Biennial Report of the Director

Overview of NIH Research Portfolio
Basic Research

Basic research is a major force driving progress across the biomedical and behavioral sciences and is paramount in uncovering the fundamental principles of biology, and ultimately, the key to our understanding of health and disease. Investments in basic biomedical 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 yielded and will continue to yield inestimable rewards and benefits to public health. Therefore, fostering a broad basic research portfolio is critical for the NIH mission.

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

Basic biomedical research seeks to understand how finely tuned biological and behavioral processes work together in harmony and, how this harmony at multiple levels of analysis can break down, forming the basis of disease. For example, at the molecular level, scientists are interested in understanding how biological macromolecules—proteins, nucleic acids, sugars, and lipids—carry out cellular processes. At the cellular level, researchers are focused on understanding how cells sense and respond to their environment. And at the behavioral level, researchers are focused on how individual organisms react to and act upon their environment.

Basic research is encompassed in the missions of all NIH ICs, and progress often requires interdisciplinary approaches to develop new technologies, improve methods of data analysis, and provide insight on fundamental disease pathways. NIH fosters collaborations that span all of the traditional and emerging disciplines of the life, physical, engineering, computer, behavioral, and social sciences.

Progress in basic research generally does not follow a linear path from test tubes to cell culture to animal models. Instead, it tends to result from a continuum of collaborative interactions between research groups across multiple disciplines. The discovery of a gene that causes a disease state in mice may spark the creation of research programs to investigate the structural basis for the interaction of the gene’s protein product with a partner molecule. Other studies may elucidate a novel molecular pathway that the protein and its partner molecule regulate and thereby generate a biological response. Conversely, the visualization of a previously unknown protein structure may provide remarkable insight into the protein’s function and generate a hypothesis for how a particular gene 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.

NIH supports a comprehensive portfolio of basic research aimed at understanding fundamental life processes. The results of such studies provide insights on fundamental aspects of biology and behavior 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.

Model Organisms and Systems

Basic research is concerned with advancing our understanding of human health and disease; however, for a number of reasons—both ethical and practical—many fundamental aspects of biology cannot be studied in people. Therefore, scientists often carry out basic research in “model systems” that are easier to work with in precisely defined and controlled settings. Basic research using model systems and organisms has provided the foundation of knowledge about human growth and development, behavior, the maintenance of health, and development of disease. 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 and thereby lead to new methods for maintaining health and diagnosing and treating disease.

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. NIH supports the development and distribution of collections of animals with defects in known genes. They 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.

Model organisms are often especially useful for understanding features of disease that have similar underlying 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 translate the findings into knowledge to benefit people with those diseases.

In addition to supporting individual 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 and non-animal models for the study of human diseases.

Molecular Mechanisms and Pathways

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 pathways have already 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 them may lead to disease and what might be done to restore disturbed pathways to their normal functions.

NIH supports a broad spectrum of research to improve the molecular-level understanding of fundamental biological processes and discovering approaches to its control. By uncovering how certain molecules function in key signaling pathways, scientists may be able to develop therapies that target these molecules for the treatment of a variety of devastating disorders. The goals of research supported by NIH in this area include an improved understanding of drug action; pharmacogenetics—the study of genetic mechanisms underlying individual responses to drugs; new methods and targets for drug discovery; advances in natural products synthesis; an enhanced understanding of biological catalysts; 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.

Molecular and Cell 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 an adult organism. The eventual goal of these studies is to improve the diagnosis, treatment, and prevention of human genetic and developmental disorders and diseases.

All cells go through different stages in the cell cycle. A new cell is formed when its parent cell divides in two; it carries out its biological functions; it reproduces by dividing, often dozens of times; and then it dies. Underlying these milestones are regular cycles. 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. 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 of cells 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 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 an internal repair system, dividing essentially without limit to replenish other cells throughout life. When a stem cell divides, each new cell has the potential either to remain a stem cell or to 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 that are directed to differentiate into specific cell types offer the possibility of a renewable source of replacement cells and tissues to treat diseases such as diabetes, heart disease, vision loss, and Parkinson’s disease. Today, donated organs and tissues may be used to replace ailing or destroyed tissue, but the need for transplantable tissues and organs far outweighs the available supply. Much research is underway to understand how to use products developed from stem cells as therapies to treat disease.

