Ego sum Daniel

An exercise in open science: The evolution of voltage-gated sodium channels

2012-02-21T23:14:00.000+01:00

>> This post describes my re-analysis of the voltage-gated sodium channel α subunit (SCNA) gene family evolution, based on a previously published study. I have shared the improved results as well as all source files and datasets openly in Figshare, together with a description of the methods: link.

This is probably not my last re-analysis of the same dataset, and I'd want to encourage others to use other phylogenetic methods on our alignments, or use our alignments to analyse their own SCNA sequences.

Last year my research group published a study on the evolution of voltage-gated sodium channel α subunits (see reference below) with me as one of the co-authors. Voltage-gated sodium channels are the proteins that permit the passage of positive charges, in this case sodium ions, across the cell membranes of neurons and thus make it possible for your nerve fibres to fire electrical signals. The α subunits are the very large proteins forming the actual pore that selects only sodium ions and allows them to pass. It's difficult to overestimate how essential they are for the function of the nervous system, and how important their evolution has been for the evolution of neuronal signaling.

Our published study used both sequence-based phylogenetic data and genomic data to clear up the muddled relationships between different subtypes of voltage-gated sodium channels in vertebrates. Us humans, and most other mammals, have ten different types of these α subunits, encoded by genes of the SCNA family. The different subtypes have acquired different properties and are expressed in different parts of the nervous system and some other tissues in the body where electrical signaling is necessary. One of the subtypes, the product of the SCN7A gene, has even evolved to such a degree that it's not a channel anymore. It's probably more like a sodium "sensor". There are also specific diseases, different types of epilepsy, seizures and paralyses, that are associated with mutations of the various subtypes.

The same gene family in true bony fishes (teleosts) encodes up to eight different subtypes, almost as many as the mammalian family. The funny evolutionary twist is that we have evolved almost the same amount of subtypes by completely different mechanisms! In tetrapods, the fleshy-limbed mostly terrestrial group that we belong to, local duplications of genes on the same chromosomes gave rise to new subtypes, while in teleost fishes it was their ancestral duplication of the whole genome that did the same on different chromosomes! You can see the difference in the image below.

Chromosome organization of the SCNA genes and some of their neighboring genes in humans and zebrafish. Each numbered line represents a different chromosome. The ten human genes are named in a series from SCN1A to SCN11A, skipping the number 6. The duplicates in teleost fish are denoted by the letters "a" and "b".

This means that when doing comparative studies, it's important to know that while all vertebrate voltage-gated sodium channels have a common origin, they're not always directly related to each other.

Using more powerful and careful methods than we'd used before, I made new evolutionary trees that agree even better with these conclusions. Most of all these new trees are better and clearer examples of the evolutionary relationships between different voltage-gated sodium channel subtypes. You can see figures of the new trees and access all the source files and datasets in Figshare.

While our previous study solved the evolutionary relationships between different SCNA subtypes, we had to rely on the genomic data on the chromosome locations of the genes to solve some inconsistencies in the original phylogenetic trees. Our study was the first to do phylogenetic analyses from alignments of the whole α subunit sequences, which are over 2000 amino acids long! This work was almost entirely carried out by my colleague Jenny Widmark and our supervisor Dan Larhammar. The fact that most previous studies had only analysed parts of the proteins was the reason they had reached the wrong conclusions about how different subunits were related.

Assembling and aligning all that sequence data from the genomic sequences of multiple vertebrate species took a lot of time and thought, so I thought it would be a shame not to use it to find out if better methods could solve what the published tree couldn't and if they could provide more and better evidence for our conclusions, especially when all the different analyses are considered together.

As a summary, I put together this tree over the relationships between the different human subtypes. As you can see, the positions of the different subtypes in the trees agree with the chromosome locations.

The most up-to-date view of the relationship between the different human voltage-gated sodium channel subtypes (the names of the proteins are in parenthesis), based on my latest re-analyses. Teleost fish have duplicates of SCN4A, SCN8A and the genes that gave rise to SCN5A, -10A and -11A and SCN1A, -2A, -3A, -9A and -7A respectively.

Previous analyses put some of the more divergent subtypes, like the products of the SCN11A and SCN7A genes at the base of the tree when they are in fact some of the newest subtypes! Now we can also say that SCN4A and the SCN5A, -10A, -11A-group are more closely related, and that SCN8A and the SCN1A, -2A, -3A, -9A, -7A-group are more closely related. You can see some the older analyses that don't actually give the correct evolutionary view displayed on IUPHAR's* database of receptors and ion channels (link). Another example is displayed in Wikipedia (link).

The next step is to contact IUPHAR and ask them to review our new data so that our updated view of the voltage-gated sodium channels reaches all the people it potentially benefits, everyone doing functional research on sodium channels. To do that I think an open science approach is clearly the best way to go.

* The International Union of Basic and Clinical Pharmacology decides on "official" receptor and ion channel nomenclature, among other things.

Widmark, J., Sundstrom, G., Ocampo Daza, D., & Larhammar, D. (2010). Differential Evolution of Voltage-Gated Sodium Channels in Tetrapods and Teleost Fishes Molecular Biology and Evolution, 28 (1), 859-871 DOI: 10.1093/molbev/msq257

Quote: A bee doubtless would...

2012-02-13T07:24:00.000+01:00

Researching yesterday's post, I found this beautiful and (unintentionally?) funny quote searching for references to bees and wasps in Darwin's writing.

All animals of same species are bound together just like buds of plants, which die at one time, though produced either sooner or later. <...> It is absurd to talk of one animal being higher than another. — We consider those, when the intellectual faculties/cerebral structure most developed, as highest. — A bee doubtless would when the instincts were —

- Charles Darwin, "Notebook B" pages 73 and 74.

It is absurd to talk of one animal being higher than another. A bee would consider itself highest in many other respects.

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Darwin Day: Darwin on cruelty

2012-02-12T20:48:00.000+01:00

Happy International Darwin day! It's been 203 years since the man was born. As usual, I'm taking the chance to open one (of my several) copies of "Origin" or "Voyage of the Beagle" more or less on a random page and bring out some Darwiniana to celebrate evolution. Check out my previous Darwin entries here.

So I've been spending the day reading some Darwin, and chapter eight of On the Origin of Species (first ed.), with the captivating title of "Instinct", caught my attention this time. Darwin has two great realizations in this chapter; first he lays out how behaviors can evolve just as physical structures can; how shared ancestry and descent with modification can explain how related species on different continents can exhibit the same or similar behaviors. The second insight lies in his explanation of the, to us, very cruel behaviors that you often find in nature. To people of Darwin's time, it would be a problem to consider that a benevolent creator would have put on the earth creatures that not only killed in order to survive, but that did it in almost unnecessarily horrific and macabre ways.

How does Darwin solve the question of the, in our eyes, unnecessary cruelty in nature? By explaining it in terms of natural selection and abandoning design and benevolence. The conclusion of chapter eight reads:

Finally, it may not be a logical deduction, but to my imagination it is far more satisfactory to look at such instincts as the young cuckoo ejecting its foster-brothers, - ants making slaves, - the larvae of ichneumonidae [parasitic wasps, see below] feeding within the live bodies of caterpillars, - not as specially endowed or created instincts, but as small consequences of one general law, leading to the advancement of all organic beings, namely, multiply, vary, let the strongest live and the weakest die.

Ichneumonid wasp. Most of the parasitic wasps of this order survive by laying their eggs within the bodies of caterpillars. The larvae feed on the living caterpillar from the inside, consuming the most life-supporting tissues last in order to ensure the longest viability of their prey, and prolonging its perceived misery. Ref: Flickr

In one of many letters to his friend, the American botanist Asa Gray, it becomes just how clear and deep this insight is:

With respect to the theological view of the question; this is always painful to me.— I am bewildered.— I had no intention to write atheistically. But I own that I cannot see, as plainly as others do, & as I shd wish to do, evidence of design & beneficence on all sides of us. There seems to me too much misery in the world. I cannot persuade myself that a beneficent & omnipotent God would have designedly created the Ichneumonidae with the express intention of their feeding within the living bodies of caterpillars, or that a cat should play with mice. Not believing this, I see no necessity in the belief that the eye was expressly designed.

Preferring to see nature as governed by laws, Darwin realizes that the laws that govern the formation of an organ such as the eye must be the same that govern the formation of instincts and behaviors, whether they be perceived as benevolent or cruel. If a design argument cannot explain the unnecessary and cruel infliction of suffering on the part of some animals, it's not likely to explain anything else in nature. Perhaps to avoid offending his good friend and supporter, who was a devout Christian and believer in design, Darwin concludes:

On the other hand I cannot anyhow be contented to view this wonderful universe & especially the nature of man, & to conclude that everything is the result of brute force. I am inclined to look at everything as resulting from designed laws, with the details, whether good or bad, left to the working out of what we may call chance. Not that this notion at all satisfies me. I feel most deeply that the whole subject is too profound for the human intellect. A dog might as well speculate on the mind of Newton.— Let each man hope & believe what he can.—

The discussion about how Darwin saw cruelty in relation to evolution and natural selection is very relevant within the context of how it applies to human societies. At best, Darwin is conflicted about the idea of "survival of the fittest", or as he put in at the very end of chapter eight - "multiply, vary, let the strongest live and the weakest die." Many attempts have been made by those that deny and criticize evolutionary theory to characterize Darwin's theories as justification for such horrible acs of cruelty as genocide and the killing of "weaker elements" in society. However, if you read chapter eight of "Origin" or Darwin's notes and correspondence on the subject, it's obvious that just as cruelty and suffering are "small consequences of a general law", so are kindness and empathy.

In chapter five of The Voyage of the Beagle Darwin describes how the Spaniards treated the indigenous population of South America:

This is a dark picture; but how much more shocking is the unquestionable fact, that all the women who appear above twenty years old are massacred in cold blood! When I exclaimed that this appeared rather inhuman. he answered, "Why, what can be done? they breed so!" Every one here is fully convinced that this is the most just war, because it is against barbarians. Who would believe in this age that such atrocities could be committed in a Christian civilized country?

Online bioinformatics tools and resources

2012-02-05T15:43:00.000+01:00

I've updated my collection of online resources for genomics, sequence analysis and phylogeny - click here or on the "BioInfo" tab above.

These are all the tools that I use regularly in my work, so they're geared towards comparative genomics (mostly vertebrates), gene and protein predictions, sequence alignment and editing as well as different methods and applications for phylogenetic analyses. If you think there's a great resource out there that's missing, let me know in a comment below! I first put the page together for the people in my lab so that we could share all the same tools, but now it's more or less our informal start page. It's fantastic that so many researchers have developed all these great methods and are willing to make them freely accessible online. My work would certainly be impossible without that spirit of cooperation and openness. It does warm the heart to be part of a scientific field and a culture where this is the norm rather than the exception.

