From the church organ to human organs
Walter would want this article to be devoted to science, and so it shall be – but first a bit of context. His papers from the 1970s and 80s form a trail from Zürich to the U.S., then on to Tübingen and Essen. It’s hard to imagine Wnt without Walter, or Walter without Wnt, or to believe that the Birchmeier genome could produce anything other than a scientist. But phenotypes sometimes take a while to emerge. Walter first earned a diploma in church music, then financed his later studies by teaching a class of fifth-to-eighth graders in a Swiss middle school. Not many institutional directors have those items on their CVs. Maybe they should – they impart some useful skills.
Walter’s career at the MDC began shortly after the institute was founded, as head of a lab and program Coordinator. Later he was appointed Deputy Director. “Right away he was recognized as someone who pursued scientific work of the highest quality and expected the same from his colleagues,” says MDC founding Director Detlev Ganten. “He developed an excellent rapport with all the former staff – from the directorate to the technical personnel. Being Swiss probably helped; he could stand aloof as the East and West settled their affairs. We had immense mutual respect and complemented each other very well.”
Later as Scientific Director, a position he held for five years, Walter Birchmeier’s administration placed an enormous emphasis on the quality of MDC science, from which all good things would follow. His leadership of the institute paid off in many ways. The marks for MDC groups steadily rose in external reviews. And the institute’s international reputation soared; a 2010 study by Thomson Reuters ranked the MDC 14th in the world in the fields of molecular biology and genetics, making it the only German institute in the top 20. This was a great achievement by any standards – especially for an institute that was not yet 20 years old at that time. Walter’s lab, and many groups established under his tenure, helped put it there. But passionate scientists don’t rest on their laurels; the minute Walter handed over the reins of the MDC to his successor he was straight back to the lab.
“Retire?” he says, looking scandalized. “How can I retire? Klaus Rajewsky is still putting out high-impact papers, isn’t he? And he’s five years older than me!”
In pursuit of a molecular pathway
Walter has always been interested in factors that help arrange cells into tissues and organs and hold them there. During embryonic development – and cancer – cells sometimes free themselves to embark on migrations. This shift is managed by complex biochemical signals that also affect how cells specialize. A handful of basic signaling pathways – including, of course, Wnt – govern these processes in different ways in different tissues. Their activity and effects change during cancer and other diseases; understanding how that happens can help explain how the diseases arise in the first place and sometimes yield potential therapeutic targets. The group’s work has helped identify the complex sets of molecules involved in passing signals along, how they interact with each other, the genes they activate, and their ultimate biological effects.
Long before his arrival at the MDC, Walter had begun taking a look at the behavior of cells called fibroblasts. These types of cells exhibit migratory behavior, for example during wound healing, but their chief function is to create factors that bind cells into larger structures and tissues. They contain “stress fibers” that expand and contract, helping with the cells’ crawling behavior as well as their structural functions. Until 1980, the composition of these fibers was unknown. That year Walter’s group at the ETH Zürich used fluorescent dyes to show that they were probably composed of actin fibers and contracted through interactions of actin and a “motor” protein called myosin. The work was published in Cell.
Over the next decades Walter developed this research further, leading to a number of important papers. In 1983 Cell accepted another paper from the group, now located at the Friedrich-Mieschner laboratory of the Max Planck Institute in Tübingen. This time the topic was cell-cell adhesion. In 1989, in a paper published in the Journal of Cell Biology the group showed that the antibody, which binds to uvomorulin, caused epithelial cells to leave the tissue and undergo migrations that lead to invade foreign tissues including, at least in the experiments, heart tissue and that epithelial cells that have been infected by sarcoma viruses become migratory. During this transformation, the cells stopped producing uvomorulin on their surfaces. Losing their adhesion properties seemed to be a key step along the road to invasive cancer.
In 1991, now at the Institute for Cell Biology of the University Medical School in Essen, Walter and his colleagues proved that a protein known as scatter factor, which strongly promoted cell motility and was secreted by cells called fibroblasts, also caused invasive behavior by epithelial cells – in fact, it was the same molecule as hepatocyte growth factor (HGF). The discovery hinted at the intricate connections between mechanisms in healthy organisms and disruptions that lead to a number of serious diseases. It was just the sort of theme that would fit in well at the new MDC.
Nailing down the details of Wnt signaling at the MDC
By 1996 Walter’s lab was well established at the MDC and the journal Nature published a landmark paper from the group on Wnt. This signal molecule usually activates a pathway that arrives at a protein called Beta-catenin, which is been locked up in a complex of proteins outside the cell nucleus until the signal arrives. Then beta-catenin is released, travels to the nucleus, interacts with transcription factors of the Lef/TCF family and activates genes. Normally cells control the molecule by blocking the signal before it arrives, or breaking down beta-catenin before it reaches its targets. But tumors often hold a form of beta-catenin that is too active; it has undergone mutations that block its breakdown and accumulates in the nucleus and other regions of the cell. Walter’s group also discovered a new protein they named conductin/Axin2; it receives Wnt signals from a molecule called APC and then binds to beta-catenin, marking it for degradation. Without this interaction, beta-catenin isn’t destroyed.