NIH has funded numerous research projects on the basic biology of human embryonic stem cells (hESCs) and has developed initiatives to support fundamental research on a new kind of stem cell, called an induced pluripotent stem (iPS) cell. 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 has seen an increase in the number of investigator-initiated research applications using iPS cells, and NIH support of this research area is growing.

The NIH Common Fund supported the establishment of an NIH Center for Regenerative Medicine (NIH CRM) within the NIH IRP to serve as a resource for the scientific community, providing stem cells and supporting protocols and standard operating procedures used to derive, culture, and differentiate the stem cells into different cell types. The program is intended to accelerate the development of cell-based therapies for repairing or replacing tissue damaged by disease or injury. Among various potential activities, NIH CRM is helping standardize research results across different laboratories by facilitating access to a set of well-characterized stem cell control and reporter lines. In addition, the center is negotiating uniform iPS cell deposit and distribution agreements with major human cell and tissue banking facilities for NIH researchers that can be more widely adopted. The NIH CRM Director has established numerous domestic and international collaborations. In addition to these efforts, a number of intramural iPS cell pilot research projects have been funded to stimulate iPS cell research at the NIH and to help translate findings in to the clinic, in part by serving as “test cases” for newly developed standardized procedures and resources.

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 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 diseases. Furthermore, the immune system of transplant recipients mounts an attack on donated organs and tissues, which imposes the need for strong drugs to prevent rejection. The lack of an immune response also can be very deleterious, 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 regulation of the immune system is achieved to protect the body while still preventing immune attack on a person’s own tissues.

Inflammation is mediated 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.

“-Omics Approaches

“-Omics” approaches characterize cellular molecules, such as genes, proteins, metabolites, carbohydrates, and lipids, and allow comparisons to be made between species and among individuals of a species. Technological advances in “-omics”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.

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. The deluge of genomic information has, in turn, generated a pressing need for computerized databases to store, organize, and index the data and for specialized tools to view and analyze the data. 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.

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. Genomics is the study of an organism’s entire genome—the complete assembly of DNA, or in some cases RNA (ribonucleic acid)—that transmits the instructions for developing and operating a living organism. Genomic research focuses not just on individual genes but also on the functioning of the entire genome as a network and, importantly, on how this network interacts with environmental factors to influence health and cause disease. Genomics is a new and challenging discipline that is increasingly used in virtually every field of biological and medical research.

DNA is made up of four chemical compounds called “nucleobases.” Four distinct nucleobases are found in the DNA of all organisms: adenine, thymine, guanine, and cytosine—denoted by the letters A, T, G, and C respectively. These nucleobases are attached to sugar molecules and phosphate groups to form strands. Two parallel strands are entwined in the form of a double helix, held together by nucleotide pairs. Each nucleotide in one strand links to the same partner on the other strand: A pairs with T, C pairs with G—forming what is called a “base pair.” The human genome consists of about 3 billion base pairs, packaged in 23 sets of chromosomes that are wrapped extremely tightly into the nucleus of virtually every cell in the body. Identifying the base pairs—and thus the letters—and the order in which they appear on any stretch of DNA is called “sequencing” that segment.

