Isaac Asimov and the fuzzy nature of knowledge

It’s an odd thing that when people list great science popularizers of the past, names like Sagan and Feynman always pop up, but most people seem to have forgotten Isaac Asimov, who wrote some fabulous essays on understanding science. Here’s one example, in which he addresses a claim we hear all the time, that the errors of the past mean our knowledge now is on very shaky ground. He’s answering a complaint from an English Lit student who chastised Asimov for thinking he knew anything at all.

The young specialist in English Lit, having quoted me, went on to lecture me severely on the fact that in every century people have thought they understood the universe at last, and in every century they were proved to be wrong. It follows that the one thing we can say about our modern “knowledge” is that it is wrong. The young man then quoted with approval what Socrates had said on learning that the Delphic oracle had proclaimed him the wisest man in Greece. “If I am the wisest man,” said Socrates, “it is because I alone know that I know nothing.” the implication was that I was very foolish because I was under the impression I knew a great deal.

My answer to him was, “John, when people thought the earth was flat, they were wrong. When people thought the earth was spherical, they were wrong. But if you think that thinking the earth is spherical is just as wrong as thinking the earth is flat, then your view is wronger than both of them put together.”

The basic trouble, you see, is that people think that “right” and “wrong” are absolute; that everything that isn’t perfectly and completely right is totally and equally wrong.

However, I don’t think that’s so. It seems to me that right and wrong are fuzzy concepts, and I will devote this essay to an explanation of why I think so.

Go read the rest, it’s worth the time.

God is a sockpuppet

So true and so hilarious: a study has found that god speaks with a remarkably egocentric voice. In tests that asked people what god’s opinion of various matters was, the unsurprising discovery was that it was the same as the individual’s opinion — and of course every person’s opinion was different. You’d expect some consistency if they were all hearing god’s word, you would think!

It fits with the typical vision of the sockpuppeteer, too: the loser whose opinions are indefensible, so he invents an army of aliases to agree with him. And what more powerful sockpuppet could there be than to have your arm up a god’s butt?

Get your geek on for Thursday

I’m going to be opening my mouth again on Thursday in Minneapolis — I’ll be giving a talk in MCB 3-120 on the Minneapolis campus at 7:30 on Thursday, 3 December. This will be open to the public, and it will also be an all-science talk, geared for a general audience. I’d say they were going to check your nerd credentials at the door, but just showing up means you’re already fully qualified.

The subject of the talk is my 3 big interests: a) evolution, or how we got here over multiple generations, b) development, or how we got here in a single generation, and c) the nervous system, the most complicated tissue we have. I intend to give a rough outline of how nervous tissue works, how it is assembled into a working brain, and how something so elaborate could have evolved. All in one hour. Wheee!

Afterwards, we’ll be joining the CASH gang for refreshments, somewhere. They haven’t told me yet where, but I know they’re fond of pizza.

IGERT2009: Sunday morning session

My little laptop is functional again, so at least I’ll be able to blog these Sunday morning IGERT sessions in real-time. I still have to transcribe my notes from yesterday; I’ll plan on getting that done on the plane this afternoon.


Kristi Montooth: Mitochondrial-nuclear epistasis for metabolic fitness in flies

How do physiological systems evolve to maintain metabolic fitness? This is a process that involves interactions between two genomes, the nuclear and mitochondrial. Energy metabolism is important and is the target of mutation, but the same players are found all across the tree of life, suggesting that there is also strong selective pressure to maintain a common system.

Montooth is looking at inducible gene expression: is there an energetic cost to switch genes off and on? She’s using respirometers that can measure the metabolic rate of single flies or larva. Flies are subjected to heat shock, which switches on HSP70. Flies normally have 6 copies of HSP70; they have mutants with 12, and they show a much greater rise in metabolic rate in response to heat shock.

Mitochondria are the source of the energy for this response. Mitochondria also have a high mutation rate and show strong linkage (no sexual recombination to cover for errors that arise). She’s arguing for selection for compensatory evolution in the nuclear genome, and the accumulation of intergenomic epistasis. To dissect the effects of coevolution of mitochondria and nuclear genomes, she transplanted mitochondria from different species into Drosophila melanogaster. These have between 18 and 100 amino acid substitutions from the Dmel sequence.

She plots mitochondrial genome in order of increasing divergence against measured fitness (she used a competition assay that she did not describe in detail). There is no correlation seen at all. Also, high fitness X/mtDNA genotypes in one sex can be low fitness genotypes in the other sex. Interactions between the X and mtDNA can maintain variation in both genomes. All of the fitness effects, with one exception, are subtle.

