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

Identification of disease genes

Variants in a single gene on chromosome 20 (hepatocyte nuclear factor 4a, or HNF4a, a transcription factor that influences insulin response to glucose) found to confer a 35 percent increased risk of type 2 diabetes in Finnish populations (NHGRI)

Identification of two genes through microarray screening—ezrin and SIX1—that regulate the metastatic phenotype of rhabdomyosarcoma cells in mouse models, suggesting the possibility of clinical interventions to prevent metastasis (NHGRI, NCI)

Identification of five chromosomal regions that harbor attention-deficit hyperactivity disorder susceptibility genes (4q13.2, 5q33.3, 8q11.23, 11q22, and 17p11) (NHGRI, NIMH)

A polymorphism in the serotonin transporter gene found to be associated with anxiety and a risk for depression in the face of adversity in female, but not male, rhesus monkeys, possibly helping to explain the increased incidence of certain stress-related disorders in women (NIAAA)

The cloning of dardarin (LRRK2), a new gene for Parkinson's disease, mutations in which cause autosomal dominant Lewy body disease and account for approximately 5 percent of cases (NIA)

A new Fanconi anemia gene for FANCB, the only one transmitted in a sex-linked manner, identified through biochemical techniques that recovered components of the purified complex of interacting Fanconi proteins (NIA)

Identification of a polymorphism in the promoter of the CYP2J2 gene that increases the risk of coronary artery disease, the first evidence of disease relevance for this P450 gene (NIEHS)

Identification of a variant in a gene that governs the activity of the brain chemical messenger glutamate that increases the risk for schizophrenia; the gene codes for the glutamate receptor GRM3, which is responsible for regulating glutamate in synapses (NIMH)

Important new animal models

A transgenic mouse model with reduced levels of Notch protein exhibited impaired communication at neuronal synapses in the hippocampus critical for learning and memory but responded to Notch activation by another protein, suggesting Notch as a new target for therapeutic interventions to improve learning and memory (NIA)

Development of a natural-challenge mouse model for plague infection and testing of an experimental plague vaccine that proved to be 100 percent effective; the model will be used to test other plague vaccines in development and to track the spread of plague bacteria through a host to study possible therapeutic interventions (NIAID)

Development of a mouse model of SARS replication that demonstrated that mice produce neutralizing antibodies to the SARS virus that protect them from re-infection and that immune sera from infected mice protected other mice from SARS infection; thus far, the mouse model has been used to demonstrate the efficacy of a DNA vaccine, an inactivated vaccine, a vectored vaccine, and three candidate immunotherapies (NIAID, CC)

A small dose of cholera toxin protected a rodent model of uveitis from developing the disease (by countering the Th1 immune response), offering proof of concept for an immunomodulatory approach to this autoimmune disease that may prove a safer alternative to chronic administration of immunosuppressive agents (NEI)

Improved heart function after ischemia-reperfusion injury in transgenic mice with cardiac-specific overexpression of the heart enzyme CYP2J2—pointing for the first time to an endogenous role for this enzyme in the heart, with implications for the treatment of ischemic heart disease (NIEHS)

Injection of a glutamate receptor agonist into the ventral tegmental area of the brain diminished contextual cue–induced relapse to heroin seeking in a rat-relapse model, suggesting that group II metabotropic glutamate receptors be targeted in the treatment of relapse to heroin and other drugs of abuse (NIDA)

Discovery and evaluation of a novel dopamine D3 receptor antagonist—the first water-soluble compound in its class—in animal models of cocaine abuse to elucidate the role of D3 receptors in drug reinforcement (NIDA)

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

Advances in understanding the developmental pathways involved in bone and joint formation, namely, the balanced interplay in Wnt signaling that results in osteoblast tissue that eventually becomes segments of bone separated by regions of cartilage that become joints (NHGRI)

Identification of two novel mechanisms that allow human antibodies to overcome HIV-1's defenses and enhance recognition of the virus, thus providing new targets for HIV-1 vaccines and therapeutics (VRC)

Demonstration that CCR5-tropic HIV preferentially infects certain dendritic cell populations, possibly enhancing infection, contributing to immune evasion, and providing a selective advantage for CCR5-tropic virus that may explain its preferential transmission in nature (VRC)

Enhanced oligodendrocyte progenitor differentiation found to promote remyelination, suggesting that drugs designed to target the sigma-1 receptor may be useful in treating demyelinating diseases or other myelination-related pathopsychiatric disorders (NIDA)