Two ways of looking at the same proteins: Insulin-like Growth Factor Binding Proteins

2011-11-30T15:52:00.000+01:00

Back in June I blogged about a research paper that we had just published with myself as the lead author. The subject of our paper was the evolution of the Insulin-like Growth Factor Binding Proteins (IGFBPs), and how this family of proteins has expanded in vertebrate evolution. Yesterday I noticed that this paper, "my" paper!, now has received its very first citation! This was a my first paper as lead author, so naturally I avidly checked it out.

The research paper that cites us is in press in the Journal of Biological Chemistry (reference below). While we were interested in finding as many IGFBP genes in as many vertebrates as we could, studying the characteristics of their genetic code and establishing their evolution, this study is more concerned with the biochemical structures of the actual proteins.

Molecular model of mouse IGFBP-5 (N-terminal), showing the locations of the cysteines that form disulfide bridges. Ref: M. Nili et. al. (see reference below).

Through mass spectrometry, the authors of this study, Mahta Nili and co-workers, have determined the presence of so called disulfide bridges in the IGFBP-5 protein from mouse. Disulfide bridges are formed by the side-chain of the amino acid cysteine and are important structural components of proteins, holding different parts of the three-dimensional structure together and in a way giving the protein part of its "shape". And when it comes to proteins, if you want to understand functions, you have to understand "shape". They could conclude that the structure of the mouse IGFBP-5, looking at the disulfide bridges, probably is very similar to the structure of most other IGFBPs (IGFBP -1,-2,-3 and -4), but not all (IGFBP-6). This is based on comparisons with already known models of a few other IGFBPs as well as our analyses of the amino acid sequences encoded by many different IGFBP genes. Their concluding citation of our paper reads:

Overall, as depicted in Fig. 5C [see above - Daniel], it is likely that the three-dimensional structure of the N-terminal domain of IGFBP-5 is very similar to IGFBP-4, and we predict that IGFBPs 1 - 3 will exhibit analogous structural features.

I agree with their prediction! It's "my" paper they're citing. Our evolutionary analyses would also allow them to say that the structure (probably) holds across all vertebrates, and that it is the ancestral one, but they haven't gone as far as stating that outright.

These are two very different ways of looking at the structure/function relationship of proteins. But at the center of both approaches is trying to connect the biochemical structures of proteins to their functions and their evolution. Each angle feeds the other. Considering all the similarities between IGFBPs I think it's a bit of an evolutionary mystery why we have so many of them - we found some fishes probably have up to 11, us mammals have 6. The structure that the authors of this new study have determined is of the part of IGFBPs (IGFBP-5 in this case) that binds to the Insulin-like Growth Factors (IGFs). This interaction regulates many molecular processed behind our metabolism, cell proliferation and growth, especially during embryonic development, so clearly this functional element is important. But maybe more clues to the evolution of several and diverse IGFBPs lie in other functional elements that have nothing to do with IGFs? Several such biological functions have been described for some IGFBPs, and in our paper from earlier this year we could start suggesting that some of the amino-acids that could underlie these IGF-independent functions show up in some IGFBPs and species, and not in others.

Still, it's only by determining the three-dimensional biochemical structures of proteins that we can start developing an idea about the evolution of functional elements in protein sequences, and how they relate to function.

Nili, M., Mukherjee, A., Shinde, U., David, L., & Rotwein, P. (2011). Defining the disulfide bonds of insulin-like growth factor binding protein-5 by tandem mass spectrometry with electron transfer dissociation and collision induced dissociation Journal of Biological Chemistry DOI: 10.1074/jbc.M111.285528

Ocampo Daza D, Sundström G, Bergqvist CA, Duan C, & Larhammar D (2011). Evolution of the Insulin-Like Growth Factor Binding Protein (IGFBP) Family. Endocrinology, 152 (6), 2278-89 PMID: 21505050

Nobel season '11: Physiology or Medicine

2011-10-03T08:28:00.000+02:00

In a few hours the Nobel committee at the Karolinska Institute in Stockholm will announce this year's Nobel prize winner in Physiology or Medicine. I'm going to be watching it all go down in this here handy live-feed video widget. The chemistry prize, which is often awarded to advancements in basic molecular biology, is being announced on Wednesday.

I've gone through some of my favorites for the prize in the previous year's pair of posts, and there's no doubt they're still current. Arthur Horwich went on to win this year's Lasker Award together with Franz-Ulrich Hartl for their work on chaperone-assisted protein folding, but sadly Ernest McCulloch died earlier this year without ever receiving the prize for his participation in the discovery of stem cells together with James Till.

I think maybe it's time again that a discovery in neuroscience was awarded the physiology or medicine prize. Neuroscience is heavily overrepresented among the physiology and medicine wins, but the last time was a whole five years ago. Maybe something related to neurogenesis and the discovery of adult neural stem cells, where we have names like Sally Temple (more women laureates!), Brent Reynolds and Samuel Weiss.

>> Update 10.20

The science reporter for Swedish morning newspaper Dagens Nyheter came out with a list of possible laureates. It covers the usual suspects that I had mentioned before, but a cool possibility I had missed is David Julius for his discovery of Trp channels, sensory proteins that respond to pressure, stretching, pain, heat and cold, and interestingly also "hot" and "cool" substances such as the capsaicin in chili and menthol in peppermint. This prize would have strong ties to basic research in neuroscience as well as interesting practical applications.

>> Update 11:45

The live video feed has some technical difficulties, but through Twitter we learn that this year's Nobel prize in Physiology or Medicine has been awarded jointly to Bruce A. Beutler and Jules A. Hoffmann "for their discoveries concerning the activation of innate immunity", and Ralph M. Steinman "for his discovery of the dendritic cell and its role in adaptive immunity". I had sort of tipped on Steinman and the dendritic cells last year, but the pairing with the discovery of Toll and Toll-like receptors by Beutler and Hoffmann makes sense since it joins together important advances in both innate and adaptive immunity. Steinman won the Lasker award in 2007.

Here is more information from the Nobel prize website.

>>Update 15:12

Shockingly, as I read from several sources, Ralph Steinman died this Friday, mere hours before the decision was made. The Nobel prizes cannot be awarded posthumously unless the death happens after the announcement. The secretary of the Nobel committee at the Karolinska Institute tells Dagens Nyheter "We will have to examine the practical consequences together with the Nobel foundation in the coming days". Clearly they were not aware Steinman had died before making the announcement. Steinman's colleagues at The Rockefeller University in New York just learned the news this morning.

Is there anything fish don't do? Tool use!

2011-09-29T14:21:00.004+02:00

This video and story have been making the rounds on the Internet in the last few days. I just saw it yesterday and it's fascinating! For the first time (allegedly), "tool-use" in a fish has been filmed and the behavior is available for all of us to see. The fish in question is a species of wrasse observed in Palau, Choerodon anchorago or orange-dotted tuskfish.

You can see the fish digging out a clam with its pectoral fin, then carrying it over to a rock or a coral head and cracking it with a characteristic sideways motion of the head. The fish was observed doing this three times in a row, the last of which was recorded. Each event lasted less than five minutes. Here are summaries of the story from Scientific American, Science Daily and AnimalWise.

This finding is being published as a short notice in the journal Coral Reefs and joins other findings from earlier this year, published in the same journal, presenting the first photographic evidence of the same behavior in another species of tuskfish, Choerodon schoenleinii. That story was summarized in Science Now and Wired Science. In fact, there have been a handful of reports of the same behavior from different species of wrasse indicating that this might be a shared ancestral behavior in the Labridae.

Whether this constitutes "real" tool use as seen in mammals and birds, or not, will depend entirely on the kind of definition you use. That question is boring to me. But I do think it would be a mistake to equate or compare this "tool use" in fish to, for example, tool use in chimpanzees. Instead I think the interesting perspective is to put this behavior within the already known complex feeding and food seeking behaviors in fish to see in which niches "tool use" might have been beneficial.

Bernardi, G. (2011). The use of tools by wrasses (Labridae) Coral Reefs (Online First™, 20 September 2011) DOI: 10.1007/s00338-011-0823-6

Jones, A., Brown, C., & Gardner, S. (2011). Tool use in the tuskfish Choerodon schoenleinii? Coral Reefs, 30 (3), 865-865 DOI: 10.1007/s00338-011-0790-y

Some notes on the Atlantic cod genome, and fish genomes in general

2011-09-08T17:32:00.000+02:00

Teleost fish genome sequences have been absolutely essential to our understanding of vertebrate genome evolution, and to vertebrate evolution in general. Last month I welcomed the addition of the Atlantic cod genome to the sequenced fish genomes, and highlighted some of the main findings of the first analysis of the whole genome sequence. The preliminary genome database is now available for browsing at the Pre!Ensembl database.

After I had written that post, I had some notes left over because I didn't want to make my text too long. But I think they're interesting enough for me to revisit the cod genome and write a new post.

The Atlantic cod, Gadus morhua

I've already highlighted some of the basic stats of the Atlantic cod genome and compared them to some other fish genomes:

The basic genome stats reveal a pretty standard vertebrate genome, if there is such a thing. The total (haploid) size is estimated at approx. 830 million base pairs, a bit lower than previous estimates, and the number of identified genes is 22,154 (20,095 protein coding). The closest related fish species with a sequenced genome is the three-spined stickleback, Gasterosteus aculeatus, with a genome of approx. 446 million base pairs and 20,787 identified genes. The best studied fish genome, that of the zebrafish Danio rerio is quite a bit longer, with about 1.5 billion base pairs, but the gene content is similar with about 26,000 identified genes.

Aside from the zebrafish and three-spined stickleback genomes, the japanese pufferfish (Takifugu rubripes), green-spotted pufferfish (Tetraodon nigroviridis) and medaka or Japanese ricefish (Oryzias latipes) genomes have been sequenced. The medaka genome sequence is about 700 million base pairs long with about 20,400 identified genes. The two pufferfish genomes are significantly shorter, with about 390 and 340 million base pairs respectively, but with similar gene contents - about 20,400 for both species. These species represent the latest 150 - 300 million years of fish evolution, more or less, which is a great coverage, but considering the vast radiation and diversity of fishes it's a pretty thin representation - five orders out of about forty, not including the largest one Perciformes (perch-like fishes). For comparison, the genomes of over thirty different species of mammal have been sequenced (with varying quality, it should be said).

Evolutionary tree of the fish species with sequenced genomes. Divergence times between the species (million years ago) are according to timetree.org estimates, except those in cursive which are estimates from Donoghue and Benton in Trends. Ecol. Evol. 22(8), 2007. The estimate of 307 MYA for the divergence of zebra fish is probably an overestimation. Click on the image to see it larger.

