Wednesday, February 22, 2006

Climate change

Viva, to all visitors from Conta Natura...

Which reminds me, Portugal has been unusually cold this Winter. The other day, my friend Manuela sighted this unusual creature in Evora.

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Tuesday, February 21, 2006

I'm feeling Dodoish today...

The Loom has given a platform to Randy "Flock" Olson where he gives us poor deluded scientists some advice on how to communicate with the public. Although I agree with much of what Olson has to say, and am very much looking forward to "Flock of Dodos" coming to Rice University, I disagree with him on a few points. For example, he opens his list with:
"[S]o much of the mass communication of evolution is so dull and uninspiring. [For example] the 8 part Evolution series by PBS released a few years ago [...]. We ordered the 7th episode of the Evolution series, on God and religion, and found it unwatchable. At one of my recent screenings a member of the audience offered up that she ordered the second episode for a museum display and found the same thing – five minutes into it they shut it off. [...] These sorts of productions need the simple, honest feedback of evolutionists who have purchased their videos, shown them to their neighbors, and watched them fall asleep. Just send them a note and say this is not good enough. Raise the bar. Its that simple. When evolution media looks bad, evolutionists look bad.
Interesting, coming from someone who tells us not to "condescend" and to "lighten up a bit" later on. Just by curiosity, did you actually watch the whole series, or just the last episode? I happen to think that the series is excellent. Some episodes (e.g., the evolution of infectious disease and the sexual selection / evolution of sex ones) are among the best popular science programs I've ever seen. My wife who is a scientist but not an evolutionary biologist (nobody's perfect!) also enjoyed them.

I suppose I just don't buy the argument that we need to aim at the lowest common denominator in order to grab people. That we need to entertain everyone at all times. (Of course, I could be wrong. Newton's Binomium isn't exactly a mass phenomenon.) No matter how flashy you make something some, perhaps most, people will still switch to "Fear Factor" or whatever. I think there's nothing wrong with creating programs aimed at the same public who watch good natural history or technology shows, even if it's only 10% of the total audience. David Attenborough never dumbed anything down, and still got big audiences. I know many biologists who were turned on to the subject by watching his shows. Dawkins' "The Selfish Gene" did the same for me. Steve Gould's prose inspired others still, even if some of Olson's students found it "arrogant, elitist, condescending, verbose". I'd hate to see these voices disappear just because they risk sending someone, somewhere to sleep.

Update: I should add that I largely concur with Olson on his points 3-5 and 7-10.

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Saturday, February 18, 2006

Blind Watchmaker or Swiss Designer? (Part II)

Although it seems easy to identify robustness in biological systems, it is usually difficult to give a precise answer to the obvious question: robust compared to what? Ideally one would like to study many different, independently evolved creatures. However, these are rarely available. For example, the number of different, naturally occurring genetic codes is small, and they are not that different from the inaccurately named "universal" code. Instead, we usually have to make do with simulated creatures. This is the approach Andreas Wagner took to study the evolution of robustness in circadian oscillators.

He began by considering one of the simplest models for a circadian oscillator, known as a Goodwin oscillator. In a Goodwin oscillator a gene expresses a mRNA molecule R that is translated into protein P. This protein is then modified (e.g., dimerized or phosphorylated) to generate an inhibitor P' of its own expression.

This model was chosen because it can "exhibit stable circadian oscillations of an appropriate frequency", and because it can correctly predict "the response of circadian rhythms to stimuli such as temperature pulses, light pulses, and an inhibitor of protein synthesis".

Now consider the case of two coupled Goodwin oscillators forming the following two-gene six-product circuit:

Wagner points out that this circuit can take one of 378 different topologies where the six regulatory interactions represented by dashed lines can be activating, inhibitory or non-existent (the interactions represented by the solid arrows are always positive). He then asks two questions:
  1. Do different topologies result in different degrees of robustness?
  2. Can an evolutionary search in a space of possible circuit topologies reach highly robust topologies when starting from circuits with low robustness?
To address the first question, Wagner took each of the 378 circuit topologies and generated 5,000 random parameter combinations "from a parameter space within which circadian oscillations are known to occur for the basic Goodwin oscillator". He then used these parameter combinations to define a measure of robustness:
"For each of these parameter combinations, I examined whether the circuit adopts limit cycle oscillations with a period of ≈24 h [...] The fraction of randomly chosen parameters that yield circadian oscillations is an estimate of the fractional volume (P) of parameter space that admits such oscillations [...] P can serve as a proxy for a circuit's robustness to perturbations: changing parameters at random in a topology with high P is more likely to yield a parameter combination leading to circadian oscillations than in a topology with low P."
Of the 378 topologies, 176 show no random parameter combinations capable of generating circadian oscillations (P less than 1/5,000). Among the 201 topologies producing oscillations, robustness (P) varies by nearly 2 orders of magnitude among circuit topologies. For most of these topologies, only one or a few of the 5,000 randomly chosen parameter combinations produce circadian oscillations (low P). But for a small fraction of topologies, over 5% of parameter combinations yield such oscillations (high P). Here are nine of the topologies with the highest associated robustness:

