Nobel Laureates: Gerald Edelman and Rodney Porter

 

The Nobel Prize in Physiology or Medicine 1972.

"for their discoveries concerning the chemical structure of antibodies"

Gerald M. Edelman (1929 - ) and Rodney R. Porter (1917 - 1985) received the Nobel Prize in Physiology or Medicine for elucidating the structure of immunoglobulins (antibodies). They determined that immunoglobulins were composed of two heavy chains and two light chains. There are three domains in the molecule. Two of them form binding sites for antigens and the third one links the two heavy chains together.

Edelman and Porter founded the field of molecular immunology, a field that today encompasses hundreds of labs. If you count all the clinical immunologists and cellular immunologists, there are as many immunology labs in the world as there are biochemistry labs. That was not true in the 1950's when Edelman and Porter began their work.

The presentation speech was in Swedish by Professor Sven Gard of the Karolinska Medico-Chirurgical Instit.

THEME:
Nobel Laureates

Your Royal Highnesses, Ladies and Gentlemen,

Immunebodies or antibodies is the designation of a group of proteins in the blood, that play an important part in the defense against infections and in the development of many different diseases. Their perhaps most characteristic property is the capacity to react and combine with substances, foreign to the organism, so-called antigens and to do so in a highly specific manner. There probably exist more than 50,000 different antibodies in the blood, each of them reactive against one particular antigen. Their main features are similar but they show individual characteristics and constitute, therefore, an extremely heterogeneous group. Since, in addition, they appear as very large molecules of a complex structure, it is understandable that the study of their chemistry for a long time offered great difficulties.

Up to 1959 the knowledge about their nature and mechanism of action was rather incomplete. That same year, however, Edelman and Porter separately and independently published their fundamental studies of the molecular structure of antibodies. Both of them had aimed at splitting the giant molecule into smaller, well defined fragments that might be more easily analysed than would the whole complex.

Porter's aim was to separate those parts of the antibody which are responsible for their specific reactivity. He hoped by this means to obtain a preparation lacking most of the biologic functions of the antibody but, on account of its capacity of combination, capable of competing with the antibody for the binding sites of the antigen. He succeeded in achieving this by means of treatment of the antibody, under strictly controlled conditions, with a protein-splitting enzyme called papain. By this treatment the antibody split into three parts. Two of these could combine specifically with the antigen and they were almost identical in other respects as well. The third fragment differed distinctly from the others, lacked binding capacity but possessed certain other biologic characteristics of the intact molecule.

Edelman for his part assumed the molecule, like those of many other proteins, to be composed of two or more separate chain structures held together by cross links of some kind, most probably so-called sulphide bonds. His assumption turned out to be correct. By means of a fairly rough treatment he was able to sever the cross bonds and release a number of separate chain molecules. Both he and Porter could later show that the antibody was in fact composed of four chains, one pair of identical, "light" chains and one pair of like- wise identical, "heavy" chains.

On the basis of the collected evidence Porter built a model of the molecule which has later, with overwhelming probability, been proven correct.

Accordingly the antibody molecule appears in the shape of the letter Y, with a stem and two angled branches. Each branch is composed of one light and one half of a heavy chain in side by side arrangement. The stem is made up of the remaining halves of the heavy chains. The specific combining capacity is accounted for by the structure of the free tips of the branches and in like measure by the light and the heavy chain; separately they are inactive. Porter's papain treatment attacks the molecule exactly at the point of branching and splits off the branches from the stem.

These discoveries incited an intense activity in laboratories in the four corners of the world. Apparently there existed a latent need for immunochemical research that could not be satisfied until today's prize winners had opened the way and provided the means. During the two decades that have since past our knowledge about the processes of immunity has broadened and deepened to an extent that perhaps has not yet been fully appreciated, even by some specialists in closely related fields. Many novel and fascinating aspects on problems in the fields of molecular biology and genetics have grown out of the immunochemical studies. We have now a new and firmer grasp of the question of the role of immunity as defense against and as cause of disease. Our possibilities to make use of immune reactions for diagnostic and therapeutic purposes have improved. It is, thus, a very important pioneer contribution that has been rewarded with this year's prize in physiology or medicine.

Gerald Edelman, Rodney Porter,

By clarifying the principal chemical structure of immunoglobulins you achieved an extremely important break-through in the field of immunochemistry. You, so to speak, opened the sluice-gates and gave impetus to the flood of research that soon started gushing forth, irrigating previously arid land, making it fertile and producing rich harvests. By awarding you the prize in 'physiology or medicine the Karolinska Institute has recognized the great significance of your accomplishments for biology in general and medicine in particular. On behalf of the Institute I wish to express our admiration and extend to you our heart-felt felicitations.

Now I ask you to proceed to receive your prize from the hands of His Royal Highness the Crown Prince.

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[Image Credit: The cartoon of an immunoglobulin molecule is from the Genetics Home Reference website of the National Institutes of Health (USA).]

How long does it take to synthetize a molecule of leucine anyway?

Bora Zivkovic asked this question on A Blog Around the Clock: How long does it take to synthesize a molecule of leucine anyway?.

A dozen or so years ago, I drove my Biochemistry prof to tears with questions - she had 200 people in front of her and she tried hard to make Biochem interesting enough not to get us all bored to tears, and she was pretty good at that, as much as it is possible not to make people bored to tears with Biochem. But my questions exasperated her mainly because she could not answer them, because, as I learned later, the field of biochemistry was not able to answer those questions yet at the time: questions about dynamics - how fast is a reaction, how long it takes for a pathway to go from beginning to end, how many individual molecules are synthesized per unit of time?, etc.

Bora, I'm sorry your Professor wasn't able to answer your questions. The answers have been known for decades. Perhaps she didn't know the answers, or perhaps there was another reason why she didn't answer.

The rate of enzymatic reactions is part of the field of enzyme kinetics. The material is usually covered in introductory biochemistry. The particular value you were looking for is called the catalytic constant, k_cat. It represents the number of moles of substrate converted to product per second per mole of enzyme under saturating conditions. In other words, it's the maximum speed of an enzyme. This is also called the turnover number.

