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Thursday, February 08, 2007
Toronto City Council
Last Tuesday the Toronto City Council met for their annual photo. Several of the more senior—and more conservative—councillors were upset because they couldn't sit in the first row, which was reserved for the Mayor and the Executive Committee.
The squabbling persisted for so long that the photo shoot had to be canceled. I love the cartoon in today's Toronto Star and I just can't resist posting a copy. It captures the mood exactly. (It also reminds me of the Discovery Institute.)
Tuition
Hundreds of students turned out yesterday for a rally at Queen's Park (Ontario Parliament Buildings). Many of the students marched from the University of Toronto campus and they waited in the freezing cold for more than an hour before the contingent from Ryerson marched along College St. and up University Ave. to join them.
Like most Professors, I want tuition to be as low as possible because education is a right. The government of Ontario should at the very least hold the current tuition at its present level for the foreseeable future. It should increase direct funding to the universities to maintain quality and allow for expansion.
The long-term goal should be to provide free education to all qualified students.
How Proteins Fold
The protein shown here is pyruvate kinase, one of the key enzymes in metabolism. This particular example comes from the common domestic cat (Felix domesticus).
Cartoons such as this one are intended to show how the backbone chain of amino acids is folded to produce the final three-dimensional structure of a protein. In this case the polypeptide chain is represented by a blue ribbon. There are spiral sections representing regions of secondary structure called α-helices and flattened sections called β-strands. The β-strand regions are often twisted.
This particular protein adopts a structure with three distinct parts called domains. As a general rule, each domain has a well-defined shape with a characteristic pattern of strands and helices. The pattern is called a fold and it it thought that there are only 1000 or so different folds in the protein universe. Different folds can be combined to make up all known proteins.
(For those who might be interested, the three domain folds in this protein are TIM beta/alpha barrel, PK beta-barrel, and the PK C-terminal domain.)
When proteins are first synthesized you can think of them as a long extended chain of amino acids with no particular secondary or tertiary structure. We refer to such unordered macromolecules as random coils. Within seconds, this random coil spontaneously folds itself into a highly ordered three-dimensional structure such that every single molecule of a given protein has the exact same shape. For example, every molecule of pyruvate kinase looks exactly like the one shown here.
The rapidity of this folding reaction tells us something about the mechanism of protein folding. We know that folding is rapid and spontaneous because proteins can be purified then unfolded by treating them with certain chemicals that cause them to become denatured or unfolded. These denatured proteins can then be allowed to re-fold when the chemicals are removed.
Cyrus Levinthal did some back-of-the-envelope calculations on the rate of protein folding. He assumed that a protein could randomly try all possible three-dimensional conformations until it found the correct one. Under those conditions it would take 1087 seconds to fold a protein of 100 amino acid residues. This is quite a bit longer than the age of the universe (6 x 1017 seconds).
Obviously, there's something wrong with the assumptions behind what came to be known as the Levinthal Paradox. As a matter of fact, the paradox was never really a paradox since the whole point of the calculation was to shown that proteins did not fold by randomly searching though the conceptual universe of all possible shapes.
The final structure of a protein minimizes the energy of the random coil by burying hydrophobic amino acids in the interior of the molecule. Hydrophobic (water fearing) amino acids are those that don't like to be exposed to water. Just as scattered oil droplets in your salad dressing will eventually coalesce to form a layer of oil over a layer of vinegar and water, so too will hydrophobic amino acids come together to form an "oily" globule in the middle of the protein. Water is excluded from this "molten globule" and this makes folding an entropically driven spontaneous reaction.
You can visualize the process by picturing a field of all possible energy levels of the random coil. The one representing the properly folded protein is the deepest well on the energy surface. The bottom of the well is the lowest energy level for the protein and this represents the stable three-dimensional structure. Protein folding, then, is like finding the well and falling down into it.
As mentioned above, the search for the lowest energy well is not a random search of all possible shapes. That would take far too long. Instead, folding proceeds in a cooperative stepwise manner with small regions of secondary structure forming first.
The most striking regions of secondary structure are the short α-helices. Certain stretches of amino acid residues will rapidly form α-helical regions involving local bonding between amino acids. These form extremely rapidly since the amino acids are already in close contact. Furthermore, the formation of these local secondary structures takes place simultaneously in many different parts of the random coil.
The helix and strand regions represent the minimal energy conformations of the local parts of the protein. Subsequent folding proceeds by forming the helices and strands into the appropriate three-dimensional folds that are characteristic of each domain. The possibilities here are much fewer than the total of all possible conformations because you are now combining blocks of amino acids that have already adopted some structure.