DNA’s double helical structure was discovered in 1953. Fifty years later, the human genome was fully sequenced by an NHGRI-led, multinational effort called the Human Genome Project, which lasted 13 years and completed its work ahead of schedule and under budget. The sequencing of the human genome generated immense scientific excitement. It provided a new means of analyzing the functions of cells, tissues, and systems in the body and offered new tools for understanding the causes of disease. It laid the foundation for broad new scientific disciplines such as proteomics, the study of the structure and function of all the proteins produced by the body (in response to instructions carried by the genes). Recent studies have demonstrated that the genome contains more information than can be interpreted from just its sequence. It is more complex, more variable in its structure, and more complicated in its internal interactions than anyone imagined just a few years ago. Almost every human disease or disorder has a genetic component and an environmental component. The genetic components for some heritable diseases, such as sickle cell disease or cystic fibrosis, result from mutations in single genes—changes that disrupt the function of the protein they encode. However, in most diseases the role of genes and the environment is more complicated. Some diseases arise as a result of spontaneous gene mutations that occur during a person’s lifetime; others are caused by complex cascades of changes in gene expression triggered, perhaps, by environmental factors. Differences as small as one letter in our 3 billion pairs of DNA letters can cause disease directly or cause a person to respond differently to particular pathogens or drugs. Multiple genetic and environmental factors play a role in myriad common diseases, such as heart disease, cancer, diabetes, and asthma, but for no common disease have all the genes involved yet been identified.

Educational resources to help the public understand genomics, including multimedia presentations, are available on the NIH Web site.16

As a result of the overwhelming influence of the genome on human health, virtually every NIH IC now engages in genome-related research. Like many NIH ICs, NCI supports a huge array of gene-oriented projects, including Genome-Wide Association Studies (GWAS)—in effect, full-body DNA scans—that recently detected new genetic factors involved in breast, prostate, and colon cancers. The first successful application of GWAS for age-related macular degeneration (AMD) identified an entirely new molecular pathway. In 2010, an NEI-led international consortium combined data from multiple GWAS on AMD to identify many new genetic loci. Similarly, in FY 2009, NEI conducted the largest glaucoma genetics study to date and identified two new highly significant pathways involved in glaucoma. Over the past four years, NHLBI and NIGMS have sponsored a research consortium that combined both genetic and clinical data to devise a computer algorithm for setting the proper dose of the blood-thinner warfarin, commonly prescribed for heart patients and others, the physical response to which is strongly influenced by genetic factors. 17 A major clinical trial began in early 2009 to test whether that new algorithm is better than the current trial-and-error method.

NIH researchers and grant recipients also have increased the pace of sequencing other nonhuman genomes. Full sequences of nearly 200 organisms now have been completed or are underway. Comparing the human genome to the genomes of other creatures, including insects and even single-celled organisms, reveals stretches of DNA that have remained similar over millions of years of evolution. These “conserved” sequences are thought to play an important role in the functioning of a living organism, even if scientists do not yet know what that role is.

Genes themselves, the “coding regions” of DNA that direct cells to make particular proteins, account for only about 2 percent of the human genome. Locating the noncoding but functional sequences throughout the rest of the genome is the main mission of the ENCODE (ENCyclopedia Of DNA Elements) research consortium. NIH also has pressed ahead with the Model ENCODE project (modENCODE) to identify all the functional elements in the genomes of two hugely important and widely used laboratory model organisms—the fruit fly Drosophila melanogaster and the roundworm Caenorhabditis elegans. 18 The strategy is to identify genomic mechanisms in these model organisms, which will elucidate novel research directions for human genomic and other researchers.

DNA sequencing and analysis projects serve to advance technology and bioinformatics that may soon bring revolutionary improvements to the practice of medicine. The development of new methods to sequence DNA faster and more cheaply is the central goal of some NIH-sponsored projects. As NIH continues to fund technological innovation in this area, the costs continue to fall remarkably. Soon, when a patient’s full genome can be sequenced for less than the cost of other routine medical tests, and ongoing genomic research programs have further broadened and deepened our understanding of the genome’s functioning, we may well be approaching a new era in medical care. The practice of medicine will move beyond a one-size-fits-all approach, and the promise of personalized medicine will be realized.

