Hodgkin lymphoma: A unique example for tumor cell reprogramming

Researchers at the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch (Germany) and the Charité University Medicine Berlin (Campus Virchow and Campus Buch) have discovered a molecular mechanism which explains why the cells of Hodgkin lymphoma, a malignancy affecting the lymph nodes, can change their appearance and take on characteristics of other cell lineages. “This is a perfect example of the ability of the B cells, a specific type of human immune cells affected by Hodgkin lymphoma, to be able to modify their differentiation program”, say Dr. Stephan Mathas and Dr. Martin Janz from Professor Bernd Dörken’s group at the MDC and the Charité. Their findings have now been published online in advance in Nature Immunology (doi:10.1038/ni1285, 2005)*. Their data also make it clear why it has been so difficult to find out which cells in the body are affected by the disease which was first described in the literature in 1832 by the English physician and pathologist Thomas Hodgkin.  Not until 1994, 160 years after he had initially described the disease, scientists had found out that it originates in the B cells, specific white blood cells of the immune system. Now, the data of the Berlin research group also help to understand the process of normal and malignant B cell development.

Harvard Biochemist Tom Rapoport Awarded Max Delbrück Medal in Berlin

Professor Tom Rapoport from Harvard Medical School in Boston, USA, has been awarded the Max Delbrück Medal in Berlin for his “seminal role in the elucidation of the mechanisms of protein transport in cells”. Proteins are the building material for the body and critical for its proper functioning. Professor Rapoport identified essential cellular structures which carry proteins across the cell membrane and deliver it to the “customers”.

Master Switch for Blood Cell Development Detected

Blood cells develop from blood stem cells in the bone marrow. Their development is regulated by roughly 20 gene regulators or transcription factors. One transcription factor, called PU.1, plays a central role in this vital process. It steers the development of two major blood cell lines of the immune system, namely the lymphocytes and the myeloid blood cells. In addition, PU.1 regulates the blood stem cells own development thereby ensuring that new blood cells are produced as needed. Yet, the question remains, “What regulates the regulator?” Now, Dr. Frank Rosenbauer, a cell biologist who recently moved from the Harvard Institutes of Medicine (Boston, USA) to the Max-Delbrück Center for Molecular Medicine (MDC) Berlin-Buch supported by the Initiative and Networking Fund of the President of the Helmholtz Association to which the MDC belongs, has detected a master switch which regulates PU.1. This master switch, termed URE (upstream regulatory element), not only turns the gene regulator on or off but also tunes it. As Dr. Rosenbauer demonstrated for the first time, URE can up- and down regulate PU.1, and, thus, determine whether B- or T-cells develop from lymphocyte progenitor cells. Animals that lack URE develop various forms of leukemias and, consequently, die within a few months. The research of Dr. Rosenbauer and his colleagues in the USA and at the MDC has now been published online in the journal Nature Genetics* (November 27, 2005, doi:10.1038/ng1679).

Some Kinds of Fat Worse Than Others – Abdominal Fat Decisive Factor

International Symposium on Obesity and Hypertension at the MDC

Some kinds of excess fat are worse than others. Until very recently, all overweight or obese people were considered to be at high risk for developing type 2 diabetes and high blood pressure which can lead to stroke, heart attack, and kidney damage. Now, based on new insights, the medical community has a more differentiated view of obesity. It is not so much the Body Mass Index (BMI) that is the decisive factor, but rather where on the body the excess fat is distributed. Particularly dangerous is stoutness around the waist and abdomen, which used to be described with the euphemism “portliness” and was considered a sign of prosperity. Doctors refer to this as “abdominal obesity”. People with this form of overweight are especially prone to develop secondary diseases of obesity early on. This is one of the newest findings that was presented at the 4^th International Symposium on Obesity and Hypertension at the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch. The symposium from October 27 – 29, 2005, in which 200 experts from Europe, North and South America and Asia participate, is organized by Professor Arya Sharma (McMaster University, Hamilton, Ontario, Canada) and Professor Friedrich Luft (Franz Volhard Clinic, Charité University Medical School Berlin/Helios Clinics Berlin-Buch and the MDC).

