This Doesn't Seem Right ...

 
Scientific American is reporting on a growing trend among field biologists. When they discover a new species they sell the right to name it [Name that species--After yourself, Purdue auction suggests].

Naming your kid after you is one thing. But imagine if an entire species were named for you.

This week, Purdue University is auctioning off the rights to name seven newly discovered bats and two turtles, the Associated Press is reporting. The winners — who will shell out a minimum of $250,000 for at least one of the bats, a Purdue spokesman told ScientificAmerican.com — can link their own name or that of a pal to the animal’s scientific name.

"Unlike naming a building or something like that, this is much more permanent. This will last as long as we have our society," John Bickham, who co-discovered the nine species, told the AP.

In the ongoing battle between splitters and lumpers, you can bet that the splitters are going to gain the upper hand if they can earn so much money by creating a new species.

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Nobel Laureate: Walter Gilbert

 

The Nobel Prize in Chemistry 1980.

"for their contributions concerning the determination of base sequences in nucleic acids"




Walter Gilbert (1932 - ) was awarded the Nobel Prize for developing a chemical method of sequencing DNA (with Allan Maxam). The method relied on chemical reactions that cleaved DNA at specific residues. By carrying out partial reactions where only one cleavage occurred in each DNA strand, it was possible to separate the cleavage products on an acrylamide gel and determine the position of each residue by the length of the fragment.

The chemical sequencing strategy has been replaced by the chain-termination technique of Fred Sanger who shared the Nobel Prize with Gilbert.

A brief description of DNA sequencing can be found on the Wikipedia site at DNA Sequencing.

On looking over the 1980 press release I came across this paragraph.

THEME:
Nobel Laureates

Gilbert and Sanger have independently developed different methods to determine the exact sequence of the nucleotide building blocks in DNA. Among applications of sequence methods may be mentioned that Gilbert has investigated the structure of those parts of a bacterial chromosome which control the reading (transcription) of the genetic message. Sanger is responsible for the first complete determination of the sequence of a DNA molecule. He has established the sequence of the 5375 building blocks in DNA from a bacterial virus called phi-X174. Sanger's method has also been used to determine the sequence of DNA from humans, which led to the surprising discovery that the genetic code is not universal, i.e. it is not the same in all living organisms, from viruses and bacteria to man.

I have no idea what they are referring to here when they mention the non-universality of the genetic code. I don't recall any revelations back in 1980. Are they referring to slight differences in mitochondria?

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The images of the Nobel Prize medals are registered trademarks of the Nobel Foundation (© The Nobel Foundation). They are used here, with permission, for educational purposes only.

[Photo Credit: NNDB, original source unknown.]

Monday's Molecule #100

 
This is the 100th edition of Monday's Molecule! Today's "molecule" is a chemical reaction in several steps.

Your task is to identify what's going on and relate it to a single Nobel Laureate.

The first one to correctly identify the molecule and name the Nobel Laureate, 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: Dale Hoyt from Athens, Georgia, Ms. Sandwalk from Mississauga, Ontario, Canada, Alex Ling of the University of Toronto, and Timothy Evans of the University of Pennsylvania. Dale and Ms. Sandwalk have offered to donate the free lunch to a deserving undergraduate so the first two undergraduates to win and collect a free lunch can also invite a friend. Alex gets the first one.

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 reserve the right to select multiple winners if several people get it right.

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

UPDATE: The reactions lead to cleavage of DNA at G residues. This is part of the chemical sequencing strategy developed by Maxam and Gilbert in 1976. The Nobel Laureate is Walter Gilbert.

I was surprised at how many old fogies well-established scientists read Sandwalk. We have now produced an entire generation of scientists who will have never experienced this sequencing method but, nevertheless, the correct answers flooded in within a few hours. The first was from John Bothwell of the Marine Biological Association of the UK in Plymouth, UK. Congratulations! Are you free for lunch tomorrow, John, or do you want to take a rain check?

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How the Gipper "Wins"

 
Over on Uncommon Descent there was a discussion about macroevolution. The new moderator, Barry Arrington, was so impressed with the responses of his fellow IDiots that he draws attention to their comments in today's posting [UD Commenters Win One for the Gipper].

Below the fold I have reproduced an interesting comment thread in which ribczynski attacks ID proponents’ criticisms of macroevolution through NDE, and two ID proponents convincingly refute the Darwinist line.

Let's see how these two IDiots "refute" the Darwinian line by picking out one of the most common falsehoods that are often repeated by those who are completely ignorant of evolution.

gpuccio writes:

First of all there are saltations. Have you ever heard of “punctuated equilibrium”? That’s not an ID theory.

Jerry writes:

Gould said the whole history of the fossil record was one of apparent saltations. That was why he developed his absurd fix for Darwinian processes called punctuated equilibrium. I suggest you read Gould and as suggested by other, his ideas on punctuated equilibrium. Everybody immediately just lapped up his ideas and it is now part of the evolutionary canon.

Punctuated equilbira have absolutely nothing to do with saltations. This particular misunderstanding has been discussed and refuted dozens of times over the past thirty years. The fact that IDiots would use it in 2008 demonstrates something related to the "Gipper" (the Ronald Regan version) but it's not what they think.

Is this the best they can do? Yes, it is.

What's surprising is that the Intelligent Design Creationists are doing so well when they are so stupid.

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What Would You Have Done?

 
The recent kerfuffle in Canada has prompted all kinds of talk from TV personalities, newspaper columnists, and bloggers. Everybody has an opinion.

One of the common threads is that all politicians in Ottawa are behaving badly and every single one of them needs to grow up and act like an adult. Some blame Harper and some blame Dion. Right now it seems to be Dion who is coming in for the most criticism.

Here's a handy way to distinguish facts from bias. Don't ask for what might have happened in an ideal world but ask instead what you would have advised when the crisis began. When you hear people spouting off about how Dion is ruining the country, for example, ask them what they would have done in his place.

Here's my take.

If Harper had called me before presenting his budget I would have told him to take out the clauses that eliminate party funding, ban civil servant's right to strike, and block pay equity challenges. I would have pointed out that all three are inflammatory and designed to alienate the opposition parties that he needs for support in the House. This is not the time for partisan politics, especially since none of these measures are necessary and, furthermore, they were not something that the Conservative Party made into election issues in October.

Obviously Harper didn't call me and didn't listen to anyone else who might have warned him of the consequences.

Once the budget was made public, what should Stéphane Dion have done? This is an important question and everyone who criticizes Dion should be prepared to answer it. Here's my answer.

The Liberal Party could not have supported such a budget because it was a deliberate slap in the face. It would have been devastating to party finances to eliminate federal funding of political parties and Harper knew that. In the previous sessions of parliament the Liberals abstained on many votes allowing the Conservatives to govern as if they were a majority. That behavior was widely, and correctly, criticized last year and it could not continue in the current session of Parliament.

