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Science is a lot like sex. Sometimes something useful comes of it, but that's not the reason we're doing it. --Richard Feynman- Welcome to the weblog of Björn Brembs, the owner of brembs.net. I'm a biologist with a wide variety of other scientific and non-scientific interests.

Björn Brembs
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  • December 26, 2011
  • 05:26 PM
  • 184 views

Impact factor predicts unreliability of research papers

by Björn Brembs in bjoern.brembs.blog

Last week, we've already seen that the most prominent way of ranking scholarly journals, Thomson Reuters' Impact Factor (IF), isn't a very good measure for predicting how many citations your scientific paper will attract. Instead, there is evidence that IF is much better at predicting the chance that your paper might get retracted.Now, I've just been sent a paper (subscription required) which provides evidence that the reliability of some research papers correlates negatively with journal IF. In other words, the higher the journal's IF in which the paper was published, the less reliable the research is. This particular evidence holds only for genome-wide association studies (GWAS), but given the high correlation between IF and retractions, it likely holds for other research as well. Now what is the data? The paper contains one figure:On the X-axis you see the impact factor and on the Y-axis a measure for the bias of the GWAS data on a logarithmic scale. How did the authors calculate this bias score? In their own words:We divided the individual study odds ratio (OR) by the pooled OR, to arrive at an estimate of the degree to which each individual study over- or underestimated the true effect size, as estimated in the corresponding meta-analysis. We have recently used this method to identify a biasing effect of research location and resources. (Munafo MR, Matheson IJ, Flint J. Mol Psychiatry 2007; 12: 454–461)Thus, the authors plot a value that indicates by how much a single study over- or underestimates the actual effect (estimated by taking many studies into account) of a gene-phenotype association. The size of the circles on the graph indicates the sample size of the study. The overall "R squared" value, or the Coefficient of Determination for this correlation is only 0.13, but at a highly significant P=0.00002. This means that the correlation is pretty weak, but it is statistically significant.This sort of correlation, low R2 but statistically significant, corresponds roughly to the pattern of correlations one can see with citations: IF is predicting citations of a paper to some degree, but not very reliably. Likewise, IF is predictive of a GWAS unrealiability, but not very reliably. Or, phrased differently, IF is about as predictive of a paper's unreliability as it is about its citations, which I'd consider quite bad for something that decides about scientific careers.But another important point can be seen in the graph: IF is also predictive of the sample size of the GWAS study: the higher the IF of the journal in which the study was published, the lower the sample size. One could interpret this as evidence that high-IF journals are more likely to publish a large GWAS effect, even though it is only backed up by a small sample size, while low-IF journals require a more solid amount of data to back up the authors' claims.Taken together, this study provides some evidence for one of the potential mechanisms underlying the very strong correlation between IF and retractions we've seen before: authors are more likely to publish unreliable data with predominantly overestimated effect sizes in high-IF journals. Importantly, this constitutes a mechanism which cannot be explained by high-IF journals being more closely scrutinized than low-IF journals. Instead, it suggests that at least a portion of the retractions in high-IF journals is due to the studies published there being more likely to be flawed than studies in low-IF journals.In the words of the authors:Our results indicate that genetic association studies published in journals with a high impact factor are more likely to provide an overestimate of the true effect size. This is likely to be in part due to the small sample sizes used and the correspondingly low statistical power that characterizes these studies. Initial reports of genetic association published in journals with a high impact factor should therefore be treated with particular caution. However, although we cannot necessarily generalize our findings to other research domains, there are no particular reasons to expect that genetic association studies are unique in this respect.Munafò, M., Stothart, G., & Flint, J. (2009). Bias in genetic association studies and impact factor Molecular Psychiatry, 14 (2), 119-120 DOI: 10.1038/mp.2008.77... Read more »

Munafò, M., Stothart, G., & Flint, J. (2009) Bias in genetic association studies and impact factor. Molecular Psychiatry, 14(2), 119-120. DOI: 10.1038/mp.2008.77  

  • December 14, 2011
  • 05:37 AM
  • 323 views

Science without journals: More evidence that journal rank is a poor predictor of citations

by Björn Brembs in bjoern.brembs.blog

In response to my last post, Dwight Kravitz from the NIH alerted me to his paper on a similar topic: Toward a new model of scientific publishing: discussion and a proposal. His paper contains some very interesting data, such as this analysis of citations and journal rank:The left-skewed form of the data is of course nothing new, but their analysis of how predictive journal rank is for actual citations opens a new aspect, I think:Our evaluation reveals that far from a perfect filter, the distribution of citations largely overlaps across all six journals (Figure 2). We then asked whether the citation count of a paper could predict the tier at which it was published and found that between adjacent tiers this could only be achieved at 66% accuracy and between the top and third tier at 79%2. Thus, even given the self-reinforcing confounds, the journals tiers are far from a perfect method of prioritizing the literature.So even if you look at very different tiers in the hierarchy, there are more than 20% of all papers that receive too many or too few citations than 'expected' from the journal they've been published in.Whatever way you look at it, journal rank is completely anachronistic and must go.Their paper contains a number of absolutely lovely quotes, some of which I just have to showcase:Scientific papers are published through a legacy system that was not designed to meet the needs of contemporary scientists, the demands of modern publishing, or to take advantage of current technology. The system is largely carried forward from one designed for publishers and scientists in 1665[...]In total, each paper was under review for an average of 122 days but with a minimum of 31 days and a maximum of 321. The average time between the first submission and acceptance, including time for revisions by the authors was 221 days (range: 31–533). This uncertainty in time makes it difficult to schedule and predict the outcome of large research projects. For example, it is difficult to be certain whether a novel result will be published before a competitor’s even it were submitted first, or to know when follow up studies can be published. It also makes it difficult for junior researchers to plan their careers, as job applications and tenure are dependent on having published papers.[...]Scientific progress is supposed to be largely incremental, with each new result fully contextualized with the extant literature and fully explored with many different analyses and manipulations. Replications, with even the tiniest additional manipulations, are critical to refining our understanding of the implications of any result. Yet, with the focus on the worthiness for publication, especially novelty, rather than on scientific merit, Reviewers look on strong links with previous literature as a weakness rather than strength. Authors are incentivized to highlight the novelty of a result, often to the detriment of linking it with the previous literature or overarching theoretical frameworks. Worse still, the novelty constraint disincentives even performing incremental research or replications, as they cost just as much as running novel studies and will likely not be published in high-tier journals.[...]Luckily, these deficiencies are structural and do not arise because of evil Authors, Reviewer, or Editors. Rather, they are largely a symptom of the legacy system of scientific publishing, which grew from a constraint on the amount of physical space available in journals. The advent of the Internet eliminates the need for physical copies of journals and with it any real space restrictions. In fact, none of the researchers in our lab had read a physical copy of a journal in the past year that was not sent to them for free. Without the space constraint there is no need to deny publication for any but the most egregiously unscientific of papers. In fact, we argue that simply guaranteeing publication for any scientifically valid empirical manuscript attenuates all of the intangible and quantifiable costs described above. Functionally, publication is already guaranteed, it is simply accomplished through a very inefficient system. 98.2% of all papers that enter the revision loop are published at that same journal and few papers are abandoned over the course of the journal loop.The authors also suggest a system without journals where publication is guaranteed after pre-publication peer-review and where a post-publication peer-review service provides some alert functionality for readers. To this I'd suggest to have, say, current GlamMag journal editors set up competing review services and after some time, users can evaluate which of these services has been more accurate (e.g., how often have selected/non-selected papers been cited and which review service predicted these results). Constant update of such performance would put the editors under pressure to perform accurate paper selection and users would be able to chose the service which selected ther papers relevant for them.Kravitz, D., & Baker, C. (2011). Toward a New Model of Scientific Publishing: Discussion and a Proposal Frontiers in Computational Neuroscience, 5 DOI: 10.3389/fncom.2011.00055... Read more »

Kravitz, D., & Baker, C. (2011) Toward a New Model of Scientific Publishing: Discussion and a Proposal. Frontiers in Computational Neuroscience. DOI: 10.3389/fncom.2011.00055  

  • November 22, 2011
  • 09:58 AM
  • 169 views

What does determinism have in common with gods, the flying spaghetti monster and pink, invisible unicorns?

