My graduate work in the laboratory of Dr. Jerry Lingrel at the University of Cincinnati (1979-1983) focused on the structure and function of goat globin genes. Similar to humans, globin gene regulation in goats undergoes developmentally regulated switching, including an extra “reversible” switch between the and isoforms. I mapped and cloned a number of these genes, including the duplicated locus specifiying the -globin genes. As part of this work (I was a co-author on 12 publications), I discovered one of the first examples of gene conversion (at the locus) and the first examples of retroposition of LINE elements in a mammalian genome.My postodctoral work in the laboratory of Dr. Argiris Efstratiadis at Harvard University (1983-1984) focused on the 3-dimensional topology of DNA in eukaryotic promoter regions. As part of that work (I was a co-author on 4 publications), we discovered the first example of triple-helical “bent” DNA that was intimately associated with the initiation of transcription in promoter regions.Beginning as an Assistant Professor, and continuing to the present day, all at Columbia University (1984-2015), my laboratory has focused on the fundamental biology of mammalian mitochondria and on the molecular genetics of human mitochondrial disease. In that time we have made significant contributions to the field (I am an author or co-author on almost 250 publications). Among our contributions was the first discovery of recombination in mammalian mitochondrial DNA and the fact that such recombination can cause large-scale deletions of mtDNA that cause human mitochondrial disease. We discovered the first case of mtDNA “depletion” syndrome characterized by the quantitative loss of mtDNA, including, notably, the discovery that treatment of HIV-positive AIDS patients with anti-retroviral therapy could also cause a severe and debilitating mtDNA depletion. We were among the first to use “cybrid” technology to dissect the pathogenesis of maternally-inherited mtDNA mutations. We performed the first, and only, analysis of the mtDNA of “Dolly” the sheep (and found that her mtDNA did not derive from the same source as did her nuclear DNA!). We performed the first example of “allotopic expression” in human cells, in which we re-coded and transferred an mtDNA-encoded gene to the nucleus, and re-targeted the encoded protein back to mitochondria, in order to rescue successfully the deleterious phenotype due to a mutation in that gene. We were the first to develop the concept of using pharmacological approaches to “shift heteroplasmy” as a way to treat mtDNA-based mitochondrial diseases. We discovered that mutations in SCO2, a cytochrome c oxidase “assembly” protein, are a cause of Leigh syndrome, a fatal encephalopathy of infancy. More recently, we were the first to show that mtDNA “nucleoids” (mtDNA-protein assemblages) are “autonomous” genetic elements within mitochondria.Recently our lab has become interested in the pathogenesis of Alzheimer disease. We discovered that presenilins-1 and -2, and -secretase activity, are localized to “mitochondria-associated ER membranes (MAM)”, a lipid raft-like subdomain of the ER that connects it to mitochondria, both physically and biochemically (I am a co-author on 7 publications describing the role of MAM in neurodegenerative disease). Moreover, ER-mitochondrial apposition, and MAM function, are upregulated massively in AD, and is likely the cause of many, if not all, of the phenotypes associated with the disease. Consistent with this idea, we have now shown that ApoE4, the greatest risk factor for developing sporadic AD, also upregulates MAM function.