Fixing Carbon: the Rubisco Reaction

Life as we know it is based on carbon. All organisms need to have a source of carbon in order to grow and multiply. Animals, such as humans, get their carbon from eating other living things but there are many other species that can assimilate carbon directly from inorganic sources. This process is known as carbon fixation.

In most cases, carbon is derived from carbon dioxide in the atmosphere or dissolved in water. There are dozens of different chemical reactions in which carbon dioxide is taken up and attached to another organic molecule. Humans can do this to limited extent but not enough to support all of our carbon needs. Bacteria, protists, plants and fungi are much better at efficiently incorporating carbon from carbon dioxide.

The reactions of carbon fixation are often expensive because they require an input of energy to drive the assimilation of the newly-fixed carbon into metabolic pathways that are operating inside the cell. Photosynthetic organisms often have an abundant supply of energy so they can take up large amounts of carbon to make organic molecules. In fact, the association between carbon fixation and photosynthesis is so obvious that it's often assumed that the processes are directly coupled.

They aren't. There are many non-photosynthetic species that can efficiently fix carbon from carbon dioxide and there are many organisms that can carry out photosynthesis but they don't fix huge amounts of carbon using the standard pathways.

Nevertheless, there is one major carbon-fixing pathway that is present in most photosynthesizing bacteria, protists, fungi, and especially plants. It's called the Calvin Cycle after its discoverer Melvin Calvin (see photo) [Nobel Laureate 1961]. In modern biochemistry courses we discuss this pathway in the photosynthesis chapter but it's no longer considered to be part of photosynthesis. Photosynthesis ends with the light-driven synthesis of the energy molecules ATP and NADPH.

The first step in this pathway is the most important; it's the step where a carbon dioxide molecule is attached to a five carbon compound and the resulting 6-carbon intermediate is split into two 3-carbon molecules. The 3-carbon molecules then enter various metabolic pathways, including a pathway that recreates the 5-carbon precursor—hence the name "cycle."

The initial reaction is shown in the schematic below where each ball represents a carbon atom. The substrate for the reaction is the 5-carbon compound with the green balls and the blue ball represents the carbon atom in carbon dioxide (CO₂). As you can see, the reaction takes place in two steps. The first step is the actual fixation reaction; it creates a 6-carbon molecule with the incorporated carbon atom from CO₂. In the second step this 6-carbon molecule is cleaved producing two 3-carbon molecules.


The 5-carbon substrate is called ribulose 1,5-bisphosphate [Monday's Molecule #34]. It's related to the ribose in ribonucleic acid (RNA) except that it's the keto form of ribose and it has two phosphate groups attached to the 1 and 5 positions. The final products are called 3-phosphoglycerate. They are common intermediates in many metabolic pathways.

Here's the complete reaction. The enzyme that catalyzes this reaction is the most abundant enzyme on the entire planet. It's called ribulose 1,5-bisphosphate carboxylase-oxygenase, or Rubisco for short.

Mechanism of Rubisco-catalyzed carboxylation of ribulose 1,5-bisphosphate to form two molecules of 3-phosphoglycerate. A proton is abstracted from C-3 of ribulose 1,5 -bisphosphate to create a 2,3 -enediolate intermediate. The nucleophilic enediolate attacks producing 2-carboxy-3-ketoarabinitol 1,5 -bisphosphate, which is hydrated to an unstable gem diol intermediate. The C-2-C-3 bond of the intermediate is immediately cleaved, generating a carbanion and one molecule of 3-phosphoglycerate. Stereospecific protonation of the carbanion yields a second molecule of 3-phosphoglycerate. This step completes the carbon fixation stage of the Calvin cycle—two molecules of 3-phosphoglycerate are formed from CO₂ and the five-carbon sugar ribulose 1,5-bisphosphate.

©Laurence A. Moran and Pearson Prentice Hall 2007

Are IDiots Creationists?

 
I have complained about misuse of the term "Darwinism" by the Intelligent Design Creationists. They seem to be unable to grasp the fact that not all evolutionary biologists are Darwinists.

Having complained about that, it's only fair to consider their complaint that not all Intelligent Design advocates are Creationists. Casey Luskin raises the issue today on the Discovery Institute website [Another Way to Defeat the ID = Creationism MemeM].

Darwinian logic often contends that because a given proportion of ID proponents are creationists, ID must therefore be creationism. It's a twist on the genetic fallacy, one I like to call the Darwinist "Genesis Genetic Argument." As noted, it implies that each any and every argument made by a creationist must be equivalent to arguing for full-blooded creationism. This fallacious argument is easy to defeat on logical grounds by pointing out that some ID proponents are not creationists, and in fact have been persuaded to support ID in the absence of religion. Thus something other than creationism or religion must be fundamental to the set of views underlying ID (big hint: it's the scientific data indicating real design in nature)!

First off, it's ridiculous to pretend that some IDiots view the intelligent designer as anyone other than God. While I've no doubt that they might dig someone like this out of the woodwork, the fact remains that 99.999% of all intelligent design advocates see God as the designer. The term "creationist" refers to someone who postulates a role for a Creator (i.e., God) in creating life. Any IDiot who says they were persuaded to support intelligent design in the absence of belief in a Creator is, well, an idiot. But I repeat myself.

Second, there is no scientific data to indicate real design in nature. In fact, there's plenty of evidence to suggest a lack of "design" in much of nature (e.g., junk DNA). (Admittedly, many evolutionists are reluctant to accept this evidence.) The entire Intelligent Design Creationist movement is dedicated to disproving evolution. That's the extent of their "data." You don't become an Intelligent Design Creationist just because you've been brainwashed into rejecting evolution. You become an Intelligent Design Creationist because you've been brainwashed to believe in a Creator God and that, in turn, leads to the rejection of the other alternative, evolution.

There are many different kinds of creationist. They include Young Earth Creationists, Old Earth Creationists, and Theistic Evolutionists. The Theistic Evolutionists restrict the role of the Creator to setting up natural laws and then operating mostly within these natural laws to guide evolution. The Intelligent Design Creationists are a special group of creationists who argue against evolution and who claim (falsely) to have discovered evidence for supernatural creation (i.e., intelligent design). It is quite legitimate to refer to them as Intelligent Design Creationists because it distinguishes their form of creationism from the other forms of creationism.

Robert Pennock discusses this in his anthology Intelligent Design Creationism and Its Critics.

Dembski chides me for never using the term "intelligent design" without conjoining it to "creationism." He implies (though never explicitly asserts) that he and others in his movement are not creationists and that it is incorrect to discuss them in such terms, suggesting that doing so is merely a rhetorical ploy to "rally the troops." Am I (and the many others who see Dembski's movement in the same way) misrepresenting their position? The basic notion of creationism is the rejection of biological evolution in favor of special creation, where the latter is understood to be supernatural. Beyond this there is considerable variability. Some creationists think the world is young while a fewer number accept that it is ancient.

Pennock then goes on to show that Dembski is a creationist and so are most (all?) of his followers.

In spite of Luskin's whining (and Dembski's) it is quite appropriate to refer to Intelligent Design Creationism since the advocates of this superstitious nonsense are creationists by definition.

Welcome to Springfield

 
The population of Springfield has just increased by one. Meet Sandwalk. Do you see a resemblance? I don't.

Correcting the Bible

 
Read The Atheist Bible. I have a small correction to Book Two, Chapter Two which reads,

The variations in the biological organisms on Earth, described as the changes in a genetic population over time, is best explained in terms of natural selection.

The correct version should be,

The variations in the biological organisms on Earth, described as the changes in the genetics of a population over time, is best explained in terms of evolution.

Don't be shocked. This is, after all, a Bible and Bibles are notoriously inaccurate.

UPDATE: It's a miracle!!!! The atheist Bible has spontaneously mutated to a correct version of evolution. Praise the Lord.