These circuits show two important properties which give us some clues as to the mechanistic causes of robustness. First, most topologies contain a mixture of transcriptional (fast) and posttranscriptional (slow) regulation. Second, inhibitory interactions are more common than activating ones. "This is not surprising, if one considers that a closed positive regulatory feedback loop may cause the increase of a gene product without bounds, thus preventing stable oscillations".

The most robust circuits are ≈1 order of magnitude more robust (i.e., have a higher P) than a circuit composed of two decoupled Goodwin oscillators. This result suggests "that the increased complexity of interlocking oscillators involving two (or more) oscillating gene products" found in nature "may not be an accident of natural history: it may indeed provide greater robustness to mutation than single oscillators." However, when the first coupled oscillator evolved it was probably not very robust. So, to repeat the second question posed above, is it likely that a robust oscillator evolved by "numerous, successive, slight modifications" (Darwin 1859) to circuit topology? Wagner introduces an original way to attack this problem:
"This question is best posed by considering the following graph or network representation of oscillator topologies. Consider a graph where each node corresponds to an oscillator topology that is capable of displaying circadian oscillations. Connect two nodes (topologies) by an edge if the two topologies differ by only one regulatory interaction [see a, below]. Such neighboring topologies can arise from each other by genetic change that affects only one regulatory interaction. The question whether robust oscillator topologies can be found through a series of such changes, i.e., through gradual evolution, is a question about the structure of this graph. There is a spectrum of possibilities with two extremes. First, the nodes (oscillator topologies) of this graph may be disconnected. That is, a topology capable of circadian oscillations has no neighboring topologies also capable of producing such oscillations. This would mean that robust topologies cannot be reached from less robust topologies, because functional oscillators are isolated islands in this graph. At the opposite extreme, this graph might consist of one densely connected component, where any two topologies are connected by a path of edges. In this case, stepwise evolutionary alteration of a circuit topology could start from any one topology and reach any other topology via intermediate topologies that admit circadian oscillations.
Part b of the figure below shows this metagraph for the 201 topologies capable of producing circadian oscillations (P at least 1/5,000).

Two properties of this metagraph stand out: it consists of a single, highly connected component, and similar topologies also tend to have similar robustness (P). Thus:
"[G]radual evolutionary changes in circuit topology can generate any circuit topology from any other topology within such a component, without transitions through circuits that do not allow circadian oscillations."
The high evolutionary accessibility of robust topologies is not trivial: metagraphs composed of random samples of 201 topologies (i.e., picked independently of their robustness) tend to show, on average, over 20 disconnected components.

In conclusion, Wagner tested whether evolution could, in principle, discover a robust coupled oscillator circuit topologies and found that the answer is yes. This is an excellent example of why the standard position taken by intelligent design creationists when faced with the appearance of design is scientifically vacuous. No doubt Dembski and Behe will come up with some post hoc criticisms of Wagner's study. What I'd like to see are similarly rigorous attempts to test their claims, instead of the usual hand-waving about mousetraps and Mount Rushmore.

Can these results be generalized to other systems? It's impossible to tell at this stage. A recurring problem in the study of robustness is that it is difficult to judge how representative any biological system really is. For example, when Meir and colleagues (Current Biology 12: 778–786, 2002) discovered that the neurogenic network of the fruit fly Drosophila melanogaster is robust against large variations in the initial concentrations of gene products and the rate constants of molecular interactions they wondered:
"Perhaps this is a generic feature of genetic organization, but perhaps it reflects a coevolution between evolved networks, biologists and theorists: modular, robust networks are the easiest to get at experimentally. Thus, they are the best understood and are the best fodder for models."
There is only one way to find out... To keep working!

Read on

Friday, February 17, 2006

Even educated water-fleas do it...

