Biennial Report of the Director

Overview of NIH Research Portfolio
Preclinical Translational Research

Translating basic discoveries from the laboratory into new or more effective diagnostics and therapeutics is essential for tackling unmet biomedical needs and improving human health. However, the translational process can be complex, costly, and risk-laden, as evidenced by the less-than-one-percent of compounds initially tested that actually make it into the patient’s medicine cabinet. The development of medical devices, imaging techniques, and behavioral interventions follow a similar path of progression. It can take more than a decade before a basic scientific finding is able to advance through preclinical and clinical studies to result in a new treatment, medical device, or prevention method. And many promising leads from basic research fail to become a proven strategy to address health, often failing in the preclinical stage.

However, today advances in biomedical research and technologies have created unprecedented opportunities to transform the translational development pipeline, especially in the preclinical stage. Recent discoveries in basic science have uncovered the molecular mechanisms underlying hundreds of diseases, resulting in many more potential strategies for intervening against disease progression. Furthermore, high-throughput technologies are more readily available to academic investigators and allow all those in biomedical research to pursue these strategies at what would have been an unimaginable pace just a few years ago. For example, this technology can be used to identify new therapeutic candidates at a dizzying speed. Finally, partnership efforts are significantly changing the research landscape, in part by spearheading the implementation of scientific projects that no one party would be able to perform independently.

NIH is uniquely poised to capitalize on these developments. Numerous NIH programs and resources are dedicated to supporting research that moves basic research through to preclinical testing and beyond. NIH also has a unique capability to foster critical multidisciplinary collaborations, whose synergistic efforts can lead to new technologies and devices for diagnosing, preventing, and curing diseases and for bringing new discoveries into common medical practice.

NIH supports the development of consortia, cooperative study groups, and networks that enable a single institution or researcher to combine knowledge and resources with others.

The federal government plays a critical role in focusing on gaps in translational research that would otherwise remain unaddressed by other entities (e.g., pharmaceutical companies, nonprofit organizations). Specifically, NIH supports translational studies unlikely to garner substantial investment by other sources because of insufficient financial incentives—for example, studies that address rare diseases, entail perceived high risk, or involve lifestyle alterations or behavioral changes. In its unique position, NIH can bring together resources that offer unprecedented opportunities. For example, NIH’s ability to create consortia is particularly useful for studying rare diseases, as they make it possible to recruit sufficient numbers of participants to provide the necessary sample for preclinical and clinical study.

The Discovery of Biomarkers

Each NIH IC supports a robust portfolio of translational research which exploits basic science discoveries for the creation of new ways to intervene against specific disease processes. One important way that basic science may be used to better clinical treatment is through the identification, development and validation of biomarkers. Biomarkers are physical, functional, or biochemical indicators of physiologic or disease processes and play important roles in the diagnosis of disease, the identification of patient populations that could benefit from particular therapies, and the monitoring of treatment effectiveness.

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is an example of an innovative public-private partnership to develop uniform standards for acquiring longitudinal, multisite biomarker data, including magnetic resonance imaging (MRI), positron emission tomography (PET), cerebrospinal fluid, and blood data to characterize the progression from normal cognition to Alzheimer’s disease with greater sensitivity. In 2010, ADNI entered its second major five-year phase (ADNI 2) focusing on participants who exhibit the very beginning stages of memory loss. One important aspect of the study is the data will be posted to a publicly accessible database and available to qualified researchers worldwide. This initiative will speed the pace of discovery by providing a centralized resource allowing investigators to access, study, and share their own high-quality data relevant to AD.

Genomics Translational Research

The rapid pace of genomics research has led to a multitude of efforts to apply this understanding to the development of better ways of preventing, detecting and treating any number of diseases and conditions.

By developing a a deeper understanding of the molecular and genetic mechanisms that cause cancer, NCI is finding new ways of identifying those at risk for certain cancers and for determining more precise strategies to treat those with cancer. Within its Center for Cancer Genomics, the Cancer Genome Atlas is a multi-institutional, collaborative study conducted jointly with NHGRI that seeks to identify the changes in each cancer’s genome that results in specific subtypes of that cancer. This knowledge will ultimately lay the foundation for improving cancer prevention, early detection and treatment. It has recently cataloged the genetic alterations in two important cancers for which early diagnostic methods, broadly applicable prevention strategies, and effective therapies are not yet available: the uniformly lethal brain cancer glioblastoma multiforme and serous ovarian carcinoma.

NHLBI has funded several genome consortia with strong translational components. Research focuses include the identification of genetic variants that may explain why some people with asthma do not benefit from inhaled corticosteroids, gene and chromosomal variations that affect pulmonary fibrosis risk and cystic fibrosis severity, improving outcome prediction for myelodysplastic syndromes, identification of genetic factors that influence blood pressure, and development of a blood test to predict the future development of diabetes.

Scientists are discovering more and more specific genetic variations that may influence an individual’s response to medications. By identifying these variations, health care providers will move beyond the current one-size-fits all approach to treatment towards prescribing drugs and dosages that are tailored to the individual’s genetic make-up. A collaborative effort across several NIH ICs, the Pharmacogenetics Research Network (PGRN) is helping meet the urgent need for experts in pharmacogenomics and personalized medicine by creating a nationwide network of researchers and numerous resources to facilitate their work. The Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB), a component of PGRN, sponsors data-sharing within and beyond the consortia. Recently, PharmGKB collaborated with several genomics groups at Stanford University to develop an integrative personal omics profile (iPOP) that combines genomic, transcriptomic, proteomic, metabolomic, and autoantibody data from a single individual over a 14-month period, providing a rich data resource for numerous studies.

