From Laboratory to Leadership

At a Glance

• Ulla Wewer’s early research revealed much of what we know today about basement membrane function and its role in disease processes
  
• Her career began with pathology. Today she is dean of the Faculty of Health and Medical Sciences at the University of Copenhagen, where she has increased enrolment, recruited world-class faculty, and raised funds to build research facilities
  
• Three new research centers have opened in less than a decade with inspiring early results, and another building will be completed next year
  
• Her focus on education continues with her work for the European Institute of Innovation and Technology, and she believes that one day, Copenhagen will serve as a model for the rest of the world as a center of scientific research and educational excellence

Not many pathologists can point to the buildings they work in and say, “I built that” – but Ulla Wewer is the exception to the rule. A researcher, a faculty dean and a Knight of the Dannebrog, Wewer is no stranger to dreaming big. For the past 30 years, she’s been a key influence on the development of the biomedical sciences in Denmark, working on research at the University of Copenhagen and raising funds to build not one, but several academic centers of excellence. But from the early days of her pathology research to her appointment as dean of the University of Copenhagen’s Faculty of Health and Medical Sciences, one thing has been a constant – her love for learning. “No matter where I go or what position I hold,” Wewer says, “my goal is to learn everything I can and to help others do the same.” Her contributions to the field range from basic research on extracellular matrix proteins and their roles in disease to designing new teaching programs, attracting innovative faculty, and building facilities in which to teach the next generation of research and medical professionals. “In looking back on my career,” says Wewer, “I can see how each step led to the next, and how my enthusiasm for experimentation and discovery has given me the opportunity to look at things as small as a single protein, or as large as our wonderful worldwide community of students and researchers.”

From model to matrix

In the early days of her research career, Wewer’s goal was to solve the mysteries of the developing cell. One of her first victories was the development of an experimental rat yolk sac tumor, which produced huge amounts of alpha-fetoprotein (imitating the visceral yolk sac) and of basement membrane material (imitating the parietal yolk sac). The latter was of great interest to many scientists because, although basement membranes are present in every tissue of the body and play key roles from tissue support to signal transmission, very little was known at that time about their composition and function. In particular, the biochemical identification of basement membrane components had been hampered by the small amounts available in normal tissues. This experimental system was an important step toward a more complete understanding of the basal lamina.

On the strength of her early work, Wewer was invited to work with Eva Engvall – the inventor of ELISA – and Erkki Ruoslahti at their La Jolla Cancer Research Foundation laboratory in California. Together, the team used Wewer’s tumor model system to identify several new proteins, including an important extracellular matrix (ECM) protein family, the laminins (1). They then studied the distribution of laminin in human breast cancer and found that neoplastic cells stained even more strongly for the protein than normal breast tissue – and that laminin staining might have potential as a method for detecting micrometastases in regional lymph nodes, whose normal cells do not stain for the protein at all (2). As there was no comparable human cell line to the rat tumor model developed by Wewer, she also prepared monoclonal antibodies to purify human laminin from placenta, allowing further research on the human laminin molecule.

Together with Wewer, the Engvall group also began work on congenital muscular dystrophy. The researchers identified the cause of one murine form as a defect in the muscle basement membranes – specifically, a mutation in the alpha 2 chain of laminin (3,4). An abnormal splice site in the Lama2 gene leads to a truncated protein that lacks the wild-type protein’s ability to stabilize muscle cell membranes and contribute to ECM adhesion. Today, much more is known about the molecular causes of various forms of muscular dystrophy, and molecular pathology and genetics have become part of everyday diagnostics.

After leaving California, Wewer moved to the opposite coast of the United States to research laminin receptors at the National Institutes of Health (NIH). During her three years there, she managed to purify the laminin receptor and collaborated with several scientists to research important extracellular molecules like heparan sulfate proteoglycans. Despite not having learnt molecular biology in medical school, Wewer took courses at the NIH, learned new methods by using them in her lab, and won the prestigious Experimental Pathologist-in-Training Award from the American Society for Investigative Pathology. Her accomplishments were so impressive – and so unique, as one of the few young doctors who did long-term research in the United States – that a Danish television station came to her lab there to interview her!

