Press releases – March 2017

 

Mar 22 2017
08:23

New technology enables detailed analysis of target proteins

Tracing down linear ubiquitination

FRANKFURT.Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many different forms, either as single molecule or in the form of distinct ubiquitin chains, leading to diverse conformations and varying cellular outcomes. Scientists often refer to it as the secret ubiquitin code, which still needs to be fully deciphered. Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have now developed a novel technology to tackle that.

Recently, scientists discovered that ubiquitin molecules are not only assembled in a non-linear manner, but also build linear chains, in which the head of one ubiquitin is linked to the tail of another ubiquitin molecule. So far, only two highly specific enzymes are known capable of synthesizing and degrading such linear ubiquitin chains, and both are being extensively studied at the Institute of Biochemistry II at the Goethe University Frankfurt. However, target proteins of linear ubiquitination, as well as their specific cellular functions, have largely remained elusive. The novel technology developed by the team around Koraljka Husnjak from the Goethe University Frankfurt now enables the systematic analysis of linear ubiquitination targets.

“The slow progress in this research area was mainly due to the lack of suitable methods for proteomic analysis of proteins modified with linear ubiquitin chains”, explains Koraljka Husnjak whose native country is Croatia. Her team solved the problem by internally modifying the ubiquitin molecule in such a way that it maintains its cellular functions whilst at the same time enabling the enrichment and further analysis of linear ubiquitin targets by mass spectrometry.

With this technology at hand, it is now possible to identify target proteins modified by linear ubiquitin, and to detect the exact position within the protein where the linear chain is attached. Scientists praise this highly sensitive approach as an important breakthrough that will strongly improve our understanding of the functions of linear ubiquitination and its role in diseases.

Dr. Husnjak already provided the proof of this concept and identified several novel proteins modified by linear ubiquitin chains. Amongst them are essential components of one of the major pro-inflammatory pathways within cells. “Linear ubiquitin chains relay signals that play an important role in the regulation of immune responses, in pathogen defence and immunological disorders. Until now we know very little about how small slips in this system contribute to severe diseases, and how we can manipulate it for therapeutic purposes” comments Husnjak the potential of the new technology.

Errors in the ubiquitin system have been linked to numerous diseases including cancer and neurodegenerative disorders such as Parkinson’s disease, but also to the development and progression of infections and inflammatory diseases.

 

Publication:

Katarzyna Kliza, Christoph Taumer, Irene Pinzuti, Mirita Franz-Wachtel, Simone Kunzelmann, Benjamin Stieglitz, Boris Macek & Koraljka Husnjak. Internally tagged ubiquitin: a tool to identify linear polyubiquitin-modified proteins by mass spectrometry. Nature Methods 2017. doi:10.1038/nmeth.4228

 

Link to image

Caption: Schematic model of two linearly linked ubiquitin molecules. The internal tagging site is marked in black.

Image by Koraljka Husnjak using PyMOL software.

 

 

Mar 15 2017
07:54

Paul Ehrlich and Ludwig Darmstaedter Prize for Young Researchers 2017

Volker Busskamp receives prize for application-oriented neurobiological research

The young researcher has been awarded for his contribution to a gene therapy approach to treat retinitis pigmentosa and for the development of artificial neuronal circuits. Retinitis pigmentosa is an inherited eye disease that leads to blindness.

FRANKFURT am MAIN. Dr. Volker Busskamp, Research Group Leader at the DFG Research Center for Regenerative Therapies at the TU Dresden (CRTD), receives today the €60,000 Paul Ehrlich and Ludwig Darmstaedter Prize for Young Researchers for 2017 in Frankfurt's Paulskirche. As a biotechnologist, neuroscientist and stem cell researcher, Busskamp is receiving recognition for his exceptional application-oriented neurobiological research, which is reflected in clinical gene therapy studies on retinitis pigmentosa and a robust and versatile tool for basic research. "Busskamp's work is a good example of translational research, the rapid transfer of basic research findings into clinical research," wrote the Scientific Council in substantiating its decision. The Paul Ehrlich and Ludwig Darmstaedter Prize for Young Researchers will be presented by Professor Harald zur Hausen.