The fact that Harper proposed an in-your-face challenge on the very first bill was an indication of how he intended to behave for the next few years. This was the only chance the Liberals were going to get to take a stand.

I would have advised Dion and the Liberals to vote against the budget no matter what the consequences. If Harper wanted to call and election, so be it. Having been forced into a corner, I don't believe the Liberals had a choice.

When the idea of a Liberal-NDP coalition came up, I would have advised Dion to agree, provided the plan did not compromise Liberal principles. If the Bloc agreed to not vote in favor of any non-confidence motion for 18 months then that would be perfectly acceptable. In other words, if I had been advising Dion I would have advised him to do exactly what he did. The coalition avoided an unnecessary election and was perfectly in line with the principles of a parliamentary democracy.

Anyone who criticizes Dion's decision should let us know what alternative was preferable. Here were the choices: abstaining, voting for the government, voting against the government?

During this waiting period we can ask ourselves the same questions. What's the best way out of the crisis? Here's my answer ...

The best solution is for Stephen Harper to resign as leader. His replacement should seek out a compromise budget that many parties can support. The new leader should announce that the three inflammatory proposals are not part of the new leader's priorities.

That's probably not going to happen.

Assuming that Stephen Harper is still Prime Minister at the end of January what should Liberals do? I don't think they can support a government led by Stephen Harper. They should vote against the budget, or the throne speech, at the first opportunity. Not only has Harper revealed his agenda in the earlier budget, he has made things much worse by lying about our system of government, stirring up regional bigotry, and provoking a constitutional crisis. Such a man cannot be Prime Minister of my country.

I really don't care whether Dion remains leader of the Liberal Party or whether he is replaced by an interim leader who becomes Prime Minister under a coalition government. The Liberals can even appoint a permanent leader if that's what they decide to do. (Not my preference.) The important point is that the Liberals cannot support Stephen Harper in January.

We cannot have an anti-French, anti-democratic, vindictive, megalomaniac, liar as Prime Minister. I hope that Conservative MPs will realize this themselves before January. If they don't, they should be moved to the Opposition benches, which they will share with the Bloc Québécois.

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More Ph.D.s?

 
There's an interesting commentary in the latest issue of Nature. Apparently the UK goverment has plans to train 2,000 new PhDs in physics and engineering.

The UK's Engineering and Physical Sciences Research Council (EPSRC) is set to spend £250 million on creating 44 centres to train 2,000 PhD students over the next 5 years.

The interdisciplinary Centres For Doctoral Training will focus on areas including climate change, sustainable energy, healthcare technologies and nanotechnology. All of the new centres will be spread across 22 UK universities, and 17 will also have strong ties with businesses.

Businesses will also contribute some cash, EPSRC says, but how much is not clear.

The new centres will accept their first batch of students in October 2009. The students will have four years of funding for their PhDs — more than the roughly three years that most PhDs receive — and will spend up to 75% of their time training with the industrial partners.

Here at the University of Toronto we've been having a discussion about increasing the number of graduate students. The goal of the university is to increase the number of graduate students by 30% over the next few years. The objective is supposed to be achieved by providing extra money to fund graduate students.

Science departments here have cautioned the university not to expect much of a change. By and large, the number of graduate students we accept is not limited by funding. We are making offers of acceptance to every qualified student who applies and we still have excess capacity. More money isn't going to help because it's the qualified students who are limiting, not the ability to fund them.

Is the situation different in the UK? Are physics and engineering departments turning away good students because they don't have the money? Wouldn't that have to be the case is this plan is going to work?

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99% Ape

 
The Natural History Museum in London (UK) is publishing a book that's supposed to explain evolution: 99% Ape: How evolution adds up. Here's part of the press release.

The book introduces the topic of evolution, and leading experts at The Open University explain this fundamental yet often complex subject, guiding the reader through the latest evidence.

Charles Darwin was mocked for suggesting that humans have apes for ancestors, but every scientific advance in the study of life in the last 150 years has confirmed the reality of evolution.

Read the latest research about how new species evolve, uncover the flaws in ‘intelligent design’, find out what evolution has to say about psychology, the development of the human mind and morality, and how we are still evolving, in this new book.

I'm certainly curious about what the book might have to say about morality but that's not my major concern.

My major concern is the title. Out of thousand of possible titles why did they choose one that is factually incorrect? Humans are NOT 99% ape—they are 100% ape. Humans are apes.

If the title is referring to our relationship to chimpanzees then even that is misleading. There are plenty of studies to suggest that the overall percent similarity might be less than 99%, especially if you take indels (insertions/deletion) into account. Why make trouble for yourself by promoting the 99% figures when there are many other titles that could have been chosen?

Judging by the title, this book may do more to contribute to confusion among the general public than to educating them. What a wasted opportunity. (The cover image isn't what I would have chosen either.)

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Let's Help Out an American Friend

 
John Aravosis asks the following question on AMERICAblog.com: I want your input. Are drugs from Canada safe or not?.

Get over there and help him out. Let him know that Canadian drug suppliers are reliable. These are same generic drugs that are sold to Canadians.

Why does John need to know whether Canadian drugs are safe? Because he can't afford the prescriptions his doctor gave him unless he buys his drugs from Canada where they are half the price. I probably wouldn't hurt to remind him of the advantages of socialized medicine.

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[Hat Tip: Canadian Cynic]

This Week's Citation Classic

 
John Dennehy (The Evilutionary Biologist) has posted "This Week's Citation Classic."¹ The classic paper demonstrated back in 1964 that the gene and the protein it encodes are colinear [This Week's Citation Classic]. Remember, this was before DNA sequencing and just around the time that the genetic code was being worked out.

Before you follow the link, try and come up with an experiment that you might have done in 1964 to show colinearity. Are you as smart as Sidney Brenner?

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1. Is it just me, or have we missed a few weeks?

The Globe and Mail Calls for Harper's Resignation

 
The Globe and Mail claims to be Canada's national newspaper. It has a status in Canada that's comparable to that of the New York Times in the USA. Traditionally, the editorial staff of the Globe and Mail has been more conservative than most of the country and they have supported Stephen Harper in the past.¹

Today's editorial calls on Harper to resign for the good of his party and the good of the country [Competence and trust in question].

Not only has Mr. Harper's government failed to adequately address the economic crisis; it has created a political crisis and potentially a national-unity crisis in the process. Rather than working co-operatively on measures to strengthen the economy – something the opposition initially appeared willing to do – Parliament is now locked down, with the government's legitimacy undermined. Meanwhile, the Conservatives' excessive attacks on the Bloc Québécois, and indirectly on the millions of Quebeckers who voted for that party, have fuelled regional divides and reinvigorated the sovereigntist movement – raising a prospect of Quebec's federalist Liberals losing power in Monday's election, or at least failing to win the majority they seemed on track for.