The figure below shows some hypothetical examples of folding pathways. Very few folding pathways have been worked out in detail but the basic principles are well understood. The biggest unsolved problem is predicting the three-dimensional structure of a protein from its amino acid sequence. This involves finding the predicted lowest energy level and that's turning out to be a tough problem indeed.
Cartoons such as this one are intended to show how the backbone chain of amino acids is folded to produce the final three-dimensional structure of a protein. In this case the polypeptide chain is represented by a blue ribbon. There are spiral sections representing regions of secondary structure called α-helices and flattened sections called β-strands. The β-strand regions are often twisted.
This particular protein adopts a structure with three distinct parts called domains. As a general rule, each domain has a well-defined shape with a characteristic pattern of strands and helices. The pattern is called a fold and it it thought that there are only 1000 or so different folds in the protein universe. Different folds can be combined to make up all known proteins.
(For those who might be interested, the three domain folds in this protein are TIM beta/alpha barrel, PK beta-barrel, and the PK C-terminal domain.)
When proteins are first synthesized you can think of them as a long extended chain of amino acids with no particular secondary or tertiary structure. We refer to such unordered macromolecules as random coils. Within seconds, this random coil spontaneously folds itself into a highly ordered three-dimensional structure such that every single molecule of a given protein has the exact same shape. For example, every molecule of pyruvate kinase looks exactly like the one shown here.
The rapidity of this folding reaction tells us something about the mechanism of protein folding. We know that folding is rapid and spontaneous because proteins can be purified then unfolded by treating them with certain chemicals that cause them to become denatured or unfolded. These denatured proteins can then be allowed to re-fold when the chemicals are removed.
Cyrus Levinthal did some back-of-the-envelope calculations on the rate of protein folding. He assumed that a protein could randomly try all possible three-dimensional conformations until it found the correct one. Under those conditions it would take 1087 seconds to fold a protein of 100 amino acid residues. This is quite a bit longer than the age of the universe (6 x 1017 seconds).
Obviously, there's something wrong with the assumptions behind what came to be known as the Levinthal Paradox. As a matter of fact, the paradox was never really a paradox since the whole point of the calculation was to shown that proteins did not fold by randomly searching though the conceptual universe of all possible shapes.
The final structure of a protein minimizes the energy of the random coil by burying hydrophobic amino acids in the interior of the molecule. Hydrophobic (water fearing) amino acids are those that don't like to be exposed to water. Just as scattered oil droplets in your salad dressing will eventually coalesce to form a layer of oil over a layer of vinegar and water, so too will hydrophobic amino acids come together to form an "oily" globule in the middle of the protein. Water is excluded from this "molten globule" and this makes folding an entropically driven spontaneous reaction.
You can visualize the process by picturing a field of all possible energy levels of the random coil. The one representing the properly folded protein is the deepest well on the energy surface. The bottom of the well is the lowest energy level for the protein and this represents the stable three-dimensional structure. Protein folding, then, is like finding the well and falling down into it.
As mentioned above, the search for the lowest energy well is not a random search of all possible shapes. That would take far too long. Instead, folding proceeds in a cooperative stepwise manner with small regions of secondary structure forming first.
The most striking regions of secondary structure are the short α-helices. Certain stretches of amino acid residues will rapidly form α-helical regions involving local bonding between amino acids. These form extremely rapidly since the amino acids are already in close contact. Furthermore, the formation of these local secondary structures takes place simultaneously in many different parts of the random coil.
The helix and strand regions represent the minimal energy conformations of the local parts of the protein. Subsequent folding proceeds by forming the helices and strands into the appropriate three-dimensional folds that are characteristic of each domain. The possibilities here are much fewer than the total of all possible conformations because you are now combining blocks of amino acids that have already adopted some structure.
The figure below shows some hypothetical examples of folding pathways. Very few folding pathways have been worked out in detail but the basic principles are well understood. The biggest unsolved problem is predicting the three-dimensional structure of a protein from its amino acid sequence. This involves finding the predicted lowest energy level and that's turning out to be a tough problem indeed.