by Björn Brembs in bjoern.brembs.blog

I usually don't blog about physics. Actually, I don't think I ever have, which is not surprising given that I'm not a physicist. This unusual post was prompted by an ongoing series of encounters with people asking me how I can be so sure that the universe is indeterministic. I'm explicitly writing this as an interested layperson, even though I took elementary quantum mechanics as special subject in high school and was supervised during my PhD by Martin Heisenberg, the youngest son of Werner Heisenberg.The reason why I'm reasonably sure that the universe is indeed indeterministic is rather simple: there is no empirical evidence to suggest that the universe is deterministic and plenty of evidence that it is indeterministic. Of course, that doesn't mean that the universe may not be deterministic after all, it only means that at the moment we don't have the slightest reason to believe in determinism - which is sort of analogous to belief in the supernatural.Because there are different concepts which people use when they talk about determinism, let me briefly clarify which of these concepts I'm referring to with 'determinism'. The kind of determinism important for behavioral biologists like me, studying spontaneous actions, is 'causal determinism', i.e., the concept that everything in the universe has a cause and every such event can eventually, in theory, be traced back to the big bang. Adherents to this idea claim that the apparent indeterminism in Quantum Mechanics is merely a testament to the finite human brain not being able to accurately account for events which are determined, but seem, to us, random or indeterminate. In essence, this is what Einstein was expressing when he exclaimed that 'god does not play dice with the universe'. Which goes to show that even geniuses like Einstein don't get everything right.One of the predictions that Einstein derived was Quantum Entanglement. He claimed that this 'spooky action at a distance' was, as a consequence of quantum mechanics, such an obviously silly idea that it had to falsify the whole theory, or at least show that it was incomplete. However, quantum entanglement is a very real phenomenon that has later been directly observed and is now used in some protocols of quantum cryptography.The most commonly used metaphor is that of 'hidden variables' which would make every event in the universe deterministic, if only we would be able to know of these variables. However, Bell's Theorem suggests that at least the 'local' variety of these hidden variables is not possible.A common misconception by many lay-determinists (non-physicists) is that Heisenberg's uncertainty principle describes a technical problem of our measurements rather than a principle of the universe. However, Stephen Hawking predicted the radiation named after him as stemming from virtual particle/antiparticle pairs being generated by quantum vacuum fluctuations right at the event horizon of black holes. A similar effect was claimed to have been observed in the lab. Just this week, another effect having to do with quantum fluctuations in a vacuum generating particle/antiparticle pairs has been observed. Forty years ago it was predicted that these same fluctuations which are thought to give rise to Hawking Radiation should become 'real', i.e., visible photons when they hit a mirror which moves at a significant fraction of the speed of light. It is this generation of photons which was directly observed and reported in the paper cited above.Another problem for determinists is radioactive decay: all nuclei of a radioactive element are thought to be physically identical. Yet, some of these nuclei decay only fractions of a second after the were generated, while others exist for millennia. There currently exists no theory trying to explain this discrepancy or predict the decay of individual nuclei. On the contrary, these processes seem to so exquisitely follow the rules of statistics, that they are used to construct genuine random-number generators.And there are many more such examples (see references below). In short, Einstein was one of the physicists who felt that there had to be something wrong with quantum mechanics and failed to show it. Now, more than eighty years later, there still is no hole in the theory and the universe is still as indeterminate as it was back in Einstein's time. Thus, as a biologist, I must say that my universe will remain indeterminate until someone unequivocally shows it to be determinate.Consequently, this would also mean that brains are, at least to the extent as they are part of this universe, indeterminate. Unlike in algae or birds, the degree to which quantum effects affect biological processes in the brain is not yet known. However, unless the brain is a bubble in which quantum effects cannot occur, some of the fluctuations in the brain which are thought to underly the generation of spontaneous behavioral variability, have some quantum origin. We don't know the fraction of these contributions, but they must be larger than zero. We also don't know how relevant they are to behavioral variability, only that they somehow contribute, simply because they occur and the nonlinear mechanisms in the brain could in principle pick them up. This, in brief, is the physics underlying the biology of free will.Further reading:Living in a quantum worldDynamics, Quantum Mechanics and the Indeterminism of NatureFree randomness amplificationNo extension of quantum theory can have improved predictive powerMany thanks to Bruno Landeros for providing most of the references linked to above!Wilson, C., Johansson, G., Pourkabirian, A., Simoen, M., Johansson, J., Duty, T., Nori, F., & Delsing, P. (2011). Observation of the dynamical Casimir effect in a superconducting circuit Nature, 479 (7373), 376-379 DOI: 10.1038/nature10561Brembs, B. (2010). Towards a scientific concept of free will as a biological trait: spontaneous actions and decision-making in invertebrates Proceedings of the Royal Society B: Biological Sciences, 278 (1707), 930-939 DOI: 10.1098/rspb.2010.2325... Read more »

Wilson, C., Johansson, G., Pourkabirian, A., Simoen, M., Johansson, J., Duty, T., Nori, F., & Delsing, P. (2011) Observation of the dynamical Casimir effect in a superconducting circuit. Nature, 479(7373), 376-379. DOI: 10.1038/nature10561  

Brembs, B. (2010) Towards a scientific concept of free will as a biological trait: spontaneous actions and decision-making in invertebrates. Proceedings of the Royal Society B: Biological Sciences, 278(1707), 930-939. DOI: 10.1098/rspb.2010.2325  

  • November 4, 2011
  • 05:28 AM
  • 179 views

Is FoxP a coin with autism on one side and schizophrenia on the other?

by Björn Brembs in bjoern.brembs.blog

The FOXP2 gene is well-known for its involvement in language disorders. We are just getting ready to publish our discovery that a relative of this gene in the fruit fly Drosophila, dFoxP, is necessary for a learning mechanism that resembles language learning in a lot of ways, operant self-learning. This discovery traces one of the evolutionary roots of language back to the 'Urbilaterian', the last common ancestor of invertebrates and vertebrates, more than half a billion years before the first word was ever spoken. A remarkable pre-adaptation (‘exaptation’) for language.Intriguingly, dFoxP-function also differentiates between self and non-self: forms of learning in which the animals had to learn about their environment, rather than about their own behavior, were unaffected by our manipulations of dFoxP function.While we were writing up the results for our manuscript, I stumbled across two papers by Bernard Crespi. The first detailed a hypothesis of how autism and schizophrenia may be conceived as two diametrically opposite ends of a continuous spectrum, the other was a test of that hypothesis. From their abstract: We used data from studies of copy-number variants (CNVs), single-gene associations, growth-signaling pathways, and intermediate phenotypes associated with brain growth to evaluate four alternative hypotheses for the genomic and developmental relationships between autism and schizophrenia: (i) autism subsumed in schizophrenia, (ii) independence, (iii) diametric, and (iv) partial overlap. Data from CNVs provides statistical support for the hypothesis that autism and schizophrenia are associated with reciprocal variants, such that at four loci, deletions predispose to one disorder, whereas duplications predispose to the other. Data from single-gene studies are inconsistent with a hypothesis based on independence, in that autism and schizophrenia share associated genes more often than expected by chance.[...]These convergent lines of evidence appear most compatible with the hypothesis that autism and schizophrenia represent diametric conditions with regard to their genomic underpinnings, neurodevelopmental bases, and phenotypic manifestations as reflecting under-development versus dysregulated over-development of the human social brain. So basically, one of the things they looked at was whether there were any genes implicated in both autism and schizophrenia. For the genes they found, they tested if different variants of these genes would be associated specifically with each disorder. Finally, they tested whether the nature of the genetic differences would say anything about the potential dysregulations of gene function involved in the two disorders.Most relevant for us was that FOXP2 showed up in their study: for the genes AHI1, APOE, DRD1, FOXP2, HLA-DRB1, and SHANK3, alternative alleles, genotypes, or haplotypes at the same loci appear to mediate risk of these two conditions.Which means that the FOXP2 gene in humans is associated with both autism and schizophrenia, but that some variants of the gene are specifically associated with autism and not with schizophrenia, while the opposite holds for other variants.What is the spectrum that Crespi et al. hypothesize autism and schizophrenia might be the opposite end points of? In their own words:Under-development of social phenotypes such as theory of mind, language, sense of self in relation to others, and reciprocal social interaction represent well-recognized manifestations of autism. [...]By contrast, such psychotic traits as auditory hallucination and thought disorder, paranoia, megalomania, and ascription of causal purpose to inanimate objects may be interpretable in terms of dysregulated hyperdevelopment of language, theory of mind and sense of self, all traits that are highly derived and elaborated in the human lineage.The important component of these factors Crespi et al. enumerate with respect to FoxP function is of course 'sense of self'. Is it really a coincidence that even in flies dFoxP function differentiates between self and non-self, a key process malfunctioning in autism and schizophrenia, or is the genetic network in which FoxP is embedded highly conserved through evolution (i.e., a case of 'deep' homology)?Crespi, B., Stead, P., & Elliot, M. (2009). Comparative genomics of autism and schizophrenia Proceedings of the National Academy of Sciences, 107 (suppl_1), 1736-1741 DOI: 10.1073/pnas.0906080106... Read more »

Crespi, B., Stead, P., & Elliot, M. (2009) Comparative genomics of autism and schizophrenia. Proceedings of the National Academy of Sciences, 107(suppl_1), 1736-1741. DOI: 10.1073/pnas.0906080106  

