New insights into Rett syndrome
A pair of papers from the lab of Fred Gage has provided new insights into the molecular and cellular processes affected in Rett syndrome. This syndrome is associated with arrested development and autistic features. It affects mainly girls, who typically show normal development until around age two, followed by a sudden and dramatic deterioration of function, regression of language skills and the emergence of autistic symptoms. It is caused mainly by mutations in the gene encoding MeCP2, which resides on the X chromosome. Complete removal of the function of this gene is effectively lethal, explaining why Rett syndrome is not observed in boys – males who inherit that mutation are not viable. Females, who have a back-up copy of the X chromosome survive but subsequently show the symptoms of the disease.
The function of the MeCP2 protein seems very far removed from the kinds of symptoms observed when it is deleted. The job of MeCP2 is to bind to DNA that carries a specific chemical tag – a methyl group – which marks DNA for repression. When MeCP2 binds, it recruits a host of other proteins which shut down that section of DNA and prevent any genes within it from being expressed. How a defect in a process that is so fundamental could result in such specific symptoms has been a mystery.
A major barrier in understanding these processes has been the inability to assay the effects of the mutation in this gene in neurons of people who carry it. After all, unlike some other cell types, one cannot easily simply extract neurons from patients. (They tend to be using them). New stem cell technologies developed over the last few years offer a way around this problem. It is possible to extract fibroblasts from patients with a simple skin biopsy. By transfecting these cells with genes that are normally expressed in embryonic stem cells it is possible to “de-differentiate” them – to turn them back into a stem cell. (The difference between a skin cell and a stem cell lies in the genes that are being expressed – transfecting the cells with the master regulatory genes that determine embryonic stem cell identity forces the expression profile back to that state). These “induced pluripotent stem cells” (iPS cells) can then be encouraged to differentiate into any of the cell-types of the body, including neurons. In this way, a virtual biopsy of a patient’s neurons can be obtained.
Gage and colleagues did exactly that, generating neurons in a dish from patients with Rett syndrome. I make that technique sound simple, but of course it isn’t, and these experiments represent a technical tour de force. They were then able to characterise various parameters of these neurons to assay more directly the molecular and cellular effects of MeCP2 mutation. These experiments revealed a not unexpected defect in the formation of synapses between Rett mutation neurons. Neurons from Rett mutation-carriers developed normally and showed normal electrophysiological properties but made fewer synapses with each other and showed a concomitant decrease in network activity. I say not unexpected because it had previously been shown that mouse neurons carrying a MeCP2 mutation show similar effects. This fits with highly convergent findings from autism genetics showing that many other implicated genes function in synapse formation.
What is important about the iPS cells, compared to the information that can be learned from studying mouse cells with MeCP2 knocked out, is that they give a picture of the effects, first, of the specific mutation in this gene in each patient, and second, of the genetic background of each patient, which may modify the effects of the MeCP2 mutation. This gives a far more direct view of the specific effects of each patient’s complete genotype on the development and function of their neurons.
While defects in synapse formation suggest a fundamental role for MeCP2 in neural development, which might imply an irreversible defect, in fact several lines of evidence suggest that the requirement for the function of MeCP2 may be ongoing, in processes of activity-dependent wiring, where neurons within networks strengthen connections based on their patterns of activity. This fits with the apparently normal early development, prior to age two, of girls with Rett syndrome, and also with evidence from mouse models that restoring MeCP2 function in adults can largely reverse the symptoms. These discoveries therefore hold out the promise that intervention in Rett syndrome patients, even in older children, may be effective.
Gage and colleagues tested a couple potential therapies on the neuronal networks derived from Rett syndrome patients and were able to show some degree of rescue of the defects. One of these, the protein insulin-like growth factor-1 (IGF-1), was previously shown to be effective in partially rescuing the defects in MeCP2 mutant mice, most likely by stimulating greater synapse production and compensating for the loss of MeCP2 activity. Clinical trials are now planned to test the efficacy of this approach in patients. Having the cells derived from patients should also greatly facilitate screening for new drugs that can correct the neuronal network defects.
