T H E   N I H    C A T A L Y S T      M A Y   –  J U N E   2001



by Michael Gottesman
Deputy Director for Intramural Research
Michael Gottesman

The intramural programs at NIH are in a period of transition. We are leaving a decade of restructuring and revitalization and moving forward to a period of evolution as the nature of how we conduct science changes.

To frame a context for exploring the directions of the next decade of intramural research, Ruth Kirschstein, NIH acting director, asked me to review for the institute and center directors the progress of the last decade and the challenges for intramural research that lie ahead. I presented my thoughts to the directors in two lively three-hour sessions April 12 and April 19.

First, let me summarize some of the statistics regarding personnel, budget, and space that informed the discussion.

There were 6,095 scientific personnel in 1990 and 7,728 in 2000, a 26 percent increase. That figure reflects a 53 percent increase in postdoctoral fellows—and a 25 percent decrease in PIs, allowing the recruitment of almost 200 PIs from outside NIH in the past five years.

There was a 78 percent increase in the intramural budget over the decade; adjusted for biomedical research inflation during the same period, however, it was really a 25 percent increase.

There was a 27 percent increase in usable space on and around the Bethesda campus, including the construction of Building 49 and the Vaccine Research Center and the acquisition of off-campus space.

With these figures as backdrop, I presented the following conclusions to the directors:

Despite only a modest growth rate in the past 10 years (about 2.2 percent a year on average), the intramural program has revitalized its scientific infrastructure, responded to public health and scientific needs, and made impressive scientific achievements (see "Intramural Research Accomplishments").

Contributors to this success include rigorous scientific review to redirect resources for new or expanded programs, better-delineated career pathways, more emphasis on technology development and clinical research, and many shared resources to maximize available intramural funds, space, and personnel. (An overview of the shared resources and training programs of the IRP will appear in the next issue of The NIH Catalyst, July–August 2001.)

Space, budget, and personnel in the intramural program are closely linked—they have grown at the same rate over the past decade—suggesting that if one of these is no longer limiting, the others will quickly become so.

Despite our scientific successes, there are continuing problems that demand our attention: increasing the diversity of scientific staff, making space more flexible and providing each person with more of it, and developing career pathways that reflect multidisciplinary needs of future scientific teams.

We would like to improve the infrastructure that responds to emerging scientific and public health needs. A schematic representation of the emerging paradigm for conducting research in the intramural program in the next decade is shown here.

A strong base in technology development and utilization will continue to be needed to support both translational and basic biological research. Basic research here and elsewhere will build on current understanding at a molecular level to create an integrative biology that addresses how molecules interact to form cells, how cells interact to form tissues and organs, how organs form organisms, and how these organisms behave in the environment.

Translation of these basic concepts into research relevant to human health and disease, including animal models of human disease and clinical research, will remain the major goal of the intramural program.

We need the infrastructure to support this research paradigm: new, flexible spaces for research that allow interactions among different ICs and research disciplines, support for expensive instrumentation, new career tracks, and ways to recognize contributions of individuals in a multidisciplinary team. The physical infrastructure for future intramural research should focus on creation of multidisciplinary centers on and near the Bethesda campus. We already have a Vaccine Research Center, and a Neuroscience Research Center and a Musculoskeletal Center are being planned.

To optimize translational and clinical research, revitalization of the Clinical Center Complex (the existing Building 10 and the new Clinical Research Center) will be needed. The NIH Master Plan also accommodates the potential creation of a center that combines advanced technologies, integrative biology, and animal models of disease. The pace of development of this physical infrastructure and its ultimate extent depend heavily on the budget situation for NIH and maintenance of an appropriate balance between extramural and intramural funding.

Organized According to Government Performance and Results Act Goals

Goal A: Add to the body of knowledge about normal and abnormal biological functions and behavior

Identification of disease genes

AP-3, a major component of the protein trafficking system, and HPS-1: defective in two forms of Hermansky-Pudlak syndrome (NICHD)

p16 and CDK4 mutations: responsible for familial melanoma (NCI, NHGRI)

Transcription factor POU4F3, cadherin 23 (Usher syndrome 1D), and claudin 14: involved in familial deafness syndromes, including Pendred syndrome (NIDCD, NHGRI)

Defect in the regulatory subunit of cAMP-dependent protein kinase: involved in Carney complex inherited cancer syndrome (NICHD)

Defect in cholesterol synthesis pathway gene: involved in Smith-Lemli-Opitz syndrome (NICHD)

Mutations in multifunctional ATM gene: responsible for ataxia telangiectasia (NHGRI)