Some of the transgenomic effects have very strong effects on female fecundity, developmental rates, and locomotion. But adult metabolic rate shows no difference! The idea is that there are lots of homeostatic mechanisms that maintain metabolism very tightly, which then have secondary effects.


Johanna Schmitt: Adaptive evolution of Arabidopsis flowering pathways in different climates

Schmitt does ecological development, looking at the timing of plant development in different environments. How does phenology respond and adapt to climate variation? We expect evolution to adapt to variation in seasonal timing. The signaling pathways in Arabidopsis are well known; they respond to hormones, photoperiod, and ambient temperature by way of a fairly complicated set of pathways she showed us in a slide…sorry, no way I can reproduce it here!

Across its range, it shows a great deal of life history variation; one pattern in the Mediterranean, another in colder northern climes, and yet another in Northern Scandinavia, varying in how much time they spend in vegetative rosettes vs. bolting and flower production. Questions: are there are genetic variants associated with different life history patterns, can they identify the genes, and can they perturb them?

The experiments involved massive plantings in different sites in Europe with different climates, with different mutants. Is natural variation in candidate genes involved in variation in flowering time? They studied FRIGIDA, a gene that effects the vernalization pathway. When you lose FRIGIDA, you should see much more rapid flowering. Loss of function in this gene has evolved multiple times in northwestern Europe. The effect depends on the timing of planting and climate.

The effect of the mutant varies across geography, and they have a photothermal model of flowering time. The plants are tracking light and temperature, and the different mutants are counting up these inputs in slightly different ways. They can use this model to make predictions on the effects of FRIGIDA on flowering time with changes in germination timing, and then test these in the next year with plantings at different times and in their different geographical sites, and the model is working accurately.

They are also plugging in predicted future climate change from NOAA, and asking what we can expect to see 100 years from now; she showed maps of expected flowering times in 2100. They are also making predictions of the expected distributions of FRIGIDA alleles over time, and they hope to do the same for many other alleles in Arabidopsis.


Artyom Kopp: How the fly got its sexy legs – the origin and evolution of Drosophila sex combs

The sex comb is a male specific structure on the front legs which most Drosophila species lack — it’s a fairly recent innovation. How do you evolve a novel structure?

It’s limited to the melanogaster and obscura species groups, with quite a bit of diversity in different species, varying from 2-50 teeth, location, and arrangement. How do you go from sexually monomorphic state of a generically hairy leg to one with a specific bristle arrangement in males? The sex comb in males is homologous to a subset of bristles also found in females; in males, that patch of epidermis rotates 90° and the bristles enlarge. He showed a very pretty developmental series of this epithelium undergoing cell shape changes that move the bristles to a new location. Other species show similar morphological remodeling, but sometimes with some significant differences: D. kikkawai doesn’t do the rotation, but instead the bristle precursors arise in their final position. These modes do not cluster together phylogenetically, so these are examples of convergent evolution, generating similar structures with different mechanisms.

They are taking apart the genetics and regulatory inputs of sex comb development. Basically, it involves just about everything. It seems to arise by an interaction between Hox and sex determination genes. Spatial modulation of Sex combs reduced controls sex comb position. Scr in pupa; stages is only expressed in a limited domain in the leg, and ectopic expression of Scr produces multiple sex combs. Expression is also sexually dimorphic, with no upregulation of Scr in female legs. In D. ficusphila, which has enormous sex combs, Scr levels are elevated yet further to 7 times the levels found in D. willistoni.

The sex determination gene Double sex is also spatially patterned, and is refined and elevated to high levels in the area around the developing sex combs. Ectopic expression of Dsx induces ectopic sex combs.

How can a new developmental pathway evolve? In the ancestral condition, Scr is controlled by spatial cues to produce segmental patterns of bristles; in the sex-comb carrying species, Scr is coupled to Dsx. This explains the spatial pattern of gene expression, but it also needs to acquire new downstream targets to, for instance, regulate epidermal rotations.

Drosophila are old, and many of these species differences are millions of years old. They are now looking at more recently diverged species with differences in sex comb morphology, and are looking for correlations between Scr and species divergence.


And with that, I have to run for the airport shuttle. Good talks, and I unfortunately have to miss Rudy Raff’s wrap-up of the meeting.

A creationist at the Chicago meeting

Last week, I described the lectures I attended at the Chicago 2009 Darwin meetings (Science Life also blogged the event). Two of the talks that were highlights of the meeting for me were the discussions of stickleback evolution by David Kingsley and oldfield mouse evolution by Hopi Hoekstra — seriously, if I were half my age right now, I’d be knocking on their doors, asking if they had room for a grad student or post-doc or bottle-washer. They are using modern techniques in genetics and molecular biology to look at variation in natural populations in the wild, and working out the precise genetic changes that led to the evolution of differences in development and morphology. They are doing stuff that, back when I actually was a graduate student, would have been regarded as technically impossible; you needed model systems in the laboratory to have the depth of molecular information required to track down the molecular basis of novel morphs, and you couldn’t possibly just grab some interesting but otherwise unknown species out on a beach or a pond and work out a map and localize genetic differences between individuals. They’re doing it now, though, and making it look easy.

