Molecular Medicine Partnership Unit

MMPU Molecular Medicine Partnership Unit

Today’s research for tomorrow’s medicine Molecular Medicine Partnership Unit A pioneering joint venture between the Medical Faculty of the University of Heidelberg and the European Molecular Biology Laboratory Contents

The Molecular Medicine Partnership Unit (MMPU) 03

The MMPU within a changing paradigm of medical research 04

The MMPU approach: From the bedside to the research lab and back again 05

The Partners 06

MMPU research themes 07

■ Diseases of mRNA metabolism 08

■ Cystic fibrosis/Chronic airway disease 10

■ Pathogenesis of colorectal cancer and development of novel approaches for early detection, diagnosis and prevention 12

■ Iron homeostasis in health and disease 14

■ Cell biology and disorders of cholesterol homeostasis 16

Getting involved in the MMPU 18

The MMPU is a collaboration between two renowned institutes located in Heidelberg, Germany. The cover image represents the city’s iconic “old bridge” against a backdrop of highly magnified cells and tissues. 03

The Molecular Medicine Partnership Unit (MMPU)

The Molecular Medicine Partnership Unit is a collaboration between two institutions with world-renowned expertise in the life sciences and medicine: the European Molecular Biology Laboratory (EMBL) and the Medical Faculty of the University of Heidelberg. Its primary aim is to speed the transformation of remarkable ongoing discoveries in the biomedical sciences into applications that can be used for the development of personalized medicine strategies.

Founded in 2002, the MMPU currently comprises five international research teams, jointly headed by a principal investigator from each organization and staffed by medical doctors, research associates, postdoctoral fellows, PhD students and technicians from both institutions. In this unique and stimulating setting, basic and clinical researchers work side-by-side to discover the molecular mechanisms that underlie common diseases. The MMPU is co-directed by Prof. Andreas Kulozik from the Angelika-Lautenschläger Hospital for Children and Adolescents at the University of Heidelberg and by Prof. Matthias Hentze from EMBL, and is housed in the Otto-Meyerhof-Zentrum on the Medical Campus of the University of Heidelberg.

Three elements are essential in the MMPU’s approach

■ a focus on important classes of diseases that makes optimum use of scientific expertise and clinical knowledge ■ a combination of clinical and molecular knowledge with the most sophisticated technologies and methodologies ■ the participation of scientists with a commitment to creativity and success

“A translational approach to biomedical research will speed up new discoveries, allowing patients to benefit from research findings sooner.” Andreas Kulozik, Co-Director MMPU

“Molecular Medicine provides great opportunities both for medicine and for basic science: medicine will benefit by achieving a deep molecular understanding of important diseases and basic science will gain important models to understand key biological processes.” Matthias Hentze, Co-Director MMPU

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The MMPU within a changing paradigm of medical medical of paradigm changing a within MMPU The

For MMPU collaborators, the road to understanding disease begins and ends with patients. with ends and begins disease understanding to road the collaborators, MMPU For

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In the MMPU, basic and clinical researchers work side by side to understand the the understand to side by side work researchers clinical and basic MMPU, the In  04 05