  • October 31, 2011
  • 08:29 AM
  • 173 views

'The neurobiology of self-learning' - the birth of a new field in neuroscience?

by Björn Brembs in bjoern.brembs.blog

It's been a while since I've last been so excited about a new finding by someone else And until today, this paper from last week even flew completely under my radar. I had seen the title and decided it's not relevant. A collaborator of mine sent it to me after she found it searching for a current affiliation of a former postdoc of hers - which was how she realized how pertinent this work was to our research and sent it to me (which says something about the way scientists are able to stay on top of the literature. Note to self: write separate post!).This paper detailing experiments in transgenic mice joins a pair of papers in invertebrate model systems (Aplysia and Drosophila), suggesting that brains have two distinct molecular learning mechanisms, one to learn about relationships among events in the world around them and one to learn about the effects of their own behavior on the world. This distinction shares several conceptual features with the distinctions that have been made between operant conditioning and classical conditioning or between declarative and procedural memory, and several other related dichotomies, but is yet slightly different.Here's a drastically simplified diagram of what the current canonical pathway looks like for 'synaptic plasticity', the kind of physiological process that modifies the connections between neurons in order to store memories (screenshot from one of my talks):Briefly, the to-be-remembered information is translated into neuronal signals which are eventually translocated into the memory-storing neuron, where an adenylyl cyclase (encoded by the rutabaga gene in flies) generates cAMP, which activates Protein Kinase A (PKA), which in turn eventually activates a protein with the acronym CREB. CREB is a transcription-factor switching on genes which modify the neuron, storing the memory. Not shown is how PKA can itself also modify the neuron to allow memories to form almost instantaneously, without the need for protein synthesis (which takes a while). OK, this is really extremely simplified, but the important point here is that there is no Protein Kinase C (PKC) involved. In fact, PKC has been shown to either not be involved at all, or only to maintain the memory, long after it's been formed. The cool thing about this learning mechanism (and why its discovery got the Nobel Prize in 2000) is that you find it in all bilaterian animals, e.g. flies, snails and mice.In 2008 I wrote here about one of our publications that we had discovered a 'Skinnerian' learning mechanism, which did not require the rutabaga gene, but PKC. Back then we couched the discovery in terms of the 70-something year-old debate about whether operant and classical conditioning share a common learning mechanism or not. The idea was that operant conditioning involves learning about the consequences of one's behavior while classical conditioning involves learning about the ring of a bell being followed by food For this experiment, we used the genetic toolkit of Drosophila to express an inhibitor of PKC (PKCi) in all cells of the fly only during the experiment. These flies had trouble learning an operant task in which all external cues had been removed, but as soon as 'classical' cues were added, they learned just fine.This discovery was followed in the same year by a paper from my postdoctoral lab that showed basically the analogous outcomes in the marine snail Aplysia. This got me very excited: flies and snails? What about the chordates?In their new paper, Rochefort et al. express the same PKCi peptide that we had used in our fly study in the cerebellum of mice. They use these mice to perform orientation and navigation experiments in which the animals either have to rely on self-motion cues (procedural learning) or on the position and identity of external cues (declarative learning) to find a particular location. It turned out that in all three of their experiments, whenever the animals could rely on external cues, they learned to find the location just fine. However, when the cues either were removed or arranged in a way to conflict with each other, the mice showed a severe decrement in performance. In other words, also these colleagues found a PKC-dependent form of learning which is mainly concerned with the behavior of the animal itself and less with learning about events in its environment.Are these experiments in three model systems enough to make a strong claim there we are in the process of opening up a new field of research, the study of 'self-learning'? I wouldn't think so if we wouldn't have yet another piece of evidence up our sleeves: we are currently in the process of submitting a manuscript that details our results on the fly gene most closely related to the 'language gene' (that wasn't), FOXP2. Briefly, language acquisition can be thought of as an operant process: babies babble and use the auditory feedback of what it sounded like when they babbled to change their babbling - eventually into language. Songbirds learn their songs in a quite similar way. Both humans and songbirds have trouble learning their respective vocalizations if the gene FoxP2 is not intact. So we went and looked for a homologous gene in Drosophila, found it (dFoxP), manipulated it and found that the manipulations had the same effect as the PKCi expression: self-learning was affected and world-learning wasn't.Thus, we (several different labs independently) now appear to have discovered not one, but two components of this new self-learning mechanism, PKC and FoxP:In fact, evidence from Aplysia suggests that this mechanism also includes cAMP, but form a different cyclase and activating a different sort of PKA. However, this has not been tested in the other systems, so far.Thus, I think there now are too many converging results from very disparate experiments to just be chance. I now have the very strong suspicion that we are on the cusp of the birth of a new research field: the neurobiology of self-learning.Rochefort, C., Arabo, A., Andre, M., Poucet, B., Save, E., & Rondi-Reig, L. (2011). Cerebellum Shapes Hippocampal Spatial Code Science, 334 (6054), 385-389 DOI: 10.1126/science.1207403... Read more »

Rochefort, C., Arabo, A., Andre, M., Poucet, B., Save, E., & Rondi-Reig, L. (2011) Cerebellum Shapes Hippocampal Spatial Code. Science, 334(6054), 385-389. DOI: 10.1126/science.1207403  

  • September 27, 2011
  • 08:38 AM
  • 196 views

In which creationism threatens patients

by Björn Brembs in bjoern.brembs.blog

Republican presidential hopeful and Texas governor Rick Perry is pushing hard in support for unapproved stem-cell therapies in Texas and allegedly had such a therapy performed on himself. In this case not coincidentally, Perry is also a self-professed creationist. There are many reasons why stem-cell therapies might be dangerous, the two recently reported deaths are among the so far unidentified causes. One other, recently discovered potential risk of stem-cell therapies involves mutation and selection - two of the key mechanisms driving evolutionary change.The first basic finding is simple: by culturing cells under conditions where they proliferate, there will be copy errors during cell division. Many of them will be rapaired by the cells themselves, others will not. However, eventually, there will be changes in the genome of these cells which make some of them divide less and some of them more quickly. To the evolutionarily inclined reader it will be already obvious where this is going: cells that proliferate more (i.e., divide more quickly) will make up a larger fraction of the cells in culture. If cultured for long enough, those cells that divide most quickly and without control will constitute the bulk of the cell culture. This is basically the second finding of this paper: the cell culture conditions for the stem cells studied in this particular report, induced pluripotent stem cells (iPSCs), essentially select for cancerous cells. While the specific mutations differ under different procedures, this new study essentially extended a previous study showing that regular embryonic stem cells (ESCs) undergo analogous (but biologically different) mutations and selection for possibly cancerous cells.In both studies, the researches have identified the genes which were most likely to be mutated: in one case, the iPSCs, tumor-suppressor genes were preferentially deleted, while duplications of oncogenes appeared more slowly and later. In the other case, the ESCs, it was the oncogenes which were duplicated. Thus, in both cases, the treatment and culture of stem-cells led to mutations favoring cancerous cells in the culture conditions tested. These papers describe some very basic evolutionary principles at work, which are obvious to anybody with even a basic, high-school understanding of evolutionary theory. No person with such a basic understanding of evolution would dream of injecting themselves with potentially cancerous cells, except maybe in some very desperate, life-threatening situation. Creationists such as Rick Perry, on the other hand, not only inject themselves with potentially cancerous cells (in his case because of 'back pain'), but use their considerable power to allow corporations to sell these premature and highly dubious therapies to unsuspecting patients. I'd project that had Perry a better grasp of the underlying evolutionary principles, he would have neither subjected himself to the unapproved therapie, not would he be pushing for these therapies to be released without proper testing.This is but one example where creationism is more than just "someone being wrong on the internet", but where a creationist agenda threatens the lives of patients. There are more than scientific reasons to combat creationism: we owe it to patients world-wide to protect them from religious delusionals.Laurent, L., Ulitsky, I., Slavin, I., Tran, H., Schork, A., Morey, R., Lynch, C., Harness, J., Lee, S., Barrero, M., Ku, S., Martynova, M., Semechkin, R., Galat, V., Gottesfeld, J., Belmonte, J., Murry, C., Keirstead, H., Park, H., Schmidt, U., Laslett, A., Muller, F., Nievergelt, C., Shamir, R., & Loring, J. (2011). Dynamic Changes in the Copy Number of Pluripotency and Cell Proliferation Genes in Human ESCs and iPSCs during Reprogramming and Time in Culture Cell Stem Cell, 8 (1), 106-118 DOI: 10.1016/j.stem.2010.12.003Hussein, S., Batada, N., Vuoristo, S., Ching, R., Autio, R., Närvä, E., Ng, S., Sourour, M., Hämäläinen, R., Olsson, C., Lundin, K., Mikkola, M., Trokovic, R., Peitz, M., Brüstle, O., Bazett-Jones, D., Alitalo, K., Lahesmaa, R., Nagy, A., & Otonkoski, T. (2011). Copy number variation and selection during reprogramming to pluripotency Nature, 471 (7336), 58-62 DOI: 10.1038/nature09871... Read more »

