Institute of Molecular Pathology
Institute of Molecular Pathology
News Article | July 7, 2017
Researchers from Case Western Reserve University School of Medicine and Cleveland Clinic Lerner Research Institute have developed a new method to screen brain tumor cells and identify potential drug targets missed by traditional methods. The team successfully used their technique to find a new drug target in glioblastoma that, when inhibited, significantly extended survival in preclinical mouse models. In the new study published in Nature, the team implanted human glioblastoma cells from patients to form human tumors inside mouse brains, closely mimicking the natural tumor environment. They simultaneously screened hundreds of genes in these tumors to understand which genes were important for cancer cell survival. They compared these screening results in the brain with those from a parallel screening they conducted in the patients' cells grown in the laboratory. What they found was surprising - 57 genes required for the cancer cells to grow in a functional tumor environment in the brain were not required when the cells were grown in the laboratory. "There was very little overlap of the targets identified in the new in vivo screening method and the traditional cell culture screen," said Jeremy Rich, MD one of the senior authors of the study, formerly of the Department of Stem Cell Biology & Regenerative Medicine at Cleveland Clinic Lerner Research Institute and Taussig Cancer Institute. "This means the field has been missing a number of potential therapeutic targets that may actually improve patient outcomes and prolong survival." Dr. Rich is now a professor at University of California San Diego. Glioblastoma is the most aggressive type of brain tumor and the median survival for patients is only 15 months even with current therapies, according to the American Brain Tumor Association. The high-throughput screening technique revealed new vulnerabilities in glioblastoma tumors that could be targeted by drug developers. Of the 57 genes identified, 12 were all related to a single process--how cancer cells respond to stress. The researchers inhibited a number of these stress response genes in the implanted tumors and the mice survived longer. However, inhibiting the gene in cells grown in traditional laboratory culture dishes did not alter glioblastoma cell growth or survival. Tyler Miller, PhD, first author on the study and medical student in the CWRU Medical Science Training Program and Cleveland Clinic Lerner Research Institute, said "Our study found that in a natural environment, tumor cells are more susceptible to inhibition of their stress response mechanisms. Current chemotherapies all target proliferating, or dividing cells. We know that type of therapy doesn't work for glioblastoma. Our findings suggest that targeting the stress response may be better at slowing tumor growth than targeting cell proliferation, which opens up a new avenue for therapeutic development." According to the researchers, their approach could be used to screen other types of cancers for potential therapeutic targets. The other senior author of the study, Paul Tesar, PhD, Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics and Associate Professor of Genetics and Genome Sciences at Case Western Reserve University School of Medicine and the Case Comprehensive Cancer Center, said "Prior attempts at discovering therapeutic targets have generally been done in cell culture, that is, patient cells on plastic dishes in artificial media to help them grow. The hope is that systems like ours that more closely mimic the natural tumor environment will identify new targets that better translate into effective therapies for patients." Joining Miller, Tesar and Rich in this research effort were co-authors Lisa Wallace, Qi Xie, Deobrat Dixit, Lian Wu, Stephen Mack, and Christopher Hubert of Cleveland Clinic Lerner Research Institute; Andrew Morton, Daniel Factor, Leo Kim, James Morrow and Peter Scacheri of Case Western Reserve University School of Medicine; Brian Liau, Shawn Gillespie, William Flavahan, Rohit Thummalapalli, and Bradley Bernstein of Harvard Medical School and Massachusetts General Hospital; Thomas Hoffman and Johannes Zuber of the Research Institute of Molecular Pathology in Vienna, Austria; Michael Hemann of the Koch Institute for Integrative Cancer Research at MIT; Patrick Paddison of the Fred Hutchinson Cancer Research Center; and Craig Horbinski of Feinberg School of Medicine, Northwestern University. This work was supported by VeloSano, New York Stem Cell Foundation, philanthropic support from the Goodman family, CIHR Banting Fellowship, and National Institutes of Health grants (F30CA183510, T32GM007250, R01CA154130, R01CA169117, R01CA197718, R01CA171652, R01NS087913, R01NS089272). For more information about the Tesar laboratory, please visit: http://tesarlab. For more information about Case Western Reserve University School of Medicine, please visit: http://case. .
