Molecular Biomedial Engineering Research Overview
Analysis and manipulation of the genome and development of processes for applying this knowledge in the clinic. Emphasis is on the discovery of novel genes active in tissue healing and adaptation as well as the development of therapeutic drugs, antibodies, vaccines, proteins and antisense products for agricultural, environmental and medical applications.
Faculty Research Interests
Laufer Center - Room 115C
Henry Laufer Endowed Associate Professor
Summary : The goal of my laboratory is to develop synthetic gene circuits (small constructs built from genes and their regulatory regions), and use them for biological discovery and practical applications (such as therapeutic gene expression control). For example, using synthetic gene circuits in yeast cells, we could demonstrate that noise (nongenetic cellular diversity) can aid microbial survival during antibiotic treatment and thereby enable the development of drug resistance. We have designed "linearizer" gene circuits in yeast cells that can tune a protein's level precisely, such that the protein concentration is proportional to an extracellular inducer and uniform within a cell population. We have moved this synthetic gene circuit into mammalian cells and can now tune the expression of a cancer-related genes precisely, to investigate how the level of tumor progression-related proteins affects invasion, migration and other metastasis-related cell behaviors. In the future, similar gene circuits may enable novel approaches to gene therapy. Our research is inherently interdisciplinary, since we use mathematical and computational models in combination with single-cell level measurements to characterize the dynamics of synthetic and natural gene networks, and to understand the cellular and multicellular behaviors they confer.
Bioengineering Building - Room 107
Summary : Our research interests are bone adaptation, mechanotransduction and osteoimmunology in normal and pathological conditions. With a particular focus on the bone marrow stem cell environment, our lab is currently using a murine model of diet-induced obesity to study how obesity affects the bone quality and quantity, as well as the immune system. This study provides insights into the relationship between an increasing adipose burden on phenotypic and dysfunctional changes in bone marrow stem cell population, immune cells and the overall health (e.g., glucose intolerance in type 2 diabetes) during obesity. More interestingly, our study showed that mechanical signals can be harnessed to mitigate these adverse effects by normalizing the hematopoietic stem cell differentiation pathways, implicating the potential of using a non-invasive, non-pharmacological means to treat consequences of obesity.
Health Sciences Tower 16-060
Summary : Our laboratory focuses on the design and development of bioactive peptides and 3-D complex extracellular matrices (ECM) that will enhance soft tissue repair and regeneration. Peptides are assayed for biological activity in vitro and in vivo for their ability to protect tissue cells and organs from injury, stimulate tissue cell migration and proliferation and modulate stem cell and tissue cell differentiation. The ECM constructs tethered with bioactive peptides are analyzed for their physical, chemical and immunologic properties by such modalities as goniometry for hydrophilicity, static and dynamic stress and strain for viscolastic material properties, atomic force microscopy for Young's elastic moduli and surface topography; HPLC, mass spectroscopy, gel permeation chromatography and gel electrophoresis for chemical analysis; and fluorescence immunoassays for immunologic epitope mapping. In addition, cell interactions with the 3-D ECM constructs are examined at the transcriptional, protein and functional level as judged by real-time PCR, DNA microarray analyses, Western blots, proteomics, quantitative fluorescence microscopy, and cell viability, migration and proliferation assays. Special in vitro systems have been created to quantify sprout angiogenesis, epithelial sheet migration and neurite axon extension. Bioactive peptides and engineered ECM containing peptide biomimetics will also be tested in a variety of animal models and hopefully enter into clinical trials. This robust array of bioactive peptides and 3-D ECM constructs will provide new therapies for soft tissue injury and disease.