Mutations in Fas receptor and other steps in JAK-STAT pathway: responsible for autoimmune lymphoproliferative syndrome and other forms of immunodeficiency (NIAID, NHGRI, NIAMS, NCI)

von Hippel–Lindau gene: responsible for a familial cancer syndrome (NCI, NICHD)

MET: involved in papillary renal carcinoma (NCI)

BRCA1 and BRCA2 mutations: major inherited causes of breast cancer (NIEHS); estimation of their contribution to risk of breast, ovarian, and prostate cancer (NCI)

IL-1b and IL-RN polymorphisms: linked to gastric carcinomas (NCI)

Mutations in the a-synuclein gene: associated with Parkinson’s disease (NHGRI, NIMH)

Identification of transporter responsible for Niemann-Pick disease (NHGRI, NINDS, NIDDK)

Identification of genes involved in familial Mediterranean fever and familial hybernium fever (NIAMS, NHGRI)

Gene for multiple endocrine neoplasia (MEN) isolated and initially characterized (NIDDK, NHGRI, NINDS)

Mutations in the patched gene: hereditary cause of nevoid basal cell carcinoma syndrome (NCI)

Myosin 15 gene: responsible for nonsyndromic deafness (NIDCD)

Serotonin 1B receptor: candidate gene predisposing to alcoholism (NIAAA)

ABC A1 cholesterol transporter: responsible for Tangier disease (NHLBI)

FOXL2 transcription factor: defective in premature ovarian failure (NIA)

Sarcomeric mutations: cause of familial hypertrophic cardiomyopathy (NHLBI)

Important new animal models

Estrogen receptor a and b knockout mice (NIEHS)

Cyclooxygenase 1 and 2 knockout mice (NIEHS)

Transgenic mice developed and validated for use in identifying environmental carcinogens (NIEHS),

Knockout mice for metabolic disorders including Gaucher (NIMH), Tay Sachs (NIDDK), and Fabry diseases (NINDS, NIDCR)

Mice that develop breast cancer (NIDDK)

Mice lacking fat (NIDDK, NCI)

Mice with chronic granulomatous disease (NIAID)

Mouse knockout of MEN1 gene (NIDDK, NHGRI, NCI)

Mice with cleft palate (NICHD)

Mice with glucose-6-phosphatase deficiency and classic glycogen storage disease type I (NICHD)

Mouse models for Beckwith-Wiedemann syndrome and Wilm’s tumor (NICHD)

ABC A1 transporter knockout for studying cholesterol transport (NHLBI)

Myosin light-chain knockout and trans-genic mice for evaluating the role of this protein in tissue structure and development (NHLBI)

p27, p21, and P27/p21 double knockout mice for evaluating vascular proliferation diseases and stem cell engraftment (NHLBI)

Cyclin-dependent kinase inhibitor and apoE knockouts for analysis of atherosclerosis formation and progression (NHLBI)

Basic discoveries in cell, molecular, and structural biology with implications for the treatment of human disease

Identification of taste and pheromone receptors (NIDCD)

Improved understanding of signal transduction, including structure of adenylate cyclase (NIDDK) and signaling via G-a-2 through Jun kinase and Rho (NIDCR)

Isolation and characterization of neural stem cells (NINDS)

Role of co-receptors in HIV entry into cells (first description of fusin and demonstration that deletions in CCR5 lead to resistance to HIV infection) (NIAID, NCI)

Mechanism of action of anthrax lethal factor through MAPKK signaling (NCI)

Structure of HIV integrase (NCI)

Structure and function of enzymes critical for HIV replication (NCI)

Discovery of prions in yeast (NIDDK)

Discovery that metalloproteinases increase after subclinical infection of the amniotic cavity, thereby weakening fetal membranes and causing 25 percent of premature births (NICHD)

Demonstration that adult hematopoietic stem cells can give rise to cardiac muscle and blood vessels in damaged mouse myocardium (NHGRI, NINDS)

Evidence that the dopamine transporter is the major molecular target for cocaine and that the serotonin transporter may also be involved (NIDA)

Demonstration that endogenous marijuana-like substances (endocannabinoids) in the brain contribute to regulation of appetite (NIAAA)

Purification and analysis of multiprotein complexes involved in faulty DNA repair in premature aging syndromes (NIA)

Identification of nitroxides as a new class of antioxidants and protectors against radiation (NCI)

Role of reactive oxygen species in cellular signal transduction in aging and hormone action (NHLBI)

Demonstration that drug-associated cues that produce craving activate brain "memory" pathways and structures (NIDA)

Ultrarapid visual reflexes that help people see clearly as they move are disrupted in patients with strabismus (NEI)

Signal transduction pathways involved in the normal proteolytic processing of a-crystallins are altered in cataracts (NEI)