NHGRI’s 1000 Genomes Project aims to discover almost all human genetic variants in order to support studies relating genetic variation to health and disease. The project is sequencing the genomes of 2,661 people from 26 populations around the world and releasing the data publicly. The sequence data will allow the project to identify variants ranging from single DNA base differences among people up to large insertions or deletions in their genomes. Many of these variants contribute to an increased risk for particular diseases or to differences in drug response. Researchers will use these data to map the genes and variants affecting disease and to study the genetics of human populations.

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, or no response at all. By understanding the differences in the genetic basis of drug responses scientists hope to enable doctors to prescribe the drugs and doses best suited for each individual. The mission of the NIH Pharmacogenetics Research Network (PGRN) is to better understand the genetic basis for variable drug responses and identify safe and effective drug therapies designed for individual patients.

Most of the genome research that will lead to direct clinical implications, improve our understanding of human health, and change clinical practice, still lies ahead. Over the next decade, research will unlock the true potential of this foundational work, leading scientists closer to better means for preventing, diagnosing, and treating disease.

When the Human Genome Project was completed in 2003, the cost to sequence a human genome was more than $10 million. NHGRI understood that human genome sequencing, far from being over, was just beginning. Conducting the research needed to dissect genomic contributions to disease would require hundreds of thousands to millions of human sequences. Lowering the cost became a high priority, so NHGRI set a goal of reducing the cost of sequencing a human genome to $1,000 in 10 years, with an intermediate goal of $100,000 in 5 years. Since launching the Advanced DNA Sequencing Technology program in 2004, NHGRI has committed more than $150 million to 60 research teams and supported a wide variety of scientific approaches. By 2009, NHGRI-supported research had contributed to achieving the five-year goal. The resulting technologies have revolutionized the study of human genetic variation in studies ranging from the 1000 Genomes Project to The Cancer Genome Atlas. The focus of the sequencing technology program has shifted toward achieving human genome sequencing for $1,000 or less, which will offer the possibility of using genome sequence information in a routine healthcare setting.

Using DNA from tissue samples, genome-wide association studies scan and compare entire genomes of people with and without a particular disease, looking for single-base differences (known as single nucleotide polymorphisms, or SNPs) that might signal the presence of a gene or some other functional sequence implicated in the disease. GWAS are based on the Haplotype Map (HapMap) of the human genome, produced via an NIH-led international research team earlier in the decade that identified more than 3 million relatively common SNPs in human genomes that serve as markers for larger neighborhoods of DNA sequences. 19 GWAS scans point to regions of the genome that are worthy of closer study in seeking the genetic cause of a disease. Over 1,600 of such studies have been conducted since the technique was first developed in 2005, flagging genetic areas that may be linked with at least 80 different diseases and disorders including heart disease, diabetes, obesity, inflammatory bowel diseases, and many types of cancer. 20

Information emerging from NIDCR investments in GWAS of dental caries complements other clinical research on caries risk factors, allowing genetic factors to be considered, along with behavioral, environmental, and microbial determinants of caries development, when treatment decisions are made. Molecular-based oral health care will transform the most fundamental principle of the dental profession—restoration of form and function—as dentists will use the precision of individual genetic and physiological information as their operational guide. In addition, a recent GWAS of cleft lip and/or cleft palate,21 the fourth most common birth defect, is providing insight into genetic variants and their interplay with non-genetic factors, which may lead to improved prevention and treatment strategies. NIDCR is also supporting efforts to identify the genetic component of areas critical to diverse patient groups, such as Sjögren’s Syndrome and periodontal disease. NIDCR investments are catalyzing tremendous progress in understanding the role of genetic variation in a wide range of conditions such as craniosynostosis (premature closing of joints between bones in the skull) using more targeted genotyping, DNA sequencing, gene expression studies in tissues, and animal models of human conditions. These investments are laying the groundwork for translation of compelling clinical leads into improved, individually tailored care.