The MMPU approach: From the bedside to the research lab and back again

The MMPU builds on existing, well- MMPU teams bring together med- MD degrees. EMBL also provides established research and clinical ical doctors, clinical researchers, affiliation for MMPU members groups, drawing them into collab- molecular biologists, physicists, to the EMBL International PhD orative teams and offering several chemists, engineers, computer Programme (EIPP) and the EMBL types of practical support as they scientists and other specialists Interdisciplinary Postdocs (EIPOD) take a unified approach to disease from across the world to solve programme, while the Medical processes. MMPU groups have challenging biological problems Faculty provides access to its unrestricted access to a complete that are typically difficult to Postdoc Fellowship Programme. range of some of the most power- address in any single clinical or These formal structures are com- ful and innovative services and laboratory setting. Support is plemented by international con- facilities available in the world, offered to research projects on the ferences, courses, seminar series housed within the University of basis of excellence. and other events in which part- Heidelberg network of institutes ners can keep abreast of devel- and clinics and the EMBL. This Such multidisciplinary teams opments in their field. The MMPU includes a number of core facilities are likely to become the stand- also hosts public research days, with state-of-the-art technologies, ard in biomedical research in the organized twice a year, aimed at screening platforms, a range of future, which will require a new communicating the exciting dis- established animal models for generation of “physician-scientists” coveries coming from the collabo- human diseases, tissue samples who are trained to work on trans- ration to the wider scientific and and data from patients at various lational themes. The MMPU medical communities. stages of a disease, access to offers hands-on practical training clinical trials, etc. A number of through the University’s Medical innovative methods and technol Faculty degree track as well as ogies have been developed within through a dedicated interdiscip the teams themselves, a process linary teaching seminar series which is strongly encouraged aimed at students preparing for within the MMPU. Master’s, Bachelor’s, PhD and 06

The Partners

The MMPU is a partnership be- methods in the life sciences and has tween EMBL and the Medical Faculty an active technology transfer pipe- of the University of Heidelberg, line to translate discoveries into drawing together a growing staff applications that benefit society. of currently more than 50 experts recruited from across the world. The Medical Faculty of the University of Heidelberg, founded The European Molecular Biology in 1386, forms part of one of the Laboratory, dedicated to basic oldest and most distinguished research in the molecular life sci- academic institutions in Europe. ences, is internationally recognized The Faculty fosters close links The EMBL Advanced Training Centre on as one of the world’s foremost between research labs and hos- the EMBL campus research institutions. Established pital wards, permitting the swift in 1974, EMBL is funded by pub- implementation of newly acquired lic research monies from 20 knowledge from clinical studies. European member states, and as- Its practically oriented modern sociate member state, Australia, teaching methods and systematic and comprises almost 100 inde- encouragement of young re- pendent groups covering the spec- searchers makes it one of the trum of molecular biology. Groups leading institutions for medical work either at the Main Laboratory research and training in Germany. in Heidelberg, or at one of four out- In 2007, the Medical Faculty was stations located across Europe. officially recognized by the German In addition to its world-class federal and state governments as research activities, EMBL provides part of its “Excellence Initiative”. a renowned training programme The Medical Faculty provides MMPU for PhD students and postdoctoral researchers with full access to fellows and offers vital services to its facilities, offers the laboratory The Otto-Meyerhof-Zentrum on the scientists in the member states. It space for the MMPU and funds Medical Campus of the University of Heidelberg has widely recognized expertise in scientists through its postdoc developing new instruments and fellowship programme.  Heidelberg is one of the leading centres in Europe for biomedical research.

“The Medical Faculty of the University of Heidelberg and EMBL share a long tradition of excellence in medical and basic research. By channeling their expertise through the MMPU, they have created one of the world’s foremost centres with remarkable potential to make real advances in finding treatments for disease.” Claus R. Bartram, Dean of the Medical Faculty of the University of Heidelberg

“The MMPU successfully bridges the gap between basic and clinical research. In order to devise new effective therapies and diagnostic tools we first need to obtain a thorough understanding of the molecular mechanisms of disease. In the MMPU biologists and medical scientists combine their complementary expertise and work hand-in-hand to pursue this goal.” Iain W. Mattaj, Director General of EMBL

MMPU research themes Disease prevention by mRNA volume and quality control Diseases of mRNA metabolism 08

Breathing fresh air into chronic lung diseases Cystic fibrosis/Chronic airway disease 10

The hunt for molecular signposts of cancer Pathogenesis of colorectal cancer and development of novel approaches for early detection, diagnosis and prevention 12

Managing the body’s supply of iron Iron homeostasis in health and disease 14

Keeping cholesterol in check Cell biology and disorders of cholesterol homeostasis 16 08

Carriers of beta-thalassemia are healthy if NMD is active, but if it is inactive, they suffer abnormalities in red blood cells (depicted above) and other serious symptoms.

