How Lipitor® Works

 
In previous postings we learned how cholesterol is made from squalene and squalene is made from the six carbon compound mevalonate [How to Make Cholesterol] [Making Squalene].

Today we'll cover the synthesis of melavonate from three molecules of the 2-carbon compound acetate.

When acetate is involved in biosynthesis reactions it is "activated" by forming a thioester linkage to coenzyme A ("thio" means sulfur). Coenzyme A was discovered by Nobel Laureate: Fritz Lipmann.

The first step in the pathway is the joining of two molecules of acetyl CoA to make the 4-carbon compound acetoacetyl CoA. Note that this molecule is still joined to coenzyme A. In the second step, another acetyl group is transferred to acetoacetyl CoA to make the 6-carbon molecule 3-hydroxyl-3-methylglutaryl CoA (HMG CoA). HMG-CoA was Monday's Molecule.

The last step is cleavage of the thioester linkage between the 6-carbon compound and CoA releasing mevalonate.

This last step is catalyzed by an enzyme called HMG-CoA reductase. This is an oxidation-reduction reaction where the reduction of HMG-CoA is coupled to the oxidation of NADPH. This enzyme is regulated inside the cell and this controls the biosynthesis of cholesterol since mevalonate is an essential intermediate in the pathway.

Lipitor® and similar drugs control cholesterol synthesis by inhibiting the enzyme HMG-CoA reductase. If we draw the substrate in a way that shows its structure, you can see that Lipitor® and Mevacor® resemble the business end of the molecule—the part that's cleaved by the enzyme. These drugs are effective inhibitors because they bind to the active site of the enzyme.



The class of HMG-CoA reductase inhibitors is called statins. They are used to control serum cholesterol levels in the hopes of reducing the risks of coronary heart disease. There don't seem to be any serious side effects to inhibiting mevalonate production in spite of the fact that mevalonate is required for synthesis of some hormones and of the essential cofactor ubiquinone [Ubiquinone and the Proton Pump].

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Parental Guidance Suggested

 

This rating was determined based on the presence of the following words:

* dead (2x)
* sex (1x)

I wonder what kind of rating I would get if Sandwalk were rated in France? Do they have a "milquetoast" rating?

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Swift Boat Funder T. Boone Pickens Reneges On John Kerry Million Dollar Offer

 
Anyone who spoke out against the war in Viet Nam and who knew Jane Fonda would get my vote. Especially if the other choice was someone who didn't even like Jane Fonda.

Do you remember the Swift Boat campaign against John Kerry? You should. It's going to be important in the next year since we're very likely to see something similar in the next Presidential election campaign.

One of the founders of Swift Boat Veterans for Truth (sic) has just offered one million dollars if Kerry can prove that there was even one lie in the ads they placed on television. Kerry takes up the challenge but, it seems as though there's some fine print ... [ Swift Boat Funder T. Boone Pickens Reneges On John Kerry Million Dollar Offer]. Imagine that.

Pickens supports Rudy Giuliani so it's unlikely that Giuliani will be swiftboated. Hmmm, I wonder who the target will be ....

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[Hat Tip: Canadian Cynic]

I'm Going to a Lecture on Intelligent Design

 
Denyse O'Leary is teaching a course on Intelligent Design at the University of St. Michael's College, University of Toronto [Denyse O'Leary's University Course on Intelligent Design].

The outline of the course was posted on Post-Darwinist [ COURSE: By Design or by Chance? An introduction to the intelligent design controversy].

Students in the course are allowed to invite a guest for one lecture and one of my friends, who shall remain nameless for now, has urged me to come along. By all accounts the course is going well and Denyse is presenting both sides of the controversy.

Tonight's lecture is ...

Session 5. Intelligent design: What the ID proponents actually say (and don’t say) Tuesday November 20, 2007

Michael Behe, author of Edge of Evolution (2007), sees actual design where, for example, Richard Dawkins, author of The Blind Watchmaker, sees the illusion of design. Who’s right? Are they both wrong?

Guest: Kirk Durston, biophysics PhD candidate at the University of Guelph.

Kirk Durston (right) is the National Director of the New Scholars Society. According to his biography on their website,

KIRK DURSTON, B.Sc (Physics), B.Sc. (Mech. Eng.), M.A. (Philosophy), Ph.D. Candidate (Biophysics) at the University of Guelph.

Kirk Durston is the National Director of the New Scholars Society. He is currently a Ph.D. candidate in Biophysics at the University of Guelph, specializing in the application of information to biopolymers. His other interests include amateur astronomy, wilderness canoeing & camping, and landscape photography & art.

What is it about creationists that they always seem to have multiple redundant degrees? In this case he has two Bachelor's degrees. What's with that?

It's easy to find out what Kirk believes because there's a Statment of Faith on the website.

The sole basis of our beliefs is the Bible, God's infallible written Word, the 66 books of the Old and New Testaments. We believe that it was uniquely, verbally and fully inspired by the Holy Spirit, and that it was written without error (inerrant) in the original manuscripts. It is the supreme and final authority in all matters on which it speaks.We accept those large areas of doctrinal teaching on which, historically, there has been general agreement among all true Christians. Because of the specialized calling of our movement, we desire to allow for freedom of conviction on other doctrinal matters, provided that any interpretation is based upon the Bible alone, and that no such interpretation shall become an issue which hinders the ministry to which God has called us.

Jeffrey Shallit had a few things to say about Kirk Durston on Recursivity [Kirk Durston: Apologist for Genocide]. This is going to be an interesting lecture.

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Who Was Adam?

 
One of the regular contributers to the comments section of Sandwalk has suggested we read Who Was Adam? by Fazale Rana and Hugh Ross. Apparently this is a very good explanation of how evolution is compatible with the Bible.

Hugh Ross is the ruler of Reasons to Believe, an organization that promotes the integration of science and fundamentalist Christianity. Here's part of their Statement of Faith.