[Hat Tip: Hemant Mehta at FriendlyAtheist.com]

Wellcome Trust Images

 
The Wellcome Trust's extensive library of images in now available through Creative Commons Licence [wellcome images].

Over on Memoirs of a Skepchick we've been challenged to find the coolest image [Something to get geeked about]. Here's my entry ....

Evolutionary Psychologists in Action

 
Alan S. Miller and Satoshi Kanazawa are evolutionary psychologists. They have written an article for Psychology Today that goes a long way toward explaining why this discipline is in such bad shape [Ten Politically Incorrect Truths About Human Nature]. Miller is a professor of social psychology in the Department of Behavioral Science at Hokkaido University, Japan. Kanazawa is a Reader in Management and Research Methodology at the London School of Economics and Political Science.

Did you know that all men prefer women with large breasts? I didn't. If true there must be a lot of very frustrated men in Asia and a lot of small-breasted spinsters wandering around somewhere. Anyway, Miller and Kanazawa have figured out why young American teenagers men like women with large breasts.

Until very recently, it was a mystery to evolutionary psychology why men prefer women with large breasts, since the size of a woman's breasts has no relationship to her ability to lactate. But Harvard anthropologist Frank Marlowe contends that larger, and hence heavier, breasts sag more conspicuously with age than do smaller breasts. Thus they make it easier for men to judge a woman's age (and her reproductive value) by sight—suggesting why men find women with large breasts more attractive.

Boy, you learn something every day from these evolutionary psychologists, don't you?

Now here's a useful bit of information. Do you know why young Muslim men are more violent and prone to suicide missions? The evolutionary psychologists have the answer,

Suicide missions are not always religiously motivated, but according to Oxford University sociologist Diego Gambetta, editor of Making Sense of Suicide Missions, when religion is involved, the attackers are always Muslim. Why? The surprising answer is that Muslim suicide bombing has nothing to do with Islam or the Quran (except for two lines). It has a lot to do with sex, or, in this case, the absence of sex.

What distinguishes Islam from other major religions is that it tolerates polygyny. By allowing some men to monopolize all women and altogether excluding many men from reproductive opportunities, polygyny creates shortages of available women. If 50 percent of men have two wives each, then the other 50 percent don't get any wives at all.

So polygyny increases competitive pressure on men, especially young men of low status. It therefore increases the likelihood that young men resort to violent means to gain access to mates. By doing so, they have little to lose and much to gain compared with men who already have wives. Across all societies, polygyny makes men violent, increasing crimes such as murder and rape, even after controlling for such obvious factors as economic development, economic inequality, population density, the level of democracy, and political factors in the region.

This is useful information. It means that we can settle all of the problems in the Middle East by withdrawing our troops and simply banning polygyny. Did somebody tell Dick Cheney?

There's lots more where this came from. Did you know that rich people have more sons than daughters? Neither did I, but lets not allow facts to interfere with a good just-so story. Here's the evolutionary explanation,

It is commonly believed that whether parents conceive a boy or a girl is up to random chance. Close, but not quite; it is largely up to chance. The normal sex ratio at birth is 105 boys for every 100 girls. But the sex ratio varies slightly in different circumstances and for different families. There are factors that subtly influence the sex of an offspring.

One of the most celebrated principles in evolutionary biology, the Trivers-Willard hypothesis, states that wealthy parents of high status have more sons, while poor parents of low status have more daughters. This is because children generally inherit the wealth and social status of their parents. Throughout history, sons from wealthy families who would themselves become wealthy could expect to have a large number of wives, mistresses and concubines, and produce dozens or hundreds of children, whereas their equally wealthy sisters can have only so many children. So natural selection designs parents to have biased sex ratio at birth depending upon their economic circumstances—more boys if they are wealthy, more girls if they are poor. (The biological mechanism by which this occurs is not yet understood.)

This hypothesis has been documented around the globe. American presidents, vice presidents, and cabinet secretaries have more sons than daughters. Poor Mukogodo herders in East Africa have more daughters than sons. Church parish records from the 17th and 18th centuries show that wealthy landowners in Leezen, Germany, had more sons than daughters, while farm laborers and tradesmen without property had more daughters than sons. In a survey of respondents from 46 nations, wealthy individuals are more likely to indicate a preference for sons if they could only have one child, whereas less wealthy individuals are more likely to indicate a preference for daughters.

If you believe this garbage then please send me an email message expressing your confidence in evolutionary psychology (and adaptationism). I'd like to talk to you about some swampland that I own in Florida. It will make a terrific vacation property.

[Hat Tip: RichardDawkins.net]

What Is Darwinism?

Over on the thread Close, but no cigar we're having a little discussion about the meaning of the term "Darwinian." I explained it as "evolution by natural selection."

Pete Dunkelberg is one of those people who emphasize natural selection in their discussion of evolution and he didn't like my description of Darwinian evolution. Pete said,

Misbegotten terminology. "darwinian processes" is creationist coinage with no meaning.

Talking of "darwinism" in biology is akin to talking of "newtonism" in physics: a bad idea. Aren't you glad physicists don't use terms like that to make polemics against each other?

wolfwalker asks: Larry, what do people mean by [these unneeded terms]? Larry tells him what Larry means. But the terms have no standard meaning. Larry's official ruling is that Darwin never heard of variable rates of morphological evolution and also thought selection was all.

It is patently untrue that the term "Darwinian" has no meaning in biology. Pete's position is that "Darwinist" refers to evolutionary biologists who no longer exist. He seems to think that everyone has become a pluralist these days. I beg to differ.

Core Darwinism, I shall suggest, is the minimal theory that evolution is guided in adaptively nonrandom directions by the nonrandom survival of small hereditary changes.... Adaptive does not imply that all evolution is adaptive, only that core Darwinism's concern is limited to the part of evolution that is.

Dawkins, R. (2003) The Devil's Chaplain p. 81 In physics, everyone knows that Newtonian physics has been extended in the twentieth century so that it's no longer accurate to refer to oneself as a Newtonian physicist since it implies ignorance of relativity. But this is a bad analogy since there are a great many evolutionary biologists (and even more of the other kinds of biologists) who are proud to call themselves Darwinists. Modern Darwinists place a great deal of emphasis on adaptation and natural selection as the main mechanisms of evolution.

Pete is dead wrong when he claims that, "Larry's official ruling is that Darwin never heard of variable rates of morphological evolution and also thought selection was all." I never said any such thing. I'm well aware of the fact that Darwin considered variable rates of natural selection and I'm well aware of the fact that he accepted other mechanisms of evolution, such as a watered down version of Lamarckism. The problem here seems to be that Pete doesn't understand the meaning of gradualism and he doesn't understand that modern Darwinists do not attribute everything in biology to selection.

As for the standard meaning of "Darwinism," Pete is correct to say that there is no universally accepted definition but that shouldn't be a surprise to anyone. There's hardly anything that all biologists can agree on.

However, there is a considerable group of evolutionary biologists who agree with Ernst Mayr when he says ...

After 1859, that is, during the first Darwinian revolution, Darwinism for almost everybody meant explaining the living world by natural processes. As we will see, during and after the evolutionary synthesis the term "Darwinism" unanimously meant adaptive evolutionary change under the influence of natural selection, and variational instead of transformational evolution. These are the only two meaningful concepts of Darwinism, the one ruling in the nineteenth century (and up to about 1930) and the other ruling in the twentieth century (a consensus having been reached during the evolutionary synthesis). Any other use of the term Darwinism by a moder author is bound to be misleading.

Mayr, E. (1991) What Is Darwinism? in One Long Argument p. 107.

See Why I'm Not a Darwinist for an earlier use of this quotation. The point is that the modern meaning of Darwinism is usually taken to mean an emphasis on natural selection.

