Jed Bartlet Advises Barack Obama

 
The West Wing was one of my favorite TV shows during its time. Maureen Dowd thinks so too 'cause she asked its creator, Aaron Sorkin, to imagine what President Jed Bartlet might say to Barack Obama if given the chance. Her op-ed piece was published in yesterday's New York Times [Seeking a President Who Gives Goose Bumps? So’s Obama].

Here's the best bit of advice from Bartlet to Obama ...

OBAMA The problem is we can’t appear angry. Bush called us the angry left. Did you see anyone in Denver who was angry?

BARTLET Well ... let me think. ...We went to war against the wrong country, Osama bin Laden just celebrated his seventh anniversary of not being caught either dead or alive, my family’s less safe than it was eight years ago, we’ve lost trillions of dollars, millions of jobs, thousands of lives and we lost an entire city due to bad weather. So, you know ... I’m a little angry.

OBAMA What would you do?

BARTLET GET ANGRIER! Call them liars, because that’s what they are. Sarah Palin didn’t say “thanks but no thanks” to the Bridge to Nowhere. She just said “Thanks.” You were raised by a single mother on food stamps — where does a guy with eight houses who was legacied into Annapolis get off calling you an elitist? And by the way, if you do nothing else, take that word back. Elite is a good word, it means well above average. I’d ask them what their problem is with excellence. While you’re at it, I want the word “patriot” back. McCain can say that the transcendent issue of our time is the spread of Islamic fanaticism or he can choose a running mate who doesn’t know the Bush doctrine from the Monroe Doctrine, but he can’t do both at the same time and call it patriotic. They have to lie — the truth isn’t their friend right now. Get angry. Mock them mercilessly; they’ve earned it. McCain decried agents of intolerance, then chose a running mate who had to ask if she was allowed to ban books from a public library. It’s not bad enough she thinks the planet Earth was created in six days 6,000 years ago complete with a man, a woman and a talking snake, she wants schools to teach the rest of our kids to deny geology, anthropology, archaeology and common sense too? It’s not bad enough she’s forcing her own daughter into a loveless marriage to a teenage hood, she wants the rest of us to guide our daughters in that direction too? It’s not enough that a woman shouldn’t have the right to choose, it should be the law of the land that she has to carry and deliver her rapist’s baby too? I don’t know whether or not Governor Palin has the tenacity of a pit bull, but I know for sure she’s got the qualifications of one. And you’re worried about seeming angry? You could eat their lunch, make them cry and tell their mamas about it and God himself would call it restrained. There are times when you are simply required to be impolite. There are times when condescension is called for!

Whoa! That doesn't sound like bipartisanship to me!

I agree with this approach but, from what I gather, there are millions of American who don't. They seem to think it's a sin to come right out and say what you really think. It's supposed to be much better to lie and pussyfoot around the issues and launch your attacks in a much more devious and underhanded manner. It's supposed to be better to pretend that you will change things in Washington by something called "bipartisanship" where you accommodate the wishes of kooks with crazy ideas about how to run a society. Play to the lowest common denominator—that's how to win an election.

This love for the lowest common denominator is the same attitude that leads to criticism of the vocal atheists (but interestingly enough, not the vocal Christian right wing). It would be nice if the "elite" were admired and respected in America, and in Canada, but is it going to happen in our lifetime? Are we ever going to see the day when people admit that Christopher Hitchens really is smarter than Rush Limbaugh and Bill Clinton really is smarter than George Bush? And so is Al Gore?¹

Jed Bartlett is advocating a different strategy. He says you should pitch our ideas to the top half of the "denominators" and leave the lower half to the other side. Maybe it's not such a bad idea. Maybe Obama will never get the votes of the bottom feeders anyway and it's time to stop trying.

OBAMA Good to get that off your chest?

BARTLET Am I keeping you from something?

OBAMA Well, it’s not as if I didn’t know all of that and it took you like 20 minutes to say.

BARTLET I know, I have a problem, but admitting it is the first step.

OBAMA What’s the second step?

