Theme: Blood Clotting

 

Theme

Blood Clotting
March 26, 2007
Monday's Molecule #19. Warfarin—an anticoagulant and a rat poison.

March 27, 2007
Vitamin K. Vitamin K plays an important role in blood clotting.

March 28, 2007
Nobel Laureates: Dam and Doisy. Dam: "for his discovery of vitamin K" Doisy: "for his discovery of the chemical nature of vitamin K"

April 2, 2007
Monday's Molecule #20. Heparin—an anticoagulant.

April 2, 2007
Blood Clotting: The Basics. Fibrinogen and how it forms clots.

April 4, 2007
Nobel Laureate: Arne Tiselius. ""for his research on electrophoresis and adsorption analysis, especially for his discoveries concerning the complex nature of the serum proteins"


April 4, 2007
Blood Clotting: Platelets. What are platelets and how do they form blood clots?

April 4, 2007
Blood Clotting: Extrinsic Activity and Platelet Activation. Description of the activity of thrombin and the activation of blood platelets.

April 5, 2007
Blood Clotting: Intrinsic Activity. The role of factors VIII and IX. Deficiencies in Factor VIII cause hemophilia A an X-linked form of hemophilia that was common in European royal families descending from Queen Victoria.

April 8, 2007
Genes for Hemophilia A & B and von Willebrand disease. Locations of the F8, F9 and vWF genes on human chromosomes X and 12.

April 12, 2007
Inhibiting Blood Clots: Anticoagulants. How does heparin inhibit blood clotting?

April 15, 2007
Human Anticoagulant Genes. Mapping the genes for anticoagulant factors.

April 16, 2007
Dicumarol and Warfarin Inhibit Blood Clotting. The role of vitamin K in blood clotting.

September 26, 2007
A Synthetic Anticoagulant Related to Heparin. Synthesis of a new anticoagulant to replace heparin.

April 26, 2008
Fibrin and Blood Clots. What does a blog clot look like?

May 10, 2008
On the Evolution of the Blood Clotting Pathway.
Ian Musgrave explains Russel Doolittle's latest results.

The Signal Hypothesis

 
Monday's Molecule #44 is signal recognition particle or SRP. The figure is a model of SRP (red) bound to a ribosome at the exit site of the tunnel in the large subunit (white asterisk) (Schaffitzel et al. 2006). In the right-hand version of the model you can see that SRP is made up of an RNA molecule and associated proteins.

Signal recognition particle is an important component of the secretory pathway. The mechanism of secretion in response to a signal on the growing polypeptide is known as the Signal Hypothesis. Here's how we describe it in our textbook Principles of Biochemistry 4/e.

Secreted proteins are synthesized on the surface of the endoplasmic reticulum, and the newly synthesized protein is passed through the membrane into the lumen. In cells that make large amounts of secreted protein, the endoplasmic reticulum membranes are covered with ribosomes.

The clue to the process by which many proteins cross the membrane of the endoplasmic reticulum appears in the first 20 or so residues of the nascent polypeptide chain. In most membrane-bound and secreted proteins, these residues are present only in the nascent polypeptide, not in the mature protein. The N-terminal sequence of residues that is proteolytically removed from the protein precursor is called the signal peptide since it is the portion of the precursor that signals the protein to cross a membrane. Signal peptides vary in length and composition, but they are typically from 16 to 30 residues long and include 4 to 15 hydrophobic residues.

In eukaryotes, many proteins destined for secretion appear to be translocated across the endoplasmic reticulum by the pathway shown in the Figure. In the first step, an 80S initiation complex—including a ribosome, a Met-tRNA_i^Met molecule, and an mRNA molecule—forms in the cytosol. Next, the ribosome begins translating the mRNA and synthesizing the signal peptide at the N-terminus of the precursor. Once the signal peptide has been synthesized and extruded from the ribosome, it binds to a protein-RNA complex called a signal recognition particle (SRP).

SRP is a small ribonucleoprotein containing a 300-nucleotide RNA molecule called 7SL RNA and four proteins. SRP recognizes and binds to the signal peptide as it emerges from the ribosome. When SRP binds, further translation is blocked. The SRP-ribosome complex then binds to an SRP receptor protein (also known as docking protein) on the cytosolic face of the endoplasmic reticulum. The ribosome is anchored to the membrane of the endoplasmic reticulum by ribosome-binding proteins called ribophorins, and the signal peptide is inserted into the membrane at a pore that is part of the complex formed by the endoplasmic reticulum proteins at the docking site.