Mayr explains the standard adaptationist view of random genetic drift by equating it with Neutral Theory and mischaracterizing the entire controversy. (This seems to be a very common trait among the defenders of strict Darwinism.)

The neutralists are reductionists, and for them the gene—more precisely the base pair—is the target of selection. Hence, any fixation of a "neutral" base pair is a case of neutral evolution. For the Darwinian evolutionists, the individual as a whole is the target of selection, and evolution takes place only if the properties of the individual change. A replacement of neutral genes is considered merely evolutionary noise and irrelevant for phenotypic evolution. (ibid p. 152)

I'm not making this up. I'm trying to do my best to represent the standard—but not universal—description of the adaptationist position. It's quite wrong for Pete Dunkelberg to pretend that the definition of Darwinism and the adaptationists is something that I created. (BTW, most pluralists treat the individual as the unit of evolution. They just believe that populations can fix alleles, even alleles with visible phenotypes, by random genetic drift as well as natural selection.)

Mayr continues,

The Darwinian wonders to what extent it is legitimate to designate as evoluton the changes in gene frequencies caused by nonselected random fixation. In some of the older (particularly nineteenth century) literature on evolution, one finds discussions on how to discriminate between evolution and mere change. There it was pointed out that the continuing changes in weather and climate, the sequences of the seasons of the year, the geomorphological changes of an eroding mountain range or a shifting river bed, and similar changes do not qualify as evolution. Interestingly, the changes in nonselected base pairs and genes are more like those nonevolutionary changes than they are like evolution. Perhaps one should not refer to non-Darwinian evolution but rather to non-Darwinian changes during evolution. (ibid p. 153)

While this position may seem extreme by 2007 standards, I believe that there are many evolutionary biologists who tend to dismiss all nonselected evolutionary change as uninteresting and unimportant. They are Darwinists. The extremists among this group attribute all kinds of things to adaptation, including most animal behavior. They are the ultra-Darwinians.

Many books have been written about the controversy in evolutionary biology between the adaptationists and the pluralists. Michael Ruse, for example, tried to explain it all last year (2006) in Darwinism and Its Discontents. Ruse is a firm believer in Darwinism, which he defines as "natural selection as the chief causal process behind all organisms." This is a common definition as explained above. However, one must read between the lines to see how Darwinists interpret that definition. A key point is what they think about random genetic drift. Here's how the Darwinist Ruse treats Sewall Wright's concept of random genetic drift.

Wright's theory is not very Darwinian. Natural selection does not play an overwhelming role. Genetic drift is a key player in Wright's world. However, although many of these ideas were taken up by later thinkers, especially by Theodosius Dobzhansky in the first edition of his influential Genetics and the Origin of Species, drift soon fell right out of fashion, thanks to discoveries that showed that many features formerly considered just random are in fact under tight control of selection (Lewontin, 1981). Today no one would want to say that drift (at the physical level) is a major direct player, although, in America particularly, there has always been a lingering fondness for it.

Michael Ruse is not an evolutionary biologist but he represents the views of Dawkins and, to a lesser extent, E.O. Wilson. They have no use for drift especially when it comes to visible characteristics. That's the hallmark of modern Darwinism.

So, is it true that no evolutionary biologist would want to say that drift is a major player in evolution? Of course not. There are lots of them who say exactly that in spite of what Michale Ruse would have you believe. Does Ruse have an answer to these "discontents?" Yes, he does ...

At the risk of damning myself in the eyes of both scholarship and God, let me be categorical. All of the critics of Darwinism are deeply mistaken,

To which I reply, you took the risk and your scholarship has been discredited. I can't speak for God.

Monday's Molecule #34

 
Today's molecule is very simple. It is well-known to all biochemistry undergraduates—or at least it was well-known at the time they wrote the exam. Let's see how many of you remember it today.

Today we need the formal IUPAC name in order to win the prize. There's an extremely obvious connection between this Monday's Molecule and Wednesday's Nobel Laureate. You will owe me a lunch if you guess the molecule correctly but can't figure out who the Nobel Prizewinner(s) is/are.

The reward (free lunch) goes to the person who correctly identifies the molecule and the Nobel Laureate(s). Previous free lunch winners are ineligible for one month from the time they first collected the prize. There are no ineligible candidates for this Wednesday's reward since many recent winners haven't collected their prize. The prize is a free lunch at the Faculty Club.

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

Stop the Press!!! ... Genes Have Regulatory Sequences!

Ira Flatow interviews John Greally (see photo) on Science Friday. Greally talks about the ENCODE project and junk DNA. You might be surprised to learn that the expression of genes is controlled by ... wait for it ... REGULATORY SEQUENCES! According to Greally the discovery of these regulatory sequences reveals that junk DNA isn't junk at all. Greally says,

It would be a very brave person who would call it junk at this stage.

Count me as a very brave person. I claim that most of the human genome is junk and I'm not alone.

This is just one more example of the hype surrounding the ENCODE project. Read Ryan Gregory's summary at More about ENCODE from Scientific American for a good summary of what the study really says about junk DNA. The study does not say that all junk DNA has a function in spite of what you might gather from the podcast (below). The study does not say that the discovery of regulatory sequences in noncoding DNA is a breakthrough in our understanding of how genes work. In fact, as almost all of you know, the existence of regulatory sequences that control gene expression has been known for four decades. John Greally misses a good opportunity to educate the public about science and instead uses inappropriate framing to hype his own interest in gene expression. Shame.


powered by ODEO

John Greely is the author of the News & Views article that described the original ENCODE work published in the June 14th issue of Nature. In that review he mentioned the role of regulatory sequences but focused much of his attention on the fact that large parts of the genome were transcribed. He expressed some appropriate skepticism of the results in the Nature piece but not when being interviewed on the radio. Is this appropriate? Is it what Nisbet and Mooney are talking about when they say that scientists should do a better job of framing?

[Hat Tip: Eye on DNA]

Mendel's Garden #16

 
The 16th version of Mendel's Garden has just been posted on Eye on DNA [Mendel’s Garden Genetics Blog Carnival #16M].

Socialized Medicine Will Make America Vulnerable to Terrorists

 
Americans are probably confused about socialized medicine after seeing Michael Moore's Sicko. Don't worry. Fox News explains why highly efficient, profit-based. corporate health care will protect America from those Jihadist Muslim doctors who are taking over the anonymous, highly bureaucratic systems in Europe.

Listen for the part about your family doctor. In America you can't have doctors who believe in stupid things because they'll be exposed by their patients and their colleagues. Apparently in socialist countries you don't have family doctors (news to me) so patients never find out what their doctors are really thinking. That's why jihadist doctors can hide out in Europe.

Why isn't there more outrage when idiotic things like this are broadcast on network television?



[Hat Tip: Canadian Cynic]

Close, but no cigar.

 
Over on Post-Darwinist Denyse O'Leary is whining about the fact that so many scientists are non-believers. She quotes from a poll of evolutionists showing that 78% don't believe in God. Having been sensitized to misuse of the word "evolutionist" she adds this at the end of her blog.

(Note for the record: "Evolutionists" here means scientists who believe that gradual Darwinian processes completely account for every aspect of life and that no design whatever is required. It does not mean scientists who merely accept that evolution occurs or that Earth is billions of years old.)

Denyse, it's the word "Darwinian" that's being misused. I'm an evolutionist but I do not believe that "gradual Darwinian processes completely account for every aspect of life." Instead I believe that evolution accounts for life and this evolution includes strict Darwinian processes as well as non-Darwinian processes.

Why do you find this so hard to understand?

I'm a Skeptic

 
I'm a Skeptic and a member of the Board of Consultants of Skeptics Canada. But it's nice to have confirmation ...

