Here's good news for elbow benders!

Our interest is mainly in genetic causation, how it works, and how traits evolved. But of course we can't resist a good, juicy story about biological cause and effect. Especially when it has major life-style implications. Here's one from the BBC that does just that, especially for any senior blogsters who may see this post!

You're always told not to drink, at least not too much. Partly this is because drinking is fun, fun is sin, and we (in the US) are damned if we're gonna sin (openly). But if you're arthritic you may have difficulty or pain when trying to get the mug up to your mug, so you have to deal soberly with your disease. Or so you may have thought!

Now, the Beeb reports on a new British study that found that drinking helps not just reduce the pain (after all, when you're zonked, you don't care!), but also the actual severity of the arthritis. The authors put in the pro-forma caveat about not overdoing it (the Church of England probably insisted on that bow to virtue), but who's gonna listen to them?

Scientists at the University of Sheffield asked two groups of patients with and without the disease to provide details of their drinking habits.

They found that patients who had drunk alcohol most frequently experienced less joint pain and swelling.

And there's more. Quaffing apparently can reduce the risk of swollen joints in the first place. So, here's to TGIF every day, and from a young age!

We must add, sadly, that this study (like so many vitally important studies our tax pounds, euros, or dollars pay for, to keep up the professoriat's lifestyle) is seriously flawed and probably will not have very wide applicability.

This is because only in Britain is it typical to get wiped by downing pints of beer. Pints are heavy-lifting (when full), so the degree of stress relief in pubs is probably greater than that in bars in the US.

We're sure that the international difference is enough to warrant an expensive study or two by NIH to see what gives in the US. We volunteer as subjects! We're not arthritic, fortunately, but any good study needs normal 'controls'.

GWAS advertising legerdemain

There's a recent GWAS review by Teri Manolio in the New England Journal of Medicine that demands a response, even in just our little blog. Dr Manolio reviews the success and (some of) the less positive issues attending to the genetic approach to disease.

This article lays out the nature, and the positive findings, of genomewide association studies. Manolio says things like:

Genomewide association studies — in which hundreds of thousands of single-nucleotide polymorphisms (SNPs) are tested for association with a disease in hundreds or thousands of persons — have revolutionized the search for genetic influences on complex traits.

And

Genomewide association studies have proved successful in identifying genetic associations with complex traits.

But she demurs from citing a number of authors who have raised substantial points critical of the GWAS approach, though the supportive literature is of course well represented.

The problem is that Dr Manolio is a bureaucrat working for the NIH's Human Genome Research Institute. She is a skilled person, but her job is advocacy of a particular program agenda--the funding of genetic research--and hence she has a vested interest in promoting the work they've decided to fund and hence advertising it as a success. Perhaps that's in her 'job description'--to be an advocate for a policy she feels is a good one. But that shouldn't be confused with science.

If the NEJM were ethically responsible (there have been many issues about that in recent years, including their relationship to the evaluation of drug safety and drug trial data), it would not publish an article evaluating GWAS written by a person vested in advancing that type of study. Such a review must be viewed as essentially a conflict of interest. And given the same suspicion that drug trials sponsored by drug companies get and have richly deserved.

It is not that GWAS are all bad or a total waste of resources. But they are far from as good as the article says. We've made many posts about GWAS and need not repeat them here (interested readers can find them by searching the blog). But a cheer-leading article in a prominent journal like the NEJM can and probably will be seen as evidence for the success of the effort to turn complex traits into genetic traits.

One legitimate issue, of course, is that investment in one place diverts funds from other avenues of research. There are areas in which the same investment might have much greater, and more immediate returns in terms of actual health improvement, even if such measures aren't as glamorous for the research industry.

And there's a further problem. Publishing this propaganda piece in the NEJM implies that GWAS have clinical relevance and are about 'medicine'. In a few rare cases (naturally, they're featured in the article) this is partly true, though the role of GWAS in their primary discovery is less clear. But generally we are so far from being able to apply GWAS in clinical practice that a review of GWAS results should not appear in a medical journal.

There are some new approaches being taken in association mapping, including those that go beyond considering just the most statistically 'significant' genome regions found for a given disease. They try to digest the information about risk from all or at least many more of the tested markers along the genome. These approaches are briefly mentioned in the article, but Dr Monolio does not say that by and large GWAS lead only to general statements of risk that have very little specific genetic value since most of the implicated regions contribute trivially to risk on their own.

And the article is naive about (and/or intentionally fails to cite) other problems, aspects related to evolution, and is downright misleading about the history of 'theory' in this area, which is much more a history of advocacy than of science.

The article provides a good summary about what GWAS are, with nice figures to show this. But it must be read as lobbying. It's too bad we have to live in an era when this is the way things are done. Science could make better progress, and contribute more directly to taxpayers who support it, if decisions about it were more centered in science itself.

Getting past evolutionary pointilism--or creationism in the journal Nature?

The July 15 issue of Nature, in true Nature style, has a high human-interest picture of a fossil cranium fragment (glaring at you from the cover!) that purportedly shows that the separation between ancestors of Old World monkeys and apes had occurred. The find was in Saudi Arabia, and while Holly is the person most appropriate to discuss the details, we have a few words to say about it until she does.

