Suffragettes

 
I started a little controversy over on Greg Laden's blog when I responded to the umteenth claim that militant approaches to a debate never achieve anything [Larry Moran]. I said,

Everyone keeps repeating this mantra as though it were the gospel truth. The historical evidence says otherwise. There are dozens of examples of things that used to be “militant” approaches that have become accepted standards today.

Here’s just one example. Do you realize that women used to march in the streets with placards demanding that they be allowed to vote? At the time the suffragettes were criticized for hurting the cause. Their radical stance was driving off the men who might have been sympathetic to women’s right to vote if only those women had stayed in their proper place.

Now I’m not saying that all militant approaches are going to win in the end. Far form it. Most of them are destined for the dustheap of history. What I am saying is that trying to shut down the “militants” on the grounds that they are counter-productive is not logical. It’s a way of “framing” the discussion to make it sound like your opposition to the militants has a scientific basis.

PZ liked the suffragette idea and expanded on it [We Aim to Misbehave] and [Rude Ladies].

Now Amanda Marcotte has picked it up at Pandagon [They didn’t realize that you got it the third time you asked with a pretty please]. Read her blog to find out just how "gentile" those women were one hundred years ago.

I see the Feminists For Life and their horrible project of trying to rewrite history so that suffrage-era feminists come across as pleasantly enamored of servitude is going well. It’s hard to generalize at all about suffragists, since, you know, the struggle went on for decades and incorporated thousands of women. One thing you can say with certainty is they were rude and offensive by definition, since for a woman to be proper, she had to accept second class citizenship uncomplainingly. But seriously, atheists aren’t even waving placards, much less holding hunger strikes, firebombing, or whipping some jujitsu on some cops.

More to the point, suffragists didn’t actually get very far until they did in fact start openly insulting men. Mere equality between men and women wasn’t considered reason enough to extend the franchise to women, but when the purity movement latched onto suffrage and started pushing the message that women were better than men, then things changed. Men were considered drunken, violent assholes who needed women’s civilizing hand to get them in shape. It was a sorry thing that it had to get to that point in order for women to get the vote, and hopefully the lesson has been learned for future reference.* Now, as PZ notes, the way different levels of oppression certainly demanded different reactions, so there’s no reason to fault the suffragists for any radical action they had to take in order to obtain justice. But it’s silly to think of them as sweet little old ladies who’d never hurt a fly. They put up with a lot of shit, from having vegetables pelted at them in public to having police arrest them in ways that maximized the violence and humiliation.

Please don't lose sight of the main point about the comparison between the women's suffrage movement and atheists like Dawkins, PZ, and me. We're not trying to justify our position by comparing it to that of the suffragettes (suffragists). All we're trying to do is destroy this silly myth that all social change came about by speaking softly and being nice to everyone. There are lots of examples where "militant" behavior triggered social change. It doesn't always justify "militant' behavior but if you're going to fight Dawkins then at least use sensible arguments.

Gene Genie #5

 
The Neurophilosopher has just posted Gene Genie #5. There are posts from Hsein-Hsein Lei at Genetics & Health; Leslie, who writes a blog called Paternal Age and De Novo Single Gene Disorders etc.; Bertalan at Scienceroll; Grrl Scientist, who blogs at Living the Scientific Life; Tim at Sciencesque; and me.

I think we knocked off another dozen genes or so. Only about 23,500 to go.

Framing Framing

 
If, like me, you're confused about the message that Mooney and Nisbet are conveying then I urge you to listen to this podcast [Matthew Nisbet]. Here's the introduction on the Point of Inquiry website.

In this discussion with D.J. Grothe, Nisbet explores the issue of “framing science” in the public mind, how scientists may be failing at effectively communicating the importance of the implications of science for society, and steps the science community may take to more expertly sell their science to a disinterested public. He also argues about Richard Dawkins and his effect on the public appreciation of science, and the impact of linking atheism with science for issues such as stem-cell research, teaching evolution in the public schools, and global warming.

Nisbet links to the podcast on his website [Podcast: More on Framing (and Dawkins)] where he says,

In this week's show, host DJ Grothe and I engage in a lively forty-five minute discussion. You can listen here.

I offer more details on:

--> the nature of framing and media influence.
--> does framing mean false spin?
--> the likely negative impact of Dawkins.
--> communication strategy specific to the teaching of evolution in schools.
--> what the Discovery Institute understood about framing (also see this post.)
--> the role of framing in the debates over climate change and stem cell research.
--> the use of "science navigators" in communication campaigns.
-->an effective means for engaging the broader American public on atheism.

I take that to mean that Nisbet thinks he did a good job of explaining these things during the interview.

I urge everyone who has an interest in this debate to take the time (45 minutes) to listen to the interview. At the end of it you should have a very good idea of the issues. Nisbet tries to frame the framing debate to make it look like it's all about "proper" media communication. He sets himself up—along with Chris Mooney—as the social scientist who really understands how society works. Scientists are the social bumpkins who need a lot of coaching from the "experts."