You Are Very Skeptical

Your personal motto is: "Prove it." While some ideas, like life after death, may seem nice... You aren't going to believe them simply because it feels good. You let science and facts be your guide... Even if it means you don't share the beliefs of those around you.

How Skeptical Are You?

[Hat Tip: GrrlScientist]

Mutation Rates

Each of us was born with at least 350 new mutations that make our DNA different from that of our parents.

Douglas Futuyma (2005) p. 162Let’s think about the number of mutations that could accumulate in a population over time. A few pages ago we looked at the origin of antibiotic resistance in bacteria in order to prove that mutations occur randomly. Now we’ll consider just how frequency those mutations could arise in bacteria. Then we’ll ask how frequently mutations occur in humans.

Our model bacterium is Esherichia coli the common, and mostly benign, intestinal bacterium. The entire genome was sequenced in 1997 (Blattner et al., 1997) and its size is 4,200,000 base pairs (4.2 × 10⁶ bp). Every time a bacterium divides this amount of DNA has to be replicated; that’s 8,400,000 nucleotides (8.4 × 10⁶).

The most common source of mutation is due to mistakes made during DNA replication when an incorrect nucleotide is incorporated into newly synthesized DNA. The mutation rate due to errors made by the DNA polymerase III replisome is one error for every one hundred million bases (nucleotides) that are incorporated into DNA. This is an error rate of 1/100,000,000, commonly written as 10^-8 in exponential notation. Technically, these aren't mutations; they count as DNA damage until the problem with mismatched bases in the double-stranded DNA has been resolved. The DNA repair mechanism fixes 99% of this damage but 1% escapes repair and becomes a mutation. The error rate of repair is 10^-2 so the overall error rate during DNA replication is 10^-10 nucleotides per replication (10^-8 × 10^-2) (Tago et al., 2005).

Since the overall mutation rate is lower than the size of the E. coli genome, on average there won’t be any mistakes made when the cell divides into two daughter cells. That is, the DNA will usually be replicated error free.

However, one error will occur for every 10 billion nucleotides (10^-10) that are incorporated into DNA. This means one mutation, on average, every 1200 replications (8.4 × 10⁶ × 1200 is about ten billion). This may not seem like much even if the average generation time of E. coli is 24 hours. It would seem to take four months for each mutation. But bacteria divide exponentially so the actual rate of mutation in a growing culture is much faster. Each cell produces two daughter cells so that after two generations there are four cells and after three generations there are eight cells. It takes only eleven generations to get 2048 cells (2¹¹ = 2048). At that point you have 2048 cells dividing and the amount of DNA that is replication in the entire population is enough to ensure at least one error every generation.

In the laboratory experiment the bacteria divided every half hour so after only a few hours the culture was accumulating mutations every time the bacteria divided. This is an unrealistic rate of growth in the real world but even if bacteria only divide every 24 hours there are still so many of them that mutations are abundant. For example, in your intestine there are billions and billions of bacteria. This means that every day these bacteria accumulate millions of mutations. That’s why there’s a great danger of developing drug resistance in a very short time.

Calculating the rate of evolution in terms of nucleotide substitutions seems to give a value so high that many of the mutations must be neutral ones.

Motoo Kimura (1968)I based my estimate of mutation rate on what we know about the properties of the replisome and repair enzymes. Independent measures of mutation rates in bacteria are consistent with this estimate. For example, the measured value for E. coli is 5.4 × 10^-10 per nucleotide per replication (Drake et al., 1998). Many of these mutations are expected to be neutral. The rate of fixation of neutral mutations is equal to the mutation rate so by measuring the accumulation of neutral mutations in various lineages of bacteria you can estimate the mutation rate provided you know the time of divergence and the generation time. (Ochman et al., 1999) have estimated that the mutation rate in bacteria is close to 10^-10 assuming that bacteria divide infrequently.

The mutation rate in eukaryotes should be about the same since the properties of the DNA replication machinery are similar to those in eukaryotes. Measured values of mutation rates in yeast, Caenorhabditis elegans, Drosophila melanogaster, mouse and humans are all close to 10^-10 (Drake et al., 1998).

The haploid human genome is about 3 × 10⁹ base pairs in size. Every time this genome is replicated about 0.3 mutations, on average, will be passed on to one of the daughter cells. We are interested in knowing how many mutations are passed on to the fertilized egg (zygote) from its parents. In order to calculate this number we need to know how many DNA replications there are between the time that one parental zygote was formed and the time that the egg or sperm cell that unite to form the progeny zygote are produced.

In the case of females, this number is about 30, which means that each female egg is the product of 30 cell divisions from the time the zygote was formed (Vogel and Rathenberg, 1975). Human females have about 500 eggs. In males, the number of cell divisions leading to mature sperm in a 30 year old male is about 400 (Vogel and Motulsky, 1997). This means that about 9 mutations (0.3 × 30) accumulate in the egg and about 120 mutations (0.3 × 400) accumulate in a sperm cell. Thus, each newly formed human zygote has approximately 129 new spontaneous mutations. This value is somewhat less than the number in most textbooks where it's common to see 300-350 mutations per genome. The updated value reflects a better estimate of the overall rate of mutation during DNA replication and a better estimate of the number of cell divisions during gametogenesis.

With a population of 6 billion individuals on the planet, there will be 120 × 6 × 10⁹ = 7.2 × 10¹¹ new mutations in the population every generation. This means that every single nucleotide in our genome will be mutated in the human population every 20 years or so.

---

Blattner,F.R., Plunkett,G., Bloch,C.A., Perna,N.T., Burland,V., Riley,M., ColladoVides,J., Glasner,J.D., Rode,C.K., Mayhew,G.F., Gregor,J., Davis,N.W., Kirkpatrick,H.A., Goeden,M.A., Rose,D.J., Mau,B., and Shao,Y. (1997) The complete genome sequence of Escherichia coli K-12. Science 277:1453-1474.

Drake,J.W., Charlesworth,B., Charlesworth,D., and Crow,J.F. (1998) Rates of spontaneous mutation. Genetics 148:1667-1686.

Ochman,H., Elwyn,S., and Moran,N.A. (1999) Calibrating bacterial evolution. Proc. Natl. Acad. Sci. (USA) 96:12638-12643.

Tago,Y., Imai,M., Ihara,M., Atofuji,H., Nagata,Y., and Yamamoto,K. (2005) Escherichia coli mutator Delta polA is defective in base mismatch correction: The nature of in vivo DNA replication errors. J. Mol. Biol. 351:299-308.

Vogel,F. and Motulsky,A. (1997) Human Genetics: Problems and Approaches. (Berlin, New York: Springer-Verlag).

Vogel,F. and Rathenberg,R. (1975) Spontaneous Mutation in Man. Adv. Hum. Genet. 5:223-318.

©Laurence A. Moran (2007)

The Evils of Darwinism in America

 
Over on the Discovery Institute website there's an important announcement [John West's Forthcoming Book] ...

Next Fall ISI Books will release CSC associate director Dr. John West's important book, Darwin Day in America: How Our Politics and Culture Have Been Dehumanized in the Name of Science.

Darwin Day in America tells the disturbing story of scientific expertise run amuck, exposing how an ideological interpretation of Darwinian biology and reductionist science have been used to degrade American culture over the past century through their impact on criminal justice, welfare, business, education, and bioethics.

Fascinating. Given that "Darwinism" has been so fiercely resisted in America its success in degrading American culture is all that more remarkable.

I look forward to Dr. West's exposé of European culture where rationalism has been even more successful than in America. I wonder what he thinks of France?

Richard Dawkins on Visible Changes and Adaptationism

On another thread [Visible Mutations and Evolution by Natural Selection] we are discussing a common adaptationist claim that once a mutation has a visible phenotype it is almost certainly subject to selection. Some people have questioned whether there is anyone who actually believes in such a thing. Here's Richard Dawkins writing in The Extended Phenotype (1982).