News Article | June 15, 2017
ABIVAX (Euronext Paris: FR0012333284 – ABVX), an innovative biotechnology company targeting the immune system to eliminate viral diseases using its unique technology platforms, congratulates today Prof. Jamal Tazi, inventor of ABX464, ABIVAX’s lead drug candidate for inducing a functional cure for HIV, and Member of its Executive Committee, on receiving the CNRS Medal of Innovation 2017. The medal, which will be awarded today at a ceremony attended by Mrs. Frédérique Vidal, French Minister of Higher Education, Research and Innovation, is in recognition of outstanding research in fields related to technology, medicine or the social sciences. Jamal Tazi is a Professor of Functional Genomics at the University of Montpellier, Senior Member at the University Institute of France and Deputy Director of the Health Center Biology "Rabelais" responsible for education and training. After a thesis on molecular and cellular biology defended in 1988, he completed a postdoctoral fellowship at the Research Institute of Molecular Pathology (Vienna, Austria), before joining the CNRS in 1990. For 20 years, he led the team "messenger RNA metabolism in metazoans" within the Institute for Molecular Genetics in Montpellier (IGMM) where he made important contributions in the understanding of the fundamental mechanisms of the expression of our genes and editing of their products. These discoveries are used today in the medical field through the development of a new therapy based on the use of small molecules to fight against viral infections and to correct anomalies of gene expression responsible for many cancers. In 2008, Truffle Capital’s Managing Director, Dr. Philippe Pouletty, founded Splicos in collaboration with Prof. Jamal Tazi and the CNRS with an exclusive global licensing agreement on Prof. Tazi’s patent application on small molecules modulating RNA biogenesis. Under the impetus of Truffle Capital, ABIVAX was founded in December 2013 by merging three French biotech companies (Wittycell, Splicos and Zophis). The company’s research activities are located in its cooperative lab with the CNRS in Montpellier. In June 2015, ABIVAX completed the largest biotech IPO in France in terms of the amount raised on Euronext Paris. “I am honored to receive the CNRS Medal of Innovation 2017, which rewards not only my work but also the dedication and commitment of my teams which have been fighting to find a cure to HIV for many years. The announcement by ABIVAX in May 2017 of the first ever evidence of treatment-induced reduction in HIV reservoir, using ABX464, provides great hope for the HIV-community. We have come a long way, but we still have more work to do. Our goal is to find a cure for the millions of people infected with the virus,” said Prof. Jamal Tazi. “We are very proud to count on Prof. Jamal Tazi as a colleague and a friend. His commitment to finding a cure for HIV is a key driver in our work. In the name of all ABIVAX team members, I would like to congratulate him on receiving this prestigious recognition from the CNRS, and we are looking forward to his continued contributions to our mission to bringing novel treatments to patients with HIV and other life-threatening viral diseases,” said Prof. Hartmut Ehrlich, M.D., CEO of ABIVAX. The National Center for Scientific Research or CNRS is a public organization under the responsibility of the French Ministry of Education and Research. The CNRS Medal of Innovation, created in 2011, rewards outstanding scientific research with innovative applications in the technological, therapeutic and societal fields, thus promoting French scientific research. Every year, a jury hands out up to five medals to researchers and engineers, either from CNRS or within other research organizations, universities and higher-education institutions, or to industrial partners involved in research initiatives. For more information, refer to http://www.cnrs.fr/en/research/awards/innovation.htm. ABIVAX is an innovative biotechnology company focused on targeting the immune system to eliminate viral disease. To do this ABIVAX leverages three technology platforms for drug discovery: antiviral, immune enhancing and polyclonal antibodies. ABX464, its most advanced compound, is currently in Phase II clinical trials to test its ability to enable a functional cure for patients with HIV/AIDS. It is a first-in-class oral small antiviral molecule which blocks HIV replication through a unique mechanism of action and, separately, also has a strong anti-inflammatory effect. In addition, ABIVAX is advancing a clinical stage immune enhancer as well as multiple preclinical candidates against additional viral targets (i.e. Chikungunya, Ebola, Dengue); several of these compounds are planned to enter clinical development within the next 18 months. ABIVAX is listed on Euronext compartment B (ISIN: FR0012333284 – Mnémo: ABVX). More information on the company is available at www.abivax.com.