Prof. Walter Birchmeier and Prof. Achim Leutz Elected EMBO Member

Cell biologists and cancer researchers Prof. Walter Birchmeier and Prof. Achim Leutz from the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch have been elected as members of the European Molecular Biology Organization (EMBO) in Heidelberg. Together with Professor Carmen Birchmeier and Dr. Thomas Sommer the MDC has now four members in this renowned organization. Prof. Walter Birchmeier, who is also Scientific Director of the MDC, investigates the mechanisms of the development of cancer and metastases, Prof. Leutz researches the mechanisms which lead to the onset of leukemias.

20 Years of Fainting Spells – Researchers in Berlin Discover Cause for Severe Neurological Disorder – First Hope for Effective Therapy

As soon as the 43-year-old patient stood upright, his blood pressure dropped from 140 to 50 mm on the mercury column within a few seconds. Over the last 20 years, he had had recurrent fainting spells with loss of consciousness.  He also reported decreased sweating, dry mouth, dry eyes, distended abdomen, and problems with digestion. His colon was so dilated that his liver had shifted from the right to the left side of his abdomen and his stomach was squeezed between his liver and spleen. He could hardly eat or drink anything anymore and was so emaciated that he was afraid he would slowly starve to death. Now, Dr. Christoph Schröder, Professor Friedrich Luft, and Professor Jens Jordan from the Clinical Research Center of the Franz Volhard Clinic (Charité and Helios Clinics Berlin Buch and the Max Delbrück Center for Molecular Medicine, MDC, Berlin-Buch) have shown that an autoantibody that blocks ganglionic receptors of the autonomous (vegetative) nervous system causes the grave and rare disease.  The autonomic nervous system regulates vital processes such as heartbeat, blood pressure, blood glucose level, metabolism, lung and bladder function, and digestion. On four consecutive days, they replaced the blood plasma of the patient with donor plasma and thus washed the antibodies out of the blood. At the same time, he received medications (prednisolone and azathioprine) to suppress antibody formation. As a result, the patient’s health condition and quality of life improved dramatically and he was able to resume his work. One year after the treatment, his condition remains stable. “For the first time, there is hope for an effective treatment for these patients”, Professor Jordan explained. The paper has now been published in the New England Journal of Medicine (NEJM)* (Vol. 353, Nr. 15, pp. 1585-1590, October 13, 2005).

MDC Researchers Identify Crucial Helper in Cellular Trash Disposal

Researchers at the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch have identified a crucial helper in cellular trash disposal. It delivers defective proteins, which have been tagged for disposal, to the transporter that will bring them to the cell’s shredder, the proteasomes. When this helper, called Ubx2 for short, is missing, the cellular disposal system is dysfunctional and many defective proteins will not be destroyed. As a consequence, diseases like Alzheimer’s, Parkinson’s, or mucoviscidosis can develop. The paper of Oliver Neuber and Dr. Thomas Sommer has now appeared in Nature Cell Biology (October 2005, Vol. 7, Nr. 10, pp. 993-998)*

Renowned U.S. Award for Dr. Rainer Glass and Dr. Michael Synowitz

For their discovery that endogenous neural precursor cells are apparently able to destroy glioblastomas, the brain researcher Dr. Rainer Glass (Max-Delbrück Center for Molecular Medicine, MDC, Berlin-Buch) and the neurosurgeon Dr. Michael Synowitz (Helios Clinics Berlin-Buch) have been awarded the Young Investigator Award by the Section on Tumors of the American Brain Tumor Association. Dr. Synowitz accepted the prize of $2,000 on behalf of both researchers at the 55th Annual Meeting of the Congress of Neurological Surgeons in Boston, Massachusetts, USA. Their paper was published in the Journal of Neuroscience (March 2005, Vol. 25, Issue 10, pp. 2637 – 2646, www.jneurosci.org/cgi/content/full/25/10/2637)*.