The biochemical controversy over neutralism is concerned with the interesting and important question of whether all gene substitutions have phenotypic effects. The adaptationism controversy is quite different. It is concerned with whether, given that we are dealing with a phenotypic effect big enough to see and ask questions about, we should assume that it is the product of natural selection. The biochemist's 'neutral mutations' are more than neutral. As far as those of us who look at gross morphology, physiology and behaviour are concerned, they are not mutations at all. It was in this spirit that Maynard Smith (1976b) wrote: "I interpret 'rate of evolution' as a rate of adaptive change. In this sense, the substitution of a neutral allele would not constitute evolution ..." If a whole-organism biologist sees a genetically determined difference among phenotypes, he already knows he cannot be dealing with neutrality in the sense of the modern controversy among biochemical geneticists.

In 2007 Dawkins would probably admit to some neutral examples of "genetically determined differences among phenotypes" but his position hasn't changed very much from 1982. For example, in The Ancestor's Tale (2005) he writes,

Contrary to my rather ludicrous reputation as an "ultra-Darwinist" (a slander I would protest more vigorously if the name sounded less of a compliment than it does), I do not think that the majority of evolutionary change at the molecular level is favoured by natural selection. On the contrary, I have always had a lot of time for the so-called neutral theory associated with the great Japanese geneticist Motoo Kimura, or its extension, the "nearly neutral" theory of his collaborator Tomoko Ohta. The real world has no interest in human tastes, of course, but as it happens I positively want such theories to be true. This is because they give us a separate, independent chronicle of evolution, unlinked to the visible features of the creatures around us., and they hold out the hope that some kind of molecular clock might really work.

Just in case the point is misunderstood, I must emphasize that the neutral theory does not in any way denigrate the importance of selection in nature. Natural selection is all-powerful with respect to those visible changes that affect survival and reproduction. Natural selection is the only explanation we know for the functional beauty and apparently "designed" complexity of living things. But if there are any changes that have no visible effect—changes that pass right under natural selection's radar—they can accumulate in the gene pool with impunity and may supply just what we need for an evolutionary clock.

Pluralists believe that all kinds of alleles are neutral or nearly neutral and are fixed in a population by random genetic drift. This includes alleles that produce a visible phenotype. Pluralists do not believe that there is a major distinction between the mechanisms of evolution at the molecular level and the mechanisms at the morphological level.

Contrary to Dawkins, I believe that Neutral Theory has reduced the importance of selection in nature. Prior to 1968 it was common to attribute almost all changes to natural selection and it was common to advocate that the presence of variation in a population was due to balancing selection. Today, one has to consider the evidence for adaptation; you can no longer just assume that it is the only game in town.

Of course it's true that natural selection is the only mechanism that affects allele frequencies once you can demonstrate that a visible change affects survival and reproduction. But Dawkins goes farther than that. He strongly implies that all visible phenotypes are subject to selection and neutral alleles are confined to the molecular level.

Nobel Laureate: Adolf Windaus

 
The Nobel Prize in Chemistry 1928.

"for the services rendered through his research into the constitution of the sterols and their connection with the vitamins"


Adolf Otto Reinhold Windaus (1876-1959) won the Nobel Prize in 1928 for his work on the structure of sterols and their functions. One of the most common sterols is cholesterol and Windaus was able to show that it is synthesized in many different species although he was not able to determine its function. (We now know that it is an important component of membranes.)

Windaus also worked out the synthesis of vitamin D from the plant sterol ergosterol [Monday's Molecule #33]. The Presentation Speech was given by Professor H.G. Söderbaum of the Royal Swedish Academy of Sciences on December 10, 1928. The speech may seem confusing since it talks about two Nobel Laureates, Wieland and Windaus, but Windaus was the sole recipient of the 1928 Nobel Prize. It turns out that the 1927 Nobel Prize in Chemistry was awarded to Heinrich Otto Wieland at the same time as the 1928 Nobel Prize.

Your Majesty, Your Royal Highnesses, Ladies and Gentlemen.

We hear continually that today science, in particular natural science, is becoming increasingly more specialized, that scientists are delving deeper and deeper into specialized studies difficult to survey, that the deep stream of research is turning into ever-shallower brooks and channels, and that in this way the unity that exists between the different branches of science is in danger of being destroyed. Indeed, most people have wondered with some disquiet where this apparently unrestricted specialization will eventually lead. The answer to this question is that, while the question itself is completely justified, the disquiet is in most cases unjustified or at least unduly great.

A stage is reached sooner or later in the development of every natural science, when research, after dealing with problems of more general importance, has of necessity to apply itself to problems of detail of apparently more limited interest. It is simply that the continuous increase in scientific knowledge necessitates a corresponding continuous increase in the division of work. Many fields of science which could once be handled by a few or even one investigator, may only one generation later provide enough or more than enough work for whole hosts of students and their attendants. However, specialization is, or should be, not an end but a means. Even at the stage of the division of work, for the true investigator the end is, and will remain, that of determining the inner connection between the changing phenomena, and, depending on the extent to which this end is achieved, the special researches will gradually merge into greater units; the detail then ceases to be an isolated thing, more or less unimportant as regards the whole, but becomes a necessary link in a connected chain of knowledge.

The work which has been awarded Alfred Nobel's Chemistry Prizes this year by the Academy of Sciences, provides an instructive example of this process.

We are dealing here with several fields of work, which are separate from the start.

First we have biles. As is well-known, biles and hence their specific constituents, bile acids, are of major importance in the digestion process. Now these bile acids have been for almost a hundred years the object of active study by a large number of prominent investigators. In this way a large amount of material was accumulated from observations, but despite this, little was known concerning the connection between the various bile acids, and almost nothing concerning the details of their structure, when Wieland began his work in this field.

Then we have the cardiac poisons. Of animal cardiac poisons chemists were acquainted in particular with so-called bufotalin, which is present in the skin secretion of certain species of the toad genus Bufo. In therapeutics, on the other hand, vegetable cardiac poisons have long been used, especially those belonging to the glucoside group and obtained from species of the plant genera Digitalis and Strophantus. But the production of these substances in the pure state and the determination of the chemical relationships between them had long remained an unresolved problem.

The so-called sterols are also an extremely interesting group from the physiological viewpoint. They too occur both in vegetation and in animals. Most numerous are the vegetable sterols, the so-called phytosterols, but the best-known is certainly cholesterol, which occurs in the animal organism, and which was first found about 150 years ago in gall stones. This substance occurs not only in bile but also in the brain, in nerve substance, in the egg, in blood, and presumably in all cells. Thus we can conclude that it plays an extremely important part in the life process of man and the animals, just as the phytosterols play an extremely important part in the life process of plants. These sterols were however an isolated group for a long time. The difficulties associated with investigation of their chemical constitution were so great that it is only during the last few decades, above all through Windaus's investigations, that a clearer picture has been obtained thereof.

Finally, we come to a group of compounds which have only been known for a relatively short time, but which during this short time have attracted very considerable attention, both from chemists and from the public at large. Who today is unacquainted with vitamins, these mysterious substances which are of such immense significance for life, vita, itself and which have thus justifiably taken their name from it? But compared with those mentioned above, the difficulties which here confronted the investigator were far greater, and in most cases it had to be regarded as sufficient to characterize these substances on the basis of their physiological effects.

Thanks to the work which this year has been found before others worthy of recognition through the award of the Nobel Prize in Chemistry, the inner connection between all these apparently isolated fields of research has been very strikingly demonstrated. Of course the way in which this took place can only be described very briefly here.

