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.

Recourse to the Miraculous is Always a Regressive, Obfuscating Move

 
The same issue of Skeptical Inquirer that contained the Michael Ruse article [Appeasers and Other Atheists] also has an article by Frederick Crews.

Crews, F. (2007) Follies of the Wise. Skeptical Inquirer March/April 2007 pp.27-31.

Crews addresses the same issue as Ruse; namely whether it's a good idea to distinguish between Intelligent Design Creationists and Theistic Evolutionists. However, he delves deeper into the issue that Ruse does. I'm tempted to say that Crews is being more scholarly than Ruse.

Whenever we (e.g., PZ, Dawkins etc.) try to make the case that Theistic Evolution is just as fuzzy-headed as Intelligent Design Creationism we are accused of over-stepping the limits of science. While everyone recognizes that scientists must practice methodological naturalism, there seem to be lots of people who don't know what that is. They seem to think that it's okay to believe in miracles and still brag about being scientific. I've tried to point out the inconsistencies in such a position in my essay [Theistic Evolution: The Fallacy of the Middle Ground]. As Crews says below, "recourse to the miraculous is always a regressive, obfuscating move." This applies to Intelligent Design Creationism of course, but it also applies to the Theistic Evolution of Ken Miller, Francis Collins, and Simon Conway-Morris. I just don't see how atheists can dismiss the miracles of Dembski, Denton, and Behe while accommodating the miracles of Miller, Collins, and Conway-Morris. That makes no sense to me.

Crews takes a different approach. He argues that metaphysical naturalism is a valid and rational extension of methodological naturalism. This is contrary to Ruse and to the people at NCSE (e.g., Eugenie Scott). I present the Crews argument below. Let me know what you think. Personally I agree with him, even though I'm prepared to argue that most of the so-called "science" in books by Theistic Evolutionists is in violation of methodological naturalism not just metaphysical naturalism.

... some scientists and philosophers who are privately indifferent or hostile to transcendent claims nevertheless seek an accommodation with them. They do so from the best of motives, in order to stem the infiltration of bumpkin "creation science" or its slick city cousin "intelligent design," into biology curricula. Their hope is to show that scientific research and education have no bearing on issues of ultimate meaning and hence needn't be feared by the pious. To that end, they emphasize that science exemplifies only methodological naturalism, whereby technical reasons alone are cited for excluding nonmaterial factors from reasoning about causes and effects. Hence, they insist, the practice of science doesn't entail metaphysical naturalism, or the atheist's claim that spiritual causation is not only inadmissible but altogether unreal.

In one sense this is an impregnable argument. Even when science is conducted by ardent believers, it has to disregard theological claims because those claims typically entail no unambiguous, real-world implications, much less quantitative ones, that might be tested for their supportive or falsifying weight. The allegation that God was responsible for a given natural fact can't be either established or refuted by any finding; it is simply devoid of scientific interest. And thus it is true enough that scientists stand under no logical compulsion to profess metaphysical naturalism.

Any God worthy of the name has to be capable of miracles, and each of the great Western religions attributes a number of very special miracles to their conception of God. What can science say about a miracle? Nothing. By definition, the miraculous is beyond explanation, beyond our understanding, beyond science.

Ken Miller in "Finding Darwin's God" p. 239Quite obviously, however, trust in the supernatural does get shaken by the overall advancement of science. This is an effect not of strict logic, but of an irreversible shrinkage in mystery's terrain. Ever since Darwin forged an exit from the previously airtight argument of design, the accumulation of corroborated materialist explanations has left the theologian's "God of the gaps" with less and less to do. An acquaintance with scientific laws and their uniform application is hardly compatible with faith-based tales about walking on water, a casting out of devils,and resurrection of the dead.

Metaphysical naturalism may be undiplomatic, but it is favored by the totality of evidence at hand. Only a secular Darwinian perspective, I believe, can make general sense of humankind and its works. Our species appears to have constituted an adaptive experiment in the partial and imperfect substitution of culture for instinct, with all the liability to self-deception and fanaticism that such an experiment involves. We chronically strain against our animality by inhabiting self-fashioned webs of significance—myths, theologies, theories—that are more likely than not to generate illusory and often murderous "wisdom." That is the price we pay for the same faculty of abstraction and pattern drawing that enables us to be not mere occupiers of an ecological niche but planners, explorers, and, yes, scientists, who can piece together facts about our world and our own emergence and makeup.

Here it may be objected that myths, theologies, and theories themselves, as nonmaterial things that can nevertheless set in motion great social movements and collisions of armies, confound a materialist or metaphysically naturalist perspective. Not at all. We materialists don't deny the force of ideas; we merely say that the minds precipitating them are wholly situated within brains that, like everything else about which we possess some fairly dependable information, seem to have emerged without any need for miracles. Although it is not a provable point, it is a necessary aid to clear thought, because now that scientific rationality has conclusively shown its formidable explanatory power, recourse to the miraculous is always a regressive, obfuscating move.

Pyruvate

Pyruvate is a very important molecule in living cells. It was Monday's Molecule #22. It's important because it's one of the essential 3-carbon (3C) intermediates in biochemical pathways. It's required in both biosynthesis and degradation pathways. If you only have to know a few molecules in the cell then this one should be near the top of your list.