Sequencing and putting together a "working" genome sequence is an arduous task. It includes the sequencing itself of innumerable small pieces of the broken-up DNA strands, then the assembly of these short fragments, called contigs, into longer pieces that can then be mapped to the different chromosomes. In this process it's also important to annotate the content of the genome - which means to identify different genes, repeat elements et c. All of this is done because the information on where different genes or other elements are located in the genome is just as important as the sequence itself. This long process is why it may take several years between the start of a genome sequencing project and the announcement and release of the sequence.

No available genome sequence, from any species, currently accounts for 100% of the genome - some parts simply seem to evade the sequencing process, either due to mistakes in the sequencing or because of the specific qualities of the particular genome region. It's also often the case that many of the short contigs cannot be assembled into large stretches of sequence, called scaffolds. This can cause a lot of trouble when it comes to puzzling the whole genome sequence together and making a map of where everything is located on the chromosomes. The zebrafish genome sequence, which is probably the best-sequenced teleost, encompasses about 87% of the projected whole genome length, which is really rather good and very "workable".

The cod genome seems to be of reasonable quality. About 90% of the estimated whole genome size is covered, but only 74% is part of the long scaffolds. The rest is made up by contigs with a minimum size of 500 base pairs that could not be put together into scaffolds. Still, it seems that these contigs represent highly variable regions, and most protein coding genes can be located within the assembled scaffold sequences. This is a good sign of quality. However, there a lot of gaps in the scaffold sequences - small regions that could not be read in the sequencing process. Together these gaps reduce the amount of the genome that was actually sequenced and assembled to about 46% of the estimated whole genome size. Since the vast majority of the already known genes could be identified, and the total gene amount is comparable to the other fish genomes, this might not be a huge problem. But it's important to remember that any genome sequencing project produces a limited dataset, not an actual whole genome.

I mentioned earlier that the cod genome database doesn't show any chromosome data. That is because the cod genome hasn't been mapped to chromosomes yet. Instead the long scaffold sequences have been compared to an existing linkage map, a collection of sequence stretches containing linked Single Nucleotide Polymorphisms, or single positions of the genome which are known to vary between individuals within the species. In this way much of the genome assembly was put together into 23 large so called linkage groups. Each different linkage group represents a number of genes that are linked with each other, which in turn is likely to represent a significant cohesive segment of a chromosome. It's these linked stretches of the genome sequence that provide the primary useful data for comparative analyses between different genomes. In total the genome sequence represented on these linkage groups is about 332 million base pairs, a match to the 46% of the genome that was actually sequenced and assembled.

By comparing these groups of linked genes to the chromosomes of the zebrafish, medaka, stickleback and green-spotted pufferfish it's possible to see that, for the most part, the same genes are linked together in all the fish genomes. This is represented by the red circles in the image below. The larger the circle, the more genes are shared between each cod linkage group and the different chromosomes in the other species.

Ref: Adapted from B. Star et al (see below).

In this way we can see that, for instance, linkage group 1 in the cod is likely to correspond to chromosome 23 in the zebrafish, 7 in the medaka, XII in the stickleback (stickleback genomes are enumerated with Roman numerals for some reason), and 9 in the pufferfish. This means that the linkage groups are likely to represent the different cod chromosomes, and that the cod shares the same basic genome organization as the other known fish genomes. There is one curious exception though - a whole block of genes in the cod linkage group 19 seem to have "changed place" compared to the other genomes. This is indicated by the blue arrows.

Overall, it seems the quality of this genome assembly is similar to the already available fish genomes. The authors of the cod genome paper note that in quality it's most similar to the medaka genome, which is not as good as the zebrafish or stickleback genomes, but better than the two pufferfish genomes and, it should be said, the majority of mammalian genomes. In my experience this means that the cod genome should be spotty in some regions, but by and large it probably contains large stretches with good "workable" sequence. I've started using it a little bit in my own research and I'm sure it's going to prove its worth.

Star, B., Nederbragt, A., Jentoft, S., Grimholt, U., Malmstrøm, M., Gregers, T., Rounge, T., Paulsen, J., Solbakken, M., Sharma, A., Wetten, O., Lanzén, A., Winer, R., Knight, J., Vogel, J., Aken, B., Andersen, Ø., Lagesen, K., Tooming-Klunderud, A., Edvardsen, R., Tina, K., Espelund, M., Nepal, C., Previti, C., Karlsen, B., Moum, T., Skage, M., Berg, P., Gjøen, T., Kuhl, H., Thorsen, J., Malde, K., Reinhardt, R., Du, L., Johansen, S., Searle, S., Lien, S., Nilsen, F., Jonassen, I., Omholt, S., Stenseth, N., &amp;amp;amp; Jakobsen, K. (2011). The genome sequence of Atlantic cod reveals a unique immune system Nature DOI: 10.1038/nature10342

The "living fossil" discussion and that "living fossil" eel you might have heard of

2011-08-17T21:49:00.009+02:00

I don't like the term "living fossil". Sure, when used well it can be eye-catching in a pedagogical way, but it's still sort of vague and problematic, and used badly it's outright confusing and may reinforce misconceptions about evolution. That's why when you see it used, you often see it between quotation marks followed by an explanation motivating why the organism in question is called a "living fossil" to begin with. Today we learn about the discovery of a really striking and interesting new species of eel from Palau, Protoanguilla palau, heralded as a "living fossil" in the title of the scientific publication made available today (see reference below) as well as in most media reports.

Ref: Video still/Jiro Sakaue, Southern Marine Laboratory, Palau.

As you guessed by now, I think this is a bit problematic. It starts with the fact that different people often mean different things when calling something a "living fossil". Darwin himself is acknowledged with originating the term in On the Origin of Species, if only in a passing comment. He wrote:

All fresh-water basins, taken together, make a small area compared with that of the sea or of the land; and, consequently, the competition between fresh-water productions will have been less severe than elsewhere; new forms will have been more slowly formed, and old forms more slowly exterminated. And it is in fresh water that we find seven genera of Ganoid fishes, remnants of a once preponderant order: and in fresh water we find some of the most anomalous forms now known in the world, as the Ornithorhynchus and Lepidosiren, which, like fossils, connect to a certain extent orders now widely separated in the natural scale. These anomalous forms may almost be called living fossils; they have endured to the present day, from having inhabited a confined area, and from having thus been exposed to less severe competition.

In this chapter Darwin is speaking to us about the different environmental conditions that are favorable to natural selection, or rather to the creation of new varieties through natural selection. Here he is trying to explain why some organisms might appear relatively unchanged by natural selection, using ganoid fishes, a now obsolete term describing gars and bichirs or reedfishes, the platypus and the South American lungfish, as examples of this. With "living fossil" he is vaguely referring to organisms that are the sole or almost sole survivors of a relatively old and mostly extinct lineage. This meaning is a bit different to the common use today which is either a species that appears practically unchanged from its ancestors found in the fossil record, like the gingko or the horseshoe crab, or a species that was only known from the fossil record until it was suddenly found to be very much still alive, like the coelacanth. None of these organisms fit comfortably into one coherent definition of what a "living fossil" might be without having to include several other groups that are not usually included.*

So as a term, "living fossil" is potentially misleading and awkwardly defined. But most of all it's just redundant. It's just not worth it. Some biologists see this as a reason to take the term lightly and use it casually, but I guess I just don't take many things lightly.

Discussions about "living fossils" aside, the finding of Protoanguilla palau is very interesting for several reasons. Firstly, I don't think we should underestimate the fantastic sense of wonder about our planet and about life that something like this might awake. The almost 18 cm long Protoanguilla type specimen was discovered in a cave at about 35 m of depth in the reef waters of Palau in the pacific ocean. This sort of mirrors the discovery of the coelacanth and makes you think about the kind of enigmatic species we have yet to find in the as yet unreached corners of the ocean.

Eels were one of the very first now living lineages of bony fish to emerge - it's one of the most basal. They first appear in the fossil record in the Cretaceous about 100 million years ago, but the evolution of the bony fishes as a whole probably goes back to the mid-Paleozoic, some 400-300 million years ago. Protoanguilla has an interesting combination of characters, sharing several with all other now living eels as well as with the fossil eels from the Cretaceous, some specifically only with the fossil eels. It also has yet another number of characters that are seemingly specific to it, and some that are characteristic of bony fish lineages that diverged before eels: notably, gill rakers - toothed protrusions of cartilage along the inner rim of the gills used to trap food particles - and the presence of less than 90 vertebrae. Most eels show an expansion of the vertebral column to include up to 200 vertebrae. In simple terms, it looks like an eel but it also looks really primitive. This pattern of old morphological characteristics paired with molecular phylogenetics analyses based on the mitochondrial genome place Protoanguilla at about 200 million years ago, very close to previous molecular estimations of the earliest divergence of eels and 100 million years before the first known eel fossils. The phylogenetic analyses also place it confidently within the eel lineage, so it's not a different kind of bony fish, and they show that it represents the most basal or oldest known lineage of eel. I checked the method descriptions and the results of the phylogenetic analyses in the supplementary data provided by the journal and it looks solid.

However, none of this makes Protoanguilla a "living fossil" in the same way the coelacanth or the gingko might be considered "living fossils". It doesn't conform to Darwin's original exemplification of some species as "living fossils" either. There are no "dead fossils" of Protoanguilla or similar eels as far back as 200 million years ago to begin with! Frankly, the use of the term in the title of the scientific publication is puzzling. It's the first described species in a new and basal group - why call it a "living fossil" when so much surrounding data is absent? The authors might have answered that question for me themselves in the fist sentence of the article:

Ever since Charles Darwin coined the term ‘living fossil’ in On the Origin of Species (...), organisms that have been called living fossils have received considerable attention.

They define "living fossils" as "extremely long-lived or geologically long-ranging taxa", probably based on the fact that several of the morphological characteristics of Protoanguilla seem to have appeared relatively early in evolution and have been kept since. But this definition would have to include several other groups of organisms that are usually not considered "living fossils" at all. They've strangely conflated "living fossil" with "conserved", which is a very useful and established term in evolutionary biology.

This discussion might be peripheral, but it's worth having and it comes up quite often in evolutionary biology. I really want to highlight how good the analyses in the paper are though, and how exciting the finding of Protoanguilla is for our understanding of early bony fish evolution.

For summarizing reports and videos of this marvelous animal, check out BBC News and Wired Science. Swedish newspaper Dagens Nyheter also reports - "Living fossil swims in the pacific ocean".

* Are birds "living fossils", for instance, having been the only dinosaur group out of a great number to survive extinction? I think most people would argue that they're not because they are very diverse and numerous, but there's no other reason not to include them. "Living fossil" seems to imply it should be a rare group of organisms, or ideally a single surviving species.