Typical values for most enzymes are between 10² and 10³. What this means is that a given enzyme can catalyze between 100 and 1000 reactions per second.

A metabolic pathway in cells is a series of reactions where a substrate is converted to a product in several steps. The pathway for leucine biosynthesis is well known. It begins with pyruvate, which is converted in three reactions to α-ketoisovalerate. That intermediate can be converted directly to valine or it can serve as the substrate for a series of four reactions leading to leucine.

All of the enzymes have been studied. I'd have to look up all of the k_cat values to give you a precise answer but it's easy to give a reasonable estimate.¹

Biochemical pathways operate, for the most part, under near-equilibrium conditions. What this means is that there is a steady state concentration of all reactants in the pathway. These concentrations correspond to the equilibrium values for each reaction.

The flux in a pathway depends on how quickly the end product is utilized. Under normal conditions leucine will be used up in protein synthesis at a nearly constant rate but that rate might rise if the cell is growing rapidly and it might fall if the cell is starved for nutrients. When leucine synthesis is required, for whatever reason, it's maximum rate of synthesis will be equal to the turnover number of the slowest enzyme in the pathway.

You can safely assume that this will be between 100 and 1000 molecules per second per enzyme. That's the answer you should have been given. In a big mammalian cell growing in tissue culture there will be lots and lots of enzyme and the flux could be a million molecules per second. It will be much less in smaller cells that are not growing.

The key to understanding metabolic pathways is to appreciate that there is a pool of leucine in the cell and a pool of the last intermediate. These pools of metabolites are at steady-state concentrations and the enzyme is constantly making leucine and converting leucine back to the intermediate because that's what happens under equilibrium conditions. The rates of the forward and reverse reactions are equal, and fast.

As soon as the leucine pool is depleted there will be some net synthesis of leucine made from the pool of the last intermediate to restore the steady-state equilibrium concentrations. The rate of this reaction is very rapid.²

Then the pool of the last intermediate is replenished from the second-last intermediate etc. etc. All of these reactions are rapid. Most students seem to think that there are no intermediates and when leucine is needed the enzymes have to grab a pyruvate molecule and run through the entire pathway to make a new molecule of leucine. Such a pathway is impossible.

Well, the field is starting to catch up with my questions lately - adding the temporal dimension to the understanding of what is going on inside the cell. In today's issue of PLoS Biology, there is a new article that is trying to address exactly this concern: Dynamics and Design Principles of a Basic Regulatory Architecture Controlling Metabolic Pathways:

That's an interesting paper but it doesn't answer any of your questions.

The paper address the induction of enzymes in yeast. When yeast cells grow in the presence of leucine they turn off synthesis of the pathway enzymes because there's no need to synthesize leucine when it's available in the medium. If you then shift the cells to leucine free medium they will begin to make the leucine pathway enzymes. It takes about one hour to make signifcant amounts of enzyme.

Enzyme induction has been studied for over 50 years. The diagram below is from Monod's Nobel Lecture of 1965. The current PLoS paper adds some information to this field but, with all due respect, it is not a breakthrough and it does not answer fundamental questions in biochemistry that were unknown when you were a student. You may not have been aware of kinetic studies when you were a student but that's a reflection on the quality of your education and not on what was known in biochemistry at the time.

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1. Perhaps your biochemistry Professor didn't want to spend the time looking up all the details? Whenever I get a question like that I assign the task to the student. It's a good exercise for them to search through the scientific literature to find the answer to their own question. It also helps them appreciate why their Professor may not have had the answer at her fingertips.

2. For the sake of simplicity, I'm ignoring regulation. Some enzymes in the pathway might be regulated in which case the steady-state concentrations might not correspond to the equilibrium concentrations. This doesn't make much difference when it comes to addressing Bora's questions.

Wordle

 
Eva Amsen is writing her thesis. It is very easy to get distracted when you are writing your thesis—everyone needs a break from time to time. Eva found a fabulous website while she was surfing the net looking for references to put in her thesis and she blogged about it on [Expression Patterns].

The website is called Wordle. Here's what it does ...

Wordle is a toy for generating “word clouds” from text that you provide. The clouds give greater prominence to words that appear more frequently in the source text. You can tweak your clouds with different fonts, layouts, and color schemes. The images you create with Wordle are yours to use however you like. You can print them out, or save them to the Wordle gallery to share with your friends.

I fed it my essay on What Is a Gene? and here's what it gave me ...

Each time you try you get a different configuration of words so it's worthwhile to experiment a bit in order to get a pleasing layout. You can change fonts, colors, background and other things afterwards. Isn't this great?

Here's how Wordle handles another essay Evolution by Accident.



Here's another example with Theistic Evolution: The Fallacy of the Middle Ground.


This is so much fun. It must be bad for you. Send me your favorite Wordles, they must be created from something you wrote.

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With or Without God

 
Come to the Centre for Inquiry's lecture by Gretta Vosper.

With or Without God: Why the Way We Live is More Important than What We Believe

Starts: Friday, June 20th at 7:30 pm
Ends: Friday, June 20th at 9:30 pm
Location: Centre for Inquiry Ontario, 216 Beverley St, Toronto ON (1 minute south of College St at St. George St)

Lecture and Book Launch:
Gretta Vosper, United Church Minister at West Hill United Church, Toronto, and founder and Chair of the Canadian Centre for Progressive Christianity

In Gretta Vosper's church there are no prayers, no miracles-performing magic Jesus and no omnipotent God at all. Vosper's book argues that the Christian church, in the form in which it exists today, has outlived its viability and either it sheds its no-longer credible myths, doctrines and dogmas, or it's toast. With a humanist worldview, Vosper proposes a radical change at the heart of faith. The new church she envisions will play a viable and transformative role in the shaping of a future society. What will save the church from certain demise, Vosper argues, is a new emphasis on just and compassionate living.

A catered receptions shall precede the talk at 6pm exclusively for Friends of the Centre.