Laurent, L., Ulitsky, I., Slavin, I., Tran, H., Schork, A., Morey, R., Lynch, C., Harness, J., Lee, S., Barrero, M.... (2011) Dynamic Changes in the Copy Number of Pluripotency and Cell Proliferation Genes in Human ESCs and iPSCs during Reprogramming and Time in Culture. Cell Stem Cell, 8(1), 106-118. DOI: 10.1016/j.stem.2010.12.003  

Hussein, S., Batada, N., Vuoristo, S., Ching, R., Autio, R., Närvä, E., Ng, S., Sourour, M., Hämäläinen, R., Olsson, C.... (2011) Copy number variation and selection during reprogramming to pluripotency. Nature, 471(7336), 58-62. DOI: 10.1038/nature09871  

  • September 13, 2011
  • 08:38 AM
  • 303 views

Programming Free Will: creative robots

by Björn Brembs in bjoern.brembs.blog

I wasn't planning to comment on Kerri Smith's piece on Free Will (probably paywalled) in the last issue of Nature magazine. However, this morning I read a paper on Free Will in robots (or rather 'agents'), which urged me to suggest some updates to the sadly (otherwise Ms. Smith is producing outstanding work, especially her podcasts!) outdated discussion in the Nature article.Her article starts out with a modern variation of Libet's famous experiments. These experiments can be caricatured like this: "press a button whenever you feel like it and watch a clock while you're making the decision to tell us when you think you've made the decision". It is then little surprise that some form of brain activity (either electrical, in the case of Libet or blood flow, in the case of the modern fMRI studies) can be recorded before the time point when the study participants self-reportedly made the decision.Detailed treatment of these experiments isn't really needed here, as any biologist realizes that all our thoughts are indeed based on brain activity and thus any conscious act or thought must be either simultaneous to or preceded by nervous activity. The amount of this time difference may vary with the task and the method of activity measurement. The fMRI brain scans allowed researchers to predict a dual choice to 60%, i.e., just above chance level. Clearly, even with modern brain scans a brain isn't even close to a system one might call 'deterministic' by any stretch of the word.From the way I read the article, the most important point drawn by the researchers is that the thought process itself is based on brain activity. John Dylan-Haynes: "I'll be very honest, I find it very difficult to deal with this," he says. "How can I call a will 'mine' if I don't even know when it occurred and what it has decided to do?" I'd counter that question with another question: what else then brain activity would you have expected when you peered into a brain? Dualism has been dead since Popper's and Eccles' "The Self and its Brain" in 1977. Why is this article still beating a dead horse?About half way through the article, this exact issue is raised: The trouble is, most current philosophers don't think about free will like that, says Mele. Many are materialists — believing that everything has a physical basis, and decisions and actions come from brain activity. So scientists are weighing in on a notion that philosophers consider irrelevant.Precisely! And yet, towards the end of the article, the dualism creeps back in, by the same philosopher who so rightly dismissed it:Philosophers are willing to admit that neuroscience could one day trouble the concept of free will. Imagine a situation (philosophers like to do this) in which researchers could always predict what someone would decide from their brain activity, before the subject became aware of their decision. "If that turned out to be true, that would be a threat to free will," says Mele.Even if this prediction were possible, any decision would still be ours, as it would still not be possible to predict the decision from the time when the decision-task was initiated. In other words: one would need to observe the decision-making process for some time in order to eventually project where it is going to end up. I think it is very likely that we will be able to go rather far with this approach, but because our brain is still calling the shots, this has absolutely no relevance for the question on how free the decision was. We are not slaves of our brains, we are our brains. And this means an upgrade for our understanding of human nature, or you are vastly underestimating the abilities of brains.But enough of the disappointing aspects of this article. I was reminded of it because of a very exciting article by a physicist in Austria, Hans J. Briegel: "On machine creativity and the notion of free will". It displayed a modern understanding of the scientific issues surrounding a materialistic (i.e., scientific) notion of free will and provided a proof of principle of how Free Will may be implemented in physical objects. And these objects don't even have to be biological in origin! As briegel writes: To put it provocatively, even if human freedom were to be an illusion, humans would still be able, in principle, to build free robots. Amusing.Amusing indeed! The paper by Briegel elaborates on a method to provide software agents with a degree of freedom without breaking any laws of nature, a method he calls 'projective simulation'.Briegel claims that Free Will by projective simulation, could, "in principle, be realized with present-day technology in form of [...] robots." Projective simulation means that the robots have a flexible sort of memory that allows the agent to simulate situations that are similar, but not identical to, events that it has encountered before. There are rules according to which these 'projections' can be generated by the robot, so they're not arbitrary, but they contain a degree of randomness (or 'spontaneity') that allows them to "increasingly detach themselves from a strict causal embedding into the surrounding world". Briegel realizes that, in biological systems, much of the required random variability is readily available, but because we don't know how it is being used, we cannot say much about the relevance of it. In fact, with reference to Quantum Indeterminacy, he arrives at almost the same wording as I did in my Proc. Roy. Soc Article: We may not need quantum mechanics to understand the principles of projective simulation, but we have it. And this is our safeguard that ensures true indeterminism on a molecular level, which is amplified to random noise on a higher level. Quantum randomness is truly irreducible and provides the seed for genuine spontaneity.It is gratifying to see how close we came of each other, without knowing of each other. Here is my way of putting it:Because of this nonlinearity, it does not matter (and it is currently unknown) if the 'tiny disturbances' are objectively random as in quantum randomness or if they can be attributed to system, or thermal noise. What can be said is that principled, quantum randomness is always some part of the phenomenon, whether it is necessary or not, simply because quantum fluctuations do occur. Other than that it must be a non-zero contribution, there is currently insufficient data to quantify the contribution of such quantum randomness. In effect, such nonlinearity may be imagined as an amplification system in the brain that can either increase or decrease the variability in behaviour by exploiting small, random fluctuations as a source for generating large-scale variability. If this topic is of any interest to you, you really ought to read Briegel's paper!Basically, the discussion about freedom today has progressed beyond the question of whether it exists (the dualistic notion, everyone agrees, does not), but how it has been implemented in a material world that is powerful and creative enough to not need any supernatural forces. It is sad that this was only briefly touched upon in the Nature piece, when it should have been the very core of the article.Smith, K. (2011). Neuroscience vs philosophy: Taking aim at free will Nature, 477 (7362), 23-25 DOI: 10.1038/477023a... Read more »

Smith, K. (2011) Neuroscience vs philosophy: Taking aim at free will. Nature, 477(7362), 23-25. DOI: 10.1038/477023a  

  • August 18, 2011
  • 03:59 AM
  • 293 views

Retractions correlate better with 'Impact Factor' than citations

by Björn Brembs in bjoern.brembs.blog

Thomson Reuters' Impact Factor (IF) is supposed to provide a measure for how often the average publication in a scientific journal is cited and thus a quantitative basis for ranking journals. However, there are (at least) three major problems with the IF:The IF is negotiable and doesn't reflect actual citation counts (source)The IF cannot be reproduced, even if it reflected actual citations (source)The IF is not statistically sound, even if it were reproducible and reflected actual citations (source)Thus, it is not surprising that there is very little correlation between the IF and what it is supposed to measure: actual citations to scientific articles:Fig. 1: Four examples of publications from individual researchers. Plotted are the actual citations of the publications against the Impact Factor of the journals they were published in (image source.)Compare these correlations to the recently published correlation between retractions and Impact Factor (in Infection and Immunity, Infect. Immun. doi:10.1128/IAI.05661-11):Now, one would need to do some thorough quantification and testing of this, but at a first glance, it appears pretty obvious to me that Retractions are a much better predictor for Impact Factor than citations. Can anyone do such a test of this hypothesis?Fang, F., & Casadevall, A. (2011). RETRACTED SCIENCE AND THE RETRACTION INDEX Infection and Immunity DOI: 10.1128/IAI.05661-11Seglen PO (1997). Why the impact factor of journals should not be used for evaluating research. BMJ (Clinical research ed.), 314 (7079), 498-502 PMID: 9056804... Read more »

Fang, F., & Casadevall, A. (2011) RETRACTED SCIENCE AND THE RETRACTION INDEX. Infection and Immunity. DOI: 10.1128/IAI.05661-11  

Seglen PO. (1997) Why the impact factor of journals should not be used for evaluating research. BMJ (Clinical research ed.), 314(7079), 498-502. PMID: 9056804  

