study Group in 2006. It consists of six participating centers that support preclinical research, innovative pilot projects, and clinical studies. Of note, the centers initiated and supported the "Roadmap to Inflammation in the NOD (nonobese diabetic) Mouse" project to identify and characterize genes and proteins involved in the development of diabetes, and study the mechanisms by which diabetes develops. One notable finding suggested by this study is that the development of type 1 diabetes can be characterized by specific differences in how normal genes and gene variants are turned on and off during disease progression. In addition, researchers found patterns of coordinated gene expression that may prove useful as biomarkers of disease onset or progression. Another study, in press, identifies an unusual form of a gene whose expression in specific immune system tissues is associated with type 1 diabetes in both mice and humans.
Basic Research on Type 1 Diabetes: NIH vigorously supports basic research on type 1 diabetes. For example, the Beta Cell Biology Consortium (BCBC) collaboratively pursues research relevant to the development of therapies for type 1 and type 2 diabetes, including studying pancreatic development, exploring the potential of stem cells as a source for making islets, and determining mechanisms underlying beta cell regeneration (cells that are the source of insulin production). The BCBC has generated research resources, such as animal models and antibodies, which are available to the scientific community. NIH also has launched initiatives to develop artificial pancreas technology for people with type 1 diabetes. One initiative solicited proposals from the small business community on the development of new technologies to advance progress toward an artificial pancreas. NIH also launched the Type 1 Diabetes Pathfinder Awards, to fund new investigators pursing innovative research on type 1 diabetes and its complications. Research supported through this program focused on areas such as cell replacement therapy, islet encapsulation, and diabetic wound healing.
Lupus: There have been significant advances in identifying disease risk genes for systemic lupus erythematosus (lupus) in recent years. Genome-wide association, linkage analysis, and direct sequencing have revealed genetic variations in lupus patients for molecules involved in immune mechanisms and regulation, inflammation, and vascular cell activities. The disease affects women disproportionately, with female lupus patients outnumbering males nine to one. African American women are three times as likely to get lupus as Caucasian women, and it also is common more in Hispanic, Asian, and American Indian women. These results are being replicated in distinct racial and ethnic populations. Long-term NIH support of disease registries and repositories of biological samples have been essential to successful projects. Another critical factor in these and future studies is the collaboration between U.S. and European researchers, supported by government agencies, private foundations, and industry. The numerous genes uncovered in these studies reflect the complex expression of lupus, which varies from patient to patient. For example, a variant in an immune regulatory gene specifically is associated with severe forms of lupus that include kidney disease, but not skin manifestations. Methods to analyze patients' blood samples are being developed to group disease-specific variations in gene expression according to pathogenic mechanisms. This system may be used to predict flares of lupus activity in the future and guide individualized treatment. Lupus risk genes also have been discovered on the X chromosome and reproduced in animal models of the disease. These important findings shed light on the female predominance of lupus.
  • Edberg JC, et al. Hum Mol Genet 2008 Apr 15;17(8):1147-55. PMID: 18182444.
    Hom G, et al. N Engl J Med 2008;358(9):900-9. PMID: 18204098.
    Nath SK, et al. Nat Genet 2008;40(2):152-4. PMID: 18204448.
    International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN), et al. Nat Genet 2008;40(2):204-10. PMID: 18204446.
    Taylor KE, et al. PLoS Genet 2008;4(5):e1000084. PMID: 18516230. PMCID: PMC2377340.
    Chaussabel D, et al. Immunity 2008;29(1):150-64. PMID: 18631455. PMCID: PMC2727981.
    Smith-Bouvier DL, et al. J Exp Med 2008;205(5):1099-108. PMID: 18443225. PMCID: PMC2373842.
    Scofield RH, et al. Arthritis Rheum 2008;58(8):2511-7. PMID: 18668569.
    Jacob CO, et al. Proc Natl Acad Sci U S A 2009;106(15):6256-61. PMID: 19329491. PMCID: PMC2669395.
  • This example also appears in Chapter 2: Autoimmune Diseases, Chapter 2: Minority Health and Health Disparities, Chapter 3: Genomics and Chapter 3: Clinical and Translational Research
  • (E/I) (NIAMS, NCI, NCRR, NHLBI, NIAID, NIDCR, NINDS)
Asthma Exacerbations: 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 asthma symptoms. Twelve projects have been funded under this initiative. 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."
Understanding the Progression from a Skin Disorder to Asthma in Children: NIH-funded researchers investigating basic biochemical mechanisms involved in development have discovered a mechanism that can explain how 50-70 percent of young children affected with the skin rashes of atopic dermatitis (a type of eczema) eventually become asthmatic. The process involves the overproduction of a specific signaling molecule by inflamed skin cells that can trigger the hypersensitivity characteristic of asthma in lung cells. This mechanism and possible ways to prevent this "atopic march" and the development of asthma in general are being actively evaluated in animal models as well as in early human studies.
Immunological Factors in Autoimmune Disease: T Helper Cells: T helper cells are a category of immune cells that orchestrate many complex mechanisms in the immune system by receiving molecular signals and, in return, releasing other molecules that control activities of other cells. As a result, these recipient cells are stimulated, or inhibited, from damaging tissues or destroying pathogenic invaders. Studies in recent years have identified a number of T helper cell (Th) subsets that have fairly specific responses to immune system molecules, and are pivotal to attacks against pathogens, as well as autoimmune reactions—when the immune system aberrantly attacks the body it is supposed to protect. NIH-supported researchers have found that one Th subset (Th17) releases molecules that start a cascade of inflammatory events. The effects of Th17 and other pro-inflammatory cells are balanced by another Th subset, T regulatory cells (Tregs), which dampen inflammation. Job's syndrome is a rare immune disorder, characterized by recurrent and often severe bacterial and fungal infections. Due to a genetic mutation affecting a complex biochemical pathway, patients with Job's syndrome lack interleukin 17 (IL17), the molecule that stimulates Th17 cells. As a result, their immune systems fail to protect them from infections, which have the potential to become life-threatening. On the other hand, patients with psoriasis, an autoimmune skin disease, have high levels of IL17 and very active Th17 cells, which drive inflammation in the skin, leading to scaly, damaged tissue. Additional studies have revealed ways that the body might inactivate Tregs. By understanding the details of failures in biochemical pathways in disease states, scientists may begin to identify ways to correct them therapeutically.
New Program to Focus on Better Defining Human Immune Profiles: In 2009, NIH requested applications for a new research program designed to build on recent advances in immune profiling to measure the diversity of human immune responses to infection or vaccination. Grantees will use a variety of modern analytical tools that will define molecular signatures of specific infections, vaccines, or immune adjuvants, as well as describe steady-state human immune status by a number of parameters. This program is a critical component of the NIH immunology research portfolio. This initiative supports studies that characterize human immune cells and their products isolated from diverse subsets of the population after vaccination, infection, or treatment with adjuvants. NIH will create a grantee consortium that will develop and manage a comprehensive database that consolidates and disseminates information for the scientific community and develop new assays and bioinformatics tools to facilitate productivity. This program, originally intended as an FY 2011 initiative, began 1 year early with ARRA funding.
Solving One of Immunity's Puzzles: NIH scientists recently identified a protein required for the crucial interactions between T and B cells that lead to production of antibodies and long-lasting immunity to infectious diseases. T cells and B cells interact to form cellular centers, where B cells proliferate and produce antibodies to fight off invading microbes. This process is crucial to normal immune function and resistance to infectious disease. Researchers demonstrated that a protein, SAP, mediates interactions between T and B cells. Specifically, the team found that T cells lacking SAP do not bind strongly to the B cells they would otherwise recognize. This in turn prevents B cells from receiving crucial signals they need to help build antibody-secreting cells. This malfunction leads to the poor immune response observed in patients with X-linked lymphoproliferative disease, a rare disorder affecting newborn boys.
  • Qi H, et al. Nature 2008;455(7214):764-9. PMID: 18843362. PMCID: PMC2652134.
  • For more information, see  http://www.genome.gov/27528397
  • This example also appears in Chapter 2: Infectious Diseases and Biodefense
  • (E, I) (NHGRI, NIAID)
Developing New Adjuvants to Boost Vaccine Effectiveness: Adjuvants activate the body's innate immune system, a prerequisite for effective responses by the adaptive immune system—antibody-producing B cells and antigen-specific T cells. In 2004, NIH launched the "Innate Immune Receptors and Adjuvant Discovery" initiative in response to the growing need to boost the effectiveness of vaccines against potential agents of bioterrorism and emerging infectious diseases. The initiative encouraged the discovery of novel adjuvants that stimulate the innate immune response through proteins known as pattern recognition receptors, which the innate immune system uses to identify microbial pathogens. To build on the success of this program, NIH initiated the Adjuvant Development program in 2008. Four groups were funded to advance identified adjuvants toward licensure for human use in vaccines against diseases such as influenza and tuberculosis, as well as infection with West Nile virus. The "Innate Immune Receptors and Adjuvant Discovery" initiative was reissued—inviting new grant applications—in FY 2009 to continue the generation of potential adjuvant candidates. The research focus on adjuvants yielded a major science advance in 2008 when several groups of NIH-supported investigators discovered that alum activates the innate immune system by stimulating clusters of proteins called inflammasomes, found inside certain cells. This new information should provide keys to better understanding adjuvant function and should facilitate the design of new vaccine adjuvants.