Let's start by learning a little bit of organic chemistry. The simplest organic molecule with only two carbon atoms is called ethane (CH₃CH₃). The one with three carbons is propane and the one with four is butane. The alcohols are called ethanol, propanol, and butanol respectively. The acids are ethanoic acid (CH₃COOH), propanoic acid (CH₃CH₂COOH), and butanoic acid (CH₃CH₂CH₂COOH). Ethanoic acid is more commonly known as acetic acid because it's found in vinegar and the Latin word for vinegar is acetum.

Pyruvate can also be called pyruvic acid. In a minute I'll explain why we call it pyruvate instead. It's related to propanoic acid (CH₃CH₂COOH) except that it has an extra oxygen on the middle carbon. The -C=O group is called a keto group and molecules that have it are ketones.

The proper chemical name for pyruvate is 2-oxopropanoic acid because it's propanoic acid with an extra oxygen (oxo-) on carbon atom #2. Keto acids usually have trivial names that aren't related to the names of the simple organic molecules and that's why pyruvate is the name everyone uses. The reason why keto acids are common in biochemistry is because they are quite reactive.

Acids are compounds that can easily give up a proton (H⁺). Protons are what makes an acid an acid. The more protons you have in solution the more acidic the solution will be. The term pH refers to the inverse of the concentration of H⁺. The lower the pH the higher the concentration of protons.

Pyruvic acid is an acid because when it's dissolved in water the proton from the carboxylate (-COOH) group dissociates leaving the negatively charged pyruvate and a free proton. The three components exist in equilibrium—that's what the double arrows mean. At any given time there will always be some pyruvic acid, some pyruvate, and some protons. The concentrations won't change because the dissociation/association reactions are at equilibrium.

The relative concentrations of pyruvic acid and pyruvate at equilibrium depend on the properties of the molecule and the conditions inside the cell. In this particular case we know for certain that there's very little pyruvic acid inside the cell. Almost all of the molecules are in the form of pyruvate. Pyruvate is the biologically significant molecule and that's why biochemists always refer to these molecules as acetate, pyruvate, butyrate, etc.

In all species, pyruvate is required for the synthesis of the amino acid alanine. It's also required for the synthesis of 6-carbon (6C) sugars such as glucose. In fact, you can think of gluconeogenesis (glucose synthesis) as just a series of steps where two pyruvate molecules are joined to make one glucose molecule (3C + 3C → 6C).

Pyruvate itself is synthesized from simpler molecules in bacteria. One common pathway is to add a carbon from carbon dioxide to a 2-carbon acetate molecule (1C + 2C → 3C). In plants and bacteria the primary product of the carbon fixing cycle (Calvin cycle) is a 3-carbon compound called glyceraldehyde 3-phosphate. It is rapidly converted to pyruvate.

Pyruvate can be activated to a phosphorylated derivative called phosphoenolpyruvate (PEP). PEP is a high energy compound used as an energy source in many reactions. (It has considerably more energy than ATP.) The direct conversion shown in the diagram below is confined to bacteria. In eukaryotes the conversion follows an indirect pathway.

There are many other fates of pyruvate as shown above. Pathways leading to synthesis of additional amino acids go through oxaloacetate. Oxaloacetate is also one of the components of the citric acid cycle. The synthesis of lipids and fatty acids requires acetyl-coenzyme A or acetyl-CoA, which is made from pyruvate in a reaction catalyzed by pyruvate dehydrogenase (more about this later—it's the main theme of this series).

Most students first encounter pyruvate as the end product of glycolysis. Glycolysis is the pathway for breaking down glucose. It is the opposite of gluconeogenesis because a 6-carbon compound is degraded to two 2-carbon compounds (6C → 3C + 3C). Even though this is a minor pathway in most kingdoms, it is important in animals and, most especially, in mammals like us. This is why glycolysis has traditionally received so much attention in schools. That's about to change.

In some species the accumulation of pyruvate leads to other pathways. One of them is synthesis of lactate, which often serves as a temporary storage depot for 3-carbon compounds. Another is synthesis of ethanol, which involves chopping off one of the carbons in the form of carbon dioxide (CO₂) and excretion of ethanol. Humans love those species that excrete ethanol. Over several millennia humans have selected strains of yeast that do a very efficient job.

Nobody needs to memorize all the pathways involving pyruvate. Not even my biochemistry students. The point here is simply to illustrate the central importance of pyruvate so you'll see why it's something you should know about.

Of all the fates of pyruvate, the one that is most interesting is the conversion to acetyl-CoA. As mentioned above, acetyl-CoA is required for fatty acid synthesis but it also serves as the substrate for the citric acid cycle where the acetate part of pyruvate is fully oxidized to CO₂. Note that the reaction catalyzed by pyruvate dehydrogenase not only makes acetyl-CoA but also accomplishes the first step in the complete oxidation of pyruvate to 3 molecules of CO₂. The energy released in this breakdown is captured by NADH.

Dicumarol and Warfarin Inhibit Blood Clotting

 
Many of the blood coagulation factors are post-translationally modified in various ways. One of these modifications is unusual and it is only seen in these factors and a few other specialized proteins. This modification converts a specific glutamyl side chain to a γ-carboxyglutamyl derivative [Vitamin K].