News Article | June 7, 2017
Sometimes, downsizing pays off. After working as a postdoctoral researcher at large institutions including the University of California, Berkeley, and the University of Oregon in Eugene, evolutionary biologist Hélène Morlon now runs her own laboratory at the École Normale Supérieure (ENS), a small college tucked into central Paris. Morlon is one of only seven principal investigators in the ecology and evolution section; Berkeley, by comparison, lists nearly 70 faculty members in its analogous integrative-biology department. Her section might be tiny, but Morlon maintains a global network of collaborators that keeps her connected. She also has no shortage of visitors, whether for a long stint in the lab or a quick conference talk. “It's easy,” she says. “Even if we give them an economy ticket, they come because it's Paris.” The ENS is ranked by the London-based Times Higher Education as one of the best small universities (defined as having fewer than 5,000 students) in the world. But in common with all such institutions, its size is both a help and a hindrance. Researchers at small universities have fewer colleagues down the hall for conversation or collaboration, and this can lead to a sense of detachment in their field. On the other hand, it forces them out of their intellectual comfort zones. Morlon says that she has much more contact with colleagues in other disciplines than she ever had at a large university. “I've never before been to so many genomic and neurobiology talks,” she says. Scientists who are considering employment at small institutions will also need to modify their expectations when applying for large grants and setting timelines for producing publications. They must also take a highly focused, hands-on approach to building collaborations and dealing with lab and administrative tasks that researchers at larger institutions can usually delegate. Still, for many (see 'Finding your niche'), small is the right fit. At Lincoln University in Christchurch — the smallest in New Zealand, with roughly 2,000 full-time students — environmental chemist Brett Robinson has learnt to rely on pluck and ingenuity to overcome a relative lack of resources. “At a small institution, we don't necessarily have all of the equipment or perhaps even the expertise that a large university would have,” he says. “You have to find new ways of doing things instead of throwing up your hands and giving up. You need a can-do attitude.” That spirit became essential after an earthquake shook the campus in 2011, causing extensive damage to the university. “We operate under a tighter financial space because we have fewer students to support basic services,” he says. “We don't have the economies of scale. That makes us more vulnerable in a crisis.” After rounds of staff cuts in the aftermath of the quake, the university now seems to be financially stable enough to survive and move forward, Robinson says. Where on-campus alliances or support are lacking, outside connections become crucial. Nic Bury, an aquatic toxicologist, recently moved from King's College London (where more than 27,600 students were enrolled in 2016) to the University of Suffolk (total enrolment about 5,000), in the small UK town of Ipswich. “I've had a lot of collaborations over the years, and I'll need to keep those alive,” he says. Robinson also relies on his networks to maintain connections with researchers at larger, more prominent organizations. “A lot of my collaborations are with European institutions, including ETH Zurich and the Institute of Soil Science in Vienna,” he says. Some scientists at small institutions appreciate what they feel is a more laid-back culture than might prevail at a large university. Bury relocated to Suffolk partly for family reasons, but he is also comfortable with its environment. “ Yet the security of Suffolk comes with some sacrifice, particularly to his research programme. He anticipates teaching three or four courses every term, a load that will make it impossible to keep up the research schedule he's been used to. “At King's College, I had five projects running at a time,” he says. “I'm going to have to cut that down to one or two.” Researchers at small institutions can also feel uneasy about their ability to win competitive grants. Karl Johnson, a neuroscientist at Pomona College in Claremont, California, says that his grants are consistently rejected. Pomona, a 4-year liberal-arts college, has an enrolment of about 1,600. “I keep getting turned down in the preliminary stages,” he says. He suspects that the size of US liberal-arts colleges — enrolment is below 5,000 for each of the top 100 such institutions, as ranked by US News and World Report — puts them at a funding disadvantage. He acknowledges that his lab could never handle a big, complicated project, but he also feels that his ideas are worth funding. And without grant money, he can't afford the experiments that could validate his concepts and justify more funding. “Once you're out of the grant cycle, it's very hard to get back in,” he says. Bury shares these concerns. Scientists at larger institutions, which can support complex, high-profile projects, have an advantage when applying