Improving Transplantation Outcomes: Organ transplantation prolongs survival and greatly improves quality of life for children and adults suffering from a wide range of congenital and acquired diseases. Yet, despite advances in transplantation, normal life expectancy and health-related quality of life are not restored fully by organ transplantation. To improve the outcomes of organ transplantation, NIH supports the Clinical Trials in Organ Transplantation (CTOT) initiative, a cooperative, multisite consortium to develop and implement interventional and observational clinical studies, accompanied by mechanistic studies.

In one notable CTOT study, NIH-supported investigators developed a regimen that included transplantation of both kidney and bone marrow from the same donor and use of immunosuppressive therapies prior to and just after transplantation. Nine to 14 months after the transplant, investigators were able to discontinue all immunosuppressive medications with this regimen in four of the five patients, without subsequent rejection of the kidney. In another study, NIH-supported investigators studied whether acute graft rejection was associated with changes in the expression of genes involved with the adaptive immune response. They measured levels of microRNAs in healthy transplanted kidneys and in transplants undergoing rejection. The team found a pattern of six microRNAs that could distinguish healthy kidneys from those in the process of being rejected. These results suggest that microRNAs may be a useful measurement for assessing human kidney transplant status. If the rejection signature appears early enough, doctors one day may be able to treat patients before organ damage occurs and to better tailor immunosuppressive therapy to the individual patient.
  • Kawai T, et al. N Engl J Med 2008 Jan 24;358(4):353-61. PMID: 18216355. PMCID: PMC2819046.
  • For more information, see  http://www.immunetolerance.org/
  • This example also appears in Chapter 2: Chronic Diseases and Organ Systems
  • (E) (NIAID, NHLBI, NIDDK)

"-Omics" Approaches

Discovery of Novel Epigenetic Marks in Mammalian Cells: The NIH Roadmap Epigenomics Program aims to accelerate the promise of epigenetics into applications that affect human health and a wide range of common complex human diseases by fostering the development of novel resources for research in this field. Epigenetics refers to various modifications to DNA, its associated proteins, or overall chromosome structure that influence whether genes are active or silent, independent of the DNA sequence. Research supported by this program will characterize the "epigenome," a catalog of the stable epigenetic modifications or "marks" that occur in the genome (and which may differ in different types of cells) and its impact on health and disease. One component of the program is an initiative to support research to identify novel epigenetic marks in mammalian cells and assess their role in the regulation of gene activity. It is anticipated that the results of these studies will be translated quickly to global epigenome mapping in human cells (conducted by the Epigenomics Roadmap Program's Reference Epigenome Mapping Centers). The eight research grants funded by this component of the program are expected to yield results that could have a significant impact on our understanding of gene regulation in mammals. In the long term, advances in these areas will enhance our ability to investigate, diagnose, and ameliorate human disease with a significant epigenetic component. For instance, NIH plans to build on these studies to examine the role of epigenomics in diabetes complications and to study effects of the intrauterine environment on the development of diabetes. Other research will examine epigenetic markers of beta cell differentiation.
Regulation of Gene Expression by Chemically Marking DNA: Studies by NIH intramural scientists of how genes are turned on (expressed) or off have provided insight into gene regulation and the overall organization of the genome. For example, a recent study indicated the importance of a mammalian protein called Vezf1 in maintaining the integrity of the genome. This protein previously had been identified by research on an "insulator" element—a segment of DNA that marks boundaries in the genome and allows neighboring genes to be regulated independently. Research on insulator elements—found in fruit flies, chickens, and mammals—has provided great insight into the molecular mechanisms used by the cell to turn on certain genes while keeping other genes turned off. In studies of Vezf1, the scientists discovered that deletion of the gene encoding the Vezf1 protein in a mouse embryonic stem cell line led to loss of specific chemical marks on the DNA at widespread sites in the genome. This type of chemical mark, known as DNA methylation, is a signal used by the cell to turn a gene off. The scientists also demonstrated that the loss of DNA methylation observed when Vezf1 was deleted was due to a decrease in the amount of a specific protein that puts this mark on the DNA. Therefore, Vezf1 is required for the DNA methylation pattern in these cells. Continued studies of insulators and their associated proteins will lead to further understanding of the regulation of genes, an essential process for health and development.
  • Gowher H, et al. Genes Dev 2008;22(15):2075-84. PMID: 18676812. PMCID: PMC2492749.
  • This example also appears in Chapter 3: Genomics
  • (I) (NIDDK)
Scientists Accomplish Initial Catalogue of the Human Salivary Proteome: Secretions from the major salivary glands (parotid, submandibular, and sublingual) contain many peptides and proteins. They contribute to saliva's important roles in maintaining oral health, including antimicrobial, lubricating, buffering, and digestive properties. Salivary gland disorders, which result in severe dry mouth, compromise quality of life because they often lead to decay and periodontal diseases, mucosal infections, halitosis, taste impairment, and difficulties in swallowing and speaking. Saliva is a complex fluid; over the years, a number of salivary proteins have been reported but a systematic approach to catalogue all the proteins present in saliva was only initiated in 2004. NIH supported three teams of investigators to conduct the first comprehensive analysis of the salivary proteome. After samples were collected and analyzed, the data were standardized and integrated, yielding a salivary proteome that comprises 1,166 proteins. Of these proteins, 152 parotid and 139 submandibular/sublingual proteins were identified by all 3 research groups; these proteins form the core proteome. Most proteins identified were extracellular or secretory proteins, and involved in numerous molecular and cellular processes. A significant number of proteins represented in the salivary proteome also have been found to exist in the plasma or tear proteomes. This initial catalogue of the salivary proteome is a significant first step toward a comprehensive understanding of what the functions of saliva are, and how salivary composition is dependent on physiological variations, including on health and disease. This proteome could be the source of potential diagnostic and prognostic biomarkers for oral and systemic conditions.
  • Denny P, et al. J Proteome Res 2008;7:1994-2006. PMID: 18361515.
  • This example also appears in Chapter 3: Genomics and Chapter 3: Technology Development
  • (E) (NIDCR)
Study Finds Unexpected Bacterial Diversity on Human Skin: One of the NIH Roadmap initiatives, the Human Microbiome Project (HMP) is a trans-NIH program that aims to expand upon traditional microbiology and discover what microbial communities exist in different parts of the human body and how they might change with disease. In a healthy adult, microbial cells far outnumber those of the human host, but remarkably little has been known until now about how these microbes behave in the body. HMP makes use of a metagenomic approach that reveals data about entire human-associated microbial communities. In 2009, data gathered by a trans-NIH team revealed unexpected bacterial diversity on human skin that, it is hoped, will lead to advances in understanding a range of disorders, such as eczema, psoriasis, and acne.
  • Grice EA, et al. Science 2009;324(5931):1190-2. PMID: 19478181.
  • For more information, see  http://nihroadmap.nih.gov/hmp/index.asp
  • This example also appears in Chapter 3: Genomics
  • (I) (NHGRI, Common Fund - all ICs participate, NCI)
Glycomics Technology Development, Basic Research, and Translation into the Clinic: Glycans are ubiquitous complex carbohydrates found on the surfaces of cells and secreted proteins. Glycan binding proteins mediate cell signaling, recognition, adherence, and motility, and play a role in inflammation, arteriosclerosis, immune defects, neural development, and cancer metastasis. Detection and analysis of carbohydrate molecules is thus critical for basic and clinical research across the spectrum of health and disease, but widely is regarded as one of the most difficult challenges in biochemistry. Four NIH programs are striving to make this easier by working together across the domains of technology development and basic and translational research.
  • Biomedical Technology Research Centers develop and share cutting-edge technologies for analysis of carbohydrates in complex biological systems.
  • Consortium for Functional Glycomics creates and provides access to technological infrastructure for carbohydrate biology and analysis in support of basic research.
  • Alliance of Glycobiologists for Detection of Cancer and Cancer Risk leverages the technology and expertise developed in NIH programs for translational research in cancer biomarker discovery.
  • A Small Business Innovation Research (SBIR)/Small Business Technology Transfer (STTR) program funds the commercial development of innovative technologies for carbohydrate analysis.
    Reference Epigenome Mapping Centers: The Reference Epigenome Mapping Centers (REMCs), one of the Roadmap Epigenomics initiatives, are developing resources in reference epigenomes that the field has been requesting for the last 5 years, as indicated by recommendations made at several workshops and conferences focused on epigenetics and human health and disease. The funded centers form a network collaborating to provide comprehensive maps of all known epigenetic marks across a set of mutually agreed-upon reference cell types. This consortium, with input from advisors, will identify the most appropriate cell populations and determine standardized methods for growing or acquiring the cells so that data can be compared and integrated maps can be generated. The network of REMCs will produce comprehensive, high resolution, experimental data on epigenetic marks in specific cell populations, such as high-quality, pluripotent human embryonic stem cells, other human differentiating stem cells, and differentiated cell types including human cell types relevant to complex diseases of high public health significance. In addition, it will provide an informatics pipeline to generate high-quality reference epigenome maps from the centers' data; facilitate additional data analyses, in collaboration with the Epigenome Data Analysis and Coordinating Center, to integrate data from maps generated by REMCs from a specific cell type for different epigenetic marks; and conduct ancillary studies to develop limited data on functional aspects of epigenetic control of gene activity.

