The Feinberg Laboratory studies the epigenetic basis of normal development and disease, includi...ng cancer, aging and neuropsychiatric illness. Early work from our group involved the discovery of altered DNA methylation in cancer as well as common epigenetic (methylation and imprinting) variants in the population that may be responsible for a significant population-attributable risk of cancer.

Over the last few years, we have pioneered the field of epigenomics (i.e., epigenetics at a genome-scale level), founding the first NIH-supported NIH epigenome center in the country and developing many novel tools for molecular and statistical analysis. Current research examines the mechanisms of epigenetic modification, the epigenetic basis of cancer, the invention of new molecular, statistical, and epidemiological tools for genome-scale epigenetics and the epigenetic basis of neuropsychiatric disease, including schizophrenia and autism. view more

The goal of research in the Beer Lab is to understand how gene regulatory information is encode...d in genomic DNA sequence. Our work uses functional genomics DNase-seq, ChIP-seq, RNA-seq, and chromatin state data to computationally identify combinations of transcription factor binding sites that operate to define the activity of cell-type specific enhancers. We are currently focused on improving SVM methodology by including more general sequence features and constraints predicting the impact of SNPs on enhancer activity (delta-SVM) and GWAS association for specific diseases, experimentally assessing the predicted impact of regulatory element mutation in mammalian cells, systematically determining regulatory element logic from ENCODE human and mouse data, and using this sequence based regulatory code to assess common modes of regulatory element evolution and variation. view more

The Berger Lab's research is focused on understanding how multi-subunit assemblies use ATP for ...overcoming topological challenges within the chromosome and controlling the flow of genetic information. A long-term goal is to develop mechanistic models that explain in atomic level detail how macromolecular machines transduce chemical energy into force and motion, and to determine how cells exploit and control these complexes and their activities for initiating DNA replication, shaping chromosome superstructure and executing myriad other essential nucleic-acid transactions.

Our principal approaches include a blend of structural (X-ray crystallography, single-particle EM, SAXS) and solution biochemical methods to define the architecture, function, evolution and regulation of biological complexes. We also have extensive interests in mechanistic enzymology and the study of small-molecule inhibitors of therapeutic potential, the development of chemical approaches to trapping weak protein/protein and protein/nucleic acid interactions, and in using microfluidics and single-molecule approaches for biochemical investigations of protein dynamics. view more

The Best Laboratory focus on therapeutic vaccine development for HPV-related diseases by develo...ping a murine model of papilloma analogous to Recurrent Respiratory Papillomatosis (RRP) for testing of DNA vaccine technology. We also work to understand the immunosuppressive tumor microenvironment that facilitates RRP development, and translate this work into novel therapies and clinical practice. view more

Dr. Braunstein's research focuses on inherited predisposition to hematologic diseases. His labo...ratory studies the inherited genetic changes in DNA that increase susceptibility to disease. Blood cancers such as myeloproliferative neoplasms and myelodysplastic syndromes are traditionally thought to be acquired disorders, however there is increasing evidence that inherited genetic changes play a role. In addition, Dr. Braunstein studies non-malignant blood diseases including atypical hemolytic uremic syndrome (aHUS) and related thrombotic disorders such as APLS, TTP and HELLP syndrome which are caused in part by genetic mutations. His work has identified a germline variants in the ERBB genes that predispose to hematologic malignancies. In addition, his research group found that patients with catastrophic APLS and HELLP syndrome frequently harbor germline mutations in complement regulatory genes. This has led directly to clinical trials designed to test the efficacy of complement inhibition in patients with these disorders. Dr. Braunstein continues to work toward translating the scientific findings from the laboratory into improved care and treatment for patients. view more

Established in 1979, the Johns Hopkins DNA Diagnostic Laboratory is a CLIA and CAP certified; M...aryland, New York, and Pennsylvania licensed clinical genetics testing laboratory specializing in rare inherited disorders. Led by renown professor of pediatrics and medical genetics Dr. Garry R. Cutting, the lab offers testing for a range of approximately 50 phenotypes and disorders totaling 3,500 tests annually. view more

Dr. Meltzer is an internationally renowned leader in the molecular pathobiology of gastrointest...inal malignancy and premalignancy. He invented molecular methods to detect loss of heterozygosity in tiny biopsies, triggering an avalanche of research on precancerous lesions. He was the first to comprehensively study coding region microsatellite instability, leading to the identification of several important tumor suppressor genes. He performed several groundbreaking genomic, epigenomic and bioinformatic studies of esophageal and colonic neoplasms, shifting the GI research paradigm toward genome-wide approaches. He directed an ambitious nationwide validation study of DNA methylation-based biomarkers for the prediction of neoplastic progression in Barrett’s esophagus.