for European Research Council (ERC) grants, he thinks. He plans to seek money from other sources, but he's still thinking big. He has applied for a grant from the Biotechnology and Biological Sciences Research Council, a major governmental funding organization in the United Kingdom. But researchers from larger institutions don't necessarily have better luck winning ERC grants, according to the organization's most recently compiled data, covering 2007–13. The ERC doesn't track overall success rates for smaller institutions, but many such places have a strong record of winning grants. The ENS won 15 grants out of 47 submissions over that period, a success rate of 31.9%. The Research Institute of Molecular Pathology in Vienna supports 200 scientists in 15 labs, but those scientists enjoyed a 71% success rate — the highest of any institution with at least 10 grant recipients. By comparison, the overall success rate for ERC applications was just over 10%. The council notes that it funds researchers at more than 600 universities and research centres of widely varying size. “The ERC is able to find excellence wherever it is and to offer opportunities to thousands of researchers regardless of the profile of their organizations,” says Jean-Pierre Bourguignon, the council's president. Researchers at small US universities have some specialized funding options. The US National Science Foundation (NSF), for instance, provides Research in Undergraduate Institutions grants to colleges that don't offer graduate degrees. The NSF funded 132 such grants in fiscal year 2015, at an average of roughly US$110,000 each. “NSF values the research and education proposals it receives from faculty at all types of academic institutions,” says Suzi Iacono, head of the NSF Office of Integrative Activities. “The participation of researchers at different types of schools brings new perspectives, research approaches and ideas to the scientific community.” Still, scientists at smaller institutions don't always require a steady stream of grants to keep their labs running. Like many of his colleagues, Johnson operates his lab on a bare-bones budget. “I'm happy with my research productivity,” he says. He works on Drosophila flies, which don't need a lot of expensive upkeep. And because Pomona is an undergraduate institution, he doesn't have to pay salaries to graduate students. Instead, he staffs his lab with undergraduates who, although short on experience, are long on enthusiasm. But the absence of a larger lab team also means fewer hands to help out. Joshua Sandquist, a cellular biologist at Grinnell College, an undergraduate liberal-arts college in Iowa, says he's extremely busy, largely because he lacks people who can help him with mundane tasks such as performing statistical analyses or procuring lab supplies. “It's not everybody's priority to get your lab up and running,” he says. He will have two undergraduate students in his lab this summer, and hopes that one will stick around once the autumn semester starts. He has, however, been able to avoid one of the more odious aspect of scientific life: grant writing. “My institution doesn't require it,” he says (although in 2014, he did win an NSF Major Research Instrumentation grant that allowed him to buy an infrared scanner to detect proteins). He thinks that his time is best spent on teaching and whatever research he can afford. “If you do win a grant, you're left with a bunch of work that you promised to do that you have to squeeze into your teaching,” Sandquist says. Indeed, small US liberal-arts colleges generally emphasize teaching above all else. “If you don't love teaching, you're going to be pretty miserable here,” Johnson says. He spends 7–13 hours in class every week, and that's just a part of the load, which can include assembling a syllabus and selecting textbooks; developing lectures and lab sessions; and assigning and marking exams, papers and lab reports. “A lot of teaching takes place outside of the classroom,” he says. And for Sandquist, even when he's in the lab, his highest priority is not necessarily churning out data and papers to further his own research career. “At a liberal-arts school, you're using your lab to train future scientists,” he says. Over the years, Johnson has given several presentations to early-career scientists about life as a small-school researcher, often as part of a panel on 'alternative' careers. “Some scientists see this as a non-traditional career,” he says. “But it's funny. I'm more traditional than someone at an R1 [top research] school. I'm teaching, and I'm at the bench. A lot of people at major research institutions don't set foot in the lab any more.” Some researchers might once have viewed small universities as a 'plan B' in case they couldn't land a job at a big-name institution. But that idea needs an update. “We get more than 200 applications for every faculty position,” Johnson says. With so many applicants, Pomona and similar institutions can afford to be picky. Increasingly, they are looking for people who fit the small-school mould. It's another example of specialization in science. Young researchers should already be thinking about what size workplace would suit them best.