If there is a saving grace in all this, it is that anger with the Conservatives is directed more toward Mr. Harper than his party. That raises the hope that, were he replaced as leader, the greatest barrier to inter-party co-operation with a Conservative minority government would be removed.

It is on that end, rather than the ascent of a coalition government, that the Liberals ought to focus. By hinting that the replacement of Mr. Harper as Tory leader could lessen the crisis, the Liberals would make clear that they are not engaged in a mere power grab – and allow themselves time to resolve their own leadership issues. If the Conservatives accepted that proposition, they could demonstrate that personal interests were secondary to those of the country. Both parties, in other words, could behave like adults. And the economy, rather than the personality of a single polarizing figure, could retake its rightful place as the primary focus of this Parliament.

I agree with the sentiment here. Replacing Harper as leader of the Conservative Party would go a long way toward restoring democracy to Canada.

Incidentally, let's not lose site of the fact that in addition to a provocative budget that the opposition could not accept, and in addition to stoking the flames of bigotry in Western Canada, Harper also misrepresented the nature of our parliamentary system by falsely claiming that it was illegitimate for Parliament to vote him out of office [Harper wrong on democracy claims: experts]. A man like Harper does not deserve to lead my country.

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1. Canadian Cynic provided a link to the Globe and Mail editorial that endorsed Stephen Harper last October 9th. I urge everyone who has an interest in this issue to read that editorial, it is astonishing in it's accuracy and warning of what might happen: Harper is growing into the job .

Say Again?

 
Stephen Harper. the current dictator Prime Minister of Canada received an award in New York City yesterday from Conference of Presidents of Major American Jewish Organizations. Here's the press release.

Prime Minister Harper Given International Leadership Award

Prime Minister Stephen Harper will be honoured today in New York City by the Conference of Presidents of Major American Jewish Organizations, which is presenting him with its first-ever International Leadership Award. Minister of Foreign Affairs Lawrence Cannon will attend the reception and awards ceremony to accept the award on behalf of the Prime Minister.

“I am deeply honoured to be recognized for helping improve Western relations with Israel,” said the Prime Minister. “Canada stands with Israel, and will stand with any nation willing to put its trust in its people and follow the principles of freedom, democracy, human rights and the rule of law.”

The Conference of Presidents of Major American Jewish Organizations was founded in 1954 to promote the State of Israel in the United States. An umbrella group representing 50 national religious, philanthropic and civic American Jewish organizations, it serves as a central coordinating body and primary forum for deliberations and discussions among its members on national and international issues of concern to Jews.

Yesterday was a busy day for Harper. He also shut down the Canadian parliament in order to avoid losing a non-confidence vote.

Interesting how his action contrasts with the words, "Canada ... will stand with any nation willing to put its trust in its people and follow the principles of freedom, democracy, human rights and the rule of law."

Stephen Harper is a threat to Canada and to democracy. He must be removed from office. If that means putting up with a temporary Prime Minister in his place then so be it. This is one of those circumstances where the greater good trumps everything.

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Conservative Lies

 
The Conservative Party under Stephen Harper has been spreading false information about how our parliamentary system works. They have been claiming that the transfer of power from the Conservative Party to the coalition under Stéphane Dion is a "coup" and that Dion does not have the right to lead a government.

Why are the Conservatives doing this? There are two possible explanations ...

• They believe what they are saying, in which case they are stupid and ignorant about how parliament works. They don't deserve to be the government.


• They know they are lying but they hope to convince Canadians that they're telling the truth. Because they are liars and because they have such a low opinion of the average Canadian, they don't deserve to lead a government.

Here's the problem. Harper and his Conservatives are doing great harm to the country by spreading lies. They are trying to convince Canadians that we have a US Presidential style of democracy and that he (Harper) was voted in as Prime Minister. Our young people are confused enough about politics without having this kind of false information spread by our Prime Minister.

Peter Russell is a Professor Emeritus in the Dept. of Political Science at the University of Toronto. We have tangled on a number of issues but always with mutual respect (I hope). He is a very smart man and you don't want him to catch you spreading lies about politics. Here's part of his column in today's Toronto Star [Constitution and precedent are on coalition's side].

If there is an alternative government available that has a reasonable prospect of being supported for a period of time by a majority in the House of Commons, she would have reason to decline Harper's request. Harper would then have to resign, and the Governor General would commission Dion to form a government.

If this happens, again there would be no "usurpation" of power but a proper application of the rules and principles of parliamentary democracy. It has been very disturbing to hear over the last few days, from people who should know better, wild unparliamentary theories about our system of government. Elections are not simple popularity contests in which the leader whose party garners the most votes gets all the power.

I am greatly concerned that there is so little public knowledge of the constitutional rules that govern our parliamentary system of government. These rules are not formally written down in a legal text or taught in our schools. Maybe the most important lesson to take from the situation we are now living through is to begin to codify as much as we can of this "unwritten" part of our Constitution and to ensure that it is well taught in our schools.

Harper is wrong. The only remaining question is whether he is stupid or a liar (or both).

Who is to blame for this mess? Peter has the correct answer ....

These precedents and many, many others illustrate the basic point that in parliamentary democracies we elect parliaments not prime ministers, and that the Governor General (or the presidential head of state in a republican parliamentary system) must be advised by ministers who are supported by a majority in the elected house of parliament.

Now let's apply these rules of parliamentary democracy to the situation Canada now faces. After the Oct. 14 election, Stephen Harper remained Prime Minister, formed a new government and prepared to face the House. Although his party had improved its seat total it was still in a minority position in the House. This meant that to continue in office Harper would have to win enough support from the opposition benches to secure the confidence of the House.

For a few days it appeared that Harper would reach out in a conciliatory manner and garner the parliamentary support he needs on order to have the right to govern.

But, to put it mildly, on Nov. 27 just a few days into the session, through his finance minister's economic update, he made an abrupt U-turn. Instead of seeking support from the opposition, his government presented an in-your-face, take-it-or-leave-it position.

The opposition parties – all three of them – decided not to take it. Instead, they announced that they would use their collective majority in the House to vote no confidence in the Harper government and support an alternative coalition government.

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Nobel Laureate: Eric Kandel

 

The Nobel Prize in Physiology or Medicine 2000.

"for their discoveries concerning signal transduction in the nervous system"

Eric R. Kandel (1929 - ) won the Noble Prize in 2000 for his work on understanding the biochemistry of memory. He discovered that short term memory in the sea slug Aplysia depended on the phosphorylation and dephosphorylation of proteins and that the regulation of these covalent modifications was under the control cyclic AMP mediated signal transduction pathways.

Kandel shared the prize with Arvid Carlsson and Paul Greengard.