While the genetic causes of most diseases and disorders are not fully understood, NIH researchers have identified individual genes or regions of DNA associated with numerous diseases and disorders, such as schizophrenia and bipolar disorder; cancers of the skin, lung, brain, pancreas, breast, prostate, and testicle, and acute lymphoblastic leukemia; diabetes; periodontitis in African Americans; asthma; high blood pressure; heart arrhythmias; inflammatory bowel diseases; kidney disease; Alzheimer’s disease; and obesity, among many others.

NIH completed full sequencing and analysis of multiple vertebrate and invertebrate animal genomes over the past four years. These include the platypus, domestic cattle, the wasp, other insects, and a large number of disease-causing organisms—such as the malaria-causing parasite Plasmodium vivax, the common intestinal parasite Giardia lamblia, the Lyme disease-causing tick Ixodes scapularis, and two species of the parasitic flatworms that cause schistosomiasis. Also sequenced were thousands of separate strains of the constantly changing human influenza viruses. NIAID now has sequenced the genomes of thousands of infectious microorganisms, including 10,000 influenza viruses.

NIH-funded analysis of genomic data from 121 African populations, 4 African American populations, and 60 non-African populations revealed that all African populations descended from 14 ancestral groups. Most African Americans trace the majority of their ancestry to West Africa, a finding that will improve scientists’ ability to identify genetic risk factors in African and African American populations.

16 For more information, see https://www.genome.gov/10000002.
17 International Warfarin Pharmacogenetics Consortium. N Engl J Med. 2009;360(8):753–64. PMID: 1922818.
18 Celniker SE, et al. Nature 2009:459(7249):927–30. PMID: 19536255.
19 For more information, see http://www.hapmap.org/ Exit Disclaimer.
20 For more information, see https://www.genome.gov/gwastudies/.
21 Beaty TH, et al., Nat Genet. 2010;42(6):525–9. PMID: 20436469.

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 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 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.

The NIH Common Fund Epigenomics Program aims to stimulate research to understand 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. In addition, new lines of research are aimed at understanding how environmental exposures may work through epigenetic mechanisms to affect susceptibility and development of disease. Ongoing epigenomic projects include studies on cognitive decline, atherosclerosis, and effects of bisphenol A exposure. 22

22 For more information, see https://nihroadmap.nih.gov/epigenomics/fundedresearch.asp.

The Microbiome

The body of a healthy human adult is home to 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 perform necessary cellular functions (such as the digestion of certain nutrients in the intestines). Through the NIH Common Fund, 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. For example, microbial communities may contribute to such diseases and conditions as obesity, diabetes, cancer, and autoimmune diseases. Sequencing technology has, as with human genomics, speeded the study of the microbiome considerably. NHGRI and other NIH ICs are using sequencing technology, among other methods, to study bacterial species in and on the human body. However, other high throughput technologies offer the potential to enrich our understanding of the contribution of the microbiome. The Common Fund is supporting studies to explore the utility of these approaches.

Dovetailing with this effort, NIDCR-supported researchers and others recently identified the more than 600 distinct microbial species that are residents of the human mouth. NIDCR-supported researchers have gathered this information in the Human Oral Microbiome Database (HOMD), the first example of a curated human body site-specific microbiome resource which is freely available to the public. Advances in studying oral microbial communities have the potential for rapid impact on research for new, more personally targeted, clinical treatment. For example, researchers have identified a microbe called Scardovia wiggsiae that appears to be linked with severe forms of early childhood caries.

Translating the Genetic Code: Transcriptomics, Proteomics, and Metabolomics

Beyond understanding genes and their regulation, NIH also supports system-wide studies to understand which 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 health and disease. 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, such studies have the capability of defining normal homeostatic and disease mechanisms. 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 the pathways.

Beyond understanding genes and their regulation, NIH also supports system-wide studies to understand which 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 health and disease. 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, such studies have the capability of defining normal homeostatic and disease mechanisms. 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 the pathways.

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 particular diseases by blocking, inhibiting, or activating specific molecules.