Canadian Centre for Progressive Christianity:

MacLeans Magazine coverage "The Jesus Problem":

Globe and Mail coverage "Taking Christ Out of Christianity"

Cost: $6 general, $4 students, FREE for Friends of the Centre

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Monday's Molecule #76

 
Name this molecule, being as specific as you can.

There's a direct connection between today's molecule and a Nobel Prize. The prize was awarded for discovering the basic structure of the molecule, although not at the level of detail depicted here. That came later.

The first person to correctly identify the molecule and name the Nobel Laureate(s), wins a free lunch at the Faculty Club. Previous winners are ineligible for one month from the time they first collected the prize. There are four ineligible candidates for this week's reward. You know who you are.

THEME:

Nobel Laureates
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 names the Nobel Laureate(s). Note that I'm not going to repeat Nobel Laureate(s) so you might want to check the list of previous Sandwalk postings by clicking on the link in the theme box.

Correct responses will be posted tomorrow. I may select multiple winners if several people get it right.

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

UPDATE: The molecule is immunoglobulin G (IgG) and the Nobel Laureates are Gerald Edelman and Rodney Porter (1972). The first correct answer was from Jon Turnbull who beat everyone else by more than one hour! Honorable mention (and a free lunch) goes to Haruhiko Ishii of UCSD. Not only did he identify the molecule as IgG, he also showed that it was very likely to be Mab231, a mouse monoclonal anti-canine lymphoma antibody composed of IGg2a heavy chains and κ light chains [PDB 1IGT].

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Café Scientifique and Nature Network Pub Night

 
CAFÉ SCIENTIFIQUE PRESENTS
The future of medicine: help, hope or hype? (download the poster)

What lies in the future for medicine and health care? Over the next 50-100 years, how will we conquer illnesses and stay healthy? Join the discussion and debate at the next Café Scientifique, The future of medicine: help, hope or hype?, where experts will peek at the potential for robotics, genomics, alternative therapies and personalized medicine to cure our ills.

Experts:

• Dr. Tony Pawson – Distinguished Investigator, Samuel Lunenfeld Research Institute of Mount Sinai Hospital
• Karl Schroeder – Science fiction author and futurist
• Dr. Calvin Gutkin – Executive Director and CEO, The College of Family Physicians of Canada

Wednesday, June 18, 2008, from 6 to 8pm
Duke of York Pub – ground floor
39 Prince Arthur Avenue -Close to the St. George subway (Bedford exit)

FREE

Presented by the Samuel Lunenfeld Research Institute of Mount Sinai Hospital and Ontario Science Centre, with generous support from Canadian Institutes of Health Research.

Café Scientifique is a place where, for the price of a cup of coffee or a pint of beer, anyone can join discussions that explore the latest ideas in science and technology.

The members of the Toronto hub of Nature Network will meet afterwards in the Duke of York (same place as Café Scientifique) [see Eva Amsen's posting on easternblot]. You get two stimulating meetings for the price of one (i.e. free!).

If you haven't yet joined the Toronto hub of Nature Network you should sign up here. Current members of the Toronto hub are here.

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Kansas vs Darwin

 
Jeff Tamblyn, the director of Kansas vs Darwin will be in town this week for the ReelHeART International Film Festival. The film will be shown on Thursday evening. Here's the trailer, details below ...

Kansas vs. Darwin screening Thursday, June 19, 7:00 PM
ReelHeART International Film Festival
RHIFF MAIN PROGRAM B Tickets $8
INNIS THEATER 222
Innis College, University of Toronto
2 Sussex Avenue [1 block south of Bloor Street, on St. George Street]
Toronto, ON M5S 1J5
Advance Sales on line April 21, 2008 at www.reelheart.com

Kansas vs. Darwin
Director, Jeff Tamblyn, USA

Kansas vs. Darwin is a smart, funny, feature-length documentary about the Kansas state school board hearings on evolution. Features intimate revealing interviews with all major players on both sides, and exclusive, multi-camera footage of the hearings. Far more than a political film, Kansas vs. Darwin skillfully weaves multiple themes into a gripping dialectic, putting you face to face with, and inside the heads of, those who oppose your most closely held beliefs. Challenging and entertaining, it’s packed with fascinating characters who will leave you in admiration and astonishment, embarrassment and exasperation, as they feverishly pursue their goals, sometimes stumbling over their own eagerness in the attempt to win the most important battle of their lives.

I'm going. Contact me if you plan to attend and you want to meet up for dinner before the show.

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Fernando

 
Fernando was one of ABBA's biggest hits. There's a lot of debate about which war it refers to. The song mentions crossing the Rio Grande and that prompts many people in America to think of the Mexican revolution of 1910-1920. However, there aren't many examples of fighting that took place near the Rio Grande and there aren't too many examples of revolutionaries who crossed into Mexico from the USA.

Most people assume the song is about the Spanish civil war and the reference to the Rio Grande is just a generic reference to a river. Keep in mind that ABBA is a European group and the Spanish Civil War is still fresh in the memories of many europeans. For many it was glorious, but losing, fight against fascism.

The song refers to Fernando, a man who fought on the losing side against tyranny and fascism. Fernando was a revolutionary and a guerrilla fighter. He is now old and gray like many of the freedom fighters from all over Europe who went to Spain in the 1930's.

John McCain likes ABBA. I hope he appreciates that this song is about people who fought to defend their country from foreign domination. (Franco was supported by Hitler and Mussolini.)

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Bias Against Female First-Author Papers

 
This is a follow-up to a posting back in January where I mentioned a recently published article by Budden et al. (2008) [see Bias Against Women?]. That article claimed to show evidence of a systematic bias against papers with women as first authors. The bias was mitigated when a particular journal switched to a double-blind reviewing system. This resulted in a significant increase in the number of published papers with women as first authors.

I was first alerted to the problem when GrrlScientist posted a favorable review of the paper, agreeing with the conclusion that journal reviewers were biased against papers with female first authors [Women, Science and Writing].