Johnson, G., Ida, H., Sakaue, J., Sado, T., Asahida, T., &amp;amp;amp;amp; Miya, M. (2011). A 'living fossil' eel (Anguilliformes: Protoanguillidae, fam. nov.) from an undersea cave in Palau Proceedings of the Royal Society B: Biological Sciences DOI: 10.1098/rspb.2011.1289

The Atlantic cod genome is available

2011-08-12T20:07:00.007+02:00

Great news for those of us who are interested in comparative genomics, and fish genomes in particular - yesterday the Atlantic cod genome was made public at the cod genome project website to coincide with the description of the genome, published online in advance by Nature (reference below).

I've been pottering about in the genome since yesterday morning, looking for the gene families I'm researching in my own work, but the database is still quite rudimentary and tricky to use. Most of the sequences I've searched for come back in fragments, and since the genome hasn't been mapped to chromosomes in the database, it's difficult to find out where in the genome individual sequences are, and to "get to know the neighborhood" of the sequence you're interested in, which is essential for comparative genomics. Thankfully it will (probably) get a more user-friendly interface soon, when it becomes integrated with the Ensembl genome browser, where the other five sequenced fish genomes are already available.

I also made this illustration for my collection of genome species.

The Atlantic cod, Gadus morhua

The basic genome stats reveal a pretty standard vertebrate genome, if there is such a thing. The total (haploid) size is estimated at approx. 830 million base pairs, a bit lower than previous estimates, and the number of identified genes is 22,154 (20,095 protein coding). The closest related fish species with a sequenced genome is the three-spined stickleback, Gasterosteus aculeatus, with a genome of approx. 446 million base pairs and 20,787 identified genes. The best studied fish genome, that of the zebrafish Danio rerio is quite a bit longer, with about 1.5 billion base pairs, but the gene content is similar with about 26,000 identified genes.

Summaries of the main findings from the overall description of the cod genome are available at Nature News and Science Now. These reports highlight the main focus of the published genome description - the loss of genes essential for adaptive immune reactions. The Atlantic cod and several of its closest relatives in the family Gadidae lack genes for the Major Histocompatibility Complex class II (MHC II), one of the proteins that presents antigens to immune cells and initiate an adaptive immune response. They also lack genes for the proteins CD4 and Ii²¹ (also known as CD74). CD4 is expressed on lymphocytes called helper T-cells and allow them to interact with the MHC II, and Ii²¹ is involved in the transportation of MHC II proteins to the surface of the cell.

Instead, the Atlantic cod has greatly expanded and diversified its setup of the other class of MHC genes, the MHC class I genes, as well as genes for proteins called Toll-like receptors. These molecules represent another side of immune responses which, seemingly, the cod lineage has recruited to complement its immune defense. It was probably this expansion of MHC I genes and Toll receptor genes that lead to the loss of MHC II, CD4 and Ii²¹ rather than the other way around.

The researchers confirmed that the genes were missing, by trying to sequence them independently, with no results (which in this case was good). But from a comparative genomics perspective, the evidence they gathered is more compelling. They matched the genomic regions containing these genes in the already known fish genomes against the cod genome sequence and found the corresponding regions.

Click on the image to see a larger version. Ref: Supplementary information to B. Star et al. in Nature (see reference below).

As you can see in the image above, the yellow MHC II genes are missing from the corresponding regions of the cod genome, as compared to the zebrafish and stickleback genomes. The same thing can be seen for the Ii²¹/CD74 genes, but for the CD4 gene they actually found a smaller fragment of the gene in the cod genome, showing that these genes are either going or gone.

These findings helps us understand fish immunity better, and might contribute to improve the aquaculture conditions for cod, as is highlighted in the reports above, but most importantly of all it's a great and interesting example of gene loss and gene duplication, an important mechanism in evolution. In addition, the method I exemplified above is a great example of the type of work you can do once you have several whole genome sequences which you can compare with each other. Once the genomic database is fully functional, many research groups will be able to explore other great questions using similar methods. With this in mind, the cod genome promises to be yet another great contribution in our understanding of how genomes, and therefore organisms, have evolved.

Star, B., Nederbragt, A., Jentoft, S., Grimholt, U., Malmstrøm, M., Gregers, T., Rounge, T., Paulsen, J., Solbakken, M., Sharma, A., Wetten, O., Lanzén, A., Winer, R., Knight, J., Vogel, J., Aken, B., Andersen, Ø., Lagesen, K., Tooming-Klunderud, A., Edvardsen, R., Tina, K., Espelund, M., Nepal, C., Previti, C., Karlsen, B., Moum, T., Skage, M., Berg, P., Gjøen, T., Kuhl, H., Thorsen, J., Malde, K., Reinhardt, R., Du, L., Johansen, S., Searle, S., Lien, S., Nilsen, F., Jonassen, I., Omholt, S., Stenseth, N., &amp;amp;amp; Jakobsen, K. (2011). The genome sequence of Atlantic cod reveals a unique immune system Nature DOI: 10.1038/nature10342

Xiaotingia

2011-07-28T18:18:00.002+02:00

The subject of feathered dinosaurs and the evolution of birds is something that fascinates me and captures my imagination, as I'm sure it does a lot of people. Not only because it changes the way we look at the world around us, specifically birds, but also because there's a lot of cool evolutionary science involved in the study of the early evolution of birds from... well, yes that's the question, isn't it? From what exactly? We know that in any evolutionary sense that matters, birds are dinosaurs, but the questions remain. How long ago did the evolution of birds start? What did the closest bird-related dinosaurs look like? What did the first birds look like, and what did they do?

A highly publicized article appeared in Nature yesterday morning, describing the lovely creature so artistically reconstructed in the image above: Xiaotingia zhengi, an early bird-like dinosaur that might help answer these questions. The findings were very quickly picked up by The Guardian, Wired Science, Not Exactly Rocket Science, Pharyngula, Live Science and Nature News, of course, among other media outlets and blogs. Partly because the archetypical "original bird" Archaeopteryx is involved. Do head over to any of those pages first for pithy summaries of the findings.

Both major Swedish newspapers were content with copying the news telegram: "Original bird was not a bird". Also here.

The description of the Xiaotingia fossil and phylogenetic analyses comparing it to other bird-like dinosaurs and early birds seems to place it together with Archaeopteryx among a dinosaur group, the Deinonychosaura, and not at the base of bird evolution. So the Xiaotingia findings call into question where the line should be drawn between birds and dinosaurs, more so than having something specific to say about Archaeopteryx itself. As with most phylogenetic trees, many of the branches are missing in the evolutionary history of the dinosaur-bird transition. The really interesting thing to consider in the light of Xiaotingia and other bird-like dinosaur findings is how beautifully gradual the transition must have been, and how remarkably early bird-like traits appeared in dinosaur evolution, in what now appears to have been a diverse and successful group of organisms. As PZ Myers put it in his Pharyngula post:

There was a whole assortment of delicate-boned, feathered, bipedal dinosaurs that were flourishing and diversifying in that window of time, and we've now got enough data that we can distinguish details in the family tree, which is absolutely fabulous.

Xu, X., You, H., Du, K., & Han, F. (2011). An Archaeopteryx-like theropod from China and the origin of Avialae Nature, 475 (7357), 465-470 DOI: 10.1038/nature10288

A quick Mendel follow-up

2011-07-22T11:32:00.002+02:00

As a footnote to my previous post about Gregor Mendel, I offer these interesting Google NGrams.

To start off, we plot the terms "Gregor Mendel", just "Mendel", "Mendelian" as well as the genus of the garden pea Mendel worked with, "Pisum".

Not surprisingly, the years 1866 and 1900 (or there around) stand out markedly.

1866 was of course the year Mendel published his paper Experiments in Plant Hybridization, and we can see that mentions of his name, or at least his surname, and mentions of the garden pea Pisum start going up significantly. Mendel's intention with the paper was explicitly to inspire others to repeat his experiments, and he was apparently disappointed over the fact that nobody did; but it does seem like there was an awareness of his work in the late 1800s, and although the mentions of Pisum couldn't all come in reference to Mendel's work, it's remarkable how 1866 sticks out. You can repeat the experiment in German.

1900 was the year Mendel's work was re-discovered in publication and introduced to a wider scientific audience, through the independent publication of papers by Hugo de Vries, Carl Correns, Erich Tschermak and William Bateson, although none of them did immediately realize the power of Mendel's work or accepted it fully to account for the patterns of heredity they had observed in their own experiments. Nonetheless, we see that the use of the term "Mendelian" as an adjective has a large impact starting in 1900, which speaks for the introduction of Mendelian inheritance laws in a broader theoretical framework. Looking at the source data reveals mentions of "Mendelian phenomena", "Mendelian allelomorph", "Mendelian characters", "Mendelian crosses", "Mendelian factor", "Mendelian inheritance" et c.

If we plot the names of these scientists together with "Mendel" and "Mendelian", there seems to be a corresponding increase in mentions around 1900, at least for de Vries and Bateson. Although it doesn't seem to be that correlated, at first glance, with the increase in mentions of Mendel and "Mendelian". Could it be that; although de Vries, Correns and Tschermak claimed the re-discovery of Mendel for themselves, and Bateson claimed the introduction of Mendel in Britan; they themselves were not as often associated with the subsequent breakthrough of Mendel's ideas?

In my previous post I wrote about whether or not Mendel has predicted the existence of genes. While the terms "gene" and "genetic" were well in use by the early 1900s, it was William Bateson who introduced the term "genetics" as the study of biological inheritance. If we plot terms such as "Genetics", "Heredity", "Mutation", "Allele", together with "Mendel", "Mendelian", "Bateson" and "de Vries", who introduced the term "mutation", we see that the era of classical genetics that was to come in the first decades of the 1900s was already brewing when the "re-discovery" of Mendel happened. But it's undoubtable that Mendel's ideas were essential for the breakthrough of genetics in biology.

If you want to read more about the rediscovery of Mendel in 1900, I recommend the following papers as an insight into the sometimes very personal stakes involved. They were the ones I researched before writing this post.

Weinstein, A. (1977). How unknown was Mendel's paper? Journal of the History of Biology, 10 (2), 341-364 DOI: 10.1007/BF00572646

Olby, R. (2009). William Bateson's Introduction of Mendelism to England: A Reassessment The British Journal for the History of Science, 20 (04) DOI: 10.1017/S0007087400024201

Lenay C (2000). Hugo De Vries: from the theory of intracellular pangenesis to the rediscovery of Mendel. Comptes rendus de l'Academie des sciences. Serie III, Sciences de la vie, 323 (12), 1053-60 PMID: 11147091

Remembering Gregor Mendel

2011-07-20T20:35:00.007+02:00

Today is the 189th anniversary of the birth of scientist Gregor Mendel, as commemorated by today's doodle on google.com. It's one of their better ones, I think.