The fossil is about 29 million years old. It does not have a specific trait found only in modern Old World monkeys, but not in apes. If the interpretation is correct, and we have no reason to question it based on our own fragmentary knowledge of this area, then it does suggest that the monkey-ape divergence occurred subsequent to when this individual lived.

Fine. Our issue, and it's yet another complaint about Nature's drive to be a pop-culture rather than serious scientific journal, is with the heading: " Parting of the Ways: Saudi Arabian fossil pinpoints divergence of Old World monkeys."

The implication in Nature is almost creationist in nature. It is the assumption that this lump of one-time bone was at the 'parting' of the ways, and that such events occur instantaneously. If not, how could a specimen 'pinpoint' the separation?

In fact, speciation is a gradual, statistical, probabilistic population phenomenon. It does not generally occur in a moment.

But suppose this is science, not Creationism on Nature's part. Even then, what is the chance that this particular specimen, or even any specimen from thousands of square kilometers or thousands of generations around this time, was the 'point' of speciation? The odds are minuscule, and in a deeper sense untestable.

Speciation, in the usual definition, would be the time at which no individual from either of the two new-lineage populations could successfully mate. But for thousands of generations, gradual divergence would in reality merely have diminished the probability that a random male from one and female from the other ancestral population could have mated successfully.

Even a mutation that by itself would make such mating impossible would not have spread throughout one of the populations so that the two species lineages were suddenly discrete and immiscible.

To melodramatize speciation and evolution in a way that almost makes it creationistic is yet another editorial decision by the journal that shows either crass grabbing for sales, the superficial understanding of science even by scientists or science journalists, or the simple dumbing down of science. The last thing it is, is a contribution to evolutionary science (we note that this is the editors' fault, not the authors: their paper makes none of these idiotic claims. Instead, they say that the fossil record may now show that the split happened during a 5 million year period after the demise of this current individual).

Sand (fleas) in your eyes! A living satire of intelligent design

After participating in the European EvoDevo meeting in Paris this month, we took some vacation days and toured some of northern France, including the Normandy coast. Part of that included the invasion beaches and some of the military cemeteries that scatter the countryside to preserve the memory of those who perished in WWI and WWII.

One day, we strolled along a beach just south of Lessay, at the water's edge just as high tide was receding. Our eye was caught by the visual buzz of countless light-tan almost transparent objects, that were clearly alive but were being blown about like grain chaff in the coastal wind -- the photo is not ours (we found it here), but it's much as we remember these animals. What were they?

They were rather elusive, as they would land (or, rather tumble apparently uncontrollably) maybe a foot or more from where they'd taken off. They did scurry about on land, but only briefly before jumping up and again being tossed chaotically by the wind.

When we could look closely at these 'bugs', they had two long protuberant antennae -- or what looked like antennae at their front end, but their oblong bodies seemed weirdly shaped: a long torso, with maybe 6 insect legs only at the rear (though later research made it seem we were wrong about the number), like a huge oil tanker with its abaft engine. How could such a thing walk, much less fly? (so camouflaged was their color, and so rapid and zigzaggy their aerial movement, that we could not see if they had wings or if they did what kind of wings -- on the ground, they looked naked of wings).

After we returned to a WiFi site in our hotel (modern research!), we tried our best to Google these creatures to find out what they were. We're not certain but we think, at least, that they are what are called sand fleas. These tumbling tumblefleas seem to populate beaches around the world. But curiously, they are classed as crustaceans rather than insects (despite what looked to us like only 6 legs).

They seemed nearly transparent, camouflaged, and apparently they act like fleas: they jump and this leaves their fate to the wind, so that they don't, and can't, control where they go or whither they land. If it's true that they burrow when the tide comes in, then perhaps they can do such business as mating then. But they can't have a permanent home location or anything like that. There's no obvious way their antennae could pick up mating pheromones in the windy chaotic beach as when we were there.  From our brief observation it seems an interesting, but bizarre lifestyle.

These creatures are apparently globally distributed, so their 'design' obviously works. But if this is a design of intelligence, the designer must have had a few too many that day. Clearly their evolutionary 'strategy' works, but just as clearly how they got this way is not clear at all.

They are not optimally 'designed' for anything other than surviving, however it is they manage it.

Squeezing the scientific lemon

James Lind, Scottish naval surgeon, in 1747 conducted the first known clinical trial, to test the curative effects of lemon juice on scurvy. Scurvy was the scourge of the navy, causing more deaths than actual combat, or so Lind was said to have said. Although the curative effects of citrus had apparently been known for centuries, Lind was the first to do a controlled test of its efficacy. As described in Wikipedia,

In his experiment he divided twelve scorbutic sailors into six groups. They all received the same diet, and in addition group one was given a quart of cider daily, group two twenty-five drops of elixir of vitriol (sulfuric acid), group three six spoonfuls of vinegar, group four half a pint of seawater, group five received two oranges and one lemon and the last group a spicy paste plus a drink of barley water. The treatment of group five stopped after six days when they ran out of fruit, but by that time one sailor was fit for duty and the other had almost recovered. Apart from that, only group one also showed some effect of its treatment.