Glycomics

NIH is also 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 broad spectrum antivirals.

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 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 that are tested in cellular systems or model organisms to 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. 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.

Environmental Factors that Impinge on Human Health and Disease

Cells not only respond to changes in their microscopic environment but also sense and respond 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 to understand how environmental factors are detected by our bodies and how, at all levels—molecular, epigenetic, cellular, organ, and behavioral systems—they influence the development and progression of human diseases. At the NIEHS, the IC devoted specifically to these goals, research programs are elucidating the effects of exposure to a range of toxic air pollutants in utero and resulting impaired development in fetuses and offspring, as well as increased potential for development of a range of chronic diseases later in life. Other programs are looking at the impacts of climate change on increased vulnerability of certain populations to a wide range of diseases such as cardiovascular disease, asthma, cancer, and mental disorders, as well as effects of exposure to a broad range of environmental chemicals including pesticides and endocrine disruptors. 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.

Basic Behavioral and Social Science Research

It has been estimated that human behavior accounts for almost 40 percent of the risk associated with preventable premature deaths in the U.S.23 Health-injuring behaviors such as smoking, drinking, and drug abuse, as well as inactivity and poor diet are known to contribute to many common diseases and adverse health conditions. Unfortunately, there are few tried and true approaches to motivate people to adopt and maintain healthy behaviors over time.

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 informs 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.

Basic behavioral and social sciences research supported by NIH is composed 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 (e.g., cognitive, social, economic, environmental, and developmental) that shape health decision-making and the conditions under which knowledge leads to action vs. inaction. Basic behavioral economic and decision research approaches—such as “choice architecture” that 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.

In 2010, the NIH Common Fund launched the Science of Behavior Change program to improve our understanding of human behavior change across a broad range of health-related behaviors. The program now supports research that integrates basic and translational science and cuts across disciplines of cognitive and affective neuroscience, neuroeconomics, behavioral genetics, and behavioral economics. The program aims to establish the groundwork for a unified science of behavior change that capitalizes on both the emerging basic science and the progress already made in the design of behavioral interventions in specific disease areas.

Also launched in FY 2010, the NIH Basic Behavioral and Social Science Opportunity Network (OppNet) is a trans-NIH initiative supported and managed by 24 ICs and four program coordination Offices within the OD. Its mission is to pursue opportunities for strengthening basic behavioral and social science research at the NIH while innovating beyond existing investments. In FY 2010, OppNet funded short-term, mentored career development awards in the basic behavioral and social sciences for mid-career and senior investigators, and competitive revisions in basic behavioral and social sciences research, HIV/AIDS-related research and Small Business Innovation Research and Small Business Transfer Technology Research Grants. In FY 2011 OppNet funded new awards to support basic research on the following topics: self-regulation; the effects of the social environment on health; sleep and the social environment; psychosocial stress; and basic mechanisms influencing behavioral maintenance. In addition, the initiative supported short- term, interdisciplinary research education programs for new investigators, scientific meetings to foster the development of interdisciplinary research teams, additional competitive revisions, and short term, mentored career development awards. By fostering basic research on behavioral and social processes, OppNet supports the NIH mission to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce the burdens of illness and disability. 24

Biopsychosocial research looks at the interaction between biological, psychological, and social processes and 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.

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.

23 Schroeder SA. N Engl J Med. 2007;357(12): 1221–8. PMID: 17881753.
24 Additional information about OppNet can be found at https://oppnet.nih.gov/index.

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 study, 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. eyeGENE®, a nationwide partnership of 250 Registered Clinical Organizations, has created a national, open-access DNA repository of genetic samples from highly characterized individuals and families. Serving both research and clinical needs, the Network has broadened accessibility of diagnostic genetic testing through a central and secure process, testing 70 genes in over 30 inherited eye diseases from 3,500 patient samples since its establishment in 2006.

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. In addition to databases, NIH also provides resources for retrieving, visualizing, and analyzing molecular biology and genome sequence data online.