Then there were all the other talks in population genetics and paleontology (and the talks on history and philosophy, which I almost entirely neglected)…this was a meeting that everywhere demonstrated major advances in our understanding of evolution. Every talk was about the successes of evolutionary theory and directions to take to overcome incomplete areas of understanding; this was a wonderfully positive and promising event that should have impressed all the attendees with the quality of the work that has been done and the excitement of the potential for future research. Like I said, there were a whole bunch of people here that I want to be when I grow up.

Well, normal people would feel that way. Paul Nelson, that creationist, was also there. Nelson is a weird guy; he’s always hanging around the edges of these scientific meetings, and you’d think that after all these years of lurking, he’d actually learn something, but no…the only skill he has mastered is the art of ignoring what he doesn’t like and incorporating fragments of sentences into his armor of ignorance. It’s very sad.

I talked with Nelson briefly at a reception at the meetings, and we both agreed on the quality of Kingsley’s work — but that’s about all. Nelson thought it supported ID better than neo-Darwinian evolutionary theory. His argument was that a) all anybody ever described was loss of features, and b) a large parent population was the source of all the allelic variation in the sub-populations studied, which is what ID predicts. He didn’t mention their favorite magic word of “front-loading”, but I could see what he was thinking.

How Nelson can hang about on the fringes of the evo-devo world and not notice that what was described by modern empirical research is exactly what the evo-devo theoreticians expected is a mystery — these were results that fit beautifully what science, not the wishful voodoo of intelligent design creationism, predicts.

Both Kingsley and Hoekstra are looking at recent species, subpopulations that separated from parent populations within the last ten thousand years, and have adapted relatively rapidly to new environmental conditions. The sticklebacks are fragments of marine species that were isolated in freshwater streams and lakes, while the beach mice are parts of a widespread population of oldfield mice that are adapting to gulf coast islands. They are also working with populations that can be bred back to the root stock, that retain the ability to do genetic crosses, so of course the variation is not on the magnitude of turning fins into limbs (we need large amounts of geological time to do that; it’s the kind of work Neil Shubin would do, and unfortunately, he can’t cross Tiktaalik with Acanthostega). Complaining that the variants the real scientists are looking at aren’t the kind that the creationists want is a particularly clueless kind of whine, since the scientists are intentionally focusing on the variants that are amenable to dissection by their techniques.

The other aspect of their work that confirms evo-devo expectations is that what they’re discovering is that the genetic mechanisms behind morphological variants are changes in regulatory DNA — that what’s happening is that regulatory genes like Pitx1 or Mc1r are being switched off or on. We anticipate that a lot of morphological novelty is going to be generated by switching genes off and on, and by recombination of patterns of gene expression. Nelson and Behe are reduced to carping on the sidelines that observed variants are just the product of getting large effects by trivially flipping switches, while all the real biologists are out there in the middle of the work happily announcing that we can get large-scale morphological effects by simply flipping switches, and hey, isn’t that cool, and doesn’t that tell us a lot about the origins of evolutionary novelties? It’s not just a to-may-to/to-mah-to difference in interpretation, this is a case of the creationists wilfully and ignorantly missing the whole point of an exciting line of research.

There’s also a fundamental failure of comprehension. Creationists see loss of a feature like pelvic spines, or a reduction in pigmentation, and declare that the evolutionary evidence is “all breaking things and losing things”. Wrong. What we have here is a complete lack of understanding of developmental genetics. What we typically find are changes in the pattern of expression of developmental genes, not wholesale losses. In the stickleback, Pitx1 is still there; what’s different is that the places in the embryo where it is turned on have changed, the map of the pattern of gene expression has shifted. You cannot describe that as simply a broken gene. Similarly, in the mouse, Hoekstra showed that the expression of genes that reduce pigmentation has expanded. We’ve seen the same thing in the blind cavefish; a creationist looks at it and says it’s just broken and has lost its eyes, but the scientists look closer and see that no, the fish have actually increased gene expression and expanded the domain of a midline gene.

Just wait for the detailed analysis of jaw morphology in cichlid fishes. These animals have radically different variants in feeding structures, which is thought to be the root of their adaptability and the radiation of different forms, and I guarantee you that the creationists will ignore the morphological novelties and focus on the fact that to achieve that, some genes will be downregulated (I also guarantee you that there will be such shifts in expression). It’s “all breaking things and losing things”, after all; just like baking a cake involves breaking eggs.