Another paper from the same group, also analysing these cells, revealed a far less expected effect – one that suggests (far more speculatively) the possible involvement of a totally different pathogenic mechanism. One of the functions of the system that methylates DNA is to defend the genome against invaders. Our genome is riddled with parasitic elements – pieces of DNA that can replicate themselves and “jump” around the genome. Fully 45% of our “human” genome is made up of these so-called transposable elements. Most of the copies of these elements are inactive but a subset can generate new copies that will integrate at random into the genome. What has this got to do with Rett syndrome?
Well, MeCP2 is apparently one of the proteins whose job it is to shut down these transposable elements. Gage and colleagues could show that one particular class of these elements, called L1 elements, was far more active in cells derived from Rett syndrome patients. The L1 elements expressed higher levels of the proteins they encode and they generated additional copies of themselves, which were scattered around the genome. Interestingly, this effect seems to be restricted to neurons, presumably because the function of MeCP2 is especially required in that cell-type.
Though highly speculative, this raises the idea that high rates of somatic mutation (somatic meaning it happens in the body, not in the germline and thus will not be inherited), caused by L1 elements jumping around and landing in the middle of genes, may contribute to the severity and also the variability of the phenotype caused by MeCP2 mutations. The alternative is that the L1 transposition has no pathogenic effect but is simply a consequence of the Rett syndrome mutations. Future experiments will be required to tell which of these possibilities is correct.
Marchetto MC, Carromeu C, Acab A, Yu D, Yeo GW, Mu Y, Chen G, Gage FH, & Muotri AR (2010). A model for neural development and treatment of rett syndrome using human induced pluripotent stem cells. Cell, 143 (4), 527-39 PMID: 21074045
Muotri AR, Marchetto MC, Coufal NG, Oefner R, Yeo G, Nakashima K, & Gage FH (2010). L1 retrotransposition in neurons is modulated by MeCP2. Nature, 468 (7322), 443-6 PMID: 21085180
A synaesthetic mouse?
An amazing study just published in Cell starts out with fruit flies insensitive to pain and ends up with what looks very like a synaesthetic mouse. Penninger and colleagues were interested in the mechanisms of pain sensation and have been using the fruit fly as a model to investigate the underlying biological processes. Like any good geneticist faced with profound ignorance of how a process works, they began by screening for mutant flies that are insensitive to pain. Making use of a very powerful genetic resource developed in Vienna (a bank of fly lines expressing RNA interference constructs for every gene in the genome) they screened through all these genes to see which ones were required in neurons for flies to respond to pain. (In particular, pain caused by excessive heat).
Why should anyone care how a fly feels pain? Well, like practically everything else you can think of, the basic physiology and molecular biology of pain sensation is very highly conserved from flies to mammals. It starts with specialized proteins called TRP channels, which are ion channels that span the cell membrane and allow ions to pass across it in response to various stimuli. Some of these TRP channels respond specifically to painful stimuli, some even more specifically to painful heat, and these molecules are highly conserved. The hope was that by screening for other genes they would identify additional conserved elements of the pathway.
Too clever by a half
On a recent BHTV Jeff Sharlet and Amy Sullivan discuss a recent trend in the conception of Islam among the military:
As I listened to them I got really annoyed. It is not accurate to say that Islam is an ideology and not a religion, but it is also not without foundation. Many Muslims would assert that Islam is a “total way of life.” Analogous to the lifestyles of Haredi Jews or Roman Catholic monks (the same “total way of life” is also used by conservative Protestants and Hindus, so it isn’t limited to Muslims).
Now listen to a more recent BHTV segment:
The attitudes described in this segment reflect perfectly the reason that some individuals might assert that Islam is not a religion, but a political ideology. They’re wrong, insofar as it is a religion, and can also be a political ideology. But the inference of American conservatives is not purely a product of their own fervid paranoia. If liberals (of which I am not one) want to communicate and persuade conservatives they would best actually understand the roots of right-wing logic, instead of dismissing it as pure fantasy.
