Colleagues: Recently Tenured

CHARLES W. BRADBERRY, PH.D., NIDA

Senior Investigator, Preclinical Pharmacology Section, National Institute on Drug Abuse

Education: University of Kansas, Lawrence, Kan., (B.S. in chemistry; Ph.D. in biochemistry)

Training: Postdoctoral training in psychiatry, Yale School of Medicine (New Haven, Conn.)

Before coming to NIH: Professor of psychiatry, University of Pittsburgh School of Medicine (Pittsburgh); research career scientist, Veterans Affairs Pittsburgh Healthcare System (Pittsburgh)

Came to NIH: In 2016

Selected professional activities: Participating in the American College of Neuropsychopharmacology and European Behavioral Pharmacology Society; engaging in collaborative exploratory neuroscience; mentoring

Outside interests: Spending time with family; traveling; enjoying real food; exercising; playing billiards

Research interests: I am interested in understanding the neurobiology of addiction to drugs and alcohol in hopes that what I learn will help in the development of effective treatments. In particular, I am using nonhuman primates to study the addictive and rewarding properties of drugs of abuse and how drug use alters cognitive performance.

Before now, most of my work focused on cocaine. Using chronic self-administration models in rhesus macaques (Macaca mulatta), we demonstrated patterns of cognitive deficits result from chronic use that are similar to impairments associated with selective lesions in the orbitofrontal cortex. We also conducted longitudinal structural magnetic resonance (MR) imaging in the same animals. We are analyzing the MR data, as well as postmortem tissues, to determine whether cocaine has regionally selective effects and what the underlying substrates might be. We have also used electrophysiological approaches to study how multiunit activity across multiple brain regions mediates the ability of drug-associated cues to engage cognitive resources. We will continue to expand that work and study the encoding of choice between drug and nondrug rewards.

A major part of my work has been collaborating with colleagues who conduct positron emission topography (PET) imaging. We used trace analytical techniques to measure drug-induced release of extracellular dopamine in the cortex during PET imaging. Our findings validated the PET approaches for measuring extracellular cortical dopamine dynamics in humans. In another important collaboration with PET imagers, we demonstrated that chronic cocaine use causes a striking decrease in the number of neuronal vesicles from which dopamine is released.

In the NIDA intramural research program, I will be expanding my work to include nicotine and tetrahydrocannabinol (the active agent in marijuana). In collaboration with MR and PET colleagues at NIH, we will use multimodal imaging approaches to continue to develop novel “systems” neuroscience approaches for studying how these widely used substances influence behavior, cognition, and the underlying brain mechanisms.

JENNIFER C. LEE, PH.D., NHLBI

Senior Investigator, Laboratory of Protein Conformation and Dynamics, National Heart, Lung, and Blood Institute

Education: University of California at Berkeley, Berkeley, Calif. (B.S. in chemistry and a B.A. in economics); California Institute of Technology, Pasadena, Calif. (Ph.D. in chemistry)

Training: One-year postdoctoral stint at the Keck School of Medicine of University of Southern California (Los Angeles); Beckman Senior Research Fellow at the Beckman Institute Laser Resource Center at the California Institute of Technology

Came to NIH: In 2006

Selected professional activities: Editorial board member of the Journal of Biological Chemistry; member of the American Chemical Society

Outside interests: Keeping up with her two boys (ages two and five); traveling; and experiencing the world

Website: https://irp.nih.gov/pi/jennifer-lee

Research interests: My laboratory integrates complementary techniques to conduct biochemical and biophysical studies of protein conformation and interactions. A particular focus is to understand the molecular mechanisms of amyloid formation. Aggregation of proteins into amyloid structures is a hallmark of Alzheimer, Parkinson, and Huntington diseases. However, amyloid fibrils can also serve essential biological roles in organisms ranging from bacteria to humans. Thus, it remains a mystery whether pathological consequences are due to the structural features of amyloids or to the loss of specific cellular functions.

