A Synthetic Anticoagulant Related to Heparin

 
Heparin (left) is an oligosaccharide bound to a very specific protein to form heparin proteoglycan. The physiologically important oligosaccharide is called heparan sulfate. It is found on the surface of normal endothelial cells and it is this molecule that binds antithrombin III. The interaction of heparan sulfate and antithrombin III inhibits blood clotting [Inhibiting Blood Clots: Anticoagulants].

It is very difficult to synthesize heparan sulfate so the synthetic drug is quite expensive. The results of a number of studies indicated that the exact structure of each of the sugar residues (rings) was very important for proper anticoagulant activity as was the position of the sulfate groups (those with "S" that are bound to the rings).

Theme

Blood Clotting
A recent paper by Chen et al. (2007) shows that simpler forms of the heparin-like oligosaccharide have significant anticoagulation activity. They started with a compound called N-sulfo heparosan, which is prepared from bacterial oligosaccharides by a combination of enzymatic and chemical steps. This starting material was then modified using various recombinant enzymes to produce a large class of heparin-like molecules. One of these derivatives, recomparin (below left) (Lindhardt and Kim, 2007) had significant anticoagulation activity. (Click on the figure to enlarge.)


The result is significant because recomparin does not have the modified rearranged sugar (iduronic acid, IdoUA)that was previously thought to be essential for anticoagulation activity. The modification of the oligosacchraide to create the iduronic acid residues was complicated an inefficient. Thus, the new recomparin drug will be much cheaper to make.

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Chen, J., Jones, C.L. and Liu, J. (2007) Using an Enzymatic Combinatorial Approach to Identify Anticoagulant Heparan Sulfate Structures. Chemistry & Biology 14: 972-973.

Lindhardt, R.J. and Kim, J-H. (2007) Combinatorial Enzymatic Synthesis of Heparan Sulfate (review of Chen et al. 2007). Chemistry & Biology 14:972-973.

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]

MMP: The Belgium Connection

 
I've encountered many critics of the Mixed Member Proportional system who are uttering the same mantra. It includes the phrase "Belgium has 33 parties." I think this is meant to be a criticism of the MMP system. Those who mention the mantra often associate it with the fact that Belgian politicans have had trouble forming an effective government since the June 10, 2007 election.

I suspect there's a common source for this Belgian story. Does anyone know where it comes from?

Here are the facts as I know them. True, there were 33 parties contesting the last election in Belgium. But only 11 of them won seats in parliament (see below). In Canada there were 5 parties with seats in parliament for most of the 1990's and that was with a First-Past-the-Post system. In the last federal election in Canada there were 21 parties seeking election [Canadian Political Parties]. This includes my favorite, the Rhinoceros Party of Canada. The Green Party didn't win a single seat in spite of the fact that it got 4.5% of the vote. The Bloc got 51 seats with 10.5% of the vote. We have a minority government in Ottawa.

Belgium has a full Proportional Representation system. In Ontario we're being asked to consider a Mixed Member Proportional system. They aren't the same thing. The Belgian example doesn't seem to be particularly relevant to the Ontario debate.

Life in Modern Iraq.

 
Maclean's magazine has the story by Patrick Graham [How George Bush became the new Saddam].

It was embarrassing putting my flak jacket on backwards and sideways, but in the darkness of the Baghdad airport car park I couldn’t see anything. “Peterik, put the flak jacket on,” the South African security contractor was saying politely, impatiently. “You know the procedure if we are attacked.”

I didn’t. He explained. One of the chase vehicles would pull up beside us and someone would drag me out of the armoured car, away from the firing. If both drivers were unconscious—nice euphemism—he said I should try to run to the nearest army checkpoint. If the checkpoint was American, things might work out if they didn’t shoot first. If it was Iraqi . . . he didn’t elaborate.

Arriving in Baghdad has always been a little weird. Under Saddam Hussein it was like going into an orderly morgue; when he ran off after the U.S.-led invasion of March 2003 put an end to his Baathist party regime, the city became a chaotic mess. I lived in Iraq for almost two years, but after three years away I wasn’t quite ready for just how deserted and worn down the place seemed in the early evening. It was as if some kind of mildew was slowly rotting away at the edges of things, breaking down the city into urban compost.

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[Hat Tip: Jennifer smith Best Cover. Ever]

Street Art

 

BigHeathenMike says this is the coolest street art he's ever seen[Wow]. Who could argue with that? Go to Mike's Weekly Skeptic Rant to find out where this drawing came from.