Evaluating Price’s Equation
I have previously written several posts on the work of George Price. This one contained general reflections on Price’s reputation; this one attempted to explain how he arrived at the first (1970) form of his famous equation; this one did the same for the later (1972) version of the equation; and this one one attempted to give a more intuitively satisfying account of the ‘covariance’ term in the equation.
I said I would conclude with some general comments and criticisms. This post will comment on aspects of the equation except its application to the problem of group selection, while the final post in the series will cover that.
Medical Knowledge
Jim Manzi has a good reply up at TAS on our degree of medical knowledge, discussing an Atlantic article I also go into here.
While he makes a number of good points, I don’t think he quite addresses some of the issues raised by Robin Hanson and the original Atlantic piece. Manzi defends medicine in general; and this may serve as a useful corrective to those who believe that medical knowledge is completely useless. But with a few exceptions (maybe Robin Hanson), I don’t think many medical skeptics fall in that camp. Perhaps the quoted estimates of medical error are on the high end. But that doesn’t take away from the fact that there are serious issues in how medical knowledge is formed.
Take, for instance, several past Hanson posts. Doctors believe in breaking fevers, though there is no evidence that helps. Flu shots also don’t seem to work. I’ve also mentioned how uclers came to be declared a disease due to “stress”, when in fact they were clearly due to bacterial infection. Meanwhile, several large-scale tests of medicine use — from the RAND insurance study, or the 2003 Medicare Drug expansion — find minimal evidence that more medicine leads to better health.
Again with this Lamarck guy
Cross-posted from Reaction Norm…
Here he is “late in life.” Everyone already thinks he’s wrong wrong WRONG. We know him now as the Wrongest Biologist Ever. When we say “Lamarckian” we mean the idea that acquired characteristics can be inherited. I can almost hear him crying from the grave, “I produced a lifetime of ideas on all kinds of stuff, yet ‘Lamarckian’ will always mean just that one thing.” No wonder he looks a little shifty and bitter. Well, most of his other stuff was wrong too, but it was like 1800 and he was trying to convince people that species evolved without divine intervention! Pardon him for not getting the details right.
But he was wrong. Except when he was right. “Lamarckian” phenomena aren’t all that uncommon, especially in prokaryotes. Of course, he was still wrong because he didn’t know about any of the phenomena that he was right about—he was basing his ideas on types of evolution that simply aren’t “Lamarckian.” It’s fashionable these days to defend Lamarck, and it’s always been fashionable to dismiss things like genetic assimilation or the Baldwin Effect as “Lamarckian,” which they aren’t. Someday, perhaps someone will describe some epigenetic phenomenon in which an environmental variable specifically alters a locus in the germ line (Weissman stirs in his grave) such that the inheritors of that altered locus are better adapted to that environment. But no one is holding their breath.
But wait! What’s this in today’s issue of Current Biology?
If you’ve done 23andMe….
The Dodecad ancestry project might be of some interest. In particular if you have ancestry from a gold-chain wearing culture.
Searching for a needle in a needlestack
Whole-genome sequencing is a game-changer for human genetics. It is now possible to deduce every base of an individual’s genome (all 6 billion of them – two copies of 3 billion each) for a couple of thousand euros, and dropping. (Yes, euros). Even Ozzy Osbourne just got his genome sequenced! For researchers searching for the causes of genetic disease (or resistance to vast quantities of drugs and alcohol), this means they no longer have to infer where a mutation is by tracking a sampling of “markers” spaced across the genome – they can directly see all of the genetic information.
The problem is, they directly see all of the genetic information. If each of us carries thousands of mutations – changes that are very rare or may even have never been seen before in any other person – then telling which one of those changes is actually causing the condition is a tough task. Researchers in psychiatric genetics are currently grappling with how to handle this glut of information.
