Press releases – March 2018

FRANKFURT. Transgenic organisms, e.g. animals or plants into which a foreign gene has been introduced, are powerful tools that can be used to analyse biological processes or to mimic human diseases. However, many of the individuals produced during the course of a study carry the transgene on only chromosome of a complementary pair of chromosomes. This limits their experimental usefulness. Researchers at Goethe University Frankfurt have now developed a concept called “AGameOfClones”, which allows to distinguish easily whether transgenic organisms carry the foreign gene on one or on both chromosomes. This facilitates breeding and also benefits animal welfare.

To understand biological processes, researchers often use model organisms, such as mice, zebrafish and various species of insects, with the underlying idea that their discoveries can also be transferred to other species. A common technique is genetic manipulation, a process where a foreign gene (also known as a transgene) is inserted into one of the chromosomes of the target organism. Many model organisms have pairs of chromosomes - one inherited from each parent. In these pairs, the genes are arranged in the same order but are not necessarily identical.

Newly created transgenic organisms, however, carry the transgene on only one of the chromosomes. This can pose a problem for researchers because many experiments require individuals that carry the foreign gene on both. Unfortunately, only costly and error-prone methods can distinguish between these individuals. To overcome these drawbacks, Frederic Strobl from the research group led by Professor Ernst Stelzer at the Buchmann Institute for Molecular Life Sciences of Goethe University Frankfurt developed a genetic concept called “AGameOfClones” and applied it to the red flour beetle Tribolium castaneum.

In this approach, the foreign gene also contains sequences for two protein markers with different fluorescent colours. After several generations of breeding, two variants of the transgene emerge that each retain only one marker. This means that in the following generation, the descendants with both markers must be the progeny that carry the transgene on both chromosomes.

The “AGameOfClones” concept has several major advantages: Individuals with different markers can be easily identified and the procedure is cost-efficient, reliable and can be applied to almost all model organisms. This benefits especially animal welfare, since individuals that are unsuitable for use in experiments can be excluded as soon as the markers become detectable.

Publication (Open Access): Frederic Strobl, Anita Anderl, Ernst H.K. Stelzer: A universal vector concept for a direct genotyping of transgenic organisms and a systematic creation of homozygous lines.

DOI: https://doi.org/10.7554/eLife.31677

Image material can be downloaded under: www.uni-frankfurt.de/70857515

Caption: The principle of the “AGameOfClones” concept shown in the red flour beetle. The left panel shows two adult individuals that carry the transgene on only one of their chromosome pairs. Both beetles have inherited variants of the transgene with different markers that have led to either green or blue fluorescent compound eyes. The right panel shows a descendant of the two adult individuals on the left which carries the transgene in both chromosomes – but with different markers. Thus, its compound eyes are fluorescent turquoise. Picture: Strobl/Stelzer, Goethe University Frankfurt.

Further information: Professor Ernst Stelzer and Frederic Strobl, Physical Biology Working Group, Faculty of Biological Sciences, and Buchmann Institute for Molecular Life Sciences, Riedberg Campus, Tel.: +49-(0)-798-42547, ernst.stelzer@physikalischebiologie.de, +49-(0)-69-798-42551, frederic.strobl@physikalischebiologie.de

FRANKFURT. Professor Tim J. Schulz from the German Institute of Human Nutrition (DIfE) in Potsdam-Rehbruecke will today receive the €60,000 Paul Ehrlich and Ludwig Darmstaedter Prize for Young Researchers for 2018 in the Paulskirche in Frankfurt. The biochemist is receiving the award for his basic research on the development of white and brown fat and on their effects on health and nutritional physiology. Schulz showed how stem cells produce white and brown fat and how white fat harms bone health in old age. Furthermore, he demonstrated that a class of drugs often used in the treatment of diabetes also reduces the harmful effects of white fat cells on bones. These medicines may improve bone health among elderly people. "The work of Tim J. Schulz addresses the highly topical issue of adiposity," wrote the Scientific Council in substantiating its decision. "Schulz not only takes into consideration the negative effects of white adipose tissue but also examines whether adiposity and the diseases it fosters can be prevented by the targeted production of more brown adipose tissue and the role of nutrition during this scenario." The Paul Ehrlich and Ludwig Darmstaedter Prize for Young Researchers will be presented by Professor Thomas Boehm, Managing Director at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg and Chairman of the Scientific Council.