Avery, MacLeod and McCarty (1944)

 

This weeks classic on John Dennehy's blog is the famous Avery, MacLeod and McCarty (1944) paper [This Week's Citation Classic]. If you already know about this paper then wander on over to The Evolutionary Biologist whenever you get a chance and refresh your memory. If you don't know what the heck we're talking about then get your butt over there immediately and correct this major deficiency in your education!

Not only was Oswald Avery one of the greatest scientists of the modern era, he was also a Canadian!

What's She Holding in her Hand?

 
Check out Eva's blog easternblot for a cartoon she just posted [Scientist Illustration]. What is the scientist holding in her hand? Try and figure it out for yourself before reading Eva's answer.

Vote for MMP

 


I'm voting for the Mixed Member Proportional (MMP) electoral system on October 10th [Vote for MMP] [Mixed Member Proportional Electoral System].

See Bloggers for MMP for a complete list.

Canadian Dollar = American Dollar

 
Today, for the first time in 30 years the value of the Canadian dollar (loonie) reached parity with the American dollar. It's big news in Canada. Most people think it's a good thing but it's not necessarily a good thing at all. A falling (collapsing?) US currency may be good for America and bad for Canada. [Click on the chart to enlarge.]

If you want to see one reason why this isn't good for Canadians see Jennifer Smith's posting The Parity Blues.

New Panda's Thumb

 
Check it out at Panda's Thumb.

A lot of people put a great deal of work into the upgrade but the person who deserves the most praise is Reed Cartwright of De Rurum Natura (and Panda's Thumb). You can thank him by going to Upgrade Starts Today.

In case you didn't know. The unofficial mascot at the Panda's Thumb is Prof. Steve Steve. Isn't he a handsome fellow? I think he's a biochemist—or possibly a paleontologist. I always get them mixed up.

Reed Cartwright is the father of Prof. Steve Steve. He's also the father of Prof. Steve Steve and Prof. Steve Steve. They have left home to gallivant around the world but they can often be found in North Carolina or Oakland CA.

There are quite a few bloggers on Panda's Thumb. I don't have a complete list but they include most of the leading lights in the fight against creationism in the USA. Some of them are adaptationists but don't let that deter you. It's good to hear what the other side has to say from time to time. (The adaptationists usually refer to the blog as Mt. Improbable. The unofficial mascot of the adaptationists is Prof. Dick Dick. )

If you aren't reading Panda's Thumb on a regular basis, now is a good time to start. There should be lots of postings as soon as the site is ready.

Mixed Member Proportional Electoral System

 
The people of Ontario will vote in a referendum on October 10th. The question on the ballot is whether to adopt a new voting mechanism called "Mixed Member Proportional." The new system is described on the government website [Ontario is facing a big decision].

Here's a brief summary of the new system.

If this system is accepted, Ontarians will have two votes in future elections: one for a ‘Local Member’ and one for a political party.

The provincial legislature would have 129 seats: Local Members’ would fill 90 seats while ‘List Members’ would fill 39 seats.

The political party with the largest number of seats in the legislature, including ‘Local Members’ and ‘List Members’, is asked to form a government.

In each electoral district, one vote would be used to elect a 'Local Member' using a First-Past-the-Post system. The candidate with the most votes in an electoral district wins.

The other vote would be for a political party. Votes for parties will be used to determine the number of 'List Members' each party gets. This is the proportional representation part.

If a political party is entitled to more seats than it won locally, 'List Members' are elected to make up the difference. 'List Members' can only be elected from a political party that received more than 3% of these votes.

In the end, a political party's overall share of seats will roughly equal its share of the total votes for parties in the province.

Anyone who meets the rules for eligibility can become a candidate for election as a ‘Local Member’. Some candidates are called “independents” while others represent a political party.

‘List Members’ are candidates from any registered political party. Before an election each political party prepares an ordered list of candidates they would like considered as ‘List Members’.

These lists, and the way they are created, would be made public well in advance of any election in a Mixed Member Proportional system.

I favor the new system because my vote will no longer be wasted if I don't like the candidate who is going to win in my riding. Furthermore, I like the idea that the new system will be more representative of the voters wishes. In many cases this will lead to minority governments and coalitions but that's what we want.