The problem is particularly acute in this field, where there is a (very slowly) growing realisation that many so-called common disorders, such as schizophrenia and autism – are really umbrella terms for collections of very rare disorders. Each of these conditions can be caused by mutations in single genes. The reason they are so common is that there are so many genes required to wire the brain properly – mutations in any of probably hundreds of genes can lead to the kinds of neurodevelopmental defects that ultimately result in psychopathology. (At least, that is the working hypothesis – see review below for a discussion of the evidence supporting it).
…Those Germans
I have a long post reviewing Shall the Religious Inherit the Earth?: Demography and Politics in the Twenty-First Century. Good book. In the process of blogging on the topic I found something kind of funny, but it was too immature to be posted there. I yanked some charts from Gallup Coexist 2009. Basically it shows differences among UK, France and Germany on social issues, as well as differences between Muslims and non-Muslims. In general Muslims are more socially conservative, though the gap is the least in France and the most in the UK. Here are the charts, with the last one the one I found funny:
Knowledge is Hard
Courtesy of Robin Hanson, I see that The Atlantic has an excellent article on medical knowledge:
One of the researchers, a biostatistician named Georgia Salanti, fired up a laptop and projector and started to take the group through a study she and a few colleagues were completing that asked this question: were drug companies manipulating published research to make their drugs look good? Salanti ticked off data that seemed to indicate they were, but the other team members almost immediately started interrupting. One noted that Salanti’s study didn’t address the fact that drug-company research wasn’t measuring critically important “hard” outcomes for patients, such as survival versus death, and instead tended to measure “softer” outcomes, such as self-reported symptoms (“my chest doesn’t hurt as much today”). Another pointed out that Salanti’s study ignored the fact that when drug-company data seemed to show patients’ health improving, the data often failed to show that the drug was responsible, or that the improvement was more than marginal.
Salanti remained poised, as if the grilling were par for the course, and gamely acknowledged that the suggestions were all good—but a single study can’t prove everything, she said. Just as I was getting the sense that the data in drug studies were endlessly malleable, Ioannidis, who had mostly been listening, delivered what felt like a coup de grâce: wasn’t it possible, he asked, that drug companies were carefully selecting the topics of their studies—for example, comparing their new drugs against those already known to be inferior to others on the market—so that they were ahead of the game even before the data juggling began? “Maybe sometimes it’s the questions that are biased, not the answers,” he said, flashing a friendly smile. Everyone nodded. Though the results of drug studies often make newspaper headlines, you have to wonder whether they prove anything at all. Indeed, given the breadth of the potential problems raised at the meeting, can any medical-research studies be trusted?
This discussion reminded me of Jim Manzi’s earlier essay. There, he argued that the Social Sciences were so far behind the hard sciences because of the problem of causal density. Without the benefits of randomization and experimentation available in the physical sciences, it’s hard to figure out causality — or so Manzi argues.
Colour my world
Colour does not exist. Not out in the world at any rate. All that exists in the world is a smooth continuum of light of different wavelengths. Colour is a construction of our brains. A lot is known about how the brain does this, beginning with complicated circuits in the retina itself. Thanks to a new paper from Greg Field and colleagues we now have an even more detailed picture of how retinal circuits are wired to enable light to be categorized into different colours. This study illustrates a dramatic and fundamental principle of brain wiring – namely that cells that fire together, wire together.
Colour discrimination begins with the absorption of light of different wavelengths. This is accomplished by photopigment proteins, called opsins, which are expressed in cone photoreceptor cells in the retina. Humans have three opsin genes, which encode proteins that preferentially absorb light of different wavelengths: short (S, in what we perceive as the blue part of the spectrum), medium (M, green) and long (L, red). Each cone expresses only one of these opsin genes and is thus particularly sensitive to light of the corresponding wavelength. However, by itself the response of a single cone cell cannot be used to determine the colour (wavelength) of incoming light. The reason is that each cone is responsive to both the wavelength and the intensity of the light – so an M-cone would respond equally to a dim green light or a strong red light.