The picture shows the plant that Mendel has become famous for, the common pea Pisum sativum, but it also cleverly shows an illustration of the "laws" that he discovered. We can see the traits green (dominant) and yellow (recessive) color be passed on through two generations in the predictable proportions dictated by Mendelian inheritance. This is good old basic school biology, and most of us must be familiar with Mendel from that context. The Guardian also commemorates the day and provides a little bit of background.

Much has been said, and probably remains to be said, about Mendel's role as "father of genetics" and whether or not he predicted the existence of genes. I always think it's fun to go back to the original source of things, so here we have the relevant piece from Mendel's 1866 paper Versuche über Pflanzen-Hybriden or Experiments in Plant Hybridization, which was first read to the Natural History Society in Brünn (now Brno in the Czech Republic) the year before. I recommend this site for insightful comments on and facts about Mendel's original paper.

With Pisum it was shown by experiment that the hybrids form egg and pollen cells of different kinds, and that herein lies the reason of the variability of their offspring. In other hybrids, likewise, whose offspring behave similarly we may assume a like cause; for those, on the other hand, which remain constant the assumption appears justifiable that their reproductive cells are all alike and agree with the foundation-cell of the hybrid. In the opinion of renowned physiologists, for the purpose of propagation one pollen cell and one egg cells unite in Phanerogams* into a single cell, which is capable by assimilation and formation of new cells to become an independent organism. This development follows a constant law, which is founded on the material composition and arrangement of the elements which meet in the cell in a vivifying union. If the reproductive cells be of the same kind and agree with the foundation cell of the mother plant, then the development of the new individual will follow the same law which rules the mother plant. If it chance that an egg cell unites with a dissimilar pollen cell, we must then assume that between those elements of both cells, which determine opposite characters some sort of compromise is effected. The resulting compound cell becomes the foundation of the hybrid organism the development of which necessarily follows a different scheme from that obtaining in each of the two original species. If the compromise be taken to be a complete one, in the sense, namely, that the hybrid embryo is formed from two similar cells, in which the differences are entirely and permanently accommodated together, the further result follows that the hybrids, like any other stable plant species, reproduce themselves truly in their offspring. The reproductive cells which are formed in their seed vessels and anthers are of one kind, and agree with the fundamental compound cell.

Mendel is clearly talking about "elements" and the arrangement of these elements within the gametes, the egg and pollen cells, and therefore of the cell that gives rise to the whole organism. He starts out by pointing out that observable variation must result from variation in the gametes: not all egg cells are the same, and not all pollen cells are the same. The cause of the variation is then the difference in the "material composition and arrangement of the elements" carried in the gametes. When the egg and pollen cells unite, these differing elements must also unite within the resulting "foundation cell" in a way that has to be constant from generation to generation. There must be a "constant law". If the two parents are the same, it follows that the offspring will be the same as its parents: they "reproduce themselves truly in their offspring". But what he's really describing is that must happen if the parents are different; then it follows the the offspring will be different from either of the two parents, it will have "a different scheme".

Now comes the part that is really brilliant.

With regard to those hybrids whose progeny is variable we may perhaps assume that between the differentiating elements of the egg and pollen cells there also occurs a compromise, in so far that the formation of a cell as the foundation of the hybrid becomes possible; but, nevertheless, the arrangement between the conflicting elements is only temporary and does not endure throughout the life of the hybrid plant. Since in the habit of the plant no changes are perceptible during the whole period of vegetation, we must further assume that it is only possible for the differentiating elements to liberate themselves from the enforced union when the fertilizing cells are developed. In the formation of these cells all existing elements participate in an entirely free and equal arrangement, by which it is only the differentiating ones which mutually separate themselves. In this way the production would be rendered possible of as many sorts of egg and pollen cells as there are combinations possible of the formative elements.

Once these differing "elements" have settled in the offspring cell, they have formed "an arrangement" between them, a "differing scheme", the whole arrangement isn't passed on to the next generation. Rather, the "elements" "liberate themselves from the enforced union", once again migrate into differing gametes, and combine independently of each other, in new ways, in the generation that follows. Mendel's "elements", just as genes, are distinct and particulate. This has become known as Mendel's laws of inheritance: The law of segregation and the law of independent assortment.

So here Mendel is laying the whole foundation for meiosis, genetic variation and heredity, entirely from the basis of keen observation and meticulous and numerous hands-on experimentation. And, we must not forget, a great deal of luck. I think this insight is more interesting and more valuable than discussing how well he predicted the existence of genes as we know them today. I prefer to think that, in a way, Mendel left a "gene-shaped" hole through which the right peg could be put.

The mighty coelacanth

2011-06-30T17:43:00.008+02:00

I've added the above illustration of a Coelacanth (Latimeria chalumnae) to my collection of illustrations together with one I had already made of a lungfish (open image). If you like you can download both high-res TIF-files here. The same Creative Common license applies as described under the "Download Illustrations" tab above.

I was prompted to add the coelacanth after reading a recent fascinating article about the secretive lives of these marvelous fish (via Deep Sea News) by Dr. Hans Fricke and co-workers. The article summarizes decades of study of the Latimeria population outside the island Grande Comore in the Indian ocean.

Latimeria live in large overlapping home ranges that can be occupied for as long as 21 years. Most individuals are conﬁned to relatively small home ranges, resting in the same caves during the day. One hundred and forty ﬁve coelacanths are individually known, and we estimate the total population size of Grande Comore as approximately 300–400 adult individuals. <...> We estimate that the mean numbers of deaths and newcomers are 3–4 individuals per year, suggesting that longevity may exceed 100 years.

I'm astounded and my imagination is fueled by the intimate detail and vivid language with which the individual lives of these fishes is described! From the re-sighting of known individuals across several decades, the description of their cave-dwellings, which their share in family groups, their nocturnal hunting habits, and how they sometimes move outside of their familiar home-ranges. You can also read this recent interview with Fricke in Wired.

Together, the coelacanths (two described species in the taxon Actinistia) and lungfishes (three ~~species~~ genuses in the taxon Dipnoi) are referred to as "lobe-finned fishes". They are the sole species offering living insight into the wonderful "era of fishes" in the late Devonian Earth. An era that would give rise to the first vertebrate animals to conquer the land. Lungfishes in fact have several adaptations for temporary life on land, among them the ability to breathe air.

The image below describes the relationships between the coelacanths, lungfishes and terrestrial vertebrates. As you can see they are less related to the ray-finned fishes, which is what we usually think about when we think of a fish, and more closely related to us terrestrial four-limbed vertebrates or tetrapods. This in effect makes "lobe-finned fishes" out of all of us, a thought that I personally find very amusing and satisfying.

Click on the image to see it full-size.

The ages displayed in the nodes of the tree are borrowed from The TimeTree of Life project. You should see them as estimates, calculated from different lines of data which usually give differing results. There is not a lot of evidence to date the divergence between coelacanths, lungfishes and tetrapods, so it's still not clear which of the two, coelacanths or lungfishes, started to diversify from a common ancestor first.

Fricke, H., Hissmann, K., Froese, R., Schauer, J., Plante, R., & Fricke, S. (2011). The population biology of the living coelacanth studied over 21 years Marine Biology, 158 (7), 1511-1522 DOI: 10.1007/s00227-011-1667-x

Hedges, S.B. (2009). Vertebrates (Vertebrata) The Timetree of Life, S. B. Hedges and S. Kumar, Eds. (Oxford University Press), 309-314 LINK: http://www.timetree.org/pdf/Hedges2009Chap39.pdf

Nicotine, appetite and the brain

2011-06-28T00:29:00.003+02:00

Nicotine is not only very, very addictive, as a central nervous system stimulant it can also affect our motivations and behaviors in a wider sense. One of the behaviors it can modify is appetitive behavior. It's a well-funded fact that smokers tend to have a lower body-mass than non-smokers, and that smokers who quit have a tendency to gain weight, although until now the neurobiological mechanism for this modulation was unknown.

Recent findings from two different publications reveal parts of this mechanism, but while most reports have pin-pointed the results involving appetite suppression through pro-opiomelanocortin neurons, there is evidence that the complete picture is more complicated than that.

The neural and endocrine substrates of appetite and hunger form an intricate web of counteracting hunger and satiety signals that give each other feedback at different levels. Add to that the cognitive neural substrates of motivation and it becomes very apparent that simply getting us to eat, or stop eating for that matter, is a very complex task for the brain. Central to this task though, is a group of neurons in the arcuate nucleus of the hypothalamus that contain the peptide pro-opiomelanocortin, or POMC. These neurons are essentially an "off button" for appetite, initiating the second-order signals in the brain that reduce hunger and food intake. They are sensitive to circulating levels of leptin and insulin, which are higher after meals.

Until recently it remained unknown if this central regulation of appetite was the neural substrate for the effect of nicotine on body weight, even though it was a likely hypothesis. A recent article in Science headed by researchers from the Yale University School of Medicine (ref. 1 below) details a series of very elegant experiments showing that nicotinic drugs can activate these POMC neurons and reduce food intake in mouse models. As a part of this, the researchers demonstrated that POMC neurons express nicotinic receptors, nACHRs, and that these receptors were likely behind the observed reduction in food intake. Of course the nicotinic receptors don't normally respond to nicotine, which is an external substance, but to the signal substance acetylcholine. The finding that nicotinic acetylcholine receptors are expressed on POMC neurons adds a new level to the regulation of appetite. You can read more about the experiments and some of the specific results at Ars Technica or 80beats.

This work is beautifully done, not only because it reveals a central mechanism, but also because it has possible future applications in medical intervention to prevent weight gain in smokers who want to quit, and perhaps also in obesity treatment. Most media reports of this finding have taken up this perspective. See for instance the reports at NPR and TIME.com.

Understanding the link between nicotine and satiety, for example, could lead to new drugs that target the nicotine receptors on appetite-controlling cells, giving smokers a way to quit without the weight gain. <...>

"If we had a medicine targeted at these receptors, then people who are not quitting smoking because they are afraid of gaining weight now might make the attempt," Picciotto says. "That's a really exciting area of drug development."
Even if such medicines were to prove effective, however, they may come with side effects. The nicotine receptors that regulate fullness and appetite are also closely linked to the body's fight-or-flight stress response, in which the body revs itself up in the face of a threat. Activating these receptors could lead to increased blood pressure and heart rate, which may not be a good thing for anyone.

However, most reports of these findings are not providing a perspective on how complex appetite and feeding regulation is. Rather than nicotine affecting only one neural substrate, it's likely that nicotine affects the whole network of hunger and satiety signals.