The lab was continuing to work on HGF, and discovered that the signal activates a receptor called Met, lodged in the plasma membrane. No one knew what happened next. In a paper in Nature, also in 1996, the lab discovered that Met binds to a particular region of a protein called Gab1, which accumulates at sites responsible for cell adhesion. Activating Gab1 with Met or by artificial means caused the cells to separate and become more mobile. In the process, they began extending tube-like structures in a pattern that resembled the formation of epithelial tissues in embryos. The work proved that Gab1 receives developmental information from c-Met and triggers a program of epithelial specialization.
By 2001 the lab had developed mice with conditional mutations, based on a new genetic engineering technique developed by Klaus Rajewsky and his colleagues at the University of Cologne. This allowed the removal a molecule like beta-catenin in specific cells and tissues at precise times, which permitted studying its activity in very specific contexts. Walter’s group used the method to deplete beta-catenin just in the skin and hair follicles as these tissues formed in the embryo. In another Cell paper, the lab showed that cells altered in this way were no longer differentiating into the structures required to produce hair follicles. Without beta-catenin, cells weren’t getting the necessary developmental signals; instead of forming follicles, they became surface skin.
Bmp enters the picture
In a 2007 paper in PNAS, Walter’s group reported on more functions of the Wnt/beta-catenin pathway – this time in the formation of specific regions of the heart. This organ begins as a tube-like structure and is guided through a series of transformations that make it asymmetrical, with a larger left side. The lab discovered that signaling through Wnt and beta-catenin needed to be active in particular regions for this to take place. Another pathway, triggered by a molecule called Bmp, seemed to be active in other regions. Producing heart structures with the proper form and shape required that different signals be received at precise times and places, in a highly coordinated way. In another paper the same year, published in the Journal of Cell Biology, the group showed that the HGF receptor Met was essential during the process of healing skin wounds.
Walter’s group continues to study the interactions of these pathways in other tissues and contexts, including defects in signaling that support the development of tumors. Cancer can arise when stem cells don’t follow their normal path of differentiation but are diverted along another route. The most aggressive tumor cells resemble stem cells and take advantage of signaling pathways to survive, reproduce at a high rate, and develop in unusual ways. In a 2013 paper published in the EMBO Journal, Walter and his colleagues showed that tumor cells in the salivary gland exhibit high Wnt and beta-catenin signaling, combined with low Bmp signaling. The Wnt signals activate a molecule called MLL. This protein remodels the knotted structure of DNA in the nucleus and switches on a number of genes associated with cancer.
An affair of the heart
These papers – and nearly 200 more – represent significant milestones along a career that’s worth taking a step back from to get a bit of perspective. In retrospect it’s a straight and logical route, but along the way some interesting side-roads have appeared. In 2004 one of those side-trips turned out to have an immediate medical impact, saving lives and becoming a great example of the MDC’s approach to molecular medicine. The story appeared in Nature Medicine that year and was widely covered in the media.
Walter’s abiding interest in cell adhesion had led the group to knock out molecules that help link neighboring cells. The lab produced a strain of mouse without one of these molecules, called plakophilin 2, a relative of beta-catenin, and made a surprising discovery: the animals died mid-way through embryonic development due to heart defects. Ludwig Thierfelder, a clinician and researcher working on the heart, had a lab right down the hall. Walter paid a visit and posed a simple question: Do any human patients with heart defects exhibit mutations in plakophilin-2?
It turns out that they do: About 30 percent of people who suffer from hereditary forms of arrhythmogenic right cardiac ventricular cardiomyopathies (ARVC) had such mutations. The discovery by Walter and Ludwig’s lab made it possible to screen family members at risk and identify those with mutations in plakophilin-2. They could be given defibrillators, and this intervention has saved many lives.
Upwards and onwards
In today’s scientific climate, even the gurus need to learn new tricks. Walter’s lab continues to keep up with the latest technological advances in pursuing the details of signaling pathways involved in development and cancer. They are currently developing a line of mice in which they can deactivate three distinct pathways, in any combination they like. The idea is to disentangle their complex contributions to states of health and disease. And Walter and his colleagues have expanded their repertoire of methods to organoids – miniature versions of human organs grown in the test tube, from patient samples. These tissues permit studies into the mechanisms that lead to disease specifically in humans, and they offer platforms for the testing of new therapeutic approaches.
Having reached the age of 75 is impressive in its own right; having done so and retained a profound passion for science is simply amazing. Walter can still be found most mornings in his lab; take the time to stop by and wish him well. As you do, try to imagine what the MDC – and science – would be like if he had remained in his organist’s loft or in a middle-school classroom. For he has left his mark profoundly on both, the MDC and his area of science.
(note: this is an updated version of the article posted in honor of Walter’s 70th birthday.)