A doyen of cancer research
When someone has been at an institution since the beginning, helped to mold it, left their unique mark on it, they can rightly be considered one of the architects of that institution. And this is very much true of cell biologist Walter Birchmeier, head of the Signal Transduction in Development and Cancer Lab at the MDC. “As scientific director, he had a hugely defining influence on the Max Delbrück Center. And his molecular-mechanistic studies set new standards in cancer research,” says Professor Claus Scheidereit, who coordinated cancer research at the MDC from 2009 to 2020. Now 80, Birchmeier is retiring.
Birchmeier joined the MDC as a lab leader in 1993, just after it had been founded. In the early years of the institute, which was the successor to three research institutes of the GDR Academy of Sciences, efforts to forge a new identity between East and West wasn’t always easy – as Birchmeier recalls. He says that Detlev Ganten, the founding director, invited him to every meeting to mediate between his East and West German colleagues: “I probably benefited from being the only Swiss person in the institute. People were less likely to suspect me of wanting to steamroller anyone,” he says with a grin. In 1996, he took up a professorship at Charité – Universitätsmedizin Berlin, which he still holds. In 1998, he became Deputy Scientific Director of the MDC, and served as Scientific Director from 2004 to 2008.
His unwavering focus on scientific excellence raised the center to a new level.
As scientific director, he always kept an eye out for the best scientists and worked hard to bring them to Berlin. He succeeded many times, appointing figures such as Professor Nikolaus Rajewsky from New York, Professor Klaus Rajewsky from Boston, and Professor Thomas Jentsch from Hamburg. “I’d often get up at four in the morning to go through papers and contracts before driving to the center,” he says. To ensure he could still spend some time in the lab, he would leave the papers in the car. His secretary, Elisabeth Schmeitzner, had a key and would go out to the car to pick them up. “She was always an immense help to me and my team,” says Birchmeier. The center benefited enormously from his leadership. “His unwavering focus on scientific excellence raised the center to a new level,” says Professor Thomas Sommer, currently the interim Scientific Director. “He did so much for the MDC. I’m extremely grateful to him for that, and for being such a faithful, genial member of our team for all these years.”
The audience at the Farewell Lecture held at MDC.C on October 20, 2022.
On the podium: Walter Birchmeier during his Farewell Lecture.
Off to California
Carmen Birchmeier-Kohler and Walter Birchmeier
Birchmeier was born on July 8, 1943, in Würenlingen, Switzerland. After training as an elementary school teacher and spending two and a half years teaching, he enrolled at the University of Zurich to study biology. Having earned his doctorate, he took a postdoc position at the University of Basel’s Biozentrum in 1973. It was during this time that he met his future wife, Professor Carmen Birchmeier-Kohler, who today also leads an MDC lab. Her work focuses on developmental biology and signal transduction in nerves and muscle cells. In July 1974, a mutual friend living in Waldshut, the small town in southern Germany where Birchmeier-Kohler grew up, invited them both to a party to watch the World Cup final. While the other guests were inside watching West Germany beat the Netherlands 2-1, Birchmeier was sitting in the garden with his future wife, eating barbecued sausages. The couple moved to the University of California San Diego in 1975, he as a postdoc, she as a student of chemistry and biochemistry. They married in 1977.
In San Diego, Birchmeier worked with Professor S. Jonathan Singer, the inventor of the fluid mosaic model. They researched membrane proteins, a field that still had many missing pieces at the time. In 1978, he returned to Europe, first taking a position at ETH Zurich. Four years later, he joined the Max Planck Society as a group leader in the Friedrich Miescher Laboratory in Tübingen. There, he worked with Christiane Nüsslein-Volhard, who would go on to win a Nobel Prize. Studying fruit flies (Drosophila melanogaster), she discovered beta-catenin, a structural protein known in this case as armadillo. It influences transcription and ensures that the fly’s body segments develop correctly at the embryonic stage. If armadillo is inactivated, the fly hatches with no wings.