A metastasis (bordered by the dotted line) invades healthy liver tissue in an image obtained through prothrombin immunohistochemistry.

 Matthias Hentze, MD Associate Director and Group Leader, EMBL

Andreas Kulozik, MD, PhD Director of the Department of Paediatric Oncology, Haematology and Immunology, Angelika Lautenschläger Hospital for Children and Adolescents, University of Heidelberg 09

Disease prevention by mRNA volume and quality control Diseases of mRNA metabolism

The scientific collaboration between if it does slip through, it may be Matthias Hentze and Andreas produced in a shortened form that Kulozik, which stretches back over ends up doing more harm than if a decade, was the original inspir there were no protein at all. ation for the establishment of the MMPU. This successful partner- NMD detects misplaced stop ship between a basic researcher codons by recognizing protein tags and a clinician has become a mod- that have been attached to mRNAs. el for the other MMPU teams. The Matthias and Andreas have dis work of their team has led to im- covered that various combinations portant new discoveries related to of these tags send the mRNAs blood diseases and revealed fun- down alternative processing path- damental new aspects of the basic ways, with different outcomes. biology of cells that are applicable This results in different dosages to a much wider range of diseases. of proteins and explains why some patients suffer a more severe form The mutation removes the Currently the team is focusing on of a disease or respond differently control, leading to abnormally common diseases such as haemo- to treatments than others with the high amounts of prothrombin globin disorders, thrombosis, in- same mutation. To demonstrate messenger RNA and protein. flammation and childhood cancer. this, the team had to develop the Many of these health problems can first method to measure the - over Even healthy people need higher often be traced to the loss of a cru- all activity of NMD. As a result, they levels of prothrombin than the cial protein, changes in the amount successfully proved the principle mRNA would normally yield. This that is made, or the production in cystic fibrosis, and they suspect led to the discovery of a second of defective versions. Matthias, that a similar process is at work in signal that counteracts the first Andreas and their colleagues have a number of other diseases. by promoting higher prothrombin traced some of these problems levels. A delicate balance between to the way messenger RNAs are A second major project also in- the two signals determines how processed as the cell attempts to volves extra information in mRNAs. much protein is produced. The translate them into proteins. The work began with a clinical signal is activated by stress study to find the gene responsible factors, such as inflammation Cells often exercise quality control for a hereditary form of thrombosis. and tumour invasion, and thereby and destroy faulty mRNA molecules It revealed that patients have a contributes to a variety of before they can do harm. For ex- mutation in the prothrombin gene pathological conditions. The team’s ample, nonsense-mediated decay which subtly increases levels of findings highlight how subtle (NMD) often breaks down mRNAs the protein in their blood and changes in gene expression can before they are used to make greatly increases their risk of have serious consequences for proteins. This process depends thrombosis. disease and point to the impor- on extra information in an mRNA tance of analyzing small changes. that is not translated into protein. The mutation affects a region in The researchers have confirmed A sequence called a stop codon the untranslated tail end of pro- that the combination of signals tells the cell where an mRNA’s prothrombin mRNA; the team dis occurs in a number of other mol tein-encoding information ends. covered that this region acts as a ecules. It is another new mecha- Mutations in genes often put a stop sort of volume control. Over a long nism that seems to explain the codon too early in the molecule, period of evolution, the volume of origins of several diseases, and which activates NMD. This may the signal has been tuned down in may provide a starting point for cause the mRNA’s destruction and the prothrombin gene of humans the development of new types of the loss of an essential molecule; and many other species. therapies. 10

Breathing fresh air into chronic lung diseases Cystic fibrosis/Chronic airway disease