“The NIH was a fantastic place for unlimited research activities for a young person,” Wewer says. “‘Just go ahead’ seemed to be the spirit I felt, and I enjoyed collaborating with friends I still see today.” The on-the-job training was particularly important to her, as it let her bring her new knowledge back to Copenhagen, where her laboratory was eventually able to clone other molecules from the extracellular environment, including tetranectin and the beta 2 chain of laminin.

Wewer’s return to Copenhagen came after three years at the NIH. When she had to decide whether to stay or go back to Denmark, family and research commitments came first – and returning to the University of Copenhagen with an assistant professorship at the Institute of Pathology allowed her to spend more time with her husband and son Nicolai, while also establishing and running her own laboratory. Once set up and funded, the Wewer laboratory conducted research on ADAM12, a disintegrin and metalloprotease that functions in myogenesis, tumor cell behavior and more specifically in cell-cell and cell-matrix interactions. “I had always been keen to understand how these ECM molecules ‘talked’ with the cells and vice versa. Communication is key, as we all know, but how?” To find out, she worked with mouse ADAM12, cloned the human protein, and made monoclonal antibodies for testing (5,6). “Our lab in Copenhagen grew fast,” she says, “and we worked hard and had fun, with collaborators and young people coming from all over world to join in with our research.”

But regardless of where in the world her laboratory is located, Wewer’s research career is dedicated to studying the structure and function of the ECM, cell-matrix interactions, and cell adhesion proteins – a worthwhile endeavor because of the vital role these cellular components play in diseases like cancer and muscular dystrophy.

Building a research community – literally

“Out of the blue, Ralf Hemmingsen – a psychiatrist at the university – contacted me and said he was running for the position of dean at the faculty, and that he would like me to be his vice dean. It took him quite some time to convince me, but in the end I was ready to try something new. I had a lot of ideas for developing the faculty. I had seen so much going on in the United States – why not Copenhagen?” Wewer’s period as vice dean began in 2002, but after Hemmingsen was appointed rector of the university, she became dean of the faculty, a position into which she was recently re-appointed. Her achievements since then have been impressive; through revamping recruitment, developing a strong infrastructure, and adding several new prestigious research groups, Wewer has taken the faculty to an international level. But that’s not all – her dream of building research centers of excellence for her school has led to fundraising victories as well.

“I think that it’s important to have common goals to successfully raise funds on a large scale,” she says. “The foundations we’ve worked with have been incredibly supportive of our projects and have placed a lot of trust in us – and I feel confident saying that we all share a common vision of continued excellence and development for the University of Copenhagen and for Denmark.”

One such victory has come in the form of generous donations from the Novo Nordisk Foundation (NNF), which were used to build three research centers of excellence – the NNF Center for Protein Research, the NNF Center for Basic Metabolic Research and DanStem, a stem cell research center. Wewer says the grants were awarded because the university and the NNF agreed on key strategic challenges in terms of overall themes: the recruitment of top international scientists, the use of novel technologies, and the support and development of top talents. All three research centers are now up and running and have been making strides in scientific research since their inception.

The Center for Protein Research was  established in 2007 and now has about 120 people using high-end technologies to study proteins involved in genomic stability and in the biology of disease. This, the first center to open, has already released a number of high-impact publications, and scientists are now moving toward translating their results to the clinic. One of our researchers, Matthias Mann, is initiating clinical proteomics studies in diabetes research using some of the population cohorts that exist in Denmark.

The Center for Basic Metabolic Research, which opened in 2010, operates on a similar scale – with about 100 scientific staff who between them have generated over 200 worldwide collaborations, 350 peer-reviewed publications, and 5,000 citations so far. Wewer and her colleagues have equally high hopes and plans for the third center, DanStem, which has been conducting basic and translational stem cell research since 2011 and is currently supported by both the NNF and the Danish Council for Strategic Research. DanStem is focusing on developmental biology and aims – together with Rigshospitalet, a part of the Copenhagen University Hospital – to be able to transplant insulin-producing beta cells into patients with severe diabetes.