IDiot "Irony"
GilDodgen is one of the IDiots who post regularly to Uncommon Descent. Recently he put up a comment on a photo of Darwin's tomb that I posted one month ago. GilDodgen thought he was being so clever that he re-posted his comment in an article on Uncommon Descent [Darwin’s Final “Resting” Place]. Here's what he said,
Over at Larry Moran’s blog, where I am identified as one of the ID movement’s stellar idiots, there is a picture of Darwin’s tombstone with the caption: “Here’s a photo of Darwin’s final resting place in Westminster Abbey.”Guess what? The "irony" isn't self-evident to me. I'm not really sure what the fuss is about. Are they objecting to the phrase "final resting place" on the grounds that Darwin's soul will survive? Is he thinking that Darwin will never rest because he has to suffer forever for his heretic views? Or is it something else that I'm missing?
I posted the following comment:Darwin doesn’t have a resting place. When he died he entered eternal oblivion. Nothing he did, and nothing that any of us do, has any lasting significance or meaning.For those familiar with me at UD, the irony should be self-evident.
One day our sun will turn into a red giant. When that happens its corona will expand beyond the orbit of the earth. The earth’s atmosphere will be stripped away, the seas will boil away, the sands will fuse into glass, and all life will be exterminated. There will be no record of anything anyone has ever done, created, or thought.
I dunno, so I did the normal thing and posted a question on Uncommon Descent—forgetting that I am persona non grata over there. Naturally my comment never made it past the IDiot censors. Can someone help me out? What's the problem?
As you might expect, the readers at UD are falling all over themselves in support of the clever, ironic comment by GilDodgen. For example, scordova posted the following comment at Uncommon Descent.
Gil, I noticed you pointed out your professional credentials to Moran. Actually, imho, when people like Moran are knocked off of their elistist horse by a lowly peasant, it’s a more satisfying victory. It’s more fun when people like Moran get taken out by people they view as their inferior…."Taken out"? I was? Hmmm ... I must have missed the take out.
Incidently, I'm unaware of the "professional credentials" of GiDodgen. All I know is that he doesn't understand science and that makes him look pretty stupid. I suppose that's a form of "professional credential."
GilDodgen replied,
Good point. However, in the case of Moran, he thinks that anyone who doubts Darwin is a rube and a simpleton who should be flunked out of college for no other reason. He should be made aware that it is possible to doubt Darwin and still be capable of rational, logical thought.Oh dear. The IDiots reveal once again that they are incapable of distinguishng between Darwinism and evolution. I have lots of doubts about the validity of Darwinism as a complete explanation of evolution and I haven't been the least bit shy about expressing those doubts.
People who doubt the exclusive role of natural selection are not rubes or simpletons. People who don't understand the real meaning of Darwinism are rubes and simpletons. There are tons of them over at Uncommon Descent.
"IDiots" is my special scientific term for those people who are anti-evoluton and anti-science. GilDodgen and scordova are IDiots. The fact that they are also rubes and simpletons is simply a nice bonus.
Flock of Dodos and Haeckel's Embryos
Randy Olson made a movie called Flock of Dodos where he pokes fun at the IDiots. Unfortunately, Olson made a mistake when he said that the old faked images of Haeckel's embryos were not in modern textbooks.
The Discovery Institute pounced on this error and made a clever video that discredits Olson. The DI video may have some errors of its own; for example, I'm not sure if the embryo picture in the Raven & Johnson biology textbook is actually based on a Haeckel drwaing as they say. Also, the picture of the Haeckel woodcut in the Alberts texbook isn't as significant as they imply.
In spite of the possible mistakes in the video (below) the DI has been quite clever. The IDiots have cast doubt on all the claims in Flock of Dodos because of one little slip-up.
Debbie Schlussel
UPDATE: PZ Myers tells us that CNN will rebroadcast the segment tonight at 8PM EST with a new panel, including Richard Dawkins (CNN must have felt the heat).
Do you remember Debbie Schlussel? She was the atheist-hating Jewish idiot who appeared on the Paul Zahn show last week (see Paula Zhan Should be Fired from CNN). Readers might recall that I was wondering whether Schlussel might have a slight bias against Muslims as well as atheists.
Well, it turns out Debbie Schlussel has been receiving emails about her remarks on CNN (Duh!). She has a blog where she has just confirmed our worst fears.
Here's part of what she says at "When Atheists a/k/a Future Muslims Attack."
I don't mind receiving the atheist hate mail, since I know that in a few years, many of these same people will either be Muslim extremists (redundant) or helping the country fall further in its fight against the creep of Islamic imposition on America . . . or both.No, your eyes aren't deceiving you. She actually said that on her blog. Go check it out if you don't believe me. She's a genuine loony nutcase.
