Disulfide Bridges Stabilize Folded Proteins

 
Cysteine is one of the common amino acids found in all proteins. Under certain conditions two cysteine molecules can be covalently linked through their sulfur atoms creating a disulfide bridge. The figure shows how this can happen with free amino acids but disulfide bridges can also form between cysteine residues in within a single polypeptide chain. The joined molecules are called cystine.

Internal disupfide bridges are very common in proteins that are excreted from the cell or in proteins that are located on the outside surface of the cell membrane. Such proteins are often exposed to harsh conditions that are very unlike the conditions inside the cell where the protein folded into its native conformation.

Pancreatic ribonuclease A (the cow version is shown on the right) is secreted into the intestine where it aids in the digestion of RNA by cleaving it into small pieces. The acidic conditions of the small intestine would cause many proteins to unfold.

RNase A is stabilized by formation of four disulfide bridges between cysteine residues that are only brought together once the protein folds into its proper conformation. For example, the cysteine residue at position 26 is part of an α-helix and it's a long way from the cysteine at position 84, which is part of a β-strand region of secondary structure.

Once the protein folds in the cytoplasm the Cys-26 and Cys-84 side chains are almost in contact and the disulfide bridge is easily created by an oxidation reaction that involves glutathione. This disulfide bridge is not easily reduced back to free side chains so it serves to lock in the correct folded conformation. Since there are four such bridges in riboneculease A, the folded structure is very resistant to denaturation in the harsh conditions outside the cell.

Recall that the correctly folded form of a protein is the lowest energy conformation. But this minimum free energy state only applies to the conditions inside the cell where folding takes place. If the protein has to function in a different environment, it might unfold and become inactive. Over time, there was selection for increased stability by substituting cysteine residues that could form disulfide bridges.

"Senators nail problem, flub solution"

 
I still haven't read the Senate report on Afghanistan so I'm only guessing at what it said based on yesterday's Toronto Star article. Thomas Walkom has read the report and he writes an excellent column in today's edition of the Toronto Star [Senators nail problem, flub solution]. Here are some excerpts,

There is a bizarre disjunction in the Senate defence committee's useful – and remarkably frank – analysis of Canada's military role in Afghanistan. It's as if the 11 senators on the committee, having successfully outlined the near insurmountable problems associated with the Afghan war, couldn't bring themselves to accept the logical conclusion of their own analysis.

On the one hand, their 16-page report convincingly paints a picture of a war that cannot be won. The Afghan government of President Hamid Karzai, it states bluntly, routinely shakes down its own citizens. Its army and police are, in the words of committee chair Colin Kenny, "corrupt and corrupter."

The real Afghanistan, they write, is backward, illiberal and hostile to foreign invaders. Ordinary Afghans may have found the former Taliban regime excessive in the way it enforced its brutal moral rules. But at least it had moral rules. "The word moral is probably the last word that comes to an ordinary Afghan's mind when describing the new (Karzai) government," the senators write.

They quote one former Canadian ambassador as saying that it would take five generations to make a difference in Afghanistan. They cite Lt.-Gen. Andrew Leslie, commander of Canadian land forces, as saying the Afghan military mission alone would take 20 years.

To ask these questions is to answer them. Most Canadians will not agree to a war that takes decades to prosecute yet produces no results. And if, as the senators conclude, this is the prognosis, then the last five years of Canadian involvement – and Canadian deaths – have been pointless.

Given this bleak but frank assessment, it would have been logical for the senators to recommend that Canada end its military involvement in Afghanistan. But that is not quite what they do.

Instead, they recommend more of the Band-Aids and non-solutions they've just dismissed as naive. They call for 250 more Canadian Forces instructors and 60 police trainers. They call on the Canadian government to spend more money on Afghan police uniforms and salaries even though, as Kenny acknowledged in a press conference yesterday, a good chunk of that will be skimmed off by corrupt local officials.