    Systems Biology

    Systems Biology and Systems Genetics: The Integrative Cancer Biology Program (ICBP) provides new insights into the development and progression of cancer as a complex biological system. Teams of researchers at ICBP Centers are integrating the disciplines of biology, medicine, engineering, math, and computer science (e.g., computational biology). ICBP Centers use a spectrum of innovative technologies such as genomics, proteomics, and molecular imaging to generate and validate computational and mathematical models. These in silico models describe and simulate the complex process of cancer, from the basic cellular processes through tumor growth and metastasis, and allow researchers to run "virtual" experiments, which ultimately should lead to better cancer prevention, diagnostics, and therapeutics. The centers have produced more than 35 computational models, developed a validated siRNA library of cancer genes, and created a set of nationally distributed breast cancer cell lines that reflect the heterogeneity of human breast cancer. 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.
    National Centers for Systems Biology: Systems biology promotes tight integration of experimental and computational approaches to solving complex problems. Currently, NIH-funded researchers at10 interdisciplinary Centers are using computational modeling and analysis to study the complex dynamics of molecular signaling and regulatory networks involved in cell proliferation, differentiation, death, and response to environmental changes; developmental pattern formation in organisms; genome organization and evolution; and drug effects on cells, organs, and tissues. The Centers advance their research fields and provide training for the next generation of computationally skilled scientists.
    Computational Modeling of Regulatory Processes: Phosphorylation, the addition of a phosphate group to a protein or other molecule, is a common mechanism of cellular processes. Proteins may contain more than 1 site of phosphorylation, and, interestingly, many key regulatory proteins are phosphorylated at 10 or more different sites. NIH-funded researchers recently have introduced novel methods, based in the sophisticated branch of mathematics known as "algebraic geometry," into a computational model of phosphorylation, giving them a new technique to explore a variety of processes related to cancer and other diseases. This advance exploits a mathematical construct named for the Austrian mathematician Wolfgang Grobner (1899-1980), and demonstrates how long-established findings in fields such as abstract mathematics can be brought to bear in the context of biological research. In this case, the mathematics allows the computational biologists to work around putting a precise numerical value to every detail of the model, thus greatly simplifying their efforts to perform computational experiments. It is anticipated that these simplifying methods, based on an area of mathematics previously far removed from work in the life sciences, will be widely applicable to modeling of many biological processes.
    • Manrai AK, Gunawardena J. Biophys J 2008; 95(12):5533-43. PMID: 18849417. PMCID: PMC2599844.
    • (E) (NIGMS)
    Metabolic Network Model of a Human Oral Pathogen: The bacterium Porphyromonas gingivalis causes severe, chronic periodontal disease. Recently NIH-supported researchers constructed a complex metabolic network map for P. gingivalis with which to model the metabolic properties of all genomically identified components of the system. The scientists used a technique known as flux-balance analysis (FBA) to construct the model, which consisted of 679 metabolic reactions involving 564 metabolites. There was significant correlation between the model's predictions and the bacterium's experimentally observed metabolism. The true power of this model became apparent when "virtual knockouts" were employed to predict the effect of the loss of certain genes or metabolic pathways on growth rate, and the model very effectively predicted disturbances affecting biosynthesis of large molecules known as lipopolysaccharides. This is the first description of a model of this type for an oral periodontal pathogen. Still in their infancy, metabolic network models are a logical extension of genome sequence data. They can provide the ability to perform virtual metabolic modeling of organisms with limited or no in vivo experimental histories. These models also could be applied to highly interdependent mixed microbial communities, including the oral microbiome, ultimately resulting in new biomedical applications. Such modeling greatly increases opportunities to discover new antibacterial drug targets. These studies provide new molecular targets for therapeutic drugs; they also can suggest the molecular mechanisms for virulence, intracellular persistence and survival, and ability of the bacteria to survive stresses from the (in this case, human) host defense mechanisms.
    • Mazumdar V, et al. J Bacteriol 2009;191(1):74-90. PMID: 18931137. PMCID: PMC2612419.
    • This example also appears in Chapter 2: Infectious Diseases and Biodefense, Chapter 2: Chronic Diseases and Organ Systems and Chapter 3: Technology Development
    • (E) (NIDCR)

    Environmental Factors

    Centers for Neurodegenerative Science: NIH has awarded three Centers for Neurodegeneration Science program grants to conduct research that combines human studies with basic mechanistic research to understand how environmental factors contribute to the origins, progression, treatment, and prevention of neurodegenerative diseases. The three projects will focus on investigating Parkinson's disease (PD). PD is linked to pesticide exposure, mitochondrial damage, and altered storage of dopamine. One project will look at how environmental and genetic factors interact in PD pathogenesis and search for biomarkers that will help identify people at risk for developing PD. A second project will investigate the importance of the ubiquitin-proteasome system, microtubules, and aldehyde dehydrogenase disruption by pesticides in conferring vulnerability to dopamine neurons. An integrated, multidisciplinary approach will be used to identify agricultural pesticides that are able to disrupt the same cellular pathways shown to alter the viability of dopaminergic neurons and determine whether these pesticides increase the risk of PD. The third project will focus on proteins known to be related to PD with the goal of determining how chemical reactions lead to damaging modifications of these proteins. Clinical implications will be explored through biomarker development and a screen to identify compounds that can preserve protein function by reducing free radical stress. The knowledge generated by these projects will provide therapeutic targets for disease intervention and prevention strategies.
    • Yu T, et al. Bioinformatics 2009;25(15):1930-6. PMID: 19414529. PMCID: PMC2712336.
      Orr AG, et al. Nat Neurosci 2009;12(7):872-8. PMID: 19525944. PMCID: PMC2712729.
      Taylor TN, et al. J Neurosci 2009;29(25):8103-13. PMID: 19553450. PMCID: PMC2813143.
      Guillot TS, Miller TW. Mol Neurobiol 2009;39(2):149-70. PMID: 19259829.
      Cho DS, et al. Science 2009;324(5923):102-5. PMID: 19342591. PMCID: PMC2823371.
      Xiong H, et al. J Clin Invest 2009;119(3):650-60. doi: 10.1172/JCI37617. PMID: 19229105. PMCID: PMC2648688. 
      Choo YS, Zhang Z. J Vis Exp 2009 Aug 19;(30). pii: 1293. doi: 10.3791/1293. PMID: 19692941.
    • This example also appears in Chapter 2: Neuroscience and Disorders of the Nervous System
    • (E) (NIEHS)
    Environmental Epigenetics: Key Mechanisms for Environmental Effects on Gene Function and Disease: Increasing evidence demonstrates that epigenetic mechanisms—cellular regulatory processes that influence the expression of genes without affecting DNA sequence—play important roles in the pathogenesis of disease. Epigenetic regulation of genes is critically important in normal developmental biology and disease development/progression, and epigenetic modifications can be influenced by environmental exposures (this may be an important mechanism for gene/environment interactions). An early NIH grant program called Environmental Influences on Epigenetic Regulation has resulted in some groundbreaking research on understanding these processes and their roles in health and disease. We know that environmental exposures early in development affect the risk of diseases and dysfunctions that occur in adulthood, many years later. Evidence is growing that exposures in utero exert their effects through epigenetic modifications such as DNA methylation (a chemical change to DNA that is associated with silencing gene expression). A recent study in yellow agouti mice demonstrated that maternal exposure to bisphenol A shifted the coat color of the offspring by decreasing methylation in a regulatory portion of the DNA sequence upstream of the coat-color gene. Moreover, maternal dietary supplementation with either folic acid or a phytoestrogen (genistein) inhibited the ability of bisphenol A to reduce DNA methylation. These and other results highlight the importance of this growing area of research for our ability to understand developmental pathogenesis and to design effective interventions.
    • Bjornsson HT, et al. JAMA 2008;299(24):2877-83. PMID: 18577732. PMCID: PMC2581898.
      Ke Q, et al. Carcinogenesis 2008 Jun;29(6):1276-81. PMID: 18375956.
      Tiwari VK, et al. PLoS Biol 2008;6(12):2911-27. PMID: 19053175. PMCID: PMC2592355.
      Yi JM, et al. Cancer Res 2008;68(19):8094-103. PMID: 18829568. PMCID: PMC2744404.
      McGarvey KM, et al. Cancer Res 2008;68(14):5753-9. PMID: 18632628. PMCID: PMC2706536.
      Chan TA, et al. PLoS Med 2008;5(5):e114. PMID: 18507500. PMCID: PMC2429944.
      Zhang W, et al. Cancer Res 2008;68(8):2764-72. PMID: 18413743. PMCID: PMC2823123.
      Ting AH, et al. Cancer Res 2008;68(8):2570-5. PMID: 18413723. PMCID: PMC2828041.
      Hsu PY, et al. Cancer Res 2009;69(14):5936-45. PMID: 19549897. PMCID: PMC2855843.
      Fleming JL, et al. Cancer Res 2008;68(22):9116-21. PMID: 19010880.
      Cheng AS, et al. Cancer Res 2008 Mar 15;68(6):1786-96. PMID: 18339859.
      Perera F, et al. PLoS One 2009;4(2):e4488. PMID: 19221603. PMCID: PMC2637989.
      Gomez-Duran A, et al. J Mol Biol 2008;380(1):1-16. PMID: 18508077. PMCID: PMC2824431.
      Baccarelli A, et al. Am J Respir Crit Care Med 2009;179(7):572-8. PMID: 19136372. PMCID: PMC2720123.
      Nagarajan RP, et al. Autism Res 2008;1(3):169-78. PMID: 19132145. PMCID: PMC2614877.
