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!