Wieland succeeded in producing from bile a saturated acid which can be regarded as the mother substance or parent acid of the bile acids, and which he studied and characterized in detail. When Windaus then produced this same parent acid, cholanic acid, from cholesterol by means of a complicated and very ingenious series of experiments, this indicated very clearly the close relationship between cholesterol and the bile acids. It should be pointed out in this connection that Wieland's investigations into bile acids themselves gave a deeper insight of the mechanism of the action of the bile in the resorption of food in the intestines.

But this is not all. As a result of patient and skilful work, Windaus succeeded in producing several of the digitalis glucosides and their components in the pure state. In this way it was shown that these vegetable cardiac poisons are directly related on the one hand to cholesterol and the bile acids, and on the other hand to the animal cardiac poison bufotoxin, which Wieland studied with great success.

Another sterol which Windaus has studied in detail, is ergosterol, which occurs partly in ergot and partly in yeast. The research carried out in recent years, in which Windaus himself has also played a leading part, has revealed the very important fact that, on being irradiated with ultraviolet light, this ergosterol assumes exactly the same properties as the antirachitic vitamin, "vitamin D", i.e. it will cure rachitis (rickets). For example, it has been found that 5 mg of irradiated ergosterol has the same action in this respect as 1 litre of good cod-liver oil. It can be considered proved, therefore, that ergosterol, or possibly a sterol, the physiological effects of which correspond completely with those of ergosterol, constitutes the antirachitic provitamin, i.e. the mother substance of vitamin D.

All the investigations which we have had to summarize so briefly here, have one thing in common with each other. They were all designed to explain the internal structure of organic materials, their relationships with one another and their transitions into each other. For this reason they are of fundamental importance for our knowledge of a number of processes occurring both in the healthy and in the diseased organism, and therefore of greatest significance not only for chemistry as such, but also for its sister sciences, physiology and medicine. But in order to reach this vantage point of knowledge, where the dividing walls separating the various special researches no longer obstruct vision, where the connection between extensive parts of organic chemistry can be surveyed and where in fact the fields of three main disciplines appear to connect and merge with each other - all this has taken years of hard, diligent, and resourceful work in the deep mines of detailed research. These are the researches which are to be rewarded here.



Professor Wieland. The decision of the Royal Academy of Sciences to award you the Nobel Prize in Chemistry for your work on bile acids and related substances, is only a just recognition of the solution of a problem which is without doubt one of the most difficult which organic chemistry has had to tackle.

The complex composition of the compounds investigated, the large number of atoms contained in the molecules of these compounds, the fact that the material was often very difficult to produce, even in small quantities, these were obstacles which could only be overcome with such striking success through a remarkable skill in experimentation and a rare capacity for finding new ways and means.

In gratitude for what you have achieved for science in this connection, and with hearty congratulations on your well-deserved distinction, the Academy asks you to accept the Nobel Prize in Chemistry for the year 1927 from the hands of his Majesty the King.



Professor Windaus. If the Royal Academy of Sciences had had only one Nobel Prize in Chemistry to award on this occasion, and had had to present it to one person, it would have been in a very difficult position.

For there is no doubt that your work on sterols, vegetable cardiac poisons and other closely related substances merits in the same high degree such an award as the work which we have just recognized.

Moreover, it is clear that your work and that of your colleague in Munich are so interrelated and supplement each other in such a way that it would have been extremely difficult to award the Prize to the one while passing over the other.

In addition, both researches display the same assiduity, the same remarkable capacity for overcoming even the greatest experimental difficulties, and the same lucidity in interpreting the results obtained, that it would obviously have been impossible to give precedence to one investigator over the other.

The fact that two Prizes were available for award this year, has fortunately freed the Academy from this quandary. For this the Academy congratulates itself no less than you, and asks you now to take the last few steps which separate you from the external symbols of the Prize.

And the Winner Is .......

 
Posted by Sam Chen on Uncommon Descent [IDURC Announces 2007 Casey Luskin Graduate Award].

The Intelligent Design Undergraduate Research Center (IDURC) is proud to present the 2007 Casey Luskin Graduate Award, presented annually to a deserving college graduate for excellence in student advocacy of intelligent design.

The recipient of the 2007 Casey Luskin Graduate Award will remain anonymous for the protection of the recipient.

I wonder if the winner will list the prestigious award on his/her CV?

Bacteria, Bloggers, and Toronto

 
Chris Condayan is the Manager for Public Outreach at the American Society for Microbiology (ASM). At the recent ASM meeting in Toronto he videotaped a number of bloggers and created a podcast that's posted on the MicrobeWorld website. Here's your chance to see some real live bloggers including; John Logsdon [Sex, Genes & Evolution], Jonathan Badger [T. taxus], Yersinia [Yersinia], Moselio Schaechter [Small Things Considered], Tara Smith [Aetiology], and me [Sandwalk].

Who Owns Your Lab Notebooks?

 
When post-docs and graduate students finish their projects in a research laboratory they leave their notebooks behind. Those belong to the principal investigator who runs the lab. Graduate students often have a hard time understanding this policy so Janet Stemwedel explains it on Adventures in Ethics and Science.

The original article is Lab notebooks and graduate research: what should the policy be? and the followup is Kept all my notebooks; what good are notebooks?.

This is a good example of an ethical problem in science.

Gene Genie #10

 
Gene Genie #10 was posted Ryan Gregory on Genomicron [Gene Genie #10 -- The Canada Day Ultraspectacular Edition].

Visible Mutations and Evolution by Natural Selection

A recent posting [Darwin Still Rules, but Some Biologists Dream of a Paradigm Shift] raised the issue of adaptationism. The controversy is over the main mechanism of genetic change in evolving populations. Adaptationists tend to attribute as much as possible to natural selection while pluralists emphasize the important role of other mechanisms of evolution, like random genetic drift.

There seems to be little doubt that most of the fixed alleles at the molecular level are probably neutral in their effect. Thus, they have been fixed by random genetic drift. This includes many amino acid substitutions in proteins. Even though these substitutions change the structure of a protein by a small amount, it does not seem reasonable to assume that they have all been selected.

Most adaptationists are content to concede this point (although there are holdouts). However, they draw the line at more "visible" mutations. According to this group, the vast majority of "visible" mutations are subject to natural selection and therefore most fixed alleles with a "visible" phenotype are adaptations. The argument seems to be that once a mutation produces a "visible" phenotype then it is not appropriate to suggest that it might be neutral with respect to natural selection. The line seems to be drawn somewhere above differences in the amino acid composition of proteins but it's not clear exactly where.

p-ter is one of those who are very reluctant to admit that a visible character could have been fixed by accident. He has posted a short article on Gene Expression [Do phenotypes evolve neutrally?]. I recommend that you read the comments to see examples of the extreme version of adaptationism. Most of these adaptationists will even argue that human blood types are adaptive. The idea that most native North Americans have type O blood is due to some undefined selective advantage and not to accident.

This argument has been going on for several decades. As usual, it's not about the existence of natural selection or random genetic drift. It's about their relative importance in evolution. To reiterate, the adaptationists believe that almost all mutations with a visible phenotype have been fixed by natural selection. The pluralists think that many of them are neutral and have been fixed by accident. The adaptationists make a distinction between what happens at the molecular level and what happens at the "visible" level while the pluralists think the same mechanims are operating at both levels.

Richard Lewontin uses the example of the Indian and African rhinoceros to focus the debate. The African rhinoceros has two horns while the Indian rhinoceros has only one. The question is whether this difference is due to natural selection—is two horns better than one in Africa? Or, is it just an accident of evolution that one species has two horns while the other has only one?



I don't understand why the adaptationist camp is so reluctant to admit that some visible characters can be fixed by random genetic drift. The idea that every feature of an organism has to be an adaptation seems so out of touch with our modern understanding of evolution that I'm really puzzled by the vehemence with which adaptationists defend their orthodoxy. It seems as though admitting that visible phenotypes might be non-adaptive is a major threat to their worldview.

