Description of Research Expertise

Primary research: energy-dependent transport and cellular detoxification processes

Our primary research activities centered on the molecular biology, cellular biochemistry and proteomics of vacuolar function with special emphasis on membrane transport proteins and the enzymic machinery responsible for the detoxification of xenobiotics, including heavy metals. Long-term objectives are to identify the proteins concerned and elucidate their mechanisms of action and regulatory characteristics. Our approach has been that of the 'basic biologist' - the search for general principles, not just principles applicable to plants. Most of our studies therefore entailed parallel molecular and biochemical manipulations of several model systems including the plant Arabidopsis thaliana, the yeast Saccharomyces cerevisiae and the worm Caenorhabditis elegans. It is through the application of this approach that we have been able to make fundamental contributions toward understanding a remarkably broad range of transport and related phenomena of general relevance. These include:

(1) ABC transporters - Identification and molecular characterization of glutathione S-conjugate pumps (GS-X pumps) in yeast and plants.

(2) Phytochelatin-dependent heavy metal detoxification - Molecular cloning, in vitro reconstitution, and elucidation of catalytic mechanism of the enzyme phytochelatin (PC) synthase responsible for the fabrication of short-chain metal-binding peptides from glutathione.

(3) Pyrophosphate-energized proton pumps - Elucidation of the basic organization and core catalytic capabilities of proton-translocating inorganic pyrophosphatases (V-PPases), a novel class of proton pump.

(4) Vacuolar proteomics - Elucidation of the protein profile of the yeast vacuole using high-purity ‘proteomics-grade’ intact vacuoles. In strict agreement with a predominantly lysosomal function for this organelle, most of the proteins identified are either canonical vacuolar proteases or proteins involved in intermediary metabolism, protein synthesis, folding or targeting, or the alleviation of oxidative stress that have entered this compartment for salvage purposes.

Secondary research: science writing

At the time of writing, our research at the interface of the life sciences and their implementation focuses on case studies that highlight the difficult transition from discovery in the laboratory to success in the market and/or toward the expansion of humanitarian efforts. Our research centers on case studies that reveal how unexpected discoveries lead to significant advances in medicine, agriculture, and public health.

Our six feature articles, written for the educated layperson and translated into several languages, each focus on a different example of this transition. In ‘Statins: From Fungus to Pharma,’ we examine how a discovery reminiscent of the penicillin breakthrough transformed our understanding of cardiovascular disease and led to the development of statins, one of the twentieth century’s most notable biomedical achievements. In ‘Ivermectin and River Blindness,’ we highlight the global health challenge of river blindness – a disease that remains obscure to many in the developed world. This article draws a surprising connection between the disease and the deworming tablets commonly used to protect pets and livestock, emphasizing the hidden links between veterinary and human medicine. The article ‘Can Skinny Fat Beat Obesity?’ presents an up-to-date account of recent discoveries regarding brown and beige fat. These fat types help counteract the harmful effects of excess white fat – a major contributor to cardiovascular disease, type 2 diabetes, and metabolic syndrome. This piece is of general interest to anyone concerned about obesity, offering insights into how these discoveries might pave the way for new therapeutic approaches. In ‘Metformin: Out of Backwaters and Into the Mainstream,’ we trace the intriguing and sometimes circuitous history of metformin. Once shrouded in folklore and uncertainty, this drug has become the standard treatment for type 2 diabetes despite its relatively simple chemical structure and a mechanism of action that remained elusive until recently. Similarly, ‘How Glyphosate Cropped Up’ recounts the remarkable story of glyphosate (better known as Roundup), the most widely used herbicide in the world. The article explains how this herbicide was accidentally discovered as a modified amino acid and how its finely tuned structure enables it to disrupt a key enzyme in the shikimate pathway, a pathway vital for plant life. Our most recent feature, ‘Gliflozins for Diabetes: From Bark to Bench to Bedside,’ explores a new class of drugs that target the kidneys to treat diabetes. These gliflozins provide unprecedented cardiorenal benefits and are the culmination of nearly two centuries of research that began with an uprooted apple orchard Each article not only highlights a unique journey in life sciences research but also demonstrates the unexpected paths and serendipitous events that frequently contribute to significant advancements in the life sciences and public health.

An extension of these research activities is the book Managing Discovery in the Life Sciences. Harnessing Creativity to Drive Biomedical Innovation (2018), Cambridge University Press). In this book, co-authored with Mark V. Pauly and Lawton R. Burns, case studies of biomedical innovations are presented whereby the reader comes to better understand how the science actually played out through the interplay of personalities and cultures within and between academic and corporate entities and the significance of serendipity not as a mysterious phenomenon but one that is intrinsic to the successes and failures of the experimental approach.

Description of Other Expertise

Co-founding director of the Roy and Diana Vagelos Life Sciences & Management Program. Science writer and educator.