  • July 18, 2011
  • 03:42 AM
  • 314 views

Assessing ancient traumatic brain injury

by Björn Brembs in bjoern.brembs.blog

Last month, a group of researchers led by Marcel Kamp in Düsseldorf. Germany, rose to fame by studying traumatic brain injury brought about by acts of violence like this:The group analyzed over 700 injuries recorded in the 34 Asterix comic books and published their results in the official journal of the European Association of Neurosurgical Societies, known as Acta Neurochirurgica. For some odd reason, I only was made aware of this groundbreaking study now. Well worth reading!Kamp, M., Slotty, P., Sarikaya-Seiwert, S., Steiger, H., & Hänggi, D. (2011). Traumatic brain injuries in illustrated literature: experience from a series of over 700 head injuries in the Asterix comic books. Acta Neurochirurgica, 153 (6), 1351-1355 DOI: 10.1007/s00701-011-0993-6... Read more »

Kamp, M., Slotty, P., Sarikaya-Seiwert, S., Steiger, H., & Hänggi, D. (2011) Traumatic brain injuries in illustrated literature: experience from a series of over 700 head injuries in the Asterix comic books. Acta Neurochirurgica, 153(6), 1351-1355. DOI: 10.1007/s00701-011-0993-6  

  • June 13, 2011
  • 12:27 PM
  • 298 views

Is the sensorimotor hypothesis based on laboratory artifacts?

by Björn Brembs in bjoern.brembs.blog

Most neuroscientists would subscribe to the sensorimotor hypothesis, according to which brains mainly evaluate sensory input to compute motor output. For instance, Mike Mauk wrote now over ten years ago: “brain function is ultimately best understood in terms of input/output transformations and how they are produced” [1]. Tony Dickinson recognized already in 1985 that “Indeed, so pervasive is the basic assumption of this model that it is common to refer to any behaviour as a ‘response’ and thus by implication […] assume that there must be an eliciting stimulus.” [2]. Textbooks to this day mostly begin with a graph showing sensory input entering the brain (usually via the eyes) and then motor-output leaving it.However, more and more information is now accumulating that to the extent that these stimulus-response relationships actually exist, they may be the exception, rather then the rule of what brains are doing when they're not in a laboratory experiment. Perhaps most recently, in the area of human brain research this change in perception has also begun. Marcus Raichle's "Two views of brain function" [3] provides plenty of evidence against the sensorimotor hypothesis. There are many more examples of this kind of evidence. For me personally, the most eye-opening one was this famous video by Ken Catania: If all behavior were always organized according to stimulus-response schemes such as the C-start response in fish, animals would be extremely vulnerable not only to predators (or prey), but of course also to competitors. Evolution is a competitive business: if you're too predictable, you lose.In our labs, reproducibility is key to success. This is precisely the reason why escape responses are so well-studied: these are the exceptions where animals have specialized in speed and sacrificed unpredictability in an evolutionary trade-off. I would hypothesize that no species would survive for long if all other behaviors sacrificed unpredictability in this way,More likely, brains need to balance input-output processing with output-input processing, with the latter probably being both the more prevalent and the ancestral form of behavioral control. It is this delicate balance that brains must constantly strike to survive, procreate and be successful. If we want to understand what the brains we study are really doing when they are not in the lab, we need to take a step back and design more experiments that don't require a response, but an action. This process has already started, but the realization that we have been heading down the stimulus-response direction for too long has not widely set in yet, IMHO.The stimulus-response approach has been hugely successful for the most derived and simplified forms of behavior - and we're still far from done with the task. Now comes the vastly more complex task of understanding how brains decide which action to take next, when there is no simple stimulus providing unambiguous information. Many labs have already started to embark on this task. In our lab, we study animals in the complete absence of discrete sensory stimulation, in order to find out how brains create "something out of nothing". Which actions are you studying?This post was originally written for the launch of the new social network for neuroscientists, NeurOnline (@SfN).[1] Mauk, M. (2000). The potential effectiveness of simulations versus phenomenological models Nature Neuroscience, 3 (7), 649-651 DOI: 10.1038/76606[2] Dickinson, A. (1985). Actions and Habits: The Development of Behavioural Autonomy Philosophical Transactions of the Royal Society B: Biological Sciences, 308 (1135), 67-78 DOI: 10.1098/rstb.1985.0010[3] Raichle, M. (2010). Two views of brain function Trends in Cognitive Sciences, 14 (4), 180-190 DOI: 10.1016/j.tics.2010.01.008... Read more »

Mauk, M. (2000) The potential effectiveness of simulations versus phenomenological models. Nature Neuroscience, 3(7), 649-651. DOI: 10.1038/76606  

Dickinson, A. (1985) Actions and Habits: The Development of Behavioural Autonomy. Philosophical Transactions of the Royal Society B: Biological Sciences, 308(1135), 67-78. DOI: 10.1098/rstb.1985.0010  

Raichle, M. (2010) Two views of brain function. Trends in Cognitive Sciences, 14(4), 180-190. DOI: 10.1016/j.tics.2010.01.008  

  • April 29, 2011
  • 08:28 AM
  • 550 views

What can the spinal cord teach us about learning and memory?

by Björn Brembs in bjoern.brembs.blog

Only very few laboratories in the world perform operant conditioning of spinal reflexes. In fact, a quick PubMed search reveals there is only a single lab which has published in this field in the last decade, the lab of Jonathan Wolpaw. Jonathan's review "What Can the Spinal Cord Teach Us about Learning and Memory?" in The Neuroscientist shows what neuroscience is missing out on by not investing more in this fascinating field.Operant conditioning of spinal reflexes is probably the most controlled operant conditioning situation imaginable: reward the animal when it responds with a reflex magnitude above or below a certain threshold, respectively. This is done by triggering the reflex with a cuff electrode around the nerve and then measuring the amplitude of the reflex with electromyography (EMG):The electrical stimulation via the cuff excites the muscle directly (the M signal in the EMG in the upper left corner) and, with a delay, indirectly via the H-reflex.Below is an image of what that setup looks like when it's implanted in a rat:The rat is running around in its cage and receives a food reward whenever the H-reflex reaches the required amplitude.Given that the textbook reflex (i.e., the spinal stretch reflex shown in the first image above) is monosynaptic, one would expect just this synapse to be modified after operant conditioning. However, this synaptic plasticity only contributes to one form of this learning, namely up-conditioning. Up-conditioning refers to the experiment where increased reflex amplitude was rewarded. In these experiments, the synaptic input from the primary 1a afferents (blue, in the first figure above) is increased, making the reflex amplitude larger. In down-conditioning, however, the synaptic input to the motor neuron is not altered, but the motor neuron itself (green) reveals an increased firing threshold and reduced postsynaptic potentials, making the motor neuron less likely to fire (and hence reflex amplitude smaller). In addition to these different forms of plasticity, correlates of the memory can be found throughout the spinal cord and even in the cortex. Some of these correlates appear to be compensatory modifications to other reflexes, preventing the increased amplitude of the conditioned reflex from making the animal limp. Again others are required for the mainteneance of the memory, but do not seem to directly contribute ot the memory trace itself. There are many more examples in the paper.Taken together, the results presented in this review open up more questions than they answer and demonstrate that this is a promising research field, with still plenty of low-hanging fruit and a large variety of basic neuroscientific lessons which are hard, if not impossible to learn from other models.What are you waiting for? Go and study operant conditioning of these reflexes already! Wolpaw, J. (2010). What Can the Spinal Cord Teach Us about Learning and Memory? The Neuroscientist, 16 (5), 532-549 DOI: 10.1177/1073858410368314... Read more »

Wolpaw, J. (2010) What Can the Spinal Cord Teach Us about Learning and Memory?. The Neuroscientist, 16(5), 532-549. DOI: 10.1177/1073858410368314  