Senate Report Questions Canada's Mission in Afghanistan

 
The Canadian Senate Defence Committee has just issued a report on Afghanistan. I haven't seen the original but here are some comments from an article in today's Toronto Star [Senate report blasts mission].

The report, titled "Taking a Hard Look at a Hard Mission," is short – just 16 pages – but blunt and stands in stark contrast to the more rosy assessments touted by Prime Minister Stephen Harper and his cabinet ministers.

"Our troops need more than patriotic bumper stickers. They deserve thoughtful assessments," reads the report, obtained by the Toronto Star.

Canada has about 2,600 soldiers in Afghanistan, most based in the Kandahar region. Since the mission began in 2002, 44 soldiers and one diplomat have been killed in Afghanistan.

"There are all kinds of problems to be solved if the Canadian deployment to Afghanistan is to achieve what any reasonable person would define as `success,'" the report says.

For starters, it says Canada's effort to win the "hearts and minds" of the local population has been badly undermined by civilian casualties caused by NATO air strikes and a development program that has little to show for its big budget.

"The combination of too many lives being lost and too little development assistance ... contributes to making life bleak and dangerous in the Kandahar region," it reads. For that reason, it says development dollars should be given to the Canadian military – $20 million a year – to make progress quickly until aid organizations are able to function safely in the region.

"We may have something more and better to offer than the Taliban, but we don't have much time to prove it," the report says.

Sounds okay up to here. Things are going badly and we're not winning the hearts and minds of the people. I agree with that. The obvious conclusion is to get the hell out and let Afghanistan solve its own problems.

But that's not what the report says. Instead it advocates escalation. More troops and more money—that's the ticket.

The report takes aim at NATO allies for doing more "saluting" than "marching." If more troops and equipment aren't delivered – as repeatedly demanded by local commanders – Canada should rethink its promise to stay in Kandahar until February 2009, it says.

"It is ... doubtful that the mission can be accomplished given the limited resources that NATO is currently investing," it says.

Canada has placed significant political and military pressure on other NATO nations to help bolster the mission in southern Afghanistan but with little success.

The report also pokes at the Afghan government, led by President Hamid Karzai, for the systemic corruption it says runs rampant through the country's institutions. It says the Karzai government should be pressed to develop a "comprehensive, transparent and effective plan" to reduce corruption as a condition of Canada's long-term commitment.

Hmmm ... we're not succeeding and the government we support is corrupt and ineffectual. What should we do? I know, let's send in more troops and give them more money. Ridiculous.

The report is based on the testimony of dozens of witnesses to the Senate committee as well as their own visits to Afghanistan, most recently in December. The report, which was unanimously adopted by the Liberal and Conservative senators on the committee, was tabled Thursday.

The report praises soldiers for their bravery, commitment and optimism.

"Like other Canadians, we want our troops to succeed and we want them to return home safely," it says.

Oh yes, the obligatory praise for the troops. We certainly can't have anyone thinking that we don't support the troops, can we?

Look, it's time we left. The soldiers who have died already have died in vain. More of them are going to die before we realize that we're wasting our time. You don't support our troops by getting them killed in a hopeless cause.

While federal New Democrats have called for troops to be withdrawn, the Senate defence committee says there are good humanitarian and strategic reasons for Canada to remain there.

Noting that "venomous" extremists still make their base in Afghanistan, the report says "neither Canada nor its allies should acquiesce to that threat."

Most of the extremists are based in Pakistan. Should we continue to acquiesce to that threat?

But the report says the key to lasting stability in the troubled nation is the ability of the Afghan National Army and police forces taking on more of the security role for themselves.

That's why the report's key recommendations urge NATO nations to provide additional troops to help train the Afghan army. As well, Canada should send 250 more of its own troops to serve as trainers, it says.

The report also says Ottawa should dispatch 60 more Canadian police officers – up from the 10 now there – to boost training of Afghan police. It also suggests the federal government "significantly augment" the $10 million contribution already made to provide uniforms and in the future improve benefits and salaries.