We believe the Bible (the 66 books of the Old and New Testaments) is the Word of God, written. As a "God-breathed" revelation, it is thus verbally inspired and completely without error (historically, scientifically, morally, and spiritually) in its original writings. While God the Holy Spirit supernaturally superintended the writing of the Bible, that writing nevertheless reflects the words and literary styles of its individual human authors. Scripture reveals the being, nature, and character of God, the nature of God's creation, and especially His will for the salvation of human beings through Jesus Christ. The Bible is therefore our supreme and final authority in all matters that it addresses.

Fazale (Fuz) Rana is a biochemist who works for Hugh Ross at Reasons to Believe.

I've seen Hugh Ross in action when he was here for a two day symposium organized by Denyse O'Leary and some of her friends. Hugh Ross is a genuine kook with nothing to say that's even remotely interesting to scientists. I don't know about Fazale Rana. Has anyone read this book?

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Gene Genie #20

 

The 20th edition of Gene Genie has just been published on Bitesize Bio [Gene Genie #20].

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Genetically Speaking All Races Are Equal

 
That's what the genetics expert, Crystal, told us in her video [Crystal Tells Us about the Human Genome] ...

Now, surprisingly enough, genetically speaking all races are equal. As a matter of fact, if you took a random sample of someone's DNA, just by looking at it you could not tell whether they were African-American, Caucasian, Asian or any other race.

I guess Crystal forgot to tell Price et al. (2007) because this is what they say in the abstract of the paper they just published in PLoS Genetics ...

European Americans are often treated as a homogeneous group, but in fact form a structured population due to historical immigration of diverse source populations. Discerning the ancestry of European Americans genotyped in association studies is important in order to prevent false positive or negative associations due to population stratification and to identify genetic variants whose contribution to disease risk differs across European ancestries. Here, we investigate empirical patterns of population structure in European Americans, analyzing 4,198 samples from four genome-wide association studies to show that components roughly corresponding to northwest European, southeast European and Ashkenazi Jewish ancestry are the main sources of European American population structure. Building on this insight, we constructed a panel of 300 validated markers that are highly informative for distinguishing these ancestries. We demonstrate that this panel of markers can be used to correct for stratification in association studies that do not generate dense genotype data.

So, not only can we distinguish Caucasians from Africans and Asians, we can also sort out different groups within Caucasians.

Isn't it amazing that scientists can do this when there's no genetic differences between races?

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Price, V. et al. (2007) Discerning the ancestry of European Americans in genetic association studies. PLoS Genet. In press. [doi:10.1371/journal.pgen.0030236.eor]

Judgment Day Online

 
Judgment Day is the PBS Nova show about the Dover trial. You can now watch it online in 12 episodes [Judgment Day].

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[Hat Tip: Monado at Science notes ( "Intelligent Design on Trial" comes to your computer)]

A World Without Writers

 

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[Hat Tip: Canadian Cynic]

Monday's Molecule #52

 
Today's molecule is a bit more complicated than some. Most of you probably haven't encountered it in your studies and those who have may have seen it drawn a bit differently. Your task is to give it a complete biochemical name as well as the shortened common name.

There's a direct connection between this molecule and Wednesday's Nobel Laureate(s).

The reward goes to the person who correctly identifies the molecule and the Nobel Laureate(s). Previous winners are ineligible for one month from the time they first collected the prize. There are three ineligible candidates for this week's reward. The prize is a free lunch at the Faculty Club.

Send your guess to Sandwalk (sandwalk(at)bioinfo.med.utoronto.ca) and I'll pick the first email message that correctly identifies the molecule and the Nobel Laureate(s). Correct responses will be posted tomorrow along with the time that the message was received on my server. I may select multiple winners if several people get it right.

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

UPDATE: We have a winner! The molecule is 3-hydroxy-3-methylglutaryl-Coenzyme A, or HMG-CoA. Wait to see who the Nobel Laureate is tomorrow.

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Crystal Tells Us about the Human Genome

According to the YouTube profile ...

Crystal is graduated from Texas A&M University w/ a degree in agricultural leadership and development with an emphasis on genetics and bio-chemistry. She is currently a professional model.

Here's her website [crystalnicole.com]. There's not much on her website about DNA or genomes. On the other hand, there's a lot of Crystal. I suspect science isn't her main interest in life.

This is a video about the human genome. Crystal tells us lots of interesting things about the size of our genome, number of genes, junk DNA, whether the DNA of different races is the same etc. etc.

It makes my blood boil. A lot of the information is basically correct but there's no explanations. For example, we know why the rice genome has more genes than the human genome—it's not a mystery. Some of the information is wrong (e.g., similarities between different species). Some of it is misleading (e.g., the definition of a gene).

I assume that this is just a regurgitation of things that Crystal learned in class. Rather than detail all of the errors I'll leave it up to you. You can list them in the comments.

The question I want answered is whether this sort of video serves a useful purpose or not. Is it better to have such a thing on YouTube than nothing at all? (I think we can all agree that the ideal situation would be to have a similar video that was accurate.)

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[Hat Tip: Curious Cat and ScienceRoll]

John Wilkins Likes Sociobiology

 
Wilkins is reviewing a soon-to-be-published paper by David Sloan Wilson and Edward O. Wilson [The two Wilsons on sociobiology]. These two are on a recent tear promoting a new, acceptable, version of group selection. John Wilkins declares that, "I have recently (i.e., in the last five years) come to be an unflinching sociobiologist ..."

This may raise some eyebrows but, as usual, John threads his way through the minefield of misconceptions about sociobiology to arrive at a position that he can support. (I don't agree with him, but that debate is for another time.)

What I particularly like about John's posting is how he separates evolutionary psychology from sociobiology by pointing out the deep flaws in the discipline of evolutionary psychology.