Here's what the press release says about Kandel's work

THEME:
Nobel Laureates

Eric Kandel

Sea slug, a model system for learning
A phosphorylation of proteins has great importance also for the discoveries for which Eric Kandel is rewarded, that is for revealing molecular mechanisms, important for the formation of memories. Eric Kandel started to study learning and memory in mammals, but realized that the conditions were too complex to provide an understanding of basic memory processes. He therefore decided to investigate a simpler experimental model, the nervous system of a sea slug, Aplysia. It has comparatively few nerve cells (around 20.000), many of which are rather large. It has a simple protective reflex that protects the gills, which can be utilized to study basic learning mechanisms.

Eric Kandel found that certain types of stimuli resulted in an amplification of the protective reflex of the sea slug. This strengthening of the reflex could remain for days and weeks and was thus a form of learning. He could then show that learning was due to an amplification of the synapse that connects the sensory nerve cells to the nerve cells that activate the muscle groups that give rise to the protective reflex.

Short and long term memory
Eric Kandel showed initially that weaker stimuli give rise to a form of short term memory, which lasts from minutes to hours. The mechanism for this "short term memory" is that particular ion channels are affected in such a manner that more calcium ions will enter the nerve terminal. This leads to an increased amount of transmitter release at the synapse, and thereby to an amplification of the reflex. This change is due to a phosphorylation of certain ion channel proteins, that is utilizing the molecular mechanism described by Paul Greengard.

A more powerful and long lasting stimulus will result in a form of long term memory that can remain for weeks. The stronger stimulus will give rise to increased levels of the messenger molecule cAMP and thereby protein kinase A. These signals will reach the cell nucleus and cause a change in a number of proteins in the synapse. The formation of certain proteins will increase, while others will decrease. The final result is that the shape of the synapse can increase and thereby create a long lasting increase of synaptic function. In contrast to short term memory, long term memory requires that new proteins are formed. If this synthesis of new proteins is prevented, the long term memory will be blocked but not the short term memory.

Synaptic plasticity, a precondition for memory
Eric Kandel thus demonstrated that short term memory, as well as long term memory in the sea slug is located at the synapse. During the 1990's he has also carried out studies in mice. He has been able to show that the same type of long term changes of synaptic function that can be seen during learning in the sea slug also applies to mammals.

The fundamental mechanisms that Eric Kandel has revealed are also applicable to humans. Our memory can be said to be "located in the synapses" and changes in synaptic function are central, when different types of memories are formed. Even if the road towards an understanding of complex memory functions still is long, the results of Eric Kandel has provided a critical building stone. It is now possible to continue and for instance study how complex memory images are stored in our nervous system, and how it is possible to recreate the memory of earlier events. Since we now understand important aspects of the cellular and molecular mechanisms which make us remember, the possibilities to develop new types of medication to improve memory function in patients with different types of dementia may be increased.

Figure 4.
A sea slug, Aplysia, has a simple nervous system and a gill withdrawal reflex that Eric Kandel has utilized to study learning and memory.

Figure 5.
A schematic description of how molecular changes in a synapse may produce "short term memory" and "long term memory" in the sea slug, Aplysia. The figure shows a synapse that is affecting another synapse. Short term memory can be produced when a weak stimulus (thin arrows in the left lower part of the figure) is causing a protein phosphorylation of ion channels, which leads to a release of an increased amount of transmitter. For a long term memory to be created, a stronger and more long-lasting stimulus is required (bold arrows in the figure). This causes an increased level of the messenger molecule cAMP, which causesa further activation of protein kinases. They will phosphorylate different proteins and affect the cell nucleus, which in turn will issue orders regarding the synthesis of new proteins. This may lead to changes in the form and function of the synapse. The efficacy of the synapse can then be increased and more transmitter released.

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[Photo Credit: Eric Kandel: Wikipedia]

Dancing to the Music

 
I have a confession to make. Every Monday night Ms. Sandwalk and I go dancing. We are taking beginner's social dancing at the local community center. This is the fifth time we've taken the beginners' classes.

After the dancing lessons we go with our friends to the pub and eat honey garlic chicken wings and French fries covered with cheese and mayonnaise. Alcohol is consumed.¹

I'm finally getting the hang of the waltz. From time to time I can do the steps without counting out loud. There is, however, one small problem. According to Ms. Sandwalk I don't keep time to the music. Apparently I have no idea how to coordinate the steps and the beats. I'll have to take her word for it 'cause it seems okay to me.

As if I didn't feel bad enough, psa over on Canadian Cynic publishes a video proving that even birds can do it [Go Parrot, Go!].


This is really embarrassing.

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1. It may sound like a bribe but I assure you that I would undoubtedly be going to the dance lessons even if we didn't visit the pub afterward. (Like I have a choice?)

Priceless

 
Canadian Cynic keeps finding these wonderful examples of Conservative stupidity. This one is from The London Free Press [Harper's appeal to flag falls flat].

OTTAWA — An attempt by Stephen Harper to wrap himself in the flag and take a dig at the opposition coalition fell flat Tuesday.

The prime minister has been portraying the Liberal-NDP-Bloc Quebecois government-in-waiting as an unholy alliance of “socialists and separatists.”

During question period, he suggested the opposition parties staged their pact-signing ceremony Monday without a Canadian flag in the background because of the separatist Bloc.

“Yesterday, as part of the culmination of the machinations of the leader of the NDP, we had these three parties together, forming this agreement, signing a document and they wouldn’t even have the Canadian flag behind them,” he said.

“They had to be photographed without it because a member of their coalition does not even believe in the country.”

Video confirms that Harper was technically right. There wasn’t a Canadian flag in the background — there were two.

Wake up Conservatives. It's time to find a new leader before he makes you look any worse than you actually are right now. You are in danger of becoming a mockery of a political party comparable to what your predecessor, the Progressive Conservatives, looked like in December 1979.

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Quote of the Day

 
From A BCer in Toronto comes this quote of the day,

Governor General Michaelle Jean:

"The prime minister and myself need to have a conversation."

which prompts me to express my disgust and point everyone to a recent posting by Ms. Sandwalk [STOP using "Myself" incorrectly].

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Michaëlle Jean

 
This is Michaëlle Jean, the Governor General of Canada. She acts as Canada's Head of State. The Prime Minister is the head of government.¹ Sometime in the next few days Michaëlle Jean is going to have to make some serious decisions. She will have to decide whether to invite the Liberal-NDP coalition to form a new government if Stephen Harper and his Conservatives lose a vote of non-confidence next Monday. I think that's a no-brainer—she has to turn to the coalition.

