Institute of Molecular Systems Biology

Zürich, Switzerland

Institute of Molecular Systems Biology

Zürich, Switzerland
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News Article | May 4, 2017

Endurance athletes such as marathon runners and long-distance cyclists know that it takes years of training to build stamina. But new research in mice suggests that it may not take much time at all. In the study, scientists gave mice that were typically sedentary a chemical called GW1516 for eight weeks, and found that these mice were able to run on a treadmill for 270 minutes before they showed signs of fatigue. Mice in a control group that did not receive the pill could run on the treadmill for only about 160 minutes. The chemical is thought to work by interacting with a gene involved in the switch from burning the body's stores of sugar to burning fat, according to the findings, published today (May 2) in the journal Cell Metabolism. [Exercise and Weight Loss: The Science of Preserving Muscle Mass] "If you reprogram the genetics, you can acquire that level of fitness without having to expend a lot of energy," said Ronald Evans, an author of the study and a molecular and developmental biologist at the Salk Institute in La Jolla, California. It's not clear whether the chemical would work the same way in humans. But if it did, the results from the study could one day lead to a pill that controls a network of genes, turning them on and off to selectively burn fat and sugar, much like exercise training. Such a therapy could mimic the benefits of exercise for those with limited mobility, such as the elderly, obese or physically impaired. In the new study, Evans and his team built on earlier work in which they found a kind of biological sensor called PPARD that, during exercise, senses fat in the muscle and then turns genes on and off to burn fat and preserve sugar. [Dieters, Beware: 9 Myths That Can Make You Fat] Previous work also showed that GW1516 interacted with that sensor, activating the same set of genes as those that would be triggered by exercise. For example, in one study, Evans and his team gave GW1516 to normal mice for four weeks and showed that it controlled their weight and insulin response. But it didn't seem to influence endurance in sedentary mice. In the new study with sedentary mice, they increased the dose of GW1516 and gave the compound over a longer period. When the scientists analyzed muscle tissue from the mice, they found a few interesting things. First, the tissue did not show any of the physiological changes associated with fitness training. There was no increase in the number of blood vessels or mitochondria, the power plants in cells that generate more than 90 percent of the energy. "What's interesting to me here is that there is no change in fiber type or mitochondrial content, and that the improvement in endurance from GW1516 is primarily, or overwhelmingly, due to differences in glucose management," said Evan Williams, senior research scientist at the Institute of Molecular Systems Biology at ETH Zurich, a university in Switzerland known for its science and technology programs. Williams is not a part of this research study. Second, Evans and his team saw that the chemical had affected a network of 975 genes. Genes that were involved in burning fat were turned on and up, and genes involved in the breakdown of sugar for energy were silenced. The scientist think that, at least in muscle, the PPARD sensor facilitates the switch to burning fat for energy, not sugar, Evans said. Even though muscle tissue can burn both, the brain can use only sugar from the blood for energy. And that is where endurance comes from, Evans said. When sugar levels in the blood drop, the brain is affected, and fatigue sets in. Endurance athletes that push themselves to their limits and deplete their sugar reserves ultimately "hit the wall," or "bonk," as it's colloquially called. But if their muscles could burn less sugar and reserve it for the brain, they could push back the wall. If the GW1516 chemical sounds like a performance enhancing drug, it is, Evans said. The compound, which is not an approved drug for use in humans in the United States, is being made and used in Russia, Evans said. "That doesn't mean we shouldn't develop the drug for the people who need it," he said. Marc Hamilton, a professor at the University of Houston and director of Texas Obesity Research Center at the Texas Medical Center, said he is skeptical that any drug would be powerful enough to raise fat and glucose metabolism in people, even to the degree that occurs during moderate exercise, which has been shown to be safe and without hazardous side effects.

