The consummate scientist

July 8 marked the 70th birthday of Walter Birchmeier, former Scientific Director of the MDC

A few years ago, upon submitting an article to Nature Reviews: Cancer, Walter Birchmeier was rewarded with the following comment from a referee:

“This is a fine review that nicely covers the long history of Wnt signaling and I cannot think of a better person than Walter Birchmeier to contribute such an article. I say this not only because he is so old, but because he has personally witnessed or directly contributed to most of the significant developments in the Wnt field.” (Italics added here.)

To set the record straight: At the time, Walter was a mere youngster of 65. The comment about his age sounds like a joke, but referees are a grim, humorless species. Instead, I think the writer was searching for a term to describe a scientist at the top of his game, someone who has continually made unique, seminal contributions to a field. Chess has a name such figures – they’re called Grand Masters – but science lacks a similar title. You’re either a “big shot,” a “guru”, or just an “old guy,” and if you’re really lucky, they call you a Nobel laureate.

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 49 unruly fifth-to-eighth graders in a Swiss middle school. Not many institutional directors have those items on their CVs. Maybe they should – you learn some useful skills.

Scientists are an unruly bunch, too, that sometimes need a firm hand to herd them along. And playing the organ requires both hands and both feet. If you have to deal with scientists, physicians, state and federal governments, and the changing landscape of health care, it’s good to be able to do four things at the same time.

A unique route to the MDC

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 – like getting the most out of a scientific Inter-rail pass. Then came a call from Berlin-Buch, where a new institute was taking shape on the site of the former Academy of Sciences of the GDR. Walter was offered a lab and a position as Coordinator, then Deputy Director; it was time to set down some roots.

“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.”

In 2004, Detlev was invited to head the Charité, and Walter became Scientific Director at the MDC. There was a lot to do: BIMSB needed to hit the ground running, and the partnership between the MDC and the Charité needed a work-over. The institutes began planning a joint Experimental and Clinical Research Center, which Walter planned with many colleagues. The project turned out to be the perfect preparation for a new grand scheme: to create the Berlin Institute of Health. That task falls to Walter Rosenthal, who became Scientific Director of the MDC in 2009.

Walter Birchmeier’s administration placed an enormous emphasis on the quality of MDC science, from which all good things would follow. It was the key to attracting excellent new group leaders and students and securing funding. And studies had shown that the best strategy for turning scientific discoveries into biomedical applications was to make strong investments in basic research. Once again, Walter held his own group to the same standards. Most days he slipped away to make at least a brief appearance in his lab, to the delight of the scientists and the consternation of his administrative assistants.

His leadership of the institute has paid off in many ways. The marks for MDC groups have steadily risen in external reviews. And the institute’s international reputation has 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. 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 (likely even 5 minutes before that), it 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!” (Sorry, Klaus… Readers, please don’t do the math.)

In pursuit of a molecular pathway

Trying to summarize Walter’s work in a short text is as hopeless as trying to see his native Switzerland from the window of a bus, in a single day, but it would be a shame to miss the highest peaks. PubMed lists him as author on 195 papers. 33 of the articles are reviews, the best place to hear his stories straight from the horse’s mouth. Here we’ll introduce a few topics that appear again and again, like the recurring theme of a Bach fugue.

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.

More than a decade 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.

Three years later 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. The lab showed that a particular monoclonal antibody, which recognized a protein called E-cadherin (at the time known under the name uvomorulin) on the surface of epithelial cells, could disrupt and loosen the adhering junctions that have cemented different cells to each other. The work established a new method to identify proteins within cell-cell junctions.

In 1989 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. In the same paper, published in the Journal of Cell Biology, the group showed 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). Its gene was located on chromosome 7, in an area rich with genes involved in cell division, development, and cancer. 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.

By 1996 Walter’s lab was well established at the MDC and was digging deeply into the signaling pathway activated by Wnt and HGF. Such signals activate proteins in their target cells, often changing the activity of genes and thus cell structure and behavior. In 1996, 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.

HGF activates a receptor called Met, lodged in the plasma membrane, but 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. This was a new genetic engineering technique developed by Klaus Rajewsky and his colleagues at the University of Cologne; it allowed the removal a molecule like beta-catenin in specific cells and tissues at precise times. Like many signaling molecules, beta-catenin has many important functions across the body; conditional mutagenesis 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 determined that cells 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.

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 paper published in the EMBO Journal this year, 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. Walter’s work reflects decisions made early on: to focus on a central biological mechanism and follow it wherever it might lead, into a range of tissues and disease processes. Only then does the true biological meaning of something like the Wnt signaling pathway become clear, showing us how a process that evolved long ago in ancient cells has been tweaked in many different ways to guide the development of diverse organs and processes in complex animals. The lab continues to explore this system in new contexts; stay tuned for more discoveries about the functions of Wnt and Met signaling in development and disease.

In retrospect it’s a straight and logical route, but along the way some interesting side-roads have appeared. Walter has never hesitated to make small detours to see where they might lead. He admits that some things never panned out, but 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 popular press.

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. People with the condition experience rhythmic disturbances in their heartbeats and have a high risk of sudden death. There is a solution – implanting a defibrillator – but until 2004 it was difficult to diagnose the disease. 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.

How to address a Guru

I haven’t mentioned one paper – all right, maybe it’s one of those urban myths of science – about the migration of a colony of microbes through a musty organ pipe (low B-flat) in a Swiss church. You can ask Walter Birchmeier about it the next time you spot him in the lab, or steering his bike across the campus. Also be sure to ask about the last concert he attended, or the book that he’s currently reading. The answer will always be interesting. And then take a minute to imagine what the MDC – and science – would be like if he had remained in his organist’s loft or become stranded in a middle-school classroom.

If you aren’t quite sure how to address him, here are some choices: Grand Master or Guru, or perhaps the Lord of Wnt. If you prefer a literary reference, “Oh Captain, my Captain” would certainly be appropriate. Maybe we can get him knighted, in which case he’ll be “Sir Walter.” Until then, just “Walter” will do.

– Russ Hodge

(with thanks to Daniel Besser for his considerable help)

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