More importantly, what will she do if Stephen Harper asks her to delay parliament for six weeks (the technical term is prorogue)? Everyone knows that Harper will only do this in order to avoid the non-confidence motion scheduled for Monday. That has never been done before and it is contrary to the standards of a parliamentary democracy. However, it is also important that the Governor General not put herself in the position of second guessing the advice of the Prime Minister. In my opinion, she will have to accept his request to prorogue parliament because to do otherwise is to set a dangerous precedent. The Governor General, like the Queen she represents, is a figurehead and not an active participant in government.

Hopefully, cooler heads will prevail and Harper won't abuse his position by requesting that parliament be suspended. Harper brought this problem upon himself by acting like a petulant, childish, bully and it's time for him to accept his fate and behave like an adult. That goes for his supporters as well.

Grow up Conservatives. You were stupid enough to force the opposition into a corner where they had only two choices, surrender and die, or unite against an unethical minority government. Much to your surprise, they were able to unite and now you must suffer the consequences of your own stupid mistake. Accept it with grace and dignity and stop acting like crybabies [Canadian Cynic].

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1. America is one of the few democracies that combine these two jobs.

Graduate Record Exams: Biochemistry, Cell and Molecular Biology

 
This is the time of year when some undergraduates are getting the results of the GREs (Graduate Record Exams) that they wrote in preparation for graduate school applications. I thought I'd take a look at the practice test for Biochemistry, Cell and Molecular Biology.

This isn't pretty. Many of the questions ask for specific details like what is the initial product of CO₂ fixation in C₃ plants? I know lots of departments that don't teach photosynthesis and CO₂ fixation so students in those departments are screwed.

More importantly, I teach this in my introductory biology class but I tell the students that they don't have to memorize the details. They are allowed to bring their notes to the exam. I try to concentrate on basic principles and concepts and not on the names of enzymes and their specific reactants and products. In the case of CO₂ fixation, the important concepts have to do with the way rubisco works, the usable product of the reaction (not the initial product), and a general understanding of how the original reactant is regenerated. They have to understand the overall stoichiometry of the pathway and how the pathway is related to the pentose phosphate pathway.

Here's the problem. Are teachers like me hurting our students' chances of doing well on the GRE by discouraging rote memorization and regurgitation?

Even worse, I teach that concepts like exergonic and endegonic reactions are almost useless in most cases because most of the reactions in a pathway operate at near-equilibrium conditions where ΔG = 0. Several of the GRE questions ask about exergonic and endergonic reactions. My students will not do well on those questions.

How common is this? Do any other biochemistry teachers find that there's a conflict between what they teach and what is taught at most other schools?

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Monday's Molecule #99

 
Name this molecule. This time we need the common name and the systematic (IUPAC) name. A Nobel Prize was awarded for discovering how this molecule is related to your ability to remember its name and recognize the structure.

The first one 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: Dima Klenchin of the University of Wisconsin, Dale Hoyt from Athens, Georgia, Ms. Sandwalk from Mississauga, Ontario, Canada and Alex Ling of the University of Toronto. Dale and Ms. Sandwalk have offered to donate the free lunch to a deserving undergraduate so the first two undergraduates to win and collect a free lunch can also invite a friend. Alex gets the first one.

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 reserve the right to select multiple winners if several people get it right.

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

UPDATE: The molecule is cyclic AMP (cAMP) or (1S,6R,8R,9R) -8-(6-aminopurin-9-yl) -3-hydroxy-3-oxo-2,4, 7-trioxa- 3λ5-phosphabicyclo [4.3.0]nonan-9-ol. The Noble Laureate is Eric Kandel. Several people guessed the molecule and Kandel but they added a second Nobel Laureate—one that I had already covered (usually Paul Greengard). Only one person picked up on the clue about memory and named Kandel alone. Congratulations to Timothy Evans of the Dept. of Neuroscience, University of Pennsylvania.

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Religious Freedom and Privacy

 
Phil Plait asks us to watch this video [Freedom of and from religion]. He says,

Watch this video. We need more like it. And I’m amazed some people can’t figure this out. it’s really pretty simple.

I'm one of those people who can't figure it out. I'm all for religious freedom. Everyone has the right to believe whatever they want as long as it doesn't interfere with the rights of others. This applies in all countries, not just in the USA.

But the video seems to imply something more when it talks about "privacy" and "respect." It sounds very much like they are advocating for protection from criticism and challenges to their beliefs.

Is this correct? Is it against the law in America to question religion or make fun of some of the most outrageous examples?

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Serious Question?

 
Nanopublic posted one of the covers of Onion Weekender with the lead story They tried to teach my baby science. Scary stuff.

If you follow the link to the Onion website you'll find all sorts of interesting Christmas gifts. If you're into giving things for Christmas just for the safe of buying presents then this is the place for you. I especially like this T-shift (below) that asks a very profound question.

I don't know the answer. I think you can start teaching them about Jesus when they are still kittens but chances are they'll never give up the idea that cats are the true gods.

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Greg Laden on "Race" (Again)

 
Greg Laden is one of those people who want to abolish use of the word "race" to define genetic subpopulations. He claims that there is no such thing in humans (or in other species). But even if it were biologically correct we shouldn't use the word because is has been misused by non-scientists.

Here's an example of his reasoning from The Scientific, Political, Social, and Pedagogical Context for the claim that "Race does not exist.".

The race concept has been very successful in its many nefarious applications, but this is not what I wish to speak about here. Rather, I want to acknowledge that a concept that divides humans into a particular set of groups in a useful way might be, well, useful and not such a bad thing. The fact that medical researchers use race to divide subjects, and find differences between races, and that these differences are important to know about, is important, even if it does not validate the races. What it means is that an unworkable race concept works sometimes, even if the races themselves don't exist. Nonetheless, it is reasonable to acknowledge that even though races don't really exist and many, if not most, applications of the race concept are obnoxious, it may be that its use is not entirely inappropriate all the time.

I will argue, however, that the down side of the use of race requires its abolition among scientists. Since race is usually not a biologically useful concept for humans (or many other species), and is never a truly valid concept, it is difficult to justify its use given the negative political and social consequences it carries.

Greg and I have been over this ground before. It think it's silly to pretend that races don't exist. That's carrying the anti-racist agenda too far.

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Best Canadian Sci/Tech Blog: Round Two

 
The first round of voting for the best Canadian Sci/Tech Blog is over.

As I said earlier, I voted for Bad Astronomy in the first round [Best Canadian Sci/Tech Blog]. I know Phil Plait isn't a Canadian, but he should be.

Here are the five finalists. I'm voting for Post Darwinist in order to make this contest look as silly as possible.

• Sync, the Tech & Gadgets Blog
• Synchro Blogue
• Post Darwinist
• DeSmogBlog
• Dusan Writer

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The Conservative Party Will Help You Write a Letter to the Editor

 
If you go to the Conservative Party website at Harper Leadership 08 you can get help in writing a letter to the editor. If you enter some sort of name and address you will eventually end up on a page that gives you the latest Conservative version of framing spin.