Global Life Science Companies, Cancer Research Leaders, and Worldwide Dignitaries Celebrate the Opening of ProCan -- an International Centre for Cancer Research -- with Goal to Transform the Way that Cancer is Diagnosed and Treated SOUTH EASTON, MA--(Marketwired - Oct 26, 2016) - Pressure BioSciences, Inc. ( : PBIO) ("PBI" and the "Company"), a leader in the development and sale of broadly enabling pressure cycling technology ("PCT")-based sample preparation solutions to the large and growing worldwide life sciences industry, today announced its featured participation in the recent opening of The ACRF International Centre for the Proteome of Human Cancer ("ProCan"), located in newly renovated laboratory facilities at the Children's Medical Research Institute ("CMRI") near Sydney, Australia. In addition to PBI, ProCan and CMRI scientists, presentations were made by other invitees, including representatives from SCIEX, Ilumina, Beckman-Coulter, and NextBio, as well as from Dr. Tiannan Guo of Professor Ruedi Aebersold's lab at the world-renowned Institute of Molecular Systems Biology (Zurich, Switzerland). Professor Aebersold is generally considered to be one of the leading proteomics scientists in the world. ProCan expects to analyze a minimum of 10,000 cancer tumor samples per year over the next seven years with cutting-edge protein analysis instruments and other lab tools. It is anticipated that data from their studies will trigger discoveries illuminating causes of cancer, providing invaluable guidance on cancer treatment options and creating a new era in standard operating procedures applied in cancer testing laboratories worldwide. "ProCan is very simple in concept but massive in scale," said CMRI Director, Professor Roger Reddel, who is also a co-leader of ProCan. "We believe the results of ProCan will greatly improve the speed and accuracy of cancer diagnosis and provide clinicians an enhanced capability to choose the most effective treatment option for each individual patient's cancer and, importantly, to avoid those treatments that are likely to be unsuccessful. This will reduce treatment toxicity and improve cancer treatment outcomes in children and adults -- worldwide." (Source of quote plus more information on ProCan and CMRI can be found at In June 2016, ProCan purchased the first three commercially released, next-generation PCT-based instruments, the Barocycler 2320EXTREME (the "2320EXT"). A short video introducing the 2320EXT can be viewed at In their planned analysis of 70,000-plus tumor samples, ProCan will combine PBI's Barocycler 2320EXT system for sample preparation with SCIEX's SWATH data independent-acquisition mass spectrometry workflow on Triple TOF® 6600 Systems. The advantages of this method ("PCT-SWATH") have been the focus of scientific journal articles by Dr. Aebersold, Dr. Guo, and others over the past several years. SCIEX is a global leader in life science analytical technologies. In January 2016, PBI and SCIEX announced an exclusive, two-year, worldwide co-marketing agreement under which PBI and SCIEX will co-promote PBI's PCT systems with SCIEX's SWATH-based proteomics workflows. Dr. Alexander Lazarev, Vice President of R&D at PBI said: "We were honored when ProCan recognized and selected the PCT platform for the significant advantages in sample preparation that it affords. Reproducibility, speed, automation, and enhanced protein extraction and digestion are all critical elements in the preparation of samples for analysis. When these sample preparation attributes of PCT are combined with the leading quality of SCIEX mass spectrometers, we believe that ProCan and other users of PCT-SWATH will significantly increase their chances to discover new and potentially important biomarkers of cancer." Dr. Nate Lawrence, Vice President of Sales and Marketing for PBI, commented: "CMRI was recently named an official collaborator of the US National Cancer Institute's "Cancer Moonshot" initiative, whose goal is to accelerate what would normally take ten years of cancer research into completion in the next five years. We believe that the Cancer Moonshot initiative will strategically support and accelerate the field of precision (personalized) medicine through studies such as those planned at CMRI, which could lead to better identification, diagnosis, treatment, and prevention of cancer. We are proud to be a part of this very important and inspiring program." Dr. Lawrence continued: "Nearly $1 Billion in new funding is planned for cancer research in the current US fiscal year, a portion of which could support the expansion of additional "industrialized proteomics" labs worldwide, similar to ProCan. With the recognition that ProCan and other cancer research programs are already giving to our recently released, next-generation 2320EXT Barocycler system, combined with our planned salesforce expansion and our SCIEX co-marketing program, we believe we will see robustly increasing sales of our PCT product line in 2017 and beyond." Pressure BioSciences, Inc. ("PBI") ( : PBIO) develops, markets, and sells proprietary laboratory instrumentation and associated consumables to the estimated $6 billion life sciences sample preparation market. Our products are based on the unique properties of both constant (i.e., static) and alternating (i.e., pressure cycling technology, or PCT) hydrostatic pressure. PCT is a patented enabling technology platform that uses alternating cycles of hydrostatic pressure between ambient and ultra-high levels to safely and reproducibly control bio-molecular interactions. To date, we have installed over 260 PCT systems in approximately 160 sites worldwide. There are over 100 publications citing the advantages of the PCT platform over competitive methods, many from key opinion leaders. Our primary application development and sales efforts are in the biomarker discovery and forensics areas. Customers also use our products in other areas, such as drug discovery & design, bio-therapeutics characterization, soil & plant biology, vaccine development, histology, and forensic applications. Forward Looking Statements Statements contained in this press release regarding PBI's intentions, hopes, beliefs, expectations, or predictions of the future are "forward-looking'' statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements are based upon the Company's current expectations, forecasts, and assumptions that are subject to risks, uncertainties, and other factors that could cause actual outcomes and results to differ materially from those indicated by these forward-looking statements. These risks, uncertainties, and other factors include, but are not limited to, the risks and uncertainties discussed under the heading "Risk Factors" in the Company's Annual Report on Form 10-K for the year ended December 31, 2015, and other reports filed by the Company from time to time with the SEC. The Company undertakes no obligation to update any of the information included in this release, except as otherwise required by law. For more information about PBI and this press release, please click on the following website link: Please visit us on Facebook, LinkedIn, and Twitter