It’´s the packaging

MDC researchers shed new light on the development of leukemias

Scientists at the Max Delbrueck Center for Molecular Medicine (MDC) Berlin-Buch shed new light on the mechanism that turns healthy white blood cells into cancer cells. They detected a novel function of a gene regulator which steers blood cell development and, when mutated, blocks the transcription of genetic information which can result in leukemia. Playing an important role in this process, the myeloblastose protein (c-Myb), not only regulates proliferation and differentiation of blood cells by binding to the DNA, but, as has now been discovered, also directs DNA packaging into a specific protein structure known as chromatin. The findings of Dr. Xianming Mo, Dr. Elisabeth Kowenz-Leutz, Dr. Yves Laumonnier, Frau Hong Xu, and Prof. Achim Leutz have now been published in the journal Genes and Development online (doi: 10.1101/gad.355405).

To Build a Tongue

MDC Scientists gain new insights into Muscle Development in Embryos

What do the tongue, arm, and leg muscles have in common? They all evolve from wandering cells and two different genes steer their development. Elena Vasyutina and Prof. Carmen Birchmeier have published these new findings in mice and chicken embryos, in the journal Genes and Development* (www.genesdev.org/cgi/doi/10.1101/gad.346205). Muscular precursor cells derive from the somite, a segmented structure which exists in vertebrates during embryogenesis. These precursor cells can unchain themselves from their neighbouring cells at a specific point in time and wander to a specific point in the connective tissue, where the muscle of the tongue and the muscles of the arms and legs normally develop. Two different genes in the muscle precursor cells control this process. One gene expresses the CXCR4 receptor, a molecule which recognizes a messenger molecule (chemokine), the second gene expresses what scientists call tyrosine kinase receptor c-Met. Both genes act as chaperones of the wandering muscle precursor cells and ensure that such cells reach their destination, the result of which is normal muscle formation. Wandering processes during embryogenesis often resemble processes during cancer development. Indeed, both receptors, CXCR4 and met, play a role in the development of metastasis in breast and bowl cancer, two diseases that likewise exist of wandering cells.

Unique Map Created of Human Protein Interactions

Who works together with whom? This is the question scientists at the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch have investigated with regard to human proteins. The answer can be found within a map – the first one in international research – showing 3,186 interactions between 1,705 human proteins. Among them: 531 previously unknown interactions involving 195 disease proteins, highly relevant for medical research. “We have laid the foundation for a comprehensive connection scheme of the human body. The map helps us understand the functions of proteins and the complex processes in our cells,” explains Professor Erich Wanker, who directed the study. The work of Professor Wanker and Dr. Ulrich Stelzl, to which scientists from the Max Planck Institute for Molecular Genetics (Berlin) and the German Resource Center for Genome Research GmbH (Heidelberg) contributed, has now been published in the online edition of Cell* (DOI: 10.1016/S0092867405008664). The researchers were able to conduct the project, which is the first extensive human protein network to be published, with the support of the National Genome Research Network (NGFN) – a large scale biomedical program initiated by the German Federal Ministry for Education and Research (BMBF). The NGFN enables scientists to systematically investigate human genes and proteins and their role in health and disease.

Molecular Uptake for Sex Hormones

How do sex hormones such as androgens and estrogens reach their final destination in the body? Scientists in Germany and Denmark have unravelled a new mechanism of how sex hormones enter those cells that are in need of them. They have been able to demonstrate that a receptor called megalin (Greek: mega = “big”) on the surface of these cells is able to recognize the transport particle that cargoes steroid hormones in the bloodstream, steering this package loaded with hormones into the cell. Thus, Megalin actually functions as a reception for delivery of sex hormones. Up until now, scientists assumed that steroid hormones simply flood all cells, regardless of whether they are needed or not. “According to our findings, this free hormone hypothesis does not hold true for all cases, at least not for androgens and estrogens. Some tissues which require large amounts of sex steroids have developed a specific mechanism for the active uptake of these important regulators”, explained Prof. Thomas Willnow from the Max Delbrueck Center for Molecular Medicine (MDC) Berlin-Buch. The studies by Dr. Annette Hammes (MDC) in the group of Prof. Willnow and their colleagues at the University of Aarhus (Denmark) has now been published in the scientific journal Cell*(Vol. 122, DOI 10.1016/j.cell.2005.06.032).