Colour information only arises by comparing the responses of multiple cone cells. This is accomplished in two distinct channels – one which compares the inputs of L and M cones (the red-green channel) and one which compares the inputs of S cones to the combined inputs of L and M cones (the blue-yellow channel). The latter of these is the original, evolutionarily older system, dating back at least 500 million years. It is found in most mammals, in which there are only two opsin genes – an S opsin and one whose absorbance is midway between L and M.
Elitism in the Senate
As Benjamin Friedman laid out in The Moral Consequences of Economic Growth; a tolerant, accepting society is predicated on running the growth treadmill. Simply being prosperous is not enough — people need to feel that conditions will steadily improve over time, or else populism, xenophobia, and other measures of intolerance go up.
So as we enter the a “New Normal” phase where the steady economic growth and low unemployment of the Great Moderation can no longer be sustainably maintained, there will be substantial political upheaval as well.
One manifestation of this is the strongly anti-elitist attitude espoused by anti-establishment political candidates, among others. Barack Obama (Columbia, Harvard Law) and Sonia Sotomayor (Princeton, Yale Law), for instance, have been attacked for holding Ivy League credentials.
Whatever one thinks of anti-elitist attacks (here is someone against them, for instance); it seems worthwhile to point out that the anti-elitists are onto something. Top College attendance remains a path to influence and wealth.
A recent post of mine pointed out that this is very much the case for income. A new paper by Lauren Cohen and Christopher Malloy (both teaching, of course, at Harvard) shows that this is the case for political power in the Senate as well.
How Worrysome is Habitat Loss?
Razib’s link to the discovery of a new mammal species in Madagascar makes the following point:
This species is probably the carnivore with one of the smallest ranges in the world, and likely to be one of the most threatened. The Lac Alaotra wetlands are under considerable pressure, and only urgent conservation work to make this species a flagship for conservation will prevent its extinction.
In the case of this particular species, that makes sense. This cat/rat looking thing appears to inhabit a threatened microclimate, and so faces a high risk of extinction.
You hear statements like this all of the time, and not always with respect to animals inhabiting odd niches. For instance, we are told that ongoing destruction of the Amazon jungle is a bad thing, as it will result in the extinction of more species.
I can’t vouch for anyone else, but my general impression in reading these press releases is that the relationship between habitat destruction and animal extinction is roughly linear. The more habitat we destroy, the more animals go extinct.
But if you think about this, that doesn’t quite make sense. A little more habitat destruction in, say, the Amazon will only erode a bit of jungle at the margins. Many animals should be able to migrate elsewhere; immobile species should still presumably have counterparts elsewhere. The only way a bit of additional logging will result in species extinction is if the extremity in question happens to be a unique microclimate home to species not found elsewhere.
And that seems to be an unreasonable model for the Amazon as a whole. To be sure, there may be certain areas of extreme biodiversity. But the Amazon jungle in general appears to be a reasonable homogenous environment, home to species that are reasonable spread out throughout the breadth of the area. To the extent species are not; this may reflect the presence of subspecies with little differentiation.
So I might instead expect habitat destruction to follow a non-linear pattern with respect to extinction in a unique environment. The first few trees you chop down may do little damage; the last several may eliminate the last survivors of a number of species.
Bjorn Lomborg has made similar arguments in the past — that large amounts of climate degradation (even in the range of 98-99 percent in the cases of Puerto Rico and the Eastern US) does not result in substantial animal extinctions, as long as some of the environment remains intact. Though I understand this remains a hotly disputed claim. The “unknown unknown” problem is bad here — we don’t know what species we are unknowingly killing off.