News Article | June 15, 2017
ABIVAX (Euronext Paris : FR0012333284 – ABVX), une société de biotechnologie ciblant le système immunitaire pour éliminer des maladies virales en se basant sur ses plateformes technologiques uniques, félicite aujourd’hui le Pr. Jamal Tazi, inventeur d’ABX464, le candidat médicament le plus avancé d’ABIVAX visant à induire une guérison fonctionnelle du VIH et membre de son Comité Exécutif, pour avoir reçu la Médaille de l’Innovation 2017 du CNRS. Cette médaille, qui lui sera remise aujourd’hui lors d’une cérémonie organisée par le CNRS en présence de Mme. Frédérique Vidal, Ministre de l'Enseignement supérieur, de la Recherche et de l'Innovation, récompense des recherches ayant conduit à une innovation marquante dans les domaines technologique, thérapeutique ou social. Jamal Tazi est Professeur de Génomique Fonctionnelle à l’Université de Montpellier, Membre Senior à l’Institut Universitaire de France et Directeur Adjoint du Pôle Biologie Santé “Rabelais” chargé de l’enseignement et de la formation. Après une thèse de biologie moléculaire et cellulaire soutenue en 1988, il effectue un stage postdoctoral au Research Institute of Molecular Pathology en Autriche, avant d’intégrer le CNRS en 1990. En 2008, le Directeur Général de Truffle Capital, le Dr. Philippe Pouletty, fonde la société Splicos en collaboration avec le Pr. Jamal Tazi et le CNRS avec un accord de licence exclusif sur la demande de brevet du Pr. Jamal Tazi sur les petites molécules modulant la biogénèse de l’ARN. C’est sous l’impulsion de Truffle Capital que la société ABIVAX est créée en décembre 2013 par la fusion de trois sociétés françaises de biotechnologies (Wittycell, Splicos and Zophis). Les principales activités de recherche de la société sont depuis lors localisées dans ses laboratoires coopératifs avec le CNRS de Montpellier. En juin 2015, ABIVAX a réalisé l’introduction en bourse la plus importante en termes de montant levé par une société biotech sur Euronext Paris. « Nous sommes très fiers de compter le Pr. Jamal Tazi parmi nos collaborateurs et nos amis. Son dévouement à trouver une guérison au VIH est un moteur essentiel de nos travaux. Au nom de l’ensemble des collaborateurs d’ABIVAX, je souhaite le féliciter pour cette distinction prestigieuse remise par le CNRS et lui rappeler que je me réjouis à l’idée de poursuivre notre collaboration afin d’atteindre notre objectif : développer de nouveaux traitements pour les patients infectés par le virus du VIH et d’autres maladies virales potentiellement mortelles, » ajoute le Pr. Hartmut Ehrlich, M.D., Directeur Général d’ABIVAX. Le Centre national de la recherche scientifique est un organisme public de recherche, placé sous la tutelle du Ministère de l'Éducation nationale, de l'Enseignement supérieur et de la Recherche. La médaille de l'innovation du CNRS, créée en 2011, honore des recherches scientifiques exceptionnelles ayant conduit à une innovation marquante sur le plan technologique, thérapeutique ou sociétal et valorisant ainsi la recherche scientifique française. Chaque année, un jury décerne entre une et cinq médailles à des chercheurs et ingénieurs du CNRS, d'autres organismes de recherche, des universités et des grandes écoles, ou encore à des industriels très engagés dans des actions de recherche. ABIVAX est une société innovante de biotechnologie qui cible le système immunitaire pour éliminer des maladies virales. ABIVAX dispose de trois plateformes technologiques : une plateforme « antivirale », « stimulation immunitaire » et « anticorps polyclonaux ». Son produit le plus avancé, ABX464, est actuellement en Phase II d’étude clinique afin d’évaluer sa capacité à devenir un élément de guérison fonctionnelle du VIH/SIDA. ABX464 est une nouvelle molécule administrée par voie orale qui inhibe la réplication virale via un mode d’action unique et qui présente indépendamment un fort effet anti-inflammatoire. ABIVAX développe également un candidat immunostimulant en phase clinique ainsi que plusieurs candidats précliniques pour d’autres cibles virales (Chikungunya, Ebola, Dengue, etc.). Plusieurs de ces composés sont susceptibles d’entrer en phase de développement clinique dans les 18 prochains mois. ABIVAX est cotée sur le compartiment B d’Euronext à Paris (ISIN : FR0012333284 – Mnémo : ABVX). ABIVAX est éligible au PEA-PME.