The carboxylation reaction is catalyzed by vitamin K-dependent carboxylase and it is coupled to the conversion of vitamin K to its oxidized form. In order for the enzyme to modify additional factors, the oxidized form of vitamin K has to be converted back to the reduced form. Recall that vitamin K is an essential vitamin in animals. It can be obtained from plants or from intestinal bacteria.

Recycling of vitamin K is catalyzed by K reductase. The mechanism involves oxidation of two sulfhydryl (-SH groups) to form a disulphide bridge [Disulfide Bridges]. The carboxlase and reductase reactions are required for synthesis of prothrombin, protein C, Protein S, and Factors VII, IX, and X because these proteins must bind C²⁺ and the γ-carboxyglutamyl group is an excellent cheator of Ca²⁺.

A vitamin K deficiency means that the carboxylation reaction cannot proceed and this leads to accumulation of inactive clotting factors in the liver. Blood clots cannot form and severe hemorraging can lead to death.

The carboxylation of clotting factors can also be prevented by inhibiting the K reductase reaction. There are many drugs that inhibit this reaction. They are related to warfarin (left) [Monday's Molecule #19]. The best known ones are dicoumarol and coumarin. These drigs, especially warfarin, are used frequently to prevent clotting in patients who have suffered a stroke or otherwise have tendencies to exhibit thrombosis.

Since the drugs prevent synthesis of clotting fators, they take a few days to have an effect. They are usually administerd with heparin, which has an immediate effect on blood clot formation.

Wafarin was a common rat poison in the past since rats are very sensitive to inhibition of K reductase. After eating food laced with wafarin for several days, the rats would die of internal bleeding.

Appeasers and Other Atheists

 
Professors are under a lot of pressure. We have certain images that we need to cultivate in order to stay in the club. One of them is the image of a messy, disorganized, eccentric. I've got that one down pat.

I have four piles of reading material. There's the one on my bedside table for reading at night when I should be sleeping. There's a stack of papers and articles in my shoulder bag that I'm supposed to read on the train and subway. There are books on my desk at home and there's a huge pile of things on the desk in my office.

Since I started blogging, none of these piles are getting smaller.

Last night I finally got around to reading an article by Michael Ruse in the current issue of Skeptical Inquirer.

Ruse, M. (2007) Fighting the Fundamenalists: Chamberlain or Churchill? Skeptical Inquirer March/April 2007:38-41.

This is one of many articles in this special issue devoted to "Science, God, and (non)Belief."

Perhaps if I'd read the article sooner I might have anticipated the stance that Nisbet and Mooney would take in the framing debate. I actually thought the appeasers had learned their lesson. I thought they discovered last Fall that they can't stifle dissent. I was wrong. Ruse is singing the same old tune. The chorus goes like this, "Why can't we just get along?" The real message is, "Why don't you arrogant atheists just shut up and learn to think like an appeaser?"

The teaser on the Ruse article sets the tone for what's coming. He says,

We who think that biblical literalism has no place in science classrooms should be standing together and fighting ignorance and prejudice. Why then do those of us against creationism live in a house divided?

Well Michael, there are several reasons. One of them is that you are setting up the division yourself by trying to define the problem on behalf of everyone else.

I'm opposed to Biblical literalism, just like you. But I'm not necessarily opposed to keeping it out of the schools at all costs. That's just not a priority for many non-Americans. As a matter of fact, I'd like to bring it into the schools and get students to debate evolution and creationism in the classroom. So, right away you're starting with an assumption. You say I'm supposed to advocate fighting religion in American schools and defending the American Constitution. You also frame the debate in terms of fighting creationism while I prefer to think of the battle as a fight between rationalism and superstition. You've lost me before you even get to the opening paragraph.

(Later on we'll see that your version of "ignorance and prejudice" is differnt than mine so we can't even agree on that.)

Ruse then goes on to describe the problem as he sees it,

... at the moment, those of us against creationism live in a house divided. One group is made up of the ardent, complete atheists. They want no truck with the enemy, which they are inclined to define as any person of religious inclination—from literalist (like a Southern Baptist) to deist (like a Unitarian)—and they think that anyone who thinks otherwise is foolish.

Okay, let's stop here for a moment and ponder how Ruse is defining his opponents. I am one of those people and there's a lot of truth in what Ruse just wrote.

I do indeed think that religion is behind the anti-science movement. I think that religion is the problem, not creationism. Creationism is just one symptom of the anti-science, anti-intellectual, stance of the most fervent believers. Theistic evolution is another symptom of what I think is fuzzy religious thinking about science, albeit not as outrageous as believing in the literal truth of Genesis [Theistic Evolution: The Fallacy of the Middle Ground].

It's easy to see the silliness of the Young Earth Creationists; however, I find it difficult to see the difference between the Intelligent Design Creationism of a Michael Behe or a Michael Denton and that of Ken Miller, Francis Collins, or Simon Conway-Morris. They look very simlilar to me.

Michael Ruse doesn't have this problem,

The second group is made up of two subgroups. One has as members liberal Christians who think that evolution is God's way of creating .... The second subgroup contains those who have no religious beliefs but who think that one should collaborate with the liberal Christians against a shared enemy, and who are inclined to think that science and religion are compatible.

