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Microproteins (miPs) – the next big thing
Stephan Feller
Cell Communication and Signaling , 2012, DOI: 10.1186/1478-811x-10-42
Abstract: In case you do not know what they are, no need to worry: nobody does.However, with proto-genes recently entering the stage [1] it seems just a small step for mankind to assume that those dye fronts of protein gels you have been cutting off and binning for decades now harbour a plethora of precious little gems and thus an amazing potential for discovering exciting regulatory molecules that will bind to proteins etc. to regulate their conformations and activities, their binding partners, their subcellular localisation and so on.They can be expected to steer embryonic development and stem cell differentiation, to play a role in cancers and neurodegenerative diseases and should also make great leads for future drugs. Clearly, miPs are yet another Nobel Prize lurking, and begging for attention.To study them is easy: just mass spec your protein gel dye fronts to death, synthesise all found miP candidates, biotinylate them and go fishing for binding partners. Then introduce your miPs into cells using cell-penetrating shuttle peptides or transfections and watch their interaction partners misbehave in cells. Finally, do miP knock-outs and -ins in animals of your fancy and observe what happens to them. Alternatively, if you do not have access to mass spec-omics, look for short transcribed ORFs of unknown function in the genome, synthesise those ORFs as biotinylated peptides on a vast scale and then go fishing.That is all there is to it really,…so…would someone look, PLEASE.Of course, if you actually find something, we told you so, and we would want to share the glory and the financial rewards; and do not dare to simply call these newly found, super-exciting, sparkling entities merely regulatory peptides or christen them with another boring name like that, or you shall never be grand.Merry Christmas and a healthy, happy and very productive 2013 to all of you.
Life v2.0 - Quo vadis Homo sapiens?
Stephan M Feller
Cell Communication and Signaling , 2010, DOI: 10.1186/1478-811x-8-9
Abstract: Some of our fellow human beings will surely see the 20th of May 2010 as the day of our second eviction from paradise, or even the first step on a sliding slope to hell. For others it may mark the day when hope for a new age of human prosperity emerged, similar to the day when Prometheus brought fire to the humans. Prometheus, of course, personally paid dearly for his action and we can only hope that history does not repeat itself in this aspect; there is no doubt in my mind that the 'infotainment' media will once again play a prominent role in hyping up this latest accomplishment, thereby generating unnecessary anxiety or even hate and a thoroughly unrealistic picture of the possible spin-offs.So what has actually happened?Craig Venter, a seemingly tireless maverick/maniac/visionary, and his team have succeeded in copying, i.e. re-producing, and slightly modifying an existing life form - something that all living cells have been able to do for a long time already. The difference is, of course, that Homo sapiens can now re-create, and - at least on the DNA level - at will modify, Mycoplasma mycoides. This is really quite an amazing accomplishment and it was over a decade in the making [1,2]. Amongst other things, this 're-booting' of a cell shows that - at least in this simple organism - the 'programmed software', i.e. the genetic blueprint, seems to be able to fully instruct and facilitate the complete replacement of the cellular 'hardware'.Although this miniscule creature is potentially the most lowly version of all cellular life forms, its re-creation is clearly the beginning of many things. Not only is it the start of a new dimension in synthetic biology, it is probably also the real birthday of systems biology. So far, most so-called systems biologist have done at best 'sub-systems biology', but the new technologies developed by Venter et al. will enable completely unprecedented ways of systematic systemic experimentation with living cells. They should also make
Early beginnings - the emergence of complex signaling systems and cell-to-cell communication
Stephan M Feller
Cell Communication and Signaling , 2010, DOI: 10.1186/1478-811x-8-16
Abstract: For example, tyrosine kinases, phosphotyrosine-recognition domains (SH2 s etc.), and also the ancestral forms of large multi-docking proteins with folded N-termini and long 'intrinsically disordered' tails, like the p130Cas, Gab or IRS family proteins [3-5], which mediate high molecular weight signal transduction and integration complexes, emerged early during metazoan evolution [6]. Later on, genome duplications occurring during vertebrate evolution [7] allowed the emergence of small families of signaling proteins from single ancestor proteins. So compared to Drosophila and C. elegans, which typically have still one prototype protein, Homo sapiens has often three or four close relatives.But why, when and how did signaling pathways and networks emerge in the first place? Clearly, the key to survival for all cells and organisms is to sense and respond appropriately to their natural surroundings. The sensing of the environment and signaling are very intimately linked, so it does not seem unlikely that