Dr. Tom Misteli had no intentions of becoming a scientist when he grew up in a small town near Berne, Switzerland.

"I wasn't one of those kids running around saying, 'I'm going to be a doctor.' I was interested in lots of different things," he explains. "After high school I was torn between studying literature and biology. Then, one day, I was on a train trip, and I bought a copy of Scientific American for whatever reason - it was a special issue on molecular biology - and it absolutely captured my attention. That's how I decided I was going to be a biologist.

"I remember my father asking me 'Are you sure about this?' And I said, 'Not at all, but I'm going to see whether I like it,'" he laughs.

Today, Dr. Misteli remains a committed cell biologist, heading the Cell Biology of Genomes Group in the Laboratory of Receptor Biology and Gene Expression in NCI's Center for Cancer Research, where he focuses on an unusual niche in molecular research: How the spatial organization of the genome within a cell's nucleus contributes to cell functioning and to the origins of disease.

After earning his Ph.D. from the University of London and the Imperial Cancer Research Fund, London, Dr. Misteli worked as a postdoctoral fellow at Cold Spring Harbor Laboratory in New York, where he became interested in genome organization.

"This is an area of research that 5 or 6 years ago, literally nobody in the United States worked on because it was extremely high risk," says Dr. Misteli. That is, few other researchers had explored this area of cell biology, leaving a gap in the scientific literature that made it difficult to justify a project on the neglected subject. "I came to NCI because it provided a lot of freedom to do high-risk research, which is increasingly more difficult in the outside [research] world."

Dr. Misteli's lab uses molecular techniques including polymerase chain reaction and microarrays to measure gene expression, in addition to time-lapse microscopic techniques that visualize the movement of gene loci in single living cells.

The work of Dr. Misteli and his colleagues is featured in the current edition of CCR connections, the news magazine of NCI's Center for Cancer Research. Please click here to read the online version of the CCR connections article: http://home.ccr.cancer.gov/ connections/features.asp

In a recent paper published in the Journal of Cell Biology, he and a colleague from his laboratory visualized major genome reorganization during early tumorigenesis in a 3D cell culture model of early breast cancer, using fluorescent microscopy.

All but one of the genes they observed undergoing repositioning during early tumor differentiation also moved during normal differentiation, but several additional genes - including genes known to drive cancer development - also changed their location within the nucleus in the tumor model. Dr. Misteli's group is now exploring these positional changes of tumor genes for diagnostic purposes.

Other recent work from the lab has shown how the proteins that repair damaged DNA physically interact with the chromosomes, and how the mutant protein responsible for Hutchinson-Gilford Progeria Syndrome - a premature aging disease - interferes with the functioning of stem cells that produce the bones, blood vessels, connective tissues, and other vital structures of the body. The next step in this field with regards to cancer, explains Dr. Misteli, is to discover the mechanisms by which higher order genome organization helps drive the process of tumorigenesis.

"We're at a point where we now understand the fundamental concepts, the fundamental principles by which genomes are organized in the nucleus, and I would argue, even the principles by which genomes function," he says. "So the next step is to link some of these morphological observations to function, to physiology, and to disease."