My first reaction was skeptical. These are biology papers and it didn't seem plausible that reviewers would be biased against papers with female first authors. There might possibly be a bias against papers from a lab run by women but that's not the same thing. In the biological sciences the principle investigator is often the last author and not the first. Furthermore, in my experience there wasn't any discrimination against female scientists at this level (publication). Half of our graduate students are women—why would we be biased against papers with one of them as first author? The study just didn't make sense.

Many Sandwalk readers interpreted my skepticism as an attempt to dismiss all forms of sexism in science. That was not my intent. Far from it, in fact, because I was very much aware of a particular case of sexism that greatly troubled me. What makes me angry is that I know of overtly sexist behaviors that are not challenged by scientists in the same department who are, themselves, not sexist. The subject of sexism came up at SciBarCamp in February where there was a session organized by physics professors to discuss sexism in physics departments. There seems to be a major problem in physics.

If you read the comments in my January posting you'll see how difficult it was to separate out the issue of whether the particular study on double-blind reviews was a legitimate scientific study, and whether sexism is common in science.

At the risk of encountering the same problem again, let's look at some recent events. A re-analysis of the original publication data has been published by Webb et al. (2008). They looked more carefully at the data from journals with double-blind review and from comparable journals that identify the authors. They found that the number of papers with women as first authors showed a general increase in most journals. The trend in the journal that initiated double-blind review back in 2001 was not significantly different. Thus, they conclude that there's no evidence of systemic bias against female first authors.

This is one of the points that I mentioned in the comments to my January posting but several other readers dismissed it. They implied that any attempt to question the data in the original paper was, itself, sexist.

The following correction appeared in the last week's (June 4th) issue of Nature.

The Editorial 'Working double-blind' (Nature 451, 605–606; 2008) referred to a study(1) that found more female first-author papers were published using a double-blind, rather than a single-blind, peer-review system. The data reported in ref. 1 have now been re-examined (2). The conclusion of ref. 1, that Behavioral Ecology published more papers with female first authors after switching to a double-blind peer-review system, is not in dispute. However, ref. 2 reports that other similar ecology journals that have single-blind peer-review systems also increased in female first-author papers over the same time period. After re-examining the analyses, Nature has concluded that ref. 1 can no longer be said to offer compelling evidence of a role for gender bias in single-blind peer review. In addition, upon closer examination of the papers listed in PubMed on gender bias and peer review, we cannot find other strong studies that support this claim. Thus, we no longer stand by the statement in the fourth paragraph of the Editorial, that double-blind peer review reduces bias against authors with female first names.

I believe that Nature has done the right thing in retracting their earlier claim. The problem of sexism in science is serious and needs to be addressed. But it doesn't do anyone any good if one side is supporting their claims with sloppy science. It would be good if we could get beyond that.

It may not be easy. The authors of the original paper have published a critique of the re-analysis (Budden et al. 2008b). They dispute the re-interpretation although they admit that their analysis is subject to different interpretations.

If the original paper was any other kind of scientific paper the criticism would be harsh. It will be interesting to see if any of the original strong supporters of the claim of sexist bias against female first authors are willing to reconsider their position on that particular issue.

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[Hat Tip: R. Ford Dennison]

Budden, A., Tregenza, T., Aarssen, L., Koricheva, J., Leimu, R. and Lortie, C. (2008a) Women, Science and Writing. Trends in Ecology & Evolution, 23(1), 4-6. [PubMed] [doi:10.1016/j.tree.2007.07.008] (ref 1.)

Budden, A.E., Lortie, C.J., Tregenza, T., Aarssen, L., Koricheva, J., and Leimu, R. (2008b) Response to Webb et al.: Double-blind review: accept with minor revisions. Trends in Ecology and Evolution [doi:10.1016/j.tree.2008.04.001]

Webb, T. J., O'Hara, B. and Freckleton, R. P. (2008) Does double-blind review benefit female authors? Trends in Ecology and Evolution [doi:10.1016/j.tree.2008.03.003] (ref 2.)

Alex Palazzo in Toronto

 
Alex Palazzo of The Daily Transcript has been in Toronto for the past few days. We were able to get together for lunch on Wednesday and for some light liquid refreshments on Wednesday evening. It should come as no surprise that we were able to find several things we agree on and several more that we don't. It was a lot of fun. (I made a bet with Alex on Wednesday evening. He'll reveal it on his blog. He will lose.)

Yesterday's departmental seminar was very impressive. Alex has a nice story to tell about targeting mRNA to the endoplasmic reticulum. He has also discovered an unusual pathway for exporting certain mRNAs from the nucleus. This pathway seems to be specific for those mRNAs that encode secreted proteins.

I think everyone in the department was impressed. Maybe he'll be my colleague next year.

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Alex Meets Toronto Bloggers

 
Alex Palazzo of The Daily Transcript met with Eva Amsen of easternblot, John Dupuis of Confessions of a Science Librarian, and Phillip Johnson of Biocurious.

Eva posted photos and a description of what they talked about [Science Bloggers].

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Friday the 13th in Port Dover

 
It's Friday the 13th and the bikers are gathering in Port Dover. This year they're hoping to set a new Guinness record for the most bikes (>10,000).

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Friday the 13th

 
Friday's Urban Legend: FALSE

[reposted from April 13, 2007]

Having a morbid fear of Friday the 13th—paraskevidekatriaphobics—is one of the most widespread superstitious beliefs in western industrialized nations. Believe it or not, there are many people who refuse to leave their house on Friday the 13th because they fear that bad luck will befall them if they venture outside. (Apparently, the bad luck doesn't find them in their homes.)

Personally, I like the attitude of the "eccentric" (rational?) men in the photo.

Members of the Eccentric Club of London at their annual Friday the 13th lunch in 1936 – surrounded by objects that are connected with superstitions. Picture: Getty Images [Unlucky roots of Friday the 13th].

There is no evidence to support the irrational fear of Friday the 13th, with the single exception of a study published 14 years ago in the British Medical Journal [Is Friday the 13th bad for your health?]. That study showed an increase in accidents on Friday the 13th compared to Friday the 6th.