BBC Radio's World Service program, Science in Action, has a running series called "Moments of Genius", and last week's (July 23) contributor chose Lind's invention of the clinical trial as his important moment. Raymond Tallis, philosopher and retired physician, said that not only did Lind's trial mark the beginning of the science of vitamins, but clinical trials are at the very heart of so-called "evidence-based medicine" (so-called when medical decisions are based on evidence collected with the scientific method; some advocates want doctors to use particular kinds of evidence in particular ways).

As Tallis puts it, we all are tempted to deceive ourselves and others, believing in what we think works even without any evidence, so that the advent of clinical trials was essential to modern medicine. For example, the theory of the four humors, that was formally accepted at least as far back as Galen, certainly seemed to be valid according to informal impressions of doctors -- or they talked themselves into it because it was considered to be the proper standard and/or they had no better ideas. Some patients did, or course, recover after being bled, but the evidence supporting this cure was not systematic or controlled by modern standards.

Clinical trials are controlled studies of the effects of a single treatment or other kinds of intervention. So, in the case of bleeding, for example, a group of people with colds would be bleed and the time to recovery would be compared with people with colds who weren't bled.  If they recovered significantly faster (significance defined statistically), than bleeding would be said to be effective.  If not, bleeding would be considered a non-treatment -- and insurance companies wouldn't cover it.  As Tallis said, "Humility is built into the very idea of a clinical trial," and is the opposite of the 'argument from authority' that is another -- very tempting -- way we have of convincing others of the efficacy of our ideas. For centuries, Galen was authority.

Though, he admits that we've still got the High Street chemist selling homeopathic medicines (see, for example, Holly's story of her adventure with homeopathy in an earlier post), evidence-based medicine has made a big difference.

Like Mendel and his peas, Lind was lucky in his choice of treatment. The effect he hypothesized -- recovery from scurvy -- was large and easily demonstrated, and led to a massive difference in the health of sailors who were on the oceans for months at a time. And certainly clinical trials are indeed fundamental to modern medicine, but as we've blogged about many times, when effects are small, or the outcomes are the accumulation of many small factors, or are complex and can be arrived at in numerous ways, experimental methods like clinical trials -- or, say, genomewide association studies (GWAS) -- aren't necessarily so straightforward. Yes, they are better than argument from authority, just on principle, but they don't necessarily lead to medicine based on evidence.

The problem is simple and it is the same one that applies to GWAS and even to evolutionary explanations: it is the idea that only one relevant factor -- be it a drug under test, or a gene, or a purportedly favored trait -- is varying between those given the drug (or cases, or organisms bearing a particular genetic variant thought to be favored by selection) and those not (or controls, or organisms without the genetic variant).

The number of relevant factors dictates the way that these kinds of statistical associations, between supposed cause and its effect, are found. More variables means larger studies that have to identify, and take into account, those variables. Thus, clinical trials are important, but not unambiguous. And here we don't refer to conflicts of interest or subtle biases in diagnosis, case and control choice, and so on, even though we know those only-too-human foibles can enter into such studies.

Even the idea of natural selection is the idea that exposure to a genetic variant, the logical equivalent to a test drug, is good for the individual. Thus evolution is viewed as a kind of clinical trial where those who have the beneficial 'drug' do well, and the others expire.

There are problems with clinical trials, and there have been recent scandals about cover-ups of relevant data, and so on. Journals have seemed complicit, investigators sometimes sponsored by a company that wants to market a drug, and so on.

But even if scandals are avoided, there are other issues that again have to do with the other, unmeasured but relevant variables. Genomic background of cases vs controls, and lifestyle exposures are among them. Lifestyle exposures of people tested in a study today may be relevant to a drug's effectiveness. But those exposures may change so that, in a decade or two, the same drug will have different effects. Likewise, as is well known, racial background can be highly relevant, and sometimes notoriously hard to control in a clinical trial study.

Nonetheless, limes and lemons do prevent scurvy, and Lind is the insightful person whose insight about how to gather persuasive evidence saved countless sailors, and many others.

Would eliminating mosquitoes really have no ill effects?

We close the week on the same subject with which we opened it, the mosquito. A short piece in this week's Nature asks whether eradicating the mosquito would have any serious ecological consequences. (The photo of mosquito larvae in a pond is from the article: M.and P. FOGDEN/MINDEN PICTURES/FLPA.) There are 3,500 named species of mosquito, and in only a few hundred do the females require a blood meal to reproduce and an even smaller subset of those cause disease in humans. But of course they are major causes of disease.

Malaria infects some 247 million people worldwide each year, and kills nearly one million. Mosquitoes cause a huge further medical and financial burden by spreading yellow fever, dengue fever, Japanese encephalitis, Rift Valley fever, Chikungunya virus and West Nile virus. Then there's the pest factor: they form swarms thick enough to asphyxiate caribou in Alaska and now, as their numbers reach a seasonal peak, their proboscises are plunged into human flesh across the Northern Hemisphere.

It's been said that malaria has killed more people in history than any other disease. And as climate changes, the distribution of mosquitoes will also change, perhaps affecting (and infecting) populations that are now free of the problem.