  • April 28, 2011
  • 08:18 AM
  • 483 views

The neurobiology of operant conditioning

by Björn Brembs in bjoern.brembs.blog

It turns out, operant conditioning is very different from other forms of learning, all the way from the genes up. When I started my research on operant conditioning in 1995, I did so with the opposite hypothesis, namely that the underlying mechanism of all learning processes was always synaptic plasticity with the well-known molecular pathway: Ca++, cAMP, PKA, CamK, CREB and so on. After all, wasn't that pathway conserved all the way from flies, snails and mice to humans? By the time I finished by PhD in 2000, Eric Kandel had received the Nobel prize for exactly these learning mechanisms - he wouldn't have gotten the prize if the pathways had not been so conserved. In principle, changing the weight of the synapses is all you need to do to store whatever information you want. There is no a priori need to have several different mechanisms by which neural networks are modified.A few years ago, I started getting data from fruit flies (Drosophila) that were exactly the opposite of what my initial hypotheis was: the genes required for standard synaptic plasticity (such as the rutabaga adenylyl cyclase) were not required in our form of operant conditioning. In contrast, a gene which had previously been shown not to be involved in classical conditioning, protein kinase C (PKC) turned out to be crucial for operant conditioning. What made the whole story even more intriguing was that the same evidence started to show up in the lab where I did my postdoc, using the marine snail Aplysia as a model system: PKC was required, but the rut-cyclase was not.Why had nobody discovered this dichotomy between the learning mechanisms before us? It turned out that the crucial experimental advance was to prevent the animals from learning about anything else besides their behavior. As soon as we let the animals learn about any external cues in addition to their behavior, the results go back to the expected canonical pathways being required and PKC not. Obviously, nobody had been able to completely isolate operant conditioning to the extent that was required. Because all our experiments were operant in nature, but only differed in whether or not the animals were able to learn about environmental cues or not, we called the PKC-dependent learning mechanism operant self-learning and the other, well-described form, operant world-learning.How far is this new form of plasticity (in Aplysia it is a form of 'intrinsic plasticity' modifying the entire neuron and not just the synapse; in Drosophila we don't know) conserved? We are currently in the process of writing up our experiments on the 'language gene' FoxP2. Drosophila has an orthologue of this gene and if we mutate it (or knock it down with RNAi), we find that it is required for operant self-learning, but not for operant world-learning, paralleling the results we had for PKC. This means we now have a new learning mechanism at hand that is clearly distinct from the well-known synaptic plasticity pathway, but is equally conserved among invertebrates and vertebrates. These results suggest an ancient evolutionary origin for operant self-learning, possibly at the root of the bilaterian branch, and a complementary role to world-learning.I have summarized these results in an invited review on occasion of the 2010 conference of SQAB in the journal "Behavioural Processes". Unfortunately, there are a few mistakes in the copy available from the publisher. Some spaces are missing between words and the references Brembs 2009a and Brembs 2009b are mixed up. I've notified the publisher, but they said it was too late to fix. I've now fixed the HTML version of my local copy, but I can't fix my PDF copy as they use a font that is not freely avaliable. So if anybody knows how I can fix my own PDF copy, please let me know!Brembs, B. (2011). Spontaneous decisions and operant conditioning in fruit flies Behavioural Processes DOI: 10.1016/j.beproc.2011.02.005... Read more »

Brembs, B. (2011) Spontaneous decisions and operant conditioning in fruit flies. Behavioural Processes. DOI: 10.1016/j.beproc.2011.02.005  

  • April 19, 2011
  • 12:12 PM
  • 606 views

Creationists, this is the evidence you have to beat

by Björn Brembs in bjoern.brembs.blog

The last decades of research on human evolution have provided an astounding body of converging evidence for an African origin of the human lineage just under about 200k years ago, with a subsequent migration across the globe starting around 60k years ago until all the main regions of this planet were inhabited by humans at around 15k years ago. Compare this scenario to the creationist story, where humans were shaped by a magic man out of clay about 6k years ago, which means it happened just after the Sumerians have invented glue.What is the converging evidence telling the "Out of Africa" story?It all started with fossils and artifacts. Archeology, with its own dating techniques and collection methods, suggested a route that looks something like this:(Image source)Later, genetic evidence came along. Geneticists, with their own dating techniques and experimental methods suggested migration routes that looked something like this:(Image source)After the genetic evidence, came evidence from a bacterium associated with humans: Helicobacter pylori. It lives in our guts and can cause stomach ulcers. It's been associated with our digestive tract for many thousands of years. Looking at the different strains of these bacteria, microbiologists, using their own dating techniques and experimental protocols, deduced that this bacterium in our guts must have traveled roughly along these routes:(Image source)Most recently, linguists came along and studied the phonemes that make up 504 of the different human languages around the globe. These linguists adopted the analysis tools from the geneticists to their own dating techniques and sampling methods and came up with a map that suggested the following main routes along which the human languages seem to have developed:(Image source)Clearly, getting the dates correct using phonemes will prove a lot harder than the previously used dating techniques. Nevertheless, these are four independent lines of evidence, collected over many decades by scientists with vastly different backgrounds and training. Yet, the results agree to an astonishing extent.However, this doesn't mean it's 'true' or 'scientifically proven'. It only means that this is the best humans can currently possibly do and anything new that comes along must not only explain the current congruence of disparate data, but also explain more data, than the current 'Out of Africa' theory can explain. A few self-contradictory passages in an ancient text do not even begin to come close to being a contender.Given this sort of evidence, it becomes rather obvious that creationists are either uninformed or unpersuadable. For the former, information like the one in this post should be more than sufficient to falsify the creationist dogma. For the latter, ridicule and derision is the best response.This post was inspired by Lapidarium Notes.Pertinent peer-reviewed literature:Green, R., Krause, J., Ptak, S., Briggs, A., Ronan, M., Simons, J., Du, L., Egholm, M., Rothberg, J., Paunovic, M., & Pääbo, S. (2006). Analysis of one million base pairs of Neanderthal DNA Nature, 444 (7117), 330-336 DOI: 10.1038/nature05336Linz, B., Balloux, F., Moodley, Y., Manica, A., Liu, H., Roumagnac, P., Falush, D., Stamer, C., Prugnolle, F., van der Merwe, S., Yamaoka, Y., Graham, D., Perez-Trallero, E., Wadstrom, T., Suerbaum, S., & Achtman, M. (2007). An African origin for the intimate association between humans and Helicobacter pylori Nature, 445 (7130), 915-918 DOI: 10.1038/nature05562Atkinson, Q. (2011). Phonemic Diversity Supports a Serial Founder Effect Model of Language Expansion from Africa Science, 332 (6027), 346-349 DOI: 10.1126/science.1199295... Read more »

Green, R., Krause, J., Ptak, S., Briggs, A., Ronan, M., Simons, J., Du, L., Egholm, M., Rothberg, J., Paunovic, M.... (2006) Analysis of one million base pairs of Neanderthal DNA. Nature, 444(7117), 330-336. DOI: 10.1038/nature05336  

Linz, B., Balloux, F., Moodley, Y., Manica, A., Liu, H., Roumagnac, P., Falush, D., Stamer, C., Prugnolle, F., van der Merwe, S.... (2007) An African origin for the intimate association between humans and Helicobacter pylori. Nature, 445(7130), 915-918. DOI: 10.1038/nature05562  

Atkinson, Q. (2011) Phonemic Diversity Supports a Serial Founder Effect Model of Language Expansion from Africa. Science, 332(6027), 346-349. DOI: 10.1126/science.1199295  

