Discoveries that add to the body of knowledge about normal and abnormal biological functions and behavior

Identification of disease genes

Identification of genes implicated in overall susceptibility to prostate cancer and of multiple loci that distinguish between more- and less-aggressive and life-threatening disease (NHGRI)

Identification of the gene—PIP5K3 —that, when mutated, causes Francois-Neetens mouchetée fleck corneal dystrophy, providing new inroads into corneal biochemistry and physiology and the role of endosome-to–trans-Golgi network transport in cellular metabolism (NEI)

Delineation of the clinical, physiological, and pathological effects of a motor neuron disease caused by mutations in the p150^glued subunit of dynactin, a protein essential for axonal transport, reinforcing the suspicion that axonal transport is impaired in many neurodegenerative disorders (NINDS)

Identification (in studies involving Caucasians in Tennessee) of a functionally relevant polymorphism in the regulatory region of the CYP2J2 gene that confers a lower risk of hypertension (NIEHS)

Variants of the melanocortin-1 receptor (MC1R) gene were found to be associated with a two- to fourfold increased risk of sporadic and familial melanoma, particularly among individuals with multiple variant alleles and those with fewer additional risk factors (NCI)

Data from the International Lymphoma Epidemiology Consortium link genetic variation in TNF and IL-10 with increased risk of non-Hodgkin's lymphoma, particularly diffuse large B-cell lymphoma, suggesting that common polymorphisms in TNF and IL-10—key cytokines for the inflammatory response and Th1-Th2 balance—could be susceptibility loci for non-Hodgkin's lymphoma; the findings underscore the importance of using consortia for investigating the genetic basis of chronic diseases such as cancer (NCI)

Results from the Spanish Bladder Cancer Study and meta-analyses show that the GSTM1 null genotype increases the overall risk of bladder cancer and the NAT2 slow-acetylator genotype increases risk particularly among cigarette smokers, providing compelling evidence for the role of common polymorphisms in cancer etiology; these polymorphisms could account for up to 31 percent of bladder cancers (NCI)

Continuing studies of specific mutations in the LRRK2 gene establish that a significant number of Parkinson s disease patients have a genetic predisposition, raising the possibility of genetic testing for this disease and facilitating the development of cell-based and animal-based models to explore etiology and related therapies (NIA, NHGRI, NIMH, NCBI)

Discovery of a new gene, FANCM, which is mutated in one subgroup of patients with Fanconi anemia (FA), provides evidence for direct enzymatic movement of the complex of FA proteins along DNA and suggests drugs that enhance the FA DNA damage response as a potential therapeutic option; the discovery also sheds light on how DNA damage signals are transmitted in the FA pathway —and in repair pathways involved in certain cancers and aging (NIA)

Identification of a common variant of plasma membrane calcium pump PMCA2 that modifies the severity of age-related hearing loss caused by a mutation in the gene encoding cadherin 23, raising the possibility that this or other variants of PMCA2 may underlie individual variability of hearing loss associated with more common causes such as noise or aging (NIDCD, NHLBI)

Evidence that mutations in a gene located on chromosome 12 cause stuttering, a disorder of unknown origins (NIDCD)

Haplotype linkage of TPH2 (the gene for tryptophan hydroxylase 2) to depression and suicide attempt in three of four ethnically diverse populations, moving the field closer to identifying specific genetic loci that contribute to this vulnerability (NIAAA)

Evidence that the short variant of the gene that codes for the serotonin transporter protein in the brain is associated with poorly regulated amygdala response and impaired emotional reactivity, thus increasing vulnerability to persistent bad moods and stress-induced depression (NIMH)

Important new animal models

A low-calorie diet was found to lessen the severity of dopamine nerve cell damage and motor dysfunction in a monkey model of Parkinson's disease, possibly by inducing increased production of two different nerve cell growth factors in the brain (NIA, CC, NIMH)

Demonstration that the Drosophila melanogaster homolog of a gene (DSCR1) in the chromosomal region involved in human Down syndrome is crucial for maintaining the function and integrity of mitochondria, suggesting that the increased level of DSCR1 may contribute to the mitochondrial dysfunction in Down syndrome (NINDS)

Demonstration that the Stat family transcription factors Stat5a and Stat5b are essential for normal lymphoid development: The development of T cells, B cells, and NK cells was severely impaired in mice in which these transcription factors were deleted using Cre-lox technology (NIAMS, NIDDK)

Demonstration in a rat model of craving and relapse that cocaine craving induced by exposure to cocaine cues was higher 30 days after withdrawal than one day after, reflecting time-dependent increases in the responsiveness of the central amygdala ERK pathway to cocaine cues, with implications for neuroadaptations related to other responses such as food craving or fear (NIDA)