I also like the idea that members can be elected from the lists. While the fear is that this will favor party hacks, the fear is outweighed by the major benefit in my opinion. People who would be excellent additions to the legislature could be elected even if they are not good campaigners. Leaders and cabinet members/critics, if elected from the list, would not have to divide their time between government business and constituency business.

Perhaps some of you who have experienced this system first hand could comment on the benefits and drawbacks? In order to pass the referendum has to be accepted by 60 per cent of all votes cast across Ontario and 50 per cent or more of the ballots cast in at least 64 of 107 ridings. There's a poll running at Mixed Member Proportional. As of today the new system has 60% of the votes.

Calling All Adaptationists (Again)

 
Have I got a treat for you! Before getting to the special excitement, let me congratulate all of you adapationists for your outstanding performance in the last contest [Calling All Adaptationists]. You did a marvelous job of making up stories to explain homosexuality in humans. Rudyard Kipling would have been proud [Just-So Stories].

Your mission for today, should you choose to accept it, is to explain odorous urine (smelly pee).

Here's the data. Some people produce odorous urine when they eat asparagus. They can transform the chemical, asparagusic acid (1,2-dithiolane-4-carboxylic acid), into smelly compounds like methanethiol, dimethyl sulfide, dimethyl disulfide, bis(methylthio)methane, dimethyl sulfoxide, and dimethyl sulfone (Mitchell, 2001). Other people can eat asparagus 'till the cows come home and their urine remains as pleasantly smelling as usual. The allele for producing the smell is an autosomal dominant trait.

There's an additional complication. Some people can't smell the odorous urine. There's no linkage between excretors and perceivers (able to smell the urine). Some can excrete but not smell and some can excrete and smell. All permutations exist in the population.

This ability to excrete smelly compounds and the ability to smell them are both examples of visible phenotypes. They're not just some neutral variation hiding away in junk DNA. Therefore, many (most?) adaptationists will certainly insist that it has to have an adaptive role in human evolution.

This is untilled soil, as far as I can gather. For some reason the experts haven't published the explanation. At least there's nothing I could find after hunting on the internet. You could become famous if your story makes sense. Let's see what you can come up with. I'll get you started ....

Once upon a time there were naked hunter men running on the savannah while their gatherer wives collected asparagus in the deep water by the sea shore ....

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Mitchell, S.C. (2001)
Food Idiosyncrasies: Beetroot and Asparagus. Drug Metabolism and Disposition 4(2):539-543.

Are These Dappers?

 
Is the first figure a dapper? How about the second figure? What about the third Figure, isn't he dapper in his nice suit?

Check out the definition of this new word from Ryan Gregory, Dog's Ass Plots (DAPs).

The Sun Revolves Around France

 
I thought the The View would take first prize when it comes to recent stupidity on TV but here's a contender. The contestant doesn't know whether the sun goes around the Earth or not so he polls the audience. 56% of them say yes.

The French accept evolution. Now we have to work on astronomy. I sure hope Phil Plait of Bad Astronomy doesn't see this.

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[Hat Tip: Casey Luskin (really!) [The French Reject Prayer while Accepting Evolution and Geocentrism]]

Toronto Catholic District School Board Allows HPV Vaccine

 
In the fight against superstition there are good days and there are bad days. Today is one of the good days when the Toronto Catholic School Board rejected the advice of the Catholic bishops and decided to go ahead with the HPV vaccination program [Catholic trustees vote to allow HPV vaccine in schools].

TORONTO -- In a move keeping with their counterparts across the province, trustees at the Toronto Catholic District School Board overwhelmingly voted in favour of allowing public health nurses to administer the controversial HPV vaccine in its schools.

After a discussion that lasted more than 90 minutes, trustees voted 9-3 in favour of the motion, rightly putting the health of their daughters over morality, one trustee said.

"I sure don't want to know that the headlines in two decades will read 'Catholic women lead in deaths for cervical cancer,' " trustee Maria Rizzo said during a passionately delivered statement to the board.

"I have a 16-year-old daughter. I'm sorry she's not in Grade 8."

In a separate motion brought forward by Ms. Rizzo, the board also agreed to lobby other levels of government to expand the free vaccination program to all eligible women.

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[Photo Credit: The photograph shows the Most Reverend James Wingle, D.D., Bishop of St. Catharines, President of the Ontario Conference of Catholic Bishops, whose advice was rejected by the Toronto Catholic School Borad.]