According to scholars, the fear of Friday the 13th is a recent invention. There is no mention of it before 1900 [Why Friday the 13th Is Unlucky]. It seems that people simply combined a fear of the number 13—triskaidekaphobia—with an obscure dead of Fridays. Nobody knows for sure why the number 13 is considered unlucky but there are several popular myths. The most common are a Norse myth about having 13 people at dinner and a Christian myth about the Last Supper.

There is no significant historical record documenting a widespread irrational fear of Fridays although there are plenty of minor examples of Friday avoidance. Some people thought it was bad luck to be married on a Friday or to set sail on a ship. In Christian cultures the day is associated with the fact that Jesus was crucified on a Friday and Friday is the day that Adam was tempted by Eve to eat the forbidden fruit.

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Tangled Bank #107

 
The latest issue of Tangled Bank is #107. It's hosted at Syaffolee [Tangled Bank #107: The CYOA Edition].

You're trapped on a cruise ship in the South Pacific, bored out of your mind. The swimming pool holds no appeal. Gambling is pointless because the advantage is on the house. The books you brought with you have long been finished. You've even resorted to registering for a cha-cha class to relieve your ennui. But that's no fun, because the instructor is always yelling at you for having two left feet.

Then on a Wednesday morning, the ship docks on a small island. Travelers are allowed to go on land for the day. You debark and after wandering past the marketplace filled with locals hawking loud jewelry and ceremonial masks (probably manufactured in Taiwan), you find yourself in a small clearing with several paths meandering off into the undergrowth. There's a sign nearby saying:

"Welcome to the one hundred and seventh edition of Tangled Bank."

At the foot of the sign is a machete.

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If you want to submit an article to Tangled Bank send an email message to host@tangledbank.net. Be sure to include the words "Tangled Bank" in the subject line. Remember that this carnival only accepts one submission per week from each blogger. For some of you that's going to be a serious problem. You have to pick your best article on biology.

Religulous

 
Coming to theaters near you in October [Religulous].

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[Hat Tip: Brian Larnder at Primordial Blog]

Graduation

 
With 72,000 students, you can appreciate that graduation ceremonies need to be spread out over several weeks at the University of Toronto. At this time of year we have graduations every day and sometimes twice a day.

Today it was the turn of St. Michael's College. It was such a beautiful day that I couldn't resist taking a picture of the graduating class as they walked across the front campus to Simcoe Hall. There were about 500 students in this line.

How many of you went to your graduation? I did.

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Charles McVety Visits the ROM

 
I was taking Bryant Ing¹ to lunch today when we decided to check out what was happening at the Royal Ontario Museum. There was supposed to be a big anti-racism rally led by "Dr." Charles McVety. He's the man who claims that Charles Darwin was a racist [Canadian Creationist: Charles McVety].

Here he is (left) speaking to his supporters right in front of the museum where the Charles Darwin exhibit is housed. One of his supporters handed us a leaflet explaining why Darwin was a racist. (I'm sure you all know the quotes and I'm sure you all know that Darwin was very enlightened for a man of his time.)

We didn't stay long. McVety was going on about the title of Darwin's famous book. He was making the point that the book is about the preservation of favoured races.² There were at least three or four people nodding their heads in agreement.

Toronto's finest were there in full riot gear to keep the huge crowd under control. You can see from the photo that they were very suspicious of Bryant and me. Some of them seem to be reaching for their weapons. You can click on the photo to see a larger version where their facial expression tells all.

The last photograph (below) is a view of the entire crowd. I figure there were about ten McVety sycophants supporters present and about ten passers-by who were curious about what was going on. There were almost as many reporters and camera crews. It was a non-event. We went to the Faculty Club for a nice lunch. Mmmmmm, fish and chips!

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1. Winner of Monday's Molecule #66.

2. The actual title is On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life.

Canadian Creationist: Charles McVety

 
"Dr."¹ Charles McVety is President of Canada Christian College in Toronto.

McVety is currently promoting the movie Expelled in Canada. He claims that it exposes the racism behind "Darwinism" as well as revealing how universities repress academic freedom by firing creationists.

I presume that Canada's Christian College is one of the last bastions of academic freedom where academics are allowed to say and think whatever they believe without fear of reprisal or dismissal. I assume this must be true because McVety feels so strongly about the importance of academic freedom. Evolutionists must be welcome at McVety's college.

The protection of academic freedom is probably behind this statement from the Canada Christian College website on college standards ...

Canada Christian College strives to maintain a distinctly Christian living and learning environment conducive to a rigorous study of God’s Word. Membership in Canada Christian College is obtained through application and invitation. Those who accept an invitation to join the College agree to uphold its standards of conduct. In return, they gain the privilege of enjoying the benefits of college membership and undertake to work for the best interests of the whole community (Phil. 2:4).

Compliance with these standards is simply one aspect of a larger commitment by students, staff, and faculty to live as responsible citizens, to pursue biblical holiness, and to follow an ethic of mutual support, Christian love in relationships, and to serve the best interests of each other and the entire community. Individuals who are invited to become members of this community but cannot with integrity pledge to uphold the application of these standards are advised not to accept the invitation and to seek instead a living-learning situation more acceptable to them.

In an effort to be much more respectful of creationists, no matter how stupid they might be, I will refrain from calling them names, like IDiot. This posting adheres to this new policy. I hope it pleases my atheist friends who favor accommodation.

Larry MoranSurprising as it might seem, there are some people who don't like Charles McVety and his activities. A recent posting from Kady O'Malley on Macleans.ca blogs isn't all that complimentary [The opposite of YPF?]. (Macleans is a Canadian newsmagazine similar to Time and Newsweek.)

Perhaps he was inspired by the turnout for Young People Fucking, or maybe he misses all that media attention he got after taking credit for getting C-10 through the House with nary a peep over the controversial changes to the film tax rebate. Whatever the reason, Reverend Charles McVety is headed back to the capital to co-host a private screening of a very different kind of film: Expelled: The Movie, the controversial anti-Darwin documentary that purports to expose a sinister anti-creationism bias within the mainstream scientific community.