A double-mutant mouse model—loss of brain-derived neurotrophic factor (BDNF) gene allele in addition to serotonin transporter (SERT) knockout—displays exacerbated brain monoamine deficiencies and increased stress; the model serves to elucidate the role of serotonin in the actions of antianxiety and antidepressant drugs and the mechanism underlying epistatic interactions between SERT and BDNF polymorphisms in human psychiatric disorders (NIMH, NICHD, NIAAA)

Demonstration of the first replication of the BK virus, a human pathogen, in an animal model (squirrel) (NIDDK, CC, NCI, CBER)

Discovery that the cytokine thymic stromal lymphopoietin (TSLP) is critical in mediating the development of asthma in a murine model and that a TSLP receptor fusion protein can block development of lung inflammation, with therapeutic implications (NHLBI, NIAID)

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

Discovery that abnormal prion protein lacking a GPI anchor into the cell membrane may be unable to signal cells to start the lethal disease process associated with transmissible spongiform encephalopathies;  this anchorless prion protein promoted the formation of amyloid plaques in brain tissue but did not cause clinical disease, which may have implications for the treatment of Alzheimer's disease (NIAID)

Discovery that CCR5, the receptor exploited by HIV for initial infection and subsequent disease progression, also functions in West Nile virus (WNV) pathogenesis, but in a beneficial way: to clear virus from the brain and to limit mortality, raising the possibility that HIV inhibitors that act by blocking CCR5 may render patients more susceptible to WNV (NIAID)

Discovery that hemoglobin C protects against malaria by disturbing the expression of a key parasite protein, PfEMP-1, that promotes adherence of infected red blood cells to the lining of blood vessels in the brain and other critical tissues, causing inflammation and circulatory obstruction (NIAID)

Elucidation of the travels of glucose transporter 4 between the adipose cell interior  and the plasma membrane in response to insulin (NICHD, NIDDK)

Finding that ocular-specific antigens are typically expressed in human thymic tissue but in widely varying degrees, suggesting that differences in susceptibility to autoimmune uveitis are at least partly the result of different levels of thymic expression of uveitogenic antigens (NEI, NIAID)

Use of a toxin from tarantulas to characterize the molecular mechanism by which voltage-activated potassium channels detect and react to changes in membrane voltage, a key but poorly understood aspect of how voltage-dependent channels carry out their essential signaling functions throughout the brain and other body systems (NINDS)

Determination that the clearance of the neurotransmitter glutamate is slower in the hippocampus of younger animals, which permits glutamate to travel longer distances and increases the importance of glutamate receptors that are located beyond the synapse in the developing brain (NINDS)

Discovery of a novel physiological mechanism for the production of tissue-specific glucocorticoid receptors, providing insights into the anti-inflammatory action of glucocorticoids, one of the worlds most prescribed class of drugs (NIEHS)

Elucidation of the regulation of genes that control cellular senescence, immortalization, tumor suppression, and organismal aging in studies of the expression of tumor suppressor p16 during replicative senescence (NIA)

Manipulating the growth conditions and thus the structure and toxic properties of amyloid-b peptide fibrils, which accumulate in the brains of patients with Alzheimer's disease, with implications for the development of treatments for Alzheimer's disease (NIDDK, NIA, DBEPS)

Identification of a novel mechanism controlling directional cell migration that is distinct from chemotaxis and depends on Rac protein activity, a finding relevant to the field of  tissue bioengineering (NIDCR)

The uncovering of a novel mechanism explaining how dietary deficiency of docosahexaenoic acid (DHA), an w-3 polyunsaturated fatty acid highly enriched in neuronal membranes, can upset the interaction between the Akt signaling pathway and membrane phospholipid levels, thereby compromising neuronal survival; these findings underscore the neurological deficits associated with w-3 fatty acid deficiency and support protective effects of DHA in pathological models such as brain ischemia or Alzheimer's disease (NIAAA)

Elucidation of the pathway by which stress may induce reinstatement of cocaine-seeking behavior in detoxified cocaine addicts and underlie the co-morbidity between addiction and other stress-related psychiatric disorders: Foot-shock stress caused the release of corticotropin-releasing factor in rats, which, in the cocaine-experienced cohort, induced glutamate release and dopamine activation, triggering relapse (NIDA)

Demonstration that the mNotch1 intracellular domain can functionally replace that of mNotch2 in vivo, suggesting that these key signaling molecules are functionally redundant (CBER)