Evolutionary psychology has two major flaws in my opinion. One is that it is almost always adaptationist even when no evidence of adaptiveness is available. Adaptation is, as G. C. Williams noted of group selection explanations, an onerous hypothesis, to be supported or not used. It is too easy to come up with "possible scenarios", let alone possible adaptations. Such explanations need to follow the evidence rather than use, as EvPsych does, a priori arguments from the self-evident truth of natural selection and the nature of evolution.

The second major flaw relates to this. On the (a priori) assumption that selection always favours modularity, EvPsychologists claim that most of the human behavioural repertoire and its underlying neurology is modular. Each module is, as the literature has it, "informationally encapsulated and domain specific", which roughly means that it does one thing well and only that thing, without hints from the rest of our cognitive and sensorimotor system.

I agree with John 100%, although I might add one or two other flaws. I'm not sure the Wilsons would agree, however. I wonder if John knows whether E.O. Wilson is as opposed to evolutionary psychology as he (John) is?

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Where Was Anderson Cooper?

 
The latest death toll from Bangladesh is 2200 and this number will almost certainly rise. Chris Mooney knew this was coming last Wednesday and he warned everyone to expect a disaster [Still No Weakening for Cyclone Sidr].

Why didn't CNN dispatch its crack team of hurricane reporters to the scene? And why, even now, is the news media treating this so lightly?

Yesterday I watched while the CNN anchors reported on the dead and injured and the millions of people who lost their homes. They then switched immediately to light-heated banter about elderly women playing basketball. We didn't see that kind of insensitivity during Katrina, did we?

Should there be a difference just because one hurricane is killing Americans while another is killing people in Bangledesh?


UPDATE: Death Toll Might Reach 10,000.

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[Photo Credits: AFP: Bangladesh cyclone dead number 2,200, millions destitute]

Adaptationist Award #2

 
Jonathan Eisen at The Tree of Life has just given out his second adaptationist award. This "award" goes to those who exemplify the famous Dr. Pangloss referred to in Gould and Lewontin (1979).

This award goes to David Brown for his article in the Washington Post. An article that begins with ...

It used to be a rule -- actually, more of an assumption -- that the genetic machinery of living organisms was never intentionally wasteful or inaccurate. It turns out this isn't always true, either.

I think you can already see why this award is so richely deserved but if you're still in doubt check out the posting [Adaptationomics Award #2 - Washington Post and David Brown].

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Gould, S.J. and Lewontin, R.C. (1979) The Spandrels of San Marco and the Panglossian Paradigm: A Critique of the Adaptationist Programme. Proc. Roy. Soc. (London) Series B, 205:581-598. [OnLine Version]

John Dennehy's Citation Classic

 
John Dennehy's citation classic for this week is a paper by Volkin and Astrachan published in 1956. That's Elliot "Ken" Volkin on the left.

I was not aware of this paper but John makes a good case for its importance in the history of molecular biology. Volkin and Astrachan deserve more recognition for discovering messenger RNA (mRNA). Get on over to The Evilutionary Biologist and read about the private meeting between Francis Crick, Sidney Brenner, and François Jabob in Brenner's room at King's College in 1960 [This Week's Citation Classic].

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[Photo Credit: Oak Ridge National Laboratory]

Bruce Alberts in Toronto

 
My Ph.D. supervisor, Bruce Alberts, was in Toronto yesterday to receive an honourary Doctor of Science degree from the University of Toronto. We had a nice luncheon in the Upper Library at Massey College. That's Bruce Alberts on the right and my former Ph.D. student and co-author Marc Perry on the left. Three "generations" of Ph.D.'s.

I'm sure three-generation pictures are quite common but four- and five-generation photographs are more unusual. Does anyone have one?

Following the luncheon we were off to the Chancellor's Office to get "gowned" for the graduation ceremony. Yesterday was graduation day for Ph.D. and Masters degree students.

The students were lined up to enter Convocation Hall. There were 391 of them and later on we waited while each one was called to the stage to receive their degree.

The procession of faculty was quite impressive with all the gowns, finery, pomp, and circumstance. Here we are (below) all dressed up on the stage of Convocation Hall. From left to right, Katherine Whiteside, Dean of Medicine; Bruce Alberts, convocation speaker and honourary degree recipient; Jack Petch, Chair Governing Council; David Peterson, Chancellor; David Naylor, President; Susan Pfeiffer, Dean School of Graduate Studies; and half of me on the end. On the right I'm delivering the citation for Bruce Alberts.


Here's part of what I said,

Bruce was very successful at Princeton where he made major advances in working out the mechanism of DNA replication, laying the groundwork for future recognition as an outstanding scientist. He has also contributed greatly to our understanding of chromosomes. In 1995 he came to Toronto to receive a Gairdner Award for his scientific achievements. He has published over 150 scientific papers.

Bruce moved to the University of California at San Francisco in 1976. He served as Chair of the Department of Biochemistry & Biophysics during the time that it rose to become one of the leading biochemistry departments in the world. Bruce’s guidance and mentorship during that time contributed in no small part to the success of the department.

Among the many honours and awards he has received I’d like to single out a few others that relate to his scientific achievements. He holds an American Cancer Society Lifetime Research Professorship. He was elected to the American National Academy of Sciences in 1981. He is a Foreign Member of the Royal Society (London) and many other international societies.

Bruce’s interest in science education was apparent from the beginning. In 1983 he and his colleagues published the very first edition of his famous textbook Alberts et al. The Molecular Biology of the Cell. The book has become familiar to students all around the world. The fifth edition is due to be published in just a few weeks. The Molecular Biology of the Cell set a standard for textbook writing that few other books have matched. I dare say many of the students here have taken at least one course that used his book.

In 1993, Bruce left San Francisco and moved to Washington to become President of the National Academy of Sciences—a post he held for twelve years. During that time he was “First Scientist” in the USA and, arguably, the most influential scientist in the world.