Molecule protects against developing Alzheimer’s Disease

A molecule expressed by nerve cells may protect humans from developing Alzheimer’s Disease (AD). In particular, it may reduce the risk of the formation of senile plaques in the brains of patients with AD, as researchers from the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch (Germany) and their collaborators in Denmark, Australia, and the USA have been able to demonstrate. The findings by Dr. Olav M. Andersen, Professor Thomas Willnow (both from the MDC) and Dr. Anders Nykjær (University of Aarhus, Denmark) have been published online in PNAS* (doi:10.1073).

Tumor cells can weaken Immune Response

Latest Findings by Researchers from the Max Delbrück Center and the Charité

Tumor cells can grow without control by weakening specific cells of the immune system, the T-cells, which normally detect and destroy tumor cells. The findings of Dr. Gerald Willimsky and Prof. Thomas Blankenstein (Max Delbrück Center for Molecular Medicine, MDC, Berlin-Buch and Charité) were generated in transgenic mice over a period of seven years and have now been published in the scientific journal Nature* (doi:10.1038/nature03954). Until now, the notion was that tumor cells escape recognition and subsequent destruction by T-cells by hiding.

Double Pack - Cancer Researchers in Berlin Confirm Existence of a Second Protection System for Cells – It Blocks Lymphoma Development

Cells under stress apparently possess two different safety systems that prevent them from turning into cancer cells. Apoptosis is one such system, which enables damaged cells to literally commit suicide in order to protect the organism as a whole. The second protection program stops the cell cycle, and – although the cells stay alive – they are prevented from further dividing a behavior that would lead to malignant growth. Evidence suggesting the existence of this second system was found a few years ago in the culture dish. Now, using animal models, cancer researchers from the Charité University Medicine Berlin and the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch in Germany have been able to confirm this second program termed senescene (Latin: senex = “old age”) and they could show that this program is capable of blocking lymphoma development. The work of Melanie Braig under the guidance of Charité- and MDC-based principal investigator Prof. Clemens A. Schmitt has now been published online in Nature* (doi:10.1038/nature03841).

Cancer Researcher Dr. Ulrike Ziebold receives Monika Kutzner Prize

For her research about the development of cancer and metastases biologist and cancer researcher Dr. Ulrike Ziebold from the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch has been awarded the Monika-Kutzner-Prize of the Berlin-Brandenburg Academy of Sciences. Dr. Ziebold received the prize worth 10 000 Euros on Friday, May 27, 2005 in Berlin. In 1999 another cancer researcher from the MDC, Dr. Jürgen Behrens (now Professor at the University of Erlangen), was given this prize. Both scientists have been working in the research group of the cell biologist and cancer researcher Prof. Walter Birchmeier.

The American Society of Hypertension honours Prof. Friedrich C. Luft for Hypertension Research

The American Society of Hypertension (ASH) has honored Prof. Friedrich Luft from Berlin, Germany with the Richard Bright Award for clarifying mechanisms of how hypertension damages the kidneys and leads to the development of severe renal disease. The physician and scientist received the prize in a ceremony on May 17, 2005 in San Francisco, CA, USA. Luft’s career has been dedicated to translating basic research into the treatment of cardiovascular disease in humans, and particularly, to training physician-scientists in cardiovascular research, the ASH pointed out. The prize, ($10,000) is named after the British physician Richard Bright (1789 – 1858). Bright first recognized renal disease as a specific entity. He could not measure blood pressure, but recognized that renal and heart disease went hand-in-hand. Bright is honored as the father of nephrology. Friedrich Luft works in the Franz Volhard Clinic for Cardiovascular Diseases, Helios Klinikum Berlin-Buch. The Franz Volhard Clinic is a part of the Medical Faculty of the Charité, University Medicine, Berlin. Friedrich Luft is responsible for a research group at the affiliated Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch.