This is how Harper is going to avoid defeat when he faces the House of Commons. (Click on the image to see a larger version.)

The idea that the opposition parties don't have a mandate to from a coalition is particularly ironic given Stephen Harper's own position just a few years ago. Here's what is reported prominently on the front page of today's Toronto Star

But opposition MPs are accusing the Prime Minister of hypocrisy, charging that Harper is overlooking his own efforts to forge a coalition to replace Paul Martin’s minority Liberal government in 2004.

Harper, then Conservative leader, even joined with NDP Leader Jack Layton and Bloc Québécois Leader Gilles Duceppe to write then-governor general Adrienne Clarkson, urging her to look at "options" if Martin's government fell in the fall of 2004, mere months after it won a minority mandate on June 28.

"We respectfully point out that the opposition parties, who together constitute a majority in the House, have been in close consultation," read the Sept. 9, 2004, letter from the three leaders.

"We believe that, should a request for dissolution arise this should give you cause, as constitutional practice has determined, to consult the opposition leaders and consider all of your options before exercising your constitutional authority."

That message is in stark contrast to the one Harper delivered Friday night, when he charged that Liberals don't "have the right to take power without an election."

"The opposition has been working on a backroom deal to overturn the results of the last election without seeking the consent of voters. They want to take power, not earn it," he said in a statement.

Now Conservative MPs are being instructed to take that message to Canadians.

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[Hat Tip: Canadian Cynic: Because they really do need babysitting, that's why]

Is Superstition the Default Belief?

 
Are you getting tired of the modern mantra about religion—you know, the one that says it's wired into our genes and therefore probably correct or at least beneficial? I am.

So, apparently, is A.C. Graying who writes in Friday's Guardian (UK) [Children of God].

Earlier this week I had occasion to debate – if the soundbite culture of radio news permits that description – with a member of Oxford University's Centre for Anthropology and Mind the "findings" of its cognition, religion and theology project, to the effect that children are hardwired to believe in a "supreme being". The research is funded by the Templeton Foundation, an organisation keen to find, or to insert, religion into science and to promote belief in their compatibility – which, note, comes down to spending money on "showing" in the end that the beliefs of ancient goatherds are as good as modern physics.

Justin Barrett, a Christian and member of the centre's research team (whether it is research or propaganda is the moot question here) says with his colleagues on the centre's website:

"Why is belief in supernatural beings so common? Because of the design of human minds. Human minds, under normal developmental conditions, have a strong receptivity to belief in gods, in the afterlife, in moral absolutes, and in other ideas commonly associated with 'religion' … In a real sense, religiousness is the natural state of affairs. Unbelief is relatively unusual and unnatural."

This claim was the subject of Barrett's lecture at Cambridge, in which he exhibited his reasons for thinking that children are innately disposed to believe in intelligent design/creationism and a supreme being. His real reasons for thinking this, of course, are that he is a man of faith funded by a faith-based organisation; but the reasons he professed were that children have an innate tendency when small to interpret what happens in the world to be the outcome of purposive agency.

Now on this point he and I, an atheist funded by no organisation keen on promoting atheism, agree. Children's earliest experiences are of purposive agency in the adults and other people around them – these being the entities of most interest to them in their first months – and for good evolutionary reasons they are extremely credulous, not only believing that things must be acting as their parents do in being self-moving and intentional, but also believing in tooth fairies, Father Christmas, and a host of other things beside, almost all of which they give up believing before puberty, unless the beliefs are socially reinforced – as with religious and, to a lesser extent, certain other superstitious beliefs. Intellectual maturation is the process in important part of weaning oneself from the assumption that trees and shadows behave as they do for the same reason that one's parents, other humans, and dogs and cats do; it is every bit as natural a fact about children that they cease to apply intentionalistic explanations to everything as that they give them to everything, on the model of their parents' behaviour, in the earliest phases of development.

...

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[Hat Tip: RichardDawkins.net

Kill Him, Kill Him Dead

 
These are interesting times in Canada. We recently re-elected the Conservative Party as the party with the most seats in Parliament—but not a majority. That means Stephen Harper becomes Prime Minister of a minority government.

What this normally means is that the government has to craft legislation that will receive the support of a majority of the house. But that's not what Harper proposes to do. Instead he has come up with a proposal that promotes a hard-core right-wing agenda. He did this because he assumed that the Liberal party would be forced to support the government in spite of the fact that they are ideologically opposed to many of the items in the legislation. Harper thought that the Liberal party was in such desperate shape to avoid an election that they would vote for the devil.

Turns out he was wrong. In an extraordinary development, the three opposition parties—Liberals, New Democratic Party, Bloc Quebecois—have forged a coalition and announced they will vote against the government bill.¹ This will bring down the government. Stephen Harper will not be Prime Minister but there will not be an election. Instead, the coalition will form a new government.

Scott Reid of The Globe and Mail has a column in yesterday's paper that illustrates the seriousness of the crisis. It's unusual to see such language in a Canadian newspaper—especially The Globe and Mail—so I thought I'd reproduce part of his column here to show the world what is going on. I agree with Scott Reid. For the good of Canada Stephen Harper must be stopped before he does serious harm to the country.

First things first: take him out.

After all, Stephen Harper is the most dangerous animal lurking in the jungles of Parliament. He is a threat to the future viability of the Liberals. A blood simple opponent of the NDP and the only serious contemporary challenge to the Bloc Quebecois. Without him, his party is an unlikely combination of Reform Party leftovers, Harris refugees and Red Tory desperates. They don't matter or even exist without Mr. Harper. So before you think a moment longer, opposition leaders, think on that.

And if that's not compelling enough, remember: He doesn't play to win. He plays to conquer. Under his guidance, the public interest is always subjugated to his personal political advancement. And he poisons Parliament with an extreme, bare-fanged breed of partisanship that has no hope of repair until he is banished.

This becomes relevant because suddenly, he is weak. In fact, at this particular moment, he is almost unable to defend himself. Owing to a ridiculously ill-considered act of hubris, he has laid himself vulnerable to his opponents. Their imperative could not be more clear: kill him. Kill him dead. Do not, whatever you do, provide him with an opportunity to extend his hold on power. Because you can be damn certain he will never again be so reckless as to give you a chance to finish him off.

Fate tends to be grudging with gifts of this significance. To ignore it would be an error every bit as historic as the one Mr. Harper himself has made.

So don't get fancy. Don't get confused. And don't get weak in the knees. If you don't put Mr. Harper in his grave, he'll put you in yours.

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1. They will also vote in favor of a non-confidence motion put forward by the Liberal party.

Biochemistry on the Web: The Citric Acid Cycle

Here are some websites that discuss the Citric Acid Cycle [Krebs animation][Wikipedia].