Dr. Meltzer founded and led the Aerodigestive Cancer and Biomarker Interdisciplinary Programs at the University of Maryland, also becoming associate director for core sciences at that school’s Cancer Center. He currently holds an endowed professorship and is the director of GI biomarker research at Johns Hopkins.

The laboratory group focuses its efforts on the molecular genetics of gastrointestinal cancers and premalignant lesions, as well as on translational research to improve early detection, prognostic evaluation, and treatment of these conditions. Below, some examples of this work are described. view more

The Greider lab uses biochemistry to study telomerase and cellular and organismal consequences ...of telomere dysfunction. Telomeres protect chromosome ends from being recognized as DNA damage and chromosomal rearrangements. Conventional replication leads to telomere shortening, but telomere length is maintained by the enzyme telomerase. Telomerase is required for cells that undergo many rounds of divisions, especially tumor cells and some stem cells. The lab has generated telomerase null mice that are viable and show progressive telomere shortening for up to six generations. In the later generations, when telomeres are short, cells die via apoptosis or senescence. Crosses of these telomerase null mice to other tumor prone mice show that tumor formation can be greatly reduced by short telomeres. The lab also is using the telomerase null mice to explore the essential role of telomerase stem cell viability. Telomerase mutations cause autosomal dominant dyskeratosis congenita. People with this disease die of bone marrow failure, likely due to stem cell loss. The lab has developed a mouse model to study this disease. Future work in the lab will focus on identifying genes that induce DNA damage in response to short telomeres, identifying how telomeres are processed and how telomere elongation is regulated. view more

The main research interests of the James Hamilton Lab are the molecular pathogenesis of hepatoc...ellular carcinoma and the development of molecular markers to help diagnose and manage cancer of the liver. In addition, we are investigating biomarkers for early diagnosis, prognosis and response to various treatment modalities. Results of this study will provide a molecular classification of HCC and allow us to identify targets for chemoprevention and treatment. Specifically, we extract genomic DNA and total RNA from liver tissues and use this genetic material for methylation-specific PCR (MSP), cDNA microarray, microRNA microarray and genomic DNA methylation array experiments. view more

In the Lee Martin Laboratory, we are testing the hypothesis that selective vulnerability--the p...henomenon in which only certain groups of neurons degenerate in adult onset neurological disorders like amyotrophic lateral sclerosis and Alzheimer's disease--is dictated by brain regional connectivity, mitochondrial function and oxidative stress. We believe it is mediated by excitotoxic cell death resulting from abnormalities in excitatory glutamatergic signal transduction pathways, including glutamate transporters and glutamate receptors as well as their downstream intracellular signaling molecules.

We are also investigating the contribution of neuronal/glial apoptosis and necrosis as cell death pathways in animal (including transgenic mice) models of acute and progressive neurodegeneration. We use a variety of anatomical and molecular neurobiological approaches, including neuronal tract-tracing techniques, immunocytochemistry, immunoblotting, antipeptide antibody production, transmission electron microscopy and DNA analysis to determine the precise regional and cellular vulnerabilities and the synaptic and molecular mechanisms that result in selective neuronal degeneration.
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Our Molecular Oncology lab seeks to understand the genomic wiring of response and resistance to... immunotherapy through integrative genomic, transcriptomic, single-cell and liquid biopsy analyses of tumor and immune evolution. Through comprehensive exome-wide sequence and genome-wide structural genomic analyses we have discovered that tumor cells evade immune surveillance by elimination of immunogenic mutations and associated neoantigens through chromosomal deletions. Additionally, we have developed non-invasive molecular platforms that incorporate ultra-sensitive measurements of circulating cell-free tumor DNA (ctDNA) to assess clonal dynamics during immunotherapy. These approaches have revealed distinct dynamic ctDNA and T cell repertoire patterns of clinical response and resistance that are superior to radiographic response assessments. Our work has provided the foundation for a molecular response-adaptive clinical trial, where therapeutic decisions are made not based on imaging but based on molecular responses derived from liquid biopsies. Overall, our group focuses on studying the temporal and spatial order of the metastatic and immune cascade under the selective pressure of immune checkpoint blockade with the ultimate goal to translate this knowledge into “next-generation” clinical trials and change the way oncologists select patients for immunotherapy. view more

Epstein-Barr virus and Kaposi's sarcoma herpesvirus are found in association with a variety of ...cancers. Our laboratory studies are aimed at better defining the role(s) of the virus in the pathogenesis of these diseases and the development of strategies to prevent, diagnose or treat them. We have become particularly interested in the unfolded protein response in activation of latent viral infection. Among the notions that we are exploring is the possibility that activation of virus-encoded enzymes will allow the targeted delivery of radation. In addition, we are investigating a variety of virus-related biomarkers including viral DNA, antibody responses, and cytokine measurements that may be clinically relevant. view more