"Most police are untrained, illiterate and don't even know what the law is," the report says in a bleak assessment of Afghan officers.

We've been "training" these police for five years now and they don't know what the law is? What does that tell us?

The report also suggests Canada, along with NATO and the Afghan government, establish a "defensible" buffer zone along the Pakistan border to stop the infiltration of Taliban fighters.

"As long as the Taliban have access to hideouts beyond the reach of our forces, our mission has little hope of success," the senators say, urging "robust action" to save the Canadian mission from being undermined.

Translation from political doublespeak: the mission is hopeless as long as the government of Pakistan refuses to cooperate against terrorists and the government of Afghanistan is too corrupt to care. However, we should continue to sacrifice Canadian soldiers because if we don't we might have to admit that we've lost. It's much better to admit defeat five years from now when things are much worse.

What is CNN up to?

 
After the firestorm of protest over their first atheist episode, the Paula Zahn show (Paula Zahn Now) gave it a second shot tonight. They scoured the entire country of 300 million for three panelists who could have an intelligent discussion about atheism.

It was a disaster of only slightly less magnitude than the first one. This time the role of ignorant bigot was played by a black pastor. If that's the best they can do then America is in a whole lot of trouble.

The Richard Dawkins interview was okay. I admire how he can keep his cool when being interviewed by people who don't have a clue (Paula Zahn).

[the video clips of the show are at onegoodmove]

Junk DNA: Scientific American Gets It Wrong (again)

In "Ask the Experts" somebody asked What is junk DNA, and what is it worth?. The question was answered by "expert" Wojciech Makalowski of Pennsylvania State University. Here's the answer ...

In 1972 the late geneticist Susumu Ohno coined the term "junk DNA" to describe all noncoding sections of a genome, most of which consist of repeated segments scattered randomly throughout the genome.

This is very misleading. First, nobody today would argue that all noncoding DNA is junk and I very much doubt that Ohno made that argument in 1972 (the orignal paper is hard to get). We know tons of examples of noncoding DNA that isn't junk.

Second, the focus on repetitive DNA is inappropriate. Lots of junk DNA is non-repetitive; pseudogenes are a prime example. Makalowski has a particular bee in his bonnet over repetitive DNA but that shouldn't be allowed to warp his judgement when responding to a question in Scientific American.

Although very catchy, the term "junk DNA" repelled mainstream researchers from studying noncoding genetic material for many years. After all, who would like to dig through genomic garbage?

Nonsense. Researchers have been exploring noncoding DNA intensely for the past 40 years. That's why we know so much about regulatory sequences. Regulatory sequences are noncoding DNA that control gene expression.

Furthermore, even when it comes to true junk DNA, properly defined, hundreds of papers have been published. Lots of us have been very interested in junk DNA—at least in part in order to find out whether it has a function. This work led to the indentification of hundreds of pseudogenes, the unimportance of most intron sequences, and the degeneracy of LINES and SINES. There's lots more. I don't know of any researchers that were "repelled" from studying junk DNA. Many took it as a challenge.

Thankfully, though, there are some clochards who, at the risk of being ridiculed, explore unpopular territories. And it is because of them that in the early 1990s, the view of junk DNA, especially repetitive elements, began to change. In fact, more and more biologists now regard repetitive elements as genomic treasures. It appears that these transposable elements are not useless DNA. Instead, they interact with the surrounding genomic environment and increase the ability of the organism to evolve by serving as hot spots for genetic recombination and by providing new and important signals for regulating gene expression.

Serving as hotspots for genetic recombination is not a "function" of most junk DNA. Furthermore, it's not at all clear that increasing recombination at a particular site will have any effect on future survival. Finally, signals for regulating gene expression have been known for decades. These signals are not junk DNA.

Genomes are dynamic entities: new functional elements appear and old ones become extinct. And so, junk DNA can evolve into functional DNA. The late evolutionary biologist Stephen Jay Gould and paleontologist Elisabeth Vrba, now at Yale University, employed the term "exaptation" to explain how different genomic entities may take on new roles regardless of their original function—even if they originally served no purpose at all. With the wealth of genomic sequence information at our disposal, we are slowly uncovering the importance of non-protein-coding DNA.