Birchmeier was appointed a full professor of molecular cell biology at Essen University Hospital in 1988. During this time, he investigated the cellular mechanisms of cell mobility. His move to the Max Delbrück Center came in 1993. His work here included continuing Nüsslein-Volhard’s Drosophila research and exploring how beta-catenin – the protein known as armadillo in fruit flies – impacts cell development and tumor formation. In his most-cited work, which was published in 1996 in Nature, his group describes the Wnt/beta-catenin signaling pathway. The growth factor Wnt activates beta-catenin, which is embedded in a protein complex outside the cell nucleus. The beta-catenin then breaks away from the complex and moves into the nucleus, where it interacts with transcription factors of the Lef-1/Tcf family and activates genes that regulate the cell cycle. This signaling pathway plays a key role during embryonic development, regulating things such as the formation of the body’s axis and the position of the organs.
How tumors spread
In mature cells, the Wnt/beta-catenin pathway is usually switched off. The cells either block the Wnt signal before it reaches the beta-catenin, or they destroy the beta-catenin before it reaches the nucleus. In tumor cells, though, mutations can switch the signaling back on again, causing beta-catenin to become overly active. The cell can’t destroy it, so it accumulates in the nucleus or other parts of the cell. Birchmeier’s group showed that it can react with E-cadherin, a molecule that helps cells adhere to each other. The process produces a cadherin that allows tumor cells to break their bonds and begin moving through the body. These findings provided an explanation of how cancer can spread and metastases can form.
Expanding cancer stem cells (green) in a colon tumor with an oncogenic activated Wnt/beta-catenin signaling pathway (red).
Birchmeier’s group published another article in Nature in 1996, describing another signaling pathway. They showed that a protein called scatter factor activates a receptor called Met, which sits in the plasma membrane. Met then binds to a protein that collects in places that are responsible for holding cells together. Contact with Met causes the cells to separate and become mobile. They form tube-shaped structures – a process that also happens in the epithelial tissue of embryos. A few years later, Birchmeier’s group used genetically modified mice to show that disrupting these signaling pathways negatively impacts embryonic development and encourages tumor formation. If beta-catenin is deactivated in the mice’s skin and hair follicles, the cells don’t develop properly. When these pathways were misregulated in mature mice, the animals developed tumors such as breast cancer.
Publishing in prestigious journals isn’t easy
Birchmeier says he had more topics with Nature potential up his sleeve in 1996, “but you have to fight for those high-level papers. They need to be well written and they have to win over the publisher and the review board. It’s a lot of hard work. You can’t just do it on the side.” And at the time, he didn’t have the capacity: Birchmeier’s father-in-law could no longer live alone, so Birchmeier and his wife brought him to live with them in Berlin. Caring for him required a lot of time and energy.
Birchmeier has spent over half a century in research. Working with a research group from Paris, he and his coworker Dr. Kamil Lisek recently identified three genes that are activated in triple-negative breast cancer, a particularly aggressive form of breast cancer in humans. The Wnt signaling pathway is also involved here, as it helps regulate the development of breast tissue. The scientists bred a mouse model in which the three genes are activated. This causes the mice to develop tumors on their teats – but not on all of them, just the upper ones, which is the same area where breast cancer develops in humans. Birchmeier thinks that’s fascinating and will be keeping an eye – albeit from a distance – on these three genes. Lisek will continue the research at the Berlin Institute for Medical Systems Biology in the Max Delbrück Center (MDC-BIMSB), collaborating with Nikolaus Rajewsky’s lab. Using single-cell analysis, they will attempt to identify the dangerous cells in human breast cancer so they can pinpoint the tumor regions in which they are activated.
“I can’t wait to see their results,” says Birchmeier, who will be visiting the MDC-BIMSB now and again to keep up to date with their progress.
Text: Jana Ehrhardt-Joswig