      Pessah IN, et al. Neurotoxicology 2008;29(3):532-45. PMID: 18394707. PMCID: PMC2475601.
      Dolinoy DC, Jirtle RL. Environ Mol Mutagen 2008;49(1):4-8. PMID: 18172876.
      Dolinoy DC. Nutr Rev 2008;66 Suppl 1:S7-11. PMID: 18673496. PMCID: PMC2822875.
      Patel MM, Miller RL. Curr Opin Pediatr 2009;21(2):235-42. PMID: 19663041. PMCID: PMC2740858.
      Miller RL. J Clin Invest 2008;118(10):3265-8. PMID: 18802486. PMCID: PMC2542856.
    • This example also appears in Chapter 2: Life Stages, Human Development, and Rehabilitation
    • (E) (NIEHS)
    Breast Cancer and the Environment Research Centers: Researchers at the Breast Cancer and Environment Research Centers (BCERC) are investigating mammary gland development in animals, as well as in young girls, to determine vulnerability to environmental agents that may influence breast cancer development in adulthood. These efforts hopefully will lead to strategies that better prevent breast cancer. The purpose of the centers' program is to answer questions on how chemical, physical, biological, and social factors in the environment work together with genetic factors to cause breast cancer. Functioning as a consortium at four grantee institutions, the centers bring together basic scientists, epidemiologists, research translational units, community outreach experts, and community advocates. At one center, a sophisticated genomics and proteomics approach explores the impact of estrogenically active chemicals such as TCDD, bisphenol A, and phthalates, during early, critical periods of development. This is facilitated by advanced informatics at another major research institution. At another center, novel approaches to studying the impact of environmental exposures on interactions between epithelial cells and stromal cells are being studied. Normal and cancer-prone mice are being examined during various stages of development to determine the effects of exposure to multiple stressors as researchers are developing more sensitive screens for carcinogenicity. In concert with these studies, an epidemiological multi-ethnic study is examining and following through puberty a cohort of 7- and 8-year-old girls from the Kaiser Foundation Health Plan. Other researchers are studying a population of white and African American public school students to see how diet affects adipose tissue and alters hormonal control of sexual maturation. Endocrine distruptors, irradiation, and psychosocial elements also will be studied for effects.
    • Lu P, Werb Z. Science 2008;322(5907):1506-9. PMID: 19056977. PMCID: PMC2645229.
      Kouros-Mehr H, et al. Cancer Cell 2008;13(2):141-52. PMID: 18242514. PMCID: PMC2262951.
      Welm BE, et al. Cell Stem Cell 2008;2(1):90-102. PMID: 18371425. PMCID: PMC2276651.
      Kouros-Mehr H, et al. Curr Opin Cell Biol 2008;20(2):164-70. PMID: 18358709. PMCID: PMC2397451.
      Ewald AJ, et al. Dev Cell 2008;14(4):570-81. PMID: 18410732. PMCID: PMC2773823.
      Sternlicht MD, Sunnarborg SW. J Mammary Gland Biol Neoplasia 2008;13(2):181-94. PMID: 18470483. PMCID: PMC2723838.
      Egeblad M, et al. Dis Model Mech 2008;1(2-3):155-67; discussion 165. PMID: 19048079. PMCID: PMC2562195.
      Aupperlee MD, et al. Endocrinology 2009;150(3):1485-94. PMID: 18988671. PMCID: PMC2654739.
      Lu P, et al. Dev Biol 2008;321(1):77-87. PMID: 18585375. PMCID: PMC2582391.
      Jenkins S, et al. Environ Health Perspect 2009;117(6):910-5. PMID: 19590682. PMCID: PMC2702405.
      Teitelbaum SL, et al. Environ Res 2008;106(2):257-69. PMID: 17976571.
      Moral R, et al. J Endocrinol 2008;196(1):101-12. PMID: 18180321. 
      Santos SJ, et al. J Steroid Biochem Mol Biol 2009;115(3-5):161-72. PMID: 19383543. PMCID: PMC2729057.
      Yang C, et al Reprod Toxicol 2009;27(3-4):299-306. PMID: 19013232.
      Smith SW, et al. J Health Commun 2009;14(3):293-307. PMID: 19440911. PMCID: PMC2718320.
      J Health Psychol 2008;13(8):1180-9. PMID: 18987091.
      Atkin CK, et al. J Health Commun 2008;13(1):3-19. PMID: 18307133.
      Kariagina A, et al. Crit Rev Eukaryot Gene Expr 2008;18(1):11-33. PMID: 18197783.
      Medvedovic M, et al. Physiol Genomics 2009;38(1):80-8. PMID: 19351911. PMCID: PMC2696152.
      Biro FM, et al. J Pediatr Adolesc Gynecol 2009;22(1):3-6. PMID: 19232295. PMCID: PMC2744147.
    • For more information, see  http://www.bcerc.org/
    • This example also appears in Chapter 2: Cancer, Chapter 2: Life Stages, Human Development, and Rehabilitation, Chapter 3: Epidemiological and Longitudinal Studies, Chapter 3: Genomics and Chapter 3: Clinical and Translational Research
    • (E) (NIEHS, NCI) (GPRA)
    National Toxicology Program/Tox21: Tox21 is a collaboration on the research, development, validation, and translation of new and innovative test methods that will better determine the toxicity of chemicals to which humans are or might be exposed. A central component is the exploration of novel high-throughput screening assays using human cells to evaluate mechanisms of toxicity. Program success will result in toxicity testing methods that are less expensive, provide higher throughput, and are better able to predict toxic effects in humans. As a result, Tox21 will increase the government's ability to evaluate large numbers of chemicals that currently lack adequate toxicological evaluation, while reducing the use of animals in regulatory testing.
    • (I) (NIEHS) (GPRA)
    Testing for Reproductive Tumors in the National Toxicology Program's Carcinogenesis Bioassay: Perinatal Dosing: The National Toxicology Program (NTP) evaluates substances for a variety of health-related effects. Two-year studies in laboratory rodents remain the primary method by which chemicals or physical agents are identified as having the potential to be hazardous to humans. In 2006, NTP convened a workshop on Hormonally Induced Reproductive Tumors, Relevance of Rodent Bioassays to discuss the adequacy of rodent models used in the 2-year bioassay for detecting reproductive tumors. The workshop recommended that in utero and lactational exposures could be added to the chronic bioassay depending upon what is known about the mode of action. For detecting tumor types such as testicular germ cell tumors, this recommendation was especially strong. In utero and lactational exposures should be considered for mammary tumor studies if there are any developmental effects associated with a substance under study that involved endocrine tissues, steroid receptor binding, a change in mammary gland morphology, or altered timing of vaginal opening. NTP has conducted such perinatal exposures on cancer bioassays in the past, but only when there was special justification for such a design to be adopted. A new default design in which dosing will start in pregnancy and be continued throughout life or to the end of a 2-year period now has been adopted unless there is a good scientific reason not to undertake such a study. NTP has initiated studies to obtain data for constructing physiologically based pharmacokinetic (PBPK) models in rodents and nonhuman primates. It is planning studies to explore the long-term consequences of perinatal exposure to Bisphenol A to understand the potential impact to humans of the developmental changes reported in numerous laboratory animal studies. It is hoped that the PBPK models will link information from rodent studies with primate studies, and potentially with human outcomes.
    • This example also appears in Chapter 2: Cancer, Chapter 2: Life Stages, Human Development, and Rehabilitation and Chapter 3: Clinical and Translational Research
    • (O) (NIEHS)
    Mercury and Autoimmunity: The causes of autoimmune diseases remain unknown although genetic and environmental factors are believed to play major roles in susceptibility. NIH supports research projects investigating heavy metal-induced autoimmune diseases. The Mercury Induced Autoimmunity Project is working on the role that interferon-gamma plays in the development of induced murine systemic autoimmunity. Another NIH-supported project is investigating links between mercury (Hg) exposure and autoimmune heart disease. This project will assess programming changes that occur during the innate immune response to infection following exposure to Hg, with an overall effect on the progression of Coxsackievirus-induced autoimmune heart disease in mice, and apply the biomarkers from the studies in animals to a Hg-exposed human population in Amazonian Brazil. Another project is investigating the effect of Hg on the neuroimmune system. Studies will investigate the effects of Hg on production of autoantibodies to brain antigens. Antibodies to brain antigens have been demonstrated in patients with different neurological diseases, including neuropsychiatric lupus, Parkinson's disease, schizophrenia, and autism spectrum disorders. An ongoing project is working on development and uses mouse models to understand the relationships between immune system dysfunction and perinatal exposure to environmental toxicants in the development of neurobehavioral disorders such as autism. Mice from this project will be used to assess the effects of perinatal exposure to low levels of methyl mercury (MeHg) on abnormal brain development and behavior mediated by the immune system. These studies should allow insight into the mechanism of induction of immune dysfunction and point to a possible means of therapeutic intervention.
    • Havarinasab S, et al. Clin Exp Immunol 2009;155(3):567-76. PMID: 19077085. PMCID: PMC2669534.
