LAUSR

The lives of individuals are marked by inflection points, events that seem prosaic at the time of their occurrence but have profound consequences as life unfolds. For me, such an inflection point happened in 1980 while I was a virologist working on mouse mammary tumor virus: My colleague Bill Weidanz, a pioneering immunoparasitologist, suggested that we should construct a genomic library of a malaria parasite from which to fish out genes encoding protective antigens to produce a malaria vaccine. Being a somewhat cocky molecular virologist, I was quick to agree, saying it would be a “piece of cake.” Bill (whom we sadly lost last November) never missed a chance to rib me for that flippant comment! Developing a vaccine for malaria has been anything but a “piece of cake.” However, it was not the fishing for antigens but a quality control experiment to determine the robustness of our genomic library from Plasmodium yoelii that had profound personal consequences for me. We detected numerous phage clones in the library bearing repetitive DNA of this eukaryotic organism, thus showing that our library was of good quality. It was the study of this 6-kb repetitive DNA that altered the course of my scientific career (and led me to cancel my subscription to Journal of Virology). We did not immediately know what this 6-kb repetitive DNA encoded but discovered that it was tandemly arranged head-to-tail in all species of malaria parasites and expressed as multiple RNA molecules of various sizes. At a molecular parasitology meeting in the mid-1980s, several investigators presented their exciting discoveries of important malaria parasite antigens that they named with clever acronyms, e.g., RESA (Ring-infected Erythrocyte Surface Antigen), FIRA (Falciparum Interspersed Repeat Antigen), and MESA (Mature parasite-infected Erythrocyte Surface Antigen). Not to be outdone, I coined an acronym for our repetitive DNA: POLARIS (Plasmodium-Origin Large Array of Relatively Invariant Sequence). Although I thought the acronym was clever, if not funny, the editor of the journal Molecular Parasitology was not amused and struck it out of the paper we published in 1987. POLARIS thus remains an obscure insider joke. Nevertheless, like its celestial namesake, POLARIS has guided the research in my laboratory for 30 years. When we completed the sequence of the 6-kb DNA molecule in 1988, it revealed itself to be the mitochondrial DNA (mtDNA) of malaria parasites. At that time, some researchers were already investigating a 35-kb circular DNA molecule that they believed to be the parasite’s mtDNA. However, based on our sequence data establishing the 6-kb tandemly repeated DNA as the mitochondrial genome, it became clear that the 35-kb circular DNA molecule was something else. Upon further sequencing, the 35-kb DNA molecule was found to be a highly reduced chloroplast DNA, which was subsequently shown to reside in a separate cytoplasmic organelle now known as the apicoplast. Not just malaria parasites but all apicomplexan parasites were thus revealed to have originated from an algal progenitor! These insights have significant