Similar research, published practically simultaneously in the June issue of the Journal of Neurophysiology (ref. 2 below) and curiously also by researchers from the Yale University School of Medicine, leads us in that direction. The researchers found that acetylcholine neurons are indeed present in the mouse arcuate nucleus and that nicotine is indeed able to activate the POMC neurons. But they also found that nicotine can activate other neurons in the arcuate nucleus that stimulate appetite and food intake, although to a lesser degree. These neurons release the neuropeptide NPY, affecting some of the same second-order signals as the POMC neurons. So NPY neurons can be seen as the corresponding "on button" to the POMC neurons' "off button", and nicotine seems to stimulate both.

These findings highlights the fact that appetite regulation in the brain consists of an intricately balanced network of hunger and satiety signals, rather than a singular mechanism, and that nicotine affects this network at different points, finely shifting the balance towards decreased appetitive behavior and therefore lower body-mass.

(1) Mineur, Y., Abizaid, A., Rao, Y., Salas, R., DiLeone, R., Gundisch, D., Diano, S., De Biasi, M., Horvath, T., Gao, X., & Picciotto, M. (2011). Nicotine Decreases Food Intake Through Activation of POMC Neurons Science, 332 (6035), 1330-1332 DOI: 10.1126/science.1201889

(2) Huang, H., Xu, Y., & van den Pol, A. (2011). Nicotine excites hypothalamic arcuate anorexigenic proopiomelanocortin neurons and orexigenic neuropeptide Y neurons: similarities and differences Journal of Neurophysiology DOI: 10.1152/jn.00740.2010

"Warm-blooded" dinosaurs and "warm blooded" fish*

2011-06-27T13:34:00.011+02:00

At 80beats (@Discover blogs) there is a post about a method of inferring the body temperature of large dinosaurs by looking at the temperature that would be needed for the enamel of Brachiosaurus and Camarasaurus teeth to form. The post references a recent study published in Science. The conclusion is that big dinosaurs were as warm as mammals, but that's not to say that they had the same temperature regulation as mammals.

Here, we used clumped isotope thermometry to determine body temperatures from the fossilized teeth of large Jurassic sauropods. Our data indicate body temperatures of 36 to 38°C, which are similar to most modern mammals. This temperature range is 4 to 7°C lower than predicted by a model that showed scaling of dinosaur body temperature with mass, which could indicate that sauropods had mechanisms to prevent excessively high body temperatures being reached due to their gigantic size.

It's always been a pet peeve of mine to note when the terms "warm-blooded" and "cold-blooded" are used indiscriminately - in popular use they are incredibly widespread - or even when the more scientific terms endothermy and ectothermy are put against each other. This doesn't actually give the right view of the diverse temperature-regulation strategies that different animals can have. At Deep Sea News, one of my favourite blogs, there is a great post about those strategies that are somewhere in between the notions of warm- and cold-bloodedness, highlighting the really interesting strategies in pelagic fish*, such as lamnid sharks, tunas, billfishes and several others.

One important pattern that emerges from these observations is that body-warming is not a taxonomic thing: it has evolved several times in several different lineages, at least twice for sharks and once each for rays, tuna/billfish and opah. Rather, body warming is an ecological thing because it occurs in many species that are not related but all share pelagic migratory habits. Doubtless a closer look at other pelagic species will show that it has evolved in quite a few other species of the open ocean too.

Considering this, it's certainly not far-fetched to assume that "warm-bloodedness" has evolved several times in land-living tetrapod vertebrates as well. To me there is little doubt that the small theropod dinosaurs that birds arose from were able to regulate their body temperature internally, but perhaps sauropods, or some other dinosaur groups, were able to do it as well to some extent.

* I use the term fish very loosely here. Lamnid sharks are as related to us humans as they are to tunas and billfishes.

IGFBP evolution: An interesting case of gene family expansion and retention

2011-06-07T16:05:00.004+02:00

Or: How I really should have come up with a better title.

A small announcement: I have an article out as a first author in this month's issue of the journal Endocrinology. It's a nice journal and we spent a long time working on the manuscript so I'm very pleased that it's out. Here's a Worlde word cloud of the whole article... pretty interesting. It sums everything up pretty well actually. It's all about the evolution of the Insulin-like Growth Factor Binding Protein family of genes, or IGFBPs.

Click to see larger.

Why is it worth studying the evolutionary history of this particular gene family you might ask? It's not very well known, generally, and I bet very few know about its functions or that some members seem to be involved in certain types of cancer, for instance. Many times these gene families disappear behind esoteric acronyms and convoluted webs of functional interactions that only the initiated understand, and it's difficult to generate some sort of general interest in them. It all becomes a bit dry. But when you look a bit closer, many "obscure" (at least to the general audience) genes and proteins have a really interesting evolutionary story to tell, something that goes beyond the mere evolution of their gene sequences.

The IGFBP family genes sit in genomic regions that have long been used to give evidence for the fact that the genome doubled twice early in vertebrate evolution. This in effect makes all extant vertebrates ancient tetraploids; for every one region in the ancient vertebrate genome, there should be 4 corresponding regions in the extant vertebrate genomes. This has become known as the 2R theory. These same genomic regions more famously include the developmentally important HOX gene clusters, which were among the very first indicators that vertebrate genomes are actually ancient tetraploids. See for instance this rewiew or this article.

But even though the IGFBP genes sit in these regions, the studies of their evolution have gone back and forth between different explanations for quite a long time and there is currently a little bit of dispute in the field. At times the IGFBP family has even been used as evidence against the two ancient genome duplications. So what we set out to do when facing this project was to solve the evolutionary history of this gene family once and for all and see if we could say something about the evolution of the different IGFBPs functions. Our analyses can be summarized in this image:

IGFBP evolution through genome duplications. Click to see larger. The lancelet and tunicate are close relatives to vertebrates. The tunicate branch is dotted due to weak support.

The evolutionary relationships between the different IGFBP types fits very well with the 2R theory. A pair of genes in an ancient chromosome region duplicated twice, along with the entire genome, and after some gene losses we get the current setup. This is supported by the evolutionary relationships of several other gene families in the same region.

In the process of finding out the evolutionary history, one also happens to discover new genes quite often. That's always fun! It's especially common for bony fish genomes since the whole group has remnants of yet another ancient genome duplication called 3R. We can also see the results of this third genome duplication in our analyses.

But along with there being a very interesting historical aspect to the analysis of IGFBP evolution when it comes to the genome duplications, there are also functional implications. IGFBPs form part of the growth-promoting hormonal axis by binding to the insulin-like growth factors, or IGFs, whose release into the blood is triggered by the actions of growth hormone. IGFs are also released by most cells in the body directly to the intercellular space acting as local promotors of cell growth and proliferation. So IGFBPs in general modulate the growth-promoting actions of IGFs, but it appears that they do it in very complex ways. Mammals have 6 different IGFBPs, and bony fish have several more. What do they all do? Why do we vertebrates seemingly need so many? Can we say anything about the evolution of their functions simply by looking at the evolution of the genes and proteins? Yes, a little bit. But I leave that for a future blog entry... or you could read the paper.

For now it's enough to say that it's a bit remarkable that throughout the evolutionary history of vertebrates, we have kept so many of the IGFBP genes that have been generated. The fact that the evolutionary history of all these duplicates goes back to the very beginnings of vertebrate evolution say something very interesting about how important their functions are.

Ocampo Daza D, Sundström G, Bergqvist CA, Duan C, & Larhammar D (2011). Evolution of the Insulin-Like Growth Factor Binding Protein (IGFBP) Family. Endocrinology, 152 (6), 2278-89 PMID: 21505050

Turn off the lights and let melatonin run free

2011-05-31T18:08:00.357+02:00

>> I started the following post about melatonin sometime in March to coincide with my lecture on biological rhythms on our undergrad neurobiology course. But I got really busy and then really sick so I never actually finished it. Here it is then at last.

An all too common sight, at least at my place. This is my Mac glaring. But how is our exposure to low-intensity artificial light before bedtime affecting our sleep cycle?

Twice every year I lecture to undergraduate students in biology and biomedicine about biological rhythms, specifically about circadian rhythms - how the brain regulates your daily cycle of sleep and wakefulness. In this process the small suprachiasmatic nuclei (SCN henceforth) in your hypothalamus and the hormone melatonin, secreted from your pineal gland, play very important roles. The SCN is the "internal clock" of your brain and receives light input from the eyes in order to "reset the clock" every morning, signaling that a new day has started. So daylight itself serves as a signal for the brain that it's daytime and we need to be awake and alert, as far as possible.

One of the things I tell my students that usually raises some eyebrows is that even quite low-intensity light, comparable to the illuminance from a computer or television screen, as seen above, can affect the brain and shift the circadian rhythm significantly. This knowledge goes back to experiments carried out in the mid 90's and raises questions as to how artificial light, such an obvious and constant component of our environment, is affecting our day-night cycle.

In a recently published article in the Journal of Clinical Endocrinology (reference 1 below) a team of researchers has shown indirectly that it's the interplay between the SCN and melatonin secretion, so essential to the regulation of nighttime behaviors, that is affected by the artificial light in our environment.

Melatonin
Melatonin is essentially a "nighttime" signal in the brain. During the dark and inactive period of the 24 hour day-night cycle, melatonin secretion rises to a sharp peak only to start going down again in response to the first morning light. This is because in the absence of light input the SCN reduces its activity, signaling to the pineal gland in the brain to start secreting melatonin. This is only one of the many functions of melatonin. It's an incredibly pleiotropic hormone, meaning that you can find it throughout the body doing many different things. However, many of the functions seem to do with time keeping, or the control of processes that have a very strong connection to time-cycles and periods.

Melatonin's functions summarized (click to see larger). Adapted from Hardeland, R., Cardinali, D., Srinivasan, V., Spence, D., Brown, G., & Pandi-Perumal, S. (2011). Melatonin—A pleiotropic, orchestrating regulator molecule Progress in Neurobiology, 93 (3), 350-384 DOI: 10.1016/j.pneurobio.2010.12.004

The release of the hormones that regulate sexual maturation, for instance, is partly regulated by melatonin (see pink arrow in the image above). During our childhood we release a lot more melatonin overall than we do as adults. The onset of puberty is marked by a sharp decrease in overall melatonin, which seems to lead to the hormonal processes that start sexual maturation. It's as if the brain is "keeping time" and using melatonin as a signal to start and end hormonal and behavioral processes in just the right time and in just the right sync with our environment. This is what happens with our day-night cycle every day. Although melatonin isn't what makes you sleepy, that process happens somewhere else in the brain, it's one of the signals telling your body that it should be in "night-mode".

Artificial light affects melatonin release
It's already known that light exposure in the hours before normal sleep onset, even quite dim light, affects your day-night cycle, shifting it back - essentially making your brain believe that it's earlier than it really is. In early experiments it was shown that exposure to a light source as low as 180 lux can shift the circadian day-night cycle by about an hour (see reference 2 below), and from more recent experiments it's known that room light can delay the start of the nightly melatonin release. But how does the "internal clock", artificial light exposure and melatonin release interplay?