Evo-Devo: Innovation and Robustness in Evolution

When I first read the paper by Ciliberti et al. (2007) I was disappointed. On the surface, the paper seems to be addressing an important issue in evolutionary theory; namely, how can you get significant innovation in light of the fact that most biological systems resist change? On closer reading, however, it seemed more complicated than that. The authors were actually dealing with a phenomenum called "robustness." This is a popular description of a simple fact—the fact that many mutations are neutral so that there can be many variants of a protein that all carry out the same function. This has been known for decades.

The people who use the word "robustness" tend to elevate it to a level of significance that makes me nervous. Furthermore, they rarely use the term "random genetic drift" or "accident" in their papers, giving the impression that "robustness" is an adaptation that favors evolution.

There's much to criticize in the field of evolutionary developmental biology or evo-devo. Some of the "theories" are little more than wide-eyed speculation. I'm thinking particularly of The Plausibility of Life by Marc Kirschner and John Gehart.
Animal Chauvinism
That's one of the problems I have with this paper. The other problem is that it's a modeling paper. The authors create a model of evolution and demonstrate that their model produces systems that evolve. I have a problem with these models. While a mathematical model is useful to show that a mechanism can work, it does not prove that it does work.

Let me give a quick example to show you why I'm skeptical of claims by modelers. It is possible to model a Lamarckian process where species inherit acquired characteristics. The result will be evolution but that does not mean that the inheritance of acquired characteristics is a real mechanism of evolution. This point is not always made clearly in papers that describe mathematical models of evolution. To often, the fact that the model produces evolution is taken as evidence that the assumptions in the model are correct and it is an accurate representation of real biological evolution. This is the same problem with just-so stories [Just-So Stories].

Let's see how Ciliberti et al. (2007) set up their experiments in the introduction to the paper.

Biologists increasingly realize that genetic systems need to be robust to both genetic and nongenetic change (7–14). Robustness means that a system keeps performing its function in the face of perturbations. For example, many proteins can continue to catalyze chemical reactions, regulate transcription, communicate signals, and serve other roles despite mutations changing many amino acids; regulatory gene networks continue to function despite noisy expression of their constituent genes; embryos continue to develop normally even when faced with substantial environmental variation. Mutational robustness means that a system produces little phenotypic variation when subjected to genotypic variation caused by mutations. At first sight, such robustness might pose a problem for evolutionary innovation, because a robust system cannot produce much of the variation that can become the basis for evolutionary innovation.

The language sounds a little strange to me but I soon realized that there were many other authors who talked about "robustness" in this way. To me, the fact that there's neutral genetic variation in a population is just a natural consequence of chance mutation and random genetic drift. I don't see why biologists think that systems "need" to be robust and I don't see why the presence of neutral variation poses a "problem" for innovative change. It's perfectly acceptable to have beneficial mutations occurring on a background of neutral variation.

The "problem" seems to be more serious for evolutionary developmental (evo-devo) biologists than for others. It has given rise to much speculation about the evolution of evolvability. If you are interested in that sort of thing you should read the book The Plausibility of Life by Marc Kirschner and John Gelhart. (Warning, the contents may not be suitable for pluralists.)

The authors of the paper (Ciliberti et al.) claim that far from being a "problem" the existence of neutral variation is actually required for innovative evolution to occur.

As we shall see, there is some truth to this appearance, but it is in other respects flawed. Robustness and the ability to innovate cannot only coexist, but the first may be a precondition for the second.

This is pretty much where I stopped reading the first time. However, Michael White over on Adaptive Complexity has highlighted this paper in a posting put up yesterday [Evolution's Balancing Act]. This suggest that the paper resonates with some evolutionary biologists and piques my interest.

The paper describes a model of an evolutionary system. It happens to be gene regulatory networks but it could be just about anything. Ciliberti et al. (2007) show that if you have a single system with no variation then the possibility for innovative change is limited. On the other hand, if you have a robust system where there are many different variants—in different species—then there are more pathways to innovative change. Seems like a pretty trivial conclusion to me. It's the sort of thing Sewell Wright was talking about (Wright, 1932).

The course of evolution through the general field [adaptive landscape-LAM] is not controlled by direction of mutation and not directly by selection, except as conditions change, but by a trial and error mechanism consisting of a largely nonadaptive differentiation of local races (due to inbreeding and by occasional crossbreeding) and a determination of long time trend by intergroup selection.

The paper doesn't mention Wright, random genetic drift, or neutral mutations; although it does talk about neutral networks.