Pfaff J.,University of Regensburg | Pfaff J.,Helmholtz Center Munich | Hennig J.,Helmholtz Center Munich | Hennig J.,Center for Integrated Protein Science Munich and Biomolecular | And 7 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2013

MicroRNAs (miRNAs) guide Argonaute (Ago) proteins to target mRNAs, leading to gene silencing. Howeèer, Ago proteins are not the actual mediators of gene silencing but interact with a member of the GW182 protein family (also known as GW proteins), which coordinates all downstream steps in gene silencing. GW proteins contain an N-terminal Ago-binding domain that is characterized by multiple GW repeats and a C-terminal silencing domain with seèeral globular domains. Within the Ago-binding domain, Trp residues mediate the direct interaction with the Ago protein. Here, we haèe characterized the interaction of Ago proteins with GW proteins in molecular detail. Using biochemical and NMR experiments, we show that only a subset of Trp residues engage in Ago interactions. The Trp residues are located in intrinsically disordered regions, where flanking residues mediate additional weak interactions, that might explain the importance of specific tryptophans. Using cross-linking followed by mass spectrometry, we map the GW protein interactions with Ago2, which allows for structural modeling of Ago-GW182 interaction. Our data further indicate that the Ago-GW protein interaction might be a two-step process inèolèing the sequential binding of two tryptophans separated by a spacer with a minimal length of 10 aa.

Tan S.L.W.,University of Cambridge | Chadha S.,University of Cambridge | Liu Y.,Institute of Molecular Systems Biology | Gabasova E.,University of Cambridge | And 8 more authors.
Cell | Year: 2017

Mutations truncating a single copy of the tumor suppressor, BRCA2, cause cancer susceptibility. In cells bearing such heterozygous mutations, we find that a cellular metabolite and ubiquitous environmental toxin, formaldehyde, stalls and destabilizes DNA replication forks, engendering structural chromosomal aberrations. Formaldehyde selectively depletes BRCA2 via proteasomal degradation, a mechanism of toxicity that affects very few additional cellular proteins. Heterozygous BRCA2 truncations, by lowering pre-existing BRCA2 expression, sensitize to BRCA2 haploinsufficiency induced by transient exposure to natural concentrations of formaldehyde. Acetaldehyde, an alcohol catabolite detoxified by ALDH2, precipitates similar effects. Ribonuclease H1 ameliorates replication fork instability and chromosomal aberrations provoked by aldehyde-induced BRCA2 haploinsufficiency, suggesting that BRCA2 inactivation triggers spontaneous mutagenesis during DNA replication via aberrant RNA-DNA hybrids (R-loops). These findings suggest a model wherein carcinogenesis in BRCA2 mutation carriers can be incited by compounds found pervasively in the environment and generated endogenously in certain tissues with implications for public health. © 2017 The Author(s)