Once the ribosome-SRP complex is bound to the membrane, the inhibition of translation is relieved and SRP dissociates in a reaction coupled to GTP hydrolysis. Thus, the role of SRP is to recognize nascent polypeptides containing a signal peptide and to target the translation complex to the surface of the endoplasmic reticulum.

Once the translation complex is bound to the membrane, translation resumes and the new polypeptide chain passes through the membrane. The signal peptide is then cleaved from the nascent polypeptide by a signal peptidase, an integral membrane protein associated with the pore complex. The transport of proteins across the membrane is assisted by chaperones in the lumen of the endoplasmic reticulum. In addition to their role in protein folding, chaperones are required for translocation, and their activity requires ATP hydrolysis. When protein synthesis terminates, the ribosome dissociates from the endoplasmic reticulum, and the translation complex disassembles.

©:L.A. Moran and Pearson/Prentice Hall

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Horton, H.R., Moran, L.A., Scrimgeour, K.G., Perry, M.D. and Rawn, J.D. (2006) Principles of Biochemistry, 4th edition. Pearson Prentice Hall, Upper Saddle River NJ (USA)

Schaffitzel, C., Oswald, M., Berger, I., Ishikawa, T., Abrahams, J.P., Koerten, H.K., Koning, R.I. and Ban, N. (2006) Structure of the E. coli signal recognition particle bound to a translating ribosome. Nature 444:503-506.

BPR3 Icon Winner

 
This is the winner in the Bloggers for Peer-Reviewed Research Reporting icon contest [… And the winner is …]. We're not supposed to start using it just yet because the designer, Uriel Klieger, is going to make a few changes based on suggestions from bloggers.

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[Hat Tip: Scienceroll who thinks that there are only two science bloggers who link to references properly. And I'm not one of them. Boo!]

Nobel Prize Gossip

 
Alex Palazzo has a wonderful and very complete list of potential Nobel Prize winners [Gaze into the crystal ball - Nobel Prize Gossip].

What do you think? Get involved in the debate on The Daily Transcript. My vote goes to James Till and Ernest McCulloch, but I may be a bit biased. I hope Alex is also rooting for the Canucks.

The Physiology & Medicine Prize will be announced on Monday, October 8th and the Chemistry Prize will be announced on Wednesday, October 10th.

How to Get Tenure

 
Janet Stemwedel is about to submit her tenure dossier. She describes the process and the dossier on Adventures in Ethics and Science [A postcard from academe: my tenure dossier]. It's worth a read to see how the process works. Note that Janet has included a section on blogging and her department recognizes that as a legitimate academic pursuit.

Good luck, Janet, although I really don't think you'll need it.

Random Genetic Drift and Population Size

One of the most persistent myths of evolutionary biology is that random genetic drift only occurs in small populations. You'll find this myth everywhere you look, even in textbooks that should know better. A few minutes ago I was looking for a simple way to explain this in the comments section of P-ter Accuses Me of Quote Mining when I came across this explanation in Modern Genetic Analysis by Anthony Griffiths, William Gelbart, Jeffrey Miller, and Richard Lewontin (1999 edition). This is the offspring of a textbook that David Suzuki started many years ago [ 17. Population and Evolutionary Genetics].

One result of random sampling is that most new mutations, even if they are not selected against, never succeed in entering the population. Suppose that a single individual is heterozygous for a new mutation. There is some chance that the individual in question will have no offspring at all. Even if it has one offspring, there is a chance of 1/2 that the new mutation will not be transmitted. If the individual has two offspring, the probability that neither offspring will carry the new mutation is 1/4 and so forth. Suppose that the new mutation is successfully transmitted to an offspring. Then the lottery is repeated in the next generation, and again the allele may be lost. In fact, if a population is of size N, the chance that a new mutation is eventually lost by chance is (2N − 1)/2N (For a derivation of this result, which is beyond the scope of this book, see Chapters 2 and 3 of Hartl and Clark, Principles of Population Genetics.) But, if the new mutation is not lost, then the only thing that can happen to it in a finite population is that eventually it will sweep through the population and become fixed. This event has the probability of 1/2N In the absence of selection, then, the history of a population looks like Figure 17-17. For some period of time, it is homozygous; then a new mutation appears. In most cases, the new mutant allele will be lost immediately or very soon after it appears. Occasionally, however, a new mutant allele drifts through the population, and the population becomes homozygous for the new allele. The process then begins again.

Even a new mutation that is slightly favorable selectively will usually be lost in the first few generations after it appears in the population, a victim of genetic drift. If a new mutation has a selective advantage of S in the heterozygote in which it appears, then the chance is only 2S that the mutation will ever succeed in taking over the population. So a mutation that is 1 percent better in fitness than the standard allele in the population will be lost 98 percent of the time by genetic drift.