Monday's Molecule #33

 
Today's molecule is complex. The short common name of this molecule is sufficient but you're more than welcome to supply the IUPAC name if you know it. There's a direct connection between this Monday's Molecule and Wednesday's Nobel Laureate. (Hint: this molecule is not mentioned in the description of the award but the class of molecules to which it belongs is mentioned.)

The reward (free lunch) goes to the person who correctly identifies the molecule and the Nobel Laureate(s). Previous free lunch winners are ineligible for one month from the time they first collected the prize. There's only one (Marc) ineligible candidates for this Wednesday's reward since many recent winners haven't collected their prize. The prize is a free lunch at the Faculty Club.

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UPDATE: The molecule is ergosterol, a plant sterol that is a precursor to vitamin D. Ultraviolet irradiation converts ergosterol to vitamin D₂.

Happy Canada Day

 


HAPPY

CANADA

DAY

Canada's official birthday was yesterday, July 1, but everyone gets a holiday today to celebrate.

Nobel Laureate: Albert von Szent-Györgyi Nagyrapolt

 
The Nobel Prize in Physiology or Medicine 1937.

"for his discoveries in connection with the biological combustion processes, with special reference to vitamin C and the catalysis of fumaric acid"

Albert von Szent-Györgyi Nagyrapolt (1893 - 1986 ) received the Nobel Prize in Physiology or Medicine for his work on the biochemistry of combustion, or respiration as we now know it. In most cases when we read the presentation speeches for past Nobel Prizes we recognize the seminal insights that have led to a better understanding of science. This recognition is usually even more obvious when we review the Nobel Lecture of the prize winner [Szent-Gyorgyi Lecture].

In this case the presentation speech seems hopelessly confusing and it's difficult to see any connection between our current understanding of metabolism and the view presented in 1937. Szent-Gyorgi worked on the metabolism of vitamin C and on the role of fumarate in basic metabolism. (Fumarate was Monday's Molecule #32.) Szent-Gyorgi thought that vitamin C was an essential cofoactor in metabolism but we now know that it plays only a minor role [Scurvy and Vitamin C]. He also though that fumarate was a cofactor bound to the surface of an enzyme—it is not. Furthermore he thought that fumarate was part of a reductive pathway where hydrogen atoms were taken up from the food and passed from oxaloacetate to malate to fumarate to succinate and then to a cytochrome complex where they were eventually combined with water. We now know that this pathway part of a large pathway (the Krebs cycle [Nobel Laureates: Hans Krebs]) that operates in the opposite direction. We also know that it is electrons, not protons, that carry the energy of metabolism.

Read the presentation speech below to see the state of knowledge in 1937. Keep in mind that at the time there were other scientists, notably Hans Krebs, who were on the right track.

Your Majesty, Your Royal Highnesses, Ladies and Gentlemen.

The Staff of Professors of the Caroline Institute, pursuant to the task devolving upon them by the terms of the will of Alfred Nobel, have awarded the Prize for Physiology or Medicine for the year 1937 to Professor Albert von Szent-Györgyi, in recognition of his discoveries concerning the biological combustion processes with especial reference to vitamin C and to the fumaric acid catalyst. The wording of the above sentence indicates that the mechanism of biological oxidation has been investigated beyond the great discoveries in this field made by Otto Warburg, Heinrich Wieland, and their successors. Their systems of catalysts for oxidation have been shown to be dependent on Szent-Györgyi's new catalysts.

It was generally known before that combustion liberates energy in living cells which can be employed there without loss - directly for the building up of new substances - for storage or for the building of functioning cell structures. The building up of living organisms then is dependent in essential respects on combustion, which is guided by catalyst systems. Thus catalyst systems are conditional for the building up of living organisms. Consequently in the unknown period during which organic life originated, the formation of these and other catalyst systems must have preceded the completion of the living animal organisms.

Preferably I should wish to confine my remarks to the new conquistador from Szeged. The survey is however of higher importance on this occasion, and moreover the course of the events is dramatically concentrated. Each one of the three has conquered new ground by intuitive daring and skill. Szent-Györgyi's greatest achievement has intimately linked up the accomplishments of the two others and of their successors, giving us for the first time a picture of a coherent oxidation process - of the interplay of three catalyst systems and the oxidation thereby in metabolism.

Warburg, who always stood alone with some few faithful co-workers, is the foremost pioneer, and he had to overcome the greatest difficulties. At this day there is none who can any longer throw doubt on his discoveries, but that was not so, when in 1931 underestimated by the majority, he was awarded the Nobel Prize by the Caroline Institute. He has shown that the inert oxygen, with which the red blood corpuscles are fully loaded, is taken up from them by a catalyst system to which many red pigments belong (for brevity's sake called «the red system»). These are related to the red blood pigment. They contain as active groups (for the most part) iron and specific proteins. In this system the oxygen combines with the iron during varying periods of time. In the case of the most rapid catalysts, it combines with the iron, is converted into a lively, reactively disposed form and is delivered - all at a speed that gives a flowing stream of active oxygen from the catalyst system. One thought that this active oxygen oxidized directly. That is not the way however. On the contrary, the active oxygen meets hydrogen - but that is another story, belonging to Szent-Györgyi's great discovery. The manner in which the life-giving active oxygen's dramatic encounter in the darkness of the cells ensues, had been unknown ever since the morning of time until, in 1933, Szent-Györgyi carried out some experiments which proved to be the prelude to the revelation of the secret.

For the moment I will leave oxygen, and direct the attention to the first, apparently unimportant, experiments carried out by Wieland. These led him to the conception of an idea, which was destined to carry him on to the disclosure of an extensive part of the mechanism of oxidation. A large number of investigators were soon attracted by Wieland's opinion. This seemed to be at variance with the oxygen activation - at any rate that was the view of a majority. This apparent inconsistency was never considered by Szent-Györgyi, nor by Warburg.

Wieland had observed that palladium is capable of absorbing hydrogen from certain organic compounds, which means their partial combustion or oxidation. Through the cooperation of many investigators the presence was revealed of extensive metal-free catalyst systems, the effect of which was shown to consist in the removal of hydrogen from metabolic substances, in agreement with Wieland's concept. These catalysts were given a name in common: dehydrogenases (hydrogen-removers, hydrogen-absorbers, or hydrogen-transporters) and the idea was held pretty generally that the hydrogen activated by this system would be capable of reacting directly with the inert oxygen molecules. Hydrogen superoxide was supposed to form an intermediate product. That is not the highway of oxidation however. On the contrary, the hydrogen first meets Szent-Györgyi's catalyst system from a different side to the one where the activated oxygen flows into it from the «red system». That again is another story, which also belongs to Szent-Györgyi's great discovery. From 1925 onwards he had been investigating a number of hydrogen-absorbers. Previously to anyone else he formed the view of these as members of a catalyst system in the service of oxidation (in other quarters loosely conceived of as being auxiliary catalysts of some kind for fermentation). He was also occupied with experiments on a yellow substance, termed flave by him, while his investigation regarding vitamin C was being completed, and conducted on to the isolation of that substance, enabling him later to insert it in the catalyst system of certain hydrogen-removers. Vitamin C and another substance, containing sulphur as a hydrogen-removing group and defined by Sir Frederick Gowland Hopkins and others, were however until 1934 the only substances belonging to the hydrogen-transporters in the oxidation-chain that had been isolated. The rank that they possess as catalysts is dependent on the velocity of the hydrogen-transportation and the degree of the activation of the hydrogen - problems that still await a satisfactory solution. On the other hand, Hugo Theorell succeeded in 1934 in isolating, in Warburg's laboratory, the first really rapid hydrogen-transporter, called «the yellow enzyme». He could also show that it was a phosphoric-acid ester of vitamin B2, linked to a specific protein. Warburg and Christian, in 1935, defined the nature of the active group in two other dehydrogenases, colourless and metal-free (co-ferment and co-zymase), which had long frustrated the attempts of other investigators. One of them was the catalyst that Szent-Györgyi had placed in this section of the oxidation-chain.