    • This example also appears in Chapter 2: Autoimmune Diseases
    • (E) (NIEHS)
    Bisphenol A Exposure and Effects: More than 90 percent of the U.S. population is exposed to low levels of BPA. Exposures may occur through use of polycarbonate drinking bottles and the resins used to line food cans. The NIH National Toxicology Program's (NTP's) Center for the Evaluation of Risks to Human Reproduction conducted an evaluation to determine whether current levels of exposure to BPA present a hazard for human reproduction and/or development. Following this evaluation of existing literature, the NTP expressed "some concern" for effects on the brain, behavior, and prostate gland based on developmental effects reported in some laboratory animal studies using BPA exposures similar to those experienced by humans. NIH is working to address and support research and testing needs identified during the NTP evaluation to understand any potential risks for humans from BPA exposure. In collaboration with scientists at the FDA National Center for Toxicological Research, the NTP has designed and begun studies to evaluate similarities and differences in how rats metabolize BPA in relation to nonhuman primates, and to further understand the long-term health consequences from exposures to low levels of BPA during rodent development. In addition, NIH is providing grant support to the extramural community for studies that focus on investigating possible long-term health outcomes from developmental exposure or chronic exposures to environmentally relevant doses of BPA. Collectively, these studies should address research gaps, reduce uncertainties, and provide perspective regarding any potential risk that BPA poses for public health.
    • Mahalingaiah S, et al. Environ Health Perspect 2008;116(2):173-8. PMID: 18288314. PMCID: PMC2235217.
      Leranth C, et al. Proc Natl Acad Sci U S A 2008;105(37):14187-91. PMID: 18768812. PMCID: PMC2544599.
      Murray TJ, et al. BMC Cancer 2009;9:267. PMID: 19650921.
      Vandenberg LN, et al. Reprod Toxicol 2008;26(3-4):210-9. PMID: 18938238.
      Prins GS, et al. Fertil Steril 2008;89(2 Suppl):e41. PMID: 18308059. PMCID: PMC2531072.
      Muhlhauser A, et al. Biol Reprod 2009;80(5):1066-71. PMID: 19164168. PMCID: PMC2804836.
      Ye X, et al. Environ Res 2008;108(2):260-7. PMID: 18774129. PMCID: PMC2628162.
      National Toxicology Program. NTP CERHR MON 2008;(22):i-III1. PMID: 19407859.
      Nepomnaschy PA, et al. Environ Res 2009;109(6):734-7. PMID: 19463991. PMCID: PMC2810154.
      Dolinoy DC. Nutr Rev 2008;66 Suppl 1:S7-11. PMID: 18673496. PMCID: PMC2822875.
      Diamanti-Kandarakis E. Endocr Rev 2009;30(4):293-342. PMID: 19502515. PMCID: PMC2726844.
      Prins GS. Endocr Relat Cancer 2008;15(3):649-56. PMID: 18524946. PMCID: PMC2822396.
      Rubin BS, Soto AM. Mol Cell Endocrinol 2009;304(1-2):55-62. PMID: 19433248. PMCID: PMC2817931.
      Soto AM, et al. Mol Cell Endocrinol 2009;304(1-2):3-7. PMID: 19433242.
      Vandenberg LN, et al. Endocr Rev 2009 Feb;30(1):75-95. PMID: 19074586. PMCID: PMC2647705.
      Soto AM, et al. Int J Androl 2008;31(2):288-93. PMID: 17971158. PMCID: PMC2817932.
      Soto AM, et al. Basic Clin Pharmacol Toxicol 2008;102(2):125-33. PMID: 18226065. PMCID: 2817934.
      Hunt PA, Hassold TJ. Trends Genet 2008;24(2):86-93. PMID: 18192063.
    • This example also appears in Chapter 2: Life Stages, Human Development, and Rehabilitation and Chapter 3: Clinical and Translational Research
    • (I) (NIEHS)

    Basic Behavioral and Social Science Research

    NIH Basic Behavioral and Social Science Opportunity Network: NIH Basic Behavioral and Social Sciences Opportunity Network (OppNet) is a new trans-NIH initiative that will identify and support research in the basic behavioral sciences. Basic research in the behavioral and social sciences examines fundamental mechanisms and patterns of behavioral and social functioning. Examples include research on how people remember, how innovative practices spread, and the effects of brain processes on behavior. Basic behavioral and social sciences research (bBSSR) involves both human and animal studies and spans the full range of scientific inquiry, from processes at the intra-individual level ("under the skin"), to mechanisms "outside the skin" that explain inter-individual, group-, organizational-, community-, and population-level patterns of collective behavior. The mission to support basic behavioral science is shared across NIH ICs. Initiated in September 2009, OppNet will provide a means for integrating NIH's assessment of its bBSSR investments, ensuring that opportunities in relevant areas of science are addressed, and that effective mechanisms are in place to advance these sciences. The initiative will support targeted initiatives of general relevance to the NIH mission, drawing from a common pool of funds.
    • (E) (NIA, NIGMS, OBSSR, FIC, NCCAM, NCI, NCMHD, NCRR, NEI, NHGRI, NHLBI, NIAAA, NIAID, NIAMS, NIBIB, NICHD, NIDA, NIDCD, NIDCR, NIDDK, NIEHS, NIMH, NINDS, NINR, NLM, OAR, ODP, ORWH)
    Facilitating Interdisciplinary Research via Innovation in the Behavioral and Social Sciences: An NIH Roadmap Funding Opportunity Announcement (FOA), Facilitating Interdisciplinary Research via Methodological and Technological Innovation in the Behavioral and Social Sciences, was released. Using a modified Exploratory/Developmental (R21) mechanism, this FOA solicits applications to develop new and innovative measures, methods, and technologies that support the integration of human social and/or behavioral science with other disciplines across varying levels of analysis. Supported projects have included: creation of tools to measure sun exposure and vitamin D, models of spinal cord injury, and an Internet-based system for providing feedback to teachers and consultants on the school readiness and mental health of children. Several national conferences have been planned in relation to this initiative, including Facilitating Interdisciplinary Research: Methodological and Technological Innovation in the Behavioral and Social Sciences (October 2009).
    CISNET—A Resource for Comparative Effectiveness Research: The Cancer Intervention and Surveillance Modeling Network (CISNET) represents a quantum leap forward in the practice of modeling to inform clinical and policy decisions. While contemporary science has enabled the collection and analysis of health-related data from numerous sectors, enormous challenges remain to integrate various sources of information into optimal decision-making tools to inform public policy. Collaborative work on key questions promotes efficient collecting and sharing of the most important data and critical evaluation of the strengths and weaknesses of each resource. Providing results from a range of models, rather than a single estimate from one model, brings credibility to the process and reassures policymakers that the results are reproducible. CISNET is a consortium of NIH-sponsored investigators who use modeling to improve understanding of the impact of cancer control interventions (e.g., prevention, screening, and treatment) on incidence and mortality trends. The consortium's work informs clinical practice and recommended guidelines by synthesizing existing information to model gaps in available knowledge. CISNET provides a suite of models that are poised to determine the most efficient and cost-effective strategies for implementing technologies in the population. Four groups of grantees focus on breast, prostate, colorectal, and lung cancers using statistical simulation and other modeling approaches. Their models incorporate data from randomized controlled trials, meta-analyses, observational studies, epidemiological studies, national surveys, and studies of practice patterns to evaluate the past and potential future impact of these interventions.
    • For more information, see  http://cisnet.cancer.gov/
    • This example also appears in Chapter 2: Cancer and Chapter 3: Disease Registries, Databases, and Biomedical Information Systems
    • (E/I) (NCI)
    Support for Collaborative Science: In FY 2009, NIH launched the Administrative Supplements for Collaborative Science (SCS) program. These supplements are intended to enhance ongoing research by stimulating and supporting new multidisciplinary collaborations among NIGMS grantees and other members of the scientific community. The program has proved to be quite popular. NIH received 217 applications for the three submission dates in FY 2009, and plans to fund at least 32 applications from Institute funds. NIGMS intends to support additional meritorious applications with funds received from the American Recovery and Reinvestment Act of 2009.
    NIH Committee on the Science of Behavior Change (SOBC): A key national goal, at the scientific and policy level, is to eliminate preventable diseases and their associated disabilities and premature deaths. To achieve this goal, the science of behavior change increasingly is being recognized as a critical area for research. While NIH historically has invested in biobehavioral research, SOBC is a crucial step to coordinate, leverage, and advance these efforts. The SOBC initiative examines topics that span the continuum of behavior change and across disciplines. The SOBC goals include the identification of new and productive paradigms for SOBC research—paradigms that will facilitate the synthesis, integration, and application of SOBC research; that will help to bridge the distances that often separate investigators and disciplines; and that will inform and identify future research directions and initiatives. On June 15-16, 2009, NIH brought together experts in the fields of basic and applied behavioral sciences, genetics, economics, and methodology with the goal of advancing an NIH-wide agenda on the science of behavior change. The main topics of discussion were the acquisition and prevention of behavior, changing existing behavior, and maintenance of behavior. The SOBC working group will use ideas generated from the meeting to develop new interdisciplinary initiatives in behavior change research.