The fact that occasionally an unselected mutation will, by chance, be incorporated into a population has given rise to a theory of neutral evolution, according to which unselected mutations are being incorporated into populations at a steady rate, which we can calculate. If the mutation rate per locus is μ, and the size of the population is N, so there are 2N copies of each gene, then the absolute number of mutations that will appear in a population per generation at a given locus is 2Nμ. But the probability that any given mutation is eventually incorporated is 1/2N so the absolute number of new mutations that will be incorporated per generation per locus is (2Nµ)(1/2N) = µ If there are k loci mutating, then in each generation there will be kμ newly incorporated mutations in the genome. This is a very powerful result, because it predicts a regular, clocklike rate of evolution that is independent of external circumstances and that depends only on the mutation rate, which we assume to be constant over long periods of time. The total genetic divergence between species should, on this theory, be proportional to the length of time since their separation in evolution. It has been proposed that much of the evolution of amino acid sequences of proteins has been without selection and that evolution of synonymous bases and other DNA that neither encodes proteins nor regulates protein synthesis should behave like a molecular clock with a constant rate over all evolutionary lineages. Different proteins will have different clock rates, depending on what portion of their amino acids is free to be substituted without selection.

This is an important conclusion. It shows that alleles are fixed in large populations by random genetic drift. I'd like it a lot if people would stop saying that drift only occurs in small populations.

Random Genetic Drift Simulation

 
We often talk about Random Genetic Drift on Sandwalk. Here's a handy-dandy simulator to help you understand the concept [Genetic Drift].

P-ter Accuses Me of Quote Mining

 
There are many adaptationists who recognize that random genetic drift exists. They will, when pressed, admit that neutral alleles can be fixed in a population. However, these adapationists pften maintain that visible phenotypes cannot be neutral with respect to survivability. Thus all visible phenotypes, with rare exceptions, are adaptations.

Several people have expressed this point of view in the comments on Sandwalk but the most prominent proponent is Richard Dawkins. I often use a quotation from The Extended Phenotype to demonstrate how Dawkins thinks about this issue. It comes from a chapter titled Constraints on Perfection. Here's the complete paragraph; I often use just the part that begins "The biochemical controversy ....[Richard Dawkins on Visible Changes and Adaptationism].

I have tried to show that adapatationism can have virtues as well as faults. But this chapter's main purpose is to list and classify constraints on perfection, to list the main reasons why a student of adaptation should proceed with caution. Before coming to my list of six constraints on perfection, I should deal with three others that have been proposed, but which I find less persuasive. Taking first, the modern controversy among biochemical geneticists about "neutral mutations", repeatedly cited in critiques of adaptationism, it is simply irrelevant. If there are neutral mutations in the biochemist's sense, what this means is that any change in polypeptide structure which they induce has no effect on the enzymatic activity of the protein. This means that the neutral mutations will not change the course of embryonic development, will have no phenotypic effect at all, as a whole-organism biologist would understand phenotypic effect. 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.

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.

Richard Dawkins
The Extended Phenotype (2005)I have discussed this quotation with Richard Dawkins and I am convinced that it fairly represents his viewpoint. The only quibble would be that Dawkins would probably admit of one or two exceptions where neutral alleles might produce a phenotypic effect. In other words, his statement above is perhaps an example of hyperbole but that's how I always read it anyway. Almost all popular science writers make generalizations of this sort and it's not a great crime.

The bottom line is that Dawkins thinks that neutral mutations cannot have an effect on embryonic development; therefore, they cannot result in a visible phenotype. Dawkins believes that almost all visible mutations will have either a beneficial or a detrimental effect on the survivability of an organism and that neutral mutations are a phenomenon that's confined to the molecular level where they may not even count as evolution.

P-ter thinks that I misrepresent Dawkins by quote mining [Larry Moran caught quote mining]. Here's what P-ter says,

This certainly seems to place Dawkins as an "adaptationist", one who thinks that all differences in phenotypes are adaptations. I was a little surprised by this, but the quote seemed clear, and I wasn't going to take the time to find my original.

Luckily, another commenter pointed out that The Extended Phenotype is searchable at Google Books [The Extended Phenotype]. And funny, the very next line after Moran stops quoting is possibly relevant:

The next lines P-ter is referring to is the beginning of a new paragraph ...

He might, nevertheless, be dealing with a neutral character in the sense of an earlier controversy (Fisher & Ford 1950; Wright 1951). A genetic difference could show itself at the phenotypic level, yet still be selectively neutral.

P-ter then continues with ...