So, Nature asked a number of scientists who work on various aspects of mosquitoes and mosquito control what would happen if they were eliminated, hard as that is to do. The scientists basically shrugged their shoulders at the ecological consequences, and said they'd love to see it happen. There might be 'collateral damage', in terms of a hole in the food chain for some fish or birds, or a missing pollinator for many plants, but those polled said the gaps would be quickly filled by some other organism, and humans would be a lot better off for it, even if it did mean human population increase through disease control.

Ultimately, there seem to be few things that mosquitoes do that other organisms can't do just as well — except perhaps for one. They are lethally efficient at sucking blood from one individual and mainlining it into another, providing an ideal route for the spread of pathogenic microbes.

This nonchalance set us to wondering -- is this a human-centric view that lauds the benefits of mosquito extinction to us and dismisses serious consequences to other species, or is it true that if this not insignificant biomass were eliminated it wouldn't be missed? We don't really know, of course, but we suspect it's a bit of both. We've written before about how science tunnels through truth, streamlining a problem until it is tractable by the methods at hand. It's difficult if not impossible to understand all the interactions within a complex ecosystem, and so surely it's not possible to predict all the consequences of mosquito elimination. And certainly history suggests this is the case.

But a fundamental principle of life is facultativeness, the ability of an organism to adapt to changing circumstances. Any species that has evolved to subsist on only one food source is extremely vulnerable to the vicissitudes of environmental change, so it's plausibly true that most birds or fish that now make mosquitoes and mosquito larvae a large part of their diet could quickly find and depend upon a different food source, and new pollinators would fill that need as well. The classic idea of the exquisite adaptation of all species to their circumstances, through natural selection, argues against this, but as we've written many times before, that idea is oversubscribed.

To date, however, in spite of the best efforts of people who've spent decades working on the problem, mosquitoes are proving to be damn near impossible to eradicate. At best, we'd have to poison ourselves and much else with insecticides to do it--or we'll need genetic means of attack such as we've posted about recently, that don't harm anything but the biters themselves. As the Nature piece puts it, "...while humans inadvertently drive beneficial species, from tuna to corals, to the edge of extinction, their best efforts can't seriously threaten an insect with few redeeming features." So the question is moot for some time to come.  But it's an interesting one.

The Professor of the Environment

In the Paris EvoDevo meeting that we attended a couple of weeks back, one speaker was the developmental biologist Scott Gilbert. Scott spends his time between Swarthmore and the University of Helsinki, and is the author of the world's foremost text on developmental biology but is also author of a long list of books and articles that put the subject in its historical context.

One point he's been making recently, as in his Paris talk, is that there has been too narrow a focus recently on genes as essentially the only cause of development or its evolution -- genes are not all that's inherited in life. Environmental effects of various kinds can be inherited in different ways, too. Some developmental biologists criticize this message for being 'anti-genetic', but Scott does his own genetics work, and certainly doesn't dismiss its importance.  His examples certainly do not undermine genetics, but simply show, convincingly, that other factors contribute to development and evolution.

We pointed this out in our book Mermaid's Tale as well, and in fact plasticity -- varying responses to environmental factors during development -- was a major theme of the EED meetings. Our gut bacteria (E coli) are vital for survival, and newborns are 'infected' from their mothers or their environment. Gilbert provided numerous other examples. Some fly eggs receive bacteria (Wolbachia) that are needed for their proper gene expression and development (as in the image to the left; Credit: PLoS / Scott O'Neill) -- without that, the egg dies. Maternal uterine conditions can cause fetal gene expression that affects the baby for its whole future life, in terms of things like obesity and blood pressure.

In this sense, laboratory organisms may be in such artificial environments that we don't really get a good picture from them, of how things are out there in the real world.

Since these various kinds of commensalism involve the genomes of more than just the species in question (and other non-genetic environmental factors are also transmitted to or needed by an organism's genome), understanding development requires a broader perspective. Information from the environment can be transmitted 'horizontally' in the sense that it is not transmitted 'vertically' from parent to offspring.

As Gilbert cleverly put it, the environment is not just the sieve of natural selection, deciding who shall live and who shall die. It is a source of information to an organism. And, because response to that information potentially affects survival and evolutionary success, the environment is like a professor: It gives information.....and then gives the recipient a test!

And these tests, like university final exams, determine whether the organism shall graduate!

A general flu vaccine! (?)

The influenza virus is a tough critter to combat. It changes shape too often for effective vaccines to train the immune system to recognize all the possible shapes. That's why we need a new vaccine each year, targeted to the strain that the authorities guess will be predominant.

The problem is that the immune system recognizes the overall shape of the virus in order to attack it. A key molecule that immune systems 'see' is the protein hemagglutinin (HA), which is located on the virus surface (the blue and red mushrooms in the figure). The name comes from the fact that this kind of molecule can cause blood cells to coagulate when exposed to it, the details of which are unrelated to this post.


The HA molecule binds to a sugar-related molecule on host cells' surfaces, and the virus then pops into the cell where it can proliferate. There are many variants, or strains, of HA, numbered H1 to H16 etc., and a vaccine must be targeted to the specific characteristics of the strain that you want to be protected against. The strain variation targeted by traditional flu vaccines is in the blue or 'head' part of the HA molecule as seen in this figure.