    • For more information, see  http://nihroadmap.nih.gov/documents/SOBC_Meeting_Summary_2009.pdf
    • This example also appears in Chapter 2: Chronic Diseases and Organ Systems and Chapter 3: Clinical and Translational Research
    • (E) (NINR, NIA, DPCPSI, FIC, NCCAM, NCI, NHGRI, NHLBI, NIAAA, NIAID, NICHD, NIDA, NIDCR, NIDDK, NIGMS, NIMH, NINDS, OBSSR)
    Edward R. Roybal Centers for Translation Research in the Behavioral and Social Sciences in Aging: NIH supports 13 Roybal Centers whose objective is to improve the health, quality of life, and productivity of middle-aged and older people by facilitating translation of basic behavioral and social science to practical outcomes by developing new technologies and stimulating new "use-inspired" basic research in the behavioral and social sciences. Roybal investigators have made several key discoveries. For example: One Center has developed tools and technologies for identifying older adults at risk for automobile crash involvement, and is working with industry partners to develop and disseminate products based on these tools. Another Center has developed two evidence-based interventions from its in-depth work on physical activity for older adults. One program, Fit and Strong!, is targeted to older adults with lower extremity osteoarthritis, and one is targeted to older adults with developmental/intellectual disabilities (primarily Down syndrome). A Roybal investigator has developed instruments for self-efficacy appropriate for use with older adults with developmental/intellectual disabilities; these have been adopted internationally. Finally, a Center has developed a "living laboratory" model methodology for in-home assessment of activity to facilitate early detection of changes in health or memory. Other companies have used this model to develop related products, and the model has spurred several new grant-funded research projects, including the development of a new medication tracker for older adults.
    NIH Revision Awards for Studying Interactions Among Social, Behavioral, and Genetic Factors in Health: NIH issued three program announcements with review (PARs) to support competitive supplements for NIH grantees to study how interactions among genetic and behavioral/social factors influence health and disease. NIH is committing $7.9 million to support 11 applications submitted in response to these announcements, which will enable the addition of a genetics/genomics component to ongoing behavioral or social science research projects. The knowledge gained by such research will improve our understanding of the determinants of disease as well as inform efforts to reduce health risks and provide treatment.
    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. Research with individuals who have a high family history of alcoholism seeks to understand how low response to alcohol contributes to dependence and how it can be used to predict risk for future alcohol problems. Research with animals is useful in identifying the mechanism(s) underlying the level of sensitivity to alcohol. Recently, a study with fruit flies implicated the Epidermal Growth Factor Receptor (EGFR) signaling pathway in regulating sensitivity to alcohol. Importantly, FDA-approved medications that inhibit EGFR increase alcohol sensitivity in mice and decrease alcohol intake in rats, suggesting that these drugs may offer therapeutic opportunities for treatment of alcohol use disorders in humans.
    • Corl AB, et al. Cell 2009;137(5):949-60. PMID: 19464045.
      Trim RS, et al. Alcohol Clin Exp Res 2009;33(9):1562-70. PMID: 19485971.
    • This example also appears in Chapter 2: Neuroscience and Disorders of the Nervous System and Chapter 2: Chronic Diseases and Organ Systems
    • (E) (NIAAA)
    The Role of Development in Drug Abuse Vulnerability: NIH supports animal, clinical, and epidemiological research across the lifespan to examine how developmental stage may influence drug abuse vulnerability or protection. The discovery of a protracted period of brain changes during early development and beyond has been critical to understanding the role of brain maturation in decision-making processes and responses to stimuli, including early (e.g., in utero) exposure to drugs. Adolescence has emerged as a particularly vulnerable period, during which an immature brain circuitry can translate into a preponderance of emotional reactivity (vs. higher cognitive control) that gives rise to the impulsive characteristics of many teenagers. This in turn may lead to dangerous risk-taking, such as experimenting with drugs that ultimately can lead to addiction. Using both animal models and clinical research, scientists are beginning to understand how environmental variables can play a key role in shaping brain maturation trajectories. In this regard, imaging, genetic, and epigenetic tools are helping interpret the effects of myriad environmental influences, such as quality of parenting, drug exposure, socioeconomic status, and neighborhood characteristics on brain development and behavior. In addition, the field of social neuroscience is harnessing the power of multidisciplinary approaches to tease apart these multilevel phenomena to better understand, for example, the neural mechanisms of peer pressure, the connections between chronic stress and risk of drug abuse initiation, and the impact that different early rearing environments can have on gene expression and behavior.
    New Genetics/Epigenetic Tools Shed Light on Addiction: NIH-supported research is taking full advantage of expanding databases and fast technologies to identify links between genetic variations and disease, health, and behavior. Such genetic studies are critical to teasing apart the molecular mechanisms underlying complex diseases like addiction, which genes strongly influence. Investigators studying various neurological and psychiatric illnesses have already linked certain genes with specific diseases using custom screening tools known as "gene chips" (e.g., the neurexin gene has been found to play a role in drug addiction). Applying these tools to addiction and other brain disorders advances our understanding not only of vulnerability to addiction and its frequent comorbidities, but also of ways to target treatments based on a patient's genetic profile. To complement these efforts, NIH is investing in the equally important field of epigenetics, which focuses on the lasting modifications to the DNA structure and function that result from exposure to various stimuli. Attention to epigenetic phenomena is crucial to understanding the interactions between genes and the environment, including the deleterious long-term changes to brain circuits from drug abuse. For example, using a powerful new technique known as ChIP-on-chip to monitor epigenetic changes correlated with gene activity, investigators recently have mapped the genomic effects of chronic cocaine use in the reward center of the mouse brain. Such analyses provide needed information about which genes are altered by cocaine and can point to new targets for medications development. Epigenetic discoveries also can inform ways to smartly alter environmental factors so as to decrease the risk for drug abuse and addiction.
    A Multidisciplinary Approach to Tobacco Addiction: Tobacco addiction is the number one preventable public health threat, with enormous associated morbidity, mortality, and economic costs. Cigarette smoking—powerfully addictive mainly because of the key ingredient nicotine—is the greatest preventable cause of cancer, accounting for at least 30 percent of all cancer deaths, 87 percent of lung cancer deaths, and nearly 80 percent of deaths from chronic obstructive pulmonary disease, according to CDC. CDC also reports that these leading causes of death could become relatively uncommon in future generations were the prevalence of smoking substantially reduced. In that vein, NIH-supported research has led to major advances in critical areas that together could greatly enhance our ability to either prevent or mitigate the impact of tobacco addiction. Convergent genomic studies recently have uncovered several genes previously not associated with nicotine reward or addiction that convey increased risk for addiction. This finding identifies markers of vulnerability, as well as new targets for medications development, with the potential to personalize, and thereby improve, treatment based on patients' genetic profiles. Clinical trials are exploring new medications and behavioral therapies for tobacco addiction. A promising approach, which already completed Phase II clinical testing, is that of immunotherapy. A nicotine vaccine (NicVAX), which binds nicotine in the blood, preventing it from ever reaching the brain, showed strong positive results in promoting abstinence among study participants who achieved sufficient antibody levels. Further studies are helping to define optimal protocols for vaccination to improve results in all smokers. This may be a particularly useful tool for tobacco cessation programs in the not-too-distant future.
    • Centers for Disease Control and Prevention. Annual smoking-attributable mortality, years of potential life lost, and productivity losses United States, 1997-2001. Morb Mortal Wkly Rep 2005;54:625-8.
      Centers for Disease Control and Prevention. Smoking-attributable mortality, years of potential life lost, and productivity losses United States, 2000-2004. Morb Mortal Wkly Rep 2008;57(45):1226-28.
      Institute of Medicine. Ending the Tobacco Problem: A Blueprint for the Nation. Washington, DC: National Academies Press; 2007.
    • For more information, see  http://www.drugabuse.gov/ResearchReports/Nicotine/Nicotine.html
    • For more information, see  http://cdc.gov/tobacco/data_statistics/sgr/sgr_2004/index.htm
    • This example also appears in Chapter 2: Neuroscience and Disorders of the Nervous System and Chapter 2: Chronic Diseases and Organ Systems
    • (E) (NIDA, NCI) (GPRA)
    According to a Government Survey, 38 Percent of Adults and 12 Percent of Children Use Complementary and Alternative Medicine: In December 2008, NIH and the National Center for Health Statistics released new findings on Americans' use of complementary and alternative medicine (CAM). The findings are from the 2007 National Health Interview Survey (NHIS), an annual in-person survey of Americans regarding their health- and illness-related experiences. According to the survey, approximately 38 percent of adults and nearly 12 percent of children use some form of CAM. For both adults and children, the most commonly used type of CAM is nonvitamin/nonmineral natural products, and the most common use for CAM is to treat pain. Although overall use of CAM among adults has remained relatively stable since 2002 (the last time NHIS included a CAM section), the use of some specific CAM therapies has varied substantially; for example, deep breathing, meditation, massage therapy, and yoga have all shown significant increases. The 2007 NHIS was the first to ask about CAM use by children. The NHIS also reports on characteristics of CAM users, such as gender, age, education, geographic region, poverty status, and health indicators. The 2007 NHIS provides the most current, comprehensive, and reliable source of information on Americans' use of CAM. These statistics confirm that CAM practices are a frequently used component of American's health care regimens, and reinforce the need for rigorous research to study the safety and effectiveness of these therapies. The data also point out the need for patients and health care providers to openly discuss CAM use to ensure safe and coordinated care. Future analyses of these data may help explain some of the observed variation in the use of individual CAM therapies and provide greater insights into CAM use patterns among Americans.
    • Barnes PM, et al. Natl Health Stat Report 2008;(12):1-23. PMID: 19361005.