White and brown fat are not the same. Brown fat regulates body temperature and protects it from cooling. White adipose tissue stores unused energy from food and is hardly utilized at all in contemporary high-calorie diets. Too much white fat is burdensome for the body and may drive disease development. Moreover, as people age they store more white fat in the organs and bones and not only in subcutaneous tissue. As a result, this fatty degeneration may contribute to the development of many diseases that occur more frequently in old age such as diabetes, fatty liver or poor bone healing.

Brown and white fat cells, like all the body's other cells, descend from stem cells. Brown fat, though, derives from specialized brown fat stem cells dedicated to that purpose.  It was once believed that only neonates and young children had this invaluable resource, but that is not the case.  Adults have brown fat, especially in the upper body, in particular along the shoulder blades, in deep regions of the neck, the large blood vessels, and along the spinal column. Schulz studies the development of brown fat cells from stem cells and was part of a team that showed that their formation can be controlled by a special signaling molecule. This fits in with a well-known approach of combating adiposity by increasing the amount of brown fat. This approach aims to convert the unnecessary calories to heat in the brown fat deposits rather than storing them in the white fat deposits. Brown fat could thus be a weight loss treatment. Schulz also showed that the brown fat stem cells lose their capability to create more brown fat during aging. He identified the relevant aspects and target molecules of this aging process and hopes that some of them can be used therapeutically.

His findings on the role of white fat in bone also have important implications. Schulz demonstrated that with advancing age and a fat-enriched diet bone stem cells produce white fat rather than healthy bone tissue. This fat is harmful for bone not only because of its presence but also because it produces other molecules that make it even more difficult for the stem cells to generate new bone tissue which might explain why bones heal poorly in old age. Added to this is the fact that white fat also damages the hematopoietic stem cells of bone marrow which could results in reduced blood cell formation in bone with excess fatty infiltration. Schulz further demonstrated that a drug class widely used to treat diabetes inhibits an enzyme that is produced by white fat cells in the bones. This class of agents is known as gliptins. It remains to be determined in clinical trials whether they can improve bone health in the elderly in addition to the known beneficial effect in diabetes. Schulz is currently involved in studying how the composition of the diet affects bone stem cells and whether certain forms of nutrition can promote bone healing through the activation of the stem cells.

Short Biography of Professor Tim Julius Schulz
Tim J. Schulz (39) was born in Northeim, Germany, and studied biochemistry at Potsdam University. He received his PhD in 2007 under Professor Michael Ristow at the Friedrich Schiller University in Jena. He was awarded the Dissertation Prize of the Biological-Pharmaceutical Faculty for his thesis. On completing his PhD, Schulz spent five years at the Joslin Diabetes Center in Boston, which is part of the Harvard Medical School. He worked there with Professor Yu-Hua Tseng in the Department of Integrative Physiology and Metabolism. From 2012 to 2016 Schulz headed the Emmy Noether Young Investigator Group "Adipocyte Development", sponsored by the German Research Foundation, at the German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE). In 2016 Schulz was appointed head of the department of "Adipocyte Development and Nutrition" at the DIfE, a partner of the German Center for Diabetes Research (DZD). At the same time he was appointed W2 professor at Potsdam University. In 2013 he was awarded a €1.5 million starting grant of the European Research Council (ERC).