a prokaryotic chemotaxis system [8] represents the first form of a cellular signaling system. The earliest presumed fossil records (stromatolites) seem to indicate that cellular life forms may have evolved over three billion years ago and it is hard to imagine that these early life forms would have been able to thrive for long without an environmental recognition and response system.And when did multicellular organisms, which needed more complex signaling systems, including cell-to-cell communication, actually start to emerge? A new study now suggests a point in time over 2 billion years ago [9]. Macroscopically visible fossil records of up to a dozen centimetres in size found in equatorial Africa (southeastern Gabon), if interpreted correctly, point to the emergence of multicellularity relatively soon after the onset of the 'great oxidation event' [10]. These newly reported fossils form flat sheets with scalloped margins and noticeable radiating structures that seem to
The dawn of a new era in cell signalling research
Stephan M Feller
Cell Communication and Signaling , 2010, DOI: 10.1186/1478-811x-8-7
Abstract: We are now beginning to appreciate that this image is far from the truth. It is in fact hindering us in designing more appropriate experiments to understand cell signalling in general and the role of specific components in particular.Similarly, attempts to describe cellular signalling events with mathematical equations that are based on solution phase diffusion chemistry by self-declared 'systems biologists' [1] are commonly doomed to failure.A number of recent publications [2-6] and conferences (e.g. the 2009 Seefeld Meeting of the Protein Modules Consortium; http://www.proteinmodules.org/ webcite) provide some insight into how we can advance our research field in the future. To give but a few examples:We must take into serious consideration that signalling mostly occurs in protein assemblies that may be highly organised but are at least specifically localised to distinct, functionally defined subcellular compartments. These complexes are often of considerable size and probably contain vast numbers of components in some cases.We must take into account that many of the utilised proteins are being produced (translated) in restricted subcellular locations and that they may not diffuse much before they meet most of their interaction partners.We need to investigate more carefully in which cases signalling enzyme - substrate interactions are primarily driven by highly specific recognition motifs and in which by close proximity of the interacting components [or by a combination of both].Some signalling proteins appear to be quite scarce, with only a few molecules present per cell, while others can be found in several distinct pools with many thousand copies in each pool. Local signal transduction component ratios within distinct cellular sites therefore deserve much more detailed investigation than is currently undertaken. In this context it should be pointed out that many standard over-expression experiments are rather likely to produce substantial artefacts: the resulti
First Honorary Medal of the Signal Transduction Society (STS) and 'CELL COMMUNICATION AND SIGNALING' awarded to Professor Anthony J. (Tony) Pawson
Stephan M Feller
Cell Communication and Signaling , 2011, DOI: 10.1186/1478-811x-9-3
Abstract: Accordingly, the molecularly targeted interference with disease-driving signal transduction pathways was a major theme of many presentations. From these it became apparent that, in addition to the by now almost 'classical' blockers of kinases, inhibitors of protein - protein interactions are beginning to make their way towards the center stage.It was therefore very timely that the newly introduced Honorary Medal of STS and CCS was presented to Prof. Tony Pawson, one of the founding fathers of protein - protein interaction research in cell signaling 'for the discovery of protein interaction domains and elucidating their essential roles in the transmission of cellular signals'.Tony and his team discovered the Src Homology 2 (SH2) domains in the mid 1980s as conserved and functionally relevant regions in cytoplasmic tyrosine kinases [1,2]. From there, it took almost another five years until the ability of SH2 domains to bind to certain tyrosine phosphorylated proteins was reported by three groups, initially at the 6th Oncogene Meeting (26-30 June 1990; Frederick, MD, USA) [3-5].From then on this research field expanded massively and Tony Pawson has been repeatedly leading the way, conceptually and experimentally. At present over 200 posttranslational protein modifications and over 100 'reader' domains for these modifications have been identified in the human proteome.One of several conference highlights in this area was the presentation of multiple novel crystal structures and an anti-oncogenic inhibitor of BET subfamily bromodomains by Panagis Filippakopoulos et al. from the Oxford branch of the Structural Genomics Consortium [6]. This first example of a specific inhibitor for a chromatin modification-reading protein interaction domain with in vivo activity is expected to add further momentum to the current shift of interests in the pharmaceutical sector towards the realm of epigenetic processes.Another important message emerged, for example, from the presentation of
Beyond journal impact factors?