Dawkins goes on to express some skepticism about some arguments for evolution by drift, but he's certainly not an "adaptationist" in the Moran sense.

I suppose I'm somewhat naive: distorting someone's argument through selective quotation is a classic creationist tactic, and Moran has written a bit about the propaganda techniques used by that crowd. Little did I know his familiarity is not of an entirely academic sort.

[1] As opposed to "pluralists", as he likes to call himself. For someone who (rightfully, in my opinion) is disdainful of "framing" (the view that scientists need to spin their results in order to resonate better with the public), he certainly knows how to frame.

This is a very serious charge. I'm accused of deliberately distorting Dawkins' position by selective quotation. According to P-ter, Dawkins does not believe what he says in the quoted paragraph. (And elswhere, I might add.) According to P-ter Dawkins believes that mutations with a visible phenotype can be neutral. (We're not talking about one or two exceptions here, we're talking about the generality that applies to a significant percentage of mutations.)

P-ter's evidence of the crime of quote mining is the first two sentences of a paragraph that appears on the bottom of page 32. You can read it for yourself but it seems obvious to me that Dawkins is raising a possible objection to his claim and then dismissing it. Here are the first few (not just two) sentences of that paragraph: I think they convey the correct intent.

He might, nevertheless, be dealing with a neutral character in the sense of an earlier controversy (Fisher & Ford 1950; Wright 1951). A genetic difference could show itself at the phenotypic level, yet still be selectively neutral. But mathematical calculations such as those of Fisher (1930b) and Haldane (1932a) show how unreliable human subjective judgement can be on the "obviously trivial" nature of some biological characters. Haldane, for example, showed that, with plausible assumptions about a typical population, a selection pressure as weak as 1 in a 1000 would take only a few thousand generations to push an initially rare mutation to fixation, a small time by geological standards. It appears that in the controversy referred to above, Wright was misunderstood (see below) ...

A careful reading of Dawkins shows that the objection to his claim doesn't stand because people misunderstood Wright. Thus, according to Dawkins, characters that appear to be neutral really aren't.

I maintain that my original characterization of the Dawkins' position is accurate and his words reflect his true beliefs. I resent P-ter's accusation that I deliberately tried to misrepresent Dawkins by quoting that passage.

Incidentally, P-ter puts words in my mouth. I recognize several different kinds of adaptationist. The worst of them are those who think every visible phenotype is an adaptation of some sort but there are many who do not hold this extreme position. It's simply not true that I say every adaptationist must deny the fixation of neutral alleles with a visible phenotype. Some are easier to mock than others, but it's pretty easy to get most of them going whenever I point out that Dawkins is an adaptationist.

Gene Genie #16

 

The 15th edition of Gene Genie has just been published on Neurophilosophy [Gene Genie #16].

There are several articles on personal genomics and the genomes of Craig Venter and Jim Watson.

Monday's Molecule #44

 
UPDATE: We have a winner. See comments.

Today's molecule (in red) is part of a larger complex. There are two view of this complex in the figure. You have to supply the common name of this molecule—the one colored red in the complex. There's a direct connection between this molecule and Wednesday's Nobel Laureate(s).

The reward 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. The prize is a free lunch at the Faculty Club.

Send your guess to Sandwalk (sandwalk(at)bioinfo.med.utoronto.ca) and I'll pick the first email message that correctly identifies the molecule and the Nobel Laureate(s). Correct responses will be posted tomorrow along with the time that the message was received on my server. This way I may select multiple winners if several people get it right.

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

Iranian President Mahmoud Ahmadinejad Speaks at Columbia University

 
Tomorrow President Mahmoud Ahmadinejad of Iran will speak at Columbia University. There are some who argue that universities should not invite controversial speakers. There are some who argue that Iran is the "enemy"—a member of the axis of evil—and once an enemy has been identified, and vilified, you must never allow them to speak in their own defense. It's especially horrible, according to these people, to allow a publicly-funded university to sponsor such a person.

Those people are dead wrong. Fortunately, the President of Columbia University has the gumption to stand up to those who would destroy the universities and free society [President Bollinger's Statement About President Ahmadinejad's Scheduled Appearance].

I would like to add a few comments on the principles that underlie this event. Columbia, as a community dedicated to learning and scholarship, is committed to confronting ideas—to understand the world as it is and as it might be. To fulfill this mission we must respect and defend the rights of our schools, our deans and our faculty to create programming for academic purposes. Necessarily, on occasion this will bring us into contact with beliefs many, most or even all of us will find offensive and even odious. We trust our community, including our students, to be fully capable of dealing with these occasions, through the powers of dialogue and reason.