Bioengineering Building - Room G19
Associate Professor & Undergraduate Program Director
Summary : Our emerging understanding of oxygen delivery to the tissues is that the blood flow within the smallest arterioles is tightly organized within repeating networks across the tissue. Central to this new paradigm are the concepts of vascular communication between the beginning and end of the network (via gap junctions), and its relation to flow sensing by the vascular endothelium. Our work has shown that different types of microvascular flow patterns can be triggered by direct stimulation of the focal adhesions (alpha-v-beta-3 integrins, i.e., wound healing), compared to adenosine (i.e., metabolic change), compared to nitric oxide (i.e., inflammation), hence we can control the flow patterns. Among the goals of this work are in vitro construction of transplantable microvascular networks, using bionanotechnology to create the sturdy scaffolding, and verification of nanofabricated drug delivery units within the vasculature. To this end, equally important are mechanotransduction of the physical forces associated with flow change (i.e., wall shear stress), the pharmacologic signal transduction systems involved (which guide drug discovery and intervention), and the molecular basis for the committed step that ensures healthy flow delivery. Our work employs computational modeling of the fluid mechanics, the physiology of arteriolar network blood flow (in vivo and in vitro), and precise genomic manipulation of key proteins in healthy and vascular disease states.
Cold Spring Harbor Labs
Howard Hughes Medical Institution Investigator
Summary : Dr. Hannon received a B.A. degree in biochemistry and a Ph.D. in molecular biology from Case Western Reserve University, where he trained in the laboratory of Tim Nilsen. From 1992 to 1995, he was a postdoctoral fellow of the Damon Runyon-Walter Winchell Cancer Research Fund in the laboratory of David Beach, where he explored cell cycle regulation in mammalian cells. Dr. Hannon, along with collaborators, was able to identify p21, p15 and p16. His work and that of others has linked each of these to major tumor suppressor pathways, with the two latter genes being tumor suppressors in their own right and p21 being a major effector of the p53 tumor suppressor. After becoming an Assistant Professor at Cold Spring Harbor Laboratory in 1996 and a Pew Scholar in Biomedical Sciences in 1997, in 2000, he began to make seminal observations in the emerging field of RNA interference. His laboratory identified the effector complex of RNAi, which is called RISC, and showed that it contained small RNAs, now known as siRNAs, that were similar in size to those originally observed by David Baulcombe in his study of plants that were silencing transgenes by co-suppression. The origin of such small RNAs was revealed with his discovery of the Dicer enzyme; an RNAseIII family member that cleaves dsRNAs into discretely sized small RNAs that enter RISC. In 2002 Dr. Hannon accepted a position as Professor at Cold Spring Harbor Laboratory where he continued his studies to reveal that endogenous non-coding RNAs, then known as small temporal RNAs and now as microRNAs, enter the RNAi pathway through Dicer and direct RISC to regulate the expression of endogenous protein coding genes. In recognition of his research, Dr. Hannon was appointed to the Faculty of 1000, received the U.S. Army Breast Cancer Research Programâ€™s Innovator Award and the American Association for Cancer Researchâ€™s Award for Outstanding Achievement in Cancer Research. He assumed his current position in 2005 and continues to explore the mechanisms and regulation of RNA interference as well as its applications to cancer research.
Bioengineering Building - Room 213
Summary : Research in this laboratory focuses on the identification of precise parameters that define skeletal tissue quantity and quality and their perturbation to applied physical stimuli. To this end, state of the art imaging techniques (e.g., microCT or synchrotron infrared spectroscopy) are combined with molecular (e.g., RT-PCR), genetic (e.g., QTL), and engineering techniques (e.g., finite element modeling) to determine genes, molecules, forces, as well as chemical and structural matrix properties. An example for a recent study includes the demonstration that extremely small amplitude oscillatory motions (~ 100µm), inducing negligible deformation in the matrix, can serve as an anabolic stimulus to osteoblasts in vivo, producing a structure that is mechanical stronger and more efficient to withstand forces. Recent results also indicate that there is not only a genetic basis for bone architecture, but also that the sensitivity of bone tissue to both anabolic and catabolic stimuli is influenced by subtle genetic variations. The identification of the specific chromosomal regions that modulate this differential sensitivity is in progress. Clinically, our studies may lead to the development of effective prophylaxes and interventions for osteoporosis, without side-effects and tailored towards the genetic make-up of an individual.