NHGRI is conducting a large pilot project to test ways in which high-throughput genome sequencing might be used in a clinical setting for diagnosing and treating patients. Using the NIH Clinical Center, the trial, dubbed “ClinSeq” (Clinical Sequencing), has enrolled 900 patients to date with a spectrum of coronary artery calcification, from normal to diseased, and will sequence 200–400 areas of their DNA that contain genes suspected of involvement in heart disease. Patients will have the option of learning the outcome of their tests, and those who carry a variant of a gene that has been linked to disease will be counseled and followed, possibly for years. The study is designed both as a pilot project to explore ways of using genome sequencing in patient treatment and as an effort to develop new data about particular genes’ involvement in heart disease. The project may expand in its later stages to cover other diseases.

In a program known as the Multiplex Initiative, individuals ages 25–40 are offered free testing for 15 genes associated with higher risk for type 2 diabetes, heart disease, high cholesterol, high blood pressure, osteoporosis, lung cancer, colorectal cancer, and malignant melanoma. 25 Those who are offered the testing use an interactive, Internet-based program designed by NHGRI researchers that helps participants ask questions about the genetic testing, get information, and decide whether to receive the testing. Meanwhile, Multiplex Initiative researchers monitor the participants’ decision process every step of the way. Those who decide to submit blood samples for the tests will be followed for some time in order to see whether they change their behavior (e.g., by adopting a healthier lifestyle or diet) in response to their test results. 26 Researchers involved with this study have found that individuals who discuss their genetic information with their doctors may be among the most motivated to take steps toward more healthy choices.

25 For more information, see https://www.multiplex.nih.gov/.
26 For more information, see https://www.genome.gov/pfv.cfm?pageID=25521052 and https://genome.gov/pvf.cfm?pageID=25521955.

Behavioral and Social Sciences Translational Research

Multiple efforts across NIH seek to translate basic behavioral and social sciences research into clinical interventions. For example, NIA supports the Edward R. Roybal Centers for Translation Research in the Behavioral and Social Sciences in Aging. As the baby boomer generation continues to celebrate milestone birthdays, improving the health of older Americans is more important than ever. The goal of the centers is to improve the health, quality of life, and productivity of middle-aged and older people. The centers work to facilitate translation of basic behavioral and social science to practical outcomes by developing new technologies and by stimulating new use-inspired research (that is, research focused on meeting a societal need, usually for a device to improve quality of life for certain populations). Roybal investigators have made several key discoveries. For example, researchers have developed tools and technologies for identifying older adults at risk for automobile crash involvement, and are working with industry partners to develop and disseminate products based on these tools. Additionally, researchers have developed a "living laboratory" model methodology for in-home assessment of activity to facilitate early detection of changes in health or memory. Several centers will focus on the social network underpinnings of selected health problems affecting older people, such as obesity and cancer, develop new interventions to improve health outcomes and financial well-being while reducing costs, and foster translation of approaches from behavioral economics to the improvement of health care delivery for older adults.27

27 https://www.nia.nih.gov/newsroom/2010/02/nia-funds-roybal-centers-translational-research-aging

Clinical and Translational Science Awards

The Clinical and Translational Science Awards (CTSA) program supports collaborative teams of investigators representing diverse specialties to tackle complex health and research challenges and accelerate translation of discoveries into treatments for patients. The consortium of 60 medical research institutions across the nation enables innovative research teams to speed discovery and advance science aimed at improving our nation's health. The program encourages CTSA-initiated changes in research infrastructure, including coordinated programs to train and educate early-stage clinical and translational scientists, and development of bioinformatics programs to manage medical record data and transform institutional research activities and resources into searchable databases. The teams are making progress across a broad range of diseases and conditions, such as cancer, diabetes, neurological disorders, and heart disease. CTSA resources to foster translational research include i2iConnect, a database of industry contacts looking for new ideas and products that researchers and other innovators can search quickly by specialty and disease area to find potential industry partners interested in their work; CTSA-IP, an online intellectual property search engine that aggregates and promotes technologies from CTSA institutions and NIH to enhance research activity and encourage private partnerships; and the CTSA Pharmaceutical Assets Portal, which enables scientists to learn more about compounds evaluated for specific diseases that might be used to treat other conditions.

Examples of CTSA-enabled Translational Research Advances

Researchers at the Scripps Translational Science Institute and the University of California, San Diego, Clinical and Translational Research Institute invented a new technique to investigate and help identify risk for coronary artery disease (CAD). They discovered variations in the DNA in one area of the genome that changed the way a gene in a totally different area functioned, thus increasing CAD risk. This discovery opens the door to new interventions that could one day predict heart attacks before they happen and may lead to insights into other conditions linked to poorly understood genetic risk factors.

Pilot research by a team at The Ohio State University Center for Clinical and Translational Science indicates that oxygen therapy can protect rodent brain cells during stroke, when a blood clot blocks the flow of oxygen-rich blood to the brain. In the study, the team found that oxygen therapy could reduce brain damage when given during a stroke but was less effective after surgeons removed the blockage, pointing to the need to begin the therapy soon after stroke onset to achieve the best results. 28 These findings easily could lead to a new therapy, because providing oxygen to stroke patients would be simple and fast.

28 Rink C, et al., J Cereb Blood Flow Metab. 2010;30(7):1275–87. PMID: 20145654.