Breathing is something most of us of Heidelberg, Marcus provides lungs of smokers. This promotes take for granted – but for the mil- clinical care for patients suffer- the destruction of the walls of the lions of people across the world who ing from cystic fibrosis and other alveoli and thus very likely contrib- suffer from chronic lung diseases, lung diseases. His lab developed a utes to the development of emphy- shortness of breath can be a mat- mouse model of cystic fibrosis lung sema. But it has been hard to get a ter of life and death. Cystic fibrosis, disease which contains a defective direct look at MMP12’s activity. for example, remains the most version of ENaC, an ion channel common lethal genetic disease, protein that causes the epithelial The team accomplished this by and chronic obstructive pulmonary cells of the airway to absorb too designing a set of probes that disease is now the fourth leading much sodium. This draws off the give off a fluorescent signal when cause of death worldwide. Through fluid present on the airwaysurfaces MMP12 becomes active on the sur- a unique combination of work and imitates the symptoms of faces of cells, observable under the with patients and animal models, cystic fibrosis. Carsten, a chemical microscope. When they used this innovative microscopy techniques biologist at EMBL, has devel- tool to examine tissue taken from and chemistry, the labs of Marcus oped small compounds that can slip mice with acutely inflamed lungs, Mall and Carsten Schultz are into cells and alter these systems to they discovered that MMP12 was developing new tools to diagnose modulate the activity of the ion chan- much more active than normal. The and monitor some of these diseases, nels and thus improve the hydration next step is to confirm this finding in gaining insights into underlying of the airway surfaces. Late- human samples, so they are adapt- mechanisms that are essential in ly, his group has been designing ing the method to measure MMP12 the search for new treatments. fluorescent probes to monitor sys- activity in cells from patients with tems within cells that control the cystic fibrosis and other chronic The main focus of the team has behaviour of ion channels. lung diseases. Since the procedure been cystic fibrosis, caused when is non-invasive and is carried out patients inherit a defective form of People with cystic fibrosis often using cell samples, they hope that a gene called CFTR. This affects a develop pulmonary inflamma- it can be used to diagnose inflam- layer of tissue called the epithelium tions that cause the destruction matory pulmonary conditions and that lines airway surfaces in the of the small, sac-like alveola and monitor disease progression in the lungs. Normally this layer should be emphysema. (Emphysema is also clinical setting. This would provide coated with a thin layer of liquid, but frequently triggered by the contin- physicians much earlier with the in- for that to happen, the epithelial ued inhalation of cigarette smoke formation they need to treat patients cells need to absorb and secrete and other chemical irritants.) One of before the lungs are damaged and salt and water in a coordinated fash- the team’s projects is to understand emphysema starts to develop. ion. The genetic problem affects a the link between inflammation and channel in the cells’ membranes, the development of emphysema. MMP12’s position on the cell sur- causing them to release chloride Their recent work has focused on face could make it an ideal candi- ions very inefficiently and to absorb the activity of a molecule called date as a drug target. The probes are too much sodium. As a result, a macrophage elastase (MMP12), allowing the team to study how the thick layer of mucus forms and cre- which is secreted by alveolar behaviour of the protein changes ates an environment that sets the macrophages in the lung in re- over the course of the disease. They stage for chronic inflammation and sponse to inflammations. are also providing a tool to search bacterial infection. Patients with for small compounds, first in mice cystic fibrosis are usually diagnosed MMP12’s normal function is to and hopefully in humans, which in their early childhood and often break down proteins in the matrix can tune down its activity. That’s a don’t survive to reach middle age. that surrounds cells, often changing first crucial step in creating a drug the architecture of a tissue. In 2002 that can control inflammation and As a clinical researcher at the another lab discovered that it is emphysema in cystic fibrosis and Children’s Hospital of the University hyperactive in inflammations of the other chronic lung diseases. 11

Marcus Mall, MD  Head of the Division of Paediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Paediatric Oncology, Haematology, Immunology and Pulmonology, Angelika Lautenschläger Hospital for Children and Adolescents, University of Heidelberg

Carsten Schultz, PhD Interdisciplinary Group Leader and Senior Scientist, EMBL

MMP12 is overactive in cells in a mouse model of cystic fibrosis. Here, fluores- cence microscopy reveals the activity of MMP12 on macrophages by cleaving a synthetic reporter molecule on the surface of cells from broncheoalveolar lavages.