Look at famous atheists and what happened to them. Adam Gadahn a/k/a Azzam Al-Amriki--now a top Al-Qaeda video "personality"--was raised by his hippie Jewish father and equally bizarre gentile mother as an atheist. And look how he turned out. Ditto for hippie-spawn John Walker Lindh.
Those two people are enemies of America, and many of those who think like them are of equally weak mind. If you don't believe in anything, you'll easily fall for virtual nothings. That's why Europe is so quickly turning Islamist--because atheism dominates and Christianity is rapidly dying there. Over there, the number one cause for which atheists are suddenly finding "god" is Islam.
All the more reason why Paula Zhan should stop pretending to be a journalist.
On her blog Schussel attacks those critics who claim they just saw the Paula Zhan show.
It's hard to believe their letters because they were all attacking me for my appearance on CNN's "Paula Zahn Now," a week ago, but coincidentally each letter claims the sender just watched me on CNN. First of all, the video of that segment appears nowhere on the net. Believe me, if it did, I'd link to it.I linked to the videos on the net and so have dozens of other bloggers who are astonished at the stupidity of CNN. It looks like Schlussel is incompetent at many different things in addition to thinking logically. Her list of failings includes searching the internet.
Read the posting on Dr. Joan Bushwell's Chimpanzee Refuge [Debbie Schlussel: A case study in 15 minutes too many] for a calmer attack on Debbie Schussel. Schlussel is a journalist who's greatest achievement to date was winning the title of "Outstanding Teen Age Republican in the Nation" in 1987 (Wikipedia). Why is it that so many kooks seem to be Republicans?
[Hat Tip: Friendly Atheist]
Wednesday, February 07, 2007
The Real Genetic Code
This is the genetic code. It shows the relationship between a sequence of nucleotides in messenger RNA (mRNA), or DNA, and the amino acids that are inserted into a growing polypeptide chain.
Each codon consists of three nucleotides and you read them from 5ʹ ("five prime") to 3ʹ ("three prime"). The first one is one the left of the box, the second one is at the top, and the third one is along the right-hand edge. The genetic code tells you that codon CUU encodes leucine (Leu), and so do codons CUC, CUA, and CUG. (The Genetic Code is redundant.)
The three STOP codons tell the protein synthesis machine to stop making protein. The methionine (Met) codon (AUG) is usually the start codon that tells the machinery to start making a protein. There are a few unusual variants of the genetic code that aren't shown in the figure.
The Genetic Code was cracked in the early 1960's when the meaning of each codon was worked out. Since then it has become routine to decode any message in the coding regions of DNA and RNA by simply referring to the genetic code shown above. For example, you can decode the following sequence of RNA if you know that it starts on the left at the initiation codon AUG.
This is the same procedure that we use to translate a string of dots and dashes sent over a telegraph line. The string of dots and dashes is the message, the Morse Code is the lookup table that we use to decode the mesage. We do not say that the string of dots and dashes is the Morse Code. We say that it's a message encrypted using the Morse Code. Similarly, we do not say that a string of nucleotides is the genetic code. It's the message that's translated using the Genetic Code.
The Wrong Version of the Genetic Code
Hsien Hsien Lei over at Genetics & Health has posted a recommendation for winter reading [Freakenetics: The Freakonomics of Genetics]. She suggests that Survival of the Sickest by Dr. Sharon Maolem and Jonathan Prince might be a good read.
Here's a quotation from the book,
…DNA isn’t destiny–it’s history. Your genetic code doesn’t determine your life. Sure, it shapes it–but exactly how it shapes it will be dramatically different depending on your parents, your environment, and your choices. Your genes are the evolutionary legacy of every organism that came before you, beginning with your parents and winding all the way back to the very beginning. Somewhere in your genetic code is the tale of every plague, every predator, every parasite, and every planetary upheaval your ancestors managed to survive. And every mutation, every change, that helped them better adapt to their circumstances is written there.Now, this may or may not be a good book but I'd like to use the quotation as a way of introducing one of my pet peeves. In doing so I don't mean to impugn the sense of what's said in the quotation.
The sequence of DNA in your genome is not the "genetic code." The Genetic Code is the lookup table shown in the accompanying posting [The Real Genetic Code]. The sequence of nucleotides in your genome is the message that may be interpreted using the genetic code in the same sense that the message received over a telegraph may be interpreted using the Morse Code.
It's appropriate to say that somewhere in this message is the record of your survival but it's inappropriate to say the genetic code is altered by evolution. (At least in this context.)