In an article from the March edition of Journal of Clinical Endocrinology (reference 1 below) a team of researchers describe a series of experiments showing that exposure to normal room light illuminance (<200 lux) before bedtime not only reduces the overall release of melatonin during sleep, but also shortens the period during which melatonin is released.

These figures illustrate some of their main findings. The A panels illustrate the experimental setup and the B panels the results:

To the left we see that when the test subjects were changed from room light conditions (<200 lux) in the 8 hours before bedtime, to dim light conditions (<3 lux) before bedtime (day 3) and all through their sleep (day 4) their melatonin profile changed! You can see the melatonin profiles of one participant in the left B panel. The arrows indicate the start of melatonin release. Under the dim light conditions the melatonin release started earlier in 99% of the participants with almost 80% showing an earlier onset of over an hour! So when exposed to room light before bedtime, the duration of melatonin release is shorter! There is also some indication that less melatonin is released during the night.

To see if melatonin release really was suppressed by the room light conditions, the experiment shown to the right was carried out. Instead of changing the test subjects from room light to dim light conditions before bedtime, they changed them to constant room light during sleep. You can see the results for five representative test subjects in the right B panel: Melatonin release was suppressed by up to approx. 90% in several of them!

These are some really sophisticated and neatly designed experiments with a large number of test subjects, but they suffer a little bit from a lack of connection to real life and relatable experiences. How intense do we perceive a light illuminance of 200 lux to be? How intense/illuminant are the lights we generally have at home or at work? How intense/illuminant is a computer screen or a TV screen? I looked around the web, and there's surprisingly little information out there. In most different studies of light exposure and circadian rhythm it's agreed that "normal" indoor room light starts somewhere below 200 lux and ranges up to about 500 lux, with "recommended office lighting" starting at around 350 lux. I decided to do a little bit of research myself, so I reached for the closest luxmeter and put it right here on my desk on a clear and sunny late spring day around 11 o'clock.

Luxmeter showing the light illuminance on my desk.

As you can see in the image, the light illuminance on my desk was around 1200 lux, far above the 500 lux that are cited as the upper limit of normal room lighting. Then again, my desk is right next to a very large window, so there is significant contribution from the sunlight outside. I've also measured the illuminance in the room when I'm lecturing about melatonin and circadian rhythms, to give the students a point of reference, and it has ranged from around 200 to 600 lux in generally pretty dim lecture halls with little contribution from outside daylight. I've also measured the illuminance from my MacBook screen and it usually ranges from 140 lux to 160 lux, more or less. These illuminances are all above or in the range of the illuminances discussed in the experiments.

These aren't exact or complete measurements, but I hope they at least give some kind of reference for the measures of illuminance given in the different experiments I've mentioned. I also hope that this post raises questions in you about your habits before bedtime. I freely admit that I love falling asleep to a DVD or reading long into the night, but quite a few of the students I lecture to are reluctant to accept that their cries of "I'm not a morning person" can be somehow related to what they did before going to bed. There are also questions concerning seasons left to consider. Here in the southern half of Sweden the sun is setting at about 10 o'clock at night right now. How does this affect our day-night cycle?

In any case, what we are seeing here is nothing less than the interplay between our brains - our behaviors and our physiology - and our environment. An interplay that in this case is mediated by the hormone melatonin. It may be the "nighttime signal" in your brain, but you can surely disturb it by changing the environmental cues that the brain has adapted to react to. What the consequences are, we don't quite know yet.

(1) Gooley, J., Chamberlain, K., Smith, K., Khalsa, S., Rajaratnam, S., Van Reen, E., Zeitzer, J., Czeisler, C., & Lockley, S. (2011). Exposure to Room Light before Bedtime Suppresses Melatonin Onset and Shortens Melatonin Duration in Humans Journal of Clinical Endocrinology & Metabolism, 96 (3) DOI: 10.1210/jc.2010-2098

(2) Boivin, D., Duffy, J., Kronauer, R., & Czeisler, C. (1996). Dose-response relationships for resetting of human circadian clock by light Nature, 379 (6565), 540-542 DOI: 10.1038/379540a0

Update/A melatonin NGram

2011-05-07T14:32:00.090+02:00

March and April disappeared in a daze and didn't lend me much time to spend on blogging. Finishing my teaching and course assistant duties for our undergraduate neurobiology course while re-working and re-submitting a research paper (now accepted in Endocrinology) took up most of March. Then to top things off I contracted a nasty Mycoplasma infection that left me floored with pneumonia for three weeks, including three days of hospitalization, so there went most of April. And the start of the year is a busy time for me as it is! I'm still a bit off-colour, but back to work!

I had started a big post about melatonin sometime in March to coincide with my lecture on biological rhythms on our neurobiology course, but as stuff happened I never actually finished it. As things have it though, I was asked to cover for another teacher lecturing last week about melatonin and the pineal gland for second term medical students, so I got a reason to re-visit melatonin and the blog post. I hope to have it up soon, but I haven't recovered completely and I'm still taking it easy with my work load so blogging is not really a priority right now. But as a short preface to that post, I thought we could take a look at what information we can extract about melatonin and the pineal gland from Google NGrams.

Melatonin is a hormone related to the neurotransmitter serotonin. Most people may have heard about it in the context of jet-lag or insomnia and perhaps different supplements or medications one might take to counteract them. Indeed melatonin is secreted when it's dark by the pineal gland in the brain as a general "night-time signal", although it doesn't stimulate sleep by itself.

We can see very clearly in the ngram above that "melatonin", "pineal gland" as well as the general term "pineal" have had a clear rise since the start of the 1960's. This makes perfect sense since melatonin was first isolated in 1958 from cow pineal glands. It was named and some of its effects were described in a 1960 paper by the same researchers. However, it was already known since the start of the 20th century that pineal gland extracts had some biological effects, before the hormone was isolated. This is detectable in another ngram, but could it also be related to the sharp peak in the term "pineal" that we see in the first decades of the 1900's in the ngram above?

The terms "pineal" and "pineal gland" go back quite far, reflecting the fact that the pineal gland has been known anatomically, and to some extent functionally, for quite a long time. The term "pineal body" is a bit of a curiosity since you often see it in old literature, but it doesn't seem to be as old or to reach the same prominence as "pineal gland" at all, which is surprising, at least to me. I thought that "pineal body" would be the older term and that it was eventually replaced by "pineal gland". Not so apparently.

Quote: Walter Gilbert predicting personal genomics

2011-02-20T18:46:00.003+01:00

I'm catching up on my reading this weekend. Right now I'm getting through Misha Angrist's "Here Is A Human Being" and getting increasingly jealous for every page. Angrist had his genome sequenced as a part of the Personal Genome Project, something I wouldn't mind having done myself.

I found this lovely 1992 quote from Walter Gilbert in the book. The number of bases of the human genome was pretty accurate even back in the early nineties.

Three billion bases of DNA sequence can be put on a single compact disc and one will be able to pull a CD out of one's pocket and say, "Here is a human being; it's me!"

This year marks the first decade since the "full" (more or less) sequence of the human genome was announced. But the advancements (and nightmarish visions) many expected still form an alluring horizon. One day, I want to be able to get my genome sequence out and say "Here I am; it's me!" Some people see all kinds of problems with personal genomics, but I can hardly wait for the day.

Happy Darwin Day! Mockingbirds and Darwin's original thought

2011-02-12T11:35:00.007+01:00

It's Darwin day! The anniversary of the old man's birthday (202nd this year) and a great opportunity to dig up some piece of Darwiniana and celebrate evolution!

Hood mockingbird, endemic to Española island, Galapagos. Ref: Wikimedia Commons.

Darwin's Galapagos finches and their differing beaks (see image here) are often credited as the original inspiration for Darwin's theory of evolution through natural selection. It's true that he brought many specimens of finches back from the Galapagos, and that they subsequently received a lot of attention in his scientific work and in "On the Origin of Species", but what many people don't know is that it was in fact a different group of birds that inspired the original thought: Mockingbirds, or Tencas in Spanish. Thanks to the wonders of the Internet, all of Darwin's writings are available online and we can go looking in his notebooks for this original thought in his own handwriting.

Amongst pages of notes about the geology of the Galapagos islands, geology being his primary focus on the voyage, he made a small note about the mockingbirds on Galapagos ("Galapagos Otaheite Lima" notebook, page 68):

The Thenca very tame & curious in these Islds. I certainly recognise S. America in ornithology, would a botanist?

Floreana mockingbird (left) and San Cristóbal mockingbird (right) from "The zoology of the voyage of H.M.S. Beagle... Part 3. Birds" by John Gould. Darwin sought expert knowledge for the description of the specimens he brought back, and edited this bird volume between 1938-41. Click on the image to see it larger.

He'd observed the mockingbirds in the west-coast of South America and could now recognize them among the birds of the Galapagos islands. The relationship between the species of the Galapagos islands and the South American mainland would form one of the pillars in his line of evidence for evolution through natural selection, but here at the very brink of uncovering the evidence it's the differences between the mockingbirds on the different islands that sparks the original thought (ornithological notes, pages 120-221).

Thenca: male: Charles Isd —
do: do: Chatham Isd. —
These birds are closely allied in appearance to the Thenca of Chile (2169) or Callandra of la Plata (1216). In their habits I cannot point out a single difference; <...> I have specimens from four of the larger islands; the two above enumerated, and (3349: female. Albermarle Isd.) & (3350: male: James Isd).—The specimens from Chatham & Albermarle Isd appear to be the same; but the other two are different. In each Isld. each kind is exclusively found: habits of all are indistinguishable. When I recollect, the fact that the form of the body, shape of scales & general size, the Spaniards can at once pronounce, from which Island any Tortoise may have been brought. When I see these Islands in sight of each other, & possessed of but a scanty stock of animals, tenanted by these birds, but slightly differing in structure & filling the same place in Nature, I must suspect they are only varieties. The only fact of a similar kind of which I am aware, is the constant asserted difference—between the wolf-like Fox of East & West Falkland Islds. — If there is the slightest foundation for these remarks the zoology of Archipelagoes—will be well worth examining; for such facts [would] undermine the stability of Species.

Here we have it, for ever recorded on paper: Darwin's original idea: ... such facts [would] undermine the stability of species! Written down in his ornithological notes on board the H.M.S. Beagle after leaving Galapagos in October of 1835, 24 years before the publication of "On the Origin of Species". If you go to the original page, you can see that in typical style, he's later added a careful "would" before "undermine the stability of Species". It says a lot about the man.