Busskamp has worked on retinitis pigmentosa for almost a decade. The retina has two types of photoreceptors, known as rods and cones. The rods are responsible for sight in twilight and at night, while the cones are needed for seeing in daylight. In retinitis pigmentosa, the rods degenerate as a result of mutations. As the disease progresses, cones also lose their light-sensitive antennae, though they persist for some time in the retina before dying off gradually. Together with Botond Roska from the Friedrich Miescher Institute in Basel, Busskamp developed three gene therapy approaches. Busskamp was involved in developing one of the concepts, while the other two are based on his work. The concepts were developed in blind mice. One of the three concepts is now in the clinical development stage.

Busskamp was involved in an approach in which a foreign light-sensitive gene was implanted into inner retina cells, thereby creating artificial photoreceptors. Perception of light was shifted from the retina's defective photoreceptors to the inner retinal layer, which is normally not involved in light perception. A second gene therapy approach was to treat the defective photoreceptors directly. Busskamp inserted a light-sensitive gene in the non-functioning cones that had not yet degenerated and thereby restored their lost sensitivity to light. Of note, this approach was successfully tested into postmortem human retinae. Based on these concepts, the French start-up company Gensight is developing gene therapy approaches for clinical use. Busskamp also showed that the light-sensitive antennae of photoreceptors remain functional if only two small ribonucleic acids are present. These sequences are also under consideration for gene therapy. 

At the CRTD, Busskamp is working on artificial neuronal circuits that he assembles from different cell types. "These artificial circuits are like small biological computers," the Young Researcher Prizewinner explains. "They can be used as disease models or in basic research." Busskamp obtains neurons by means of differentiation of induced human pluripotent stem cells. Since this process has to be standardized so that the same neuronal cell types are produced and thus identical neuronal circuits can be assembled, Busskamp is investigating the conditions for robust differentiation. He aims to reliably produce as many as possible of the 320 different neuronal cell types. His approach is based on systems biology. "If we know the factors involved in the various differentiation processes, we can engineer certain cell types to obtain a unique toolbox for research," says Busskamp. "Something like a switch panel for directed neuronal differentiation from stem cells. The assembled circuits will contribute in understanding human neuronal processing and transmission in health and disease." 

 

Short biography of Dr. Volker Busskamp

Volker Busskamp was born in Bocholt, Germany, in 1980. He studied biotechnology at the TU Braunschweig. In 2006 Busskamp was accepted for the international "Frontiers in Genetics" program in Geneva, where he did his postgraduate diploma in biology. Busskamp completed his PhD with Prof. Botond Roska at the Friedrich Miescher Institute in Basel and was a postdoctoral fellow with Prof. George Church at the Harvard Medical School in Boston. In 2014, Busskamp was appointed Research Group Leader at theDFG Research Center for Regenerative Therapies at the TU Dresden (CRTD). The VolkswagenStiftung awarded a 'Freigeist' Fellowship to Busskamp and he received a starting grant from 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 the German Federal President, who also appoints the elected members of the Scientific Council and the Board of Trustees. The Chairman of the Scientific Council is Professor Harald zur Hausen, and 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 the Press Office of the Paul Ehrlich Foundation, c/o Dr. Hildegard Kaulen, phone: +49 (0) 6122/52718, email: h.k@kaulen.wi.shuttle.de and at www.paul-ehrlich-stiftung.de.

 

Mar 15 2017
07:41

Paul Ehrlich and Ludwig Darmstaedter Prize 2017 awarded to Pitt Cancer Researchers

Yuan Chang and Patrick Moore win prize for the discovery of two cancer viruses

Scientists looking for new tumor viruses have to keep an eye out for the virus genes rather than the viral particles. This year's winners of the Paul Ehrlich and Ludwig Darmstaedter Prize were twice successful with this strategy.

FRANKFURT am MAIN. Two Americans, Yuan Chang and Patrick S. Moore, will receive the 2017 Paul Ehrlich and Ludwig Darmstaedter Prize today in Frankfurt's Paulskirche for their discovery of the tumor viruses HHV-8 and MCV by means of a clever subtraction strategy. HHV-8 is the human herpesvirus 8, and MCV stands for Merkel cell polyomavirus.  "With their decision to search for the viral genes rather than the viral particles, the prizewinners have taken a major step forward in the hunt for new human tumor viruses and have laid the foundation for further discoveries. The discovery of further human tumor viruses in future remains a distinct possibility," wrote the Scientific Council in substantiating its decision. One in every six cancers in the world is related to a viral infection However, the risk of cancer from a viral infection is lower in the Western industrial countries than in the developing world. Yuan Chang is Professor of Pathology at the University of Pittsburgh Cancer Institute. Patrick Moore is Professor and Director of the Cancer Virology Program at the University of Pittsburgh Cancer Institute. They are a wife and husband team.