Kowalski J.,IST Austria Institute of Science and Technology Austria |
Kowalski J.,University of Basel |
Gan J.,IST Austria Institute of Science and Technology Austria |
Jonas P.,IST Austria Institute of Science and Technology Austria |
And 3 more authors.
Hippocampus | Year: 2016
The hippocampus plays a key role in learning and memory. Previous studies suggested that the main types of principal neurons, dentate gyrus granule cells (GCs), CA3 pyramidal neurons, and CA1 pyramidal neurons, differ in their activity pattern, with sparse firing in GCs and more frequent firing in CA3 and CA1 pyramidal neurons. It has been assumed but never shown that such different activity may be caused by differential synaptic excitation. To test this hypothesis, we performed high-resolution whole-cell patch-clamp recordings in anesthetized rats in vivo. In contrast to previous in vitro data, both CA3 and CA1 pyramidal neurons fired action potentials spontaneously, with a frequency of ∼3-6 Hz, whereas GCs were silent. Furthermore, both CA3 and CA1 cells primarily fired in bursts. To determine the underlying mechanisms, we quantitatively assessed the frequency of spontaneous excitatory synaptic input, the passive membrane properties, and the active membrane characteristics. Surprisingly, GCs showed comparable synaptic excitation to CA3 and CA1 cells and the highest ratio of excitation versus hyperpolarizing inhibition. Thus, differential synaptic excitation is not responsible for differences in firing. Moreover, the three types of hippocampal neurons markedly differed in their passive properties. While GCs showed the most negative membrane potential, CA3 pyramidal neurons had the highest input resistance and the slowest membrane time constant. The three types of neurons also differed in the active membrane characteristics. GCs showed the highest action potential threshold, but displayed the largest gain of the input-output curves. In conclusion, our results reveal that differential firing of the three main types of hippocampal principal neurons in vivo is not primarily caused by differences in the characteristics of the synaptic input, but by the distinct properties of synaptic integration and input-output transformation. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.
Lin C.-Y.,National Tsing Hua University |
Chuang C.-C.,National Center for High Performance Computing |
Chuang C.-C.,National Chiao Tung University |
Hua T.-E.,National Tsing Hua University |
And 6 more authors.
Cell Reports | Year: 2013
How the brain perceives sensory information and generates meaningful behavior depends critically on its underlying circuitry. The protocerebral bridge (PB) is a major part of the insect central complex (CX), a premotor center that may be analogous to the human basal ganglia. Here, by deconstructing hundreds of PB single neurons and reconstructing them into a common three-dimensional framework, we have constructed a comprehensive map of PB circuits with labeled polarity and predicted directions of information flow. Our analysis reveals a highly ordered information processing system that involves directed information flow among CX subunits through 194 distinct PB neuron types. Circuitry properties such as mirroring, convergence, divergence, tiling, reverberation, and parallel signal propagation were observed; their functional and evolutional significance is discussed. This layout of PB neuronal circuitry may provide guidelines for further investigations on transformation of sensory (e.g., visual) input into locomotor commands in fly brains. © 2013 The Authors.