500 Sunnyside Blvd
Summary : Our lab is taking a proactive approach to the genome information explosion by developing databases, data-analysis tools, and user interfaces to organize, manage, and visualize that vast body of information. One current project is the development of a third-party annotation system for the Caenorhabditis elegans genome sequence. This system will allow researchers to add comments and observations to the C. elegans database and to conveniently view the annotations of others with a Web browser. The system uses the ACEDB database in conjunction with the Java and Perl interfaces that have been developed in our lab. A second project is the development of a genome informatics tool kit, a modular collection of database query tools, sequence-analysis programs, and user interfaces that will allow biologists to solve data-management problems without the assistance of a computer programmer.
Cold Spring Harbor Labs
Summary : My laboratory is interested in the identification and functional characterization of cancer genes (oncogenes and tumor suppressors). Our main motivation for studying cancer genes is their proven practical value in serving as targets for new cancer therapies and as biomarkers that can guide treatment decisions. Additionally, cancer genes have normal functions and their characterization can often lead to deeper understanding of basic biology. In the past, our focus has been on the use of high-resolution genome arrays to pinpoint candidate oncogenes that are amplified in human cancer. We have validated many of these amplified genes as functional oncogenes in model systems and some of these validated oncogenes have served as starting points for cancer drug discovery programs. More recently, weâ€™ve branched out to include analysis of additional genomic alterations relevant to human cancer. Weâ€™ve also begun purely functional genomic approaches to identify genes involved in important cancer-related processes such as response to specific therapeutics.
Bioengineering Building - Room 217A
Distinguished Professor & Chair
Summary : Encouraging results show that the application of extremely low level strains to animals and humans will increase bone formation, and thus may represent the much sought after "anabolic" stimulus in bone. More than 15 years of research into non-invasive, non-pharmacological intervention to control osteoporosis, was referenced in Dr. Rubin's paper published in the journal Nature (August 9, 2001; 412:603-604). Dr. Rubin's studies suggest that gentle vibrations on a regular basis will help strengthen the bones in osteoporosis sufferers and increase bone formation. In his study, adult female sheep treated with gentle vibration to their hind legs for 20 minutes daily showed almost 35% more bone density. Clinical trials have been completed on post-menopausal women, children with cerebral palsy, and young women with osteoporosis, all with encouraging results. In expanding the research platform into other physiologic systems, current work demonstrates that these low-level signals influence mesenchymal stem cell differentiation, such that their path to adipocytes is suppressed, and markedly reduces adipose tissue.
Biochemistry and Cell Biology and Pathology
Summary : Acute and chronic inflammatory responses are important host defenses against foreign substances or pathogens. These responses are largely mediated by neutrophils and macrophages, which release proteases, cytokines, and a number of other mediators of inflammation in the course of defending the host. We study the mechanisms of action of serine proteases and metalloproteases from activated neutrophils and develop specific inhibitors to control the tissue destruction which may otherwise injure the host during an inflammatory response. Because invasiveness and metastatic spread of tumor cells involves tissue degradation by the same families of proteinases as is seen in inflammation, we have extended our studies to include evaluation of agents intended to block tumor spread or tumor-stimulated vessel growth (angiogenesis). Our methods include biophysical probes of enzyme active sites and kinetic measurements. We also measure neutrophil and macrophage phagocytic activity and release of oxidants by flow cytometry. We have made extensive use of a complete interstitial extracellular matrix from rat smooth muscle cells which we label biosynthetically and employ as a substrate for inflammatory cells and tumor cells and their proteases. We employ matrices on porous membrane filters to quantitate inhibition of invasive migration of neutrophils, macrophages, endothelial cells, and tumor cells by proteinase inhibitors and other modulatory agents. Our collaboration with colleagues in the Department of Oral Biology and Pathology has led to a series of clinical trials on a class of proteinase inhibitors with additional pleiotropic downregulatory actions on inflammatory and tumor cells. The trials of these inhibitors, which are nonantimicrobial derivatives of tetracyclines, target potential applications in management of cancer, acute respiratory distress syndrome, periodontal disease, and cardiovascular complications of smoking. To understand how inflammatory cells communicate we study paracrine mechanisms of activation by cytokines, using immunofluorescence and flow cytometry to measure levels of expression of cell surface receptors and other marker proteins which are sensitive to the state of activation of the cells.