Identification of the basolateral complex of the amygdala as a key factor in environmental triggers of drug-induced brain reward and therefore a key target for antirelapse therapies for alcoholism and drug addiction—hitherto poorly understood and poorly treatable (NIDA)

Elucidation of the underlying mechanism of mental retardation in Down's syndrome through the finding in Drosophila that overexpression mutants in the homologous relevant human region results in severe learning defects induced by biochemical alterations, not by maldevelopment of the brain (NINDS)

Use of the hunger hormone ghrelin found to inhibit proinflammatory cytokine expression upon immune activation in vitro and within in vivo sepsis models; strategies to treat human inflammatory and autoimmune disorders might be entertained (NIA)

The finding that autophagy is a key immune cell death mechanism and is, paradoxically, induced by inhibiting one of the very enzymes that initiates apoptosis, caspase-8—along with the identification of beclin1 and ATG7 as key genes involved in autophagy—suggests the protein products of these genes as targets for drug discovery in the effort to inhibit this form of cell death; awareness of this previously unrecognized pathway may also aid in the design of treatments for autoimmunity (NIAID)

Identification of critical basic molecular mechanisms whereby small GTP-binding proteins of the Rho family coordinate rapid changes in cell shape, motility, and overall cytoskeletal function with the nuclear expression of growth-related genes involved in both normal and cancerous cell growth (NIDCR)

Demonstration that estrogen promotes angiogenesis and tumor growth by downregulating a naturally occurring soluble "decoy" protein, suggesting that inhibition of sVEGFR-1 expression represents a novel mechanism of an estrogen-driven "angiogenic switch" that is responsible for breast carcinoma progression (NIDCR)

Demonstration that SLPI, a protease inhibitor in mucosal secretions, inhibits HIV from infecting macrophages by binding to annexin 2, a newly recognized HIV cofactor (NIDCR)

The discovery that human cells can splice proteins, strongly enhancing the understanding of protein antigens and T-cell immunology (NCI, NIAID)

Demonstration that growth factors interleukin-2 and interleukin-15 have contrasting roles in the life and death of lymphocytes, which allows understanding of the maintenance and survival of T cells that confer long-term specific memory immune response (NCI)

Infusions of nitrite ions into several mammalian species shown to induce production of nitric oxide and resultant blood flow changes, suggesting that pharmacological use of nitrite solutions for various diseases may be possible (NIDDK, CC, NHLBI)

Demonstration that the mouse X chromosome is enriched for all genes preferentially expressed in sexually dimorphic tissues (such as the uterus, ovaries, prostate), thereby reconciling all previously published data on this subject from flies, worms, mice, and humans (NIDDK)

Shuffling the prion domain of Ure2p (randomizing the amino acid sequence without changing the amino acid content) found to produce sequences that can still form prions (NIDDK, NIAMS)

Demonstration through mutation studies and quantum chemical calculations that Ser113 of heat shock protein 90 (HSP90) is critical for the binding of the anticancer compound geldanamycin to HSP90 (NCI, CIT)

Overexpression of the enzyme Cdk5 found to decrease the activity of the Src enzyme and inhibit cell migration and wound closure in corneal epithelium, suggesting a new approach for treating persistent corneal ulcers and other conditions with impaired wound healing (NEI)

Discovery that adiponectin, an adipokine secreted by adipose cells, directly activates endothelial nitric oxide synthase and stimulate production of nitric oxide in vascular endothelial cells, providing a molecular basis for the ability of adiponectin to improve insulin sensitivity and oppose accelerated atherosclerosis in diseases associated with insulin resistance (diabetes, obesity, hypertension, dyslipidemias, and coronary heart disease) (NCCAM)

First report to demonstrate that it is the human pregnane X receptor that mediates induction of the drug-metabolizing enzyme CYP2C9 by rifampicin, phenobarbital, and hyperforin (found in St. John’s wort), explaining how concomitant exposure with certain prescribed drugs (such as anticoagulatory, antidiabetic, and antihypertensive agents) leads to increasing the rate of disappearance of drugs and compromised efficacy (NIEHS)

Endocannabinoids demonstrated to tonically suppress cardiac contractility in hypertension and to normalize blood pressure in three different models of experimental hypertension, suggesting the endocannabinoid system as a novel therapeutic target in hypertension (NIAAA)

Interleukin-6 found to ameliorate alcohol- and obesity-associated fatty liver disease and to prevent ischemia-reperfusion injury of fatty livers, suggesting therapeutic potential for IL-6 in human fatty liver disease (NIAAA)

