Faculty Profile - Diane Heck, PhD
Diane E. Heck, Ph.D.
Professor and Chair, Department of Environmental Health Science
“The supreme reality of our time is… the vulnerability of our planet.”
--John F. Kennedy, 1963
What are you best known for?
During my scientific career I have been fortunate to make several discoveries that contribute to the body of scientific knowledge. Perhaps the most significant is the finding that the enzyme catalase produces reactive oxygen species when stimulated by ultraviolet light. This discovery led to insights in mammalian biology where it provided a scientifically sound mechanism for oxidant generation in skin cells when irradiated by ultraviolet light. This clarified an important role of catalase in the development of skin cancer.
These findings also provide insight into evolutionary processes. Through the activities of catalase ancient organisms were able to catalyze the conversion of water to molecular oxygen. Potentially, the generation of reactive oxygen species in response to ultraviolet light, and then conversion of the resultant oxidants to molecular oxygen in the peroxide degrading actions of the enzyme, may be a fundamental factor contributing to the development of the planet’s aerobic atmosphere.
We discovered that skin keratinocytes produce nitric oxide a process critical for wound healing as well as anti-microbial responses. We were the first to directly measure the radius of diffusion of nitric oxide from a mammalian cell. We identified a role for nitric oxide in the motility of sea urchin sperm, thus elucidating a potential role for this molecule in the invertebrate neuromuscular junction. In these later studies we determined that nitric oxide is produced following a complex series of events initiated by the activation of a nitric oxide insensitive membrane bound guanylate cyclase, providing a model for the activities of these enzymes.
We created several classes of novel light-activated chemical compounds with anti-cancer activities that may prove useful in chemotherapy. We have developed light insensitive analogs of these agents with anti-inflammatory and/or anti-microbial activities including activity against drug resistant tuberculosis and potential activity against the deadly pulmonary inflammation generated in humans by the H5N1 (avian) flu virus.
What are you proudest of?
The discovery of several previously unrecognized functions for the enzyme catalase that have provided insights important for cell biology, carcinogenesis, infectious disease and molecular evolution.
Name one thing that struck you as you were making your decision to work or study at New York Medical College.
The faculty and staff at the school were so friendly, helpful and interesting.
What is your next goal?
Our next goals are to translate our biochemical insights into new therapeutics for some difficult clinical problems, including tuberculosis and chemical injury.
What do you want prospective students to know about New York Medical College?
Large and metropolitan as it is, the College still retains a “small town” feeling, with the education and individual concerns of each student being the primary focus of the faculty and staff.
Dr. Heck’s research focuses on integrating biochemical and mechanistic insights into the harmful effects from human interactions with toxicants found in the environment, and extends to the complex network of underlying physiological and genetic factors. She has studied the effects of numerous toxicants, including those of inhaled silica, mechanisms of immune modulation by chlorinated hydrocarbon contaminants, biochemical events that mediate the carcinogenic effects of ultraviolet light and the processes mediating the toxicity of vesicant chemicals, such as “mustard,” a blistering agent used in chemical warfare.
“In my laboratory it is our contention that the best approaches for effective interventions into many human maladies depend on efficiently integrating biochemical and mechanistic insights into the disease process, while considering the complex network of underlying genetic and environmental factors that lead to these conditions.
“For the past half century the development of therapeutics centered on studying a small number of proteins that may be important in the disease process. In some instances this has led to success, but the use of this strategy for developing interventions into many diseases has been far less fruitful. To gain more global insights into the process of tissue regeneration we employ a multifaceted approach in which we endeavor to integrate biochemical, molecular, structural, genetic and environmental factors likely to mediate the pathological process.
“To facilitate this we have established and continue to develop collaborations with researchers with expertise in diverse disciplines, which we believe is our greatest strength. In the laboratory we currently have two major projects underway, one funded by the National Cancer Institute (NCI) focusing on carcinogenesis and another funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), centering on the development of counter agents for sulfur mustard toxicity.”
“Mechanisms of Carcinogenesis.” We have discovered that UVB light rapidly stimulates the production of hydroperoxides by the enzyme catalase in mouse and human keratinocytes, and through the actions of catalase, high energy DNA damaging short wave ultraviolet light is converted to reactive chemical intermediates that can be further metabolized and detoxified by cellular antioxidant enzymes. The long-tem goals of this proposal are to determine if reactive peroxides produced in excessive or inappropriate quantities through the actions of catalase have the capacity to induce oxidative stress in keratinocytes, damage DNA and contribute to the development of skin cancer.
Our ongoing studies on “Mechanisms of Carcinogenesis” are multi-faceted in approach. We are further investigating the mechanisms of oxidant generation using site-directed mutagenesis. To date we have created mutants with deletions that disable subunit interactions we have speculated are critical for charge transfer networks linking the heme residues. We have hypothesized that the tetromeric enzyme acts as a functional dimer; each subunit has a charge-relay network linking two heme residues with one molecule of enzyme-bound NADPH. We speculate that the extremely high rate of catalysis of the hydrogen peroxide degrading activity is driven through this network; the oxidative half of the reaction occurs at one heme while the reduction occurs at the other. The flow of electrons between these subunits provides the kinetic force for the enhanced reaction speed. Our mutants are designed to disrupt this process.
“CORE: Pharmacology and Drug Development” The overall mission of the UMDNJ/Rutgers CounterAct Center of Excellence is to identify, evaluate and develop efficacious agents potentially useful for therapeutic intervention in vesicant-induced injury. Our Drug Discovery and Development Core will identify and choose relevant targets and create lead compounds. The lead compounds will then be optimized to enhance efficacy and limit toxicity. To these ends we have developed a proprietary target-based platform to screen compounds as countermeasures for vesicant induced toxicity. To fulfill our mission we will use a tiered approach to evaluate and maximize the activity and beneficial characteristics of each potential drug, and progress toward FDA approval, until it is surpassed in the process by the superior characteristics of one of our other agents.
Starting with two broad classes of drugs found to exhibit some efficacy against vesicant toxicity, we envision immediate approval for antivesicant use of minimally active drugs currently approved for alternative uses as well as the development a robust pipeline of counter agents with increasing efficacy.
The Education and Communication Core focuses on intra and extra center communication of findings as well as education on the techniques and approaches developed in this center.
In other studies we are investigating our observation that catalase also functions as a NADH oxidase. In the presence of ultraviolet light or an abundance of mitochondrial oxidants catalase expresses a high NADH oxidase activity. We speculate that this enzyme activity, one previously held to be an in vitro artifact (1-3), may be important for regulating mitochondrial activity. It is our thesis that, acting as a rheostat, oxidation of NADH to NAD+ by catalase facilitates glucose uptake and glycolysis thus maintaining pyruvate levels sufficient for mitochondrial respiration in the face of high levels of NADH generating mitochondrial activity. We are investigating this process through altering the expression of unaltered and mutant catalases in cultured cells. In these studies some experiments explore NADH oxidation by cells expressing catalase where the region of the protein that binds NADPH has been altered. We are also examining the effects of ultraviolet light, and nutrient availability on this process. Mitochondrial activity, nutrient availability and oxidant status are important parameters regulating the proliferation and invasion of tumor cells. We believe that NADH oxidation by catalase may be an important factor mediating carcinogenesis and tumor promotion.
We are also involved in the early stages of a project focusing on the role of host defense in the establishment of tuberculosis and the development of novel therapeutics to interfere with the development of drug-resistant TB.