Bioengineering Building - Room 115
Summary : Our laboratory seeks to integrate advances in nanoscience and technology with the biological sciences and clinical medicine to achieve significant advances in simultaneous molecular diagnostics and therapeutics (theragnosis), drug delivery, and bioengineering. Towards these ends, our research interests involve a multidisciplinary approach for the development of functional (electronic, optical, magnetic, or structural) bionanosystems as contrast agents for molecular imaging, as carriers for drug delivery, and as structural scaffolds for tissue engineering. Our current projects capitalize on the unique properties of carbon nanobiomaterials to develop a) advanced contrast agents (CAs) for molecular magnetic resonance imaging (MRI), b) nanocomposites to improve the physical and biological (osteoconduction and osteoinduction) properties of polymer scaffolds for bone tissue engineering and c) non-viral vectors for gene transfection. We have exploited the potential of Gd-based carbon nanostructures: Gd@C60 metallofullerenes (gadofullerenes) and Gd@Ultrashort-tubes (gadonanotubes) as a new generation of advanced CAs for MRI and shown them to have efficacies up to 100 times greater than current clinical CAs. Our recent studies show that they are particularly well suited for passive (magnetic labels for cellular MRI) and active (pH sensitive probes for cancer detection) MRI-based Molecular Imaging. Single-walled carbon nanotubes (SWNTs) have been proposed as the ideal foundation for the next generation of materials due to their excellent mechanical properties. We have dispersed SWNTs and ultra short SWNTs into fumarate-based polymers to form nanocomposite scaffolds that exhibit mechanical properties far superior to the polymers alone and are osteoconductive as well osteoinductive. Our research work involves material synthesis techniques, physico-chemical characterization techniques, tissue culture and in vivo studies.
Bioengineering Building - Room G13
Summary : Nature's ability to assemble simple molecular building blocks into highly ordered materials, such as those found in cell membranes, cell nuclei, cytoskeleton, cartilage, or bone presents many fascinating and unanswered questions. We are interested in how to tune the interactions of water-soluble building blocks so as to induce their self-assembly into useful microstructures much needed for the next generation of controlled drug delivery, biosensors and DNA sequencing applications. In particular, we are working on long-range ordered polyelectrolyte-surfactant microemulsions that are used as templates for solid nanoporous materials using polymerization and/or cross-linking strategies. Such materials, because of their well-ordered porous structure, will allow more efficient molecular separation and drug delivery. In addition, we are developing biosensors that are based on biopolymer chiral liquid crystals and quantum dot colloidal crystals. In both cases the softness of the systems allows the induction of a strong optical response to external stimuli. Such sensors should be able to quantitatively detect and measure analyte concentrations at hormonal levels.
350 Community Drive
Director, Feinstein Institute for Medical Research
Summary : Systemic inflammation is an important process in the development of shock, rheumatoid arthritis, inflammatory bowel disease, stroke, and other diseases. Our research focuses on the roles of individual mediators of systemic inflammation, and their regulation by interactions between the brain and the innate immune system. Our discovery of the inflammatory action of TNF in non-malignant disease led directly to clinically approved treatments for rheumatoid arthritis and inflammatory bowel disease. To discover new mediators of systemic inflammation, we screened products of endotoxin-stimulated macrophage cultures. This resulted in the discovery that HMG-1, a DNA binding protein that was widely studied for its intracellular roles, is a mediator of endotoxin lethality. In contrast to TNF and IL-1, which are released early after endotoxin exposure, HMG-1 is released late after exposure to endotoxin. Antibodies to HMG-1 completely protect mice from endotoxin lethality, even when treatment is delayed several hours. In critically ill patients, the highest serum HMG-1 levels exist in lethal cases, indicating that HMG-1 may be a therapeutic agent. Ongoing research addresses the mechanisms of HMG-1 toxicity and action, as well as the identification of signal transduction pathways.