In the current issue of Science, Paland & Lynch report on some new evidence in favor one of the "Weismann-family" theories for the evolution of sex I mentioned the other day. They compared sexual and asexual populations of water-fleas (Daphnia pulex) and found that sexual populations are more efficient at eliminating deleterious mutations than asexuals, as predicted by (among others) the mutational deterministic hypothesis:

"Of the amino acid altering mutations arising in mitochondrial protein-coding genes of D. pulex, we estimate that 73.2% have strongly deleterious effects and are subject to purifying selection irrespective of the population's breeding system, 13.3% have moderately deleterious effects and persist only in asexual populations, 4.4% are mildly deleterious and allowed to persist in the short-term even in sexual populations, and 9.1% are effectively neutral. Thus, the rate of accumulation of deleterious amino acid–altering mutations in asexual lineages, 4.4+13.3=17.7%, is four times as high as that for sexual lineages (4.4%)."

Read on

Blind Watchmaker or Swiss Designer? (Part I)

Another topic I've been working on is robustness, one of the abstract nouns du jour. Robustness is defined as resistance to some kind of perturbation, such as mutation, heat-shock, or a poison. This is an old idea in biology: it is closely related, for example, to CH Waddington's "canalization", and to Claude Bernard's "homeostasis". It also has obvious parallels in other fields, such as the concept of "stability" in community ecology and "control theory" in engineering.

What fascinates biologists is that organisms appear to be riddled with robustness to all sorts of perturbations. This seems to be true at all levels of biological organization, from the genetic code to metabolic pathways, from RNA and protein structure to genetic regulatory networks. This robustness has important evolutionary consequences because it affects the expression of phenotypic variation within populations, the fuel for natural selection. (For a detailed survey of these topics I'd recommend a book I'm reading at the moment: "Robustness and Evolvability in Living Systems" by Andreas Wagner. Some chapters are previewed in his recent papers. Or you can listen to this talk.)

To make some of these issues clearer I'll discuss a concrete example reported in a paper by Wagner ("Circuit topology and the evolution of robustness in two-gene circadian oscillators". PNAS 102: 11775–11780, 2005). One class of biological systems that has been shown to be highly robust are the genetic oscillators underlying circadian rhythms (i.e., endogenous activity cycles with a period of approximately 24h) in a variety of organisms, including cyanobacteria, fungi, insects and mammals. Although some of these clocks may have evolved independently, they tend to share some basic characteristics according to Wagner:
"First, the principal clock mechanism is simple. It minimally involves one gene that is expressed to produce a mRNA and a protein product that may undergo further modification and exerts direct or indirect negative feedback on the expression of its own gene. Examples include the frequency (frq) gene in the fungus Neurospora crassa, the timeless (tim) gene in the fruit fly Drosophila melanogaster, and the kaiC gene in the cyanobacterium Synechococcus spp. This simple mechanism will generate sustained oscillations in protein concentrations only if the negative feedback is slow. That is, there must be a delay between the time at which the gene product's concentration rises because of its expression and the time at which the gene product represses its own expression. [...] The second common feature of many circadian oscillators is that they consist of not one but two or more oscillating gene products whose regulation is linked. This holds in organisms as different as the fungus Neurospora, the fruit fly Drosophila, and mammals."
More interestingly, like Swiss watches, they show remarkable accuracy and precision under a range of conditions. In his paper, Wagner asks:
"[W]hether interlocked circadian oscillators may be an accident of life's history (there are infinitely many ways to obtain limit cycle oscillations in regulatory systems), or whether such interlocking may exist because it provides especially robust oscillations."
There is, of course, another, if less scientific, alternative that Wagner forgot to mention: that an intelligent designer decided to make circadian clocks that way. Maybe the designer was even Swiss! William Paley seems to have been thinking about this problem two centuries ago:
"But suppose I had found a watch upon the ground, and it should be inquired how the watch happened to be in that place. [...] When we come to inspect the watch, we perceive [...] that its several parts are framed and put together for a purpose [...]; that, if the different parts had been differently shaped from what they are, of a different size from what they are, or placed after any other manner, or in any other order, than that in which they are placed, either no motion at all would have been carried on in the machine, or none which would have answered the use that is now served by it. [...] This mechanism being observed [...], the inference, we think, is inevitable, that the watch must have had a maker: that there must have existed, at some time, and at some place or other, an artificer or artificers who formed it for the purpose which we find it actually to answer; who comprehended its construction, and designed its use."
Interestingly, Wagner actually tested all three hypotheses, something that the proponents of intelligent design creationism seem incapable of doing themselves. I'll explain how in the next post.

[Meanwhile, you can check out Circadiana and Pharyngula replying to a creationist's claim that circadian clocks contradict evolution...]

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Thursday, February 16, 2006

Why do fish need bicycles?

The evolution of sexual reproduction is one of the great mysteries of evolutionary biology. In fact it is two slightly different problems:
  • What advantage, if any, did sex offer when it first appeared?