X-ray images of the chest of cystic fibrosis patients reveal the development of lung disease. 12

Bioinformatics comprises a set of powerful tools which enable researchers to compile and interpret vast amounts of information about diseases. The results often reveal new targets for drugs and may lead to the design of new diagnostic tools.

Colorectal cancer tissue stained to detect expression of HLA class II antigens

 Peer Bork, PhD Group Leader and Senior Scientist, EMBL

Magnus von Knebel Doeberitz, MD, PhD Director of the Department of Applied Tumour Biology, Institute of Pathology, University of Heidelberg and Group Leader Cooperation Unit Cancer Early Detection, DKFZ Heidelberg 13

The hunt for molecular signposts of cancer Pathogenesis of colorectal cancer and development of novel approaches for early detection, diagnosis and prevention

What makes healthy cells lose ome that lists all the regions with example, during their refinement control of the normal programmes repetitive DNA sequences. Based in the cell, many proteins are that guide their differentiation and on this information, they scan for glycosylated – coated with sugars. start down a path toward becom patterns that appear uniquely Magnus and Peer discovered ing cancer? In most cases, re- in cancer cells of a specific type altered patterns of glycosylation searchers believe, the cause is an and therefore might be used to in MSI tumours, and they are now accumulation of changes in their detect them. They have estab- using high-throughput technologies genomes, mainly mutations in lished a bioinformatics model that to try to identify them systematical- important genes. Every cell accu- predicts the frequency at which a ly. This may yield another way to dis- mulates mutations when it divides, mutation is likely to occur in any tinguish different types of tumour through chance or the influence particular position in the genome cells from healthy tissue. of environmental factors such as that contains long, repeated DNA carcinogenic chemicals. Evolution sequences. They found that spe- If the immune system can recognize has given our cells protective cific sites undergo unusually high mutated proteins, or be trained mechanisms to detect most of the rates of mutations, suggesting that to do so, it might be possible mistakes and repair them, or to they are functionally relevant and to develop vaccines that target commit suicide in a process called promote tumour development. tumours. Another of the group’s apoptosis, if the damage can’t be The method revealed novel target projects aims to train white blood repaired. Even so, enough muta- genes involved in colorectal cancer cells called T cells – major players tions slip past the controls to make development. Moreover, they have in immune responses – to detect cancer a leading cause of death set up a unique model for a heredi- specific mutated proteins and elim- worldwide. Magnus von Knebel tary form of colorectal cancer inate the cells on which they are Doeberitz and Peer Bork are en- known as Lynch syndrome. expressed. The group demon- gaged in a hunt for molecular sign- strated that the strategy works with posts of the disease – particularly The scientists have discovered new tumours grown in cell culture, so in colorectal cancer – that could links between several genes and a clinical trial has been designed be used to diagnose it at early the probability that a tumour will to test these so-called frameshift stages and treat it more effectively. take a malignant turn or the likeli- antigens as vaccines. Phase I/II hood that therapies will succeed. of the trial, scheduled to begin in As cells accumulate mutations, This information may be useful in 2010, aims to determine whether their genomes usually become un- the design of new diagnostic tools the vaccines have any toxic side stable, often making it likely that and in coming up with treatment effects, and what dosage may be more mistakes will occur at a faster plans for individual patients. Now necessary to successfully treat pace. Mutations affecting one type they are extending their analysis to patients’ tumours. of cellular control, called the DNA shorter repeats in the genome and mismatch repair system, occur epigenetic alterations, such as the predominantly in regions that have methylation of gene promoter re- repeats of a single letter of the gions, in hopes of finding more genes genetic code – like a key that has and mechanisms that underlie the become stuck on a computer, early steps of cancer formation. repeating the same character over and over. Cancers that develop in A mutation often leads to a molecule this way are called microsatellite with unusual characteristics; some- unstable or MSI tumours. times it is visible on the surfaces of cells. That might call it to the attention Magnus and Peer have compiled of the immune system and offer a a database of the human gen- potential handle for therapies. For 14