HHV-8 causes Kaposi's sarcoma, a tumor of the blood vessel cells, which can be seen on the skin with the naked eye owing to its pronounced red or purplish spots. The tumor occurs mainly in AIDS patients. In their search for HHV-8, Chang and Moore subtracted the entire human genome from the genomic DNA of the tumor cells. The idea behind this approach was that the remaining sequences would, in the best case, belong to the tumor virus and not to the human genome. Following this strategy, the prizewinners isolated two small DNA fragments that they were eventually able to assign to a new herpesvirus. When they published their findings in 1994, they named the virus Kaposi's sarcoma-associated herpesvirus (KSHV). It was later given the official name HHV-8.

MCV is responsible for causing Merkel cell carcinoma, an extremely rare, malignant skin cancer. Chang and Moore refined their strategy in the search for the virus causing Merkel cell carcinoma. Fourteen years after the discovery of HHV-8, their approach was no longer to subtract the entire human genome from the tumor DNA but only the RNA sequences, thereby greatly simplifying the search. In addition, the sequences were not subtracted in a laboratory experiment but computationally, for which they used the published human genome sequences.

Chang and Moore not only discovered the viruses but also showed that they are in fact responsible for the two types of cancer. All Kaposi's sarcomas everywhere in the world contain HHV-8, in other words, not only those that occur in the context of AIDS but also the rare sarcomas that occur sporadically in the USA, Europe and Africa. The infection also precedes the tumor development. It was more difficult to demonstrate that MCV is the culprit in Merkel cell carcinoma because the virus is present in humans' normal skin flora. Chang and Moore showed that in all cells of a givenMerkel cell carcinoma the virus is located at the same site in the genome – although the sites will differ between different Merkel cell carcinoma patients. The tumor must therefore have developed from a single cell with integrated MCV, and this fact, along with further findings, confirmed its causal role.

If some tumor viruses are ubiquitous, why does not everyone fall ill? The tumor viruses first have to overcome the cell's defenses – either by means of cancer genes that they bring with them as with HHV-8 or through mutations as with MCV – and the immune system has to be weakened for cancer to actually develop. Is there a vaccine or treatment for HHV-8 or MCV? "The situation with Kaposi's sarcoma is disappointing for us," says Moore. "Although the community of researchers has found candidates for a vaccine and target molecules for therapy, there is little commercial interest in developing a vaccine or a specific drug therapy." Chang adds: "For Merkel cell carcinoma, however, we're optimistic. Many patients respond to checkpoint inhibitors, some even go into complete remission." Checkpoint inhibition is a promising new therapeutic principle in cancer treatment.

The €120,000 Paul Ehrlich and Ludwig Darmstaedter Prize is among the most prestigious international awards granted in the Federal Republic of Germany in the field of medicine. The Prize will be presented by Professor Harald zur Hausen, Chairman of the Scientific Council.

 

Short biography of Prof. Yuan Chang

Yuan Chang (57 years of age) is a virologist and pathologist. She was born in Taiwan and grew up in Salt Lake City. She studied medicine at the University of Utah and holds a Bachelor of Science degree from Stanford University.  Chang worked at Stanford University Medical Center, at the DNAX Research Institute of Molecular Biology in Palo Alto, and at Columbia University`s College of Physicians and Surgeons in New York, before moving to the University of Pittsburgh in 2002. She is currently American Cancer Society Research Professor, Distinguished Professor of Pathology, and UPMC Endowed Chair in Cancer Virology at the University of Pittsburgh School of Medicine. Yuan Chang has won numerous awards. This year she will receive the 2017 Passano Foundation Award together with her husband Patrick Moore.