  • Why does sex persist in modern organisms? That is, what stops them from becoming asexual again?
These questions, although related, might actually have slightly different answers. It may seem strange to ask such questions at all, but the reason is that there are many costs associated with reproducing sexually. I'll give two examples. First, sexually transmitted diseases are widespread in sexually reproducing populations, which makes sex risky. Second, there's the so-called "two-fold cost of sex". As feminists have been telling us for a while, males are pretty useless. Well, this is seems to be true in evolutionary terms as well. A mutant human female able to reproduce asexually and give birth to more females like her, would give rise to a population with twice the reproductive rate per capita of the normal human population, and these mutants would probably become dominant within a few centuries. (Actually, this is extremely unlikely to happen in our case because, due to a genetic quirk of mammals called genomic imprinting, asexual reproduction is very difficult to evolve in humans. However, asexuality can and has re-evolved many times in other animals, such as reptiles, fish and insects.)

Evolutionary biologists have been grappling with these questions for over a century and many hypotheses (over 20 by a recent count) have been proposed to explain the origin and maintenance of sexual reproduction. However, there is still a lot of debate, partly because many of the hypotheses are not mutually exclusive and are difficult to test. Many of the hypotheses that are currently favored have in common a central idea originally proposed by August Weismann over a century ago. This is that the benefits of sex are not direct (in the sense that the offspring of sexually reproducing individuals have a higher mean fitness than those of asexually reproducing ones) but indirect such that the offspring of sexually reproducing individuals have a higher variance in fitness than that of asexually reproducing ones. In other words, according to Weismann, sex makes natural selection more efficient, thus allowing sexual populations to adapt better to their environments. This can be achieved in many ways (hence the different hypotheses), such as eliminating deleterious (bad) mutations or allowing the spread of beneficial (good) mutations.

One of the main hypotheses from the Weismann "family" is the mutational deterministic hypothesis (MDH), developed by Alex Kondrashov and others. MDH postulates that sexual reproduction confers an advantage by helping natural selection remove bad mutations from the population. The MDH is very attractive because, in order for sexual populations to overcome the two-fold cost of sex, only two things must be true, and these can, in principle, be tested using data from real organisms.
  1. The rate of production of bad mutations must be relatively high, such that each individual acquires on average one or more bad germline mutations not inherited from their parents. This has been observed in some species, but not all. For example, humans have an even higher deleterious mutation rate than the one required by the MDH. The jury is still out over whether this assumption is generally valid in the real world -- there's a lot more work to be done there.

  2. The bad mutations must interact in a special way, called negative epistasis, such that adding more and more bad mutations makes you disproportionately sicker and sicker. For example, imagine that a single bad mutation lowers your fitness by 5% on average. If bad mutations don't interact, adding successive mutations should lead to a progressive decline in 5% steps. Negative epistasis would occur if, for example, the second mutation decreased fitness by 10%, the third by 15%, and so on. The evidence for this second assumption is also equivocal, partly because it is even more difficult to measure than the deleterious mutation rate.
In the next post I'll introduce the other concept needed to understand our paper: robustness.

Read on

The Nature of My Blogging

Nature has a lot to do with my blogging. It all started last year when I got a paper into it -- apologies for the shameless self-promotion. One of the most interesting consequences of that was that two bloggers picked up on the article. One of them was PZ Myers. It's an example of Pharyngula at its best: in a few paragraphs it cuts through ideas that took several years to develop in our collective minds (and were then compressed into the highly compact Nature style) and hits the nail on the head. (The other blog post, in Catalan, is also excellent.)

This was my first real introduction to blogs and I was impressed. I started reading PZ regularly, one thing led to another (literally, or perhaps better, virtually) and I've been hooked ever since. A few months later I decided to give it a try myself. Unfortunately, I quickly found that I rarely have time to write on the blog. When I do, I feel guilty about all the other things I should be doing instead, such as replying to that friend's email, writing the next paper or grant application, planning next week's lecture, ... or reading the latest issue of Nature (authors get a nice subscription discount, you see).

Fortunately, one of the reasons for my low blog output is coming out in two weeks in, well, Nature. I think it's pretty exciting stuff, so I'm going to try and explain what it's all about here. (After all, PZ may have something better to do that week... Dawkins may send him another DVD or something.) Because of their embargo policy, I'll have to limit myself to background for the moment: the evolution of sex and robustness. Sounds kinky, doesn't it?

Read on

Wednesday, February 15, 2006


Spot the differences! (Via Conta Natura.)

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Tuesday, February 14, 2006

Good news from Ohio

In a memorable passage from his landmark ruling, Judge Jones argued that science could not be defined differently for "students than it is defined in the scientific community as an affirmative action program". Ohio seems to have followed this sound advice. Could Kansas be next?

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