The magnificent series of Szent-Györgyi's discoveries commenced in 1933. They were carried out and pursued at Szeged with extraordinary rapidity and precision. His clear vision for essentials induced him, in spite of his isolation of ascorbic acid and of his identification of it with the so-termed vitamin C - a feat that was justly hailed with enthusiasm - to hand over to others for the time being the tempting pursuit of the further development of that discovery, and to devote the whole of his energy to the problem of combustion, notwithstanding the difficulties it presented. Many investigators had been working at the so-called plant acids in the muscular system, and had observed their capacity for intensifying oxidation in that tissue. The readiest explanation however of how that came about, viz. that they are easily combusted themselves, simply did not fit in with Szent-Györgyi's intuitive perception. By elaborating reliable methods of analysis for the substances in question, and by means of consistent experiments, he and his co-workers proved that the plant acids were not consumed by combustion, were not ordinary nutrient substances, but were on the contrary themselves active groups of catalysts which served to maintain the combustion without themselves suffering any diminution thereby. The process involves a peregrination of hydrogen more intricate than the adventurous journeys of Odysseus, though more rapid. Hydrogen is released out of the metabolic substances, probably through cooperation between Szent-Györgyi's and Warburg's co-ferment and Theorell's yellow enzyme, and encounters the plant acids, entering in that way Szent-Györgyi's's system. These acids transfer the system into the order: oxalacetic acid, malic acid, fumaric acid, and succinic acid, then, in the form of active hydrogen, to encounter the active oxygen from «the red system» and form water and free energy - a series of providentially subdued explosions which I alluded to before as a dramatic encounter. The plant acids act as catalysts by cooperation with specific proteins, and the effect of the yellow enzyme probably extends some way into this Szent-Györgyi's intermediate system.

Thus, the oxygen-activation in the red iron system and hydrogen-transfer from nutrients by the yellow metal-free system along with co-agents have been united by Szent-Györgyi through the discovery of this intermediate system. The interplay of «the red system»'s cytochrome-group and the yellow enzyme might probably also, according to Theorell, proceed directly. The flaws are numerous, but not of a character to constitute any essential breach in the highway of the oxidation-chain. Numerous ramifications of the latter however already begin to be discernible.

It is of especially great importance that at least two vitamins - C and B2, and possibly B1, and P - are in cooperation in the oxidation chain and are catalysts, illustrating the way in which these vitamins act in the organism. It may be that development in the near future will reveal the importance for our organism of copper concerning oxidation and of vitamin C with certain followers in plants, viz. oxidating enzyme, and oxidizable and reducible substances (Szent-Györgyi's flavonoles, termed vitamin P), which are capable of forming a sensitively attuned system with the vitamin, hydrogen-superoxide and proteins, or parts of them, with active and activating sulphur in the molecule. The sulphur of the alchemists of old, out of which everything was to radiate, is destined to experience a renaissance.



Professor Albert von Szent-Györgyi. As a representative for the Caroline Institute on this occasion, I am commissioned to give expression to our high estimation of your researches.

You never swerved from your unyielding purpose to study the primary and fundamental processes of biological oxidation. Entering upon this difficult field of biochemical research you soon became a pioneer by interpreting the position and real function of co-ferment as an important link in the chain of dehydrogenating catalysts. Not even your important discoveries regarding vitamin C could deter you from following a certain strain of thought. I am deducing now from a close observation of your work that you were drawing distinctions in your mind at this occasion between your interesting discovery of ascorbic acid and the bare possibility of some other audacious plans of yours coming true. At this early stage they must have involved the investigation of the fundamental mechanism of connecting hydrogen activation with that of oxygen activation. Your intuitive mind decided in favour of the possibility of success, and you won through. In the year 1933 the first signs became visible for outsiders, and from then on the pace set by you and your co-workers at Szeged was astonishing, and your results were fundamentally new and highly important. In the midst of fervent research work with most promising aspects you are the discoverer and idealist to the mind of Alfred Nobel.

I ask you, Professor Szent-Györgyi, to receive the prize from the hands of His Majesty, our gracious King.

Darwin Still Rules, but Some Biologists Dream of a Paradigm Shift

 
That's the title of an article in today's New York times. It's written by Douglas H. Erwin, "a senior scientist at the National Museum of Natural History at the Smithsonian Institution and a research professor at the Santa Fe Institute." You can read the entire article here.

Erwin says some rather silly things about "paradigm shifts" but I'll leave that to people like John Wilkins who know what Thomas Kuhn really meant. Suffice to say, the term is very much abused these days.

Putting that aside, Erwin makes some good points about the controversies in modern evolutionary theory. He points out that most of the old "paradigm" about evolution by natural selection is being challenged in one way or another. For example,

In the past few years every element of this paradigm has been attacked. Concerns about the sources of evolutionary innovation and discoveries about how DNA evolves have led some to propose that mutations, not selection, drive much of evolution, or at least the main episodes of innovation, like the origin of major animal groups, including vertebrates.

This is correct. There's a resurgence of "mutationism" that puts more emphasis on the role of mutation in evolution. This re-emphasis is not popular among evolutionary biologists but it's gaining ground.

Comparative studies of development have illuminated how genes operate, and evolve, and this places less emphasis on the gradual accumulation of small genetic changes emphasized by the modern synthesis. Work in ecology has emphasized the role organisms play in building their own environments, and studies of the fossil record raise questions about the role of competition. The last major challenge to the modern synthesis came in the 1970s and 1980s as my paleontological colleagues, including the late Stephen Jay Gould, argued for a hierarchical view of evolution, with selection occurring at many levels, including between species.

Again, these new ideas are all in play in modern evolutionary theory. The first refers to "evo-devo" and there's no question that some evolutionary biologists are rethinking evolution in light of the discoveries in developmental biology. (I think they're wrong, but that's not the point here.)

The last item refers to punctuated equilibria and hierarchical theory. There's little doubt that Gould's ideas have shaken up the old "paradigms."

I was disappointed that Erwin omitted the biggest threat to the old view of evolution, namely random genetic drift. While we've known about drift for decades the full scale of it's role in evolution is only now beginning to be appreciated. Most people still don't realize that random genetic drift is by far the most common mechanism of evolution.

[Hat Tip: Greg Laden]

Monday's Molecule #32

 
Today's molecule is very simple. We don't need a long complicated name this time; the short common name will do. (But you're welcome to supply the IUPAC name if you know it.) The trick here is to recognize why this molecular is important and then connect it to Wednesday's Nobel Laureate(s).

Here's a hint; with hindsight, this is probably one of the most undeserving Nobel Prizes in the biological sciences.

The reward (free lunch) goes to the person who correctly identifies the molecule and the Nobel Laureate(s). Previous free lunch winners are ineligible for one month from the time they first collected the prize. There's only one (Marc) ineligible candidates for this Wednesday's reward since many recent winners haven't collected their prize. The prize is a free lunch at the Faculty Club. I've been eating there a lot recently because we've had many meeting concerning an upcoming big event at the Faculty Club on this Friday evening. (My daughter, Jane, is getting married.)

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Is antibiotic resistance evidence for Darwinian evolution?

 
Here's a short video where the IDiots discuss antibiotic resistance in bacteria. This is part of the new attack on evolution. It's the main point of Michael Behe's new book, The Edge of Evolution. The idea is that random mutation and natural selection can only break things but they can't make new structures.

I suspect that very few people can scientifically refute the arguments in this video. It can be done, but it's going to take a bit of effort.