Interestingly, in his come-one-come-all invite to the film - which was forwarded to all MPs and staffers via parliamentary email by Conservative MP Maurice Vellacott - McVety doesn’t even mention the religious aspect of the debate; instead, he accuses Darwin of “overt racism”, and calls on Canadians to “blot out out this terrible scourge in our society.”

McVety and his friend(s) are holding an anti-racism rally today at 12:30 outside the Darwin exhibit at the Royal Ontario Museum, Toronto. You'd better get there early if you want to be at the front of the crowd where you can touch the great man. I assume traffic on Bloor Street will be tied up for hours.

Canadian Cynic might be there. (Warning! If you follow the link to Canadian Cynic you might be disappointed 'cause Canadian Cynic doesn't adhere to my new policy of accommodating accommodationists. Neither does PZ Myers who uses a rude word in referring to McVety and his somewhat misleading interpretation of Charles Darwin.

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1. Here's a description of Charles McVety's degree Degree or Not Degree?.

Spring in Nova Scotia

 
One of my colleagues, David Tinker, has retired and moved to the Annapolis valley in Nova Scotia (Canada). He sent me a picture of a woodland path and it's so beautiful that I thought I'd share it with Sandwalk readers. Another one of my colleagues, Michael Paul, just retired and left yesterday to live near David in the Annapolis Valley. I can see why.

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Nobel Laureates: Stanford Moore and William Stein

 

The Nobel Prize in Chemistry 1972.

"for their contribution to the understanding of the connection between chemical structure and catalytic activity of the active centre of the ribonuclease molecule"


Stanford Moore (1913 - 1983) and William Stein (1911 - 1980) were awarded the 1972 Nobel Prize in Chemistry for working out the role of amino acid side chains in the mechanism of catalysis by bovine ribonuclease A [see How Enzymes Work].

This is one of the most important achievements in biochemistry although it could hardly have been considered a breakthrough since the result was widely anticipated and predicted. Many other enzymes were being studied at the time and the award was, in a sense, a recognition of the general concept and not the particular contributions of Moore and Stein. Moore and Stein also developed the technique of automated amino acid analysis of proteins and peptides.

Moore and Stein shared their Nobel Prize with Christian Anfinsen.

The presentation speech was delivered by Professor Bo Malmström of the Royal Academy of Science.THEME: Nobel Laureates

Your Royal Highnesses, Ladies and Gentlemen,

The key substances of life are called enzymes. Everything we humans undertake - if we sit here enjoying the splendour of a Nobel ceremony, if we perform work, or even if we simply feel joy or sorrow - occurs by means of enzyme reactions. The phenomenon described as life is a network of coupled enzymatic processes. In chemical terminology the enzymes are catalysts, i.e. substances which accelerate chemical reactions without being consumed themselves. The concept of catalysis was introduced about 150 years ago by the great Swedish chemist Jöns Jacob Berzelius, who also, with astonishing intuition, suggested that the tissues of a living organism have catalytic activity. Around the turn of the century scientists started to associate this catalytic effect with specific substances, enzymes. This year's three Nobel Prize winners in Chemistry, Christian B. Anfinsen, Stanford Moore and William H. Stein, have performed fundamental studies with the enzyme ribonuclease making it possible for us now to approach the problem of enzymatic activity on a molecular level.

From a chemical point of view enzymes are proteins. These are built up of 20 different amino acids which are linked together into long chains. Despite the fact that proteins have only 20 building blocks, there are thousands of enzymes, each with its specific properties. This large degree of variation becomes possible because the number and sequence of the amino acids in the chain can be varied. Ribonuclease was the first enzyme for which the complete amino acid sequence was determined thanks to contributions from Anfinsen and from Moore and Stein.

Every living organism has its own characteristic pattern of enzymes. It can also produce a copy of itself, and this progeny has the same enzymes. An important question concerns the source of the information which has to be passed on from generation to generation for the enzyme pattern to be preserved. We know, thanks to contributions which have led to earlier Nobel Prize awards, that a specific molecule, called DNA, serves as the carrier of the traits of inheritance. These traits are expressed by DNA controlling the synthesis of enzymes. DNA accomplishes this by determining the sequence of the amino acids making up a particular protein molecule. An active enzyme does not, however, consist just of a long chain of amino acids linked together, but the chain is folded in space in a way which gives the molecule a globular form. What is the source of the information responsible for this specific folding of the peptide chain? It is this question in particular which has been the concern of Anfinsen's investigations. In a series of elegant experiments he showed that the necessary information is inherent in the linear sequence of amino acids in the peptide chain, so that no further genetic information than that found in DNA is necessary.

The contributions of Moore and Stein concern another fundamental question regarding ribonuclease, namely the basis for its catalytic activity. The reacting substances, the substrates, are bound to an enzyme in what is generally called its active site. In the complex so formed there is an interaction between enzyme and substrate leading to a changed reactivity of the substrate. Knowledge about the structure of an enzyme is of little help in understanding this interaction if it is not possible to find the active site and to determine the chemical groups in it. Moore and Stein discovered as an important principle that the active site contains amino acids with an anomalously high reactivity compared to the same amino acids in free form. This high reactivity is of direct importance for the catalytic activity of the enzyme, but Moore and Stein also found it possible to utilize it to label two amino acids in the active site by chemical modification. In this way the position of these amino acids in the long peptide chain could be unambigously determined. Through these investigations Moore and Stein were able to provide a detailed picture of the active site of ribonuclease long before the three-dimensional structure of the enzyme had been determined.

Dr. Anfinsen,

I have tried to explain your pioneering investigations showing that the linear sequence of amino acids in the enzyme ribonuclease determines the biologically active conformation of this enzyme. This finding has profound implications for our understanding of the way in which active enzyme molecules are formed in living cells.

Drs. Moore and Stein,

I have attempted to summarize your fundamental contributions to our understanding of the relationship between chemical structure and catalytic activity in the enzyme ribonuclease. In particular, I have stressed your studies leading to the localization of two specific histidine residues in the active site of the enzyme. It is for these pioneering experiments that the Royal Academy of Sciences has decided to award this year's Nobel Prize in Chemistry to you together with Dr. Anfinsen.

