Samuel Wilks on the need for multidisciplinary neurologic research (in 1864)

A history of dementia often starts in 1907 with the work of Alois Alzheimer, but in reality it should start much sooner. In 1864 Samuel Wilks wrote “Clinical Notes on the Atrophy of the Brain,” which was one of the first studies to point out gross atrophy of the sulci in the brains of persons who had dementia prior to death. This is a great paper! I loved the intro:

WERE an occasional comparison instituted between the experiences of those who practise in special but different departments of the profession, it would conduce not only to the fulfilment of some higher general truths than we now possess, but afford to the individual labourer in his department a more just and less narrow view of the field of observation which is always more immediately before his eye. A close observance to one section of medicine may produce much accurate and minute knowledge, but since the division of our art into branches is artificial rather than real, the knowledge therein obtained is regarded apart from its natural relations, and becomes so distorted as to lose much of its value as truth. If the various sciences into which we divide nature for the purposes of study are artificial, and it be true that an exclusive devotion to one of them can never give to its follower a correct insight into the operations of nature, so more true must it be that the general laws of human pathology can scarcely be gleaned in an exclusive practice in one single department.

It may seem almost impertinent to make these remarks in a Journal devoted to a special object, nor were they, indeed, intended to apply to the study of mental disorders, which must be undertaken in an almost isolated manner; and yet an opinion has obtained hold of me (which, however, may be erroneous) that even here some too narrow views may be held of cerebral pathology, and this opinion, right or wrong, has suggested the remarks in the present communication. To be more explicit: I have thought that those who are occupied in the practice and study of any one department might possibly look upon some morbid condition or other feature in a case, as peculiar to a certain form of disease. Thus, in connection with the subject on which I purpose to make a few remarks, it has seemed to be inferred that a certain morbid phenomenon has been found exclusively in lunatic asylums; and, at the same time, to be inferred by a writer on infantile diseases, and who is probably destitute of the knowledge just mentioned, that this phenomenon is intimately connected with the cerebral affections of children. So, also, with the general subject of the following observations, atrophy of the brain: this has appeared to me to have been regarded by some as a condition attaching to those who have died of mental affections, and not only so, but of some special form of insanity; others would describe a similar condition as resulting from repeated attacks of delirium tremens; whilst others write of a state not distinguishable from these as the ordinary result of old age. From having no inclination towards any of these special departments, I have endeavoured to take a comprehensive view of such pathological changes, and, as regards the subject before us, to discover at what stage our knowledge has reached of this morbid condition, and what is its true pathological significance; leaving it for further research to elucidate its varieties and the different methods by which these are brought about.

Making a shiny app to visualize brain cell type gene expression

Attention conservation notice: A post-mortem of a small side project that is probably not interesting to you unless you’re interested in molecular neuroscience.


This weekend I put together an R/Shiny app to visualize brain cell type gene expression patterns from 5 different public data sets. Here it is. Putting together a Shiny application turned out to be way easier than expected — I had something public within 3 hours, and most of the rest of my time on the project (for a total of ~ 10 hours?) was spent on cleaning the data on the back end to get it into a presentable format for the website.

What is the actual project? The goal is to visualize gene expression in different brain cell types. This is important because many disease-relevant genes are only expressed in one brain cell type but not others, and figuring this out can be critical to learning about the etiology of that disease.

There’s already a widely-used web app that does this for two data sets, but since this data is pretty noisy and there are subtle but important differences in the data collection processes, I figured that it’d be helpful to allow people to quickly query other data sets as well.

As an example, the gene that causes Huntington’s disease has the symbol HTT. (I say “cause” because variability in the number of repeat regions in this gene correlate almost perfectly with the risk of Huntington’s disease development and disease onset.) People usually discuss neurons when it comes to Huntington’s disease, and while this might be pathologically valid, by analyzing the data sets I’ve assembled you can see that this gene is expressed across a large number of brain cell types. This raises the question of why — and/or if — variation in its number of repeats only causes pathology in neurons.

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Here’s another link to the web app. If you get a chance to check it out, please let me know if you encounter are any problems, and please share if you find it helpful.

References

Aziz NA, Jurgens CK, Landwehrmeyer GB, et al, et al. Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease. Neurology. 2009;73(16):1280-5.

Huang B, Wei W, Wang G, et al. Mutant huntingtin downregulates myelin regulatory factor-mediated myelin gene expression and affects mature oligodendrocytes. Neuron. 2015;85(6):1212-26.

Classic Papers #1: On the diagram, by John Venn

Title: “On the diagrammatic and mechanical representation of propositions and reasonings

Author: John Venn

Journal: Philosophical Magazine

Date published: July 1880

Builds upon: Euler diagrams

Citations (Google Scholar): 336

Citations Since 2010: 152

Best figure: Not satisfied with two sets, he jumped right to the symmetry-preserving extreme of his system and drew out a four set intersection with a place for labels:

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This would hardly be out of place in a genomics article published today.

Best sentence: “The fact is, as I have explained at length in the article above referred to, that the five distinct relations of classes to one another (viz. the inclusion of X in Y, their coextension, the inclusion of Y in X, their intersection, and their mutual exclusion), which are thus pictured by these circular diagrams, rest upon a totally distinct view as to the import of a proposition from that which underlies the statements of common life and common logic.”

Oddest moment: “I have no high estimate myself of the interest or importance of what are sometimes called logical machines, and this on two grounds. In the first place, it is very seldom that intricate logical calculations are practically forced upon us; it is rather we who look about for complicated examples in order to illustrate our rules and methods. In this respect logical calculations stand in marked contrast with those of mathematics, where economical devices of any kind may subserve a really valuable purpose by enabling us to avoid otherwise inevitable labour. Moreover, in the second place, it does not seem to me that any contrivances at present known or likely to be discovered really deserve the name of logical machines. It is but a very small part of the entire process which goes to form a piece of reasoning which they are capable of performing.”

(No wonder Turing proposed his test of whether something was a “true” AI.)

(Runner up: Venn’s use of the word “especial” instead of “special.”)

Lasting impact: This paper is a classic that jumps directly to the tough questions of how to visualize sets and set differences and even directly addresses the utility of a sort of artificial intelligence, or as Venn calls it, a “logical machine.” And of course, it introduced what we now know as the Venn diagram.


Editorial note: This is the first entry in what will hopefully be a series of classic papers cutting across disciplines that I’m interested in. For some reason, papers don’t seem to be discussed as commonly as books in my circles, which is strange because they’re shorter, usually more novel, and more information dense. This series is an attempt to write the blog posts I want to see in the world.