Stephan M Feller
Cell Communication and Signaling , 2010, DOI: 10.1186/1478-811x-8-4
Abstract: Nowadays, many scientists will simply not publish in a journal that does not have an impact factor. There are multiple reasons for this. One is that many universities have started to distribute funds according to formulas that are directly linked to the number of publications a researcher produces and the impact factors of the publishing journals. Therefore, getting a paper into a certain journal and publishing two short papers rather than one longer one (with the same data) can have a major impact on the financial viability of a research group or department. Whether this increasing dependency of researchers on journal impact factors has a positive impact on the speed and quality of their research and of the resulting publications, i.e. their public visibility and the actual output of data and whether it is beneficial to science and society in general, is at least somewhat doubtful, as I shall detail further below.It has become a way of life for many researchers to create, for each emerging manuscript, a list of possibly suitable journals, which are ranked strictly according to their impact factors. Submission of the manuscript then starts at the top of the list. Quite often even the authors know that the chances for acceptance of their work in this top-tier journal are minimal, but nevertheless 'one might get very lucky', or 'one might at least get a foot in the door' (i.e. a chance to resubmit after a very major revision), or 'one might get good suggestions for further experiments from the reviewers', or... In reality, however, this strategy almost always leads to multiple rejections in a row, while numerous hours are spent on reviewing, reformatting and rewriting the manuscript, leading to a substantial loss in productive research time for both authors and reviewers.A second reason for the prominent role of journal impact factors is that they are used in an ever-growing number of career-deciding evaluations by review boards of funding agencies, recruitment commit
Obituary: Hidesaburo Hanafusa 1929–2009
Stephan M Feller
Cell Communication and Signaling , 2009, DOI: 10.1186/1478-811x-7-7
Abstract: 'Saburo' [meaning 'third-born son'], as most people knew him, was an inspiring scientist and a much beloved mentor to a large number of scientist currently conducting ground breaking research around the world. Modestly omitting the glorifying portion of his first name 'Hide-', i.e. 'excellent', was a clear tell-tale-sign of his personality.Saburo always presented himself very calmly and gentlemanly, even shy, and he was never aggressive in promoting his outstanding research contributions, a somewhat rare trait in this day and age. For this he was greatly admired by many colleagues and his soft-spoken and well-chosen words carried much gravitas. As such, he was a vital figure in steering academic life at the renowned Rockefeller University in New York City, where he spent most of his scientific career.Born on 1 December 1929 in Nishinomiya, Japan, Saburo received his bachelor degree in 1953, and his doctorate in 1960, both from Osaka University. In 1958, he married Teruko Inoue, a fellow student, who would also become an important and lifelong scientific colleague with whom he published over 35 papers between 1959 and 1992.In 1961 Saburo accepted a postdoctoral position in the US, joining the laboratory of Harry Rubin, a pioneer in tumor virus research at Berkeley (University of California). This is where he began to work on the Rous Sarcoma Virus (RSV), the focus of his research for decades to come and one of the areas where his seminal findings gained him worldwide recognition and in 1982 the Lasker Award, often called the 'American Nobel Price'. In 1985 he was elected into the US National Academy of Sciences.Saburo also received many other awards, including the Alfred P. Sloan, Jr. Prize in 1993 and the highly prestigious 'Bunka Kunsho', Japan's Order of Culture Award, presented to him by the Japanese Emperor, in 1995 and an honorary doctoral degree from Rockefeller University in June 2000.Following his first research successes with RSV in the Rubin laboratory, Sa
Science, democracy and emerging threats to scientific progress
Stephan M Feller
Cell Communication and Signaling , 2012, DOI: 10.1186/1478-811x-10-24
Abstract: At present the vast majority of scientifically leading countries are ruled by democratic systems, with the USA, the EU, Japan and Australia dominating research output and quality. But this may change rapidly, at least in terms of output.Clearly, even in the USA, Europe etc. the current peer review systems is not fool-proof ( https://www.scienceexchange.com/reproducibility webcite) [1,2] and article retractions due to fabrication of data are on the rise in a fiercely competitive environment created by an economically difficult climate [3].But are matters much worse in countries where people get promoted based on party membership and non-scientific network connections rather then on the quality of their scientific output? Does it hurt scientific progress if governments are able to suppress unpleasant data on environmental issues, the population health effects of pollutants, and negative effects of rigid population restriction measures on mental