It doesn't work for me. To me it reveals that Nisbet is simply expressing his own personal opinion about many issues. For example, he makes it very clear that, in his opinion, Dawkins is harming the cause of science education. The interview is full of spin framing about how unimportant it is that Dawkins has a book on the bestseller list. Some of the contortions that Nisbet puts us through are actually quite funny. The interviewer (Grothe) really has him twisting in the wind at several points.

After listing to the interview I think I now know enough about Nisbet to ignore him from now on. He doesn't have anything useful to say as far as I'm concerned so this is the end of my involvement in this debate. The fans of framing will no doubt be ecstatic about the interview.

I'm reminded of the two cultures debates in the 1960's. If you don't know what I'm talking about then please follow the link to the Wikipedia article.

Human Genes for the Pyruvate Dehydrogenase Complex

 
The pyruvate dehydrogenase complex (PDC) catalyzes a very important metabolic reaction: the conversion of pyruvate to acetyl-CoA [Pyruvate Dehydrogenase Reaction]. The complex consists of three components: E₁ a dimer of E₁α and E₁β polypeptides; E₂, and E₃ [The Structure of the Pyruvate Dehydrogenase Complex].

Each of them are encoded by separate genes so there are four human genes required. We'll see shortly that there are two additional genes for a total of six. The E₃ subunit is shared with two other enzymes: 2-oxoglutarate dehydrogenase (a citric acid cycle enzyme) and 2-oxo acid dehydrogenase (a enzyme required for amino acid degradation) [Pyruvate Dehydrogenase Evolution].

The gene for E₁α: is called PDHA1 and it's located on the X chromosome at p22.2-p22.1 [Entrez Gene = 5160]. There are more than three dozen alleles that give rise to symptoms ranging from mild lactic acidosis to developmental defects. The accumulation of lactate is due to the fact that it can't be converted to pyruvate because the defect in pyruvate dehydrogenase causes buildup of pyruvate in the cell [Pyruvate]. Males often die at an early age. (Note that males are homozygous for mutant alleles because the gene is on the X chromosome) [OMIM 300502]. Females are also affected because only one X chromosome is active and if it happens to be the one carrying the mutations the entire cell is affected [Calico Cats].

A testis specific copy of the E₁α: gene is called PDHA2 and it's located on chromosome 4 (q22-q23) [Entrez Gene = 5161].

The gene for E₁β: is called PDHB on chromosome 3 near p21.1-p14.2 [Entrez Gene = 5162]. There are only two known alleles that cause a problem. Both are homozygous lethals but only after birth. The infants have severe problems and fail to develop normally [OMIM 179060]. Death usually occurs within a year of birth. It's likely that other mutations are embryonic lethals so we never see them as genetic diseases [Most Metabolic Diseases Affect Unimportant Genes].

The gene for the E₂ subunit is called DLAT (dihydrolipoamide s-acetyltransferase). It is located on the chromosome 11 at q23.1 [Entrez Gene = 1737 ]. Two alleles are known to cause problems but the patients respond well to dietary treatment [OMIM 608770]. It's very likely that more severe genetic defects are embryonic lethals.

The gene for the E₃ subunit is called DLD [Entrez Gene = 1738]. It is located on chromosome 7 at q31-q32. There are many alleles of this gene and some of them cause genetic diseases. The phenotype results from a defect in amino acid metabolism and not from a defect in pyruvate dehydrogenase. Recall that the E₃ subunit of PDC is shared with 2-oxo acid dehydrogenase, an enzyme required for the breakdown of branched chain amino acids. Deficiencies in the enzyme activity lead to accumulation of breakdown products that are secreted in the urine. This gives rise to a characteristic odor resembling maple syrup [OMIM 238331]. The particular genetic disease associated with the DLD genes is called maple syrup urine disease type III

There is one other minor component of the pyruvate dehydrogenase complex in humans. Protein X binds to E₃. It is encoded by the PDHX gene on chromosome 11 (p13). There are no known alleles in the OMIM database.

Pyruvate Dehydrogenase Evolution

Before discussing the origin of the pyruvate dehydrogenase complex (PDC) we need a little background information. There are three different reactions catalyzed by enzyme complexes resembling the pyruvate dehydrogenase complex. For example, one of the reactions of the citric acid cycle is the conversion of 2-oxoglutarate (α-ketoglutarate) to succinyl-CoA. As you can see from the reaction below it is very similar to the pyruvate dehydrogenase reaction. The main difference is that the substrate, 2-oxoglutarate, has five carbons while pyruvate only has three. The part of the molecule that reacts is the top part with a carboxyl (-COO^-) that is lost as CO₂ and a keto (-C=O) that ends up being attached to coenzyme A via a sulfhydryl linkage.


It should come as no surprise that this reaction is catalyzed by an enzyme called 2-oxoglutarate dehydrogenase (OGDH, also known by its old name: α-ketoglutarate dehydrogenase) (EC 1.1.4.2) that's almost identical to pyruvate dehydrogenase. In fact, both PDC and OGDH evolved from a common ancestral enzyme. We know that the citric acid cycle enzyme is a late comer because many species of bacteria don't have it. Indeed, they don't even have a citric acid cycle.