  • February 9, 2011
  • 10:19 AM
  • 402 views

Even in science, sometimes it really seems there is nothing new under the sun

by Björn Brembs in bjoern.brembs.blog

In this week's journal club, we talked about an old paper from 1918! "The reactions to light and to gravity in Drosophila and its mutants" by Robert McEwen, in the Journal of Experimental Zoology.As the title says, the author studied how the fruit fly Drosophila responds to light and gravity. He tested this in walking flies and compared flies both with intact wings and clipped wings, wing mutations, clipped antennae, glued wings or clipped middle legs. He discovered that flies without wings or with mutated wing shape, show less movement towards light (i.e., less phototaxis). This finding was later confirmed by one of the founders of modern neurogenetics, Seymour Benzer (1967) and we also find this in our experiments. We have now set out to find out which neuronal mechanisms are involved in this drastic change in behavior.In order to get the flies to show phototaxis, McEwen developed a machine to gently tap the tube in which the flies were placed, to get them to walk. He described the necessity for flies to be active in order to show a consistent orientation towards a light source: without walking behavior being either initiated spontaneously or by the tapping machine, flies would not walk towards the light themselves. If the flies were at rest, light was not an orienting stimulus for them. This key insight was formulated by McEwen at the very end of the paper:Lastly, it may be well to emphasize the peculiar relation which exists in Drosophila between general activity and phototropism. This phenomenon has been clearly recognized by Carpenter and in general I agree with this author’s conclusions. The fact seems to be that this insect is not phototropic unless it is in a certain physiological state brought on by, or at least accompanied by, activity. When the fly reaches a certain degree of activity, induced by various means, it suddenly becomes phototropic. When it quiets down, however, it may still crawl about but ceases to be phototropic. Thus, when an insect has been exposed to constant illumination for some time, it no longer orients to light but wanders aimlessly up and down the tube. Eventually such an animal may even come to rest with its head away from the source of light. The technique described mimics what other colleagues have later developed in other fly paradigms based on vision and walking, such as the "fly-stampede" paradigm. But the insight reaches much further than that. More recent research has shown that the state of the animal has minute control over how the environment is processed. For instance, leeches respond with various behaviors to local mechanosensory stimulation (i.e., touch). However, when they feed, the biogenic amine serotonin is released and prevents the mechanosensory neurons from transmitting the stimuli - the animal becomes unresponsive when it feeds (Gaudry & Kristan, 2009). Another study showed that motion-sensitive neurons in the optic lobes of the fly brain increase their gain when the fly is flying, as opposed to when it is not flying (Maimon et al., 2010). Analogous results were obtained when walking vs. sitting flies were compared (Chiappe et al. 2010). In another, also very sophisticated study, Haag et al. (2010) showed how an identified motor neuron responds more strongly to visual input when the animal is flying than when it is at rest. Finally, Tang and Juusola (2010) report evidence that the direction in which a fly attempts to turn changes the way in which the optic lobes process the visual information on the side towards the fly attempts to turn, compared to the contralateral side.All these groups have, largely independently of each other, discovered the biological mechanisms for something that already McEwen (and Carpenter, cited there) had understood: animals don't just respond to stimuli in always the same, stereotypical way: all animals have many different ways to treat and evaluate the incoming sensory stream, depending on what they are doing at the moment. The decisive factor for understanding animal behavior is not the environment, or the sensory organs, it is the animal itself. Apparently, this profound insight was known long ago and we're just rediscovering it now, in various places, all over the world.Something was new in all the recent studies, though: they all provide first mechanistic insight into how brains balance internal and external processing. All these studies show that there seems to be a smooth gradient between decision-making and attention-like processing, even in invertebrates: Gaudry and Kristan call it decision-making, when their leeches 'decide' to ignore stimuli while they feed, even though the incoming sensory stimuli are blocked already at the very first synapse. Chiappe et al., on the other hand, relate their phenomenon to attention and Haag et al. also mention attention in their paper, with their effects being observed many synapses downstream of the sensory neurons - the word 'decision' does not occur in either of the two papers. It appears as if future neurophysiological research is bound to show that the distinction between attention-like mechanisms and decision-making, which seems so intuitive and clear-cut, may dissolve when we start to unravel how brains actually do it. Now when will we come accross the ancient text that already pre-empts that insight? References:McEwen, R. (1918). The reactions to light and to gravity in Drosophila and its mutants Journal of Experimental Zoology, 25 (1), 49-106 DOI: 10.1002/jez.1400250103Zhu, Y., & Frye, M. (2009). Neurogenetics and the "fly-stampede": dissecting neural circuits involved in visual behaviors Fly, 3 (3), 209-211 DOI: 10.4161/fly.3.3.9139Gaudry, Q., & Kristan, W. (2009). Behavioral choice by presynaptic inhibition of tactile sensory terminals Nature Neuroscience, 12 (11), 1450-1457 DOI: 10.1038/nn.2400... Read more »

McEwen, R. (1918) The reactions to light and to gravity in Drosophila and its mutants. Journal of Experimental Zoology, 25(1), 49-106. DOI: 10.1002/jez.1400250103  

Zhu, Y., & Frye, M. (2009) Neurogenetics and the "fly-stampede": dissecting neural circuits involved in visual behaviors. Fly, 3(3), 209-211. DOI: 10.4161/fly.3.3.9139  

Gaudry, Q., & Kristan, W. (2009) Behavioral choice by presynaptic inhibition of tactile sensory terminals. Nature Neuroscience, 12(11), 1450-1457. DOI: 10.1038/nn.2400  

Maimon, G., Straw, A., & Dickinson, M. (2010) Active flight increases the gain of visual motion processing in Drosophila. Nature Neuroscience, 13(3), 393-399. DOI: 10.1038/nn.2492  

Chiappe, M., Seelig, J., Reiser, M., & Jayaraman, V. (2010) Walking Modulates Speed Sensitivity in Drosophila Motion Vision. Current Biology, 20(16), 1470-1475. DOI: 10.1016/j.cub.2010.06.072  

Haag, J., Wertz, A., & Borst, A. (2010) Central gating of fly optomotor response. Proceedings of the National Academy of Sciences, 107(46), 20104-20109. DOI: 10.1073/pnas.1009381107  

Tang, S., & Juusola, M. (2010) Intrinsic Activity in the Fly Brain Gates Visual Information during Behavioral Choices. PLoS ONE, 5(12). DOI: 10.1371/journal.pone.0014455  

  • January 31, 2011
  • 12:55 AM
  • 333 views

Do fruit flies dream of electric bananas?

by Björn Brembs in bjoern.brembs.blog

That's the title of my 'Thought Experiment' column in the next issue of 'The Scientist', due to appear on February 1. Sarah Greene from The Scientist approached me in my role as F1000 faculty member at this year's SfN annual meeting in San Diego and asked me if I didn't want to write something for The Scientist.The short article is about visualizing neuronal activity in small brains. I've recently applied for a starting grant at the European Research Council to develop a microscope which can record the activity in most of the Drosophila brain in 4D (space + time). This application is a revised version after the first one got good reviews but wasn't funded due to the technique being too risky. We have since tested the originally proposed technique and found that indeed it didn't work, as the reviewers assumed. Therefore, we are now proposing to develop a new kind of microscope, rather than just using an existing one.Interestingly, just around the time I was writing this article, a paper was published by colleagues from UCLA that used a related, but slightly different technique to record in 4D from mouse brains: "Simultaneous two-photon calcium imaging at different depths with spatiotemporal multiplexing" Their technique is not identical to what we have tried in flies, but similar. The authors are using multiple laser beams to excite molecules in the mouse brain that act as reporters of neural activity. If the neuron they are incorporated in is active, they fluoresce in one wavelength when hit by the laser, and in a different one when the neuron is inactive. Previous studies had just picked one plane in the brain and then recorded the activity of neurons in this plane. One of several reasons why it wasn't possible, until now, to record from more than one plane, was that the speed with which one could move the laser around was too slow. The authors of this study overcome this problem by using multiple beams at the same time. This allowed them to monitor 100-200 neurons in a ~400 × 400 μm cube of mouse cortex.While I'm not surprised that this technique works great in mice, there is one main reason why this method does not work in flies. In order to capture sufficient light in the much denser fly brain, we need dwelling times of around one microsecond per voxel (a 3D pixel). If we do this with more than one laser, the heat being transfered into the fly brain is just too great: the brain will literally boil (ask us how we know: this was exactly the method we suggested in the previous grant and tried out before applying again in this round). While this is obviously a lesser problem for the much larger mouse brain, where the heat can dissipate much more easily, I'd still like to know the temperature of the cube Cheng at al. were recording from. After all, we wouldn't want to interfere more than absolutely necessary with the object we're attempting to measure.Overall, this is the way microscopy is heading these days: after having increased the spatial resolution to below the optical diffraction limit, now researchers all over the world are turning towards increasing the temporal resolution. This will allow us to record 3D videos of brain activity, very similar to the way currently being done with fMRI in humans, but with ten times the temporal and many times the spatial resolution. This latest study (and hopefully our project, if the ERC funds it) is a great step in this direction. Hopefully, many more will follow.Attached at the end of my article in The Scientist is a 5min video where I'm giving a brief summary of our latest research on the Drosophila orthologue of the FOXP2 gene. This work was presented as a poster at the abovementioned SfN meeting and is also uploaded to the F1000 website.Cheng, A., Gonçalves, J., Golshani, P., Arisaka, K., & Portera-Cailliau, C. (2011). Simultaneous two-photon calcium imaging at different depths with spatiotemporal multiplexing Nature Methods, 8 (2), 139-142 DOI: 10.1038/nmeth.1552... Read more »

Cheng, A., Gonçalves, J., Golshani, P., Arisaka, K., & Portera-Cailliau, C. (2011) Simultaneous two-photon calcium imaging at different depths with spatiotemporal multiplexing. Nature Methods, 8(2), 139-142. DOI: 10.1038/nmeth.1552  