Paul Ehrlich and Ludwig Darmstaedter Prize for Young Researchers
The Paul Ehrlich and Ludwig Darmstaedter Prize for Young Researchers, awarded for the first time in 2006, is conferred once a year by the Paul Ehrlich Foundation on a young investigator working in Germany for his or her outstanding achievements in the field of biomedical research. The prize money must be used for research purposes. University faculty members and leading scientists at German research institutions are eligible for nomination. The selection of the prizewinner is made by the Scientific Council on a proposal by the eight-person selection committee.

The Paul Ehrlich Foundation
The Paul Ehrlich Foundation is a legally dependent foundation which is managed in a fiduciary capacity by the Association of Friends and Sponsors of the Goethe University, Frankfurt. The Honorary Chairman of the Foundation, which was established by Hedwig Ehrlich in 1929, is Professor Dr. Peter Strohschneider, president of the German Research Foundation, who also appoints the elected members of the Scientific Council and the Board of Trustees. The Chairman of the Scientific Council is Professor Thomas Boehm, Managing Director at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, the Chair of the Board of Trustees is Professor Dr. Jochen Maas, Head of Research and Development and Member of the Management Board, Sanofi-Aventis Deutschland GmbH. Professor Wilhelm Bender, in his function as Chair of the Association of Friends and Sponsors of the Goethe University, is Member of the Scientific Council. The President of the Goethe University is at the same time a member of the Board of Trustees.

Further information You can obtain selected publications, the list of publications and a photograph of the prizewinner from Dr. Hildegard Kaulen, phone: +49 (0) 6122/52718, e-mail: h.k@kaulen.wi.shuttle.de and at www.paul-ehrlich-stiftung.de.

FRANKFURT. Anthony Cerami from the United States and David Wallach from Israel will today receive the Paul Ehrlich and Ludwig Darmstaedter Prize for 2018 in the Paulskirche, Frankfurt. The award is being given in recognition of their basic research into one of the immune system's most important cytokines, TNF. "Basic research in medicine sets itself the goal of creating new and better treatments. It is based on translation. The research conducted by the two prize-winners is a unique example of the successful translation of fundamental immunological findings into a clinically relevant therapy," wrote the Scientific Council in substantiating its decision. Rheumatoid arthritis, psoriasis, Crohn's disease, and other chronic-inflammatory diseases are now treated everywhere with antibodies or proteins that neutralize this cytokine. The prize will be presented by Professor Thomas Boehm, Managing Director at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg and Chairman of the Scientific Council.

Cerami and Wallach are among the very earliest TNF researchers. Many of the important discoveries for which they are receiving the prize were made decades ago. The two scientists came across TNF from entirely different angles. Cerami was searching for a molecule that caused pathological weight loss, and he named it cachectin. Wallach was studying a molecule that was able to selectively induce programmed cell death. He called the molecule cytotoxin. It only emerged later that both these molecules were one and the same – TNF.  At the time, TNF was being touted as a treatment for cancer, and oncologists were pinning great hopes on it – erroneously, as Anthony Cerami showed. He made it absolutely clear in 1985 that TNF is an immune system signaling molecule and that its proinflammatory effect would preclude its use as an anti-tumor agent in patients. As early as 1981, however, he had already anticipated anti-TNF therapy for inflammatory diseases in a United States patent application. Although he had not precisely identified cachectin as TNF at that time, this approach was confirmed in 1985 when he determined that these two molecules were identical, and proved that TNF/cachectin neutralization using antibodies prevented septic shock in an animal model. This work provided a cornerstone for the development of anti-TNF therapy for treating a wide spectrum of inflammatory diseases, including rheumatoid arthritis and Crohn’s disease, among many others.

TNF basically works like a fire alarm. The molecule appears in the blood within minutes of an injury, an infection or a stress reaction and sets an inflammation in motion as a response to the emerging danger. Sometimes, however, the inflammation spins out of control, does not peter out or – as in chronic-inflammatory diseases – turns against the person's own body. This explains why TNF is a suitable target molecule for the treatment of chronic-inflammatory conditions, just as Cerami had seen early on.