Drs. Anfinsen, Moore and Stein,

On behalf of the Royal Academy of Sciences I wish to convey to you our warmest congratulations, and I now ask you to receive your Prizes from the hands of His Royal Highness the Crown Prince.

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How Enzymes Work

Enzymes are protein catalysts that speed up reactions. In the most extreme cases the catalyzed reaction will take place 10²³ times faster than the rate of the uncatalyzed reaction. Typical values are about 10¹⁴. What this means is that a reaction that would normally take years can occur within a second inside the cell because the reaction is catalyzed by an enzyme.

How do enzymes do this? The answer is surprisingly complicated. Let's look at a simple reaction forming part of the glycolysis pathway.


In this reaction, one molecule of DHAP is converted to one molecule of G3P, and vice versa (the reaction is readily reversible). The reaction is catalyzed by a famous enzyme called triose phosphate isomerase or TPI.

As the reaction proceeds, there will be a point when neither DHAP or G3P exist. Instead, there will be a transition state whose structure is somewhere in between that of the product and the substrate. This transition state only exists for a nanosecond or less. One of the things that enzymes do is to create a pocket where the binding of the transition state intermediate¹ is favored. What this does is to lower the activation energy between the reactant and product making the transition from one to the other much easier. The net effect is to speed up the process by many order of magnitude.

Transition state stabilization is one of the most important mechanisms of enzyme catalysis. There are very few direct proofs of this in the scientific literature because the hypothetical transition state is so unstable and transient. However, there is a huge number of indirect experiments that confirm the importance of this mechanism. They include the binding of more stable transition state analogues and the modeling of hypothetical transition states into the active site of an enzyme.

Another important mechanism of catalysis is substrate binding. The role of an enzyme is to recruit reactants such as DHAP into the active site of the enzyme where it is precisely positioned for the subsequent reaction. In the example show here, the reactant has bound to the active site of trisose phosphate isomerase where it aligned with two important amino acid side chains: histidine (His, dark blue) and glutamate (Glu, red). In this case, a single reactant is oriented correctly for the subsequent reaction. In other cases the role of binding is more obvious since two different reactions are correctly positioned to react with each other.

The enzyme serves as a stable platform for aligning the substrates in the correct orientation. The arrangement of the active site pocket and the surrounding channel can greatly increase the probability that the reaction will take place. In solution, without enzyme, many collisions between molecules will be nonproductive.

In addition to transition state stabilization, and substrate binding effects, enzymes also exhibit catalytic effects on acceleration of reactions. There are many different kinds of catalytic effects but the main ones are ionization effects, acid-base catalysis, and covalent catalysis. In all cases, the effect is mediated by the side chains of amino acid at the active site.

An example of acid-base catalysis in triose phosphate isomerase is shown in the diagram on the right. You don't need to follow the specifics of the reaction. The idea is that a histidine side chain (His-95) forms a hydrogen bond with the substrate while a glutamate residue (Glu-165) acts as an acid-base catalyst to extract a proton from DHAP.

The role of amino acid side chains in catalysis and substrate binding was mostly worked out the 1970's when the first enzyme structures were being solved. One of the first examples was ribonuclease A [Monday's Molecule #75]. Stanford Moore and William Stein received the Nobel Prize in 1972 for being among the very first biochemists to demonstrate how enzyme work at the molecular level.

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1. A transition state is not an intermediate. The difference is too technical for this posting. I just want to make sure we don't get any quibbles in the comments section.

God Is Not Winning

 
John Brockman runs a website called The Edge. Most (all?) of the contributers are authors and many of them are clients of Brockman. He is, among other things, a literary agent for prominent authors (Richard Dawkins, Daniel Dennett, Jared Diamond). If you want to understand what The Edge is all about, read Brockman's essay on The Third Culture.

Gregory Paul and Phil Zuckerman have just published an article on The Edge titled WHY THE GODS ARE NOT WINNING. They make some important points that are often overlooked and frequently misrepresented. Here are some quotes ...

It is well documented that Christianity has withered dramatically in Europe, Canada, Australia, New Zealand and Japan. The failure of the faith in the west is regularly denounced by Popes and Protestant leaders. Churches are being converted into libraries, laundromats and pubs. Those who disbelieve in deities typically make up large portions of the population, according to some surveys they make up the majority of citizens in Scandinavia, France and Japan. Evolution is accepted by the majority in all secular nations, up to four in five in some.

......

Nor is it all that surprising that faith has imploded in most of the west. Every single 1st world nation that is irreligious shares a set of distinctive attributes. These include handgun control, anti-corporal punishment and anti-bullying policies, rehabilitative rather than punitive incarceration, intensive sex education that emphasizes condom use, reduced socio-economic disparity via tax and welfare systems combined with comprehensive health care, increased leisure time that can be dedicated to family needs and stress reduction, and so forth.

As a result the great majority enjoy long, safe, comfortable, middle class lives that they can be confident will not be lost due to factors beyond their control. It is hard to lose one's middle class status in Europe, Canada and so forth, and modern medicine is always accessible regardless of income. Nor do these egalitarians culture emphasize the attainment of immense wealth and luxury, so most folks are reasonably satisfied with what they have got. Such circumstances dramatically reduces peoples' need to believe in supernatural forces that protect them from life's calamities, help them get what they don't have, or at least make up for them with the ultimate Club Med of heaven. One of us (Zuckerman) interviewed secular Europeans and verified that the process of secularization is casual; most hardly think about the issue of God, not finding the concept relevant to their contented lives.

The result is plain to see. Not a single advanced democracy that enjoys benign, progressive socio-economic conditions retains a high level of popular religiosity. They all go material.

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[Hat Tip: Brian Larnder at Primordial Blog]

 

The 3rd issue of the Molecular and Cell Biology Carnival has been posted by Bertalan Meskó at ScienceRoll [Molecular and Cell Biology Carnival #3: Animations].