Research in the Salzberg Lab focuses on the development of new computational methods for analys...is of DNA from the latest sequencing technologies. Over the years, we have developed and applied software to many problems in gene finding, genome assembly, comparative genomics, evolutionary genomics and sequencing technology itself. Our current work emphasizes analysis of DNA and RNA sequenced with next-generation technology. view more

The Stivers Lab is broadly interested in the biology of the RNA base uracil when it is present ...in DNA. Our work involves structural and biophysical studies of uracil recognition by DNA repair enzymes, the central role of uracil in adapative and innate immunity, and the function of uracil in antifolate and fluoropyrimidine chemotherapy. We use a wide breadth of structural, chemical, genetic and biophysical approaches that provide a fundamental understanding of molecular function. Our long-range goal is to use this understanding to design novel small molecules that alter biological pathways within a cellular environment. One approach we are developing is the high-throughput synthesis and screening of small molecule libraries directed at important targets in cancer and HIV-1 pathogenesis. view more

The Arking Lab studies the genomics of complex human disease, with the primary goal of identify...ing and characterizing genetics variants that modify risk for human disease. The group has pioneered the use of genome-wide association studies (GWAS), which allow for an unbiased screen of virtually all common genetic variants in the genome. The lab is currently developing improved GWAS methodology, as well as exploring the integration of additional genome level data (RNA expression, DNA methylation, protein expression) to improve the power to identify specific genetic influences of disease.

The Arking Lab is actively involved in researching:
• autism, a childhood neuropsychiatric disorder
• cardiovascular genomics, with a focus on electrophysiology and sudden cardiac death (SCD)
• electrophysiology is the study of the flow of ions in biological tissues

Dan E. Arking, PhD, is an associate professor at the McKusick-Nathans Institute of Genetic Medicine and Department of Medicine, Division of Cardiology, Johns Hopkins University. view more

We are devoted to developing and deploying cutting edge technologies that can be used to define... human immune responses. Much of our work leverages ‘next generation’ DNA sequencing, which enables massively parallel molecular measurements. Examples of our technologies include:
- bacteriophage display of synthetic peptidome libraries for comprehensive, quantitative profiling of antibodies;
- display of ORFeome libraries for antigen discovery, protein-protein interaction studies, and drug target identification;
- ultrasensitive, multiplex RNA quantification techniques to monitor gene expression and detect microbes;
- pooled genetic screening to elucidate immune cell function and identify new therapeutic targets.

The Larman Laboratory uses these and other approaches to identify opportunities for monitoring and manipulating immune responses. view more

Research in the Vestibular NeuroEngineering Lab (VNEL) focuses on restoring inner ear function ...through “bionic” electrical stimulation, inner ear gene therapy, and enhancing the central nervous system’s ability to learn ways to use sensory input from a damaged inner ear. VNEL research involves basic and applied neurophysiology, biomedical engineering, clinical investigation and population-based epidemiologic studies. We employ techniques including single-unit electrophysiologic recording; histologic examination; 3-D video-oculography and magnetic scleral search coil measurements of eye movements; microCT; micro MRI; and finite element analysis. Our research subjects include computer models, circuits, animals and humans. For more information about VNEL, click here.
VNEL is currently recruiting subjects for two first-in-human clinical trials:
1) The MVI Multichannel Vestibular Implant Trial involves implantation of a “bionic” inner ear stimulator intended to partially restore sensation of head movement. Without that sensation, the brain’s image- and posture-stabilizing reflexes fail, so affected individuals suffer difficulty with blurry vision, unsteady walking, chronic dizziness, mental fogginess and a high risk of falling. Based on designs developed and tested successfully in animals over the past the past 15 years at VNEL, the system used in this trial is very similar to a cochlear implant (in fact, future versions could include cochlear electrodes for use in patients who also have hearing loss). Instead of a microphone and cochlear electrodes, it uses gyroscopes to sense head movement, and its electrodes are implanted in the vestibular labyrinth. For more information on the MVI trial, click here.
2) The CGF166 Inner Ear Gene Therapy Trial involves inner ear injection of a genetically engineered DNA sequence intended to restore hearing and balance sensation by creating new sensory cells (called “hair cells”). Performed at VNEL with the support of Novartis and through a collaboration with the University of Kansas and Columbia University, this is the world’s first trial of inner ear gene therapy in human subjects. Individuals with severe or profound hearing loss in both ears are invited to participate. For more information on the CGF166 trial, click here. view more

The lab currently focuses on identifying genetic alterations in cancer affecting sensitivity an...d resistance to targeted therapies, and connecting such changes to key clinical characteristics and novel therapeutic approaches. We have recently developed methods that allow noninvasive characterization of cancer, including the PARE method that provided the first whole genome analysis of tumor DNA in the circulation of cancer patients. These analyses provide a window into real-time genomic analyses of cancer patients and provide new avenues for personalized diagnostic and therapeutic intervention. view more