Managing the body’s supply of iron Iron homeostasis in health and disease

As life evolved, it had to cope with of us carry the relevant mutation, Cells release iron through channels the presence and abundance of and one in every 250-300 people in their membranes made from a elements such as iron in the envir inherit two defective copies of the protein called ferroportin, mainly onment. Iron plays a crucial role in gene, leading to symptoms of the found in cells of the liver, small living systems: It drives chemical disease. The team helped prove intestine, and blood cells called reactions within cells, captures that Hfe’s presence in liver cells is macrophages. Hepcidin binds to oxygen in our lungs and carries it required for the proper production this gate-like molecule to control in red blood cells, and is used to of a molecule called hepcidin, a how much of it is present on the cell combat bacteria and other para- hormone that blocks the release of surface: rising levels of hepcidin sites. The amount is crucial: Either iron from cells. Without hepcidin, lower the number of iron transport too much or too little iron can lead too much iron enters the blood- channels and reduce iron levels in to serious diseases. How the body stream and the body becomes the blood. The lab is also using the maintains this balance has been overloaded. Previously most re- new siRNA method and modern the subject of years of study by searchers looked to the duodenum microscopy techniques (in collab- Martina Muckenthaler and Matthias itself for the key to the body’s oration with Rainer Pepperkok’s Hentze. They have developed regulation of iron; this discovery lab) to discover how it does so. This creative new methods and used proved HH to be a ’liver disease’ might allow them to learn to control a wide range of technologies to and highlighted the key role of this the behaviour of the channel with probe the causes of iron-related organ in iron metabolism. drugs or other substances. disorders, along the way un- covering fundamental cellular A central theme of the group’s Recently scientists have dis- processes that contribute to many research is to understand the func- covered that cells produce vast other diseases. tions of the hepcidin hormone and numbers of small microRNAs the factors that influence its pro- that naturally block the activity of Our bodies extract a small amount duction and release. In a collab- genes. Defects in these molecules of iron from foods such as red oration with Michael Boutros’ lab have been linked to a number of dis- meat, poultry, fish and beans at the German Cancer Research eases. Martina, Matthias and their as they leave the stomach and Center, the team is using the power- colleagues suspected that they enter a section of the small in- ful approach of blocking the activity also play a role in the regulation testine called the duodenum. But of specific genes across the entire of iron levels, but it has been hard the body uses most of its iron by genome using molecules called to find miRNAs and study their recycling what is already there. small interfering RNAs (siRNAs). If a effects. The team has devel- Martina and Matthias have helped particular siRNA disrupts hepcidin oped an innovative technology prove that a complex network of synthesis, this is a good hint that called miChip which can monitor interactions throughout the body its target gene may be involved miRNAs. The scientists are par- monitors global amounts of iron, in the regulation of systemic iron ticularly interested in studying makes adjustments that tell duo- levels – which can be confirmed miRNAs in mouse models that denal cells when to absorb more through other experiments. Using replicate iron diseases in humans. or less, and regulates how much is this approach, the group has Their search has revealed that an released from storage. already discovered one factor miRNA specifically produced in the (called SMAD7) that normally sup- liver (miR122) controls hepcidin A molecule called Hfe plays a presses hepcidin expression. In production. The miChip technology central role in iron regulation. the longer term, knowledge of the can also be used to clarify the Mutations in its gene cause the molecules that influence hepcidin roles of miRNAs in other diseases, iron overload disease hereditary levels will be useful in identifying and the team has entered into haemochromatosis (HH), which is existing drugs or discovering new a number of collaborations with the most common genetic disorder ones that can be used in the treat- other laboratories worldwide to in the Western world: one-eighth ment of iron disorders. do so. 1516