To understand the differences between functional and pathological amyloids, I am investigating the mechanisms of amyloid formation for two human proteins: alpha-synuclein, which is localized to nerve terminals and associated with Parkinson disease; and premelanosome protein 17, which serves as a template for melanin deposition in the skin and eyes. To determine the critical features guiding amyloid formation, I am characterizing how individual residues affect protein-protein interaction during the amyloid-assembly process. I am trying to determine the role of membranes in the aggregation process of alpha-synuclein.

Due to the complexity of the amyloid problem, I am using a multitude of biophysical techniques including time-resolved fluorescence anisotropy measurements to probe local conformational changes, circular dichroism and Raman spectroscopy to determine protein secondary structure, and transmission electron microscopy to visualize filament morphology. I am also pioneering the use of neutron reflectometry to investigate protein-membrane interactions. More recently, I have been studying the interaction between alpha-synuclein and glucocerebrosidase, the enzyme deficient in Gaucher disease, to explain why mutations in GBA, the gene encoding glucocerebrosidase, is a risk factor for Parkinsonism.

Ultimately, I would like to understand the mechanisms of amyloid formation and how cellular interactions of amyloids contribute to disease.

MATTHIAS P. MACHNER, PH.D., NICHD

Senior Investigator; Head, Section on Microbial Pathogenesis, Division of Molecular and Cellular Biology, National Institute of Child Health and Human Development

Education: University of Osnabrück, Osnabrück, Germany (M.S. in biology); Technical University of Braunschweig, Braunschweig, Germany (Ph.D. in natural sciences)

Training: Postdoctoral Howard Hughes Medical Institute fellow at Tufts University School of Medicine (Boston)

Came to NIH: In 2008

Selected professional activities: Symposium organizer and chair for the American Society for Microbiology meeting (2015, 2012) and the American Society for Cell Biology meeting (2014); topic editor for Frontiers in Cellular and Infection Microbiology

Outside interests: Being outdoors; taking long walks with the dog; listening to music (anything from Hawaiian to classical music); spending quality time with friends and family

Website: https://irp.nih.gov/pi/matthias-machner

Research interests: Our main research goal is to obtain a detailed understanding of the molecular mechanisms by which pathogenic bacteria can manipulate host cells during infection.

We use as a model organism the bacterium Legionella pneumophila, which is commonly found within freshwater reservoirs as a natural parasite of ameba. When inhaled by humans, L. pneumophila can cause a potentially fatal pneumonia known as Legionnaires’ disease. Contrary to what its name may imply, Legionnaires’ disease occurs in individuals of all ages including children who receive respiratory therapy, newborns who recently underwent surgery or underwater birth, and children who are immune-compromised.

When a person inhales contaminated water droplets, L. pneumophila enters the lungs and is phagocytosed (taken up) by specialized immune cells called alveolar macrophages. Instead of being degraded by these cells, the pathogen establishes a protective membrane compartment around itself, the Legionella-containing vacuole (LCV). Within this protective chamber, L. pneumophila can replicate in high numbers before it kills the host cell and infects neighboring cells.

Intracellular survival of L. pneumophila depends on the activity of close to 300 proteins, or effectors, that the bacterium injects into the host cell, where they create conditions favorable for infection. L. pneumophila mutants that are defective in effector-protein delivery fail to escape endolysosomal degradation, underscoring the key role of microbial effectors for bacterial virulence.

Our goal is to obtain a detailed mechanistic insight into the regulation and function of L. pneumophila effectors by investigating host-pathogen interactions at the molecular, cellular, and structural levels. Deciphering the virulence program of this dangerous pathogen will set the stage for the development of novel therapeutics aimed at treating or preventing Legionnaires’ disease and related illnesses.

HELEN C. SU, M.D., PH.D., NIAID

Senior Investigator; Chief, Human Immunological Diseases Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases

Education: Brown University, Providence, R.I. (A.B. in biochemistry, M.D., and Ph.D. in pathobiology)

Training: Residency in pediatrics at St. Louis Children’s Hospital, Washington University (St. Louis); clinical fellowship and research fellowship in allergy and immunology at NIAID

Came to NIH: In 2001 for training; became tenure-track investigator in 2007

Selected professional activities: Adjunct faculty member in the NIH–University of Pennsylvania Immunology Graduate Partnership Program

Outside interests: Reading; listening to music and playing the piano; hiking; sleeping!