Blocking a Gene Regulator Prevents Heart Damage in Hypertension Collaborative Research by Clinicians and Scientists

Hypertension is one of the main causes for cardiac hypertrophy. According to the American Framingham study, about one per cent of the population suffers from this disease which impairs the heart severely over time and is one of the main causes for breathing difficulties and disability in the elderly. Now, researchers and clinicians from the Franz Volhard Klinik (FVK) for Cardiovascular Diseases (Helios Klinikum Berlin-Buch/Charité Berlin-Buch Campus University Medicine Berlin) and the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch in Germany were able to show that blocking the gene regulator, nuclear factor (NF) kappaB, is sufficient to protect the heart from being damaged in mice with hypertension. The findings of Christian Freund and Dr. Martin Bergmann (FVK) as well as Dr. Ruth Schmidt-Ullrich and Prof. Claus Scheidereit (MDC) were published in the latest issue of the American journal Circulation on May 10, 2005 (www.circulationaha.org). The MDC, a national research institution of the Helmholtz-Association, financed this research as part of its special programme which fosters cooperation between basic researchers and clinicians. Next, researchers and clinicians plan to conduct clinical trials to find out if NF-kappaB inhibitors, currently being tested in inflammatory lung and bowel diseases, will also prove effective in cardiac hypertrophy.

A Protein Promotes Synapse Development after Birth

While humans are born with a complete set of nerve cells, the development of the connections between neurons via the building of synapses, occurs primarily after birth. This process is modulated by sensory experience. Despite recent advances in our understanding of how synapses work, the molecular mechanism whereby synapses develop remains largely unknown.

“"Biopolitics and Regenerative Medicine - Pros and Cons”"

International Conference with German Federal Research Secretary Edelgard Bulmahn and Scientists from EU Countries

During a two-day meeting (April 7-8, 2005) in Berlin, Germany entitled “Biopolitics and Regenerative Medicine - Pros and Cons”, politicians and scientists from various member countries of the European Union convened to discuss state of the art of human embryonic stem cell research and its regulation in Europe. Research on human embryonic stem cells has been heavily debated, especially in Germany. This research also includes the new field of “regenerative medicine” wherin researchers aim to use their knowledge of the body’s natural regeneration processes to improve the treatment of severe diseases. Organizers of the international conference were the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, a member of the Helmholtz Association of National Research Laboratories, and the Friedrich Ebert Foundation.

New Insights into the Development of Nerve Cells of the Spinal Cord

The most important relay center for transmitting sensory perceptions from the body into the brain is the spinal cord in the vertebral column. One zone plays a significant role in this ─ the dorsal horn in which the nerve cells are found that receive, process, and transmit sensory perceptions. For instance, a touch on the skin can be experienced consciously because neurons of the dorsal horn transmit this sensory perception. The complex closed loops in which these neurons are active are already established during embryonic development. Two different classes of neurons in the dorsal horn of the spinal cord, A and B, can be differentiated during embryonic development. Class A neurons are responsible, among other things, for the transmission of information about the position of the body and the extremities; class B neurons are responsible for sensations of touch, temperature, and pain of the skin. However, to date very little has been known about the factors that steer the development of these different neuron classes. Now, developmental biologists from the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, in collaboration with researchers from the European Molecular Biological Laboratory (EMBL) in Heidelberg, have gained new insights into the development of neurons in the dorsal horn of the spinal cord. They were able to show in animal experiments that the transcription factor Olig3 directs the development of class A neurons. The antagonist of Olig3 is the transcription factor Lbx1, which the researchers discovered several years previously and which is important for the development of class B neurons. The research paper of Dr. Thomas Müller, from the laboratory of Prof. Carmen Birchmeier, in collaboration with Dr. Mathias Treier (EMBL) has now been published online in the renowned journal Genes and Development* (Vol. 19, Issue 6, pp.733-743, March 15, 2005).

