Uncovering the surprising role of ceramide in different diseases motivates an accomplished young professor.
Erich Gulbins has an arresting idea. The director of the Institute of Molecular Biology, at the University of Duisburg-Essen, reckons that a generic tricyclic antidepressant, the nonselective serotonin reuptake inhibitor amitriptyline, could play a beneficial role in conditions as diverse and apparently unrelated as cystic fibrosis and cancer. Evidence to support this hypothesis is in place. And the translational work needed to convert these findings into clinical applications is getting underway.
Gulbins is part of a new generation of scientists who have recently energized the university's life sciences effort. A medical graduate of the University of Heidelberg, Gulbins oscillated between posts in Germany and the United States for the past decade and a half. The influence of the latter is still in evidence. Gulbins exudes the kind of easygoing, can-do attitude...
However, Germany came calling again in 2002, when he was tempted by the offer to head up his own institute at just 35 years of age. The decision to return was "very difficult," he says, given the conditions and support available in Memphis. He also misses the departmental structure of American universities, which he says encourages greater communication among colleagues. But a decent offer from Essen, in the heart of Germany's Ruhr Valley industrial belt, combined with newly renovated facilities and an influx of other young faculty members convinced him to return—for now at least. He does not rule out a return to the United States at some point. However, Essen is a good city in which to raise a young family. "From a cultural point of view this area is really great," he says, enthusing about the city's symphony orchestra, opera company (Beethoven's Fidelio is his favorite) and its renowned music academy, the Folkwang Hochschule.
Although the geography of Gulbins' career has shifted regularly, the focus of his research has remained constant since his initial PhD studies. "I stayed with lipids, I was fascinated by lipids," he says. Gulbins is one of several researchers, who from the mid-1990s onwards, began to unpack the biological functions of sphingolipids, particularly ceramides, which are present in high concentrations in the phospholipid bilayer of the cell membrane. Long thought to be purely structural components of the membrane, sphingolipids actually play important roles in cell signaling and regulation and are involved in key biological processes, such as apoptosis, angiogenesis and inflammation. They are, therefore, emerging as promising drug targets that offer novel mechanisms of action.
Gulbins' group has amassed a raft of animal data in support of a therapeutic rationale for modulating levels of ceramide by targeting acid sphingomyelinase (Asm), the enzyme responsible for its production (via the hydrolysis of sphingomyelin). Their work suggests a link between ceramide concentration and susceptibility to infection with Pseudomonas aeruginosa, one of the key bacterial pathogens that affect cysitc fibrosis (CF) patients. Knockout mice lacking the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), which is also absent in CF patients, accumulate ceramide in their respiratory tract and display heightened sensitivity to P. aeruginosa infection, as well as elevated inflammation and cell death. Intriguingly, administration of amitriptyline an Asm inhibitor abolishes this diseased state (Nature Med, 14:382–91, 2008).
"If you normalize the ceramide in the lungs of those CF mice, you also normalize the susceptibility of the mice to the infection," Gulbins says. Nasal and lung cells taken from human CF patients also exhibit elevated ceramide levels which is thought to be due to an alteration in the internal pH of cells lacking CFTR. This disrupts the normal equilibrium between Asm, which leads to ceramide production, and acid ceramidase, which leads to its breakdown. An initial clinical trial in 18 CF patients, conducted by Gulbins' clinical collaborator Joachim Riethmüller, of the University of Tübingen, showed that the strategy has some promise in terms of improved lung function, but the data were inconclusive. The study was conducted in winter and all but five of the subjects dropped out because they picked up other infections. Gulbins and Riethmüller now want to undertake a second study in 40 patients and at a different time of year.
Levels of ceramide are not altered in cancer patients, but the molecule is implicated in tumor biology as well, and Gulbins is developing a therapeutic strategy based on short-term manipulation of its concentration. "Tumor cells don't metastasize in mice lacking the acid sphingomyelinase," he observes. That's because ceramide is involved in a series of activation events involving tumor cells and blood platelets, which are required for metastasis. Disruption of this process when cancer patients are at risk of metastasis—during surgical or biopsy procedures, for example—could provide benefit.
Translating basic research findings into clinical practice is, of course, a lengthy and painstaking process. But it is clear that Gulbins' effort, wherever it's located, is well underway.