Moreover, Cerami identified a variant of erythropoietin (EPO), a protein necessary for the production of red blood cells, as a natural antagonist of TNF. After all, every inflammatory reaction not only requires a trigger to set it in motion but also has to be ended again after some time so as to minimize damage to tissue. Cerami demonstrated that EPO is produced in the inflamed tissue and binds there to a novel innate EPO receptor that is expressed in response to inflammation. EPO ensures through this binding that cell death is limited and that cell regeneration takes place. A protein fragment that imitates this effect but does not possess the effect of EPO on red blood cell production – undesirable for inhibiting inflammation – and its adverse effects is currently undergoing clinical investigation. In addition to his research on TNF and EPO, Anthony Cerami also developed a test to determine HbA1c levels, which allows conclusions to be made on the average plasma glucose concentration in the preceding weeks. The measurement of HbA1c has long become a routine test in diabetes.

David Wallach discovered the two TNF receptors and showed early on that TNF has two diametrically opposite effects. For one thing, the cytokine can force cells to commit programmed cell death; for another, it can ensure resistance to cell death. Wallach worked from the start on elucidating both these signaling pathways owing to his interest in these different effects. It was not apparent at that time that this approach would open up a huge field of research. Wallach discovered the two TNF receptors while searching for a natural antagonist to TNF. Wallach's simple but powerful assumption was that, if cells induce something as radical as their own suicide, there must be antagonists that can prevent this death. The prizewinner was able to demonstrate that the receptor domains located on the outside of the cell can be cleaved and capture TNF before it binds to the membrane-bound receptors with their downstream signaling pathways. This principle is now also exploited clinically. In this therapy, a large quantity of the soluble receptor molecules neutralize the excess TNF produced in the event of chronic inflammation before it causes any damage.  Although soluble forms of a few receptors have been known before, Wallach was the first to show clearly that such molecules are functional at physiological levels. This resulted in explosion of interest in the occurrence and function of soluble forms of many other receptors.

Wallach's name is also closely associated with the decoding of the two signaling pathways triggered by TNF that lead either to the cell's death or to its survival. Which of the two signaling pathways is set in motion depends on occupancy of the two receptors and the resulting activity. Although a number of other scientists contributed to the work Wallach anteceded all in discovering and cloning major proteins – e.g. FADD and Caspase-8 – from the cell death pathway triggered by TNF. He was thus the first to show that an intracellular protease (Caspase-8) can serve as a signaling protein, directly activated by a cell-surface receptor. Today, this pathway is called extrinsic cell death pathway distinguishing it from a second cell death pathway initiated from inside the cell, called the intrinsic cell death pathway. Wallach’s discovery that a death mediating protein like TNF can also have vital function(s), has since then been shown to be the rule for almost any protein that participates in mediating programmed death. Scientists now use to say that each of the proteins that participate in death induction has a ‘night job’ (related to death) and a ‘day job’ (a vital function). Wallach's research is recognized as an important conceptual contribution to the entire field of signaling.

Anthony Cerami (77) had a long academic career and is founder of Araim Pharmaceuticals and Chairman of the Scientific Advisory Board in Tarrytown, New York. David Wallach (72) has worked for 40 years at the Weizmann Institute of Science in Rehovot.

Short biography of Professor Anthony Cerami
Antony Cerami (77) studied biochemistry at Rutgers University and received his PhD from Rockefeller University.  Cerami was Professor at Rockefeller University for 20 years and also Dean of Graduate and Post Graduate Studies. He later established the Feinstein Institute for Medical Research. Cerami is the recipient of three honorary doctorates and is involved in a number of companies. He has more than 150 US patents and their international counterparts. He sat on the editorial board of various scientific publications during his career. Cerami has received numerous awards including the Luft Award in Diabetes and the Banting Medal for Scientific Achievement. He is a member of the National Academy of Sciences, the American Academy of Arts and Sciences, and the Institute of Medicine of the National Academy of Sciences. He is also an Honorary Member of American Society for Clinical Investigation and Fellow of the American Academy of Microbiology.