Meanwhile, the continued existence of various species even in the event of large natural climate disasters has been taken as evidence for the existence of various refuga that sustain whole ecosystems. For instance, glaciation appears to have disrupted various tropical forests, yet many animals survived — though with odd geographic dispersion patterns. The Toba volcano incident ~70k years ago resulted in massive layers of ash spread throughout South and South East Asia; yet the nearby Mentawai islands appear to have suffered no species loss. On the other hand, the introduction of humans (even when it does not result in massive environmental change) seems to be clearly linked to mass megafauna extinction. That would seem to suggest that “poaching” is far more destructive than cutting down a few trees.
If this is true, than ongoing destruction of Amazon, say, would not by itself be particularly troubling on the grounds of animal extinction. As long as we keep sufficiently large patches of the original jungle (or several different patches if we think there are a few microclimates), we should be able to keep the vast majority of the existing species. Even if some large fraction of the jungle is required to maintain a water cycle; presumably that is less forest than currently exists. We already recognize that some areas are more important conservation-wise than others (ie, coral reefs v. Russian forests). It may also be more important to maintain the existence of unique refuga environments (even in sharply reduced form) than the quantity of overall protected space.
But I realize this isn’t my area of speciality, and would like to hear back from more knowledgable commenters. Hopefully, you’re smart enough to see that my point isn’t to support rainforest destruction. I’d also like to hear back from anyone who can tell me how much a species is “worth.” While I’m opposed to animal extinction, I don’t have a good sense why other than a vague sense that it’s wrong, and a desire to see more National Geographic specials. Yes, I understand that there are some pharmaceutical applications, but that doesn’t seem to be a good reason by itself to maintain large non-human occupied environments. Tourism is more plausible, but presumably only redirects tourist dollars from some alternate attraction.
South Park + Jersey Shore
This should be good. Perhaps even top the D-Yikes! espide:
Mice with fully functioning human brains
I wouldn’t usually discuss politics in a blog like this, but a recent story caught my eye, as it provides an example of the depressing and sometimes bizarre level of scientific illiteracy among elected officials or some people who hope to be elected. The example is from the United States, which is an easy target in this regard, but we have had a similar episode in Ireland recently so I don’t think we (or indeed any other non-Americans) can feel particularly smug about it. This one is especially funny, though.
Christine O’Donnell has recently won the Republican nomination in Delaware for the upcoming election to the Senate. I just love her – for comic entertainment this woman is very good value. She makes Sarah Palin look like the most reasonable, well-informed, level-headed person around. Among many clangers that she has dropped in the past, the one that really got my attention was the following assertion, made during a debate on stem cells on The O’Reilly Factor show on Fox News a few years ago:
“American scientific companies are cross-breeding humans and animals and coming up with mice with fully functioning human brains. So they’re already into this experiment.”
That’s right, cross-breeding humans and animals. I’m not sure how she imagines that to have taken place and would rather not know. And yes, she did say: mice with fully functioning human brains. Now, the average mouse weighs around 20 grams. The average human brain (clearly there are exceptions) weighs around 1.4 kilograms. I’m not sure Ms. O’Donnell really thought that through, even from a purely mechanical standpoint. However, she apparently had the opportunity to qualify or alter her assertion but did not, so one can assume she meant something like what she actually said.
(She also thinks evolution is a myth, because if we evolved from monkeys, then how come the monkeys are not still evolving into humans? That some people buy that kind of “argument” exemplifies the poor grasp that many people have of geological time. And of the fact that we did not evolve from monkeys – monkeys and humans evolved from a common ancestor. It reminds me of an even funnier comment I read from another creationist: if we evolved from monkeys, then how come we don’t speak monkey? There’s just no answer to that.)
What the imaginative Ms. O’Donnell may have been trying to refer to was a story that got some press coverage at the time of scientists who had transplanted a small number of human cells into a mouse brain to see if they would migrate and integrate normally. Apparently, about 100 such cells survived, in a brain that contains over 20 million cells. So, transplantation, not cross-breeding, and not fully functioning human brains, but to be fair to her she did, in an incredibly inept and confused manner, raise an interesting issue.