I realize that when science writers use the term "genetic code" they are writing for the general public. Those writers may know the difference between the real Genetic Code and what they say in a popular article. They may know the difference, but somehow I doubt it. Most people who know the difference wouldn't make the common mistake of confusing the code with the message.
In any case, the book would be no less accurate if it talked about the message in your genome instead of the genetic code. So why not use the correct term?
Similarly, I'm getting tired of hearing about the latest sequencing project that "cracked" the genetic code. The real Genetic Code was cracked forty years ago in an astounding display of technology that earned the decoders a Nobel Prize. What sequencing projects do is determine the sequence of a genome, not its genetic code. The standard Genetic Code is (almost) universal. All species use the same Genetic Code.
Dilbert Parody
This is priceless. I know every one of my blogger friends is going to post this parody of Dilbert by The Bronze Blog but I can't resist. For those of you who haven't been following the saga of Scott Adams and his IDiocy, see "Is Scott Adams an IDiot?."
Click on the cartoon to enlarge.
Tuesday, February 06, 2007
Nobel Laureates: Arber, Nathans, and Smith
The Nobel Prize in Physiology or Medicine 1978.
"for the discovery of restriction enzymes and their application to problems of molecular genetics"
Werner Arber, Daniel Nathans, and Hamilton O. Smith received the Nobel Prize in 1978 for working out the mechanism of restriction enzymes (see Restriction, Modification, and Epigenetics).
By the time the Nobel Prize was awarded it was quite clear that the discovery of restriction enzymes was transforming biology and the new era of recombinant DNA technology was upon us. Read what this meant for Hamilton Smith below the fold.
The short history of this remarkable transformation was nicely summarized in the presentation speech by Peter Reichard.
Restriction enzymes are the tools which make it possible to open the sealed book. Werner Arber discovered these enzymes in the early 1960s when he analyzed an apparently obscure phenomenon in bacteria, discovered 10 years earlier by Bertani and Weigle, called host-controlled modification. In a series of simple but elegant experiments Arber showed that this phenomenon was caused by a change in DNA and apparently served to protect the host from foreign genes. Foreign DNA is degraded, and Arber postulated that bacteria contain restriction enzymes with the capacity to recognize and bind to recurring structural elements of DNA. At these locations the DNA-helix is severed: the pages of the book are separated.By the early 1990's the revolution had passed Hamilton Smith by. He lost his funding in 1989 and was relegated to sitting on committees and puttering in the lab on small projects. Then he met Craig Venter.
Hamilton Smith verified Arber's hypothesis. He purified one restriction enzyme and showed that it could cleave foreign DNA. He determined the chemical structure of the regions of DNA which were severed by the enzyme and discovered certain rules which later could be applied to other restriction enzymes. Today maybe 100 such enzymes are known. They all cleave DNA, each at different, defined regions. With their aid, these giant molecules can be dissected into well-defined segments which subsequently can be used for structural investigations or in genetic experiments.
'The last step in this development was taken by Dan Nathans. He pioneered the application of restriction enzymes in genetics and his work has been a source of inspiration for scientists all over the world. He constructed the first genetic map using restriction enzymes by cleaving the DNA from a monkey virus. The methodology devised by him for this purpose was later used by others to construct increasingly more complicated maps. Today we can write the complete chemical formula for the genes of the monkey virus that Nathans started to investigate.
Venter was about to fund TIGR (The Institute for Genome Research) and he needed a man like Hamilton Smith. Now only did Smith have the magic hands of a brilliant bench scientist, he also had a Nobel Prize. It's not clear which of these was more important to Ventor but the result was astounding.
Smith was responsible for making the libraries that allowed genome sequencing. He was very good at it and that's why TIGR turned out the sequence of Haemophilus influenzae in record time. (H. influenzae was the organism that Smith had worked on all his life. Later on Smith built many more bacteria libraries and in 1998 he made the Drosophila melanogaster (fruit fly) library that really put TIGR on the map and led to the creation of Celera.