It’s my pleasure to host the 3rd edition of the Molecular and Cell Biology Carnival. This is the first time I host a non medicine-related carnival, so I really hope you will like the posts I found.

Submit your articles here.

The previous editions are ...

1. the skeptical alchemist
2. Cotch.net
3. ScienceRoll

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Come to This Seminar!

 
Alex Palazzo of The Daily Transcript is giving a talk in our Department ....

Department of Biochemistry Special Seminar

"Beyond The Signal Sequence Hypothesis: Nuclear Export and Endoplasmic
Reticulum Targeting of mRNAs."

Dr. Alexander Palazzo Ph.D.
Department of Cell Biology
Harvard Medical School

Thursday, June 12th

Room 4171 MSB
11:00 a.m.

Dr. Palazzo is a candidate for a Faculty position in the Department
of Biochemistry.

Contact me by email if you want to meet Alex for lunch tomorrow.

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One Million!!!

 
I'm fascinated by the statistics of blogging. Who reads blogs? Why do they read blogs? Do blogs serve a useful purpose or are they just for fun? What's the future of blogging?

Part of the fascination is looking at the data to see which postings attract the most attention and how many people regularly check in each day. Are some blogs better than others? Are some blogs more popular? Why?¹

A few minutes ago somebody logged on to Sandwalk to view a page and registered the one millionth page view since this blog began collecting data. That's pretty interesting. It means that Sandwalk is an average science blog in terms of popularity, far behind the best ones that have one million views per month.



One of the interesting things about science blogging is that there's a 25% dropoff in readers during the months of May, June, July, and August. (Other bloggers see this too.) I assume this is mostly students who don't read blogs during the summer. Is it because they only have high speed internet access when they're at school or is it because they're not interested in blogs during the summer?

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1. I wonder if there's a direct correlation between the number of readers and the number of postings per day? Some blogs put up lots of articles every day even though many of those articles don't take much effort. Does this build readership so that when you post something important it's more likely to get attention? That doesn't work for me as a reader. There are quite a few excellent blogs that I scan every day even though the postings are infrequent. On the other hand, when I've tried posting several times a day over a period of a few weeks, the number of visits does increase significantly.

Monday's Molecule #75

 
Some readers have been complaining that Monday's Molecule is too easy.¹ That's why I've chosen a more difficult task for you today.

You have to examine the structure and figure out what's going on. The molecule you have to identify isn't even shown in the figure—only small fragments are depicted. You need to identify the invisible molecule and explain why this figure is so important. Its importance is mostly historical. The elucidation of what's happening is a defining moment in biochemistry and helped open up a whole new field of study.

There's a direct connection between today's molecule and a Nobel Prize. The prize was awarded for discovering exactly what the figure depicts. The first person to correctly identify the molecule, describe what the figure shows, and name the Nobel Laureate(s), wins a free lunch at the Faculty Club. Previous winners are ineligible for one month from the time they first collected the prize. There are three ineligible candidates for this week's reward.

THEME:

Nobel Laureates
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 names the Nobel Laureate(s). Note that I'm not going to repeat Nobel Laureate(s) so you might want to check the list of previous Sandwalk postings by clicking on the link in the theme box. [Hint: A co-recipient of this week's Nobel Laureates is already on the list.]

Correct responses will be posted tomorrow. I may select multiple winners if several people get it right. (Like that's going to happen this week!)

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

UPDATE: Turns out it wasn't as difficult as I thought. The winning answer arrived within one hour, followed shortly by several other correct answers. The image shows a small piece of RNA about to be cleaved in the active site of Ribonuclease A. The key residues are His12, His119, and Lys 41 and their interactions with the substrate are shown. Note how they form weak interactions with the phosphodiester linkage. This causes destabilization of the bonds in preparation for cleavage. The Nobel Laureates are Stanford Moore and William Stein who received the Nobel Prize in 1972 for working out the mechanism of Ribonuclease A. This was the first detailed demonstration of how enzymes worked at the molecular level.

The winner is Michael Clarkson. Congratulations Michael.

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1. Okay, maybe not "some" readers. Maybe it's only one reader. In fact, maybe I'm the reader.

Gene Genie #33

 
The 33rd edition of Gene Genie has been posted at Neurophilosophy [Gene Genie 33].

Welcome to the 33rd edition of Gene Genie, the blog carnival devoted to genes and genetic diseases.

In this edition, there is a strong emphasis on cancer. There's also a focus on leukodystrophy, and a special section on personalized genetics.

The beautiful logo was created by Ricardo at My Biotech Life.

The purpose of this carnival is to highlight the genetics of one particular species, Homo sapiens.

Here are all the previous editions .....

1. Scienceroll
2. Sciencesque
3. Genetics and Health
4. Sandwalk
5. Neurophilosophy
6. Scienceroll
7. Gene Sherpa
8. Eye on DNA
9. DNA Direct Talk
10. Genomicron
11. Med Journal Watch
12. My Biotech Life
13. The Genetic Genealogist
14. MicrobiologyBytes
15. Cancer Genetics
16. Neurophilosophy
17. The Gene Sherpa
18. Eye on DNA
19. Scienceroll
20. Bitesize Bio
21. BabyLab
22. Sandwalk
23. Scienceroll
24. biomarker-driven mental health 2.0
25. The Gene Sherpa
26. Sciencebase
27. DNA Direct Talk
28. Greg Laden’s Blog
29. My Biotech Life
30. Gene Expression
31. Adaptive Complexity
32. Highlight Health
33. Neurophilosophy

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America: The Greatest Experiment in the History of Mankind

 
Here's one of the men who could be "leader of the free world." There's no doubt in his mind that Christianity is the superior religion. I wonder if the other candidate thinks differently?



BTW, how's that experiment working out?

See Jim Lippard's comment at McCain thinks the Constitution establishes a Christian nation. I don't think Jim is going to vote for this man!

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[Hat Tip: Canadian Cynic]

 
Stephen Jay Gould is one of my heroes. This video in six parts was made back in 1984 but most of it is as true and accurate today as it was back then. Thanks to Laelaps for finding it on YouTube.

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