    • For more information, see  http://www.cdc.gov/nchs/data/nhsr/nhsr012.pdf
    • This example also appears in Chapter 2: Chronic Diseases and Organ Systems and Chapter 3: Epidemiological and Longitudinal Studies
    • (E) (NCCAM, CDC)
    Half of Surveyed Physicians Use Placebo Treatments for Patients: Treating patients with placebos has a long, complicated, and often controversial history. Nonetheless, little actually is known about U.S. physicians' current attitudes toward and use of placebo treatments. A national survey funded in part by NIH looked at placebo-prescribing practices among 679 internists and rheumatologists—specialties that commonly treat patients with debilitating chronic conditions. The survey found that about half of the physician respondents prescribed placebo treatments on a regular basis. Most (62%) said they think the practice is ethical. Among physicians who prescribed placebos, few said they used inert treatments such as saline injections or sugar pills; they were more likely to recommend over-the-counter analgesics (41%) or vitamins (38%), and some used antibiotics (13%) or sedatives (13%) as placebos. The survey also found that the physicians who used placebos rarely described them as such to patients. Instead, physicians most commonly described the treatments as medicine that typically is not used for the patient's condition but that might be beneficial. The survey provides insights into the complex relationship between placebo use and physicians' traditional role in promoting positive expectations in their patients. It also raises concerns about the use of "active" placebos, particularly antibiotics and sedatives, when they are not medically indicated. Prescribing placebo treatments remains an appropriate topic for ethical and policy debates.
    • Tilburt JC, et al. BMJ 2008 Oct 23;337:a1938. PMID: 18948346. PMCID: PMC2572204.
    • For more information, see  http://nccam.nih.gov/research/results/spotlight/102408.htm
    • This example also appears in Chapter 2: Chronic Diseases and Organ Systems and Chapter 3: Epidemiological and Longitudinal Studies
    • (E) (NCCAM)

    Research Resources, Infrastructure and Technology

    Unique Compounds Added to Chemical Libraries: Potent, drug-like molecules that selectively bind to the kappa opioid receptor have potential utility in the treatment of drug addiction, depression, psychosis and dementia, pain, and even HIV infection. Well more than 100 unique, new molecules constructed independently by two NIH-supported groups have been found to provide entirely new classes of kappa opioid binders. These molecules are potent and display a diversity of pharmacological activities that are under intensive active investigation.
    National Centers for Biomedical Computing: There are seven NIH Roadmap National Centers for Biomedical Computing (NCBC). Funded as cooperative agreements, these centers collectively cover broad areas of neuroinformatics, functional genomics, image post processing, multiscale modeling, cellular pathways, semantic data integration and ontologies, information networks, cellular networks and pathways, clinical informatics, disease-gene-environment analysis, and clinical decisions support.
    • For more information, see  http://ncbcs.org/
    • This example also appears in Chapter 3: Disease Registries, Databases, and Biomedical Information Systems and Chapter 3: Technology Development
    • (E) (NIGMS, Common Fund - all ICs participate)
    Influenza Virus Resources: NIH maintains the Influenza Virus Resource, a database of influenza virus sequences that enables 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 using publicly accessible data from laboratories worldwide in addition to targeted sequencing programs such as NIH's Influenza Genome Sequencing Project. Updated daily, this comprehensive sequence resource includes more than 90,000 influenza sequences and more than 2,000 complete genomes. In the spring of 2009, with the rapid emergence of the 2009 H1N1 pandemic, the database received more than 2,200 influenza sequences from publicly accessible databases and included sequences from CDC and labs from 35 countries. By the end of 2009, nearly 10,000 H1N1 sequences were in the database. The combination of extensive sequence data and advanced analytic tools provided researchers worldwide immediate access for investigating the rapid spread of this flu and developing vaccines for combating it. Other influenza virus information resources also were developed in response to 2009 H1N1. To facilitate access to the scientific literature, a pre-formulated search for 2009 H1N1 papers was added to PubMed. A 2009 H1N1 Flu page with comprehensive information on Federal response, international resources, transmission, prevention, treatment, genetic makeup, and veterinary resources was added to Enviro-Health Links, which provides links to toxicology and environmental health topics of recent special interest, including information in Spanish. For the general public, patients, family members, and caregivers, a health topic on 2009 H1N1 flu, in Spanish and English, was added to the MedlinePlus consumer health resource.
    Centers of Excellence for Influenza Research and Surveillance: NIH established the Centers of Excellence for Influenza Research and Surveillance (CEIRS) program in March 2007 to continue and expand its animal influenza surveillance program internationally and domestically, and to focus on several high-priority areas in influenza research. The program provides the government with information and public health tools and strategies to control and lessen the impact of epidemic influenza and the increasing threat of pandemic influenza. CEIRS activities lay the groundwork for the development of new and improved control measures for emerging and reemerging influenza viruses. Such measures include determining the prevalence of avian influenza viruses in animals in close contact with humans; understanding how influenza viruses evolve, adapt, and transmit; and identifying immunological factors that determine disease outcome. Each CEIRS site focuses on either (1) animal influenza surveillance for the rapid detection and characterization of influenza viruses with pandemic potential, or (2) pathogenesis and host response research to enhance understanding of the molecular, ecological, and/or environmental factors that influence pathogenesis, transmission, and evolution of influenza viruses; and to characterize the protective immune response. Currently, the CEIRS are responding to the 2009 H1N1 influenza outbreak by conducting research on pathogenicity and transmission of H1N1 and studying immune response to this novel influenza strain.
    Collective Intelligence for Knowledge Discovery: NIH has started a new NIH initiative in collective intelligence. The goal is to create deep repositories of knowledge backed by controlled vocabularies or ontologies, and to create or enhance semantically interoperable applications capable of discovering knowledge hidden within these repositories. Current applications such as the Human Salivary Proteome Annotation System, the Common Assay Reporting System, and the caBIG Protocol Lifecycle Tracking Tool are among the initial steps of a knowledge infrastructure. These applications harvest the collective knowledge of targeted scientific communities to store protocols, data, and results. Other tools developed for this initiative (e.g., the context-sensitive text mining system for identification of high-risk, high-reward research) use statistical natural language processing to discover new knowledge, such as, whether in peer review, an application for funding was considered high-risk and high-reward. Additional pilot studies are evaluating computational linguistics and knowledge management tools for biomedical and clinical informatics, portfolio analysis, systems biology, proteomics, genomics, and knowledge representation paradigms. The collective-intelligence initiative will lead to a knowledge infrastructure that can shift the paradigms of data re-use and knowledge discovery dramatically.
    • This example also appears in Chapter 3: Disease Registries, Databases, and Biomedical Information Systems
    • (I) (CIT, CC, NCI, NHGRI, NIDCR, NIMH, OD)
    NIGMS/NCI Collaborative Access Team (GM/CA-CAT): Structural biology is a field in which scientists learn about molecules by determining their 3-D structures in atom-by-atom detail. Large user facilities called synchrotrons allow researchers to use X-rays to determine molecular structures more easily, quickly, and cheaply than ever before. Two NIH institutes (NIGMS and NCI) funded the development of a new experimental station at the Advanced Photon Source at Argonne National Laboratory. The new station includes three X-ray beamlines for use by scientists from across the United States to determine the detailed, three-dimensional structures of molecules. Two of these beamlines provide world-leading capabilities for X-ray diffraction data from very small protein crystals only a few microns in dimension. This research capability is important to understand basic biological processes and for drug design. The facility now is in full operation.
    • For more information, see  http://www.gmca.anl.gov
    • This example also appears in Chapter 3: Technology Development
    • (E) (NIGMS, NCI)
    Collaborations Between Minority-Serving Institutions and Cancer Centers: The Minority Institution (MI)/Cancer Center (CC) Partnership (MI/CCP) is a flagship program that has been instrumental in establishing strong collaborations between minority-serving institutions (MSIs) and CCs. MI/CCP has fostered strong cancer research partnerships throughout the United States. This program established new cancer research curricula, recruited new faculty, increased awareness about health care disparities and cultural sensitivities, and developed programs and outreach efforts in educating underserved communities. The MI/CCP has provided research education and training to individuals at all levels including postdoctoral fellows, medical students, graduate students, students at master's level, and baccalaureate and high school students. Establishing new collaborations and partnerships in communities has been a hallmark of this program, culminating in increases in numbers of awarded grant applications and numbers of manuscripts, oral presentations, and poster presentations at both regional and national levels. Many research advances are emerging from the Partnership. For example, through the Morehouse School of Medicine and University of Alabama Partnership, researchers have identified a possible genetic cause for increased risk for a more advanced form of colorectal cancer in blacks that leads to shorter survival. Understanding the relationship between molecular defects and differences in colorectal cancer incidence, aggressiveness, and clinical outcomes is important in individualizing the treatment and in eliminating racial disparities.
    Biomedical Technology Research Centers (BTRCs): The BTRCs develop versatile new technologies and methods that help researchers who are studying virtually every human disease, each creating innovative technologies in one of five broad areas: informatics and computation, optics and spectroscopy, imaging, structural biology, and systems biology. This is accomplished through a synergistic interaction of technical and biomedical expertise, both within the Centers and through intensive collaborations with other leading laboratories. The BTRCs are used annually by nearly 5,000 scientists from across the United States and beyond, representing more than $700 million of NIH funding from 22 ICs. As an example, optical technologies enable researchers to:
    • Harness the power of light to "see" biological objects, from single molecules to cells and tissues, which are otherwise invisible. New technologies using fluorescence and infrared spectroscopies revealed exquisite details of how proteins fold and interact.
    • Detect and assess malignancy in a rapid, noninvasive manner. Optical technologies have been used successfully to measure responses of breast tumors to chemotherapy and define the margin of tumors so that surgeons can more precisely remove cancerous tissue during surgery.