Bruce soon became known as the “Education President” for his efforts to improve science education beginning in kindergarten and the primary grades. He is highly respected for his tireless efforts in bettering science education and research policies in the USA and around the world. This effort has continued since he left Washington. He has received numerous awards for his achievements in education including Outstanding Volunteer Coordinator in California schools, the Leadership in Education Award from Keystone Center, the Distinguished Service Award from the National Association of Biology Teachers, and the Victor Hamburger Outstanding Educator Prize from the American Association for Developmental Biology.

There are even more awards and honours, for example Bruce Alberts is a Commander of the Order of the British Empire.

Outstanding scientist, caring mentor, renowned author, and distinguished educator.

Mr, Chancellor, on behalf of the Governing Council, I ask you to confer the degree of Doctor Of Science, honoris causa, upon Bruce Alberts.

After the graduation ceremony we came back to the Biochemistry Department for a reception in Bruce's honour. Many of the graduate and undergraduate students showed up with copies of their textbooks and Bruce was delighted to sign them.

We had a wonderful, but short, visit. I hope he comes back again real soon.

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Are You as Smart as a Second Year University Student? Q2

 
Here's another question from my test.

In Icons of Evolution Jonathan Wells defines evolution as,

Biological evolution is the theory that all living things are modified descendants of a common ancestor that lived in the distant past.

Does this definition differ from the one you learned in biology class? Does it differ from the definitions of evolution commonly found in textbooks? Why does Wells choose this definition over any others?

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Are You as Smart as a Second Year University Student? Q1

 
Here's a question from last month's test in our class on the evolution/creationism debate. How would you have done?

Philip Johnson is one of the leading advocates of intelligent design creationism, He argues that science is unnecessarily atheistic because it requires methodological naturalism.

Creationists are disqualified from making a positive case, because science by definition is based on naturalism. The rules of science also disqualify any purely negative argumentation designed to dilute the persuasiveness of the theory of evolution. Creationism is thus out of court—and out of the classroom—before any consideration of evidence. Put yourself in the place of a creationist who has been silenced by that logic, and you may feel like a criminal defendant who has just been told that the law does not recognize so absurd a concept as "innocence."

Is this a good argument for intelligent design creationism? Explain your answer.

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The Johnson quotation is from Johnson, P.E. (1990) "Evolution as Dogma: The Establishment of Naturalism" first published in First Things 6:15-22. reprinted in Intelligent Design Creationism and Its Critics Robert T. Pennock ed.

Judgment Day

 
I just saw the show last night. I had to tape it on Tuesday night because the only way I could see it was on WCTS Seattle and that was too late for me to stay up [Judgment Day Is Coming].

The show was very good. I was impressed with the way it was edited and with the lack of unnecessary hype. The courtroom scenes were a bit silly but I can't think of any way to improve them short of making them look too theatrical. At least this way you weren't under any illusions that it was anything but a simulation.

I liked the emphasis on the divisions within the community. What it shows us is that no courtroom victory is going to make this issue go away. The creationists simply don't accept the results of the trial as having any relevance to their religion. Americans are going to have to go through this trauma several more times in the next few years.

I'm still a bit sad that programs like this have to go out of their way to show that evolutionists can be religious. There were obligatory scenes of Ken Miller in church and of one of the Dover evolutionist supporters teaching Bible class. This is a debate about science and religion. The whole point was to show that Intelligent Design Creationism is religion and not science. Evolution is science. So why is it necessary to focus on the religious beliefs of evolution supporters? Shouldn't their personal beliefs be irrelevant?

There are lots of interesting things on the Judgment Day website [NOVA: Judgment Day]. One of them is a brief talk by Ken Miller on "Science and Religion" (follow the link "Defining Science"). I wonder if most people agree with Miller's explanation of the supernatural and how it impinges on science?

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Framing Evolution

 
Clive Thompson wrote an article for Wired titled Clive Thompson on Why Science Will Triumph Only When Theory Becomes Law.

It falls into the category of "with friends like this who need enemies." Thompson is upset about the way in which creationists misuse the word theory.

This is the central argument of evolution deniers: Evolution is an unproven "theory." For science-savvy people, this is an incredibly annoying ploy. While it's true that scientists refer to evolution as a theory, in science the word theory means an explanation of how the world works that has stood up to repeated, rigorous testing. It's hardly a term of disparagement.

But for most people, theory means a haphazard guess you've pulled out of your, uh, hat. It's an insult, really, a glib way to dismiss a point of view: "Ah, well, that's just your theory." Scientists use theory in one specific way, the public another — and opponents of evolution have expertly exploited this disconnect.

We all agree that this is a problem when we're trying to explain evolutionary theory to the general public. We need to explain that a theory is not just some wide-eyed speculation but a solid explanation of facts that has stood the test of time. Theories are as good as it gets in science. The Theory of Natural Selection, for example, is not in dispute.

It's a pain to have to do this but it's our obligation as scientists to explain science correctly, right? Clive Thompson has another suggestion.

For truly solid-gold, well-established science, let's stop using the word theory entirely. Instead, let's revive much more venerable language and refer to such knowledge as "law." As with Newton's law of gravity, people intuitively understand that a law is a rule that holds true and must be obeyed. The word law conveys precisely the same sense of authority with the public as theory does with scientists, but without the linguistic baggage.

Evolution is supersolid. We even base the vaccine industry on it: When we troop into the doctor's office each winter to get a flu shot — an inoculation against the latest evolved strains of the disease — we're treating evolution as a law. So why not just say "the law of evolution"?

Best of all, it performs a neat bit of linguistic jujitsu. If someone says, "I don't believe in the theory of evolution," they may sound fairly reasonable. But if someone announces, "I don't believe in the law of evolution," they sound insane. It's tantamount to saying, "I don't believe in the law of gravity."

It's time to realize that we're simply never going to school enough of the public in the precise scientific meaning of particular words. We're never going to fully communicate what's beautiful and noble about scientific caution and rigor. Public discourse is inevitably political, so we need to talk about science in a way that wins the political battle — in no uncertain terms.

No, no, no! Theories are not laws and under no circumstances should scientists abandon science in order to score political points.