This is one of the fundamental biochemical pathways yet both of these sites contain errors. This is the time of the year when I challenge the students in my introductory biochemistry class to find one single website that correctly shows the reactions of the citric acid cycle with all the correct substrates and products (including water and protons). There are two sites that don't count: ones with images from my book (Horton et al.) and ones that are direct copies of the International Biochemistry and Molecular Biology (IUBMB) website. In five years my students have not succeeded. Can any Sandwalk reader find one?

Here are the links to the IUBMB reactions. They all have the correct reaction at some location. You may have to follow one or more of the links to the reaction to see the complete, correct version.

Enzymes of the Citric Acid Cycle

citrate synthase [EC 2.3.3.1]
aconitase [EC 4.2.1.3]
isocitrate dehydrogenase [EC 1.1.1.41][EC 1.1.1.42]
α-ketoglutarate dehydrogenase [EC 1.2.4.2]
succinyl-CoA synthetase [EC 6.2.1.4][EC 6.2.1.5]
succinate dehydrogenase [EC 1.3.5.1]
fumarase [EC 4.2.1.2]
malate dehydrogenase [1.1.1.37]

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The Yale Experience with Alternative Medicine

 
Do you think that modern medical schools at major universities will never be advocates of quackery? Wrong!

The experience of Yale University's School of Medicine should be a warning that those who believe in evidence-based medicine have to be vigilant. Yale recently held an "Integrative Medicine Scientific Symposium." One of the speaker was David L. Katz, MD, MPH, FACPM, FACP. Katz is associate professor, adjunct, of Public Health and director of the Prevention Research Center (PRC) at the Yale University School of Medicine. He is a proponent of almost every form of non-evidence based medicine that you can imagine.

A short video of his presentation is included below. It's from the blog DC's Improbable Science: Integrative baloney @ Yale. I'm including it because it illustrates the length to which these quacks will go in order to make their point. Note that the quack is introduced by the Dean of Education at Yale—listen to how easily he may have been bamboozled into thinking that this is about legitimate science.

The most important points in the video are the ones where Dr. Katz explains away evidence-based medicine. You see, the problem isn't so much with the lack of "evidence" as with the concept of "evidence" itself. The practitioners of alternative medicine advocate changing the very concept of "evidence" to a "more fluid concept of evidence." What this means is that if a large-scale, double-blind experiment shows no effect it's not the end of the story. There are other kinds of evidence that may show the effectiveness of alternative medicine. (One of them seems to be anecdote.)



I hope that the University of Toronto is not going in this direction.

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Snopes Warns Against Embedded Tracker Programs - Pass It on

 
Friday's Urban Legend: False

Have you ever received an email messgage like this?

Snopes Warning

Pass this one on to all your e-mail buddies and take the time to read the Snopes.com article listed below. It is full of good advice especially about the "cookies."

To whom it may concern:

Just a word to the wise. E-mail petitions are NOT acceptable to Congress or any other municipality. To be acceptable petitions must have a signed signature and full address.

Almost all e-mails that ask you to add your name and forward on to others are similar to that mass letter years ago that asked people to send business cards to the little kid in Florida who wanted to break the Guinness Book of Records for the most cards. All it was, and all this type of e-mail is, to get names and "cookie" tracking info for tele-marketers and spammers to validate active e-mail accounts for their own purposes.

Any time you see an e-mail that says forward this on to "10" of your friends, sign this petition, or you'll get good luck, or whatever, it has either an e- mail tracker program attached that tracks the cookies and e mails of those folks you forward to, or the host sender is getting a copy each time it gets forwarded and then is able to get lists of "active" e mails to use in spam e-mails, or sell to others that do.

Please forward this notice to others and you will be providing a good service to your friends, and will be rewarded by not getting 30,000 spam e-mails in the future.

(If you have been sending out the above kinds of email, now you know why you get so much spam!)

According to snopes.com they have never warned against "tracking programs" embedded in email messages [False Advice]. It may be good advice to not spam your friends but nothing in this email message is directly from the snopes.com website and nobody at snopes.com have authorized it.

If there was such a thing as an embedded email tracking program then passing on this message would be an excellent way to spread it!

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So Many Turkeys

 
This is almost as much fun as curling! Ms. Sandwalk will love this game [Turkey Shoot].

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[Hat Tip: Chaotic Utopia]

Online Curling

 
Even if you don't like computer games, you won't be able to resist this one. It's an online curling game on the Little Mosque on the Prairie website.

Ms. Sandwalk, Jane and Gordon are going to be so excited about this. I can hardly wait to get a tournament going with my children and their American partners, Michael, and Rachel. Such an easy way to teach them the best things about Canadian culture!!

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[Hat Tip: The Unexamined Life]

Thanksgiving Day in the USA

 
Some people give thanks for turkey or pumpkin pie. Some people give thanks for football. Others are truly thankful that they have been blessed with good fortune.

Sean Carroll gives thanks for the spin-statistics theorem.

Most people wouldn't understand but I do. I've hung out with physicists and astronomers. This really is how they think.

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Complimentary and Alternative Medicine at the University of Toronto

 
The Faculty of Arts & Science at the University of Toronto offers a program called "Human Biology." Students who complete the program will graduate with an Honours B.Sc. degree. One of the courses is HMB434H1: Complementary and Alternative Medicine.

The textbook for the course is Fundamentals of Complementary and Integrative Medicine by Marc S. Micozzi.

Here's the course description.

Complementary/ alternative medicine (“CAM”) is used in health care systems not only in North America, but also in countries such as China, India, and Vietnam (WHO, 2002). It involves the use of non-biomedical, “holistic” and/or culturally-specific health services and practices in the treatment of illness and disease (such as Chinese acupuncture), and an expanded concept of health, illness, and wellness. This course provides an introduction to the concepts, theoretical basis, evidence-based analysis, and pressing challenges and issues in CAM today. Specific topics include introductions to: complementary/ alternative medicine in industrialized countries and commonly used modalities such as homeopathy and naturopathic medicine; traditional medicine (TM) and primary health care (PHC); traditional Chinese Medicine (TCM) and China; Ayurvedic medicine in India; Canada’s First Nations; and integrative health systems and models. Course format includes lectures, guest-presentations, films/documentaries, and inter-active class discussions/exercises. Students will also have the opportunity to analyze CAM systems and modalities.

I've been pretty nervous about this course ever since one of our students blogged about it last year [U of T has a course in complementary and alternative medicine]. I was hoping that the course would present both sides of the story.

That idea was just blown out of the water at a meeting that I just returned from. I got a chance to talk to one of the instructors, Daniel Hollenberg. What I was hearing was not good so I steered to conversation around to homeopathy thinking that this might relieve my fears. It didn't.

Here, without comment, is what I was told by a man who teaches science students at my university.