The occasional piece of junk DNA may be co-opted to become part of a newly evolved function. This does not mean that all junk DNA has a function. That's a classic error in logic more common in freshmen undegraduates than in "expert" Professors.

... These and countless other examples demonstrate that repetitive elements are hardly "junk" but rather are important, integral components of eukaryotic genomes. Risking the personification of biological processes, we can say that evolution is too wise to waste this valuable information.

From time to time we will find examples of some little bit of junk DNA that acquires a function. This does not mean that all junk DNA has a function. And it certainly doesn't mean that all DNA has now been shown to be "important, integral components of eukaryotic genomes." Most of our DNA is still junk. It turns out that evolution really isn't so smart after all.

Lying for Jesus

 
Today's New York Times has an article about Marcus R. Ross [Believing Scripture but Playing by Science’s Rules]. Ross teaches earth science at Liberty University. He is a Young Earth Creationist who believes that the Earth is less than ten thousand years old.

Marcus Ross recently obtained his Ph.D. in paleontology from the University of Rhode Island and there's the rub. According to his supervisors, his thesis was very good—it analyzed the extinction of marine reptiles 65 million years ago.

How can Ross reconcile the thesis work with his belief that the Earth is less that 10,000 years old? Here's how,

For him, Dr. Ross said, the methods and theories of paleontology are one “paradigm” for studying the past, and Scripture is another. In the paleontological paradigm, he said, the dates in his dissertation are entirely appropriate. The fact that as a young earth creationist he has a different view just means, he said, “that I am separating the different paradigms.”

He likened his situation to that of a socialist studying economics in a department with a supply-side bent. “People hold all sorts of opinions different from the department in which they graduate,” he said. “What’s that to anybody else?”

Whoa! Let's unpack that statement and see where it takes us.

First, the analogy to differing points of view in an economics department is entirely specious. Capitalism and socialism are both valid positions on a controversial topic. The issue about which view is correct hasn't been settled—pehaps neither one is correct. If a socialist graduate student were to defend a thesis in front of a group of capitalist Professors, you'd expect some tough questions. The student would be expected to defend her point of view in a rational manner with evidence and facts to back up the argument.

The same thing would happen if the student was a supply-sider and the Professors were Marxists. In neither case would the student be in danger of failing just because she disagreed with her Professors. As a matter of fact, the Marxist Professors would be just as hard on a Marxist student. That's what Ph.D. orals are all about. If you can't think straight then you don't get a Ph.D., but there are many perfectly valid ways of thinking in economics.

Now, what would happen if a known Marxist student tried to deceive the Ph.D. oral committee by pretending to be a capitalist? The goal is to appease the Professors by telling them what they (presumably) want to hear, in order to get the Ph.D. That student would fail, I hope. Universities are no place for lies and deceit. You must stand up for what you believe and learn to defend it in an academic context. Otherwise, you don't deserve a Ph.D.

Marcus Ross thinks it's okay to write a thesis about 65 million year old reptiles when, in fact, he doesn't believe a word of it. He justifies this by referring to "different paradigms." Apparently, there's one kind of "paradigm" when you are trying to get your Professors to give you a Ph.D. and another kind of "paradigm" at all other times. This is just a euphemism for "lying." In this case, it's lying for Jesus.

If I had been on the Ph.D. oral exam, I would have honed in on the discrepancy between the dates in the thesis and the known beliefs of Marcus Ross. It is not intellectually honest to write something in a thesis that you "know" to be incorrect. I would want to know what Ross means when he writes that his marine reptiles went extinct 65 million years ago and I would expect an answer that's not intended to deceive me. If I'm not convinced, he doesn't get a "yes" vote from me no matter what the thesis says.

[Hat Tip: RichardDawkins.net]

Thinking Blogger Award

 
I won an award! It's called the Thinking Blogger Award. Thanks to Greg Laden for electing me.