I would also like to invoke a major theme in the development of freedom of speech as a central value in our society. It should never be thought that merely to listen to ideas we deplore in any way implies our endorsement of those ideas, or the weakness of our resolve to resist those ideas or our naiveté about the very real dangers inherent in such ideas. It is a critical premise of freedom of speech that we do not honor the dishonorable when we open the public forum to their voices. To hold otherwise would make vigorous debate impossible.

That such a forum could not take place on a university campus in Iran today sharpens the point of what we do here. To commit oneself to a life—and a civil society—prepared to examine critically all ideas arises from a deep faith in the myriad benefits of a long-term process of meeting bad beliefs with better beliefs and hateful words with wiser words. That faith in freedom has always been and remains today our nation’s most potent weapon against repressive regimes everywhere in the world. This is America at its best.

If you don't understand this then you don't understand anything about the purpose of a university and the importance of listening to the other side.

What Happens When Alternative Medicine Doesn't Work?

 
Skeptico reports that Merck has just pulled a new AIDs drig because tests were showing that it didn't work [When will CAM do this?]. That's the way the system is supposed to work.

The sound, effective kind of medicine is based on science and evidence. Medicine that is not evidence-based is called "alternative." "complementary" or "traditional" medicine. Don't be fooled by these terms. They all mean the same thing; namely, that the medicine doesn't pass the test of evidence-based.

Skepico asks when was the last time that an alternative treatment was canceled because it wasn't working? There are lots of examples in the posting.

Homeopaths pulling (say) Belladonna for the treatment of urinary tract infections, because they determined it doesn’t work for that.

Astronomy Picture of the Day: Sept. 22, 2007

 
Today's Astronomy Picture of the Day is a bit unusual. It shows a time in the distant future when I'll be able to drive from Toronto to Cape Town in just a few days. Unfortunately, Cape Town will no longer be on the cape.

Jena, Louisiana

 
Jena is a small town in Louisiana. It was named for Jena in Germany, the site of a famous victory by Napoleon in 1806. I'm a (very amateur) student of military history so I'm familiar with this battle [Battle of Jena-Auerstedt].

The American town is in the news because of allegations of racism at the local high school. The local prosecutor seems to have been motivated by less than honorable motives in charging six young black men with attempted murder in a schoolyard fight.

While watching coverage on television, I was struck by the modern name of the town. It's pronounced "Geena" in Louisiana. There's nothing wrong with this. They can call pronounce the name of the town however they want. But just for the record, the name of the German city, and the battle, is pronounced "yaene." You can hear it here: Jena.

The Dangers of Creationism in Education

 
The Committee on Culture, Science and Education of the Parliamentary Assembly, Council of Europe has issued a report on The dangers of creationism in education. One of the most interesting parts of this report is that the committee does not back away from labeling Intelligent Design as a form of creationism. For example, in the opening paragraphs the report says,

Creationism in any of its forms, such as “intelligent design”, is not based on facts, does not use any scientific reasoning and its contents are definitely inappropriate for science classes.

However, some people call for creationist theories to be taught in European schools alongside or even in place of the theory of evolution. From a scientific view point, there is absolutely no doubt that evolution is a central theory for our understanding of life on Earth.

The Assembly calls on education authorities in member states to promote scientific knowledge and the teaching of evolution and to oppose firmly any attempts at teaching creationism as a scientific discipline.

Later on they define creationism using a great deal of common sense.

Creationists question the scientific character of certain items of knowledge and argue that the theory of evolution is only one interpretation among others. They accuse scientists of not providing enough evidence to establish the theory of evolution as scientifically valid. On the contrary, they defend their own statements as scientific. None of this stands up to objective analysis. ...

Creationism has many contradictory aspects. The “intelligent design” idea, which is the latest, more refined version of creationism, does not deny a certain degree of evolution but claims that this is the work of a superior intelligence. Though more subtle in its presentation, the doctrine of intelligent design is no less dangerous.

I will continue to refer to Intelligent Design Creationism as an accurate representation of the views of people like Dembski, Behe, Phillips etc. Their allies, like Denyse O'Leary, are also creationists by my definition. They aren't Young Earth Creationists, they are Intelligent Design Creationists.

Readers might recall that I have been accused of inventing a new definition of "creationism" [Creationism Continuum]. Some people, even evolutionists, think that the only creationists are those who believe in the literal truth of Genesis. They maintain that it is wrong to refer to intelligent design proponents as creationists. Obviously, I disagree and I'm not alone. In fact, I'd go one step farther than the Committee on Culture, Science and Education, I'd say that Theistic Evolutionists are also creationists because they believe in a creator.

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[Hat Tip: Panda's Thumb]