    Extramural Construction Program Expands Research Capacity: The American Recovery and Reinvestment Act (ARRA) provided $1 billion to NIH for the Extramural Construction program. The program will build capacity to conduct biomedical and behavioral research by supporting the costs of improving non-Federal basic research, clinical research, and animal facilities to meet the research, research training, or research support needs of institutions. One component of the program, the Extramural Research Improvement Program, awards grants to public and nonprofit private entities to expand, remodel, renovate, or alter existing research facilities or construct new research facilities for biomedical and behavioral research. Another component of the program, the Core Facility Renovation, Repair, and Improvement activity, awards grants to public and nonprofit private entities to renovate, repair, or improve core facilities. A core facility is a centralized shared resource that provides access to instruments or technologies or services, as well as expert consultation to investigators supported by the core. Institutions apply for construction grants by submitting applications, which are selected using NIH's standard, competitive, peer-reviewed process. Funding decisions are based on the scientific and technical merit of the application as determined by first and second level of peer review, the availability of funds, the relevance of the application to NIH program priorities, the national geographic distribution of awards, and the priorities specified in the ARRA, such as energy efficiency and job creation. The objective of the ARRA Extramural Construction program aligns with the objective of the existing Research Facilities Improvement Program, which is also administered by NIH.
    Shared Instrumentation Grant and High-End Instrumentation Programs: The goal of the NIH instrumentation programs is to provide new-generation technologies to groups of NIH-supported investigators for a broad array of basic, translational, and clinical research. These programs provide essential instruments that are too expensive to be obtained through regular research grants. The Shared Instrumentation Grant (SIG) program funds equipment in the $100,000-$500,000 range, while the High-End Instrumentation (HEI) program funds instrumentation in the $750,000-$2 million range. New research technologies supported by these programs enable novel modes of inquiry, which in turn lead to increases in knowledge, and ultimately have the potential for improving human health. To increase cost-effectiveness, the instruments are located at core facilities with trained technical staff to assist in protocol development and to facilitate integration of new technologies into basic and translational research. In FY 2008, the SIG program funded a total of 82 grants for $30,623,406; the HEI funded a total of 20 awards for $33,309,434. In FY 2009, NIH received $300 million in ARRA funding to provide shared instrumentation to extramural researchers through the SIG and HEI programs. To best serve the needs of NIH-supported investigators, the range of HEI awards funded by ARRA was expanded and now is $600,000 to $8 million.

    Stimulating Innovation

    The NIH Director's New Innovator Award Program: The NIH Director's New Innovator Award addresses two important goals: stimulating highly innovative research and supporting promising new investigators. The award supports new investigators who propose exceptionally innovative research ideas but lack the preliminary data required to fare well in the traditional NIH peer review system. Award recipients have discovered important insights about Parkinson's genes and manganese poisoning, and protein folding and diabetes.

    • Link between Parkinson's disease genes and manganese poisoning: Manganese poisoning, prevalent in such occupations as mining, welding, and steel manufacturing, damages the central nervous system, producing motor and dementia symptoms that resemble Parkinson's disease. One New Innovator recipient's team found a genetic interaction between two Parkinson's disease genes (alpha-synuclein and PARK9) and determined that the PARK9 protein can protect cells from manganese poisoning. Yeast cells contain a gene nearly identical to PARK9, and the team showed that expression of this gene protects yeast cells from the toxicity caused by alpha-synuclein. The team found that the PARK9 gene in yeast also codes for a metal transporter protein. Cells with a defect in this gene, coupled with manganese exposure, did not grow well. These results may explain the origin of at least one type of Parkinson's disease.
    • Protein folding and diabetes: Individual protein molecules do not always fold correctly into their normal shapes. A compartment within cells called the endoplasmic reticulum (ER) acts as a protein-folding factory for secreted proteins such as insulin. Another New Innovator recipient hypothesized that unrelenting insulin production can overtax the ER, leading to the condition of "ER stress." This triggers a chain of events that leads the insulin-making beta cells to commit suicide. This new knowledge could be used to identify new molecules as targets for the development of what may prove to be totally new types of drugs to fight diabetes.
    The NIH Director's Pioneer Award: The NIH Director's Pioneer Award Program is designed to support highly innovative approaches to addressing major challenges in biomedical and behavioral research. By supporting scientists of exceptional creativity who propose pioneering and possibly transformative approaches, NIH intends to encourage novel investigator-initiated research that would have an unusually high scientific impact. Already, several recipients of the Award have discovered important insights, e.g., in Parkinson's disease, therapies for neurodegenerative diseases, and targets for cancer therapies.
    • Parkinson's disease and possible treatments: Using an approach dubbed "optigenetics," one Pioneer Award recipient found that stimulating axons that connect directly to the subthalamic nucleus from areas closer to the surface of the brain in rodents has the biggest effect on treating "parkinsonism." This insight could lead to the development of less invasive treatments for patients with Parkinson's disease.
    • Personalized therapies for neurodegenerative diseases using RNA to reprogram cells: Another recipient has shown that by flooding a nerve cell with a specific type of messenger RNA from another cell type, researchers could reprogram the nerve cell. The approach, called Transcriptome Induced Phenotype Remodeling, suggests a new type of cell-based therapy for neurodegenerative and other diseases.
    • Research in mice and human cells suggests new cancer therapeutic targets: Another Pioneer Award study showed that a single extra copy of a particular gene on chromosome 21 is sufficient to significantly suppress angiogenesis (growth of new blood vessels) and tumor growth in mice, as well as angiogenesis in human cells. The study also showed that the protein expressed by the gene under study, DSCR1, is elevated in tissues from people with Down syndrome and in a mouse model of the disease. Given that the incidence of many cancers is significantly reduced in individuals with Down syndrome, this finding suggests a new target for cancer therapies.
    Building Interdisciplinary Research Teams (BIRT) Awards: The scale and complexity of biomedical research demands that scientists move beyond the confines of their individual disciplines and explore new organizational models for team science. Integrating different disciplines holds the promise of opening scientific avenues of inquiry and, in the process, potentially forms new disciplines for addressing increasingly complex questions. The BIRT award was created by NIH to promote interdisciplinary research by supplementing collaborations with high innovation and potentially high impact in general areas of arthritis, musculoskeletal, and skin biology and diseases. In 2008, 11 grants were awarded for the following areas of collaboration: developmental biology—systems biology, soft tissue biology—imaging technologies, tissue engineering—immunology, and tissue engineering—developmental biology.
    Cancer Health Disparities Research Programs and Initiatives: NIH has expanded research on the basic biologic factors of cancer disparities to provide a foundation for minimizing risk, identifying targets, developing preventive and therapeutic interventions, and understanding how genetic susceptibility may be influenced by social, economic, race/ethnicity, and geographic factors. Thus, the research programs involve multidisciplinary teams, which contribute to understanding the etiology of cancer and build prevention and intervention evidence-based models to eliminate cancer disparities. Several programs at NIH address disparities along the cancer continuum from prevention to survival.
    • The trans-disciplinary Geographic Management Program (GMaP) pilot initiative builds regional networks to support research, training, and infrastructure to develop state-of-the-art networks/centers to ensure a continuous supply of high-quality human biospecimens from multi-ethnic communities.
    • The Community Networks Program engages communities experiencing cancer disparities to design, test, and evaluate evidence-based strategies to address critical needs, such as access to screening, mentoring, and training; policy development; and community outreach and education.
    • The Patient Navigation Research Program builds partnerships to ensure that racial/ethnic minorities and underserved populations with abnormal cancer screening results receive appropriate care.
    • The Community Clinical Oncology Program is a network for conducting cancer prevention and treatment clinical trials by connecting academic centers with community physicians.
    • The NIH Centers for Population Health and Health Disparities catalyze transdisciplinary research to improve the understanding of complex interactions of biological, social, cultural, environmental, and behavioral factors that contribute to health inequities, and to develop and implement novel intervention strategies that are multilevel and multifactorial.
    • The Tobacco Research Network on Disparities' mission is to understand and address tobacco-related disparities by advancing the science, translating that scientific knowledge into practice, and informing public policy.
    • The Centers of Excellence in Cancer Communication Research continue to use best practices in communication science to extend the reach of biomedical benefits equitably throughout the population.
    Cooperation in Space-Related Health Research: In FY 2009, NIH and the National Aeronautics and Space Administration (NASA) issued a funding opportunity announcement to support biomedical experiments that astronauts could perform on the International Space Station (ISS). The ISS provides a special microgravity and radiological environment that Earth-based laboratories cannot replicate. Congress, recognizing the immense promise the facility holds for American-led science and technology efforts, opened the U.S. portion of the ISS to other Federal agencies and university and private sector researchers when it designated the U.S. resources as a National Laboratory in 2005. Recently published ISS experiments from investigators supported by NIH and NASA have offered new insights into how bacteria cause infectious disease. The FY 2009 solicitation is the next step in a partnership to apply the National Laboratory to research that complements NASA's space exploration efforts. The program encourages a new cadre of health researchers from a variety of disciplines to incorporate the space environment into their experiments, and will support them as they prepare their experiments for launch and analyze their data following a mission. Applications particularly are encouraged from researchers who are interested in molecular or cellular biology, biomaterials, or telemedicine. NIH expects to fund applications in FY 2010, FY 2011, and FY 2012, and to send experiments into space by 2011.