News Article | November 9, 2015

Biologists at ETH Zurich have developed a method that, for the first time, makes it possible to measure concentration changes of several hundred metabolic products simultaneously, and almost in real-time. The technique could inspire basic biological research and the search for new pharmaceutical agents. Genomics, proteomics, metabolomics. Scientists who work in a field that ends with the suffix -omics analyse the totality of something. In the case of metabolomics, it is the totality of all metabolites of a cell or organism. The research groups of Uwe Sauer, professor of Systems Biology at ETH Zurich, and Nicola Zamboni, group leader at the Institute of Molecular Systems Biology, are among the leaders in this field. They have now developed a method by which they can identify the concentration of hundreds of metabolites simultaneously and almost in real time. The analysis of all metabolites in one go is not particularly easy since metabolites are a very diverse class of biological substances. “Various sugars, fats, messenger materials and amino acids belong to this group – thus, completely different molecules. Their only similarity is that they are small, at least compared with proteins and RNA molecules that occur on a mass scale in cells,” explains Sauer. For a long time, the simultaneous measurement of hundreds of metabolites in a fluid – for instance, urine or blood – or in cells was very time consuming. Most biologists used methods in which the substance mixture was first separated by chromatography and then the separated ingredients were identified in a mass spectrometer. A few years ago Sauer, Zamboni and their colleagues developed a method that made chromatographic separation unnecessary. “We can now analyse a sample directly in a mass spectrometer and filter out information about the ingredients from a huge amount of data using a software that we developed,” says Sauer. Identification of 300 to 800 different metabolites in a sample takes only a minute, which means that analysis of thousands of samples in one day – previously only a dream – has now become a reality. “The success of this high-throughput measurement method brought us to the idea of real-time measurements,” says Sauer. This is helpful because metabolism responds very quickly to stimulus changes: “If, for example, you shine a light on a plant in the dark, the concentrations of its metabolites change in just a few seconds.” The precise timing of a concentration change in response to new stimuli is important and meaningful information in biology. The ETH scientists implemented their real-time measurement idea by using different cells in a culture: two bacterial species, a yeast species and mice cells. The researchers let the cells grow in a growth medium directly next to a measuring instrument. An automatic pump system extracted a tiny amount from the cell culture every 10 seconds in order to analyse it in the instrument. The researchers not only managed to prove that, in principle, such on-line measurements are possible with all types of cell cultures; thanks to their technology, they also gained new insights into how E. coli bacteria switch from a ‘stand-by’ mode into a growth phase. They let the bacteria starve for two hours by keeping them in the growth medium without sugar. As a consequence the bacteria switch to the ‘stand-by’ programme by stopping production of most metabolites and breaking down the existing ones in order to gain energy for survival. Following this starvation phase, the scientists again provided the bacteria with sugar. Within one minute, the cells resumed production of metabolites in order to grow and divide. However, the scientists were baffled by the behaviour of 10 of the nearly 300 metabolites studied, which behaved differently from the majority: their concentration increased during the starvation phase and decreased during the optimal supply phase. The researchers believe that these are key metabolites that influence the extremely fast switch of the overall metabolism between the two phases. These 10 metabolites are eight specific amino acids – the building blocks of proteins – and two molecules, from which the cells produce DNA and RNA building blocks. And they have one thing in common: the cells have to expend a large amount of energy to produce them. “We assume that the cells do not break down such valuable building blocks during the starvation phase, but instead save them to have the best possible starting conditions for the subsequent growth phase,” says Sauer. Using a systems biological computer model, the scientists were able to show how the regulation works: the 10 metabolites saved during the starvation phase prevent the cells from producing more of them at the beginning of the growth phase by means of a feedback mechanism. As a result, the cells do not waste energy in the expensive construction of the 10 metabolites, but put their resources entirely into the synthesis of the other molecules. Helpful in the development of medication Sauer is currently making the new real-time method known to the scientific community. “It is a very useful method to get a first overview of how cells react to an external stimulus. This makes it suitable for the analysis of all metabolic processes that take place over a period of time of half an hour to several hours,” he says. He sees possible applications not only in basic biological research, but also, for example, in the screening of potential new pharmaceutical agents. This would make it possible to discover how a drug alters metabolism – a method that Sauer’s group now uses for such investigations.

Herzig S.,University of Geneva | Raemy E.,University of Geneva | Montessuit S.,University of Geneva | Veuthey J.-L.,University of Geneva | And 4 more authors.
Science | Year: 2012

The transport of pyruvate, the end product of glycolysis, into mitochondria is an essential process that provides the organelle with a major oxidative fuel. Although the existence of a specific mitochondrial pyruvate carrier (MPC) has been anticipated, its molecular identity remained unknown. We report that MPC is a heterocomplex formed by two members of a family of previously uncharacterized membrane proteins that are conserved from yeast to mammals. Members of the MPC family were found in the inner mitochondrial membrane, and yeast mutants lacking MPC proteins showed severe defects in mitochondrial pyruvate uptake. Coexpression of mouse MPC1 and MPC2 in Lactococcus lactis promoted transport of pyruvate across the membrane. These observations firmly establish these proteins as essential components of the MPC.