On the other hand, Mooney and Nisbet would be proud [What Is Framing?].

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[Photo Credit: Clive Thompson from University of British Columbia]

[Hat Tip: RichardDawkins.net]

Nobel Laureate: John Cornforth

 

The Nobel Prize in Chemistry 1975.

"for his work on the stereochemistry of enzyme-catalyzed reactions"




In 1975, Sir John Warcup 'Kappa' Cornforth (1917- ) won the Nobel Prize in Chemistry for elucidating the squalene biosynthesis pathway and other pathways that generate stereospecific products [Making Squalene]. The prize was shared with Vladimir Prelog for his work on the spereospecificity of chemical reactions.

Cornforth has been deaf since he was 20 years old but overcame his deafness to become an outstanding biochemist. He is a Professor at the University of Sussex (UK). He has written a brief history of the work on the cholesterol pathway (Cornforth 2002). Here's a remarkable interview with Cornforth from the Vega Science Programmes [How to be Right and Wrong].

The presentation speech was delivered, in Swedish, by Professor Arne Fredga of the Royal Academy of Sciences.

Your Majesties, Your Royal Highnesses, Ladies and Gentlemen,

The laureates in chemistry of this year have both studied reaction mechanisms, especially from a stereochemical, i.e. a geometrical point of view. In a chemical experiment some compounds are mixed, then something happens, and finally one can isolate one or more other compounds. What has really happened, and why, and how? The situation is as if someone had abbreviated a classical tragedy, say Hamlet, by showing only the opening scenes of the play and the final scene of the last act. The principal characters are introduced, then the scene closes and when the curtain rises again you see a number of dead bodies on the stage and a few survivors. Of course the spectators would like to know what has happened in the meantime.

What I have said is valid not least for enzymatic reactions. Many such reactions are perpetually going on in all living organisms; one could say that they really concern all of us although we don't observe them. When a chemist tries to find out what really happens, he often comes across the problem: right or left? It is the same in common life. If you leave Stockholm by Norrtull, you soon come to a place where the main road branches: the left branch leads to Oslo, the right one to Sundsvall or, if you like, to Haparanda.

Professor Cornforth has among other things studied the biological synthesis of the hydrocarbon squalene from six molecules of mevalonic acid. This hydrocarbon is necessary for the formation of steroids, which are of vital importance in many respects. The synthesis of squalene takes place in 14 steps and at each the enzyme must find the proper way. That means that there are just 214 = 16384 different routes and only one of them leads to squalene. If the enzyme should make a mistake in the first step (which it does not), the final result could be rubber or various other things but definitely not squalene. The problem at each step concerns which of two hydrogen atoms is to be eliminated, the right one or the left one. Professor Cornforth has shown which choice the enzyme makes at each of the 14 steps. For this purpose he has, with brilliant mastership, utilized the properties of the hydrogen isotopes: the ordinary hydrogen, the heavy hydrogen and the radioactive hydrogen. The lastmentioned isotope can only be used in tracer quantities, which means that only about one part per million of the participating molecules are radioactive. In a similar way, Professor Cornforth has studied several other biologically important reactions. All problems connected with the reaction mechanisms are not solved at that point, but the results constitute a very important step on the way.

Professor Prelog has worked in many fields of stereochemistry, and often the problems have been connected with the geometrical shapes of the molecules and their influence on the course of the reactions.

An impressive series of investigations deal with the "medium rings", i.e. molecules containing rings of 8 to 11 carbon atoms. Such rings are not rigid but rather limp. Parts of the ring which may seem rather distant may come into close contact with each other leading to unexpected reactions. Professor Prelog has been able to elucidate such reactions by utilizing the carbon isotopes.

Many important investigations refer to reactions between chiral molecules. The term chiral is derived from a word in ancient Greek, meaning hand. The molecules are unsymmetrical and may exist in two forms differing in the same way as a right hand and a left hand. The molecules are so small that you can't see them, but one can gain much knowledge by studying the reactions between chiral molecules of different kind.

Professor Prelog has also made important contributions to enzyme chemistry. He has studied enzymatic reactions on small molecules and in particular oxidation or reduction processes. The experiments may be more or less successful depending on how the enzyme and the other molecule fit together geometrically. By systematic experiments with various small molecules of well-defined shapes, it was possible to construct a "map" of the active part of the enzyme molecule. The results have recently been confirmed in a special case by Swedish scientists using x-ray methods.

Professor Prelog has also with ingenuity and penetration discussed and analysed the fundamental concepts of stereochemistry, not least the conditions for chirality in large and complicated molecules.

Professor Cornforth. Enzymatic reactions have always had a certain air of magic, perhaps witchcraft. Of course this is due to our imperfect knowledge of what really happens. This air of magic is, however, gradually dispersing, and your contributions, utilizing the isotopes of hydrogen, imply most striking advances. The handling of compounds with chiral methyl groups is an achievement of the highest intellectual standard.

Let me also express our admiration for the skill and perseverance with which you have pursued your work in spite of a serious physical handicap. Perhaps it had not been possible without the never-failing help and support of Mrs. Cornforth. I think she should not be forgotten on this day. In recognition of your services to chemistry and to natural science as a whole, the Royal Academy of Sciences has decided to confer upon you the Nobel Prize. To me has been granted the privilege to convey to you the most heartly congratulations of the Academy.

Professor Prelog. Ich habe hier versucht, einen Kurzbericht über Ihre wichtigsten Leistungen in der Stereochemie zu erstatten. Das war gewiss etwas schwierig. Ihre schönen Experimentalarbeiten erstrecken sich über weite Felder der heutigen organischen Chemie. Öfters haben Sie die Fortführung Ihrer Arbeiten anderen Forschern überlassen, und viele Chemiker hohen Ranges sind zurzeit auf den Gebieten tätig, die Sie einst eröffnet haben. Sie haben auch die fundamentalen Grundlagen der Stereochemie, besonders den Chiralitätsbegriff, in tiefsinnigen Auseinandersetzungen diskutiert und klargelegt.

