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 secondary research efforts are concerned with the interface between the life sciences and their implementation; the difficult transition from discovery in the laboratory to success in the market and/or toward the expansion of humanitarian efforts. To date we have published three articles in this area. The first of these articles, entitled “Statins: from fungus to pharma” was largely derived from our teaching activities for the Roy and Diana Vagelos Program in Life Sciences & Management. The model we had in mind was a historical scientific narrative on the discovery and implementation of the statins as drugs for the prevention and treatment of cardiovascular disease (CVD). The impetus for preparing the statins article was a sense that material of this nature would be of immense interest to educated members of the general public because it has something for everyone. It is an example of how our understanding of CVD has undergone radical revision, and in so doing given us a better understanding of how statins do what they do (something that would not have happened if not for the introduction of these drugs); how a serendipitous discovery with striking parallels at all levels to the discovery of the penicillins is quite possibly one of the most significant biomedical accomplishments of the twentieth century; how the convergence and application of basic but disparate cellular biochemical concepts and methodologies spawned one of the best selling drugs; how the original discovery of a drug, or class of drugs, made by one company, required the engagement of another company, either as competitor or collaborator, to bring the drug in question to market; how the juxtaposition of economic with biomedical imperatives can be the deciding factor in determining whether to aggressively push for the implementation of a fundamental discovery; how "plan B" compounds can end up being billion dollar pills (Lipitor in this case). The need for the second feature article, entitled “Ivermectin and River Blindness” came from the realization that despite the immensity of the river blindness problem very few of us in this part of the world know of the existence of this disease, and even fewer know of the connection between it and something that most of us know something about, the "deworming tablets" given to pets and livestock to protect them from heartworm and similar parasitic infections. Yet, the fact of the matter is that if your dog has been given preventative medication for heartworm it was almost certainly given the very same drug, ivermectin, that has and continues to be used to treat literally tens of millions of people in the developing world; people who would otherwise have to live lives of interminable suffering and anguish. The third feature article, entitled “Can Skinny Fat Beat Obesity?”, is an up to date account of the roles played by brown and beige fat (‘skinny fat’) in keeping white fat, a surplus of which is associated with cardiovascular disease, type 2 diabetes and the metabolic syndrome, at bay. Whether the readers are themselves overweight or know others who are, this article is of general interest because it encompasses several unprecedented discoveries made only in the last few years (some only in the last few months) which when explained provide readers with a platform for better understanding the role played by classical brown fat in newborns and hibernating mammals, how beige fat was discovered in animals and human adults, what it is and does, the biochemical basis of thermogenesis, and recent advances in the identification of a new class of therapeutic agents that might eventually be used to combat obesity.

Description of Other Expertise

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