All the biological processes to which we owe our existence - from the fusion of egg and sperm to the extraordinarily complex development of our brains - depend on precisely orchestrated interactions between the cells in our bodies. “So we try to understand this complexity by studying the function of single cells, the basic units of organization in our tissues,” says molecular biologist Dr. Mihaela Zigman. “To do so, we must explore the interplay between different molecules. But detecting single molecules in cells and body fluids and defining their functions is no easy task. “This requires novel, non-invasive technologies,” she says. How the chemical constituents of living systems control the development of multicellular organisms is a question that has long fascinated the Slovenian researcher, who studied molecular biology in Ljubljana University and obtained her PhD in Vienna.
“To be successful at the forefront of biological science, one must choose the right problem, frame one’s question in the simplest and most appropriate way, and set out to answer it in a structured and logical fashion,” she says. As a postdoc in Dr. Jürgen Knoblich’s group at the Institute for Molecular Pathology (IMP/IMBA) in Vienna, Mihaela Zigman did precisely that. “We were the first to discover in higher organisms a process that enables stem cells to differentially target specific molecules to individual daughter cells during cell divisions. This process of asymmetric cell division produces one daughter that goes on to differentiate, while the other retains the stem-cell character of the mother cell. In this way, the progenitor cell can generate lineages of daughter cells that adopt a particular cell fate, developing into neurons in the brain, for example,” she explains.
To learn more about the molecular basis for asymmetric cell division, Zigman decided to use high-resolution imaging techniques to observe single living cells. She therefore moved as a Howard Hughes Medical Institute (HHMI) Research Affiliate to the Fred Hutchinson Cancer Research Institute in Seattle (USA). There, in collaboration with Dr. Cecilia Moens, she was able to put the necessary instrumentation together. Turning to the zebrafish as a model system (because their embryos are transparent), she was able to study the molecules that determine the planes of stem-cell divisions during embryogenesis. These factors serve as a kind of internal compass, conferring ‘polarity’ on cells. And since cell differentiation and tissue formation depend on spatially defined interactions between cells, cell polarization, i.e., precise regulation of the orientation of cell division, is crucial for ordered development.
At the end of her stay in Seattle, Mihaela Zigman returned to Europe to take up a position in as Leader of a Junior Research Group in the Centre for Organismal Studies (COS) at Heidelberg University. With her team, she elucidated the molecular function of a gene product involved in carcinogenesis, and showed that a previously identified regulatory gene plays a central role in controlling polarized cell divisions during brain development.
Mihaela Zigman’s career trajectory has now brought her to Munich as a member of the MAP Excellence Cluster. Here, she will supervise the biomedical side of a new interdisciplinary project in Prof. Dr. Ferenc Krausz’s Department. The project aims to employ high-intensity femtosecond pulses of infrared laser light to detect specific molecules present in vanishingly small amounts in human cells, blood samples or respired air. “A number of characteristic molecular differences that distinguish healthy from sick individuals at the cellular level are already known,” Zigman says. With the aid of unprecedentedly sensitive analytical techniques, it should in principle be possible to detect minimal molecular perturbations at a very early stage in pathogenesis - and early diagnosis is the key to successful cancer treatment. “We have a lot of development work to do before we reach that stage. After all, we need to be able to pinpoint and interpret pathologically relevant molecular alterations in small numbers of diseased cells against the background of the billions of cells in the body,” she points out.
“Physicists helped to invent modern molecular genetics over 70 years ago, and technological advances have always given basic and applied biomedical sciences access to new levels of investigation and understanding,” says Mihaela Zigman. “We will certainly encounter roadblocks on the way, but we have good reason to hope that innovative sensor technology will be in a position to solve problems of physiological and pathological relevance in clinical medicine in the future.”
text: Thorsten Naeser