There's the rub. The appeasers are atheists who think that Theistic Evolution is compatible with science.

Ruse makes it clear that he disagrees with "ardent atheists." To his credit, he raises then dismisses the argument that "ardent atheists" should keep quiet because they provide aid and comfort to the enemy. Instead, he raises anther point. Ruse criticizes the atheists like Dawkins because of their lack of scholarship.

If I thought Dawkins and company were right, I would defend them one hundred percent and let the chips fall where they may. My real problem is one of scholarship, put simply, which is I guess what you would expect of a university professor like myself. I would be a lot more impressed with the ardent atheists if I felt that they were making a genuine effort to engage in dialog with those whom they criticize. I do not mean actual physical dialog, but at the least intense study of the claims of those against whom they fulminate. Take, for example, Richard Dawkins's The God Delusion, and his critiques of the various arguments for the existence of God. Why does he not acknowledge that few if any Christians have ever claimed that the proofs are the true reason for the belief in God?

Booooooring. We've heard this whining before. Why doesn't Ruse acknowledge that people like me and PZ have carefully read Finding Darwin's God, Life's Solution, and The Language of God? We've examined the arguments made by the Theistic Evolutionists and found them wanting. What more can we do? I'm not a mind reader. I can't guess what sort of secret "sophisticated" arguments they might have lying in reserve. They haven't told us.

Ken Miller, Francis Collins, and Simon Conway-Morris are among the leading proponents of Theistic Evolution. They're the people Ruse wants to ally with. They've told us exactly why they believe in God and why they think science is compatible with their religion. I'm not buying it. I seriously wonder whether Ruse does either but I guess we'll never know since, as his allies, they are immune to the kind of criticism leveled at Dawkins.

Have you ever thought about why you'll never hear Ruse criticizing Miller and Collins for their lack of scholarship? Can you say "hypocrite"?

Maybe PZ, Dawkins and I are wrong. Maybe there really are rational arguments that reconcile Christianity (and other religions) with science. Maybe the conflict that everyone talks about is imaginary and people like Francis Collins have already found the solution. Maybe, but I doubt it. That's not the point. If Ruse truly believes we are wrong then let him engage in debate instead of just falsely accusing us of sloppy scholarship.

Having ordained that the "ardent atheists" are not scholars, he summarizes his opinion of us like this.

I start to suspect that these people ... in their way are tarred with the same features of which they accuse the creationists. There is a dogmatism, a refusal to listen to others, a contempt for nonbelievers, a feeling that they alone have the truth, that is the mark of so many of the cults and sects that have sprung on American soil since the nation's founding.

Hmmm ... so we're no different than religious cults, eh? What's the solution?

Please God-or non-God—let us quit fighting among ourselves and get on with the real job that faces us.

Wow! For an appeaser you sure have a funny notion of how to stop fighting among ourselves. First you insult and demean us then you say we should get along. That's ridiculous.

When I disagree with someone I don't pull any punches. In that sense I'm no different that Michael Ruse. However, I don't then turn around and ask my opponent to give up the beliefs I've just trashed and join me in fighting another battle—especially one that they're not interested in. That would suggest I wasn't listening to a word they said. But that's exactly what Michael Ruse is doing.

We need to accept the fact that atheists disagree on the mild form of creationism called Theistic Evolution. Some of us oppose it on the grounds that the logic behind it is no different than the logic of Intelligent Design Creationism. Other atheists don't see a problem with Theistic Evolution because, according to them, science and religion are compatible. Fine. We can agree to disagree and have lots of fun debating it at the same time.

But please don't try to shut me up by calling for a big tent strategy against the more extreme creationists. That's the whole point of the Ruse article in spite of the brief disclaimer in the middle. From the opening teaser to the very last sentence, the take-home message is for all atheists to come together. But it's a very special kind of coming together, isn't it? Our side has to give up everything. That sort of coming together usually goes another name. It's called surrender.

So here's my message to the appeaser athiests. If you don't like what we say then by all means speak out. Challenge us. Debate us. Show us why you think Theistic Evolution is very different from Intelligent Design Creationism. Write an article comparing Nature's Destiny by Michael Denton and Life's Solution by Simon Conway-Morris. Tell us why you choose to ally with Conway-Morris but oppose an intelligent design creationist like Denton. Make your case with scholarship. But please, please, stop whining about the fact we disagree. That's not going to change anything.

(Are you listening Chris Mooney and Matt Nisbet? This applies to you as well. If you support Theistic Evolution then tell us why. Don't try and confuse the issue with talk of "framing." We all know about frames. It's just a fancy word for spin.)

Monday's Molecule #22

 
Name this molecule. This is very easy for any student who's ever taken a biochemistry course. The goal here is to show everyone else just how important this molecule is for understanding basic biochemistry.

As usual, there's a connection between Monday's molecule and this Wednesday's Nobel Laureate. This one's hard because the connection isn't obvious. (Hint: It's related to last week's molecule and Nobel Laureate.) The prize (free lunch) goes to the person who correctly identifies both the molecule and the Nobel Laureate. (Previous free lunch winners are ineligible for one month from the time they first won.)