Craig Venter and Celara could not have entered the race to sequence the human genome without the technical expertise of Nobel Laureate Hamilton Smith. I recommend The Genome War by James Shreeve. It's a wonderful account of Venter, Celera, and the race to sequence the human genome. Here's an excerpt,
On the morning of July 7, 1998, Hamilton Smith drove down from his farm in Howard County and pulled into the TIGR parking lot. His 1987 Mercury Grand Marquis rumbled along the rows of cherry Corollas and silver Civics like an old tug trying to dock in a marina. The car had a long piece of trim missing on the driver's side, exposing a parallel row of rusted holes, as if the car had been strafed long ago. The odometer read 244,000 miles. The radio was playing—the knob had stuck in the "on" position a couple of months before—and a sucking sound was emanating from somewhere deep in the steering column. Smith didn't mind, because he had his hearing aid turned down low. The Mercury was among his most beloved possessions. He was more ambivalent about his Nobel Prize.
Smith maneuvered the car into a spot, gathered up his briefcase, and quietly made his way through TIGR's elegant lobby. He was on his way to pop in on Craig when the receptionist called out to him, "Something came for you FedEx, Dr. Smith," she said.
Canadian Scientists Are Refusing to Sit on Grants Panels
The results of the September 2006 CIHR grants competition are now available. The Canadian Institutes of Health Research (CIHR) is the main funding body for biological research in Canada. The funding crisis will have a devastating effect on the careers of many of my colleagues.
A total of 310 grant renewals were submitted and 91 were funded. This represents a renewal rate of 29%. Keep in mind that most of these applications were submitted by well-established scientists with a long history of funding and publications. At this rate of renewal, 71% of functioning labs might have to shut down unless they're successful in the next competition.
When your grant is not renewed, you revert to the "new" category of applications. In the latest competition, 240 "new" applications were funded out of 1707 submissions. This is a 14% success rate. Remember, most of these "new" applications are from scientists who are in the prime of their career but who failed in their renewal last year.
Of those grants that were funded, 26.1% of the funding awarded by the peer review committees was clawed back in order to spread the money a bit further. What this means is that some of the "renewals" were funded at lower levels than the current grants. Post-docs and research assistants will be let go even when a grant is renewed.
The average grant was $109,000 and no equipment was funded. This is not enough money to run an effective biochemistry lab.
Pierre Chartrand is the Vice President, Research Portfolio, at CIHR. He posted a wimpy message on the CIHR website [A Word on the September 2006 Operating Grants Competition]. Here's part of what he had to say.
Competition for available funding has grown increasingly intense. This trend is unlikely to change as Canada continues to expand its infrastructure for health research. For this reason, within the Research Portfolio of CIHR, we cannot afford to be consumed by disappointment. Canada owes its reputation for research excellence to an open, accountable and very rigorous peer review system for funding applications. We must re-double our efforts to ensure that the peer review processes used to guide CIHR's funding decisions are the very best that they can be. In light of the recent competition results, we have heard from a small number of active peer reviewers and others who are frustrated to the point of no longer wishing to participate in the peer review process. Such frustration, no matter how limited, leaves me gravely concerned because CIHR is at a point in time where the participation of the absolute best in its peer review processes is critical.Let me tell you, Pierre, you damn well better be "gravely concerned." Some of my friends are sick and tired of sitting on committees where they have to reject excellent grants from their colleagues knowing that this will be a knockout blow to their future careers as scientists. Is it any wonder that they don't want to act as executioners?
Now you tell us that things aren't likely to change but you still expect Canadian scientists to volunteer to do the dirty work. Not gonna happen. About 70% of those volunteers whose grants were up for renewal have just stopped being "peers." Don't expect them to be happy. As for the rest, I urge them to boycott the process until there's a change in the CIHR leadership that got us into this mess.
God Doesn't Like Chicago
Here's a picture of the winning football team praying together after the big game on Sunday [New York Times]. I assume they're thanking God for the victory. I wonder what was going on in the other dressing room? Do you suppose there was a mass conversion to atheism?
Restriction, Modification, and Epigenetics
Bacteria have the ability to restrict bacteriophage (virus) infection by cutting up the 'phage DNA once it's injected into the cell. The enzyme that cuts DNA is called a restriction enzyme, or more properly, a restriction endonuclease.
Endonucleases are enzymes that cleave DNA internally by binding to the middle of a DNA strand and breaking one of the linkages that join the nucleotides. In the case of restriction endonucleases, both strands of the double helix are cut thus breaking apart the 'phage DNA before it can make new proteins and new virus particles.
The enzymes don't cut randomly. They bind to specific sequences and only cut at those sites. An example is one of the restriction endonucleases from Escherichia coli called EcoR1. It binds to the sequence GAATTC.