Instead, the paper seems to be fitting in with the evo-devo concepts of evolvability and facilitated variation. In other words the idea here seems to be getting very close to the concept that the variations in different species are selected because they increase the long term potential for innovative evolution. This is very different from what Wright was saying. He said—and I agree with him—that the variation is strictly accidental and just happens to provide potential for future evolution. The distinction is important for our understanding of evolution. Does evolution see into the future? Is there a hidden purpose?

Is "robustness" selected? I doubt that any of the authors would answer yes if the question was put directly but the paper certainly gives the impression that there's something positive going on. So does the description offered by Michael White when he says thing like,

Evolution carries out an incredibly tricky balancing act: the genetic program of a species has to be resistant to small changes, yet also susceptible to the adaptive remodeling of natural selection ....

So how does evolution maintain both stability and the potential for innovation?

This could be just metaphoric. The personification of "evolution" as acting to creat robustness may be excusable on that grounds. Nevertheless, a lot of this sort of language is creeping into the evo-devo literature and I wonder if it doesn't mean something more.

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S. Ciliberti, s., Martin, O.C. and Wagner, A. (2007) Innovation and robustness in complex regulatory gene networks. Proc. Natl. Acad. Sci. (USA) 104:13591-13596. Abstract

Wright, S. (1932) The roles of mutation, selection, inbreeding, crossbreeding, and selection in evolution. Proc. VI Intl. Cong. Genet. 1:356-366.

Sherri Shepherd of The View Doesn't Believe in Evolution

 
The earlier clip showed that Sherri Shepherd doesn't know if the Earth is flat. Here's a longer version where she admits to not believing in evolution. Whoopi seems to have a problem with this. So do I. There's something about this video clip that's deeply disturbing.

Catholic Public Schools: Constitutional Right or Archaic Privilege

 
Come to the lecture [Centre for Inquiry]. Unfortunately, I'll be out of town but I'm counting on many of you to attend and tell me all about it.

Starts: Friday, September 21st at 7:00 pm
Ends: Friday, September 21st at 10:00 pm
Location: University of Toronto, MacLeod Auditorium (Room 2158), Medical Sciences Building, U of Toronto, 1 King's College Circle.

CATHOLIC PUBLIC SCHOOLS: CONSTITUTIONAL RIGHT OR ARCHAIC PRIVILEGE

A FREE PUBLIC EVENT

Why did the UN condemn Ontario twice for human rights violations?

Why are we spending $0.5 billion/year on a second educational bureaucracy?

Is it true public catholic schools have the right to fire a teacher who isn't catholic?

But aren't separate catholic schools guaranteed indefinitely in the constitution?

And doesn't multiculturalism mean the best solution is to religiously segregate?

Learn why a secular democracy SHOULD NOT publicly fund catholic or other faith based schools and how we can fix the current situation

University of Toronto, Fri, Sept 21, 7pm, MacLeod Auditorium (Room 2158),Medical Sciences Building, U of Toronto, 1 King's College Crl.

Jan Johnstone, Progressive trustees network and trustee for the Bluewater District School Board,
Co-sponsored by University of Toronto Secular Alliance

(also Tues, Sept 18 at U of Guelph and Tues, Sept 25 at Carleton U - see web calendar)

A member of the Green Party-strong one school system supporters-will speak at each event

Learn the truth behind the ongoing debate on the #1 provincial election issue of 2007!

Get your questions answered and engage in a public forum on this crucial issue.

Is the World Flat?

 
Sherri Shepherd doesn't believe in evolution. She's not sure whether the world is flat or not. After watching this clip of The View you have to wonder about the intelligence of people on television. This really is flabbergasting. If I didn't know any better, I'd say it was all an act. Nobody could possibly be that stupid.

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[Hat Tip: BigHeathenMike (Sherri Shepherd Is a Retard)]

Catholic Bishops Block HPV Vaccinations

 
The Ontario government will provide free access to Gardasil®, a vaccine aginst Human Papillomavirus (HPV), for all Grade 8 girls in the province. The vaccine protects against 70% of all cervical cancers. HPV is acquired through sexual activity.

The vaccine will be administered in the public schools in three separate injections spread out over 6 months. The normal cost of the vaccine is $400. Once the series of shots is complete, women will be immune to the virus for many years.