Comments will be blocked for 24 hours. Comments are now open.

Play the DNA Double Helix Game

 


Warning! This is a lot harder than it looks! [Double Helix Game].

Human Anticoagulant Genes

 
One of the most important factors in anticoagulation is antithrombin III [Inhibiting Blood Clots: Anticoagulants]. The official name of this protein is serpin peptidase inhibitor and gene for antithrombin III is called SERPINC1 [GeneID=462]. The gene is located on chromosome 1 at q23-q25.1.

Deficiencies in antithrombin III cause thrombosis, or excess clotting. Dozens of different alleles are known. The defective proteins show a variety of effects including reduced binding to heparan sulfate, reduced binding to thrombin, and decreased stability [OMIM 107300]. In most cases the affected individuals contain only one copy of the mutant allele suggesting that both copies must be active for effective anticoagulant activity.

The other anticoagulant pathway requires thrombomodulin plus protein C and protein S. The gene for thrombomodulin is called THRM [GeneID=7056] and it is found on chromosome 20 at p11.2.

Mutations in THRM are associated with mild thrombosis and increased risk of myocardial infarction (heart attacks). People with this susceptibility are heterozygous for the mutant allele. Most alleles that have a physiological phenotype are recessive lethals resulting in late fetal deaths (spontaneous abortion). The defect is associated with the formation of excessive blood clots at the region where placental blood and maternal blood vessels are in close contact [OMIM 188040].

The gene for protein C is PROC [GeneID=5624] on chromosome 2 at q13-q14.

Deficiencies in protein C cause congenital thrombotic disease or thrombphilia (due to PC deficiency). The type patient ("propositus") and his family are described on the Online Mendelian Inheritance in Man entry for PROC [OMIM 176860].

Their propositus was a 22-year-old Caucasian male with recurrent thrombophlebitis complicated by pulmonary embolism. His 56-year-old father had thrombophlebitis with pulmonary embolism following a minor leg injury at age 24, a cerebrovascular accident at age 43, and a myocardial infarction at age 45. A paternal uncle had thrombophlebitis and recurrent pulmonary emboli dating from age 20. The paternal grandfather died abruptly at age 45. He had sustained a leg injury in a fall from a horse. While he was confined to bed, pulmonary infiltrates developed. These resolved, but on his first day out of bed he collapsed and died after taking a few steps. The paternal great-grandfather died unexpectedly of a cerebrovascular accident at age 61. The propositus, his father, and his paternal uncle showed levels of plasma protein C antigen (determined immunologically by the Laurell rocket technique) 38 to 49% of normal. Clinically unaffected members of the kindred had normal levels.

There are at least 25 known variants of PROC causing increased risk of thrombosis and heat attacks.

The gene for protein S is called PROS1 [GeneID=5627], located at the centromere of chromosome 3 (3p11.1-q11.2). Deficiencies in protein S produce symptoms very similar to those desribed for protein C deficiencies. As is the case with PROC mutants, PROS1 mutant alleles are dominant although the penetrance is less than 100%. What this means is that some people who are heterozygous don’t show any increased risk of thrombosis while others do. This suggests there are other factors that are required for thrombosis [OMIM 176880].

Blogger's Code of Conduct?

 
Tim O'Reilly is concerned about "civility" on blogs so he proposes a Blogger's Code of Conduct. Part of the code requires censoring comments and not allowing anonymous comments. I can't aggree to that. There are other things about the code that I disagree with.

If you follow the code you're supposed to put this sheriff's badge on your blog. I'm not going to follow the code and even if I were, the idea of advertising it with a sheriff's badge is offensive. It makes you look like a policeman.

If you're not going to follow the Blogger's Code of Conduct, this is what you're supposed to put on your blog.

This is an open, uncensored forum. We are not responsible for the comments of any poster, and when discussions get heated, crude language, insults and other "off color" comments may be encountered. Participate in this site at your own risk.

That's exactly the message I want you to hear. The only thing I censor is spam.

Nisbet & Mooney Reveal Their True Colors

As it turns out, this isn't about about framing at all. It's about religion. Here's an excerpt from an article published by Matthew C. Nisbet and Chris Mooney in tomorrow's Washington Post [Thanks for the Facts. Now Sell Them.].

If the defenders of evolution wanted to give their creationist adversaries a boost, it's hard to see how they could do better than Richard Dawkins, the famed Oxford scientist who had a bestseller with "The God Delusion." Dawkins, who rose to fame with his lucid expositions of evolution in such books as "The Selfish Gene," has never gone easy on religion. But recently he has ramped up his atheist message, further mixing his defense of evolution with his attack on belief.

Leave aside for a moment the validity of Dawkins's arguments against religion. The fact remains: The public cannot be expected to differentiate between his advocacy of evolution and his atheism. More than 80 percent of Americans believe in God, after all, and many fear that teaching evolution in our schools could undermine the belief system they consider the foundation of morality (and perhaps even civilization itself). Dawkins not only reinforces and validates such fears -- baseless though they may be -- but lends them an exclamation point.

So now we see what "framing" is all about. It's about conforming to the Nisbet & Mooney view of how we should combat superstition. According to them, Dawkins is bad, bad, bad.