Bensimon A.,Institute of Molecular Systems Biology | Bensimon A.,ETH Zurich | Aebersold R.,Institute of Molecular Systems Biology | Aebersold R.,ETH Zurich | And 2 more authors.
FEBS Letters | Year: 2011

The DNA of all organisms is constantly subjected to damaging agents, both exogenous and endogenous. One extremely harmful lesion is the double-strand break (DSB), which activates a massive signaling network - the DNA damage response (DDR). The chief activator of the DSB response is the ATM protein kinase, which phosphorylates numerous key players in its various branches. Recent phosphoproteomic screens have extended the scope of damage-induced phosphorylations beyond the direct ATM substrates. We review the evidence for the involvement of numerous other protein kinases in the DDR, obtained from documentation of specific pathways as well as high-throughput screens. The emerging picture of the protein phosphorylation landscape in the DDR broadens the current view on the role of this protein modification in the maintenance of genomic stability. Extensive cross-talk between many of these protein kinases forms an interlaced signaling network that spans numerous cellular processes. Versatile protein kinases in this network affect pathways that are different from those they have been identified with to date. The DDR appears to be one of the most extensive signaling responses to cellular stimuli. © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Bensimon A.,Institute of Molecular Systems Biology | Bensimon A.,ETH Zurich | Heck A.J.R.,Institute of Molecular Systems Biology | Heck A.J.R.,University Utrecht | And 3 more authors.
Annual Review of Biochemistry | Year: 2012

In the life sciences, a new paradigm is emerging that places networks of interacting molecules between genotype and phenotype. These networks are dynamically modulated by a multitude of factors, and the properties emerging from the network as a whole determine observable phenotypes. This paradigm is usually referred to as systems biology, network biology, or integrative biology. Mass spectrometry (MS)-based proteomics is a central life science technology that has realized great progress toward the identification, quantification, and characterization of the proteins that constitute a proteome. Here, we review how MS-based proteomics has been applied to network biology to identify the nodes and edges of biological networks, to detect and quantify perturbation-induced network changes, and to correlate dynamic network rewiring with the cellular phenotype. We discuss future directions for MS-based proteomics within the network biology paradigm. © 2012 by Annual Reviews. All rights reserved.

Maiolica A.,Institute of Molecular Systems Biology | Junger M.A.,Institute of Molecular Systems Biology | Ezkurdia I.,Spanish National Cancer Research Center | Aebersold R.,Institute of Molecular Systems Biology | Aebersold R.,University of Zürich
Journal of Proteomics | Year: 2012

Due to the enormous complexity of proteomes which constitute the entirety of protein species expressed by a certain cell or tissue, proteome-wide studies performed in discovery mode are still limited in their ability to reproducibly identify and quantify all proteins present in complex biological samples. Therefore, the targeted analysis of informative subsets of the proteome has been beneficial to generate reproducible data sets across multiple samples. Here we review the repertoire of antibody- and mass spectrometry (MS) -based analytical tools which is currently available for the directed analysis of predefined sets of proteins. The topics of emphasis for this review are Selected Reaction Monitoring (SRM) mass spectrometry, emerging tools to control error rates in targeted proteomic experiments, and some representative examples of applications. The ability to cost- and time-efficiently generate specific and quantitative assays for large numbers of proteins and posttranslational modifications has the potential to greatly expand the range of targeted proteomic coverage in biological studies. This article is part of a Special Section entitled: Understanding genome regulation and genetic diversity by mass spectrometry. © 2012 Elsevier B.V.

Gillet L.C.,Institute of Molecular Systems Biology
Molecular & cellular proteomics : MCP | Year: 2012

Most proteomic studies use liquid chromatography coupled to tandem mass spectrometry to identify and quantify the peptides generated by the proteolysis of a biological sample. However, with the current methods it remains challenging to rapidly, consistently, reproducibly, accurately, and sensitively detect and quantify large fractions of proteomes across multiple samples. Here we present a new strategy that systematically queries sample sets for the presence and quantity of essentially any protein of interest. It consists of using the information available in fragment ion spectral libraries to mine the complete fragment ion maps generated using a data-independent acquisition method. For this study, the data were acquired on a fast, high resolution quadrupole-quadrupole time-of-flight (TOF) instrument by repeatedly cycling through 32 consecutive 25-Da precursor isolation windows (swaths). This SWATH MS acquisition setup generates, in a single sample injection, time-resolved fragment ion spectra for all the analytes detectable within the 400-1200 m/z precursor range and the user-defined retention time window. We show that suitable combinations of fragment ions extracted from these data sets are sufficiently specific to confidently identify query peptides over a dynamic range of 4 orders of magnitude, even if the precursors of the queried peptides are not detectable in the survey scans. We also show that queried peptides are quantified with a consistency and accuracy comparable with that of selected reaction monitoring, the gold standard proteomic quantification method. Moreover, targeted data extraction enables ad libitum quantification refinement and dynamic extension of protein probing by iterative re-mining of the once-and-forever acquired data sets. This combination of unbiased, broad range precursor ion fragmentation and targeted data extraction alleviates most constraints of present proteomic methods and should be equally applicable to the comprehensive analysis of other classes of analytes, beyond proteomics.

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