Website: https://irp.nih.gov/pi/helen-su

Research interests: My laboratory carries out research to elucidate novel molecular mechanisms that regulate the human immune system. In particular, we study lymphocytes and how their derangements cause susceptibility to viral and other infections. We use state-of-the-art genomic approaches to study patients who have rare and poorly characterized inherited immunodeficiencies. By carefully investigating these “experiments of nature,” we can draw inferences about molecular functions based on patient phenotype. Cell-mediated immunity is crucial in protecting against viral infections. We have observed that these patients usually have partial T-cell or combined immunodeficiencies, which are often accompanied by autoimmunity or lymphoproliferation.

Through a broad program that integrates the patients’ clinical evaluations; assessments of their leukocyte function; and genetic and biochemical analyses, including use of new technologies such as whole-genome analysis and two-photon excitation microscopy, we gain profound insights into the molecular and cellular bases of immunity against viruses. In some instances, parallel insights can be gained from experimental animals. In other instances, we learned unique lessons from investigating the human disease. Therefore, my approach as both a clinical and a basic-science researcher is to combine the powerful clinical-investigatory resources of the NIH Clinical Center with the extensive basic-science capability within NIAID’s Division of Intramural Research to define new clinical entities and their molecular pathogenesis. By using the latest molecular, genomic, and cellular technologies to elucidate the fundamental mechanisms that normally regulate human lymphocytes for host defense, we also aim to improve the diagnosis and treatment for these and related immunological conditions.

CARMEN WILLIAMS, M.D., PH.D., NIEHS

Senior Investigator, Reproductive Medicine Group, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences

Education: Duke University, Durham, N.C. (B.S.E in electrical engineering; M.D.); University of Pennsylvania, Philadelphia (Ph.D. in molecular and cell biology)

Training: Residency in obstetrics and gynecology at Pennsylvania Hospital (Philadelphia); fellowship in reproductive endocrinology and infertility at the University of Pennsylvania; postdoctoral fellowship at the University of Pennsylvania

Before coming to NIH: Assistant professor, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Pennsylvania

Came to NIH: In 2007

Selected professional activities: Editor of Molecular Reproduction and Development; serving on various committees of the Society for the Study of Reproduction; section director, “Frontiers in Reproduction” course, Woods Hole, Mass.

Outside Interests: Reading science-fiction novels; power walking

Website: https://irp.nih.gov/pi/carmen-williams

Research Interests: We study mammalian reproductive biology with a focus on fertilization and embryo development. My group prioritizes questions that are directly relevant to human reproduction and how the environment influences fertilization and embryo development.

We are trying to understand the mechanisms that underlie the effects of environmental chemical exposures on early reproduction. Phytoestrogens, found in plants, occur naturally and act like estrogen. Phytoestrogens are readily available in the diet, and many other estrogenic chemicals are released into the environment. Depending on the dose and timing of exposure, these chemicals may have both beneficial and detrimental effects on health. We use a mouse model to study the effects of estrogenic chemicals on female reproductive health including how this exposure may lead to defects in the reproductive tract that can affect fertilization and embryo development.

We are also investigating the role that calcium plays in the preimplantation embryo. The transition of a fertilized egg into a developing embryo, known as “egg activation,” is initiated by repetitive cycles, or oscillations, of intracellular calcium. These oscillations begin after sperm-egg plasma-membrane fusion, when the sperm releases the enzyme phospholipase C zeta into the egg’s cytoplasm. Continuation of these oscillations requires calcium entry into the egg to replenish calcium stores. We are studying the calcium channels that support this entry. We hypothesize that inadequate calcium entry, which can lead to abnormal calcium oscillatory patterns during fertilization, could explain one of several causes of human infertility. These possibilities include failed fertilization, poor preimplantation embryo development, and miscarriage.