Forget about the fact that Dawkins has done more to change the climate of the debate than Nisbet & Mooney have ever done with their appeasement policy. That dosen't matter. If you're a fan of "framing" then you've got to modify your opinion so you never disagree with anyone.

Well, phooey on that. No wonder "framing" has such a bad name.

We agree with Dawkins on evolution and admire his books, so we don't enjoy singling him out. But he stands as a particularly stark example of scientists' failure to explain hot-button issues, such as global warming and evolution, to a wary public.

Hmmm ... so scientists have failed to explain global warming and evolution to the general public? Well, silly them. They made the terrible mistake of speaking the truth, just like Richard Dawkins.

As we've seen during the framing debates on various blogs, Nisbet & Mooney seem to be incapable of making the distinction between explaining science and what you do with that knowledge. Evolutionists have done a good job of explaining evolution. If Nisbet & Mooney don't think this is true then I challenge them to come up with a better way of describing the science of evolutionary biology.

What they're upset about is the fact that a segment of the population doesn't buy the scientific explanation. That's true, but it doesn't matter how well you explain it to those people, they still won't accept it. They won't accept it even it's economically beneficial and leads to medical advances.

Why won't they accept it? Because it's against their religion. How do we change their minds? Part of the solution is to show them that their religion is false if it conflicts with science. This doesn't have anything to do with explaining the facts of science. It has to do with fighting superstition and anti-science attitudes.

Scientists excel at research; creating knowledge is their forte. But presenting this knowledge to the public is something else altogether. It's here that scientists and their allies are stumbling in our information-overloaded society -- even as scientific information itself is being yanked to center stage in high-profile debates.

Scientists have traditionally communicated with the rest of us by inundating the public with facts; but data dumps often don't work.

Wait a minute. Nisbet & Mooney are spinning so fast here it's hard to keep up. They start by criticizing Dawkins for promoting his opinion on religion and now they're switching to criticism of scientists who inundate the public with data dumps. Did they forget that this is the same Richard Dawkins who's sold several hundred thousand books like The Blind Watchmaker? That's a data dump? What about The Ancestor's Tale? Another data dump?

People generally make up their minds by studying more subtle, less rational factors. In 2000 Americans didn't pore over explanations of President Bush's policies; they asked whether he was the kind of guy they wanted to have a beer with.

So Richard Dawkins should concentrate on projecting the same image as George Bush, Jerry Flawell, or Ronald Regan? Matt, Chris, please tell me this is satirical comedy. You can't be serious.

So in today's America, like it or not, those seeking a broader public acceptance of science must rethink their strategies for conveying knowledge. Especially on divisive issues, scientists should package their research to resonate with specific segments of the public. Data dumping -- about, say, the technical details of embryology -- is dull and off-putting to most people. And the Dawkins-inspired "science vs. religion" way of viewing things alienates those with strong religious convictions. Do scientists really have to portray their knowledge as a threat to the public's beliefs? Can't science and religion just get along? A "science and religion coexistence" message -- conveyed in Sunday sermons by church leaders -- might better convince even many devout Christians that evolution is no real threat to their faith.

Oops. You guys haven't been listening, have you? Dawkins thinks that religion is the enemy (so do I). What you're suggesting isn't framing, it's surrender. You want Dawkins to give up his fight entirely and form an alliance with the very people he is opposing. Time for a reality check. You are so far off base, you're not even in the game.

Paul Zachary "PZ" Myers, a biology professor at the University of Minnesota at Morris, wrote on his blog, Pharyngula, that if he took our advice, "I'd end up giving fluff talks that play up economic advantages and how evolution contributes to medicine . . . and I'd never talk about mechanisms and evidence again. That sounds like a formula for disaster to me -- it turns scientists into guys with suits who have opinions, and puts us in competition with lawyers and bureaucrats in the media." Myers also accused us of appeasing religion.

Yet he misses the point. There will always be a small audience of science enthusiasts who have a deep interest in the "mechanisms and evidence" about evolution, just as there will always be an audience for criticism of religion. But these messages are unlikely to reach a wider public, and even if they do they will probably be ignored or, in the case of atheistic attacks on religion, backfire.

Someone's missing the point here and it sure ain't PZ. After decades of appeasement in America we have a situation where it's the only Western industrialized country in the world objecting to the teaching of evolution. What do Nisbet & Mooney propose to do about it? More of the same, that's what.

What is Dawkins doing about it? Pointing out that there's a hippo in the room. In the past six months since the publication of The God Delusion, we've made more progress than the Nisbet's & Mooney's of this world made in decades. The very fact that the appeasers have been forced to defend their failed strategy is proof of that.

More proof can be seen on television, newspapers, and magazines. All of a sudden people are talking about atheists and asking questions about religion. (Incidentally, Mooney could have gained a lot of credibility with me if he'd mentioned that PZ Myers is a columnist who writes for SEED magazine as well as being a blogger.)

We're not saying scientists and their allies should "spin" information; doing that would only harm their credibility. But discussing issues in new ways and with new messengers can be accomplished without distorting the underlying science. Good communication is by its very nature informative rather than misleading. Making complicated issues personally meaningful will activate public support much more effectively than blinding people with science.

I know spin when I see it and I see it clearly in the Nisbet & Mooney articles.