 Matthias Hentze, MD Associate Director and Group Leader, EMBL

Martina Muckenthaler, PhD

Head of the Molecular Medicine Laboratory, Department of Paediatric Haematology, Oncology and Immunology, Angelika Lautenschläger Hospital for Children and Adolescents, University of Heidelberg

The “iron chip” reveals differences in gene expression patterns between cells taken from healthy patients and from those suffering from iron-related diseases.

The team‘s investigations of hereditary haemochromatosis have revealed a central role for the liver in regulating the body‘s uptake of iron. 16

Keeping cholesterol in check Cell biology and disorders of cholesterol homeostasis

Doctors constantly advise us to (NPC) disease, and other choles- In further studies they identified a get enough exercise and follow a terol-related disorders. One project role for one of these genes in NPC diet low in fatty foods and high in aims to identify genes that may disease, a rare inborn condition fruits and vegetables. Not doing contribute to raising levels of that is caused by mutations in the so can lead to an accumulation cholesterol in the blood. The re- genes NPC1 or NPC2. Infants’ cells of cholesterol in the blood, a searchers first monitored the cells’ are unable to transport cholesterol major risk factor in two diseases genomes to discover genes that and other types of fatty molecules, that are leading causes of death were being activated or silenced resulting in inefficient metabolism in the Western world: athero- when cells were exposed to low and dangerous accumulations sclerosis and coronary heart dis- levels of cholesterol. Once they of these molecules within the ease. MMPU collaborators Heiko had a list, they tested the function cell. This eventually leads to Runz and Rainer Pepperkok are of these genes using a powerful death through the degeneration trying to get a handle on these technique called RNA interfer- of a patient’s nervous system diseases by studying the body’s ence (RNAi). This method is based and liver. Using their new cholesterol and the factors that on small RNA sequences called screening method, the researchers regulate its production, uptake siRNAs that are inserted into the are currently searching for genes and metabolism. cell, blocking the production of that help to restore the faulty proteins from specific genes. transport mechanism and that Despite a bad reputation, choles- may serve as targets in the terol is not always harmful; it plays development of a treatment. an important role in vital processes in the body such as digestion and Ultimately they hope that their the synthesis of hormones and vi- studies will open new avenues tamins. Most cholesterol is prod- to design targeted therapies for uced in the liver, but we also get cholesterol-related diseases, for some through our diets. For it to do example by finding small mol- its job correctly, cholesterol from ecules that can affect genes either source must be taken up involved in cholesterol metabol from the bloodstream and metabolism. They have already identified ized by cells. This process is nor- some promising targets and will mally tightly regulated by a network soon test them in animal models. of proteins inside cells, but under certain conditions, the system can become dangerously unbalanced. To discover the functions of the The team combines the expertise genes they found, they used in of Heiko, a human geneticist who novative technology developed by has worked on diseases related Rainer’s group at EMBL. The method to the storage and release of cho- allowed them to expose cells to lesterol, and Rainer, a cell biolo- many different siRNAs at once gist who uses cutting-edge light and monitor the effects under the microscopy techniques to study the microscope. It permitted the parallel transport of cholesterol and other analysis of several hundred genes, molecules through the cell. leading to the identification of 20 genes that had not been previ- Their current work includes ously associated with cholesterol searching for genes and cellular metabolism, but are likely to have processes involved in hyperchol- an important effect on balancing esterolemia, Niemann-Pick Type C levels of the molecule. 17

The team uses automated high-throughput microscope studies of fluorescent molecules to observe crucial compo- nents of cholesterol metabolism. The image shows cholesterol (green), a lysosomal marker (red) and cell nuclei (blue).