So we need to look elsewhere if we are going to find the source of PDC. The most primitive enzymatic reaction is almost certainly one that's required in amino acid metabolism.¹ In this case it's a reaction involved in the degradation of the branched chain amino acids; leucine, valine, and isoleucine. Look at the pathway below.

The first step in the degradation is the removal of the amino group (-NH₃⁺) and its replacement with an oxygen to form a keto (-C=O) group. This creates three similar 2-oxo acids (α-keto acids) all of which resemble 2-oxoglutarate and pyruvate. All three of the 2-oxo (α-keto) acids are acted upon by the same enzyme called branched chain 2-oxoacid dehygrogenase (OADH, BCOADH, α-ketoacid dehydrogenase) (EC 1.2.4.4) to create an acyl-CoA product. This is the same reaction as that catalyze by the pyruvate dehydrogenase complex except that the R group in pyruvate is -CH₃ while in the case of the branched chain dehydrogenase it's a three, four, or five carbon branched structure.

BCOADH is found in all species. It is the most "primitive" enzyme. Like PDC it has a complex structure with three different subunits. E₁ catalyzes the decarboxylation reaction. E₂ catalyzes the formation of acyl-CoA—it has the lipoamide swinging arm. E₃ catalyzes the oxidation of the lipoamide and the reduction of NAD⁺.

It looks like the "primitive" BCOADH could also catalyze the oxidative decarboxylation of pyruvate. In fact some of the modern enzymes still have residual activity towards the other substrates. Over time, the genes for some of the subunits duplicated and the two enzymes (PDC and BCOADH) diverged as they became more specialized for their modern substrates.

We can see the result if we look at the phylogenetic tree for the E₂ subunit (below). This figure is from a paper by Scharrenberger & Martin (2002). They use a slightly different nomenclature (PDH=pyruvate dehydrogenase complex). This is an unrooted tree so you can't really tell which enzyme came first but, as I explained above, there is good reason to believe that the E₂ from PDC and the E₂ from OGDH evolved from the E₂ gene for BCOADH via successive duplications.


Recall that the E₂ subunits form the core of the complex (left). They contain the lipoamide swinging arm that carries substrate to three different active sites. The E₃ subunits of the three enzymes are identical. There is only one E₃ gene and it supplies the dihydrolipoamide dehydrogenase activity for BCOADH, PDC, and OADH.

The situation with the E₁ subunit is more complicated. This is the part of the enzyme that recognizes the different types of substrate (e.g. pyruvate, 2-oxo acids, 2-oxoglutarate) so it makes sense that the three enzymes have different E₁ subunits. All the eukaryotic versions of the PDC E₁ subunit are related to the E₁ subunit from BOADH. So are most of the bacterial versions. Other bacterial versions of the PDC E₁ subunit are not related to those of the other enzymes (Schreiner et al. 2005).

The conclusion from the molecular data is that the pyruvate dehydrogenase complex evolved from the branched chain 2-oxo acid complex about 2 billion years ago. Subsequently, in some bacterial lineages a different E₁ subunit replaced the one that's homologous to the BCOADH subunit. The α-proteobacteria and cyanobacteria lineages that gave rise to mitochondria and chloroplast respectively, retained the PDC E₁ subunit that is related to BCOADH enzymes. This explains the eukaryotic versions of PDC.

1. This is a common theme in the evolution of metabolic enzymes. The evidence suggests strongly that amino acid metabolism is more ancient than most carbohydrate metabolism.

Schreiner, M.E., Fiur, D., Holatko, J., Patek, M. and Eikmanns, B.J. (2005) E1 enzyme of the pyruvate dehydrogenase complex in Corynebacterium glutamicum: molecular analysis of the gene and phylogenetic aspects. J Bacteriol. 187:6005-18.

Schnarrenberger, C. and Martin, W.. (2002) Evolution of the enzymes of the citric acid cycle and the glyoxylate cycle of higher plants. A case study of endosymbiotic gene transfer. Eur J Biochem. 269:868-83.

Some Bacteria Don't Need Pyruvate Dehydrogenase

Recall that the pyruvate dehydrogenase complex catalyzes the conversion of pyruvate to acetyl-CoA. This is an important reaction in all living cells because acetyl-CoA is required for fatty acid synthesis. The reaction is important in animals because acetyl-CoA enters the citric acid cycle where it is broken down to carbon dioxide and the energy is captured by the mitochondrial electron transport system in the form of ATP. This step isn't so important in most bacteria because they don't have a citric acid cycle. Most species can also save the two carbon atoms of the acetyl group in acetyl-CoA and use them to build carbohydrates such as glucose. Animals can't do this.

You would think that the pyruvate dehydrogenase complex (PDC) must be ubiquitous since it catalyzes such an important reaction. Not so. PDC is the only enzyme in eukaryotes but some bacteria have another enzyme that can make acetyl-CoA. As you might expect, the bacteria that gave rise to mitochondria do have a PDC that's related to the eukaryotic enzyme. This is because the genes were transferred from those bacteria to their eukaryotic hosts when the endosymbiotic event occurred about two billion years ago.