I wish they'd get their story straight. Are they complaining about how we scientists teach science or are they complaining about our opinions on other issues such as the influence of religion or what we should do about global warming? Who knows?

Oh, and by the way, who are the "new messengers" and what are Nisbet & Mooney going to do with the old ones? Do they honestly believe that their silly arguments are going to shut up Richard Dawkins and PZ Myers and all the rest of us who disagree with Nisbet & Mooney? Like that's going to happen.

One thing is clear. No matter how much you know about framing this isn't a question of whether you should be aware of the literature and the field. I mention this because many bloggers have criticised me for not being an expert on "framing." This isn't about framing. This is a straightforward disagreement over an important issue—is religion a problem? Nisbet & Mooney say no and that's why they're opposed to Dawkins. The fact that they couch this in terms of proper "framing" is intellectually dishonest. They're trying to "frame" this as a debate over who knows the most about "framing." Can you say "spin?"

The Demise of Scientific American

Yesterday one of my colleagues delivered a lecture on the cracking of the genetic code. I ended up discussing it with a student during the afternoon. That was an exciting time back in the early 1960's and as a teenager I followed the new biology in the pages of Scientific American. All the big names had articles in Scientific American.

Later on as a graduate student, a postdoc, and a young faculty member, I still looked forward to reading the monthly issue of Scientific American for accurate summaries of what was going on in science. But something happened in the 1990's. I started to see articles by scientists I'd never heard of even though they were writing on areas close to my interests. Furthermore, the quality of the articles was way below the standards set in previous decades. Often the authors were clearly promoting their own work and downplaying or ignoring the work of others. I started to lose confidence in Scientific American because I recognized that in my own areas of expertise the articles were no better than what you find in the tabloid science magazines. I assume this is true for all other disciplines as well.

I've criticized some of these articles in previous postings. For example, an article by Gil Ast on The Alternate Genome makes silly statements about basic molecular biology [Facts and Myths Concerning the Historical Estimates of the Number of Genes in the Human Genome]. Also see [Junk DNA: Scientific American Gets It Wrong (again)] and [The Hypocrisy of Scientific American].

[Duesberg has] proposed the hypothesis that the various American/European AIDS diseases are brought on by the long-term consumption of recreational drugs and/or AZT itself, which is prescribed to prevent or treat AIDS.
... from Peter Duesberg's website
April 14, 2007Imagine my lack of surprise when I picked up the latest issue and noticed that Peter Duesberg was the author of one of the feature articles. The editors know full well that this will provoke controversy so here's what they say in their editorial.

Even mentioning the name Peter Duesberg inflames strong feelings, both pro and con. After gaining fame in 1970 as the virologist who first identified a cancer-causing gene, in the 1980s he became the leading scientific torchbearer for the so-called AIDS dissidents who dispute that HIV causes the immunodeficiency disorder. To the dissidents, Duesberg is Galileo, oppressed for proclaiming scientific truth against biomedical dogma. A far larger number of AIDS activists, physicians and researchers, however, think Duesberg has become a crank who refuses to accept abundant proof that he is wrong. To them, he is at best a nuisance and at worst a source of dangerous disinformation on public health.

Readers may therefore be shocked to see Duesberg as an author in this month's issue. He is not here because we have misgivings about the HIV-AIDS link. Rather Duesberg has also developed a novel theory about the origins of cancer, one that supposes a derangement of the chromosomes, rather than of individual genes, is the spark that ignites malignant changes in cells. That concept is still on the fringe of cancer research, but laboratories are investigating it seriously. Thus, as wrong as Duesberg surely is about HIV, there is at least a chance that he is significantly right about cancer. We consider the case worthy of bringing to your attention.

Now let's unpack that opinion and put it in a different perspective to see where it takes us.

When it comes to AIDS, Peter Duesberg is a kook. He has consistently ignored scientific evidence in order to promote himself and his losing cause. In the face of overwhelming evidence that HIV causes AIDS he has steadfastly maintained a contrary position.

It's okay to take a minority position in science. We all do that from time to time. It's how science advances. However, there is such a thing as scientific integrity and scientific honesty. When your favorite theory goes against all scientific evidence you have two choices. You give up your theory or you stop being a credible scientist. Duesberg has chosen the second option.

There may be a chance that Duesberg is right about his new cancer theory but that's not the point. He has stopped being a scientist and he should not be given a platform in any magazine that pretends to be scientific. Once you lose your scientific credibility you have lost it forever. We don't reward such people by continuing to take them seriously as long as they avoid the one topic where their lack of integrity is known.

There are plenty of credible scientists out there who could write about cancer. The fact that Scientific American has chosen to put it's reputation behind Duesberg is just one more example of the demise of a good journal. The fact that the editors knew exactly what they were doing is not mark in their favor. They don't get bonus points for doing something wrong with their eyes wide open.

I will now put Scientific American in the same class as kooks like Duesberg. It does not deserve respect.

Jesse Cook

 
We just got back from seeing Jesse Cook. If you don't live in the Toronto area you'll just have to wait until he goes on tour in two weeks.

Testing the Macaque Genome

 
We've already been looking at the macaque genome for several months but now that the genome paper is being published I thought some of you might be interested in how the preliminary data stacks up to what we expect.