The top figure shows EcoR1 bound to DNA. Notice that the restriction site is palindromic—it reads the same way in opposite directions on opposite strands (see below). In order to appreciate this you need to understand that the two strands of DNA run in opposite directions and the direction of reading is important. We always read a DNA strand in the 5ʹ to 3ʹ direction. Thus, on the top strand the sequence is GAATTC while on the bottom strand the sequence is also GAATTC but read in the opposite direction.
The two identical subunits of EcoR1 (blue and purple) bind to opposite strands of the double helix and cut at exactly the same spot; in this case between the G and the A. The DNA is chopped in two.
The sequence GAATTC will occur, on average, once every 4096 base pairs (46). This means there's a good chance of cutting any bacteriophage DNA that enters the cell since most bacteriophage genomes are much larger than 4096 base pairs.
This is an effective way of restricting bacteriophage infection except for one minor problem. How does the bacterium prevent it's own DNA from being cut by the restriction endonucleases?
The secret lies in blocking the restriction site in host DNA so that the restriction enzyme doesn't recognize it. One of the nucleotides is modified by an methylase enzyme (modification enzyme) that attaches a methyl group to one of the bases. The restriction enzyme doesn't bind to sites where one of the bases is modified by methylation; so all you have to do is make a methylase enzyme that recognizes the same site as the restriction enzyme.
EcorR1 methylase binds to the sequence GAATTC and methylates the first A to form N6-methyladenine (see Monday's Molecule #12). Like the endonuclease, the methylase has two subunits that bind symmetrically to double-stranded DNA. Both of the A's on opposite strands are methylated so neither strand can be recognized by EcoR1 and neither strand will be cut.
So far, so good, but we still have a problem. Why isn't the 'phage DNA methylated as well?
This is the cool part. Look at the figure on the left. Imagine that both strands are methylated. Following DNA replication, the sequence GAATTC will be copied but the newly synthesized strand isn't methylated. The hemimethylated DNA won't be recognized by the restriction enzyme so it's in no danger of being cut. In a very short time the methylase will bind and methylate the new strand of DNA.
The methylase binds specifically to hemimethylated DNA and not to unmethylated DNA. Thus, it will keep the host DNA fully methylated but it won't methylate the incoming 'phage DNA since the 'phage DNA is completely unmethylated.
As bacteria grow and divide they continue to inherit DNA that's methylated at the restriction site even though this inheritance isn't your typical genetic inheritance. It's called epigenetic inheritance. If something happens to the methylase, the cell will commit suicide by chopping up its own DNA. If both the methylase and restriction enzyme genes are mutated the cell survives quite nicely except that it's more susceptible to bacteriophage infection.
Epigenetic inheritance is common in mammals, including us. In this case it's not related to restriction/modification. It's a separate phenomenon where gene expression is controlled by the presence or absence of 5-methyl cytosine. The cytosine methylase works just like the modification enzymes—it binds preferentially to hemimethylated DNA. In this way, methylated regions of DNA are inherited from one generation to another.
Endonucleases are enzymes that cleave DNA internally by binding to the middle of a DNA strand and breaking one of the linkages that join the nucleotides. In the case of restriction endonucleases, both strands of the double helix are cut thus breaking apart the 'phage DNA before it can make new proteins and new virus particles.
The enzymes don't cut randomly. They bind to specific sequences and only cut at those sites. An example is one of the restriction endonucleases from Escherichia coli called EcoR1. It binds to the sequence GAATTC.
The top figure shows EcoR1 bound to DNA. Notice that the restriction site is palindromic—it reads the same way in opposite directions on opposite strands (see below). In order to appreciate this you need to understand that the two strands of DNA run in opposite directions and the direction of reading is important. We always read a DNA strand in the 5ʹ to 3ʹ direction. Thus, on the top strand the sequence is GAATTC while on the bottom strand the sequence is also GAATTC but read in the opposite direction.
The two identical subunits of EcoR1 (blue and purple) bind to opposite strands of the double helix and cut at exactly the same spot; in this case between the G and the A. The DNA is chopped in two.
The sequence GAATTC will occur, on average, once every 4096 base pairs (46). This means there's a good chance of cutting any bacteriophage DNA that enters the cell since most bacteriophage genomes are much larger than 4096 base pairs.
This is an effective way of restricting bacteriophage infection except for one minor problem. How does the bacterium prevent it's own DNA from being cut by the restriction endonucleases?
The secret lies in blocking the restriction site in host DNA so that the restriction enzyme doesn't recognize it. One of the nucleotides is modified by an methylase enzyme (modification enzyme) that attaches a methyl group to one of the bases. The restriction enzyme doesn't bind to sites where one of the bases is modified by methylation; so all you have to do is make a methylase enzyme that recognizes the same site as the restriction enzyme.