health and crime? Is it bad for scientific progress if people are protected from punishment for scientific fraud and for stealing the data of colleagues because a family member is high up in the party hierarchy? Can we trust clinical studies from countries where patients have little or no means to ensure they get decent treatment and where hospitals are used for the cheap and uncontrolled testing of new drugs? Which areas of scientific research, if any, can remain unaffected by uncontrolled governmental intervention and/or lack of protection of human rights?Scientific journal publishers should tread very carefully and must not ignore these issues.If they do, scientists concerned about growing obstacles to scientific progress might take the publishing of scientific papers back into their own hands.After all, these days it needs little more than some relatively simple (and widely available) computer software and a couple of servers to publish electronic science journals. In the era of the internet, scientific societies of suffici
Science under the lamppost
Stephan M Feller
Cell Communication and Signaling , 2011, DOI: 10.1186/1478-811x-9-21
Abstract: As we have moved from the age of manic predator capitalism into the embarrassing age of 'pampers capitalism' (i.e. the common man has to clean up the mess created by irresponsible bankers and is even expected to pay for the nappies to catch the future fallout that is very likely to occur), the pressure grows immensely to fund only science that appears to have such an obvious and quick payoff for society that any dimwit can spot without a problem.Short-sighted science administrators/managers who are primarily eager to keep a low profile and politicians who are largely focussed on being re-elected love this kind of science, especially if it is linked to fancy gadgets.This coincides nicely with the flourishing of high-throughput (HTP) platform technologies that produce monstrous amounts of data. So far physics has been the science to churn out terabytes of data per day, but soon biomedicine, for example large nucleic acid sequencing projects and high throughput proteomics, will surpass the physicists with ease in their ability to generate vast piles of data that no one understands. It will be all but impossible to effectively extract most information from these piles, in part because the conceptual frameworks for this are still missing.Cell signalling networks are a case in point. Even the most complex network charts or depictions of signalling hub collections and their connections still resemble the drawings primary school children in their simplicity. An overarching concept of how large signalling networks really function in vivo does not exist [1], in part because the molecular architectures of large signalling complexes and their in vivo connections remain practically unknown. So far, the fact that signalling occurs in an extremely crowded intracellular environment, and therefore must be highly coordinated not only in time but also in 'nanospace', is only on the agenda of a relatively small number of scientists. This is not surprising, because this research area st
What’s in a loop?
Stephan M Feller, Marc Lewitzky
Cell Communication and Signaling , 2012, DOI: 10.1186/1478-811x-10-31
Abstract: DNAs are different from proteins in many ways. Our genomic DNA molecules are vast, even when compared to the largest proteins we know. DNA is essentially composed of 4 building blocks that are at best modified with a few extra side bits here and there. In proteins we find at least 20 different amino acids and more than one hundred types of posttranslational modifications.The genomic DNAs of eukaryotes live mostly in one confined cell compartment, while proteins lurk in virtually every corner of the cell and many of them whiz about.DNA seems to be usually just able to coil into spirals that coil into bigger spirals (30 nm fibre) that coil into even bigger spirals (200 nm fibre/chromosome), while proteins can take up a plethora of diverse and highly complex shapes, or, for intrinsically disordered proteins, no apparent shapes at all.Most DNA seems to have the capacity to live forever, while probably all proteins have a quite limited lifespan.Despite all of these differences, DNA and proteins have of course a number of things in common. Both are extremely important classes of biomolecules and both are, for example, able to store information. In addition, they share an architectural feature related to complex information processing: substantially sized loop structures.In genomic DNAs, these loops have already been studied for decades and in some detail, but exciting new results are still constantly emerging [1-3].To reveal its information, DNA must be untangled and often distant regions within one molecule or between fellow DNA molecules have to interact. These communicating loops enable promoters, enhancers and other regulatory elements, which are sometimes megabases apart, to come together in space and time in a highly dynamic process which is not entirely understood [4,5]. An early example for this type of long-distance interaction was the finding that the beta-globin enhancer, which is located far upstream of the globin genes, comes into close proximity when the gen
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