I don’t know how the creationists fit known variations in the coding sequences of genes (how do you translate a single-nucleotide polymorphism into their vision of all change being a matter of losses?) into their idea that all evolution is a matter of breaking DNA, or how they can claim all novelty requires a designer when people can track the progression of morphological shifts in the tetrapod transition, for instance, across tens of millions of years. It seems to be their desperate 21st century excuse in the face of the overwhelming progression of information from 21st century biological science.

Nelson ends his skewed summary of the meeting with the comment that “It’s a heck of a lot of fun to attend a conference like this, if you don’t mind being the butt of jokes.” I’m sure. I suppose Nelson could have even more fun if he put on a dunce cap and drooled a lot, because that’s basically his role at these meetings anyway — he’s the butt of jokes because he shows up and then happily demonstrates his ignorance about what’s going on. It’s not a role I’d enjoy, but the gang at the clown college called the Discovery Institute have a slightly different perspective, I suppose.

William Wimsatt—Why Development is Crucial to Cultural Evolution

Man, philosophers sure take a long time to get to the point.

OK, his outline: 1) development and differential entrenchment in evolution. 2) application of these principles to culture. 3) what new phenomena this theory can capture.

Plunges into “thick, thin, and medium viscosity theories of culture”. I have no idea what he’s talking about: I hope he’ll get into some specifics I can grapple with soon, because right now this is just a wall of words.

Any evolving system must meet Darwin’s principles: variation, which is heritable, which has consequences on fitness. Wimsatt suggests two additional principles: structures generated over time have a developmental history, and they have parts which have larger or more pervasive effects than others on that production. Wimsatt says that life cycles emerge from these principles, and illustrates it with some strange models.


I give up. I have no idea where this talk is going. I keep waiting for an empirical foundation to be dragged in from offstage, but it’s just not happening. He seems to be saying some interesting stuff (or stuff that should be interesting), but it all seems to be built on air.

I don’t think I could ever be a philosopher.

Hopi Hoekstra—The Causes of Evolutionary Change: What Darwin Did and Didn’t Know

Darwin didn’t know the basic mechanisms of evolutionary change. Mechanism of inheritance was a black box. Darwin’s last publication before his death was “on the dispersal of bivalves”. Why are freshwater bivalves so homogeneous in morphology? Describes a beetle with a conch attached to its leg, which provided a mechanism of dispersal. Turns out the specimen was sent to Darwin by Crick’s grandfather.

How is variation generated and maintained in natural populations? What genes matter? What will finding the genes tell us?

We find genes underlying phenotypic diversity by comparison of highly divergent taxa (flies vs. mice, for instance), or the study of variation within species. Latter gives us the opportunity to use genetics, also allows us to know something about the environmental context that drives the differences.

Looks for phenotypic differences in the wild that contribute to fitness, then works out the genetics and development to see how it works. Hoekstra looks at color, the genetics of mammalian pigmentation in Peromyscus. These mice show lots of variation in color. The oldfield mouse of the American south lives in abandoned fields and on beaches. Beach sand is white, with low levels of vegetation, which means they are subject to high levels of predation. They wanted to document the selective advantage of light pigmentation on the beach environment, so made model mice out of clay with different colors,. and measured predation on the models. Color matters, and dark models were attacked preferentially on light sand, light models attacked in dark environments. 50% more likely to survive if your color matches your background.

Made crosses of dark and light genes and used QTL analysis to search for candidate genes. Found 3 genes correlated with the color patterns seen in Peromyscus, Mc1r, Agouti, and Corin. Mc1r is a g-coupled receptor with many mutations scattered throughout the gene. One difference is found between light and dark mice: changing one amino acid reduces the activity of the gene product.

Mc1r is the receptor; agouti is a repressor of mc1r; and Corin is an upstream regulator of agouti.

Looked at populations in the wild. Do populations on the gulf coast have the same mutation as atlantic coast mice? No — atlantic mice do not have the same mutation im mc1r, and no significant mutations were found in the atlantic mc1r.

Going even further afield, mc1r was sequenced in mammoths, and the same mutation found in light mice was found in mammoths; were mammoths polymorphic in coat color?

What do these genes tell us? 1) how many and and what are the effect sizes of genes that contribute to adaptive phenotypes? A few genes can have a large affect. 2) Do adaptive alleles tend to be dominant or recessive? Adaptive alleles are rarely completely recessive. 3) What is the relative role of epistasis versus additivity? Epistasis is very important. 4) Are the same genes responsible for convergent phenotypes? sometimes, but not the case within beach mice. 5)Are adaptive mutations in protein-coding or cis-regulatory regions? Both.