BARTLET I don’t care.

OBAMA So what about hope? Chuck it for outrage and put-downs?

BARTLET No. You’re elite, you can do both. Four weeks ago you had the best week of your campaign, followed — granted, inexplicably — by the worst week of your campaign. And you’re still in a statistical dead heat. You’re a 47-year-old black man with a foreign-sounding name who went to Harvard and thinks devotion to your country and lapel pins aren’t the same thing and you’re in a statistical tie with a war hero and a Cinemax heroine. To these aged eyes, Senator, that’s what progress looks like. You guys got four debates. Get out of my house and go back to work.

Gee, I almost forgot about the lapel pins. It's how you demonstrate that you've sold out to the framers.

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1. And, in Canada, Stéphane Dion really is a whole lot smarter than Stephan Harper or Jack Layton?

[Big Hat Tip to Chance and Necsssity]

How Should Scientists Talk to a Politician?

 
Janet Stemwedel refers us to a video on how scientists should talk to politicians [Retired congresscritter offers communication tips to scientists].

The congresscritter in question being Sherwood Boehlert, who represented New York's 24th Congressional district (1983-2007), and chaired the House Science Committee (2001-2007). Boehlert offers this advice in a video called "Speaking for Science: Bringing Your Message to Policymakers," available for download from the American Chemical Society website.*

The video presents two scenarios in which a group of scientists meets with their Congressional representative (who happens to be a member of the House Science Committee, played by Boehlert). As you might guess, the idea is to contrast the effective meeting with the disastrous one.

As you might guess, the effective way to talk to a politician about science is to be brief and to the point and avoid all that sciency stuff that only confuses everyone. You need to stop trying to explain science to the staff member and concentrate on what's in it for the politician.

I'm not naive. I know that this is the way to be effective when you're asking a politician to do something for science. However, I'm enough of an idealist to dream about a future where scientists would make videos explaining to politicians how they should behave when prominent scientists make an effort to come by their office in an attempt to teach them some science so they can do their jobs better.

Why do politicians always think that everyone has to play by their rules? I thought they were there to serve the people, not the other way around.

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An Example of Faulty Logic from Cold Spring Harbor

A press release from Cold Spring Harbor Laboratory promotes the work of Michael Zhang and Adrian Krainer who work with splicing factors. In a typical attempt to hype the significance of the work, the press release claims that each human gene has many different variants produced by alternative splicing [CSHL team traces extensive networks regulating alternative RNA splicing].

That may or may not be correct—I happen to think it's mostly an artifact of EST cloning—but that's not the point I want to make here. The main point is the rationalization explained thus,

Biologists involved in the Human Genome Project were frankly astonished to discover that everything that makes us human is the product of a set of only 23,000 or so genes.¹ That number in itself, though several times smaller than prior estimates, is not shocking; it is the relative size of other genomes that surprised scientists.

The common fruit fly that hovers over your ripening bananas, for instance, possesses some 14,000 genes. It's perfectly obvious that human beings are vastly more complex, biologically, than a fly. Molecular biologists have demonstrated in recent years that it is not the number of genes that is the key to complexity but rather the number and diversity of gene products that a given set of genes can instruct cells to manufacture.

Rather than a single gene ordering the production of a single kind of protein, as scientists used to assume, it turns out that individual genes can in some cases give rise to dozens or even thousands of different proteins, thanks to a phenomenon called alternative splicing.

This is one version of what I call The Deflated Ego Problem. The "problem" is that some people are really, really, upset about the fact that humans may only have a few thousand genes more than a fruit fly.

So they look for some way to reflate their egos and one of the most common arguments is the one shown above. (It's excuse #1 on the list.) It goes like this.... Humans are so much more complex that fruit flies even though they have only a few thousand more genes because each human gene does double, or triple duty. Each human gene makes several different proteins by alternative splicing of the primary RNA transcript.

Viola! Problem solved.

Except for one little nasty fact. Drosophila genes also show abundant levels of alternative splicing. In fact they produce just as many variants per gene as humans, if you believe the EST data (which I don't).