 

Short biography of Prof. Patrick S. Moore

Patrick S. Moore (60 years of age) is an epidemiologist and virologist. He studied biology at Westminster College in Salt Lake City and completed his master's degree in chemistry at Stanford University. He studied medicine at the University of Utah and obtained a Master of Public Health at the University of California, Berkeley. He worked in Ghana in 1985 and then in Liberia in 1986. He then joined the Centers for Disease Control and Prevention, where he was involved in international public health interventions in Chad, Ethiopia, Saipan, Nigeria, Nepal and Somalia. He worked for a short time as Deputy Commissioner of the New York City Department of Health in 1993 before moving with his wife to Columbia University in New York. Moore was Professor of Public Health Division of Epidemiology at Columbia University until 2002, when he took up a position at the University of Pittsburgh. He is the Director of the Cancer Virology Program at the University of Pittsburgh Cancer Institute, American Cancer Society Research Professor, Distinguished Professor of Microbiology and Molecular Genetics and the Pittsburgh Foundation Chair in Innovative Cancer Research at the University of Pittsburgh School of Medicine. Patrick S. Moore has won numerous awards.

 

 

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 companies. 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 the German Federal President, who also appoints the elected members of the Scientific Council and the Board of Trustees. The Chairman of the Scientific Council is Professor Harald zur Hausen, and 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 the Press Office of the Paul Ehrlich Foundation, c/o Dr. Hildegard Kaulen, phone: +49 (0)6122/52718, email: h.k@kaulen.wi.shuttle.de and at www.paul-ehrlich-stiftung.de

 

 

Mar 13 2017
12:37

Pre-product for innovative biofuels/Two patents filed

How to brew high-value fatty acids with brewer’s yeast

FRANKFURT.Short-chain fatty acids are high-value constituents of cosmetics, active pharmaceutical ingredients, antimicrobial substances, aromas or soap. To date, it has only been possible to extract them from crude oil by chemical means or from certain plants, such as coconut, using a complex process. Research groups led by Professor Martin Grininger and Professor Eckhard Boles at Goethe University Frankfurt have now succeeded in producing such fatty acids in large quantities from sugar or waste containing sugar with the help of yeasts. The process is simple and similar to that of beer brewing.

As the researchers reported in the latest issues of the renowned journals “Nature Chemical Biology” and “Nature Communications”, the short-chain fatty acids are also much sought after as a pre-product for fuels. “The new technology can be a key step to finding an alternative approach, using yeasts, to innovative types of biofuels whose properties almost equate to those of fossil fuels”, explains Eckhard Boles from the Institute of Molecular Biosciences.

The fatty acids produced by plants and animals are to a large extent made up of chains of eighteen carbon atoms. That means they are longer than the short-chain compounds required. In living cells, large protein complexes - fatty acid synthases - produce fatty acids by joining nine building blocks of two carbon atoms in an eight-cycle process. Martin Grininger, Lichtenberg Professor of the Volkswagen Foundation at Goethe University Frankfurt and research group leader at the Buchmann Institute for Molecular Life Sciences (BMLS), was involved in solving the three-dimensional structure of the fatty acid synthases. His extensive know-how in this field allowed him to intervene in their mode of action.

“First we examined how the fatty acid synthase counts cycles in order to decide when the chain is finished. We found a type of ruler which measures the length of the fatty acid”, explains Martin Grininger. “We modified this ruler in such a way that the fatty acid synthase measures incorrectly and releases shorter chains. All this took place first of all on the computer and in the test tube.”

Together with Eckhard Boles, who is conducting research on yeast metabolism at the neighbouring biocentre, the idea evolved to use Grininger’s modified fatty acid synthases in yeasts. “These yeasts all at once started to secrete short-chain fatty acids in remarkable quantities”, reports Boles. “Like in beer brewing, we can use these now to produce - instead of alcohol - high-quality short-chain fatty acids.” Grininger and Boles add: “This development is just the start. We want now, through similar modifications on other large enzyme complexes, that is, polyketide synthases, to synthesize other new types of molecule for the chemical and pharmaceutical industry which are not readily available otherwise.”

Goethe University Frankfurt has protected these developments by filing two European and international patents and is now looking for licensees for commercial applications.

Grininger and Boles are currently developing their technology further and in different directions. The aim of the “Chassy” project funded by the European Commission is to scale up the technology for industrial use. In addition, the LOEWE project “MegaSyn” financed by the Federal State of Hesse focuses on the production of further chemical compounds through the modification of polyketide synthases. And in the “Alk2Bio” project funded by the Federal Ministry of Food and Agriculture yeasts are being enhanced in such a way that they produce octanol and heptane biofuels from short-chain fatty acids.

