Thanks to initiatives such as the Human Genome Project, biologists now have a near complete inventory of the thousands of proteins, nucleic acids and other molecules that make up the typical cell. But how these molecules all come together to form a living cell or multicellular organism remains unclear. Martin Wühr, who joined the Department of Molecular Biology and the Lewis-Sigler Institute for Integrative Genomics as an assistant professor in July, seeks to understand how biological molecules organize themselves into cells using global, “systems biology” approaches that can analyze the behavior of thousands of proteins at once.

Traditionally, biologists have tried to understand the inner workings of the cell one molecule at a time, with individual researchers often spending their entire careers studying just one or two proteins in great detail. Wühr, who grew up in a small village outside Munich, Germany, experienced this approach as an undergraduate. “The training was great, but I felt like something was missing,” he recalls. “You can’t really understand how the properties of a living cell emerge by looking at the function of just one protein.”

Wühr therefore joined the Systems Biology program at Harvard for his PhD, learning how cell behaviors arise from the synchronized activities of multiple proteins, and how to analyze these different activities simultaneously. He continued this approach as a postdoc, also at Harvard, examining how proteins partition between the nucleus and cytoplasm of frog eggs. Wühr was able to dissect these large cells and use mass spectrometry to precisely measure the levels of ~9000 different proteins in each cellular compartment. “It’s almost like we’re using the mass spectrometer as a microscope, except that we can look at the localization of many thousands of proteins at once,” Wühr explains.

Understanding how cells partition proteins between the nucleus and cytoplasm is crucial because the protein composition of the nucleus controls many important processes, such as the activation and repression of specific genes that help cells differentiate into the various tissues of the body. Wühr’s mass spectrometry-based approach provided new information about how cells control whether a protein accumulates in the nucleus or remains in the cytoplasm.

Martin Wühr (middle) and lab members.

At Princeton, Wühr wants to further explore the mechanisms of nucleocytoplasmic partitioning, and to determine whether they operate in human cells as well. He also wants to investigate how partitioning changes as cells differentiate, and to begin examining the composition of other important parts of the cell, including the mitotic spindle machinery that segregates chromosomes during cell division.

In addition, Wühr seeks to improve the sensitivity of his mass spectrometry methods so that he can detect even more proteins in the cell. “At the moment, we can see approximately 9000 proteins,” he says. “That sounds like a lot but we’re missing thousands of proteins that are only present at very low abundance.” Among these ‘missing’ molecules are some of the most important proteins in the cell, including many transcription factors that regulate gene expression. “So we’re continuing to develop new technologies that we can use to better understand the biology of the cell,” Wühr says.