Interleukin-22, a T cell–derived cytokine, demonstrated to be a novel hepatoprotective cytokine that may have therapeutic potential in treating acute liver failure (NIAAA)

Establishing that a major role of WRN, the protein found to be deficient in Werner syndrome (WS), is at the telomere end, where it functionally interacts with other telomere proteins and where it participates in maintenance and repair, the lack of which leads to genomic instability, a key feature of WS cells (NIA)

Determination of a series of high-resolution structures of sequence-specific as well as nonspecific endonucleases, thereby resolving the dilemma of substrate specificity and metal ion requirement and gaining insights into DNA repair, phage restriction, retroviral replication, and integration (NIDDK, NICHD)

Evidence from a decade-long MRI study of normal brain development from ages 4 to 21 that the prefrontal cortex, the center of reasoning and problem solving, is among the last areas of the brain to mature and does not fully develop until young adulthood (NIMH)

Findings suggesting that the basal ganglia are involved in both initiation and suppression of saccadic eye movements in complex behavioral contexts (NEI)

Elucidation of the role of brain-derived neurotrophic factor in synapse formation and in achieving long-term hippocampal plasticity (NICHD)

Findings in an ex vivo human lymphoid tissue system that suggest that triggering in vivo HIV viral production in latently infected cells in combination with therapies may become a meaningful strategy to purge latent viral reservoirs (NICHD)

Enhanced understanding of the kainate receptor gene family: solving the structures of the GluR5 and GluR6 ligand-binding cores, demonstrating that kainate receptor efficacy is controlled by domain closure, and elucidating their slow recovery from desensitization (NICHD)

Further elucidation of the role of mammalian mitochodrial fission and fusion mediators in apoptosis (NINDS)

Demonstration that multivesicular release at mammalian ribbon synapses is coordinated among release sites (NINDS)

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

Advances in imaging

Development of an automated, fault-tolerant system to enhance high-throughput NMR protein structure determination (CIT, NIDDK, NCI, NHLBI)

Development of a novel functional MRI technique for measuring cerebral blood volume, blood flow, and blood oxygenation signals in a single scan (NIDA)

Demonstration that MRI can detect single particles (single, micrometer-sized iron oxide particles) and that single-particle detection should prove useful for cellular imaging (NINDS, NHLBI)

Development of a dynamic micro–magnetic resonance mammolymphangiography method to visualize lymphatic flow from breast tumor tissue to draining lymph nodes to identify a sentinal lymph node and determine the presence or absence of nodal involvement; this approach may provide surgeons with a precise map of involved and uninvolved lymph nodes (NCI, NIDDK)

Development of the technique of picosecond time-resolved X-ray crystallography, achieving stunning agreement with molecular dynamics simulations (NIDDK)

The use of atomic force microscopy to visualize individual rhodopsin molecules (a key vision signal transduction protein) in native disk and reconstituted membranes, providing a foundation to study medically important proteins in biological membranes, with possible applications in nanotechnology (DBEPS, NIAAA)

Novel fluorescence and photoactivatable imaging tools to document that the behavior of chromosomes, cytoskeleton, and Golgi during mitosis is coordinated through the activity of the small GTPase Arf1, elucidating the activity of organelles and raft-associated plasma membrane proteins (NICHD)

Identification of a new series of compounds with extremely high affinity for a4 b2 nicotinic acetylcholine receptors (nAChRs) that show promise as imaging agents for extrathalamic nAChRs (NIDA)

Development of a new PET radioligand for 5-HT1A receptor to use in the study of the molecular basis of mood disorders (CC, NIMH)

Advances in bioinformatics

Implementation of a web-based protocol-tracking system that enables PIs to manage clinical studies as well as monitor review processes, view status changes, and respond to requests for additional information and allows protocol coordinators to manage the entire Institutional Review Board approval process (NINDS, CIT)

Advances in biotechnology

Identification of stem cells in human postnatal periodontal ligament that regenerate cementum-like and periodontal ligament—like structures when transplanted into im-munocompromised mice; these findings suggest that these easily accessible cells may be useful in repair of periodontal tissue (NIDCR)

Development of a simple plasmid transfection method for efficient intracellular production of papillomavirus-based gene transfer vectors utilizing the viral L1 and L2 proteins; the availability of high-titer papilloma-virus vector stocks should facilitate future studies of papillomavirus replication and tropism, and the vectors may have future utility as vaccine or gene therapy vehicles (NCI)

Demonstration that highly proliferativeprecursor cells for islets of Langerhans can be generated from cadaver pancreases and then redifferentiated in cell culture (NIDDK)