News Article | November 18, 2015
In the cells of fruit flies, Chinese scientists say that they have found a biological compass needle: a rod-shaped complex of proteins that can align with Earth’s weak magnetic field. The biocompass — whose constituent proteins exist in related forms in other species, including humans — could explain a long-standing puzzle: how animals such as birds and insects sense magnetism. It might also become an invaluable tool for using magnetic fields to control cells, report researchers led by biophysicist Xie Can at Peking University in Beijing, in a paper published on 16 November in Nature Materials (S. Qin et al. Nature Mater. http://dx.doi.org/10.1038/nmat4484; 2015). “It’s an extraordinary paper,” says Peter Hore, a biochemist at the University of Oxford, UK. But Xie’s team has not shown that the complex actually behaves as a biocompass inside living cells, nor explained exactly how it senses magnetism. “It’s either a very important paper or totally wrong. I strongly suspect the latter,” says David Keays, a neuroscientist who studies magnetoreception at the Institute of Molecular Pathology in Vienna. Many organisms — ranging from whales to butterflies, and termites to pigeons — use Earth’s magnetic field to navigate or orient themselves in space. But the molecular mechanism behind this ability, termed magneto-reception, is unclear. Some researchers have pointed to magnetically sensitive proteins called ‘cryptochromes’, or ‘Cry’. Fruit flies lacking the proteins lose their sensitivity to magnetic fields, for example. But the Cry proteins alone cannot act as a compass, says Xie, because they cannot sense the polarity (north–south orientation) of magnetic fields. Others have suggested that iron-based minerals might be responsible. Magnetite, a form of iron oxide, has been found in the beak cells of homing pigeons. Yet studies suggest that magnetite plays no part in pigeon magnetoreception. Xie says that he has found a protein in fruit flies that both binds to iron and interacts with Cry. Known as CG8198, it binds iron and sulfur atoms and is involved in fruit-fly circadian rhythms. Together with Cry, it forms a nanoscale ‘needle’: a rod-like core of CG8198 polymers with an outer layer of Cry proteins that twists around the core (see 'Protein biocompass'). Using an electron microscope, Xie’s team saw assemblies of these rods orienting themselves in a weak magnetic field in the same way as compass needles. Xie gave CG8198 the new name of MagR, for magnetic receptor. The discovery offers scientists the prospect of using magnetic fields to control cells. Over the past decade, scientists have commandeered the light-sensing capacity of some proteins to manipulate neurons, usually by inserting a fibre-optic cable directly into the brain — a tool called optogenetics. But magnetosensing proteins have the advantage that they could be manipulated by magnetic fields outside the brain. Zhang Sheng-jia, a neuroscientist at Tsinghua University in Beijing, claims to have already demonstrated this ‘magnetogenetic’ capability. In September, he provided a surprise preview of Xie’s work when he published a paper reporting use of the biocompass to manipulate neurons in worms (X. Long et al. Sci. Bull. http://doi.org/883; 2015). Xie and others complained that Zhang’s early publication violated a collaboration agreement between the two researchers — the details of which are disputed — and asked for it to be retracted. In October, Zhang was fired from his university, a decision that he is contesting. Xie says that in April, he submitted a Chinese patent application that includes the use of magnetogenetics and the protein’s magnetic capacity to manipulate large molecules. He is also starting to look at the structure of MagR proteins in other animals, including humans. Variants in the human version of MagR might even relate to differences in people’s sense of direction, he suggests. Other scientists are not convinced that the biological needles function like compasses in living organisms. Xie’s team has shown that MagR and Cry are produced in the same cells in pigeon retinas — the birds’ proposed magnetoreception centre — but MagR and Cry are found in many cells, says Keays. “With such a small amount of iron, one has to ask whether in vivo, at physiological temperatures, MagR is capable of possessing magnetic properties at all,” he says. “If MagR is the real magnetoreceptor, I’ll eat my hat.” Xie hopes that others will strengthen his case with further experiments, such as inactivating the gene for MagR in certain fruit-fly tissues to see whether it affects the animals’ sense of direction. He published without doing this work, he says, because he just wanted to report the findings, which he has been working on for six years. The lack of an exact mechanism for how the protein complex senses magnetism, or how any signal it sends might be processed by the brain, gives some researchers pause. MagR’s biocompass activity might simply be the result of experimental contamination, says Michael Winklhofer, a magnetism specialist and Earth scientist at Ludwig Maximilian University of Munich in Germany. He is planning experiments to follow up on Xie’s team’s findings. If it holds up, says Winklhofer, then the discovery of MagR “appears to be a major step forward towards unravelling the molecular basis of magnetoreception”.