I'd like to thank my agent, my loving wife, my wonderful children, and my mother. Most of all I'd like to thank God, without Him this blogger just wouldn't be the same.

The rules of the Thinking Bloggere Awards are [here]. According to the rules I have to nominate five other thinking bloggers—presumably ones that haven't already won. (This could get difficult very quickly.)

In alphabetical order, here are the five nominees for Thinking Blogger ...

Brian at Primordial Blog one of the newest thinkers in blogdom.

Carl Zimmer of The Loom who doesn't think enough. More blogging, Carl.

Jim Lippard of The Lippard Blog who thinks most of the time except when we disagree.

John Wilkins of Evolving Thoughts who perhaps thinks too much. But that's what philosophers do.

Monado a fellow Torontonian thinker at Science Notes who deserves more recognition.

Happy Birthday Charles Darwin

 
Today is the birthday of the greatest scientist who ever lived. When you visit Darwin's home (Down House) you get a sense of what he must have been like. One of the things that's obvious is the number of bedrooms for the children. The house must have been alive with the activities of young children. It's no wonder that Darwin needed some peace and quiet from time to time.

Gwen Raverat was Darwin's granddaughter (daughter of George Darwin). She described Down House as she knew it in the years shortly after Darwin died.

Of all places at Down, the Sandwalk seemed most to belong to my grandfather. It was a path running round a little wood which he had planted himself; and it always seemed to be a very long way from the house. You went right to the furthest end of the kitchen garden, and then through a wooden door in the high hedge, which quite cut you off from human society. Here a fenced path ran along between two great lonely meadows, till you came to the wood. The path ran straight down the outside of the wood--the Light Side--till it came to a summer-house at the far end; it was very lonely there; to this day you cannot see a single building anywhere, only woods and valleys.

I became interested in Darwin's children about fifteen years ago when I first began to appreciate the influence they had on his life. We all know the story of Annie's death when she was ten years old and how this led to Darwin's rejection of religion. There were other tragedies but Charles and Emma turned out to be very good parents.

Here's a short biography of each of Darwin's children from AboutDarwin.com

William Erasmus Darwin
The first of Darwin's children was born on December 27, 1839. He was a graduate of Christ’s College at Cambridge University, and was a banker in Southampton. He married Sara Ashburner from New York, but they had no children. William died in 1914.

Anne Elizabeth Darwin
Born on March 2 1841, and died at the age of ten of tuberculosis on April 22, 1851. It was the death of Annie that radically altered Darwin’s belief in Christianity.

Mary Eleanor Darwin
Born on September 23, 1842 but died a few weeks later on October 16th.

Henrietta Emma Darwin ("Etty")
Born on September 25, 1843 and married Richard Buckley Litchfield in August of 1871. She lived 86 years and edited Emma's (her mother) personal letters and had them published in 1904. She had no children.

George Howard Darwin
Born on July 9, 1845. He was an astronomer and mathematician, and became a Fellow of the Royal Society ... in 1879. In 1883 he became the Plumian Professor of Astronomy and Experimental Philosophy at Cambridge University, and was a Barrister-at-Law. He studied the evolution and origins of the solar system. George married Martha (Maud) du Puy from Philadelphia. They had two sons, and two daughters. He died in 1912.

Elizabeth Darwin
Born on July 8, 1847 and died in 1926. She never married and had no children.

Francis Darwin
Born on August 16, 1848. He became a botanist specializing in plant physiology. He helped his father with his experiments on plants and was of great influence in Darwin's writing of "The Power of Movement in Plants" (1880). He was made a Fellow of the Royal Society in 1879, and taught at Cambridge University from 1884, as a Professor of Botany, until 1904. He edited many of Darwin's correspondence and published "Life and Letters of Charles Darwin" in 1887, and "More Letters of Charles Darwin" in 1903. He also edited and published Darwin’s Autobiography. He married Amy Ruck but she died when their first child, Bernard, was born in September of 1876. He then married Ellen Crofts in September of 1883, and they had one daughter, Frances in 1886. Francis was knighted in 1913, and died in 1925.

