Laboratory of Molecular Parasitology
Trypanosomes remain a problem for humans and other animals throughout large regions of Africa and South America. African sleeping sickness and Chagas disease are invariably fatal, though it may take weeks or years to succumb, depending on the species and the strain. Dr. Cross’s laboratory focuses on how trypanosomes evade our immune systems and on overcoming the obstacles that have prevented the development of a successful vaccine.
Dr. Cross’s laboratory studies the novel biochemical and genetic characteristics of trypanosomes. These organisms branched very early in eukaryotic evolution, and they have significant, and sometimes bizarre, variations from the conventional mechanisms of gene expression. Research on trypanosomes also sheds light on how more complex, higher eukaryotic regulatory systems have evolved.
Trypanosoma brucei is one species of trypanosome that causes African sleeping sickness and is transmitted by the Glossina species, commonly known as the tsetse. Ten million copies of a single glycoprotein form the surface coat of the parasite, a dense structure that surrounds the entire cell body and the flagellum. Using recombinatorial mechanisms, trypanosomes possess an infinite capacity for switching among the hundreds of genes encoding members of the variant surface glycoprotein (VSG) family, allowing infections to evade the mammalian host’s immune system so the parasites survive and proliferate indefinitely, until death of the host.
The main focus of Dr. Cross’s lab is to identify the mechanisms that regulate VSG switching and expression. The parasite exerts very tight control over VSG expression, making only one VSG at any given time. The genes involved in VSG production are close to the ends of the chromosomes, called the telomeres, which is somehow important for regulating their expression.
Using biochemical methods, Dr. Cross’s lab has identified and analyzed VSGs and, through advances in trypanosome genetics, many pioneered in his lab, has learned how the parasite regulates their production. They have found that two predominant mechanisms are used to switch a VSG gene: the telomeric expression site that is being transcribed can be switched, or VSG genes can be shuttled from locations on other chromosomes to an active expression site. Neither method guarantees activation of the appropriate VSG, however, and Dr. Cross’s lab is researching how changes in telomere length and the presence of novel histone modifications may regulate the transcription of VSG genes in particular and gene expression in general in trypanosomes. In collaboration with F. Nina Papavasiliou’s Laboratory of Lymphocyte Biology, the lab is also studying mechanisms involved in VSG gene switching mediated by recombination machinery and determining the entire repertoire of VSG genes and their evolutionary relationships in the genomes of several trypanosome clones.
Dr. Cross also maintains interests in genome-wide analysis of trypanosome gene expression, including developmental regulation and the role of histone modifications in regulating the polycistronic transcription that is a feature of trypanosomes and is unique among eukaryotic cells.
Dr. Cross was the first to identify the constituents of the coat as numerous copies of a single glycoprotein. Dr. Cross’s lab was also the first to characterize a mechanism for protein anchoring to the cell membrane, called glycophosphatidylinositol (GPI) anchoring, that has since been found to be used for numerous proteins in a wide range of organisms. Trypanosomes use GPI anchoring to a greater extent than any other cell type, and there are some unique features of GPI anchoring in these parasites that are still not well understood.
Born in Cheshire, England, Dr. Cross received his undergraduate degree in 1964 and his Ph.D. in biochemistry in 1968 from the University of Cambridge, where he held a Medical Research Council Research Training Scholarship and was an Imperial Chemical Industries Fellow during his postdoc. From 1970 to 1977 he worked in the biochemical parasitology unit of the Medical Research Council. He then joined the Wellcome Research Laboratories of the Wellcome Trust in England, where he was the head of the department of immunochemistry and molecular biology. Dr. Cross came to Rockefeller in 1982. In 1984 Dr. Cross was corecipient of the Paul Ehrlich and Ludwig Darmstaedter Prize, awarded in Germany, and received the Chalmers Memorial Medal of the Royal Society of Tropical Medicine and Hygiene in 1983. He was elected a fellow of The Royal Society in 1984.