In Anerkennung Ihrer Verdienste um die Entwicklung der Chemie hat die Konigliche Akademie der Wissenschaften entschlossen, Ihnen den Nobelpreis zu verleihen. Mir ist die Aufgabe zugefallen, Ihnen die wärmsten Glückwünsche der Akademie zu überbringen.

Professor Cornforth. In the name of the Academy I invite you to receive your prize from the hands of His Majesty the King.

Professor Prelog, Im Namen der Akademie bitte ich Sie aus den Händen Seiner Majestät des Königs den Nobelpreis in Empfang zu nehmen.

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Cornforth, J.W. (2002) Sterol biosynthesis: the early days. Biochem. Biophys. Res. Commun. 292:1129-38. [PubMed]

Making Squalene

 
Squalene is the essential precursor for making cholesterol [How to Make Cholesterol]. The pathway for synthesis of squalene is complicated and it was only worked out in second half of the last century.

The initial substrate is a compound called mevalonate. It's a six carbon branched organic acid. In a later posting we'll wee how cells make mevalonate and learn how that pathway can be controlled by Lipitor® and other drugs that regulate cholesterol levels.

Mevalonate is first phosphorylated by mevalonate kinase in a reaction that requires ATP.


The product of this reaction is mevalonate-5-phosphate and it is immediately phosphorylated again to produce the disphospate derivative. The next step removes the carboxylate group, which is released as a bicarbonate ion (CO₂ dissolved in water produces bicarbonate). This decarboxylation reaction is associated with the formation of a double bond at the end of the product molecule, isopentenyyl diphosphate. This is an important step in the pathway to squalene since squalene has a lot of carbon-carbon double bonds.

The five-carbon isopentenyl group of isopentenyl diphosphate is known as an isoprenyl unit. This molecule (isopentenyl diphosphate) is the source of isoprenyl units for many other biosynthesis reactions in addition to squalene synthesis. &Beta:-carotene and the lipid vitamin A (retinol) are good example of compounds with these isoprene units [Vitamin A (retinol)]. Ubiquinone is an absolutely essential cofactor in many important biochemical reactions an it has an isoprenoid tail [Ubiquinone and the Proton Pump]. Vitamin K, which is required for blood clotting, has a derived isoprenoid tail [THEME: Blood Clotting].

The pathway from isopentenyl diphosphate to squalene is complicated but the basic strategy is quite simple. The idea is to join two five carbon (C₅) isoprene units to make the C₁₀ molecule geranyl diphosphate. Then another C₅ isoprenyl unit is added to make C₁₅ farnesyl diphosphate. Finally, two molecule of farnesyl diphosphate are joined head-to-head to make C₃₀ squalene.


The difficult part of this reaction was figuring out the mechanism so that all of the double bonds would be in the trans conformation. Most of the work was done by John Cornforth who received the Nobel Prize in 1975 [Nobel Laureate: John Cornforth].

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Praying for Rain

 
Here's a video from CNN of Georgia Governor Sonny Perdue praying for rain [Georgia's governor prays for rain on Capitol steps]. It's the sort of thing you might expect from a tribe of hunter-gathers about 50,000 years ago. It didn't work very well back then. I wonder if it will work today?

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Free Your Mind

 

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[Hat Tip: PZ Myers]

DNA Is Life T-Shirt

 

Edmund Scientific is selling a T-shirt with a picture of a replicating DNA molecule [DNA is Life T-Shirt].

The caption reads "DNA Is Life. THE REST IS JUST DETAILS." Clever, but sometimes those details are important.

Look closely at the T-shirt. How many of you recognize what's wrong with the molecule on the T-shirt? It may be "just a detail" but I wonder why they couldn't have designed a logo that was scientifically accurate?

How difficult can it be? Would they sell fewer T-shirts if the molecule was accurately depicted?

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[Hat Tip: Hsien-Hsien Lei]

How to Make Cholesterol

 
Monday's Molecule was squalene, a thirty carbon lipid with a characteristic set of double bonds [Monday's Molecule #51]. Most species can synthesize squalene. In some, it serves as the precursor for biosynthesis of cholesterol and other complex steroids.

Cholesterol is an essential component of cell membranes and the initial substrate in pathways leading to hormones such as testosterone and β-estradiol.

A brief outline of the pathway from squalene to cholesterol is shown on the right. The first thing to note is that squalene can fold into a form that already resembles cholesterol. The reactions in the pathway result in closing the rings to make the four ring structure that's characteristic of steroids.

Lanosterol is a key intermediate in this pathway. Note that in addition to the ring closing reactions, an oxygen—in the form of a hydroxyl group—has been added to the ring.

The conversion of lanosterol to cholesterol requires up to 20 enzyme-catalyzed steps. There's more than one way to make cholesterol from lanosterol but in the end all molecules of cholesterol are identical.

Most species, including humans, are capable of synthesizing all the cholesterol they will ever need. In animals, the biosynthesis pathway is regulated by the amount of cholesterol in the blood plasma. If a large amount of cholesterol is derived from food then the biosynthesis pathway is down-regulated to compensate.

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National Center for Science Education

 
The National Center for Science Education (NCSE) has a new log by graphic artist Andrew Conti. Do you know what it depicts? [NCSE Logo Contest Winner].

Check out the NCSE homepage for a ton of useful information about the evolution/creationism debate [NCSE]. You can even sign up for a Grand Canyon River Raft Expedition with NCSE geologist Alan Gishlick to explain the real scientific history and "creationist" Eugenie Scott to explain the other kind of history.

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[Hat Tip: John Pieret]

Monday's Molecule Copycat

 
One of my offspring—who shall remain nameless—has decided to make fun of my Monday's Molecule feature. Go to her blog and tell her to behave herself [The Monday Molecule - Belgium Version].

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Monday's Molecule #51

 
Today's molecule may seem very simple but your task is to give it a complete IUPAC name as well as the common name. You also have to identify the origin of the common name. Pay close attention to the structure before you venture a guess.