See update
below.
The program is proceeding in the public schools but some Roman Catholic schools are threatening to block the vaccination of their young female students [Catholic schools debating moral issue of HPV shot]. The opposition in the Catholic schools is being stimulated by a letter from the Roman Catholic Bishops who oppose the vaccination program on the grounds that adolescent teenage girls should not be having sex in the first place.

Let's look at the letter sent to district school boards from the Ontario Council of Catholic Bishops [A message to Directors of Education of Catholic School Boards and to the Catholic educational community].

In August 2007, the Government of Ontario announced the introduction of the Human Papilloma Virus (HPV) vaccine into the publicly funded immunization program. This means that female students in all grade 8 classrooms in our school system will be offered the vaccine over the course of this year. This is a voluntary program and parents have the final decision on whether their daughters will be vaccinated.

The Bishops affirm that parents have the right and responsibility to decide whether their daughters should be vaccinated. We encourage parents to keep in mind some important considerations.

First, infection with HPV or other sexually transmitted diseases can occur only through sexual activity, which carries with it profound risks to a young person's spiritual, emotional, moral, and physical health. The Bishops note that, at best, a vaccine can only be potentially effective against one of these risks, that to physical health, and may have other unintended and unwanted consequences. Sexuality is a great and powerful gift. Sexual activity is appropriate only within marriage. Outside of marriage, abstinence is not only clearly the choice that leads to spiritual and moral wellbeing, but it is obviously the best protection against risks of disease.

Now, abstinence may be the choice that the Bishops have made but it's not a choice that's going to appeal to most teenagers. The Bishops can't really be this stupid, can they? Do they really think that most of their students are going to refrain from all sexual activity until they get married? What planet are they living on?

Second, there is no consensus among those involved in public health in Canada that HPV vaccination is the most prudent strategy in terms of allocating health care resources to address the goal of preventing deaths resulting from cervical cancer.

As we discussed in class today, when confronted with powerful scientific evidence—in this case that the vaccine prevents cancer—the goal is to discredit the data in any way possible. Here the Bishops are raising the issue of better cures. The implication is that parents should not support the HPV vaccination program because the the government could possibly have developed a "more prudent" strategy. Do the Bishops know of a better way to prevent cervical cancer? If so, why aren't they telling us?

The argument is bogus for two reasons. First, the real reason for opposition is that the vaccine may encourage promiscuity. Anything else is a red herring. Second, the program is under way and it's known to work. Refusing to protect our children from a known cancer using a known available treatment on the ground that there may have been something better is—how shall we say—really stupid.

Note the use of the "controversy" tactic. By bringing up the point that there may not be a consensus among public health officials, you cast doubt on the validity of the program. This gives you an excuse to criticize it without having to look like a prude who's completely out of touch with reality.

Further research is required. The Bishops of Ontario encourage parents to learn the medical facts concerning this vaccination.

This is classic spin framing. Make it sound like there's a real scientific problem here even if there isn't. What's the harm in waiting? Well, I'll tell you what's the harm. Cervical cancer.

Although the HPV vaccination program properly leaves the choice of participation to parents, the Bishops of Ontario regret its introduction without further opportunity for thorough study of all of the effects of this program. The best interests of children demands that parents and guardians be fully informed before granting consent.

The Bishops don't want to vaccinate young girls because those young girls shouldn't behaving sex. Everything else is obfuscation. You can tell it's obfuscation because this debate is not going on in the public schools were the vaccination is underway. If there really was legitimate concern about the safety of the vaccine then surely it would be debated in the public schools.

Parents and educators want to prepare children well for their future in all aspects of their lives. A proper education in chastity helps young people to embrace their sexuality with confidence and joy. We ask that Catholic school boards include this message in the information package that parents receive
concerning the program.

That's better. The real reason the Bishops are against protecting their young women against cancer is because chastity helps them embrace their sexuality. (There's a pun in there somewhere but I'm not going to touch it.)

Yours in Christ
Most Reverend James Wingle,
Bishop of St. Catharines
President
Ontario Conference of Catholic Bishops

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[Photo Credit: St. Thomas Aquinas is in the Halton Catholic District School Board next to where I live. he Halton board narrowly rejected the recommendation of the Bishops and decided to go ahead with the vaccinations. The lower photo is from the Toronto Star website.]

UPDATE: Jennifer Smith of Runesmith's Canadian Content lives in Halton district. She is relieved that her school district came to their senses and rejected the request of the Bishops [Health Trumps Religon]