Lots of different kinds of bacteria have a similar PDC but some have a completely different enzyme called pyruvate:ferredoxin oxidoreducatase (PFOR) (E.C. 1.2.7.1) (Chabrière et al. 2001). This enzyme catalyzes a very similar reaction where pyruvate undergoes an oxidative decarboxylation yielding CO₂ and acetyl-CoA. The difference is that instead of having a complicated electron transport chain where electrons are passed to lipoamide, FAD⁺, and finally NAD⁺ [Pyruvate Dehydrogenase Reaction], the PFOR reaction is much simpler. Here electrons are transferred to ferredoxin, a small iron-containing protein.

The structure of pyruvate:ferredoxin oxidoreductase has been worked out from a combination of X-ray diffraction data and electron microscopy, just as we saw with the pyruvate dehydrogenase complex [The Structure of the Pyruvate Dehydrogenase Complex]. The structure of one such enzyme, from the bacterium Desulfovibrio vulgaris, is shown in the figure above. This complex consists of eight copies of the enzyme (Garczarek et al. 2007). In other species a simple two-copy complex suffices.

Ferredoxin is a cofactor in many biochemical reactions. As a general rule, enzymes that use ferredoxin are more ancient than enzymes that involve NAD⁺ as a cofactor. Ferredoxin metabolism doesn't need oxygen and the available evidence suggests that oxygen wasn't present in the ancient atmosphere. Modern bacteria that use pyruvate:ferredoxin oxidoreductase (PFOR) instead of the pyruvate dehydrogenase complex (PDC) are capable of anaerobic growth (without oxygen).

The structure of many ferredoxins have been solved. The one shown on the left is from Pseudomonas aeruginosa. It's a typical example (Giastas et al. 2006). The protein is quite small and most ferredoxins contain two iron-suflur (Fe-S) complexes. These are box-like structures formed from iron molecules (red) and sulfur molecules (yellow). They are bound to the protein through the sulfhydyl groups of the amino acid cysteine. Electrons are carried by the iron ions.

Fe³⁺ + e^- → Fe²⁺

There's another important reason why PFOR is important in some bacteria. Look at the PDC reaction shown above. The arrow points in one direction indicating that this reaction is essentially irreversible. It can't be used to fix carbon dioxide by combining it with the acetyl group to make pyruvate. That's not true of the much simpler PFOR reaction. In fact, the reverse reaction is the main CO₂ fixing reaction in many photosynthetic bacteria and in methanogens (bacteria that use methane as a carbon source).

But we're getting distracted. The point is that the pyruvate dehydrogenase complex probably arose late in evolution after photosynthetic bacteria had transformed the atmosphere into one that contained significant levels of oxygen. Where did such a complicated protein complex come from?

Chabriere, E., Vernede, X., Guigliarelli, B., Charon, M.H., Hatchikian, E.C. and Fontecilla-Camps, J.C. (2001) Crystal structure of the free radical intermediate of pyruvate:ferredoxin oxidoreductase. Science 294:2559-63.

Garczarek, F., Dong, M., Typke, D., Witkowska, H.E., Hazen, T.C., Nogales, E., Biggin, M.D., and Glaeser, R.M..(2007) Octomeric pyruvate-ferredoxin oxidoreductase from Desulfovibrio vulgaris. J Struct Biol. 2007 Feb 17; [Epub ahead of print] .

Giastas, P., Pinotsis, N., Efthymiou, G., Wilmanns, M., Kyritsis, P., Moulis, J.M., and Mavridis, I.M..(2006) The structure of the 2[4Fe-4S] ferredoxin from Pseudomonas aeruginosa at 1.32-Å resolution: comparison with other high-resolution structures of ferredoxins and contributing structural features to reduction potential values. J. Biol. Inorg. Chem. 11:445-58.

Killer Cellphones Destroy Bees

 
Friday's Urban Legend: Probably FALSE

An article in our local newspaper (The Toronto Star) suggests a link between the mass kill off of bees and cellular phones [Cellular phone uses linked to bee deaths]. A similar report appeared in The Independent in the UK [ Are mobile phones wiping out our bees?].

Here's the problem. There are reports in Canada and the United States of disappearing honey bees. Apparently, entire colonies are being abandoned. The phenomenon is somewhat localized. In Canada, for example, excessive bee loss is only reported in central British Columbia and the Niagara peninsula in Ontario. The phenomenon is called colony collapse disorder.

If the bee disappeared off the surface of the globe, then man would only have four years of life left.
.... Albert Einstein

This quote appears in several newspaper articles and on many blogs. Snopes is on to it and so far there's no proof that Einstein ever said this [Einstein on bees].We are told that "German researchers" have linked cellphone radiation to the disappearance of bees. The business reporter checked with Martin Weatherall to see if this is correct. Who is Martin Weatherall, you might ask?

Weatherall, a retired Toronto police officer who was forced out of his Woodstock, Ont., home after high levels of radio waves from nearby hydro-electric poles and cellphone towers made him electro-hypersensitive, is better able than most to understand the German study, which shows that bees refuse to return to their hive when cellphones are placed nearby.

Near the end of the story in the Toronto Star the reporter also checks with Ernesto Guzman, an expert on bees at the University of Guelph in Ontarion, Canada. Guelph is one of the top schools in veterinary medicine and agriculture.