  • December 15, 2010
  • 02:35 PM
  • 424 views

Towards a scientific concept of free will

by Björn Brembs in bjoern.brembs.blog

Today, the Royal Society published my article reviewing the invertebrate data supporting a scientific concept of free will. In it, I first reiterate that the metaphysical concept of free will is long dead (since the 1970s). Then I emphasize that determinism has been dead for even longer (basically since quantum mechanics). Finally, I propose that the ability to behave differently in identical circumstances forms the basis for a scientific concept of free will. Basically, IMHO, free will is a biological brain function, not some ghost in our heads. I argue that the evolutionary ancestry to this brain function can be traced back to invertebrate species living today, which also show this fundamental capacity. In fact, I propose that brains who are not free to behave as they will, would not do very well in a competitive situation such as evolution.The article has been through several rounds of peer-review, both informal and formal (by two anonymous referees selected by the editor of the journal, Lars Chittka) since august this year. Of course, the real discussion, I would hope, isn't starting until today, when the article actually became accessible. Nevertheless, a bunch of colleagues have looked through it to make sure it's not all totally screwed up .In keeping with my committment to the open access movement, I paid ~2k€ for everyone to be able to download the article 'for free', so you can go ahead and read it for yourself.Here's the abstract, just to whet your appetite Until the advent of modern neuroscience, free will used to be a theological and a metaphysical concept, debated with little reference to brain function. Today, with ever increasing understanding of neurons, circuits and cognition, this concept has become outdated and any metaphysical account of free will is rightfully rejected. The consequence is not, however, that we become mindless automata responding predictably to external stimuli. On the contrary, accumulating evidence also from brains much smaller than ours points towards a general organization of brain function that incorporates flexible decision-making on the basis of complex computations negotiating internal and external processing. The adaptive value of such an organization consists of being unpredictable for competitors, prey or predators, as well as being able to explore the hidden resource deterministic automats would never find. At the same time, this organization allows all animals to respond efficiently with tried-and-tested behaviours to predictable and reliable stimuli. As has been the case so many times in the history of neuroscience, invertebrate model systems are spearheading these research efforts. This comparatively recent evidence indicates that one common ability of most if not all brains is to choose among different behavioural options even in the absence of differences in the environment and perform genuinely novel acts. Therefore, it seems a reasonable effort for any neurobiologist to join and support a rather illustrious list of scholars who are trying to wrestle the term ‘free will’ from its metaphysical ancestry. The goal is to arrive at a scientific concept of free will, starting from these recently discovered processes with a strong emphasis on the neurobiological mechanisms underlying them. Björn Brembs (2010). Towards a scientific concept of free will as a biological trait: spontaneous actions and decision-making in invertebrates Proc. R. Soc. B... Read more »

Björn Brembs. (2010) Towards a scientific concept of free will as a biological trait: spontaneous actions and decision-making in invertebrates. Proc. R. Soc. B. info:/

  • December 6, 2010
  • 04:09 AM
  • 371 views

Unquestioning dogma: the gatekeepers of science

by Björn Brembs in bjoern.brembs.blog

This morning my friend Ramy reminded us of the recent spats over PLoS One publications (Darwinius, Red Sea) and how they were used to question the 'reputation' of PLoS One as a journal. Of course, it is about as meaningful to talk about the reputation of a journal as it is to talk about the reputation of the cover of a book. Journals are containers which say very little about their content. But on to the really relevant point:Specifically, Ramy pointed out how the current spat about a publication in the journal Science on a purportedly arsenic-based lifeform (see, e.g., Pharyngula and especially Rosie Redfield) didn't reflect on Science at all, despite the basically identical story-line of media hype before publication followed by more sober commentary from the scientific community after publication. Why is PLoS One criticized in the first two cases, but nobody questions Science in this (or the numerous other) cases? Clearly, the two GlamMagz Nature and Science both have their share of in some cases pretty embarrassing blunders. My personal favorite is a paper in Nature about fly thermosensation, easily the worst conducted study in this field in quite a few years. Yet, nobody questions the 'reputation' of Nature. Also in this case, none of the critical commenters questions the legitimacy of the gatekeeper function that the GlamMagz are so happy to tout.Let's be honest about it: there's no journal without fault. Everyone makes mistakes. Journals are no more gatekeepers than the persons working there. Any perceived hierarchy among journals is merely that: perceived. A perception caused by visibility, historical baggage, group-think and circular reasoning.It doesn't matter where something is published - what matters is what is being published. Given the obscene subscription rates some of these journals charge, if anything, they should be held to a higher standard and their 'reputation' (i.e., their justification for charging these outrageous subscription fees!) being constantly questioned, rather than this unquestioning dogma that anything published there must be relevant, because it was published there. If anything, every single contested paper should be used to question the level of subscription fees raised by these journals.In fact, every retraction should lead to an immediate reduction in subscription fees for the journal in which the retracted paper was published, because the journals failed to serve its gatekeeper purpose. If the journals justify, as they do, their obscene subscription extortion with their outstanding peer-review process, their price needs to drop every time it fails. Given the hyper-inflation of retractions, we should see a precipitous drop in subscription charges immediately, should such a policy be enforced.Wolfe-Simon, F., Blum, J., Kulp, T., Gordon, G., Hoeft, S., Pett-Ridge, J., Stolz, J., Webb, S., Weber, P., Davies, P., Anbar, A., & Oremland, R. (2010). A Bacterium That Can Grow by Using Arsenic Instead of Phosphorus Science DOI: 10.1126/science.1197258... Read more »

Wolfe-Simon, F., Blum, J., Kulp, T., Gordon, G., Hoeft, S., Pett-Ridge, J., Stolz, J., Webb, S., Weber, P., Davies, P.... (2010) A Bacterium That Can Grow by Using Arsenic Instead of Phosphorus. Science. DOI: 10.1126/science.1197258  

  • October 25, 2010
  • 04:28 AM
  • 474 views

The brain creates something out of nothing

by Björn Brembs in bjoern.brembs.blog

Brains are what mathematicians call "information sources". At least this is one of the results of a set of elaborate experiments together with sophisticated analyses and computations reported in the current issue of Nature Neuroscience (subscription required). The article, entitled "Intrinsic biophysical diversity decorrelates neuronal firing while increasing information content", studies a set of neurons in the brain's main olfactory center, the olfactory bulb. These neurons, mitral cells, receive input from olfactory sensory neurons with their receptors in the olfactory epithelium in the nose. The authors looked at particular subsets of these neurons in the mouse brain, namely the ones that receive their input within a single identical so-called 'glomerulus', a neuropil structure characterized by the fact that it contains only the terminals from olfactory receptor neurons that express the same olfactory receptor. This means that the input these mitral cells receive is highly correlated. In other words, these mitral cells receive virtually identical stimulation and the authors looked at the output these neurons generate in response to the input.... Read more »

Padmanabhan, K., & Urban, N. (2010) Intrinsic biophysical diversity decorrelates neuronal firing while increasing information content. Nature Neuroscience, 13(10), 1276-1282. DOI: 10.1038/nn.2630  

  • August 19, 2010
  • 12:00 PM
  • 395 views

After 40 years of research, there may be a reason why Aplysia can learn

by Björn Brembs in bjoern.brembs.blog

I'm currently in sunny southern California for some experiments at UCSD. This is the place where one can find the marine snail Aplysia in its natural habitat. As I've been working with Aplysia for about ten years now, I felt it was about time to see Aplysia in the wild and observe what these animals do when they're not in a tank waiting to be experimented upon. Just this morning, before heading out to UCSD, I went snorkeling in La Jolla Cove in the hope of seeing some specimens. All these years working on Aplysia and I had never seen one in the wild. What do they do? Why can they learn? Do they only learn about how to handle their food? I always imagined these snails as sort of the cows of the sea, living happily on their food and, being hermaphrodites, not really having any trouble finding mates, either. Any other forms of learning are probably purely coincidental of neurons in general being plastic. Unfortunately, I didn't find any Aplysia at all today. scuba.png However, when I checked the table of contents of the latest issue of the Journal of Neuroscience later in the evening, I found this great paper that was so long overdue: "Lobster Attack Induces Sensitization in the Sea Hare, Aplysia californica".... Read more »

Watkins, A., Goldstein, D., Lee, L., Pepino, C., Tillett, S., Ross, F., Wilder, E., Zachary, V., & Wright, W. (2010) Lobster Attack Induces Sensitization in the Sea Hare, Aplysia californica. Journal of Neuroscience, 30(33), 11028-11031. DOI: 10.1523/JNEUROSCI.1317-10.2010  

  • August 3, 2010
  • 03:22 PM
  • 413 views

ICN2010: One of the genetic roots of language points to self-learning in fruit flies

by Björn Brembs in bjoern.brembs.blog

In 2001, an article was published in the journal Nature that a mutation in the forkhead-domain gene FOXP2 is involved in a hereditary speech and language disorder in a family in Great Britain. Today, many refer to FOXP2 colloquially as a 'language' gene and accumulating evidence suggests that FOXP2 is involved in language-like behavior in other animals, most prominently in song-learning in birds. Language as well as song learning in birds is an operant learning process, i.e., the birds and us humans are trying out different sounds. At first, they sound nothing like speech or song, but by comparing the consequences of the 'babbling' - the sounds produced - with the desired outcome, step by step, the sounds are modified and slowly become speech or song.... Read more »

Santos, M., Athanasiadis, A., Leitao, A., DuPasquier, L., & Sucena, E. (2010) Alternative splicing and gene duplication in the evolution of the FoxP gene sub-family. Molecular Biology and Evolution. DOI: 10.1093/molbev/msq182  

Fisher, S., & Scharff, C. (2009) FOXP2 as a molecular window into speech and language. Trends in Genetics, 25(4), 166-177. DOI: 10.1016/j.tig.2009.03.002  

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