Kudithipudi S.,University of Stuttgart |
Lungu C.,University of Stuttgart |
Rathert P.,Jacobs University Bremen |
Rathert P.,Institute of Molecular Pathology |
And 2 more authors.
Chemistry and Biology | Year: 2014
The nuclear receptor binding SET [su(var) 3-9, enhancer of zeste, trithorax] domain-containing protein 1 (NSD1) protein lysine methyltransferase (PKMT) was known to methylate histone H3 lysine 36 (H3K36). We show here that NSD1 prefers aromatic, hydrophobic, and basic residues at the -2, -1 and +2, and +1 sites of its substrate peptide, respectively. We show methylation of 25 nonhistone peptide substrates by NSD1, two of which were (weakly) methylated at the protein level, suggesting that unstructured protein regions are preferred NSD1 substrates. Methylation of H4K20 and p65 was not observed. We discovered strong methylation of H1.5 K168, which represents the best NSD1 substrate protein identified so far, and methylation of H4K44 which was weaker than H3K36. Furthermore, we show that Sotos mutations in the SET domain of NSD1 inactivate the enzyme. Our results illustrate the importance of specificity analyses of PKMTs for understanding protein lysine methylation signaling pathways. © 2014 Elsevier Ltd. All rights reserved.
Maier H.J.,University of Ulm |
Wirth T.,University of Ulm |
Beug H.,Institute of Molecular Pathology
Cancers | Year: 2010
Pancreatic carcinoma is the fourth-leading cause of cancer death and is characterized by early invasion and metastasis. The developmental program of epithelial-mesenchymal transition (EMT) is of potential importance for this rapid tumor progression. During EMT, tumor cells lose their epithelial characteristics and gain properties of mesenchymal cells, such as enhanced motility and invasive features. This review will discuss recent findings pertinent to EMT in pancreatic carcinoma. Evidence for and molecular characteristics of EMT in pancreatic carcinoma will be outlined, as well as the connection of EMT to related topics, e.g., cancer stem cells and drug resistance. © 2010 by the authors; licensee MDPI, Basel, Switzerland.
Breuss M.,Institute of Molecular Pathology |
Keays D.A.,Institute of Molecular Pathology
Advances in experimental medicine and biology | Year: 2014
The development of the mammalian cortex requires the generation, migration and differentiation of neurons. Each of these cellular events requires a dynamic microtubule cytoskeleton. Microtubules are required for interkinetic nuclear migration, the separation of chromatids in mitosis, nuclear translocation during migration and the outgrowth of neurites. Their importance is underlined by the finding that mutations in a host of microtubule associated proteins cause detrimental neurological disorders. More recently, the structural subunits of microtubules, the tubulin proteins, have been implicated in a spectrum of human diseases collectively known as the tubulinopathies. This chapter reviews the discovery of microtubules, the role they play in neurodevelopment, and catalogues the tubulin isoforms associated with neurodevelopmental disease. Our focus is on the molecular and cellular mechanisms that underlie the pathology of tubulin-associated diseases. Finally, we reflect on whether different tubulin genes have distinct intrinsic functions.