Colleagues: Recently Tenured
EDWARD GINIGER, PH.D., NINDS
Senior Investigator and Chief, Axon Guidance and Neural Connectivity Section, National Institute of Neurological Disorders and Stroke
Education: Yale University, New Haven, Conn. (B.S. and M.S. in molecular biophysics and biochemistry); Harvard University, Cambridge, Mass. (Ph.D. in biochemistry and molecular biology)
Training: Postdoctoral research in developmental neuroscience at the University of California, San Francisco (San Francisco)
Before coming to NIH: Associate member, Fred Hutchinson Cancer Research Center (Seattle, Wash.)
Came to NIH: In 2004
Selected professional activities: Adjunct investigator, NHGRI; associate editor PloS ONE; associate editor (ad hoc) PLoS Genetics
Outside interests: Alpine mountaineering
Research interests: My lab studies neural wiring: how it is established during development and why it is disassembled during neurodegenerative disease.
In our studies of development, we focus on axon guidance, the process by which neurons send out axons to the correct targets. We first showed that the cell-surface receptor Notch, which is well known for controlling cell fates during development, has a second career: locally controlling the Abelson (Abl) tyrosine kinase signaling pathway in axons to direct their growth and guidance.
More recently this finding has led to our conducting live imaging of single, Notch-dependent axons as they extend in their native environment in developing Drosophila melanogaster. To our surprise, we have found that axons growing in intact tissue have a morphology that is very different from what one sees in axons grown in culture dishes. This unexpected morphology implies an unexpected cell biology in the axonal growth cone in vivo. In our current experiments, we are teasing apart exactly what each of the axon’s cytoplasmic signaling proteins is contributing to its morphogenesis and movement.
In our studies of neurodegeneration, we have been examining a mutant gene of D. melanogaster (called Cdk5-alpha) whose protein causes adult-onset neurodegeneration and a severely reduced lifespan. The protein disrupts the subcellular organization of neurons, leading to altered excitability, swollen axons, and eventually axonal and dendritic fragmentation. Remarkably, however, there is also a second side to the effects of this mutation: It accelerates the absolute rate of aging in the fly. This mutation thereby causes or exacerbates defects in several functions including innate immunity, stress sensitivity, and proteostasis. Current efforts are focused on understanding the interplay between these two faces of Cdk5-associated neuropathology and their respective roles in human neurodegenerative disease.
HORMUZD A. KATKI, PH.D., NCI-DCEG
Senior Investigator, Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute
Education: University of Chicago, Chicago (B.S. in applied mathematics and statistics); Carnegie Mellon University, Pittsburgh (M.S. in statistics); Johns Hopkins University, Baltimore (Ph.D. in biostatistics)
Training: Post-baccalaureate training at NIH’s former Division of Computer Research and Technology (now CIT)
Came to NIH: In 1995 for training; in 1999 became staff scientist in NCI-DCEG; appointed principal investigator in 2009
Selected professional activities: Statistical reviewer for the Journal of the National Cancer Institute; associate editor for the American Journal of Epidemiology; member of the American Society for Colposcopy and Cervical Pathology
Outside interests: Reading nonfiction; biking; raising his three children
Research interests: My research focuses on developing and applying quantitative methods to epidemiologic findings to understand how they could be used for cancer screening and prevention. I am particularly interested in developing risk-based approaches to cancer screening.
I led a team that calculated cervical cancer risk for women with different combinations of human papillomavirus (HPV), Pap, and biopsy test results over time using data on 1.4 million women. These calculations are the foundation for the new cervical-cancer screening guidelines available in the official guidelines App (http://www.asccp.org/Bookstore/ASCCP-Mobile-App). These calculations are based on a new statistical model, called the logistic-Weibull model, that we developed.
I also lead a team to estimate the benefits and harms of undergoing computed-tomography (CT) lung-cancer screening. We developed new risk models for lung cancer and used them to identify a smoker’s benefit (reduction in risk of lung-cancer death) and harm (risk of false-positive CT). We project that our risk-based approach to targeting CT lung screening might save 20 percent more lives from lung-cancer death over five years compared with screening the same number of smokers under current U.S. Preventive Services Task Force guidelines.