Leonard Darwin
Born on January 15, 1850. He became a soldier in the Royal Engineers in 1871, and was a Major from 1890 onwards. He taught at the School of Military Engineering at Chatham from 1877 to 1882, and served in the Ministry of War, Intelligence Division, from 1885-90. He later became a liberal-unionist MP for the town of Lichfield in Staffordshire 1892-95, and was president of the Royal Geological Society 1908-11. Leonard married Elizabeth Fraser in July of 1882. He married a second time, but had no children and died in 1943.

Horace Darwin
Born on May 13, 1851. He was a graduate of Trinity College, Cambridge, and became an engineer and a builder of scientific instruments. In 1885 he founded the Cambridge Scientific Instrument Company. He was the Mayor of Cambridge from 1896-97, and was made a Fellow of the Royal Society in 1903. Horace married Emma Farrer in January of 1880 and they had three children. He died in 1928.

Charles Waring Darwin
Born on December 6, 1856 but died on June 28 1858.

Monday's Molecule #13

 
Name this molecule. You must be specific. We need the correct scientific name. This one's a bit difficult.

As usual, there's a connection between Monday's molecule and this Wednesday's Nobel Laureate. Bonus points for finding the connection.

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

Not Ready to Make Nice

 
I'm not usually a fan of country music and I'm not usually fond of people from Texas, but I'll make an exception for the Dixie Chicks. I just watched them sing Not Ready to Make Nice on the Grammy Awards show. Introduced by Joan Baez, no less (see below).

Joan Baez and Friend

 

Joan Baez: The Night They Drove Old Dixie Down

 
I think you have to be over 50 to remember her and what she stood for.

Gene Genie Carnival

 
There's a new Carnival in town. It's called gene genie and the description is,

A blog carnival on genes, gene-related diseases. We plan to cover the whole genome before 2082.

I'm going to assume that they're talking about the human genome. Dibs on the chaperone genes.

The plan is to publish a collection of articles every two weeks. That's 26 per year. In order to get done by 2085 we'll have to post articles on eleven different genes every two weeks. Better get busy.

Heat Shock and Molecular Chaperones

 
Protein folding takes place inside cells at their normal temperature. This temperature is 37°C in the case of mammals. If cells encounter higher temperatures, their proteins become unfolded since the minimal energy conformation at one temperature isn't the same minimum at a another temperature.

The difference in temperature isn't large. Many mammalian proteins become unstable at 42°C. This is a temperature encountered with high fever but it's also common in skin cells that have been exposed to the sun or the water in a hot tub. Temperature differences are even more common in species that do not regulate their temperature (e.g., plants, fungi, bacteria, invertebrates).

All living cells have defense mechanisms that protect against exposure to high temperature. They produce special proteins called heat shock proteins in order to recover damaged proteins that have unfolded at the high temperature. Many of the heat shock proteins are molecular chaperones. These are proteins that guide proper refolding of damaged proteins.

Shortly after the discovery of heat shock proteins we learned that these proteins are always present even in cells that haven't been stressed. In other words, molecular chaperones play a role in normal protein folding as well as helping to recover from damage. This role is illustrated in the energy diagram (top left).

One of the pathways to the energy minimum follows the line labeled "B." This traverses a local energy well and proteins can get trapped in this pit. What happens is that they adopt a less-than-optimal conformation but they can't easily unfold and refold to fall down into the deeper well because that would require an increase in energy. It will happen eventually, but it could take a long time. Chaperones help direct folding along the proper pathway and his speeds up the folding process.

Recall from the earlier discussion of How Proteins Fold that folding is an entropy-driven process where the end result is to bury hydrophobic residues in the central core of the protein. Another thing that can happen during folding is that exposed hydrophobic surfaces of one protein can interact with similar surfaces in another protein leading to aggregation. Chaperones can bind to these hydrophobic surfaces and prevent aggregation. This is another way of speeding up folding.