The finding that loss of memory CD4+ T cells during acute SIV infection is considerably more marked than previously thought—rapid and throughout the body, not just in mucosal tissue—with critical implications for vaccine development and interventional therapies (VRC, NIAID)

The finding that CCR5-tropic HIV virus infection of immature dendritic cells (DC) allows the development of a reservoir of infected DCs that infect T cells efficiently upon maturation (VRC, NIAID)

Identification of the superior colliculus as the region of the brain that not only generates saccadic eye movements but also contributes to directing attention to specific features in the visual field, providing a first step towards understanding the circuits in the brain that underlie visual attention and how perception is affected when there are deficits in shifts of attention (NEI)

Discovery that myosin-XVa, a protein found to be defective in some forms of deafness, delivers whirlin to the tips of stereocilia of auditory sensory cells and is a key event in hair-bundle morphogenesis (NIDCD, NHLBI)

Identification of a protein complex involved in the trafficking of NMDA receptors, contributing to the understanding of this process in normal and disease states (NIDCD)

Identification of the genes that encode receptors for bitter tastants and demonstration that bitter taste is hard-wired in dedicated cells at the periphery (NIDCR)

Elucidation of the structure of amyloid fibrils of human amylin, present in 90 percent of patients with Type 2 diabetes (NIAMS)

Awakening of the mobile somatic "Sleeping Beauty"  transposon system (jumping genes) to expose the weak points in cancer genes and gain insights into better treatment approaches (NCI)

Identification of cross-talk between nitric oxide (NO) and thrombospondin-1 in NO-mediated regulation of angiogenesis, with implications for therapeutic approaches to angiogenic aspects of cancer progression (NCI)

Elucidation of the underlying mechanisms of hemolysis-associated pulmonary hypertension—which occurs in 30 percent of patients with sickle cell disease and is a major cause of mortality in this population—and its strong association with high hemolytic rate, arginase release from red cells, iron overload, and kidney disease (NHLBI, CC, NIDDK)

Discovery of cannabinoid receptors (CB1) in hepatocytes whose activation by endocannabinoids stimulates fatty acid synthesis, suggesting that the endocannabinoid anandamide contributes to diet-induced obesity and that the fatty acid synthase pathway may be a common molecular target for central and peripheral metabolic regulation (NIAAA)

Brain scan evidence that sniffing oxytocin (compared with placebo) dampens amygdala response to threatening scenes, especially to threatening faces, as well as communication between the amygdala and upper brainstem fear-response sites, suggesting a pivotal role for oxytocin in regulating social fear and its possible value in treating autism, which has been linked to overactivation in the amygdala when looking at faces (NIMH)

Clarification of the neural mechanism underlying the risk for schizophrenia conferred by COMT gene variants (NIMH)

Demonstration by fMRI that the amygdala of patients with Williams syndrome—who have 21 missing genes on chromosome 7 and atypical responses to people and events expected to induce fear and anxiety —undergoes less activation than that of healthy volunteers when confronted with pictures of threatening people and more activation when confronted with threatening scenes with no social component; three areas of the prefrontal cortex were implicated in this atypical amygdala response (NIMH)

Elucidation of the "yin-yang"  regulation of synaptic plasticity by proneurotrophins and mature neurotrophins through activation of two different receptors, with implications for understanding a wide range of cellular processes (NICHD)

Study of the locust olfactory system to elucidate the manner in which neural circuits process sensory information (NICHD)

Elucidation of the antiviral protein kinase PKR (and other stress-responsive protein kinases) activation pathway (NICHD)

Elucidation of the role of Notch signaling in neural development (NICHD)

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

Advances in imaging

The use of real-time MRI to treat congenital aortic coarctation in an animal model demonstrated the clinical potential of this single modality to diagnose, treat, and promptly identify complications—without exposing children and staff to ionizing radiation (NHLBI)

Development of an automated system—virtual colonoscopy computer-aided polyp detection—that can locate precancerous polyps on CT scans with high sensitivity comparable with that of optical colonoscopy, a minimally invasive procedure that may increase the use of asymptomatic screening (CC)

Application of a comprehensive image reconstruction methodology to the first human positron emission tomography data acquired from the NIH High Resolution Research Tomograph (CC, CIT, NIMH, NINDS)

Development of a registration, segmentation, and three-dimensional fusion tool to support radiofrequency ablation treatment planning (CC, CIT)

Demonstration that disparate NMR and X-ray crystallography measurements yield quantitatively consistent information about the motion of a small, rigid protein (NIDDK, CIT)