A general flue vaccine would not have to be targeted to any given HA variant. It would in principle lead your immune system to recognize all strains, but that's not how flu vaccines have worked so far. However, a new tactic may be about to bear fruit. Part of the HA molecule is apparently not as visible to the immune system (shown as the red stems under the blue head in the figure), but it doesn't vary nearly as much as the head of the molecule--apparently, if it changes, the virus's protein coat won't form properly. This conservation of structure makes this a vulnerable region in the virus. The new strategy would target the stem, perhaps along with a seasonal supplement for a specific HA strain when/if needed. The hope is that this will generate broad long lasting, or even lifetime, immunity after a single vaccination in early childhood. Here is a release from Gary Nabel at NIH who is one of the investigators, explaining the approach, although we cannot yet find a detailed description of how the vaccine allows the immune system to 'see' the HA stem.

This is an evolutionary approach to vaccination because it targets the part of HA that is conserved, presumably by strong natural selection. You attack the pathogen at a place it cannot easily vary, so it can't quickly evolve a defense. Exactly why the HA stem section cannot vary very much is probably known, but not by us--perhaps it has to do with the proper assembly of the virus's protein packaging--all the coat proteins must fit tightly together, etc. There would thus be no stem-variant viruses that could take the place of those destroyed by the vaccine-boosted immune system.

Why natural immunity does not also generate antibodies that recognize the stem is an interesting question. Virologists may know the answer.....but we don't.

'Pre-clinical' Alzheimers, and a bonanza for an already overstressed health care system'

Well, the vested interests are at it again. Here's a story that reports evidence based largely on brain scans that 2-3 times more Americans will be diagnosed with Alzheimer's dementia than currently. The idea is that there are early signs of the diseases in aging, but not yet old, adults and these can be detected by brain scans.

Dementia is an awful disease that plagues a population, like ours, in which so many live to such old ages. Prevention or even adequate treatment would be life-changing for its victims. A couple of drug trials are under way, and there are various other approaches being tested--it's in the news almost every day. This is the good side.

The down side is that the health care system is already badly overstressed financially, and with an aging population this will get much worse, as we all know. Alzheimer's will require 'maintenance' therapy--not just a single vaccine or week of pills, but treatment that goes on for life. And early diagnosis means years -- decades -- of this or other therapies. And making the new diagnosis requires expensive tests like brain scans. So guess who's in favor? The industry that will supply these therapies.

Here's a genuine conflict of interest. As long as we live long lives, we should hope to make those lives worth living, and controlling dementia would be a great contribution to that. But how can we afford it, and should we allow this to be a huge financial bonanza to some corporate entities whose natural interest will be to push the amount of treatment ever upward?

There's no easy answer. Dementia is complex and it's not clear whether the genetically based pharmaceutical approaches to it will work. If they don't, diagnosing people decades before they show symptoms will lead to a lot of essentially over-treatment and expense, not to mention great anxiety.

There's something else that we can predict: as diagnostic approaches increase, so will diagnosis--and so will the heterogeneity and complexity of the 'disease'. Getting old involves changes and the more we look the more we'll find. Even if "Alzheimer's" were a refined diagnosis, other brain pre-disorders will be found. Each will then be used to justify extensive research projects, treatments, and the like.

It's part of the conundrum that Nature throws our way, in which there are usually no easy answers.

Gut check!

A new article in PLoS Pathogens by a collaborative group led by Michael Riehle at the University of Arizona shows some progress in a long-sought genetic approach to disease control. While the news is, as usual, far ahead of the reality, the approach is interesting and may hold real promise for eventually helping to control one of the scourges of humankind--malaria.

The path is indirect and complicated to explain--but clever. Basically humans, and insects like mosquitoes, use insulin-like signaling among cells for their development. Mosquitoes depend on this from their blood meal. Riehle and colleagues have engineered a mosquito that carries a genetic change that over-activates a molecule (called Akt) in the insulin gene cascade, in the mosquito's gut.

The investigators said that a homozygous transgenic mosquito--one with two copies of the over-expressed gene--is 100% resistant to infection by the parasite.

The mosquito's lifespan is shortened by the insulin-cascade modification, so that the parasite's necessary time spent in its gut is too short for the parasite to fully develop, hence it's not ready to survive in the bitten human's blood stream. Hence, no malaria!

The idea that people have had in mind is not new, but this is a new approach. It's to 'seed' malaria-affected areas with these genetically modified mosquitoes, so that they would replace the native mosquitoes. The latter would simply die out by being out-competed in a sped-up evolutionary sense. If that happens, the parasite would have no insect gut in which to hide. That's why there would be no malaria.

Unfortunately, the engineered mosquitoes have a shortened lifespan and would likely be quickly out-competed by the local mosquitoes. Thus, the investigators will have to try some other genetic modification to give them a competitive advantage over the native mosquitoes. So we're years away from this kind of miracle.

