A Planck Walk

A Planck Walk © Edgar Zippel, Berlin / www.edgarzippel.de A shift in focus - and a couple of robots - have helped researchers at a Max Planck Institute pinpoint the genetics underlying entire systems. By Stephen Pincock Related Articles 1-3 For some time, systems biology as a concept garnered less than the full support of the biological community, Lehrach notes. "There are a few people who really understand and push it, but some who are opposed," he says. "But I think it is naïve in the extreme to believe that we can't understand a cell phone without modeling it, but that we can understand cancer without doing the same. Systems biology is an essential next step." Lehrach is one of four department heads who guide operations at the institute. Between them, these senior investigators oversee 481 group leaders, researchers, students, and administrative staff who work in its headquarters in a leafy Berlin suburb, not far from the sprawling US Embassy compound. "We want to explain what a phenotype means. I decided more than 10 years ago that we needed to do genome-wide analysis of gene expression."-Bernhard Herrmann The institute is part of the Max Planck Society, an independent, nonprofit research community that gains around 80% of its €1.4 billion annual funding from the German federal and state governments (4 It's work that his institute colleagues find useful, as demonstrated by the roughly half-dozen collaborations he has underway, including one with Sylvia Krobitch and her team, who are trying to decipher the molecular pathways involved in neurodegenerative disorders. Tim Hucho Meanwhile, Konthur says, he is part of the German national "Antibody Factory" initiative and a European collaboration known as ProteomeBinders, a consortium that aims to build a comprehensive resource of affinity reagents such as antibodies, to facilitate analysis of the human proteome.5 Downstairs from Konthur's first-floor office, the data being churned out by the successors of Lehrach's machines is being used by Herrmann and his group to understand the systems biology of development. "We want to explain what a phenotype means," says Herrmann, a serious man with a sparse corona of grey hair. "I decided more than 10 years ago that we needed to do genome-wide analysis of gene expression. We want to know how the wild-type organism is producing a [mammalian] trunk." Mouse embryos To this end, his group uses large-scale analysis platforms to probe the gene regulatory network that controls the development of the trunk, including segmentation and somite formation. Among the genes already identified using these methods is Axin2, an inhibitor of the Wnt/beta-catenin signaling pathway.6 In a small microscopy room nearby, Lars Wittler, who leads a group in Herrmann's department, is beginning an experiment to try and understand the major players in the process of trunk development. Raising his eyes to the eyepiece, gloved hands carefully holding a tungsten wire needle in his hands, he begins dissecting parts of a mouse embryo that are important for organization of the organism. "This is an excellent group investigating the regulatory networks of genes in a very systematic way." -Gudrun Rappold "The idea is to find novel factors important for the different stem cell populations in the organizer region," he says, carefully manipulating the needle into position, "that is, for those stem cells that are located in the posterior organizer or anterior primitive streak and give rise to the paraxial mesoderm and therefore to the somite progenitor cells." To do this, he needs to isolate the crucial parts responsible for organization in the mouse embryo, then sequence them using the institute's Solexa instrument, which will produce the whole transcriptome for that part of the organism. But the structures are tiny, and the dissection process is painstaking. "It's the first time I've done this sort of thing, and it's not as easy as I first thought," Wittler says resignedly. The independent research group that Stefan Mundlos leads is working on related areas, focusing on the molecular mechanisms that regulate form and structure of the skeleton during vertebrate development. It's work that has led them to study congenital hand abnormalities, cystic renal disease7 and Marfan syndrome,8 and has impressed collaborators. "This is an excellent group investigating the regulatory networks of genes in a very systematic way," says Gudrun Rappold, from the Institute for Human Genetics at the University Clinic Heidelberg. Silke Sperling and daughter Lola Researchers who come to Berlin, either from other parts of Germany