Basic discoveries in biology

Clarification of iron metabolism regulation at the translational level (NICHD)

Role of small RNAs in regulation of genes responsive to oxidative stress (NICHD, NCI)

Mechanisms of DNA recombination (NIDDK)

Transcription factors can have acetylating and de-acetylating activity (NICHD)

Discovery of natural killer cell receptor that interacts with HLA class I molecules (NIAID)

Identification and characterization of novel human mitochondrial DNA polymerases (NIEHS)

Goal B: Develop new or improved instruments and technologies for use in research and medicine

Advances in imaging

Improved methods to use NMR for structural determinations of proteins (NIDDK)

New approaches for functional MRI applications to cardiac and brain imaging (NHLBI, NINDS, NICHD)

New imaging contrast mechanism in MRI based on the exchange of magnetization of water with macromolecules, termed magnetization transfer contrast (now used in most commercial MRI scanners) (NHLBI)

Improved 3-D tomographic reconstruction techniques for virology, small animal, and clinical imaging (CIT, NIAMS, CC, NCI)

New optical reflectance spectroscope for clinical optimal imaging (NICHD)

Hall effect imaging, a new modality based on the interaction of ultrasound with biological tissues in high magnetic fields (NHLBI)

Advances in bioinformatics

Database development, including dbEST (NLM)

Software development, including universal medical language (NLM)

Web sites, including PubMed (NLM), visible human project (NLM), cGAP (NCI, CIT), human genome site (NHGRI, NLM), and the clinical trials database (NLM)

Advances in biotechnology

Development of spectral karyotyping for all human chromosomes (NHGRI)

Development of laser capture microdissection technology (NCI, BEPS, NICHD, CIT)

Goal C: Develop new or improved approaches for preventing or delaying the onset or progression of disease and disability

Vaccine development

Clinical testing and FDA approval of vaccines against Haemophilus influenza (NICHD), hepatitis A (NIAID), and rotavirus (NIAID) (rotavirus vaccine use currently being evaluated)

Polysaccharide conjugate vaccines against Salmonella (typhoid) and Shigella in successful clinical trials (NICHD)

Successful use of acellular pertussis vaccine in Sweden (NICHD)

New vaccine against Escherichia coli 0157, now being tested (NICHD)

Preclinical work underway for a vaccine against papillomavirus (NCI) and B19 parvovirus (NHBLI)

Improved chemoprevention of disease

Caloric restriction delays aging in nonhuman primates (NIA)

Monoclonal antibody against respiratory syncytial virus (NIAID)

Vitamin E supplementation reduces risk of prostate cancer (NCI)

Antioxidant combination of b-carotene, vitamin E, and selenium reduces risk of stomach cancer (NCI)

Diet high in carotenoids or other dietary antioxidants is associated with a decreased risk of neovascular age-related macular degeneration (NEI)

Goal D: Develop new or improved methods for diagnosing disease and disability

Gene Expression Patterns

For diagnosis (and treatment) of breast and prostate cancer, among others (NHGRI, NCI, CIT)

For diagnosis (and treatment) of anemias, hyperlipidemias, and vascular diseases (NHLBI)

For evaluation of mechanisms of environmental toxicants (NIEHS)

To analyze the aging process (NIA)

(Note: See "Goal A" for new diagnostic tests based on isolation of the disease gene)

Goal E: Develop new or improved approaches for treating disease and disability

Improved disease treatment

Taxol to reduce smooth muscle hyperplasia after angioplasty (NIA)

High-dose immunosuppression to treat autoimmune aplastic anemia (NHLBI)

a-Glucosidase replacement therapy for Fabry disease (NCI)

Immunotoxins to treat cancer (NCI)

IL-2 with HAART to improve HIV and AIDS treatment (NIAID)

Cysteamine to treat cystinosis (NICHD)

Growth hormone to treat osteogenesis imperfecta (NICHD)

Uteroglobin to treat IgA nephropathy (NICHD)

Successful gene therapy for chronic granulomatous disease (NIAID)

Plasmapheresis to treat pediatric autoimmune neuropsychiatric disorders associated with streptococcus (NIMH)

Synthesis of novel cocaine analogs to treat cocaine dependence (NIDA)

Stem cell allotransplantation to treat metastatic renal cell cancer and metastatic melanoma (NHLBI)

Paclitaxel to treat Kaposi’s sarcoma (NCI)

Hydroxyurea to treat sickle cell anemia and inhaled nitric oxide to treat pulmonary hypertension in sickle cell anemia (NIDDK, NHLBI, CC)

Treatment guidelines for diabetic retinopathy (NEI)

New therapies for the ocular complications of AIDS (NEI)


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