Oops. There goes that solution. Humans don't have that many more proteins than fruit flies after all.

This is such an obviously bogus argument that I'm surprised it still appears in the scientific literature. Doesn't anyone realize that in order for it to salvage deflated egos there has to be no—or much less— alternative splicing in fruit flies?

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Some people were surprised and embarrassed by the "low" number of genes in the human genome but others were pretty happy that their estimates were close to the mark [Facts and Myths Concerning the Historical Estimates of the Number of Genes in the Human Genome].

The Altenberg 16 Make It into Nature

 
Nature News has an article on the recent conference in Altenberg, Austria that brought together 16 biologists who want to change evolutionary theory. The article by John Whitfield covers both sides of the story reasonably well [Biological theory: Postmodern evolution?].

The bottom line is that many of the participants at the conference are advocating changes to evolutionary theory that are either unnecessary or wrong. This is especially true of the evo-devo crowd as Whitfield makes clear from his interview with opponents of evo-devo.

But lost in all the hype is a real need to address some problems with the Modern Synthesis that didn't even come up at the meeting. The problem is very clear from the article. Here's how John Whitfield describes the current version of the Modern Synthesis.

Leaving aside the troublesome adjective, what is the modernism that the Altenburg meeting is meant to move beyond — or to use Pigliucci's preferred term, 'extend'1? Between about 1920 and 1940, researchers such as the American Sewall Wright and the Englishmen Ronald Fisher and J. B. S. Haldane took Charles Darwin's ideas about natural selection and Gregor Mendel's insights into how traits pass from parents to offspring — which many biologists of the time believed antithetical — and fused them into a mathematical description of the genetic makeup of populations and how it changes. That fusion was the modern synthesis. It treats an organism's form, or phenotype, as a readout of its hereditary information, or genotype. Change is explained as one version of a gene being replaced by another. Natural selection acts by changing the frequency of genes in the next generation according to the fitness of phenotypes in this one. In this world view, the gene is a black box, its relationship to phenotype is a one-way street, and the environment, both cellular and external, is a selective filter imposed on the readout of the genes, rather than something that can influence an organism's form directly.

This is a view of evolution that doesn't recognize random genetic drift as an important mechanism of evolution. Surely in 2008, a publication like Nature shouldn't be publishing the old-fashioned adaptationist view of evolution? What's wrong with adding one sentence to say that Sewall Wright also took an idea that Charles Darwin never heard of, random genetic drift, and incorporated that idea into our modern understanding of evolution so that we now recognize that random genetic drift is one of the main mechanisms of evolution?

I think the main reason we don't see such a description is because people like John Whitfield are completely unaware of any mechanism other than natural selection. Or, at least, unaware of the fact that it could be important and needs to be part of modern evolutionary theory.

The Modern Synthesis needs to be updated but updated in the manner described by Stephen Jay Gould and not by the Altenberg 16.

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NCSE on the Michael Reiss Affair

 
The National Center for Science Education has issued a press release on the recent resignation of Michael Reiss from his role as Director of Education for the Royal Society of London (UK) [Royal Society furor over creationism].

The NCSE is highly critical of the way Reiss' remarks were misrepresented in the popular press. NCSE is indirectly critical of those Nobel Laureates who called for Michael Reiss to resign based on those false reports in British newspapers.

Under the circumstances, the press release from NCSE is pretty good but it stops short of taking a position. I would have been happier if NCSE had told us their official stance on: (a) whether creationism should be challenged in British schools, (b) whether Michael Reiss should have resigned, and (c) whether it is appropriate for clergy to play a leading role in deciding policies about science and religion in a scientific organization.

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Alex Palazzo Is in Toronto

 
Alex has temporarily suspended blogging on The Daily Transcript because he is Off to Toronto.

We hope he will consider moving here permanently in the very near future. Please help him make up his mind by posting encouraging comments about the Dept. of Biochemistry, the University of Toronto, Toronto, Ontario, and Canada.