or from overseas, find the city expensive, but stimulating, says Nathalie Veron, a PhD student originally from Freiburg, a city close to the French border. "Berlin is certainly a good place to work," she says, "because if there is a machine missing here, there is always another institute that surely has it." Tim Hucho, a native Berliner who studies the genetics of chronic pain, agrees. "Berlin is a good situation for collaboration, with the Free University and Charité [hospital] not far away." Veron, like many of her colleagues, was drawn to the institute partly by the good reputation of the Max Planck Society, and partly by the caliber of the senior researchers. "There's lots of competition for places because it has well known names," she says. Another benefit is the ability to do interdisciplinary work, says Silke Sperling, who is studying the genetics of cardiac development. "From my point of view, our institute is unique because of its interdisciplinary nature, with a bioinformatics department beside wet-lab departments," says Sperling, who arrived at the institute in 2000 after training as a cardiologist, bringing with her a collection of samples of cardiac tissue from children she had treated. "I was always interested in cardiac development and spent 18 months working in pediatric cardiology in Berlin," she explains. After doing a PhD in cardiac physiology, she found herself struggling to explain the molecular basis of what she was observing. "It seemed sensible to do molecular research," she says, so after stints at the Max Delbruck Center for Molecular Medicine and the Free University, both in Berlin, she made her way to Lehrach's vertebrate genetics group. "I thought Hans would give me the support and freedom to do what I wanted," she says. Using her cardiac samples, her multidisciplinary team employs expression-profiling microarrays and other techniques to study the mechanisms of normal and abnormal heart development. "From my point of view, our institute is unique because of its interdisciplinary nature, with a bioinformatics department beside wet-lab departments." -Silke Sperling In April, the Sperling team published the results of its integrative approach, analyzing the transcription levels of 42 genes from cardiac biopsies of 190 patients and healthy individuals, then correlating them with a detailed phenotypic description of the heart malformations. It's work that is leading to a better understanding of the mechanisms underlying some of the most common birth defects in humans.9 Sitting in his office at the end of the day, Hans Lehrach suggests that the institute's researchers are united by a common focus on making a difference to human health. "There's a spirit [that] is very universal," he says. "There's a strong emphasis on diseases and real-world problems, and of development as a complex problem." Any incremental improvement of a real-world problem is important, he says, leaning in for emphasis. "If we can develop predictive models that extend the lifespan for 10% of cancer patients, for example, then that is more important than any number of high-impact papers." Correction: When originally posted, this story identified a picture of Tim Hucho as Lars Wittler, and a photo of Hans Lehrach as Tim Hucho. We have corrected the captions, and regret the error. References 1. M.T. Ross et al., "The DNA sequence of the human X chromosome," Nature, 434:325-37, 2005. 2. M. Hattori et al., "The chromosome 21 mapping and sequencing consortium," Nature, 405:311-9, 2000. 3. H. Watanabe et al., "DNA sequence and comparative analysis of chimpanzee chromosome 22," Nature, 429:382-8, 2004. 4. Z. Konthur et al., "Perspectives for systematic in vitro antibody generation," Gene, 364:19-29, 2005. 5. M.J. Taussig et al., "ProteomeBinders: planning a European resource of affinity reagents for analysis of the human genome," Nat Methods, 4:13-7, 2007. 6. A. Aulehla et al., "Wnt3a plays a major role in the segmentation clock controlling somitogenesis," Dev Cell, 4:395-406, 2003. 7. D. Muller et al., "A complex phenotype with cystic renal disease," Kidney Int, 70:1656-60, 2006. 8. P.N. Robinson et al., "The molecular genetics of Marfan syndrome and related disorders," J Med Genet, 43:769-87, 2006. 9. M. Toenjes et al., "Prediction of cardiac transcription networks based on molecular data and complex clinical phenotypes," Mol BioSyst, 4:589-98, 2008.

A Planck Walk

Jul 1, 2008

A Planck Walk

A shift in focus - and a couple of robots - have helped researchers at a Max Planck Institute pinpoint the genetics underlying entire systems.

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