Despite the new German research, bee researchers remain skeptical of the impact of radio waves on bees. They claim it is just one of several theories that include global warming and genetically modified crops.

"All of these are speculation. They deserve to be investigated. They are good hypotheses, some of them. Others are out of reality, in my opinion," said Ernesto Guzman, associate professor with the University of Guelph's department of environmental biology.

Guzman, a specialist in bee research, says he believes stress is the major factor in the situation south of the border while in Canada a combination of poor weather on fall food supply levels and an influx of mites is the likely cause.

Personally, I will take Guzman's word over that of a retired police officer suffering from "electro-sensitivity." If I were writing the headline it would be "Cellphone link to bee deaths discredited by expert." I guess it all depends on how you want to frame spin the article.

Orzel Is Confused

 
On his blog Uncertain Principles, Chad Orzel posted on "framing" [The Final Word on Framing. He said,

That's a thought, but I think the answer is much simpler: PZ and Larry Moran are not primarily interested in promoting science.

"That's crazy," you say. But here it is from the horse's mouth, Larry Moran in Chris Mooney's comments:

I think religion is the problem and I'll continue to make the case against religion and superstition. One of the many ways where you and Nisbet go wrong is to assume that people like PZ, Dawkins, and me are primarily fighting for evolution. That's why you argue that in the fight to save evolution it's "wrong" (e.g., not part of your frame) to attack religion.

When are you going to realize that our primary goal in many cases is to combat the worst faults of religion? Asking us to stop criticizing religion is like asking us to give up fighting for something we really care about. That's not "framing," it's surrender.

That's the beginning and end of the problem. The entire problem with "framing" is that Nisbet and Mooney are looking for the best way to promote science, while PZ and Larry are looking for the best way to smash religion. The goals are not the same, and the appropriate methods are not the same-- in particular, Nisbet and Mooney argue that the best way to promote science would be to show a little tact when dealing with religious people, and that runs directly counter to the real goals of PZ and Larry.

It's not a simple as that Chad. I try to do both things. I try to write about science with the hope that I'm telling people something they don't know. If you would take the time to look at my blog I think you might see the occasional posting on science-related topics. Religion isn't mentioned.

On the other hand, there are times when I post about the conflict between rationality and superstition. I think there's a problem there and religion is a big part of it. Quite frankly, I don't find the arguments of the Theistic Evolutionists the least bit effective. Why should I ignore them when they spout their silliness?

Telling me that I should not criticize religion because it's not helping science education is just nonsense. It's like telling me to abandon something I feel very strongly about just because you don't like it. If that's what framing is all about then I'm not interested.

The problem with the framers is that they get terribly confused about issues. For some reason they think I'm a one dimensional person who's only interest is science education. They think that when I criticize superstitious nonsense I must always be wearing my science education hat. That's why they tell me and Dawkins and PZ not to criticize religion if we're trying to educate people about science.

Well, I got news for them. We are involved in several issues. One of them is teaching science. One of them is fighting superstition. There are others. Don't tell me not to fight superstition because I should only be concerned about science education. I'm concerned about both. In an ideal world people would understand science and reject superstition. I'd like to work toward that goal.

New Ways of Looking at Evolution

 
John Logsdon over at Sex, Genes, and Evolution recommends a new book, The Origins of Genome Architecture by Michael Lynch. John also points us to a review article by Lynch [The Origins of Eukaryotic Gene Structure]. I second both recommendations. Read the article. Buy the book.

Here's a quotation from the article by Lynch,

Despite the enormous progress in molecular genetics over the past 50 years, no general theory for the evolution of the basic architectural features of genes has been formulated. Many attempts have been made to explain the features of genes, genomes, and genetic networks in the context of putatively adaptive cellular and/or developmental features, but few of these efforts have been accompanied by a formal evolutionary analysis. Because evolution is a population-level process, any theory for the origins of the genetic machinery must ultimately be consistent with basic population-genetic mechanisms. However, because natural selection is just one of several forces contributing to the evolutionary process, an uncritical reliance on adaptive Darwinian mechanisms to explain all aspects of organismal diversity is not greatly different than invoking an intelligent designer.

Some of you will probably see why I like this guy! He warns against "uncritical reliance on adaptive Darwinian mechanisms."

This paper represents a first step toward the formal development of a general theory for the evolution of the gene that incorporates the universal properties of random genetic drift and mutation pressure. Although the ideas presented are unlikely to be correct in every detail, at a minimum they serve as a null model. For if verbal adaptive arguments are to provide confident explanations for any aspect of gene or genomic structure, something must be known about patterns expected in the absence of selection. This is a significant challenge because at this point it is difficult to reject the hypothesis that the basic embellishments of the eukaryotic gene originated largely as a consequence of nonadaptive processes operating contrary to the expected direction of natural selection. A significant area of future research will be to take these observations on gene and genome complexity to the next level, to evaluate whether natural selection is a necessary and/or sufficient force to explain the evolution of the cellular and developmental complexities of eukaryotes.

Everyone needs to start paying attention. Random genetic drift is just as important for evolution as natural selection. That's not speculation. As far as I'm concerned, it's hard incontrovertible fact.