Development of new pepitomimetic ligands for integrin targeting that will provide a new approach for targeted delivery of nanoparticles into human vasculature (CC)

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

Genetic counseling shown to improve adherence to recommendations for colon cancer screening and prevention in both mutation-positive and mutation-negative individuals in families with hereditary nonpolyposis colorectal cancer, supporting the clinical practice of genetic susceptibility testing (NHGRI, NCI, NNMC)

Dietary fiber intake, especially from grains, cereals, and fruit, found to lower the risk of colorectal adenoma among individuals enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (NCI)

Determination that breastfed babies in the United States have a 20 percent lower chance of dying between one month and one year of age across all causes of death, including the most common at that age—SIDS, infections, and trauma; about 720 deaths could be prevented if all children under one were breastfed (NIEHS)

Finding that asthmatic children with a genetic deficiency of glutathione S-transferase M1GSTM1 may be more susceptible to the deleterious effects of ozone on the small airways and might derive greater benefit from antioxidant (vitamins C and E) supplementation (NIEHS)

The finding that intake of fiber, specifically from fruits and soy products, is related to a decreased risk of developing persistent cough with phlegm production (NIEHS)

Decreasing levels of free testosterone among men enrolled in the Baltimore Longitudinal Study on Aging found to predict increased risk of developing Alzheimer’s disease (NIA, NCCAM)

The first direct experimental demonstration in humans that calorie restriction increases psychoactive drug self-administration, using cigarette smoking (nicotine) as the drug (NIDA)

Establishment that exposure to benzene at levels even lower than the U.S. occupational standard of 1 part per million results in lowered white blood cell and platelet counts, with especially marked effects on progenitor cell colony formation; individuals with genetic variants in two metabolizing enzymes—myeloperoxidase and NAD(P)H:quinone oxidoreductase—identified as especially susceptibility to benzene hematotoxicity (NCI)

Establishment of the magnitude of risk for subsequent uterine cancer among breast cancer patients treated with tamoxifen who survived 5 years or more: an 8-fold relative risk of rare but aggressive malignant mixed müllerian tumors, as well as a 2.3-fold risk for endometrial adenocarcinoma (NCI)

Vaccine development

Development of a recombinant DNA vaccine against SARS coronavirus that induced neutralizing antibodies in mice; a Phase I clinical trial is underway (VRC)

Phase I clinical trials at various stages to evaluate the safety and immunogenicity of a DNA vaccine against Ebola virus in adult volunteers, a recombinant adenoviral vaccine against multiple clades and genes of HIV-1 in uninfected adult volunteers, and a six-plasmid DNA vaccine against multiple clades of HIV-1 in uninfected adult volunteers (VRC)

Ongoing clinical trials, in Baltimore and Costa Rica, of an HPV 16 (human papillomavirus type 16) L1 virus-like particle vaccine to prevent cervical cancer(NCI)

Develop new or improved methods for diagnosing disease and disability

Development of a "lab-on-a-chip" rapid immunoassay for the measurement of hormones in real time, enabling rapid patient assessment with minimal intervention during other clinical or surgical procedures (DBEPS, NICHD, NIDDK)

Development of a minimally invasive sample procurement needle, based on a 32-gauge acupuncture needle, enabling in vivo sampling of skin, muscle, or other organs while causing no discomfort beyond that associated with acupuncture (DBEPS, NCI, NIAMS)

Development of a new microanalytic technique to distinguish patients with and without painful myofascial trigger points through continuous myofascial fluid sampling (CC)

Temporarily disabling dopamine receptors in monkeys’ brains found to result in the performance of all tasks as if a reward were anticipated for each one, suggesting that highly specific manipulations of brain receptors could be a useful approach in discerning the molecular mechanisms that control other cognitive functions (NIMH)

Brain imaging to pinpoint the site of a defect in a brain circuit associated with a specific thinking deficit in Williams syndrome, a rare genetic disorder, offers clues on how genetic flaws may translate into cognitive symptoms in more common and complex major mental disorders (NIMH)

Identification of an area near the left temple of the monkey brain as the site of processing species-specific vocalizations suggests that this is not only a higher-order auditory processing area but also one that is a precursor for acoustic language circuits in humans (NIMH, CC)

The finding that an emotion-regulating brain circuit is overactive in people prone to depression and that depression relapse is induced by a depletion of tryptophan, the chemical precursor of serotonin, suggests that tryptophan depletion unmasks an inborn trait associated with depression and that a genetic predisposition to inadequate serotonin activity may be at the root of the mood disorder (NIMH, CC)