Design of an electron paramagnetic resonance imaging system that allows for noninvasive in vivo functional imaging in small animal models for the investigation of tissue oxygen concentrations and the development of tumor treatment strategies (NCI, CIT)

Development of novel diagnostic methods using new kinds of spectroscopic imaging: high-throughput Fourier transform infrared spectroscopic imaging of tissue microarrays, coupled with the statistical pattern recognition of spectra indicative of endogenous molecular composition, enabling histopathologic characterizations of, for example, prostatic tissue without need for dyes or molecular probes and differentiating between benign and malignant prostatic epithelium (NIDDK, NCI)

Localization of the minor capsid protein L2 of the human papillomavirus, a possible vaccine antigen, by cryoelectron microscopy and three-dimensional image reconstruction (CIT, NCI, NIAMS)

Advances in bioinformatics

Development of a computer search tool that rapidly compares DNA sequences among animal species and identifies those sequences that have remained essentially unchanged during evolution, a strong indication that the DNA segment is essential to gene function (NINDS, NIMH))

Complete sequencing of the canine genome, opening the door to comparative studies of cancer susceptibility genes in dogs and humans—species whose malignancies resemble one another in clinical presentation, histology, and biology (NHGRI)

Advances in biotechnology

Replication and production of infectious hepatitis C virus (HCV) from a cloned viral genome in tissue culture, providing an in vitro means to better study the biology of HCV and to screen a wider range of potential therapeutic compounds (NIDDK)

Development of a method for circulating endothelial cell isolation and validation, used to probe vascular disease, which includes multiple marker verification, high-sensitivity mRNA amplification, and confirmation of endothelial-specific genes by microarrays and real-time PCR (CC, NHLBI, CIT)

Creation of a model to improve understanding of the molecular mechanisms for optimal transport of metabolites through large channels (NICHD, CIT)

Synthesis of a compound that blocks the effects of anthrax lethal toxin at the protective antigen channel in cell and animal studies, paving the way for rational design of new drugs to treat inhalational anthrax (NICHD, NIAID)

Development and characterization of monoclonal antibodies that can neutralize the protective antigen toxin of Bacillus anthracis (NIAID, DBEPS)

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

Discovery that farnesyltransferase inhibitors, a class of experimental anticancer drugs, prevent a crucial event in the development of progeria, raising the hope that these agents may be used to treat children with this otherwise-fatal genetic disorder (NHGRI)

Characterization of heart lesions in rats associated with ingestion of ephedrine and caffeine, the active ingredients in ephedra-based dietary supplements, contributing to the FDA's ability to evaluate the heart toxicity of ephedra-containing herbal medicines and the banning of such dietary supplements (NIEHS)

Findings from the ongoing Agricultural Health Study that farmers who use agricultural insecticides experience lasting neurological symptoms—including headaches, fatigue, insomnia, dizziness, cognitive problems, poor balance, hand tremors, and numbness—even when they are no longer using the products, exposing the health effects of everyday agricultural chemical use, in contrast to previous studies that focused on pesticide poisoning or high-dose exposures (NIEHS, NCI)

Development of a clinical protocol to evaluate the efficacy of erythropoietin in reducing infarct size and left ventricular remodeling in patients with large myocardial infarctions, with the aim of preventing such common clinical complications as congestive heart failure and arrhythmia (NIA)

Continuing studies of of monoclonal antibody for IL-2 receptor blockade in patients with uveitis suggest that treatment-related induction of CD^56bright is responsible for the therapeutic lessening of inflammation and that CD^56bright may be the body's natural agent in calming uveitis and other autoimmune conditions such as multiple sclerosis; a Phase III study of the IL-2 receptor blocker daclizumab to treat uveitis is in preparation (NEI)

Identification of a novel mechanism by which inflammatory mediators (prostaglandin E2) activate growth-promoting pathways, shedding light on the relationship between inflammatory processes and tumor progression and the observed association between the use of anti-inflammatory agents and a reduced incidence of colon cancer; the findings may provide a molecular framework to evaluate new anticancer chemopreventive strategies  (NIDCR, NIAID)

Data gathered from studies involving more than 70,000 individuals show that minorities participate in clinical research at the same rate as non-Hispanic whites when they are made aware of the study and meet the medical requirements, countering the widely held notion that minorities are less willing to participate and suggesting that minority involvement in clinical research is more a matter of access than attitude (CC, OBSSR)

Demonstration that infused nitrite solutions prevent hepatic and cardiac ischemia-reperfusion injury and infarction in mice (NHLBI, CC, NIDDK)