One of the "new ways" of looking at evolution is to consider mutation pressure, loosely defined as differences in the frequency of mutation. I'm not a big fan of this but it does emphasize that modern evolutionary theorists are thinking outside the Darwinian box—not surprising since Darwin died 125 years ago (today). I prefer mutationism, which is a way of emphasizing the imprtant role of mutation in directing evolution. Mutationism and mutation pressure are not the same thing.

Haldane's Dilemma

This is very interesting. Dembski has teamed up with Walter ReMine, demonstrating once again that the old addage "opposites attract" does not apply to kooks.

ReMine has an article on Uncommon Descent where he pushes his usual whine about evil scientists and how their world-wide conspiracy has kept him from revealing the fatal flaw in evolution [Evolutionist withholds evidence on Haldane’s Dilemma]. I can see how similar this is to Intelligent Design Creationism.

Some of you may not be familiar with the so-called "dilemma" of Haldane. Fortunately, ReMine provides a nice short summary.

For many years I have publicly claimed Haldane’s Dilemma is a major unsolved problem for evolution. A problem so severe it threatens macroevolution as a “fact” and evolutionary genetics as an empirical science. The problem, briefly, is that evolutionary geneticist, J.B.S. Haldane (1957), discovered an important argument that limits the speed of evolution. Under his calculations, an ape-human-like population, given a generous ten million years, could substitute no more than 1,667 beneficial mutations — which, according to evolutionary geneticists, are each typically a single nucleotide. All the human adaptations within that time would have to be explained with this small number of substitutions. For more information, see here: Haldane's Dilemma.

That's it. Fifty years ago J.B.S. Haldane did a quick calculation suggesting that if you make certain assumptions (now shown to be inaccurate) then you could only fix 1,667 beneficial human mutations in 10 million years. Apparently ReMine thinks this is way too little evolving, even if all it has to do is produce the likes of him and Dembski.

We don't need to thrash out why ReMine is wrong. That's been done many times. What's interesting about this is the Wikipedia article that ReMine wrote. Go there right now and take a look because it won't look like that for long now that ReMine has let the cat out of the bag. Oops! It's not on Wikipedia it's on another Wiki called ResearchID.org. My goof—thanks to Torbjörn Larsson for pointing this out. The real Wikipedia article [Haldane's dilemma] is pretty good. So now the only reason for taking note of this is the fact that ReMine is being promoted by Dembski. That's hardly news. Move along. There's nothing to see here.

For all you talk.origins fans, I found a little bit of history when I did the research for this article. Follow this link to a message from Saint Andrew (you know who that is). It's about a 1995 post from Ted Holden (yes, the famous Ted Holden who coined the term "Howler monkeys") defending Walter ReMine. Proving once again that kooks will recognize each other.

The picture of ReMine is from the video of a lecture on his book The Biotic Message. You can only watch a few minutes but that's enough. He does a fine job of spining "framing" his message for an audience of true believers.

[If you mention his name, he will come.]

Charles Darwin Died in 1882

 
In honor of Charles Darwin, who died on this day, I'm posting the opening paragraphs of a manuscript that might eventually be a book called Evolution by Accident.

I approached Westminster Abbey from the south side, crossing Abingdon Street in front of the Houses of Parliament. There was a long line of tourists in front of the ticket window and, not wanting to waste a beautiful Spring day, I decided to do a bit of exploring before joining the queue.

An old three story building caught my eye. It was the Jewel Tower, built 650 years ago to house the treasures of King Edward III. The Jewel Tower is all that remains of the medieval Palace of Westminster that was mostly destroyed by fire in 1834. The Houses of Parliament and Big Ben off to my left were built to replace the original palace—they look old but they have "only" been there for 175 years.

Going behind the Jewel Tower I spot the remains of the old moat and walls that used to surround Westminster Palace. They don’t serve any purpose now since they are well below ground level and, besides, Abingdon Street cuts right through the place where the wall and moat used to protect the old palace buildings.

I cross the street by Victoria Tower at the south-west corner of the Houses of Parliament and enter Victoria Tower Gardens. According to the medieval map in the Jewel Tower, this used to be in the middle of the Thames and there was a quay for loading and unloading boats along the edge of the palace where Victoria Tower now stands. The park is quiet and peaceful at this time of day. I imagine it gets more traffic at lunch time. The Thames is also quiet, but muddy. I watch a family of ducks swim by.

The object of my pilgrimage was inside Westminster Abbey and it was time to return to the entrance. Fortunately, the long line had dissipated and I was able to purchase my ticket (£2) after a short wait. The designated route takes you through the Great North Door where you enter the Transept. Turning left, I follow the other tourists as we are herded around the back of the Abbey through the rooms behind the alter. We pass the tombs of Queen Mary the First (1516-1558), Queen Elizabeth the First (1533-1603), and Mary, Queen of Scots (1542-1587) in the Lady Chapel. We stop to admire the shrine of Saint Edward the Confessor (1002-1066).