Short biography of Professor David Wallach
David Wallach (72) studied biology at the Hebrew University in Jerusalem, where he also received his PhD. He was then a postdoc at the NIH in Bethesda. Wallach joined the Weizmann Institute of Science in Rehovot in 1977 where he has held various positions, including that of full professor since 1995. He has received a number of prizes for his scientific work, including the Outstanding Achievement Award from the International Cell Death Society, the Merck-Serono Prize, the EMET Prize in Life Sciences/Biotechnology of the A.M.N. Foundation, the Teva Founders Prize, and the Rappaport Prize in Biomedical Sciences. Wallach was president of the International Cytokine Society and one of the founders and co-organizers of the series of international TNF Conferences held every two years. He sits on various editorial boards and established an international organization devoted to the cultural heritage of the millions of Jews that lived in Galicia and Bukovina. He is currently the Chairman of this organization.

The Paul Ehrlich and Ludwig Darmstaedter Prize
The Paul Ehrlich and Ludwig Darmstaedter Prize is traditionally awarded on Paul Ehrlich's birthday, March 14, in the Paulskirche, Frankfurt. It honors scientists who have made significant contributions in Paul Ehrlich's field of research, in particular immunology, cancer research, microbiology, and chemotherapy. The Prize, which has been awarded since 1952, is financed by the German Federal Ministry of Health, the German association of research-based pharmaceutical company vfa e.V. and specially earmarked donations from the following companies, foundations and organizations: Christa Verhein Stiftung, Else Kröner-Fresenius-Stiftung, Sanofi-Aventis Deutschland GmbH, C.H. Boehringer Sohn AG & Co. KG, Biotest AG, Hans und Wolfgang Schleussner-Stiftung, Fresenius SE & Co. KGaA, F. Hoffmann-LaRoche Ltd., Grünenthal Group, Janssen-Cilag GmbH, Merck Financial Services GmbH, Bayer AG, Holtzbrinck Publishing Group, Abbie Deutschland GmbH & Co. KG, Goethe Universität und die Rittershaus Rechtsanwälte Partnergesellschaft mbH. The prizewinner is selected by the Scientific Council of the Paul Ehrlich Foundation.

The Paul Ehrlich Foundation
The Paul Ehrlich Foundation is a legally dependent foundation which is managed in a fiduciary capacity by the Association of Friends and Sponsors of the Goethe University, Frankfurt. The Honorary Chairman of the Foundation, which was established by Hedwig Ehrlich in 1929, is Professor Dr. Peter Strohschneider, president of the German Research Foundation, who also appoints the elected members of the Scientific Council and the Board of Trustees. The Chairman of the Scientific Council is Professor Thomas Boehm, Managing Director at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, the Chair of the Board of Trustees is Professor Dr. Jochen Maas, Head of Research and Development and Member of the Management Board, Sanofi-Aventis Deutschland GmbH. Professor Wilhelm Bender, in his function as Chair of the Association of Friends and Sponsors of the Goethe University, is Member of the Scientific Council. The President of the Goethe University is at the same time a member of the Board of Trustees.

Further information You can obtain selected publications, the list of publications and a photograph of the laureates from Dr. Hildegard Kaulen, phone: +49 (0)6122/52718, email: h.k@kaulen.wi.shuttle.de and at www.paul-ehrlich-stiftung.de

From 1964 to 1968, the General Students’ Committee (AStA) of the Frankfurt Goethe University ran a gallery in the student building on the Bockenheim campus. Called the “Studiogalerie”, this establishment introduced the international avant-garde in art shows and events. The programme mirrored the latest trends in progressive, experimental art. Featuring paintings and objects of Light Art, Kinetic Art, Concrete Art, New Realism and Op Art, works of Hard-Edge and Colour Painting, but also Fluxus concerts and happenings, the exhibitions were conceived of as the students’ contribution to the democratization of art and society.