Insecticides and anti-malarial drugs have the expected problem that they lead to resistance in Nature. The race to control mosquitoes by poisoning them, or to kill the parasite in humans, faces this kind of evolutionary arms race problem. The investigators hope their genetic approach might be added to the weapons we have against malaria.

Of course, there is every reason to expect that the parasite or transgenic mosquitoes would also develop genetic changes that could lead to reconnecting the pathogenic life cycles. There are many kinds of mosquitoes that carry lots of different malaria parasites, each of them different and naturally variable. So Nature can be predicted to out-wit any single genetic strategy. However, if the approach can be 'automated' and sped up, technology could continue to develop new attacks as current ones become ineffective.

In a different approach, British investigators are attempting to develop transgenic strategies against Dengue fever, another major killer (A story can be heard on the July 16 Science in Action program on the BBC). Again the idea is to seed the wild mosquito population with flies that in this case carry a gene expressing a toxin. The gene is inherited but in the absence of an antidote (which is not present in the wild), the descendants will die. If the transgenic flies mate successfully enough, the local population will die out. And so will the disease.  And, in yet another transgenic strategy, researchers are developing a female mosquito that can't fly; they project that the release of these mosquitoes into the wild would reduce the mosquito population drastically within 6-9 months, and thus reduce the Dengue fever problem.

It's still early days, but these strategies have in common the idea of strong artificial selection targeting specific genetic pathways in pathogens. One can hope they'll work.

Capture the flag...or, the slipperly slope of selection?

On Bastille Day, we were in the arty town of Honfleur, at the estuary of the Seine. A crowd was assembled to watch a contest in which various young men attempted to walk up a greased bowsprit-like pole, to see who would be the first to grab the flag positioned at the end (see image). A large hushed crowd, of all ages, eating gourmet ice cream or sitting at harbor-side cafes drinking beer in the hot afternoon, watched with anticipation.

Each contestant went as far as he could before wiggling, writhing, grappling, and finally slipping into the harbor water below the pole. Here's a link we found on the web to a video of this little holiday contest (the web is amazing).

One by one, however, either the grease was worn off the pole or the lads got better at running out without falling. Eventually, they got closer and closer to the flag until one contestant got all the way to the end, grabbed the flag, and jumped into the water to the cheers and approval of the crowd.

Then the contest was over. No more chances, no more improvement on the pole-walking method.

Since we're always looking for a link from real life to science, we thought that this episode of Capture the Flag seemed somewhat analogous to many views expressed about evolution. Adaptive selection is said to refine (fine-tune) organisms until they are tightly fit to their environment. In this model, in each generation there is one best genotype and it leaves more offspring than the rest. Every other genotype is, by comparison, 'deleterious' and, by definition, viewed as selected against. When the organisms are adapted, the process is over.

This is a sightly--but only slightly--oversimplified version of the common hyper-darwinian view of life. But life is not a slippery-bowsprit contest. In real life, there are many chances, many ways to succeed, the process is never over. Adaptation is not a constantly intensified struggle (an ever-narrowing pole) as is often suggested in popular media, Discover and Nova, or even by many scientists. It is less precise--by analogy, a less narrow and slippery path to success.

The contest on Bastille Day was fun for all and a cooling dip in the sea even for the 'losers', as at the end it was for the winner. In reality, the life of every organism ends in the permanent tragedy of death. But that doesn't imply that all but one are losers.

And now it's time for an espresso under the awning of a nice waterfront cafe....

Beat Takeshi Kitano at Fondation Cartier, Paris

Our daughter suggested we go to the special exhibit of Beat Takeshi Kitano's art at the Fondation Cartier pour l'art contemporain while we were in Paris. She had been planning to go for months herself, and we were happy to go with her. We enjoyed it a lot, but had no idea he'd be so pertinent to MT.

Beat Takeshi is a very well-known Japanese actor, artist, television personality, filmmaker and much more. He's outrageous, funny, slapstick, pointed, whimsical, quirky and poignant, and the exhibit was all that.

His T Rex piece really hit home (we're hoping the video, including this piece from the exhibit, that we're trying to embed will work, but if not it's here). He'd built an 8 foot tall dinosaur, and surrounded it by illustrations with possible explanations for why the dinosaurs went extinct, including that:

• They couldn't stop smoking
• Their front limbs were so short that they couldn't reach to wipe their behinds
• And they couldn't reach to hit their opponents back in a fist fight
• They got metabolic syndrome (from drinking soda and eating junk food)
• They always came out scissors when they played Paper Scissors Rock (their digits are scissors-like)
  

And so on. It struck us not only as funny and whimsical, but as a commentary, whether intended or not, on the often hopeless search for causation in science. Indeed, they couldn't wipe their behinds and might well have gotten metabolic syndrome, but again, correlation is not causation.

Another piece that was pertinent was the large watch Beat Takeshi had disassembled-- he'd placed the pieces inside a shaking dome and labeled it something like, "The probability of life on Earth is less than the probability that vibration will reassemble this watch."

This is the famous argument by William Paley that a watch is so well-organized that it implies the existence of a watchmaker. The Watchmaker is God, according to Paley. Richard Dawkins made the argument, known as the argument-from-design, famous in modern popular-science culture. Creationists love to argue (smugly) that the hundreds of individual pieces of a watch could simply never be assembled by random chance -- which they erroneously (and by now knowingly) say is the evolutionists' view of natural selection.