 

Publications: Gajewski, J., Buelens, F., Serdjukow, S., Janßen,M., Cortina, N., Grubmüller, H. and Grininger, M. (2017) Engineering fatty acid synthases for directed polyketide production. Nat. Chem. Biol. doi:10.1038/nchembio.2314.

Gajewski, J., Pavlovic, R., Fischer, M., Boles, E. and Grininger, M. (2017) Engineering fungal de novo fatty acid synthesis for short chain fatty acid production. Nat. Commun. doi:10.1038/NCOMMS14650. http://rdcu.be/pX6c

A photograph can be downloaded from:www.uni-frankfurt.de/65728223 

Caption: A modified fatty acid synthase (illustrated schematically in the blue box on the basis of its synthetic properties) can induce short-chain fatty acid production in a yeast cell. Synthesis can be compared with a multistep industrial process. By means of targeted modifications to the natural synthesis, individual processes are accelerated or slowed down (green and red arrows) in order to trigger premature release of short-chain fatty acids.

Further information: Professor Martin Grininger, Lichtenberg Professor of the Volkswagen Foundation, Institute for Organic and Chemical Biology and Buchmann Institute for Molecular Life Sciences (BMLS), Riedberg Campus, Tel.: +49(0)69-798-42705; grininger@chemie.uni-frankfurt.de

Professor Eckhard Boles, Institute of Molecular Biosciences, Riedberg Campus, Tel.: +49(0)69-798-29513, e.boles@bio.uni-frankfurt.de

 

Mar 10 2017
10:38

First tumor-specific study among patients with advanced-stage cancer

Gastrointestinal cancer: Physical exercise helps during chemo

FRANKFURT. Walking or jogging helps patients with advanced gastrointestinal cancer to cope better with the side effects of chemotherapy. This has now been shown by a study conducted by Katrin Stücher in the framework of her doctorate at the Department of Sports Medicine of Goethe University Frankfurt.

Exercise as a therapy to complement chemotherapy has a positive effect on muscles, balance and tumor-related fatigue syndrome. Patients tolerate the therapy better and experience less disease recurrence (relapses) later on. This has already been substantiated by many studies in the past. However, these examined patients in the early stages of their illness and did not differentiate between various types of tumor.

The study, a joint initiative of the Department of Sports Medicine headed by Professor Winfried Banzer and of Medical Clinic I together with the Gastrointestinal Centre of Agaplesion Markus Hospital in Frankfurt, both led by Professor Axel Dignaß, shows that patients with an advanced gastrointestinal tumor can also profit from exercise therapy. In accordance with the recommendations of the American College of Sports Medicine, the participants exercised either three times a week for 50 minutes or five times a week for 30 minutes at a pace which they considered to be “slightly strenuous”. If they were unable to manage this, then they were allowed to shorten their training sessions on the basis of a standardized model.

“For some patients, it was difficult to carry out the walking or jogging program in accordance with the recommendations,” explains Katrin Stücher. “A frequent obstacle was the weather: either it was too cold, too hot or too wet. But the side effects of the chemotherapy, such as loss of sensation, weakness, exhaustion, infections or severe diarrhea, also often meant that they had to reduce or even discontinue the program.”

For the participants in the study, the complementary exercise therapy proved valuable despite the need for occasional breaks. Muscle mass improved as did functional properties, such as balance, walking speed and leg strength. The study also showed first indications that the toxicity of the chemotherapy can be reduced through moderate activity. This is important because it is especially due to severe toxic effects that patients with gastrointestinal cancer often have to reduce the dose or even discontinue the chemotherapy altogether.

“I go walking every morning. It’s good for both my mind and my body and I’m sure it’s contributing to my recovery. I think that if you hadn’t encouraged me to continue exercising I would probably not have dared to push myself so far physically”, reported one of the participants to Katrin Stücher.

“We believe that it will make sense in future to offer patients opportunities for physical exercise during chemotherapy. To eliminate adversities through the weather, exercise rooms could be set up in hospitals. In addition, we should motivate patients to continue with the program after they have taken a break because of side effects”, says Professor Winfried Banzer, Head of the Department of Sports Medicine at Goethe University Frankfurt.

Further information: Professor Dr. Dr. Winfried Banzer, Department of Sports Medicine, Faculty of Medicine, Frankfurt University Hospital, Tel.: +49(0)69-798-24543, or Katrin Stücher, nutritionist, Katrin.Stuecher@erfolgreich-essen.de.