Founded in 1964 with a spirit of optimism – the belief in art as a means of changing the world we live in –, the Studiogalerie discontinued its activities in 1968 within the context of the increasing radicalization of the student body.

“Space for Art” retraces the history of the Studiogalerie. A 1967 show entitled “Serielle Formationen” is considered one of the highlights of that student initiative. It was the first ever to unite art by exponents of American Minimal Art, for example Donald Judd, Frank Stella and Sol LeWitt, with works by artists of the European avant-garde such as Jan Henderikse, Adolf Luther, Peter Roehr and Jan Schoonhoven. Cooperation with the Daimler Art Collection has now made it possible to present that legendary show in its essence.

The exhibition on the Studiogalerie is the Museum Giersch’s art-historical contribution to “50 Jahre 68”, a Goethe University project commemorating the epoch-making year 1968 with numerous events.

FRANKFURT. Cases of multi-resistant bacteria in hospitals have increased dramatically in recent years and the health system faces tremendous problems as a result. Alongside “old acquaintances”, such as Staphylococcus aureus (MRSA) or Klebsiella pneumonia, another pathogen has now arrived on the scene: Acinetobacter baumannii. In order to find new weapons for the fight against this aggressive germ, in 2014 the German Research Foundation established a Research Unit led by Goethe University Frankfurt which has now been extended for a further three years.

Infections with Acinetobacter baumannii are often fatal due to this bacterium’s increasing antibiotic resistance. In some European countries, over 90 percent of isolates no longer respond to antibiotic therapy. Particularly worrying is the fact that the pathogen is continuing its rapid advance throughout the whole world.

In order to obtain results in this situation that can be put to use as quickly as possible in clinical practice, natural scientists and physicians are working closely together in the Research Unit “Adaptation and Persistence of Acinetobacter baumannii”. Several institutes at Goethe University Frankfurt – Molecular Microbiology & Bioenergetics, Medical Microbiology & Infection Control, the Institute of Cell Biology & Neuroscience and the Institute of Biochemistry – are involved in the project together with the Robert Koch Institute and the universities in Cologne and Regensburg.  

“We have achieved something quite unique: We use patient isolates, sequence their genome and analyse their pathogenic properties, which are then characterized with regard to countermeasures,” explain Professor Volker Müller, microbiologist, and Professor Volkhard Kempf, microbiologist and physician, who are the Research Unit’s two spokespersons. It has already been possible to identify first virulence traits by means of this approach.

The researchers know meanwhile what the bacterium feeds on, how it survives stress, how it adheres to animate and inanimate surfaces and how it withstands antibiotics. This knowledge enables them to test new targets for deactivating the bacterium. They discovered, for example, that bacteria are no longer able to trigger infections if you take away their ability to synthesise a certain sugar (trehalose). The research team is now working hard to shed light on this sugar’s biosynthesis process so that inhibitors can be developed.

The evaluators found this work so convincing that the German Research Foundation has not only extended the project but also increased its budget. The work undertaken in future will produce new answers to the question of how this increasingly threatening bacterium can be treated.

A picture can be downloaded from: www.uni-frankfurt.de/70620941

Caption: Petri dish with colonies of the dangerous hospital pathogen Acinetobacter baumannii.

Photo: Goethe University Frankfurt

Further information: Professor Volker Müller, spokesperson of Research Unit 2251, Molecular Microbiology & Bioenergetics, Faculty of Biological Sciences, Riedberg Campus, Tel.: +49(0)69-798-29507; vmueller@bio.uni-frankfurt.de.

Professor Volkhard Kempf, University Hospital Frankfurt, Institute for Medical Microbiology and Infection Control, Faculty of Medicine, Niederrad Campus, Tel.: +49(0)69- 6301-5019, volkhard.kempf@kgu.de, http://www.bio.unifrankfurt.de/51172482