Of course, this is a straw man argument by creationists because no legitimate evolutionary biologist means this when saying that selection screens genetic variation that arises 'by chance'; what we mean is mutation happens 'by chance relative to functions it might have', and that natural selection provides the organizing force. How that works is a separate question, but Beat Takeshi's exhibit of a vibrating table with dissassembled watch parts makes the point: in decades of vibrating, the parts are still separate -- they've not (yet) formed themselves into a watch!

Evolutionary theory would actually go several layers better. As Jonathan Swift famously wrote:

"So nat'ralists observe, a flea
Hath smaller fleas that on him prey,
And these have smaller fleas that bite 'em,
And so proceed ad infinitum."

The relevance here is that the parts of the watch themselves would have needed a 'blind partsmaker'. Screws, watch-faces, housing, crystal glass, springs, gears, arrowed hands, and the like themselves do not exist in Nature. They have to have evolved. For an organism, one might say that we have parts (stomachs, fingers, eyes) and they have their own evolutionary history.

The wonder of evolution is that this nesting of 'origins' proceeds ad infinitum. At least, all the way back to the origin of life; the same thing is true even of the molecules acting in a cell. And in a sense it is that ever-nested nature of all aspects of life that makes evolutionary theory (and, we believe, the principles of organization we've written about here and in the MT book) so fascinating and powerful an explanation.

And if that's the story of life, Beat Takashi has put some life into the story.

Social behavior?

We are in northern France this week, in a zone where the main trench-warfare lines moved slaughteringly back and forth for several years. You can't avoid the massive cemeteries from the world wars everywhere you turn. This is sobering enough in and of itself -- a British cemetery near our B&B is well-maintained, the gravesite of 2000 British and Canadian soldiers from World War I, buried beneath uniform white headstones, a minority named, somewhat more of identifed regiment, all "Known Unto God". A few miles down the road there's a much simpler German cemetery for the losing side (pictured), where the remains of up to four soldiers are marked by a single wooden cross.

We're near now to where the D-Day landings took place 20 years or so after the first World War (the 'war to end all wars'). Here, too, are consecrated grave sites of Allies and Axis fallen. In both cases, the scene is now peaceful, green, with flowers and birds chirping. It's hard to comprehend what it must have been like, in either area, with corpses (human and otherwise) everywhere, the landscape barren of healthy trees, plants, or birds, buildings wrecked, the ground pitted with shell-holes. How can people do this to each other? And themselves?

Coming here from the EED meeting, it's impossible not to draw connections with some of the work we heard about there. In particular, Chris Thompson's talk on the social life of Dictyostelium (a model organism often used in evo-devo circles, and a creature we blogged about some time ago), in which cells live separately until the food supply is depleted, and then mass together to eventually reproduce by building a fruiting body that releases new spores when it matures.

Thompson's interest is in how the cooperation this requires evolved. He described how some species lose (voluntarily) more than others -- the cells at the front of the aggregation die at a much higher rate than those at the rear, and thus they don't contribute to the next generation, except in as much as they are genetically similar to those that do. Some species, as Thompson put it, don't do the hard work (of apoptosis), and benefit at a higher rate from the sporulation process. That is, their fitness is higher than that of other cells. They 'cheat' to get reproductively ahead. How did this evolve? (Of course, as there is still remarkable variation in the cheater trait, clearly it's not all that successful of a strategy.)

Is it stretching it too far to make an analogy between Dictyostelium and the soldiers of WWI and II? Each of the soldiers buried in the cemeteries across Northern France gave up his life for a greater good, so to speak. It's not simply allegorical to say that each of the soldiers was similarly part of an organism, an army, that survived even after the death of a given soldier (or even a million soldiers). Each soldier was responding to orders from above -- external signals of a sort he was primed to respond to -- but died within an immediate local context, just as Dicty cells are responding to signals from neighboring cells, including signals that induce some of them to commit suicide at the appointed hour.

Each soldier presumably did know what he was fighting for, at least in theory, but it didn't matter what he knew or why he did what he did. All that mattered was that he killed and was killed, and yet the organism -- the army, and the nation -- lived on. Yes, an army has a central command, but we don't think it's not too far-fetched to consider the evolution of chemical signals as equivalent to the central command in how Dictyostelium live and reproduce.

Evolution has trained and constrained the genome of these particular cells to respond to signals the way they do, to live and reproduce or die as a result, just as the evolution of human consciousness allows a soldier to be trained to let himself be killed. In one case, culture and the mind define the greater good, and in the other it's the successful perpetuation of the species. But they have a lot in common, including signaling, cooperation, cheating, and the sacrifice of individual components of the organism in the perpetuation of the whole. Indeed, a major point we try to make in our book is that a similar logic of causation, based on information exchange between semi-autonomous, partially isolated units, is a pervasive characteristic of how life works.