The finding that couples diagnosed as clinically infertile due merely to not having achieved pregnancy after a year of trying (without additional clinical indicators of reproductive dysfunction) should continue attempting for up to two years before considering potentially risky assisted reproductive technologies (NIEHS)

Gene expression patterns

Development of an expression microdissection instrument that facilitates more rapid and precise genomic and proteomic analysis (NCI, NICHD, CIT)

Development of a novel model for quantitatively analyzing cell cycle gene expression that promises enhanced understanding of tumor cell growth and the effects of genotoxic agents on specific cell cycle checkpoint genes (NIEHS)

Identification of transcription factor nuclear factor–kappa B (NF-kB) as an important mod-ulator of the altered gene expression profile and malignant phenotype in squamous carcinoma; inactivation of NF-kB inhibited malignant phenotypic features, including proliferation, cell survival, migration, angiogenesis, and tumorigenesis (NIDCD, NCI)

Patterns of genes active in tumor cells shown to predict whether patients with diffuse large B cell lymphoma are likely to be cured by chemotherapy, suggesting that gene expression profiling may facilitate clinical treatment options for standard or other therapies (NCI)

Identification of a target RNA motif for RNA-binding protein HuR by immunoprecipitation of HuR-RNA ribonucleoprotein complexes, cDNA array analysis of target RNAs, and elucidation of the primary and secondary structures of the bound transcripts (NIA)

Continuing development of a microfluidic, flow-through immunoassay for simultaneous quantification of multiple proteins in sub-microliter samples; advantages over existing array technology include protein detection by single-point capture and reusable capture antibodies (DBEPS, CIT)

Develop new or improved approaches for treating disease and disability

Clinical trial evidence that retroviral gene therapy yields gene-corrected lymphocytes and clinical improvement in patients with X-linked severe combined immunodeficiency disorder who have failed standard bone marrow transplant and have no other therapeutic options (NHGRI, NIAID)

A clinical trial of humanized anti-CD25 (daclizumab, developed in the NCI intramural program) shown to inhibit disease activity (both on imaging and in daily activities) in multiple sclerosis patients not responding to interferon-b, the standard therapy (NINDS, NCI)

A novel magnetic resonance imaging biomarker identifies blood-brain barrier disruption early enough in the course of stroke-induced ischemia and reperfusion to inform decisions regarding adjunctive therapy to reduce complications associated with acute thrombolytic therapy (NINDS)

Evidence supporting the potential role of regulatory T cells in the diminution of HIV-specific immune responses in HIV-infected individuals may lead to improved therapeutic and vaccination approaches designed to enhance or elicit HIV-specific immune responses (NIAID)

Monoclonal anti-IL-12 proved to be an effective treatment of active Crohn’s disease in an early-phase clinical trial, paving the way for a phase III trial in a large patient cohort; the trial also provided solid proof that a Th1 process is the final common T-cell pathway of inflammation in Crohn’s disease (NIAID)

Allogeneic T lymphocytes from a genetically matched donor found to induce tumor regression in patients with metastatic breast cancer—demonstrating for the first time that a graft-vs-host tumor effect may have therapeutic value in metastatic breast cancer (NCI, CC)

The launching of a double-blind, placebo-controlled, cross-over trial to determine if dark chocolate (which contains antioxidants, including polyphenol epicatechin) lowers blood pressure and improves insulin resistance and endothelial function in people with essential hypertension—relevant to the treatment of diabetes, obesity, hypertension, and atherosclerosis (NCCAM)

Expansion of a clinical study of electro-acupuncture for the treatment of delayed nausea and vomiting due to chemotherapy in patients with pediatric solid tumors; the study is now a multicenter study in collaboration with the Children’s Oncology Group (NCCAM, NCI)

The launching of the first clinical study of a mistletoe-chemotherapy (gemcitabine) combination in patients with advanced solid tumors; this phase I trial is a model for the study of botanical-drug interactions in combination regimens for treating cancer (NCCAM, NCI)

Launching of the first "proof of principle" clinical trial to test the ability of the CB1 receptor antagonist rimonabant to reduce the desire to drink in heavy drinkers (NIAAA)

** For this year’s IRP research roundup, IC scientific directors were asked to limit their selections to four to six "discoveries/new models/new tools reported in 2004 that . . . most advance the knowledge base in the field or have a significant impact on diagnosis, prevention, or treatment of heretofore poorly understood conditions or conditions that are important from a public health standpoint . . . . [also] clinical trials of new therapies/strategies launched in 2004 that address the types of conditions noted above."

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