I’m getting impatient but I can’t move any faster because of the crowd of tourists. Eventually we wind around the Monastery and finally enter the Nave. Ignoring the monument to Winston Churchill (1874-1965) and hardly bothering to look up and admire the high ceiling, I head for the back left corner where I can see the statue of Isaac Newton (1643-1727). This is the same statue that plays such an important role in the Da Vinci Code but today I’m not interested in Newton or his orb. It takes me only a few seconds to find the marked stone on the floor. I’m standing on the grave of Charles Robert Darwin.

I can picture the scene on Wednesday, April 26, 1882—a grand funeral attended by all of London’s high society and the leading intellectuals of the most powerful nation in the world. Darwin would not have been pleased. He wanted to be buried quietly in the Downe cemetery with his brother Erasmus and two of his children. Darwin's family was persuaded by his friends Galton, Hooker, Huxley and the President of the Royal Society, William Spottiswoode, that, for the sake of England, Darwin should be laid to rest in Westminster Abbey. As Janet Browne writes in her biography of Charles Darwin, "Dying was the most political thing Darwin could have done."²

Looking around I can see the tombs of two of the scientists who were Darwin’s pallbearers, Joseph Hooker and Alfred Wallace. (Another pallbearer, Thomas Henry Huxley, is buried elsewhere.) Nearby are the final resting places of a host of famous scientists; Kelvin, Joule, Clerk-Maxwell, Faraday, Herschell, and Sir Charles Lyell. (Lyell was Darwin’s hero and mentor. We are told that Darwin’s wife Emma wished he were buried closer to Lyell.)

I am not overly sentimental but this visit has a powerful effect. I think Charles Darwin is the greatest scientist who ever lived—yes, even greater than Sir Isaac Newton whose huge statue overshadows Darwin’s humble marker in the floor. Natural selection is one of the greatest scientific ideas of all time. Darwin discovered it and he deserves enormous praise for his achievement. But Charles Darwin died on April 19, 1882 and that was a long time ago.

Temple Universit Students Respond

 
Last week I posted an article about Intelligent Design Creationists giving a talk at Temple University. I wondered what the students must have been thinking to invite two Young Earth Creationists (Marcus Ross, Paul Nelson) to come and talk to them as part of a series entitled: DECIDE FOR YOURSELF: Evolution and Intelligent Design.

Two Temple University students who attended the event have now responded. Both choose to remain anonymous. You can read their comments at [Marcus Ross, Michael Behe, and Paul Nelson at Temple University].

Here are some teasers ..

To start, your judgmental and self-righteous words have proven to me that your whole position is without credibility as you refused to attend Temple's event.

and .....

Because you chose not to participate, is it really right to take potshots at students from the web? Are you in a superior position professionally, educationally, or morally to condemn the students and therefore the other professional educators under whose approval and encouragement the students are working? Your intolerant conceit is more disagreeable than the students' supposed ignorance.

Gee, I wonder what they "decided for themselves" at the lectures? Anyone wanna take a wild guess?

Nobel Laureate: Aaron Klug

 

The Nobel Prize in Chemistry 1982.



Aaron Klug (1926- ): "for his development of crystallographic electron microscopy and his structural elucidation of biologically important nucleic acid-protein complexes"

Aaron Klug won the Nobel Prize in 1982 for his work on a special technique for solving the structures of large molecules that can't be crystallized. He used it to determine the structure of the nucleosome. Here's how Klug's contribution is described in the presentation speech.

Large molecular aggregates can seldom be obtained in a form which allows structural determination by X-ray diffraction. The investigator who has been awarded with this year's Nobel Prize in chemistry, Aaron Klug, has developed a method to study the structure of molecular aggregates from biological systems. His technique is based on an ingenious combination of electron microscopy with principles taken from diffraction methods. Electron microscopy has long been used to depict the structural components of the cell, but its power of resolution is after, limited by a lack of contrast in the picture. Klug has shown that even picture; seemingly lacking in contrast may contain a large amount of structural information, which can be made available by a mathematical manipulation of the picture.

With this technique, in combination with other methods of structural chemistry, Klug has inter alia investigated viruses and chromatin of the cell nucleus. His virus studies have illuminated an important biochemical principle, according to which the complicated molecular aggregates in the cell are formed spontaneously from their components. The chromatin investigations have provided clues to the structural control of the reading of the genetic message in DNA. In a long-term perspective they will undoubtedly be of crucial importance for our understanding of the nature of cancer, in which the control of the growth and division of cells by the genetic material no longer functions.

Klug started working on tobacco mosaic virus in 1954 when be began a collaboration with Rosalind Franklin who had just abandoned DNA. Klug and Franklin remained close associates until she died a few years later.

Klug solved the structure of TMV using X-ray diffraction but this proved inadequate for other large structures. In order to solve the structures of more complex viruses (e.g., bacteriophage T4) and chromatin, Klug turned to high resolution electron microscopy. He developed techniques for assembling and refining multiple images with the aid of complex computer programs. Basically, he was able to solve the three dimensional shape using multiple two dimensional images as shown in the diagram (right) from his Nobel Lecture.

Klug's work has been modified an improved over the years. Today the electron microscopic images are much better and special low temperature electron microscopes (cryo-EM) can be used to obain images from material that would be destroyed at normal temperature. The enormous increase in computing power and modern software have led to the solution of many complex structures such as the pyruvate dehydrogenase complex.