3D-visualization of multiparametric data from RNAi-screening for novel cholesterol regulators

Heiko Runz, MD  Group Leader Molecular Metabolic Disease Unit, Institute of Human Genetics, University of Heidelberg

Rainer Pepperkok, PhD Team Leader in Cell Biology and Cell Biophysics Unit and Head of Advanced Light Microscopy Facility, EMBL 18

Getting involved in the MMPU Whether you are a student set- For postdocs … ample searching for genes that ting out on a career in the life Postdoctoral researchers may contribute to a disease, or finding sciences, a postdoc looking for join the MMPU through a number new targets for drugs based on a new challenge, an experienced of well-established postdoc- an understanding of a biological researcher interested in apply- toral programmes, including the process. ing your scientific knowledge to EMBL Interdisciplinary Postdocs questions related to human (EIPOD) Programme and the For the wider scientific and health, a physician looking to Postdoc Fellowship Programme medical communities … learn more about the molecular of the Medical Faculty of the The MMPU hosts public research basis behind a disease – or if you University of Heidelberg. days, organized twice a year, aimed simply want to know more about at communicating the exciting the exciting research being con- For established scientists … discoveries arising from the part- ducted on the diseases studied EMBL and the Medical Faculty both nership to a wider audience. by our groups, the MMPU has have active Visitors Programmes something for you. that allow experienced researchers interested in collaborating to For MD and PhD students ... join MMPU teams to share their For more information on how to The MMPU provides extraordinary knowledge, perform joint experi- get involved in MMPU activities, opportunities for highly talented, ments, acquire new skills and contact us at: motivated students who wish to learn specific techniques. make the most of a career in the [email protected] biomedical sciences. MD and PhD For physicians … students may join the MMPU The MMPU also offers possi- www.klinikum.uni-heidelberg.de/ through the University of Heidel- bilities for medical doctors who Molecular-Medicine-Partnership- berg’s Medical Faculty degree would like to explore the funda- Unit-MMPU.101349.0.html track or through the internation- mental mechanisms underlying ally renowned EMBL International a disease within the research www.embl.de/research/partner- PhD Programme (EIPP). spectrum of the MMPU, for ex- ships/mmpu/index.html

The MMPU would like to thank the following organizations which, in addition to the core funding provided by EMBL and the University of Heidelberg, provide generous funding for research projects: Ara Parseghian Medical Research Foundation, Bundesministerium für Bildung und Forschung, Deutsche Forschungsgemeinschaft, Dietmar Hopp Stiftung, European Commission, European Research Projects on Rare Diseases, Fondation Leducq, Fritz Thyssen Stiftung, Manfred Lautenschläger Stiftung, Mukoviszidose e.V..

Credits

Written and edited by Sarah Sherwood, Barcelona and Russ Hodge, Berlin

Layout and design by Sybille Sukop, Medienzentrum / Unternehmenskommunikation Stabsstelle des Universitätsklinikums und der Medizinischen Fakultät Heidelberg Leitung, Markus Winter www.klinikum.uni-heidelberg.de/medien

Photography by Hendrik Schröder and Markus Winter Medienzentrum Marietta Schupp, Photolab, EMBL and iStockphoto

Cover design by Petra Riedinger, OIPA, EMBL

MMPU ’cubes’ by Leo Burger, Workshop, EMBL

Project coordination by Britta Schläger, kobris, Sandhausen

Printed by Nino Druck GmbH, Neustadt/ Weinstraße

Published for the Molecular Medicine Partnership Unit by the Medical Faculty of the University of Heidelberg and the European Molecular Biology Laboratory (EMBL)

©November 2010. All rights reserved. For more information: [email protected] www.embl.de/research/partnerships/mmpu/index.html www.klinikum.uni-heidelberg.de/Molecular-Medicine-Partnership-Unit-MMPU.101349.0.html