Oxytocin taking off

2011-02-11T18:46:00.000+01:00

Since I posted my two entries on the oxytocin/ethnocentrism link last week - part 1, part 2 - they have really taken off and gotten more attention than my very modest blog is used to. The first one has been linked on economist Tyler Cowen's blog Marginal Revolution, which generated a surge of over 3000 visitors over the following few days, on BigThink.com - "Hormones Are Not Deterministic" and it's even been translated into Spanish by Eduardo of the blog La revolución naturalista - "Oxitocina, etnocentrismo y determinismo hormonal", with an interesting discussion following in the comments. Both posts were also recently linked by Daniel Lende of the blog Neuroanthropology with the words "It’s always great to discover an exciting new blog!" Right back at you! His post linking me is also currently featured on the front page of PLoS Blogs.

The two entries have also been tweeted a few times, notably by Bora Zivkovic (@BoraZ) of A Blog Around The Clock, @CulturalNeuro and Maria Popova (@brainpicker) of BrainPickings.org.

I've also gotten a bunch of new Twitter followers in the process, and I'm averaging 200 visitors a day on the blog, which is about 10 times more (I told you it was modest) than before the oxytocin posts. I also seem to notice an increase in the amount of comments on other blog posts as well.

Finally I also wanted to mention a few blog posts that also comment on the oxytocin/ethnocentrism findings that I neglected to mention in my original entries. Ed Yong has a post on Not Exactly Rocket Science that veers a little bit towards the "hormonal determinism" side. He also writes that this finding "makes a degree of evolutionary sense", which I would argue against. On The Frontal Cortex Jonah Lehrer thankfully focuses on oxytocin effects and the complexity of the neurobiological substrates. Both posts are less critical of the original findings by De Dreu and co-workers, which balances my two posts nicely.

Some more history of neuroscience visualized through Google NGrams

2011-02-11T11:13:00.000+01:00

This is the second post where I take a look at Google NGram visualizations of the history of neuroscience. If you haven't seen the first one, you probably should before continuing to read this one.

In my previous post I completely ignored a large number of the cells in the brain: glial cells! It's often said they outnumber neurons by a ratio of 10:1, a truth that is still open for modification, but at the very least in some brain regions they are just as many as the neurons. Let's plot some different general terms for these cells against the terms "neurons", "nerve cells" and "nerve fibres" as references. In plural just because I've already plotted the singular forms in the previous post.

We can see that mentions of "neuroglia" go back to roughly the same period as "nerve cells" and "nerve fibres", some 2-3 decades before "neurons". Around this time "neuroglia" was a general term referring to the "connective tissue" of the nervous system, according to the OED, as opposed to the fibres which were considered the actual nervous tissue. The word neuroglia literally means "cement of the nerves". Nowadays it's known that they have so many other functions than providing support and nutrients for neurons, including very important modulations of signaling in the brain.

The use of simply "glia" starts taking off around the same time as "neuron", showing the co-incidence of the neuron doctrine and the characterization of the actual cells that made up this previously so vague "connective tissue". To find the first use of "glial cells", which is quite a common term nowadays, we have to fast forward to the 1940's and 50's. If you take a look at this following NGram there's some indication that both the plural "glial cells" and the singular "glial cell" are more commonly used than "neuroglia", but the differences are not very big.

In my previous NGram post I plotted the more general terms "neurology, "neuroscience" and "neurobiology" against each other, but what if we add as many sub-fields of neuroscience and neurobiology as we can come up with to see it it's possible to see how the field has diversified and developed? I include "neurology" as well for reference.

I notice a couple of really interesting things instantly. First of all, "neurology" does seem to be the oldest term by far, and many of the more specialized terms seem to predate "neuroscience" and "neurobiology" as well (see the first post). I propose that the diversification of the field seems to have happened in three "bursts" (arrows) during the 20th century! "Neuropathology" seems to be quite old, but together with "neurophysiology", "neurosurgery" and "neuroanatomy" it forms a cluster that starts going up during the 1930's. The second burst was during the mid 1950's to mid 1960's when "neurochemistry", neuropharmacology, "neuroendocrinology" and "neuropsychology" start going up (the latter two practically overlap). Sort of associated in time to this cluster is "neurolinguistics", that for some reason strikes me as a true child of the 70's.

The last burst is perhaps less certain, but we see the marked increase in the use of "neuroimaging" during the 1980's, showing the awesome technological development of the late 1900's. "Cognitive neuroscience" also forms part of this later burst and seems to be intimately associated with the rise of neuroimaging technologies. The NGram viewer wouldn't allow me to add more terms, but in this ngram you can see that "neuroethology" has a small little bump around the same time.

It's remarkable how you can really read the development of the field, from an early focus on the "mechanics" and "physics" of the nervous system to a subsequent discovery of the chemistry of the brain, when else but in the 60's!, and a progressive realization that it affects our cognition and behaviors, paired with technological advances.

What are then the terms of the future? What are the neuro-terms on the rise? After doing several experiments, I came up with these: "neuroethics", "neurotechnology", "neuromarketing", "neuroeconomics" and "neurotheology".

"Neurotechnology" is not surprising. But perhaps what we're seeing here more than anything are the growing attempts to reconcile or explain questions of morality, spirituality and philosophy with neuroscience as well as a growing obsession with the cognitive and neurobiological processes behind money-making/spending. Seems like a weird and wonderful future.

How to be a (good) neuroscientist

2011-02-10T21:54:00.002+01:00

Having written recently about falsehoods associated with the hormone oxytocin, and having taught about neuroimaging today, I find myself inspired by a couple of recent posts from the scientific blogosphere that expose falsehoods about the brain's activity and functional magnetic resonance imaging (fMRI).

Over at his blog Oscillatory Thoughts, neuroscientist Bradley Voytek reminds us how we should properly interpret neuroimaging studies to avoid making false claims about "where" in the brain different functions, such as behaviors and mental abilities, are localized: How to be a neuroscientist.

The interpretation of these localization results is confounded, however, by a lack of clarity in what is meant for a "function" to be localized. For example, Young and colleagues (2000) noted that for a given function to be localizable that function "must be capable of being considered both structurally and functionally discrete"; a property that the brain is incapable of assuming due to the intricate, large-scale neuronal interconnectivity.

This is sort of one level higher to what I argued in my first oxytocin post. Just as there is no one gene for any particular property, or indeed no one hormone for any particular property; a particular function is not localized to any particular region of the brain, even though neuroimaging studies sometimes give that impression. Voytek identifies two important principles to go by.

- Behaviors or mental abilities are not discrete/particular definable entities and cannot be "dissected out" and isolated from the whole gamut of behaviors and abilities. I argued the same thing in my second oxytocin post.
- Different regions of the brain interact and interplay, giving feedback to each other and cooperating in very complex ways to produce the brain's functions. Therefore it's unlikely that one particular function, however defined, is localized in any one region of the brain.

Elsewhere Audrey Lustig lists 4 things to keep in mind when you're reading about fMRI:

- Brain pictures of regions "lighting up" (see image below) are often misleading.
- Some fMRI studies are good, some are bad.
- fMRI images don't show what's happening in the brain in real time.
- Neuroscientists can't "read your mind".

Both posts are worth a read!

The religious brain compared to the nonreligious brain... see reference here.

Brain imaging studies that study function, especially fMRI, are task dependent and show brain activity during a specific task, subtracting the brain activity from a control state. This means that other brain regions that aren't shown "lighting up" in the brain pictures are active as well during the task, only that they were also active during the control. fMRI reveals differences between one state and the other and if the researchers are not careful about the statistical analysis of their data, they could end up showing the equivalent of brain activity in a dead salmon (original dead salmon fMRI paper).

If you want to see an example of an fMRI study done right, go no longer than to Neuroskeptic and read about Imaging the Brain Better, Faster, Thinner.

A brief history of neuroscience in Google NGrams

2011-02-06T08:30:00.000+01:00

In the days and weeks following the release of Google's NGram Viewer I got completely addicted and started plotting everything between heaven and earth, just like everyone else. The scientific merits of Google's NGram Viewer have been discussed over and again, especially the term "culturomics", and some of its inherent errors have been revealed, and some fixed. These discussions notwithstanding, I'm amazed at the course of events that actually can be visualized and analyzed in this way. Just take a look at these NGrams applied to the history of neuroscience. Click on the images to see the original graphs on the Google NGram Viewer.

To start out, let's see if we can trace the origin of the field's object of study, the neuron. I've included the two accepted spellings "neuron and "neurone" as well as "nerve cell" and "nerve fibre".*

We see that the last decades of the 19th century were absolutely decisive in the history of neuroscience. What we're really seeing is the emergence of the neuron doctrine; the idea that the nervous system is made up by discrete but interconnected cellular components, or neurons. This revolution was made possible by the works of Santiago Ramón y Cajal and Camillo Golgi (among others, but these two were the heavy hitters and received the Nobel prize in 1906), and the anatomist Heinrich Waldeyer-Hartz was the first to formally propose the doctrine in 1891. Do you see how clearly the use of "neuron" practically started around 1891? Incredible!

The fact that there are two spellings, with or without a terminal e, is a cool curiosity. We can see how the use of "neurone" sinks after the 1930's, but the two alternative variants really competed there. The use of "nerve cell" and "nerve fibre" seem to predate both of them, but their origin is definitely after 1850 and they don't rise in the same way as the 20th century comes along.

The name "Waldeyer" also has a peak before 1890. Names are always tricky, but what if we include the general prefix "neuro" in the analysis together with "Waldeyer", "nerve cell" and "nerve fibre"?

The field was clearly developing in the decades before the neuron doctrine in the 1890's, and Waldeyer seems to have been prominent in that development. We see that the use of neuro-related terms has an upward slope that follows Waldeyer's almost exactly. Waldeyer was a very prominent general anatomist and histologist of the time, so if we add the term "histology" to the analysis we can probably confirm the incredible development that lead to the emergence of modern neuroscience: the ability to chemically stain tissues and individual cells in preparation for the study under the microscope.

Much of this development seems to have had it's start in the 1850's.

Next I want to find out when the collective terms for the field like "neurology, "neuroscience" and "neurobiology" came up. Let's add those to the general "neuro"-prefix and "neuron" as references.

Although the foundations of modern neuroscience and neurobiology were laid in the late 19th century, the terms themselves don't show up until well into the 20th century! "Neurology" seems to be a much older term, perhaps indicating that the arrangement and disease states of the nervous system were under study well before the underlying mechanisms were understood. Or maybe that it used to be a more general term? It's an interesting question. According to the Oxford English Dictionary "neurology" goes back to 1681 meaning something like "systematic arrangement of nerves".

There are some more interesting experiments one could do, but this is enough for now.

*) Including "nerve" doesn't add anything useful since it's such a common word. According to the OED it goes back to the 1400's, originally meaning sinew or tendon.