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Ian Meinertzhagen

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Ian Meinertzhagen’s work has pioneered studies on simple invertebrate nervous systems, especially the immaculately precise fly's visual system and the numerically diminutive nervous system of the ascidian tadpole larva, and has examined structurally identified circuits of neurons, their functional anatomy, their origins in both ontogeny and evolution, and their plasticity in adult animals.  He is a University Research Professor at Dalhousie University, in Halifax, Nova Scotia, a location visited rather more frequently at 30,000 feet, but in fact far nicer at ground level.  After graduating from the University of St. Andrews, he pursued postdoctoral studies at the Australian National University and at Harvard before joining Dalhousie.  Supported generously by more than 30 continuous years from the National Institutes of Health, and by Guggenheim, Killam, and Canada Council fellowships, his research there has been dominated by various approaches to a single question.  The question itself is simple enough.  The brain is a network, one that is formed by the synaptic contacts between neurons.  The network these form therefore becomes a formal definition of the brain, one that is essential for us to know if we are to establish the circuit basis for animal behaviour.  Few people would question this, but many still do not accept that the level of effort required to extract the relevant information merits the endeavour to do so.  Indeed that level of effort has until recently been unthinkable except for the simplest brains.  Some brave exceptions chose the numerically simplest brains as a means to get around the problem, and the work of Cy Levinthal on the crustacean Daphnia magna was one example, as was the better known analysis of the nematode C. elegans initiated by the group of Sydney Brenner.  A common alternative belief is that when connections are defined from the patterns of either opto- or electrophysiological interactions they support, these either average the pattern of real connections, or assume that the latter are both exclusive and optimal.  But only the pattern of real anatomical connections can distinguish between the different alternatives.  A different view acknowledges the role played by circuit activity, but nevertheless holds that networks are influenced by the local release of neuromodulators, so that the output of a circuit is not readily predictable from its synaptic wiring.  But at least for short-lived activity, such as is required to process transient stimuli, for example for much of vision, the primary mode of processing must surely be circuit based, and the complete wiring diagram, or connectome, its substrate. 

Based on this thinking and using electron microscopy, Meinertzhagen has undertaken analyses of the structural circuits of the visual system in the fruit fly Drosophila melanogaster, in studies conducted for many years under NIH sponsorship but now continued as part of the FlyEM team at Janelia.  His Drosophila studies are part of a wider approach in which he has exploited simple nervous systems not only in insects, especially flies, but also spiders and larval ascidians.  All have nervous systems with small fixed numbers of stereotyped neurons, and each has additional biological advantages: large cells (spiders), ready comparison to vertebrate ancestors (larval ascidians), and big-time genetic tools (Drosophila).  The impetus for this approach came from his thesis supervisor, Adrian Horridge, who first suggested trying to identify the structural elements of the fly’s elementary motion detector (EMD) circuit by means of EM.  That task proved far beyond the technology then available, but lay dormant as a possibility while other labs pursued alternative approaches to the same end.  Using EM photographic technology his lab revisited the project twice, but the work was slow, concussively tedious, and left postdocs more bruised and discouraged than enlightened.  However with the advent of digital EM imaging, a talented postdoctoral fellow (Shinya Takemura) and highly skilled technician (Zhiyuan Lu) had already made considerable progress towards reconstructing medulla cells at Dalhousie.  Not in fact until this work was taken with them to Janelia, however, where reconstructions could be generated by a pipeline of workers first assembled by Mitya Chklovskii, were candidate elements of the EMD first identified.  Now more advanced than for any other region of the fly’s brain, their identification has held some surprises and begins to close a chapter on the longstanding question first formulated half a century ago, of how flies see motion and its direction.

These studies and their background have yielded a compendium of background information on the ultrastructure of Drosophila visual neurons, one that has enabled the Meinertzhagen lab to use this model visual system in more instrumental studies.  Many functional studies have been addressed to this tiny constituency of identified neurons, identifying with the Pyza lab for example plastic and circadian changes among synapses, and undertaking phenotypic analyses of different mutant neural genes.  Many of these have involved collaborations.  For example: with the Schwarz lab his lab first diagnosed the absence of mitochondria from synaptic terminals in milton, identifying the first TRAK/Milton kinesin adapter protein for orthograde transport of mitochondria; while with the Taghert lab it documented the phenotypic conversion of fly photoreceptors by dimmed, a master gene for neuroendocrine fate, which transforms photoreceptors from fast histaminergic neurons to peptidergic cells capable of the biosynthesis of dense-core vesicles.  Likewise, the exquisite ultrastructural detail of photoreceptors made homozygous mutant has been used to characterize a number of human disease genes, for example with the Hiesinger lab mutations in rab7 that induce a Charcot-Marie-Tooth 2B phenotype.