There's a direct connection between this molecule and Wednesday's Nobel Laureate(s).

The reward goes to the person who correctly identifies the molecule and the Nobel Laureate(s). Previous winners are ineligible for one month from the time they first collected the prize. There are two ineligible candidates for this week's reward. The prize is a free lunch at the Faculty Club.

Send your guess to Sandwalk (sandwalk(at)bioinfo.med.utoronto.ca) and I'll pick the first email message that correctly identifies the molecule, the origin of the common name, and the Nobel Laureate(s). Correct responses will be posted tomorrow along with the time that the message was received on my server. I may select multiple winners if several people get it right.

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

UPDATE: We have a winner! Satoris guessed that the molecule was squalene [2,6,10,15,19,23-Hexamethyl-2,6,10,14,18,22-tetracosahexaene] and the name squalene is derived from squalus meaning "shark." Squalene was first isolated from shark liver. The word squalus comes from the Latin word squalus. It originally meant any marine fish.

Several people got this part right but Sartoris was the only person to guess the correct Nobel Laureate. I was thinking of the person who worked out the detailed pathway for biosynthesis of squalene. You will find out tomorrow.

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Reading Level Comparison

 
BarryA has posted the following comment on Uncommon Descent [Reading Level Comparison].

Thanks to one of our commenters for pointing out this website that calculates the reading level of blogs. Just for fun I inserted UD and it came back “High School,” which means that the general discussion at this blog is at a high school level. I then inserted Pandas Thumb and it came back “Elementary School.”

Make of this what you will.

This seems curious so I tried it myself. Here's the result for "www.uncommondescent.com."

Uncommon Descent

and here's the result for "pandasthumb.org"

The Panda's Thumb

Make of this what you will. For me, it brings to mind the word "IDiot."

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The Salem Conjecture

The Salem Conjecture was proposed by Bruce Salem on the newsgroup talk.origins [The Salem Conjecture]. Here's how he described it on Sept. 5, 1996.

My position is not that most creationists are engineers or even that engineering predisposes one to Creationism. In fact, most engineers are not Creationists and more well-educated people are less predisposed to Creationism, the points the statistics in the study bear out. My position was that of those Creationists who presented themselves with professional credentials, or with training that they wished to represent as giving them competence to be critics of Evolution while offering Creationism as the alternative, a significant number turned out to be engineers.

This should not be confused with the "hard" version of the Salem Conjecture (Hypothesis), which says that engineers are more likely to be creationists. Both versions are described in the Wikipedia entry [Salem Hypothesis].

Joshua Rosenau discusses the possibility that the hard version of the Salem Conjecture might be correct and this explains the soft version [The Salem Hypothesis explained!]. Read the comments.

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[Photo Credit: I pretty sure this is a photograph of Bruce Salem.]

Beyond Belief II: Enlightenment 2.0

 
By all accounts this year's Beyond Belief symposium in San Diego was a lot less exciting than last year's [Beyond Belief II: Enlightenment 2.0]. Perhaps it's because Richard Dawkins wasn't there. On the other hand, PZ Myers was there [Speakers].

There's a short review of the highlights in this week's issue of New Scientist [Does God have a place in a rational world?]. From the sounds of it, the lack of clear-headed atheists led to some very sloppy thinking.

The first firebrand is lobbed into the audience by Edward Slingerland, an expert on ancient Chinese thought and human cognition at the University of British Columbia in Vancouver, Canada. "Religion is not going away," he announced. Even those of us who fancy ourselves rationalists and scientists, he said, rely on moral values - a set of distinctly unscientific beliefs.

Oops. I've got news for you, Prof. Slingerland, you can't count yourself as a rationalist if you think that morality requires religion. And you can't lay claim to being a scientist if you think that moral values are unscientific. That's two strikes.

Where, for instance, does our conviction that human rights are universal come from? "Humans' rights to me are as mysterious as the holy trinity," he told the audience at the Salk Institute for Biological Studies. "You can't do a CT scan to show where humans' rights are, you can't cut someone open and show us their human rights," he pointed out. "It's not an empirical thing, it's just something we strongly believe. It's a purely metaphysical entity."

Strike three. It's a good thing Dawkins wasn't there or this kind of sloppy thinking would have been exposed.

Who said we all have a conviction that human rights are universal? Not me, that's for sure. I can't think of a single "human right" that qualifies. Furthermore, those human rights that we generally agree upon in the 21st century are not mysterious to me. They're mostly common sense designed to maximize our ability to live in groups. It's an empirical thing—and we're still working on the best compromises between absolute rights and qualified ones.

The mood at this follow-up conference was different. Last year's event was something of an "atheist love fest" said some, who urged a more wide-ranging discourse this time round. While all present agreed that rational, evidence-based thinking should always be the basis of how we live our lives, it was also conceded that people are irrational by nature, and that faith, religion, culture and emotion must also be recognised as part of the human condition. Even the title of this year's meeting, "Beyond Belief II: Enlightenment 2.0", suggested the need for revision, reform and a little more tolerance.

Hmmm ... I guess I can go along with that. I've known for some years that people are attracted to irrationality and superstition—we call it religion. We tolerate those who ignore rationality and evidence-based thinking but that doesn't mean we shouldn't criticize those who think that way, right? Tolerance doesn't mean the same as acceptance, does it?

There's one comment in that paragraph that puzzles me. Is it true that people are irrational by nature and it's part of human nature? My observations suggest the opposite. It seems to me that most humans strive to be rational as opposed to irrational. They may get confused from time to time about what is rational and what isn't but over the centuries rationalism tends to win out over superstition. Why do we have to concede that superstition is here to stay because it's pat of the human condition. That doesn't make sense.

Such was the message from evolutionary biologist David Sloan Wilson of Binghamton University, New York. He suggested that humans' religious beliefs may have evolved over time, thanks to the advantages they conferred as a sort of social glue holding together groups that developed them.