There are many different chaperones. My personal favorite is HSP70 (Heat Shock Protein of relative molecular mass 70,000). This is a protein that's found in every type of living species. It is the most highly conserved protein in all of biology so it's an excellent protein for looking at deep phylogeny. The role of HSP70 as a molecular chaperone is to bind to proteins as they are being synthesized in order to prevent improper folding. It also prevents aggregation.

Another famous chaperone used to be called HSP60 since it was a heat shock protein of M_r= 60,000. It was also known as GroE since it allowed for the growth of bacteriophage λ gene E mutants. Now it's known as chaperonin. Note that the term "chaperonin" refers to a specific molecular chaperone.

Chaperonin is a barrel-shaped molecule consisting of two rings of seven subunits surrounding a central cavity (one subunit is colored green in the image) . The top of the cavity is sealed by cap of seven smaller subunits. The chaperone works by capturing small unfolded proteins in the cavity where the hydrophobic environment encourages rapid folding to the correct conformation. Aggregation is also prevented by keeping the folding protein away from other proteins.

The inside of the cavity is referred to as an Anfinsen cage after Christian Anfinsen, a Nobel Laureate who worked on protein folding (see next Wednesday's Nobel Laureate). The release of unfolded protein is coupled to the hydrolysis of ATP. This is a common feature of most molecular chaperones.

Daniel vs the Christians

Let me make it clear that I'm not a fan of Daniel Dennett. I think his version of evolution is sophomoric and wrong. His book "Darwins' Dangerous Idea" was one of the worst books on evolutionary theory that has ever been published.

Nevertheless, from time to time Dennett gets things right. One of those times was in the New York Review of Books last month where he took on Allen Orr [letter from Daniel Dennett].

You might recall the kerfuffle over Orr's review of The God Delusion. Orr claimed that Dawkins had ignored all the more sophisticated arguments for the existence of God. Here's part of Dennett's reply,

H. Allen Orr, in "A Mission to Convert" [NYR, January 11], his review of Richard Dawkins's The God Delusion and other recent books on science and religion, says that Dawkins is an amateur, not professional, atheist, and has failed to come to grips with "religious thought" with its "meticulous reasoning" in any serious way. He notes that the book is "defiantly middlebrow," and I wonder just which highbrow thinkers about religion Orr believes Dawkins should have grappled with. I myself have looked over large piles of recent religious thought in the last few years in the course of researching my own book on these topics, and I have found almost all of it to be so dreadful that ignoring it entirely seemed both the most charitable and most constructive policy. (I devote a scant six pages of Breaking the Spell to the arguments for and against the existence of God, while Dawkins devotes roughly a hundred, laying out the standard arguments with admirable clarity and fairness, and skewering them efficiently.) There are indeed recherché versions of these traditional arguments that perhaps have not yet been exhaustively eviscerated by scholars, but Dawkins ignores them (as do I) and says why: his book is a consciousness-raiser aimed at the general religious public, not an attempt to contribute to the academic microdiscipline of philosophical theology. The arguments Dawkins exposes and rebuts are the arguments that waft from thousands of pulpits every week and reach millions of television viewers every day, and neither the televangelists nor the authors of best-selling spiritual books pay the slightest heed to the subtleties of the theologians either.

Who does Orr favor? Polkinghorne, Peacocke, Plantinga, or some more recondite thinkers? Orr brandishes the names of two philosophers, William James and Ludwig Wittgenstein, and cites C.S. Lewis's Mere Christianity, a fairly nauseating example of middle-brow homiletic in roughly the same league on the undergraduate hit parade as Lee Strobel's The Case for Christ (1998) and transparently evasive when it comes to "meticulous reasoning." If it were a book in biology—Orr's discipline—I daresay he'd pounce on it like a pit bull, but like many others he adopts a double standard when the topic is religion....

[Hat Tip: [RichardDawkins.net]