The Structure of the Pyruvate Dehydrogenase Complex

 
The pyruvate dehydrogenase complex catalyzes the reaction that converts pyruvate to acetyl-CoA with the release of CO₂. The reaction is coupled to the reduction of NAD⁺ to NADH₂ [Pyruvate Dehydrogenase Reaction]. The three components of the complex, E₁, E₂, and E₃ catalyze different steps.

The size of the pyruvate dehydrogenase complex is enormous. It is several times bigger than a ribosome. In bacteria these complexes are located in the cytosol and in eukaryotic cells they are found in the mitochondrial matrix. Pyruvate dehydrogenase complexes are also present in chloroplasts.

The eukaryotic pyruvate dehydrogenase complex is the largest multienzyme complex known. The core of the complex is formed from 60 E2 subunits arranged in the shape of a pentagonal dodecahedron (12 pentagons joined at their edges to form a ball). This shape has 20 vertices and each vertex is occupied by an E2 trimer. Each of the E2 subunits has a linker region projecting upward from the surface. This linker contacts an outer ring of E1 subunits that surround the inner core. The linker region contains the lipoamide swinging arm.

The outer shell has 60 E1 subunits. Each E1 enzyme contacts one of the underlying E2 enzymes and makes additional contacts with its neighbors. The E1 enzyme consists of two α subunits and two β subunits (α2β2) so it is considerably larger than the E2 enzyme of the core. The E3 enzyme (an α2 dimer) lies in the center of the pentagon formed by the core E2 enzymes. There are 12 E3 enzymes in the complete complex corresponding to the 12 pentagons in the pentagonal dodecahedron shape. In eukaryotes, the E3 enzymes are associated with a small binding protein (BP) that’s part of the complex.

The model shown above has been constructed from high resolution electron microscopy images of pyruvate dehydrogenase complexes at low temperature (cryo-EM) (below). In this technique, a large number of individual images are combined and a three-dimensional image is built with the help of a computer. The model is then matched with the structures of any of the individual subunits that have been solved by X-ray crystallography or NMR.

A similar pyruvate dehydrogenase complex is present in many species of bacteria although some, such as gram negative bacteria, have a smaller version where there are only 24 E2 enzymes in the core. In these bacteria, the core enzymes are arranged as a cube with one trimer at each of the 8 vertices. The E2 subunits of the two different bacterial enzymes and the eukaryotic mitochondrial and chloroplast versions are all closely related. However, the gram negative bacterial enzymes contain E1 enzymes that are unrelated to the eukaryotic versions.

So far, it has not been possible to grow large crystals of the entire pyruvate dehydrogenase complex on Earth. Experiments were undertaken to grow crystals on the International Space Station where the absence of gravity might have led to better results. Unfortunately, none of the esperiments were successful so, for the time being, the best model of the pyruvate dehydrogenase complex is the one constructed from the cryo-EM images.


[This is a slightly modified version of material in Horton et al. (2006) Principles of Biochemistry 4th ed.©L.A. Moran and Pearson/Prentice Hall]

Pyruvate Dehydrogenase Reaction

 
Pyruvate dehydrogenase catalyzes the conversion of pyruvate to acetyl-Coenzyme A (acetyl-CoA). The reaction is coupled to the reduction of NAD⁺ to NADH. The reaction is an example of an oxidative decarboxylation since the other product is carbon dioxide (CO₂). [Pyruvate] [Fritz Lipmann and Coenzyme A]

Acetyl-CoA is subsequently used up in the citric acid cycle and in fatty acid synthesis.

This is a very complicated reaction. It turns out that the enzyme pyruvate dehydrogenase is actually a complex of several different activities. From now on I'll refer to it as the pyruvate dehydrogenase complex (PDC).

The first step in the reaction is the decarboxylation step and it requires a special cofactor called thiamine pyrophosphate (TPP). This is vitamin B₁ and it explains why that vitamin is essential. Carbon dioxide is released in this step and the remaining 2-carbon fragment of pyruvate is attached to TPP. This part of the reaction is catalyzed by a part of PDC composed of E₁ subunits.

In the next step, the 2-carbon fragment is transferred to a "swinging arm" composed of a lipid arm (blue zigzag) and a head containing two sulfur (S) atoms. The swinging arm actually swings to carry the red acetyl group from one active site in the complex to another. The second site is where the acetyl group is attached to CoA. This part of the reaction is carried out by the E₂ subunits in the complex.

The swinging arm carries excess electrons from the previous reaction in the form of two -SH groups. The next site visited by the swinging arm is the site where electrons are passed to another cofactor called FAD. This is the dihydrolipoamide dehydrogenase activity and it's the E₃ subunits that do the job. Electrons are then passed from FADH₂ to NAD⁺ to produce NADH₂.

The complete reaction is a classic example of an electron transport chain involving three groups: the lipoamide head of the swinging arm, FAD, and NAD⁺. In the next article we'll look at the structure of the pyruvate dehydrogenase complex. It's one of the largest multienzyme complexes found in living cells.