Wilson was not saying religion is good or bad, simply that it has evolved to be hard-wired into our brains, and therefore cannot be ignored. "Adaptation is the gold standard against which reality must be judged," he said. "The unpredictability and unknown nature of our environment may mean that factual knowledge isn't as useful as the behaviours we have evolved to deal with this world."

Hmmm ... if irrationality and superstition are hard-wired into our brains then how come it's so easy for many of us to escape from this sort of thinking?

I often wonder whether people like Wilson have thought seriously about what they're saying. Does he imagine a time when primitive humans didn't have religion because it hadn't yet evolved? How did those groups manage to survive? I wonder what went on in their brains when they couldn't think about supernatural explanations?

Or did the religion allele(s) arise before the hominid lineage? Have chimps got religion and that's what what makes them stick together? (Instead of sex.) What about gorillas? Who do they worship? Howler monkeys? Meerkats?

Chemist Peter Atkins of the University of Oxford, one of the more hard-line atheists in the room, did not let this go unchallenged. He chided fellow participants for not being sufficiently proud about what science can accomplish. Given time and persistence, science will conquer all of nature's mysteries, he said.

I'm glad to see there was at least one rationalist present.

So can scientific and religious world views ever be reconciled? Harris, author of The End of Faith, declared that they could not, and provided an uncompromising exposition on the evils of religion.

Away from the meeting, philosopher Daniel Dennett of Tufts University in Medford, Massachusetts, told New Scientist that as irrational as human minds may be, calm, firm introduction of reason into the world's classrooms could over time purge them of religion.

Maybe there were more rationalists present than the author of the piece is willing to admit?

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[PhotoCredits: Beyond Belief II: Enlightenment 2.0, Meerkats]

With Friends Like This ....

 
Greta Christina has a blog called Greta Christina's Blog (naturally). She posts lots of interesting stuff about atheism and other things. Today she strayed into science and posted a video about macroevolution (see below) [Macro-evolution" Vs. "Micro-evolution": More Video Fun]. Greta introduced it with ...

First, just so everyone's clear: "Macro-evolution" and "micro-evolution" are made-up words concocted by creationists to make themselves sound scientific. Biologists don't use them. They're scientifically meaningless. They're just different stages in the evolutionary process; "macro" is just "micro" over a longer period of time.

I posted this comment on her blog.

I'm afraid you have been mislead. Microevolution and macroevolution are perfectly good scientific terms and they are used by evolutionary biologists all the time.

There is legitimate scientific debate about whether macroevolution is more than just lots of microevolution or whether macroevolution encompasses mechanisms not seen in microevolution. It's the sufficiency of microevolution argument.

I happen to be one of those scientists who agree with Stephen Jay Gould that there are many levels of evolution (hierarchical theory). Thus, macroevolution cannot be sufficiently explained by lots of microevolution. There are other things going on at the higher levels [Macroevolution].

The video is very misleading because it assumes a simplistic version of macroevolution. There aren't any evolutionary biologists who believe in that kind of macroevolution. Thus, I have to conclude that the makers of the video are as ignorant of evolution as the creationists they mock.¹

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¹The video was made by cdk007 who claims to have a Masters degree in Biology and a Ph.D. in Molecular Neuroscience.

[The science book covers pictured are:

Macroevolution: Diversity, Disparity, Contingency: Essays in Honor of Stephen Jay Gould

At the Water's Edge: Macroevolution and the Transformation of Life

Genetics, Paleontology, and Macroevolution]

The Photosynthesis Song and a Pet Peeve

Photosynthesis is a process where light energy is captured and converted to chemical energy in the form of ATP. The basic process is similar to that in membrane-associated electron transport. In both cases an energy source (light or reducing equivalents respectively) is used to create a proton gradient across a membrane. The dissipation of this gradient as protons move back into the cell drives the synthesis of ATP.

In addition to ATP, most types of photosynthesis can also be coupled to synthesis of NADPH. The chemical energy molecules derived from photosynthesis (ATP and NADPH) are used in many different biochemical pathways such as DNA synthesis, protein synthesis, fatty acid synthesis and carbohydrate synthesis.

Most photosynthetic organisms can fix carbon dioxide and make carbohydrates using ATP and NADPH [The Calvin Cycle] [Fixing Carbon: the Rubisco Reaction]. Many nonphotosynthetic organisms can do this too. In photosynthetic bacteria and photosynthetic protists this pathway uses only a small part of the chemical energy created by photosynthesis. In large plants the synthesis of carbohydrates can use up a significant portion of the ATP and NADPH generated by photosynthesis.

The fixation of CO₂ and the synthesis of carbohydrates used to be called the "dark reactions" of photosynthesis back in the days when all we knew about were big plants. We didn't know anything about the biochemistry of photosynthetic bacteria or other species. Because our attention was focused on big plants, it was thought that photosynthesis was always coupled to the carbohydrate synthesis pathways. Now we know that this isn't true, so the old-fashioned equation,


is just not a valid representation of photosynthesis. The real products of photosynthesis don't even appear in the equation and, furthermore, those products are used for many different purposes inside the cell (especially in bacteria). Not only that, in some photosynthetic bacteria the electron donor isn't water but some other inorganic molecule like H₂S and S₂ is produced instead of oxygen. The equation is very misleading on many levels and should be abandoned.

Greg Laden has posted the video shown below and commented on the fact that the word "miracle" is used [The Photosynthesis Song ... Bad Word Choice?]. I'm much more worried about the misleading science in the video than I am about one instance of the word "miracle."

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FOX News Anchor Want USA to Support Terrorism

 
This is really quite incredible. Brain Kilmeade is the co-host of of the Fox and Friends morning news program. He thinks the USA should support terrorists inside Iran who will set off car bombs in Tehran. The conservative right really doesn't get it, do they?

The war against Iran is coming soon to a theater near you.

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[Hat Tip: Jim Lippard]