EcorR1 methylase binds to the sequence GAATTC and methylates the first A to form N6-methyladenine (see Monday's Molecule #12). Like the endonuclease, the methylase has two subunits that bind symmetrically to double-stranded DNA. Both of the A's on opposite strands are methylated so neither strand can be recognized by EcoR1 and neither strand will be cut.
So far, so good, but we still have a problem. Why isn't the 'phage DNA methylated as well?
This is the cool part. Look at the figure on the left. Imagine that both strands are methylated. Following DNA replication, the sequence GAATTC will be copied but the newly synthesized strand isn't methylated. The hemimethylated DNA won't be recognized by the restriction enzyme so it's in no danger of being cut. In a very short time the methylase will bind and methylate the new strand of DNA.
The methylase binds specifically to hemimethylated DNA and not to unmethylated DNA. Thus, it will keep the host DNA fully methylated but it won't methylate the incoming 'phage DNA since the 'phage DNA is completely unmethylated.
As bacteria grow and divide they continue to inherit DNA that's methylated at the restriction site even though this inheritance isn't your typical genetic inheritance. It's called epigenetic inheritance. If something happens to the methylase, the cell will commit suicide by chopping up its own DNA. If both the methylase and restriction enzyme genes are mutated the cell survives quite nicely except that it's more susceptible to bacteriophage infection.
Epigenetic inheritance is common in mammals, including us. In this case it's not related to restriction/modification. It's a separate phenomenon where gene expression is controlled by the presence or absence of 5-methyl cytosine. The cytosine methylase works just like the modification enzymes—it binds preferentially to hemimethylated DNA. In this way, methylated regions of DNA are inherited from one generation to another.
Paula Zahn Should be Fired from CNN
I've just about had it with Paula Zahn. She's almost the most stupid "journalist" on TV, a fact she demonstrated in her January 31st report on atheism in America. [TRANSCRIPT]
Several bloggers have been all over this. The disgusting part is the so-called "discussion" that follows the airing of a short segment on discrimination against atheists. Paula let her invited guests get away with the most stupid and outrageous statements. She should apologize on air for inviting them on the show.
Did it never occur to CNN that having an atheist-hating Jew and two evangelical Christians discuss atheism was a bad idea? Where were the atheists on a show about atheism?
(UPDATE: Read the discussion at RichardDawkins.net.)
Here are two quotations from the ignorant atheist-hater named Debbie Schlussel. The first was in response to a question from Paula Zahn. Following a rant by the evangelical Christian Karen Hunter, Paula asked whether anyone was going to defend atheists .
No, I agree with her 100 percent. I think that the real discrimination is atheists against Americans who are religious. Listen, we are a Christian nation. I'm not a Christian. I'm Jewish, but I recognize we're a Christian country and freedom of religion doesn't mean freedom from religion. And the problem is that, you have these atheists selectively I believe attacking Christianity. You had a case in California where school children were forced to dress as Muslims and learn from the Koran. In Michigan they're saying high school (INAUDIBLE) in high school where they say Muslim prayers at the football games, public high school, (INAUDIBLE) in high school. You don't see atheists complaining about that. I really believe that they are the ones who are the intolerant ones against Christians.Did you get that? America is a Christian country and freedom of religion doesn't mean freedom from religion! What cave did they find her in? Do you think that Debbie Schlussel might have a slight problem with Muslims as well as atheists?
Look where there are more atheists and where they've lost God, where the church is not that strong. Europe is becoming Islamist. It's fast falling and intolerance is increasing. That's the one reason our country has not become like Europe because we have strong Christians and because atheists are not strong. And I think that's a good thing.
See the complete show here.
Prince at the Superbowl
Apparently there was a big game last Sunday. I heard the Prince was there so I looked him up on the Uncyclopedia [Prince].
Prince Charles is one of the most widely respected individuals alive today. He is renowned for his intelligence, bravery and hard-working nature. The Prince is considered to be an expert in the fields of nuclear astro-physics, ancient Egypt, paper cutting and contemporary literature.
His recent marriage to Wallis Simpson was one of the most glamorous weddings of modern times only marred slightly by the disappointment felt among many of his female subjects.
There is not a hint of genetic inbreeding in his appearance or his demeanor. He is furthermore regarded as one of the most intelligent species of moss known by current scientists.
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