More recently, Wewer and her colleagues have been focusing on future strategies in regenerative medicine. Thus, along with Maiken Nedergaard and Steven Goldman from the University of Rochester Medical Center, they are establishing the Center for Basic and Translational Neuroscience, whose aim is to fully elucidate the role and modulation of neural stem cells and their glial derivatives. With that information, they hope to develop new strategies for cell therapeutics in the nervous system, spanning disease targets as diverse as myelin deficiencies and neurodegenerative diseases. “We want to be based on excellence in research,” says Wewer, “and in the years to come, we hope to use this knowledge together with our public and private partners to contribute to better health – as we say, from molecule to society.”

The newest research facility is thanks to the AP Møller Foundation, which gave the University of Copenhagen a donation to create a new research building intended to complement and advance its existing facilities. The 42,000m² Mærsk building (pictured) will be finished next year and will provide a new home for the Center for Basic Metabolic Research, as well as housing research into healthy aging, cardiovascular diseases, glycomics and immunology. Wewer hopes that the new facilities will encourage research across disciplines. And especially, she hopes that new initiates into the biomedical sciences will feel at home there. “I look forward to welcoming new students there in September of 2016!”

A lot has happened over the years, but Wewer is emphatic that she didn’t do any of it singlehandedly – she attributes her successes to the incredible support and engagement of everybody involved in the projects. “I think one of the key routes to progress is academic leadership,” she says. “Rather than establishing an environment where only a few people have power, I like to have one where all of us have fun and work together.” She particularly emphasizes the good fortune of having world-class scientists in her faculty who have dedicated all their creativity and endurance to setting and meeting the university’s goals. “It’s a positive spiral; the scientists are an essential part of my leadership. We’re lucky to have been able to recruit top researchers not only from Denmark, but from all over the world, and I hope that more will come and be a part of our faculty. The students, too, have been instrumental in helping us to develop a modern facility that works for them. And I’d like to stress that our excellent administrative department has been vital – without their skills and support, I would never have been able to accomplish all the changes.” She emphasizes that the key to her success is keeping things realistic. “Great progress is made in small steps! It’s been a fantastic period of growth for the University of Copenhagen, and I hope that many future generations will enjoy dedicated and engaged work at the leading edge of international science and education.”

Innovation for education

Away from her research, fundraising and administrative work as dean, Wewer also manages to dedicate time to educational initiatives. The European Institute of Innovation and Technology (EIT), a body of the European Union, has established a set of projects called Knowledge Innovation Communities (KICs). These communities bring together people from all sides of the “knowledge triangle” – namely, higher education, research and business. Wewer is the interim director of education for the EIT Health KIC, in charge of developing innovative educational programs. The KIC’s main goals are to encourage students and health professionals to solve real-life problems, to bring them together with mentors and business leaders, and to educate executives on the needs of the society they serve. But it’s citizens who are at the center of the knowledge triangle – Wewer believes that medical researchers need to think and act in a much more citizen-centric way. To that end, the Health KIC is establishing the EIT Health Campus, a virtual “marketplace” where learners can access educational activities that combine knowledge with best pedagogic practices. Wewer hopes that the Campus will inspire and educate through offerings ranging from short, online quizzes directed at the general population, to full EIT-accredited higher degree programs for graduate students.

It all started with pathology…

Wewer feels that her own training and experience in pathology have prepared her for her current roles. “Pathology is about ‘seeing’ and ‘reading’ – and in leadership, you also need to be able to ‘see’ to make and execute plans, and ‘read’ to work in teams to make things happen.” But throughout the stages of her career, the common thread has always been a desire to learn and understand as much as possible. “My experience in experimental pathology and biomedical research has kept me curious and given me countless opportunities to find out more about the world around – and within – us,” she says. In particular, though, she emphasizes her love of seeing people grow and projects succeed, viewing her work with students and young researchers as a gift and an inspiration. “I find that nothing motivates me as much as the opportunity to build something new that will lead to new initiatives and new learning. Ultimately, my goal is to ensure that the University of Copenhagen can serve as a model for the rest of the world by being an inspiring place for research and education.” For young pathologists, she suggests working closely not just with clinicians, but with researchers involved in – “omics” and big data. “I think the clever pathologist of tomorrow may be vitally important to integrating patient information, allowing us to come closer than ever to precision personalized medicine.”

Ulla Wewer is dean of the Faculty of Health and Medical Sciences at the University of Copenhagen, Denmark, and interim director of education for the European Institute of Innovation and Technology’s Health Knowledge Innovation Community.