Heads of Laboratories
André and Bella Meyer Professor
Laboratory of Molecular Parasitology
gamc@rockefeller.edu
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 upon 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. Dr. Cross’s research 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 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. The trypanosome is able to evade the human immune system because it has the ability to switch the glycoprotein that makes up its surface coat, enabling it to evade the immune response indefinitely.
Using recombinatorial mechanisms, trypanosomes possess an infinite capacity for variation of the genes encoding the family of surface glycoproteins. As they repeatedly switch the proteins that are expressed on their surface, members of the trypanosome population always survive repeated onslaughts from the immune system, allowing the parasites to survive and proliferate. The main focus of Dr. Cross’s lab is to identify the mechanisms that regulate glycoprotein switching and expression. An individual gene encodes each of several hundred glycoproteins, representing about 10 percent of the trypanosomes’ genome. The parasite exerts very tight controls over their expression, so that it only makes one glycoprotein at any given time. The genes involved in glycoprotein production are close to the ends of the chromosomes, called the telomeres, and Dr. Cross suggests that this location may be important for limiting expression to only one gene at a time.
Using biochemical methods, Dr. Cross’s lab has identified and analyzed trypanosome antigens 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 glycoprotein gene: The telomeric expression site that is being transcribed can be switched, or glycoprotein genes can be shuttled from locations on other chromosomes to an active expression site. Neither method guarantees activation of the appropriate gene, 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 glycoprotein 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 glycoprotein gene switching mediated by recombination machinery.
Dr. Cross’s lab is also working on genome-wide analysis of 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 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.
CAREER
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.
|
| Return to full listing |
|