These risk-based approaches to cancer screening depend on the principle of “equal management of people at equal cancer risk.” This principle ensures simplified and consistent management of people with different test results or risk factors, but with the same cancer risk. We are examining the limitations of this principle to develop a comprehensive intellectual approach to risk-based precision medicine.
HISATAKA KOBAYASHI, M.D., PH.D., NCI-CCR
Senior Investigator and Chief, Laboratory of Molecular Theranostics, Molecular Imaging Program, Center for Cancer Research, National Cancer Institute
Education: Kyoto University, Kyoto, Japan (M.D. in radiology; Ph.D. in immunology/medicine)
Training: Residency in radiology, Kyoto National Hospital (Kyoto); postdoctoral training in nuclear medicine and diagnostic radiology, Kyoto University
Came to NIH: In 1995–1998 as visiting (Fogarty) fellow, Nuclear Medicine Department, NIH Clinical Center; returned in 2001–2004 as a senior visiting fellow in the Metabolism Branch of NCI-CCR; in 2004–2015 was chief/staff scientist, and later chief/associate scientist, in NCI’s Molecular Imaging Program
Selected professional activities: Serving on editorial boards for several scientific journals including Bioconjugate Chemistry and Contrast Media and Molecular Imaging
Outside interests: Spending time with his son by playing tennis and skiing in winter
Research interests: I am developing novel molecular-imaging and therapeutic agents and technologies for diagnosing and treating cancers. My work is based on multidisciplinary sciences including chemistry, pharmacology, physics, and engineering. My group focuses on optical, radionuclide, and magnetic-resonance molecular-imaging methods.
To help physicians detect small cancers during endoscopic surgery procedures, we created targeted activatable optical agents—including a sprayable optical-imaging probe—that turned on the signal only when they hit cancer cells. We have developed instruments and cameras that can help the surgeons, too, as well as other agents for use during prostate-cancer surgery.
My group also has developed antibody-targeted photosensitizers to selectively treat cancer cells with light, a process that has been termed near-infrared photoimmunotherapy (NIR-PIT). Using a variety of antibody-photosensitizer conjugates, we have shown that applying near-infrared light causes dramatic, rapid immunogenic cell death in tumors that have been previously exposed to the conjugate. As the conjugate only binds to the target cells, cell death occurs only where the NIR light is applied. The adjacent normal cells and tissue are left untouched. We have also shown that NIR-PIT preserves the tumor vasculature so there is a dramatic increase in the flow through and permeability of tumor vessels. This increase allows up to 25-fold higher concentrations of nano-sized agents, including anticancer drugs such as doxorubicin and Abraxane, to be deposited and reach the tumor bed.
Recently, we discovered that NIR-PIT induced a marked immunological response that may further aid in treatment of head and neck, pancreas, lung, and colon cancers. The first clinical NIR-PIT trial for head and neck cancer patients targeting the epidermal growth factor receptor has been approved by the FDA and opened in the United States this year.
KEIR C. NEUMAN, PH.D., NHLBI
Senior Investigator, Laboratory of Single Molecule Biophysics, National Heart, Lung, and Blood Institute
Education: University of California, Berkeley (B.A. in physics and applied math); Princeton University, Princeton, N.J. (M.A. and Ph.D. in physics)
Training: Postdoctoral training at Stanford University (Stanford, Calif.); Human Frontiers Postdoctoral Fellow at the Laboratoire de Physique Statistique, l’École Normale Supérieure (Paris)
Came to NIH: In 2007
Selected professional activities: Editorial board member of Biophysical Journal and Journal of General Physiology
Outside interests: Spending time with his family; backpacking; cycling
Research interests: Enzyme mechanisms have traditionally been elucidated from experiments that involve thousands or millions of molecules. But such ensemble approaches don’t reveal the complexities and features of individual enzymes. Single-molecule visualization and manipulation techniques, however, can probe distances on the subnanometer scale and forces on the piconewton scale with millisecond temporal resolution. My laboratory develops and uses these techniques—including optical and magnetic tweezers and fluorescence imaging, in combination with conventional molecular biology approaches—to examine enzyme mechanisms and regulation at the molecular level.