I'm interested in a family of gene known as the HSP70 gene family. The genes encode the major cellular chaperone that's responsible for correct protein folding. HSP70 is the most highly conserved gene known [Evolution of the HSP70 Gene Family].

We know how many genes there are in mammalian genomes so we can search the macaque genome at Rhesus Macaque Genome Resources to see if the expected genes are present. Here's the result.

HSPA1A: not present, probably due to incomplete sequence or annotation

HSPA1B: correct gene/protein

HSPA1L: correct gene/protein + one incorrect isoform that's really a splicing artifact

HSPA2: not present, probably due to incomplete genome or annotation

HSPA5/BiP: correct gene/protein + one incorrect alternatively spliced isoform that's really an artifact

HSPA8: one single correct gene/protein

HSP9B/mtHSP70: correct gene/protein + three incorrect isoforms generated by EST artifacts

That's not too bad for an initial draft sequence. Two genes are missing and so are several pseudogenes. I assume they'll turn up later when the genome sequence is being finished. Most of the splicing artifacts have been ignored by the annotators but a few have slipped through. They'll be deleted later on when the annotators are informed that the isoforms don't exist.

All in all, this is much better than most genome sequences at this stage. It's a bit better than the chimp genome but still a long way from the quality of the human genome. The mouse genome is almost as good as the human genome. Keep in mind that dozens of labs have been working on the human genome annotation for over six years since the sequence was first published. The cow, dog, frog and several fish genomes are in much worse shape and the chicken and sea urchin genomes are practically useless.

Horse, opossum, rat, pig, rabbit, cat, sheep, tree shrew, guinea pig, hedgehog, elephant, and platypus genomes are still at the assembly stage [Ensemble Genome Browser].

Do You Ever Wonder Why We Call them IDiots?

 
Someone named Granville Sewell has just posted a message on Uncommon Descent [Is ID Really Rooted in Science?]. He says,

Given that the most spectacular documented successes of natural selection are: changing the color of the peppered moth and the length of the beak of the Galapagos Finch, and the development of resistance to antibiotics by bacteria, and that even these trivial examples are now all in dispute, and that no competing natural explanation for evolution has ever been taken seriously by more than a small band of scientists, where is the “overwhelming” evidence that the development of life is due to natural (unintelligent) causes alone?

Hmmm ... there are only three spectacular documented examples of natural selection and all three "trivial" examples are disputed. I didn't know that. Has anyone told the textbook writers?

Natural selection is the only game in town according to Granville Sewell. No other explanations have been take seriously by more than a "small band of scientists." I didn't know that either. The textook writers need to be informed. There are entire chapers that have to be purged.

It seem no matter how much information we supply to the IDiots they refuse to listen. I know for a fact that Dembski and O'Leary have been told about other explanations. I have records of them both agreeing that there's more to evolution than just natural selection. I have written confirmation that they understand the concept of random genetic drift and why it's so incredibly important in molecular evolution.

So, let's sit back and see how long it takes them to correct their colleague. I'm gonna hold my breath 'cause it won't be long. Dembski and O'Leary are honorable people, aren't they?

Technology reveals 'lock and key' proteins behind diseases

 
A University of Toronto press release [here] announces a paper that's just been published in Molecular Cell [Paumi et al. 2007].

Paumi, C.M., Menendez, J., Arnoldo, A., Engels, E., Iyer, K.R., Thaminy, S., Georgiev, O., Barral, Y., Michaelis, S., and Stagljar, I. (2007) Mapping Protein-Protein Interactions for the Yeast ABC Transporter Ycf1p by Integrated Split-Ubiquitin Membrane Yeast Two-Hybrid Analysis. Molecular Cell 26:15-25.

One of the lead authors is my friend Igor Stagljar (that's him in the picture). The study is a collaboration between him and Susan Michaelis' group at Johns Hopkins in Baltimore MD (USA). It's a pretty decent press release without too much hype. I just wish there was more emphasis on basic biochemistry and less on possible applications in medicine. The paper describes a new technique called "Integrated Split-Ubiquitin Yeast Two-Hybrid Analysis" or iMYTH—a variant of MYTH technology. The paper has nothing to do with medicine.

The idea is to identify proteins that interact with membrane bound proteins. There are many membrane receptors that have been identified in the human genome on the basis of their similarity to known receptors. Their functions are unknown and one way to discover what they do is to detect other, hopefully known, proteins that bind to the receptors. The MYTH technology has been used to identify these interactions since it was first developed by Igor almost ten years ago. The modification in this paper is to integrate the "bait" construct into the yeast genome thus improving the sensitivity of detection (see Figure 1).

This is a proof of principle paper using a yeast ABC transporter that's being characterized by the Michaelis lab. Paumi et al. were able to identify six proteins that interact with the transporter, including Tus1P, a well-characterized guanine nucleotide exchange factor (GEF).

The exciting thing about this technique is that Igor has just introduced it into our Advanced Biochemistry Lab for undergraduates [BCH471Y]. The students are completing the final discussion day today. They identified a number of different proteins from a human brain library that interact with a human membrane receptor. One of them was a protein that had escaped detection when the experiments were first done in the Stadljar lab.