Results from a nested study within the Childhood Cancer Survivor Study show that the risk of subsequent primary thyroid cancer among survivors who received upper-body or head and neck radiotherapy increases with rising therapeutic radiation doses up to 20 to 29 grays, with declines at higher doses consistent with a cell-killing effect; these findings support long-term follow-up of childhood survivors of any cancer treated with radiotherapy, not just Hodgkin's lymphoma (NCI)

Vaccine development

Development of a recombinant, live, attenuated respiratory syncytial virus vaccine for intranasal administration that proved to be well-tolerated, immunogenic, and protective against a second vaccine dose in infants one to two months old (NIAID)

Testing of the VRC's HIV preventive prime-boost vaccine strategy in three Phase I/II clinical trials conducted by three international networks—the HIV Vaccine Trials Network, the International AIDS Vaccine Initiative, and the United States Military HIV Research Program (VRC)

Development of a recombinant DNA vaccine candidate against West Nile Virus, developed under a CRADA with Vical, Inc.,  now in Phase I clinical trial (VRC)

A DNA prime-recombinant adenoviral boost vaccine targeted at one of the influenza viral proteins, nucleoprotein (NP), induced strong antibody and T-cell responses in mice and protected against lethal challenge with highly pathogenic H5N1 virus, demonstrating that gene-based vaccination with NP may contribute to protective immunity against diverse influenza viruses (VRC, CBER)

Identification of a gene in Moraxell catarrhalis responsible for the biosynthesis of endotoxin, enabling the creation of a highly immunogenic, endotoxin-free knockout mutant without endotoxin with promise as a vaccine candidate or vaccine vehicle (NIDCD)

Development of new or improved ways to diagnose disease and disability

Women who tested positive for human papillomavirus (HPV) type 16 or 18 were at higher risk of developing cervical cancer over the next 10 years than were women who tested positive on a general screen for oncogenic HPV types but negative for those two specific types, suggesting that HPV screening that distinguishes HPV16 and HPV18 from other oncogenic HPV types may be useful clinically in deciding how best to manage women with these HPV infections (NCI)

Gene expression patterns

Development of a novel genetic model to identify genes that interact in head development in a dosage-specific manner, including BMP, hedgehog pathway members, and Zic gene family members (CBER)

Gene expression profiling of human bone and soft tissue sarcomas to delineate tumor classes and identify associated genes of potential biological and therapeutic interest (NHGRI, NCI)

The use of gene expression profiling and artificial neural networks to predict survival in neuroblastoma patients, including the identification of 19 predictor genes to distinguish between lower and higher survival potential in already stratified high-risk patients (NCI)

Development of new or improved ways to treat disease and disability

Demonstration that intermittent administration of IL-2 prolongs the lifespan of naïve and central memory CD4 T cells in HIV-infected patients (CC, NIAID, NCI)

Combination chemotherapy and infusion of autologous stimulated lymphocytes—adoptive cell-transfer therapy after nonmyeloablative but lymphodepleting chemotherapy—achieved tumor regression in patients with refractory metastatic melanoma  (NCI, NEI)

A pilot study of nitisinone in patients with alkaptonuria, an inborn error of metabolism, achieved a 95 percent reduction of homogentisic acid, the accumulation of which causes the destruction of large joints and cardiac valves characteristic of the condition; a larger clinical trial with clinical outcome measures is now ongoing (NHGRI, CC, NEI)

Development of nucleoside analogs that block DNA synthesis beyond the point of HIV-1 incorporation—delayed chain termination—and should therefore be relatively resistant to excision and effective against drug-resistant HIV-1 reverse transcriptases, suggesting a research direction to complement already approved HIV-1 therapies  (NCI)

Development of drug-device combination therapy—heat-activated chemotherapy encapsulated in a liposomal vector and delivered intravenously—to enhance effectiveness of local thermal ablation in the treatment of unresectable liver cancer (CC, NCI)

Identification of the enzyme that regenerates the 11-cis vitamin A required for light sensitivity of the retina, with implications for gene therapy for treating inherited blindness caused by RPE65 mutations; clinical trials are planned (NEI)

Determination in primate studies that intravenous infusion of sodium nitrite, a drug designed to increase levels of the regulatory molecule nitric oxide, can prevent the cerebral vasospasm that may follow surgery for intracranial aneurysm (NINDS, NIDDK, CC, NHLBI)

Demonstration that inhaled nitrite reverses hypoxic neonatal pulmonary hypertension in sheep (NHLBI, CC, NIDDK)

Demonstration that neonatal multisystem inflammatory disorder is highly responsive to agents that inhibit IL-1, a significant advance in the treatment of autoinflammatory disorders (NIAMS)    

Return to Table of Contents