Approximately two meters of DNA is crammed into a cell’s tiny nucleus. The constraints of such a tiny space can contribute to complications during the chromosomes’ replication, transcription, and segregation processes. We are deciphering the molecular mechanisms of enzymes called topoisomerases, which regulate DNA topology and are important drug targets. We hope to determine how chemotherapeutic and antibiotic agents can inhibit topoisomerase activity.
More recently, we have turned our attention away from the cell nucleus to study interactions between the structural protein collagen and the matrix metalloproteinase enzymes (collagenases) that degrade it. By studying the motion of individual collagenase enzymes as they degrade intact native collagen fibers, we have discovered a spontaneous periodic dynamic patterning of collagen fibers and elucidated the molecular mechanisms of fibrillar collagen degradation. Our findings may shed light on human pathological and physiological processes such as the rupture of atherosclerotic plaques and cancer metastasis.
Finally, we are developing fluorescent nanodiamonds as indefinitely stable fluorescent probes for in vitro and in vivo imaging. We have applied a weak alternating magnetic field to demonstrate in vivo background-free imaging of fluorescent nanodiamonds. This promising technique could lead to advances in the depth and resolution of in vivo imaging with potential applications in biomedical optical imaging and diagnostics.
CHARLES VENDITTI, M.D., PH.D., NHGRI
Senior Investigator, Head, Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute; attending physician, NIH Clinical Center
Education: Massachusetts Institute of Technology, Cambridge, Mass. (S.B. in biology); Pennsylvania State College of Medicine, Hershey, Pa. (M.D., Ph.D. in microbiology and immunology)
Training: Residency in pediatrics at Massachusetts General Hospital/Harvard Medical School (Boston); combined clinical and biochemical genetics fellowship at the Children’s Hospital of Philadelphia/University of Pennsylvania School of Medicine (Philadelphia)
Came to NIH: In 2003 joined NHGRI as a member of the Physician-Scientist Development Program; in 2009 became a tenure-track investigator in the Genetics and Molecular Biology Branch
Selected professional activities: Board of Medical Advisors, Organic Acid Association; editorial board, Molecular Therapy—Methods and Clinical Development
Outside interests: Reading; bike riding with family; swimming; building bikes
Research interests: My lab studies the hereditary methylmalonic acidemias (MMA) and disorders of vitamin B12 metabolism—conditions that cause increased concentrations of methylmalonic acid and/or homocysteine to accumulate in body fluids. MMA is one of the most common inborn errors of organic acid metabolism. People with MMA are medically fragile and suffer from multisystem complications ranging from developmental delay to metabolic stroke to end-stage renal failure. The American College of Medical Genetics recommends newborn screening for MMA.
My colleagues and I conduct clinical research aimed at defining the natural history of the MMAs and disorders of vitamin B12 metabolism. We also conduct laboratory studies that use metabolic, genetic, and genomic approaches to better understand the basic biology underlying these disorders.
By studying mouse models of vitamin B12–nonresponsive MMA, my group determined that mitochondrial dysfunction is a cardinal feature of the disorder and may underlie the tissue-specific manifestations seen in patients. In addition, we found that a large source of methylmalonic acid is skeletal muscle, which may explain the clinical observation of persistent MMA in patients after liver or liver-kidney transplantation.
We have also developed zebrafish (Danio rerio) models to study the metabolism of cobalamin (various chemical forms of vitamin B12), specifically cobalamin C disorder (cblC; also known as methylmalonic aciduria with homocystinuria), a form of combined MMA and hyperhomocysteinemia and the most common inborn error of intracellular cobalamin metabolism. Its clinical manifestations range from intrauterine effects—such as congenital microcephaly—to cognitive deterioration in adulthood. Some patients develop progressive retinal degeneration that leads to blindness. We plan to use the cblC zebrafish model for genomic and proteomic studies in an effort to shed light on the human disorder.
Another active effort includes the development and testing of gene therapy for MMA and cblC deficiency. For MMA, we have demonstrated that systemic gene delivery using adeno-associated viral (AAV) vectors effectively treats mice with MMA and provides long-term correction. We hope to perform a clinical trial at the NIH using AAV vectors to treat patients with MMA.