German Cancer Prize 2005 goes to Prof. Claus Scheidereit (MDC) and Prof. Bernd Dörken (Charité) – Molecular Basis of Hodgkin’s Lymphoma Decoded

Prof. Claus Scheidereit from the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch and Prof. Bernd Dörken (Charité – University Hospital Berlin, Campus Berlin-Buch, Campus Virchow and the MDC) have been awarded the German Cancer Prize 2005 for deciphering the molecular mechanism of Hodgkin’s lymphoma, a common cancer of the lymphatic system. The award was presented to them at the Congress of the German Cancer Society on March 14, 2005 in Würzburg. The researcher and the clinician have “contributed significantly to the understanding of the molecular causes of Hodgkin’s lymphoma with their excellent research work, which was in part done in close cooperation, and have thus enabled the development of new therapeutic approaches”, as was stated in the announcement of the award. The German Cancer Prize goes to researchers from the MDC and clinicians from the Charité for the second time. In 1999 Prof. Walter Birchmeier (MDC) and Prof. Peter M. Schlag (Charité – Campus Berlin-Buch and MDC) received this award. Since its founding in 1992, the MDC, an institution of the Helmholtz Association, has worked closely with clinicians of the Charité. One main scientific focus at the MDC is cancer research.

Prevention of Leukemia Relapses:

165,000 Euros for research project to detect minimal residual disease (MRD)

Therapy for leukemia aims at destroying all malignant cells in order to prevent the disease from recurring. However, despite all therapy efforts, some cancer cells are able to survive and can therefore result in recurrence of the disease termed minimal residual disease (MRD) by physicians. When such persistent leukemia cells are detected, treatment can often be redirected and intensified in time to cure the patient. In order to assess whether the treatment has been successful or whether the therapy must be intensified, physicians use flow cytometry and molecular biological methods to analyze blood cells. In flow cytometry, the cells flow in single file through a thin cell-sorting column which utilizes a laser beam to sort cells by size, and interior structure, as well as four additional characteristics marked by antibodies.

International Conference

“Biopolitics and Regenerative Medicine - Pros and Cons”

Thursday April 7, - Friday, April 8 2005

Detecting the Genetic Causes of the Metabolic Syndrome

About 20 million people in Germany suffer from what doctors call the metabolic syndrome. In the U.S., an estimated 47 million people are affected. The patients have a number of disorders that have a negative influence on each other including obesity, hypertension, insulin resistance, and dyslipidemia. These risk factors increase the chance for suffering from type II diabetes, heart attack, and stroke. In addition to an unhealthy diet too little exercise, genetic risk factors, too, are considered triggers for the very complex clinical picture of the metabolic syndrome.

New Insights into the Rejection of Kidney Transplants

Researchers at the Charité (Mitte), the Franz Volhard Clinic, Helios Klinikum-Berlin, and the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch have discovered that kidney transplant patients with humoral rejection commonly make antibodies directed against the angiotensin (AT1) receptor. Humoral rejection accounts for about 10 per cent of all graft losses. The autoantibodies activate the receptor and may cause severe hypertension and organ damage. The report appeared in the New England Journal of Medicine (online; Vol. 352 No. 6, pp 558-69, 2005)* accompanied by an editorial. The work follows earlier studies from the Franz Volhard Clinic and the MDC suggesting that similar antibodies are involved in preeclampsia, a life-threatening hypertension crisis during pregnancy. The investigators were able to develop a relatively specific therapy, such as Angiotensin 1 receptor blockers in combination with the removal of the antibodies for their kidney transplant patients. They also transferred the condition to an animal model. However, much work remains to be done. Eighteen investigators participated in the work. The study is an example of close cooperation between clinicians and MDC investigators. The first author is Duska Dragun (now Charité Mitte, erstwhile Franz Volhard Clinic) and the last author is Gerd Wallukat (MDC).

Cholesterol and Brain Development

Holoprosencephaly (HPE) is the most common developmental forebrain anomaly in humans and is caused by the failure of the embryonic forebrain (the prosencephalon) to sufficiently divide into the two lobes of the cerebral hemispheres. The result is a single-lobed brain structure and severe skull and facial defects. About 1 in 250 pregnancies miscarries as a result of severe HPE. In less severe cases, about one in 16,000 babies is born with minor brain developmental and facial deformities that may affect the eyes, nose, and upper lip, such as median cleft lip and palate. HPE has several causes including prenatal viral infections or alcohol abuse during pregnancy. In many cases, a genetic defect in the metabolism of cholesterol results in HPE. Thus, some individuals with HPE are unable to produce cholesterol.