• Philosphers of science recognize that there are several different kinds of evidence—not just the reductionist evidence of traditional medicine. In particular, epistemologists talk about holistic evidence. Alternative medicine is supported by holistic evidence not reductionist evidence.


• Evidence in support of homeopathy has been published in Lancet, and he teaches that to his students.


• While there may be examples of some homeopathic medicines that don't work, the theory of homeopathic medicine is understood and supported by physicists who have published papers explaining how water retains the memory of molecules that used to be dissolved in it. He mentioned Ursala Franklin as a supporter of homeopathy.

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Nobel Laureates: George Hitchings and Gertrude Elion

 

The Nobel Prize in Physiology or Medicine 1988.

"for their discoveries of important principles for drug treatment"

Gertrude B. Elion (1918 - 1995) and George H. Hitchings (1905 - 1998) won the Noble Prize for their work on the treatment of disease and organ transplantation. They developed a number of drugs that interfered with nucleic acid synthesis leading to effective treatment of malaria as well as bacterial and viral infections. They are especially noted for the development of drugs that inhibit the body's ability to reject the transplant. One of the most famous of these immunosuppression drugs is azathioprine, a drug that is still used in some cases to suppress the immune response.

Elion and Hitchings worked together at the Wellcome Research Laboratories in Research Triangle Park, NC, USA. They are among a select group of Nobel Prize winners who did their prize winning research outside of academia. Elion and Hitchings shared the Nobel Prize with Sir James W. Black.

Here's what the press release said about Elion and Hitchings

THEME:
Nobel Laureates

Studies of Nucleic Acid Synthesis Result in the Discovery of New Drugs

Gertrude Elion and George Hitchings have collaborated since 1945. Their original research idea was to look for differences in nucleic acid metabolism between normal human cells, cancer cells, protozoa, bacteria and virus, which could be utilized to develop drugs that selectively block the growth of cancer cells and of noxious organisms. Over the years this research philosophy has formed the basis for the development of drugs against a variety of disorders including leukemia, malaria, virus infections and gout.

When Elion and Hitchings presented their ideas at the end of the 1940s the knowledge about nucleic acid metabolism was very limited. It was known, however, that purines and pyrimidines are incorporated into nucleic acids. Elion and Hitchings studied the growth of the Lactobacillus casei, a bacterium dependent on folic acid or a combination of purines (hypoxanthine, guanine) and pyrimidines (thymine). The purpose was twofold, to characterize the metabolic pathways involved in the biosynthesis of nucleic acids and to identify antimetabolites in the nucleic acid metabolism (Figure 3).
Figure 3.

Figure 3. Purine bases (adenine, guanine and hypoxanthine) are synthesized from simple precursors. Nucleosides are then formed by the addition of sugar moieties (deoxyribose or ribose) and subsequently converted into nucleotides by the addition of phosphate (mono-, di- and triphosphate). Nucleotides take part in cellular metabolism and are the building blocks in the synthesis of RNA and DNA. Structural analogues of the natural substances can specifically block the different metabolic steps. Some examples are given in the figure.

Already in 1948 Elion and Hitchings discovered a substance, diaminopurine, an adenine antagonist, which inhibited the growth of L. casei (Figure 3). It was also found to have an effect on experimentally induced leukemia. Clinical trials in patients were initially promising but had to be interrupted due to toxic side effects. Stimulated by this finding Elion and Hitchings continued their research which soon resulted in two new chemotherapeutic drugs, thioguanine (1950) and 6-mercaptopurine (1951). In collaboration with the Sloan-Kettering Institute 6-mercaptopurine was tried in leukemic patients who were resistant to methotrexate. About one third of the patients responded with complete remission (1953). The finding was soon confirmed, and 6-mercaptopurine (as well as thioguanine) are still used in the treatment of leukemia (Table II).

Elion and Hitchings tried to improve the therapeutic properties of 6-mercaptopurine by using sulphur-substituted compounds. The result was azathioprine (1957) which replaced mercaptopurine as an inhibitor of the immune response. For a long time azathioprine was the only drug available to prevent rejection of transplanted organs. It is still used for that purpose but also for the treatment of autoimmune diseases.

Attempts were also made to prolong the effect of 6-mercaptopurine by blocking its metabolism by xanthine oxidase which is involved in the endogenous production of uric acid (Figure 3). In 1963 this research resulted in another new drug, allopurinol, which blocks the formation of uric acid and therefore is used in the treatment of primary and secondary gout.

Hitchings and collaborators also developed pyrimethamine (1950) and trimethoprim (1956) which were found to be effective in the treatment of malara and bacterial infections, respectively. Both drugs have a strong affinity to the enzyme dihydrofolate reductase, but pyrimethamine is 2000 times more toxic to the enzyme system in the malaria parasite than in the host. Trimethoprim has 100 000 times higher affinity to the bacterial compared to the human enzyme. An important discovery was that the chemotherapeutic effects of these two compounds were markedly enhanced by sulphonamides, drugs which inhibit the synthesis of folic acid. This pharmacotherapeutic principle is used in the combination drugs trimethoprim-sulfa and pyrimethamine-sulfa which are used in the treatment of bacterial infections and malaria, respectively.

A more recent application of Elion's and Hitchings' research philosophy is acyclovir, a drug used in the treatment of infections with herpes virus. Already in the 1950s they had shown that antipurines had to be transformed into nucleotides in order to become active in the cell. The herpes virus carries information which leads to the production of a new enzyme which transforms nucleosides to nucleotides (thymidine kinase) in the infected cell. This enzyme has considerably less substrate specificity than the cell's normal enzyme. Therefore, acyclovir is transformed into its corresponding nucleotide which is the active antimetabolite and the growth of the virus is inhibited (Figure 3).

Acyclovir was described by Elion and coworkers in 1977 and is a modern example of the realization of the basic ideas from 1950. An even more recent application of these ideas is the development of azidothymidine (AZT) which was described in 1985 by other scientists from the same institute, and which is the hitherto best documented drug in the treatment of AIDS. It can be added that trimethoprim-sulfa is used in the treatment of Pneumocystis carinii, a relatively common complication to AIDS.

The clinical use of the drugs discovered by Elion and Hitchings is summarized in Table II.
Table 2.



References

G. Gahrton, B. Lundh: Blodsjukdomar. Lärobok i hematologi. Natur och Kultur, Stockholm, 1983.

Läkemedelsboken 1987/88, Apoteksbolaget, Stockholm, sid, 87-88, 150-151, 249, 625.

J.H. Shelley: Creativity in Drug Research. Trends in Pharmacological Sciences. 1983, vol. 4.

L. Stryer: Biochemistry, 3rd edition. W.H. Freeman and Company, San Francisco, 1988, chapter 25, 601-625.

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[Photo Credit: George Hitchings and Gertrude Elion (top) from Welcome Images]