We'll leave this analogy between humans and Dictyostelium at that though, because we don't want to push it to the point of suggesting that all human behavior is built in. To us, as we've said numerous times before, most evolutionary explanations of human behavior are unconvincing; people can talk themselves into all manner of things, no matter how much it curtails their fitness (going to war, suicide bombing, induced abortion, celibacy are just a few examples), and darwinian explanations just don't fit such things, except in some theoretical ways under very specialized conditions. Not to deny that how these kinds of behaviors evolved may certainly be interesting, and important, but explanations are often forced to fit a preconceived idea (such as that of inclusive fitness, for those familiar with the argument in evolutionary behavior).

But we just couldn't leave these similarities unremarked as we travel through Normandy with echoes of evo-devo in our heads.

Complexity made simply

The European Evo-Devo association meeting has ended, after many very interesting presentations and posters by the 450 attendees. The topics ranged from microbes to plants to humans, and from relatively simple phenotypes to more obviously complex ones.

Major attention was given to the neural crest and its evolution, as seen in comparative development and in the fossil record (because neural-crest-related tissues are known and can be explored in some kinds of fossils, and because, at least in the opinion of one speaker, the neural-crest is what's interesting about vertebrates). The neural crest is a 4th primary, or 'germ' tissue layer in vertebrates and is important in many of our structures, especially on the outside, like hair, teeth, scales, nipples and others.

Many papers dealt with morphometrics and their genetic basis and evolution, and plasticity and the importance of the environment in more and more aspects of development. Scott Gilbert, in particular, stressed this, but so did others. Jose Maria Gomez from Spain reported on studies of the shape of flower petals and their relative ability, in different environments in Spain, to attract particular species of pollinating insects. Another speaker studied the evolution of details of fruit-fly wing shape and how it is affected by ambient temperature during development. Several talks were about vertebrate morphology (Ken talked about the skull, representing the research group we're in). Chris Thompson discussed the aggregation of otherwise-independent cells in the slime mold Dictyostelium to form fruiting bodies in which only a subset of the cells actually reproduce--why would they do that? His interest is in the evolution of cooperation and cheating.

One major point we made in our book was that from what we now know about developmental genetics, the processes can be rather straightforward and understandable even for complex traits. We referred to this as 'complexity made simply'. The papers at this meeting showed that research in developmental biology continues to support this idea. Traits that involve many different genes and seem complex in that sense, can be made simply, in the sense that the signaling among different types of cells that is the basis of the trait's development is a simple logical process of information exchange. For example, many different genes are involved in the sending or receiving of a chemical signal (such as a growth factor), but it is the sending and receiving of the signal that is most important.

We're reporting from a rural bed and breakfast in northern France, where we're traveling. And we hope to have more opportunities to post in the next week before our return. But the gist of the meeting on Evo-Devo research is that the science continues to document the ways in which identifiable factors interact in 4-dimensional ways in space and time among cells within organisms, and among organisms in ecological systems, to generate the forms of Nature.

Going after God

We've been in Oxford for a few days, and Sunday we went to the Cowley Street Carnival, a local Oxfordshire festival with a parade of a few floats, prancing girls, and school bands. On the grounds of South Park was a crowd enjoying the usual carnival atmosphere: food booths of all sorts, band shells with dancing and music, and tables for various groups working one form of social advocacy or another.

One of these was the Humanist Society (pictured here). We chatted with the congenial people tending the booth. There we learned that, as in any other cause, there is a schism. The high profile Oxford 'gown' Atheists' organization, with the strident-atheist scientists likes of Richard Dawkins and Peter Atkins is one side, and the 'town' equivalent--the Oxford Humanists--who are independent is the other. The people we talked to were very nice, friendly, and intelligent. But some of them were elderly and nearing their realization point, at which they are likely to find out whether they or religious believers are really right.

Ok, we're kidding about the schism. There was no sense of tension or competition between the groups, but why they were separate is not clear (and we didn't ask). But what seems an unfair competition is between these groups and the withering Church of England. England is loaded with beautiful, old, ivy-covered churches and their ancient adjacent graveyards. Wonderful to look at while on country walks, most of which can be counted on to go past a church. But attendance is very low, and rather heavily among the aged. So much for its one-time power and influence as is so familiar in Victorian novels.

Blasting away at religion, by glib scientists who are convinced of their particular ideology, seems dated and unfair under these conditions, which are very different from the US where at least religious believers are numerous and vigorous enough to defend themselves (if often using false reasoning when it comes to debating whether biblical truths include things about real world history--such as the age of the earth, Noah's ark, and so on.

There are so many strident atheist-science blogs that we try not to get involved in the food fights. Scientists can come to believe in not-believing, and science can effectively challenge the material claims of received truth. But scientists cannot use science as we know it today to refute the possibility of a God nor the personal experience claimed by many religious believers.

But it was interesting to see the presence of the Humanists in the Cowley Street carnival, a mild-mannered slice of British civility that went well with the kebabs, burgers, children's rides, and folk-dance and rock-music groups in the band shells.

We're off to Paris tomorrow and the EED society meetings, a source of many things to blog about, we are sure.

Paleontology in action

I posted some photos from my fieldwork over on Facebook because I can't get them to upload to Blogger from my field internet connection. You don't need an account to see them. Enjoy!