Comments about the wonderful weather, the high quality of our undergraduates, the easy access to the downtown core, the outstanding faculty, the high speed internet connection, free health care, Tim Horton's, fabulous research opportunities, lunch at the Faculty Club and anything else that might occur to you, are especially welcome.

Oh, and don't forget to mention that PZ Myers is coming next month!

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Join the Center for Inquiry

 
Center for Inquiry, Ontario
Center for Inquiry, Amherst, N.Y. (headquarters)
Center for Inquiry, Los Angeles
Center for Inquiry, New York City
Center for Inquiry, Tampa
Center for Inquiry, Washington D.C.
Center for Inquiry, Indiana
Center for Inquiry, Austin
Center for Inquiry, San Francisco
Center for Inquiry, Chicago
Center for Inquiry, Michigan

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Richard Dawkins on the Michael Reiss Affair

 
Here's a letter that Richard Dawkins sent to New Scientist [Letter: Richard Dawkins on the Royal Society row

The Reverend Michael Reiss, the Royal Society's Director of Education, is in trouble because of his views on the teaching of creationism.

Although I disagree with him, what he actually said at the British Association is not obviously silly like creationism itself, nor is it a self-evidently inappropriate stance for the Royal Society to take.

Scientists divide into two camps over this issue: the accommodationists, who 'respect' creationists while disagreeing with them; and the rest of us, who see no reason to respect ignorance or stupidity.

The accommodationists include such godless luminaries as Eugenie Scott, whose National Center for Science Education is doing splendid work in fighting the creationist wingnuts in America. She and her fellow accommodationists bend over backwards to woo the relatively sensible minority among Christians, who accept evolution.

Get the bishops and theologians on the side of science – so the argument runs – and they'll be valuable allies against the naive creationists (who probably include the majority of Christians and certainly almost all Muslims, by the way).

No politician could deny at least the superficial plausibility of this expedient, although it is disappointing how ineffective as allies the 'sensible' minority of Christians turn out to be.

The official line of the US National Academy, the American equivalent of the Royal Society, is shamelessly accommodationist. They repeatedly plug the mantra that there is 'no conflict' between evolution and religion. Michael Reiss could argue that he is simply following the standard accommodationist line, and therefore doesn't deserve the censure now being heaped upon him.

Unfortunately for him as a would-be spokesman for the Royal Society, Michael Reiss is also an ordained minister. To call for his resignation on those grounds, as several Nobel-prize-winning Fellows are now doing, comes a little too close to a witch-hunt for my squeamish taste.

Nevertheless – it's regrettable but true – the fact that he is a priest undermines him as an effective spokesman for accommodationism: "Well, he would say that, wouldn't he!"

If the Royal Society wanted to attack creationism with all fists flying, as I would hope, an ordained priest might make a politically effective spokesman, however much we might deplore his inconsistency.

This is the role that Kenneth Miller, not a priest but a devout Christian, plays in America, where he is arguably creationism's most formidable critic. But if the Society really wants to promote the accommodationist line, a clergyman is the very last advocate they should choose.

Perhaps I was a little uncharitable to liken the appointment of a vicar as the Royal Society's Education Director to a Monty Python sketch. Nevertheless, thoughts of Trojan Horses are now disturbing many Fellows, already concerned as they are by the signals the Society recently sent out through its flirtation with the infamous Templeton Foundation.

Accommodationism is playing politics, while teetering on the brink of scientific dishonesty. I'd rather not play that kind of politics at all but, if the Royal Society is going to go down that devious road, they should at least be shrewd about it. Perhaps, rather than resign his job with the Royal Society, Professor Reiss might consider resigning his Orders?

I agree with Dawkins that the position taken by Michael Reiss was not "obviously silly." In fact I think it was a really good idea.

I disagree with Dawkins when he labels Michael Reiss as an "accommodationist."¹ Yes, there's an aspect of accommodation in what Reiss said, but mostly he was saying that we should confront creationist nonsense in class and explain why creationism is not science. To me, those people who want to avoid ever addressing the controversy between science and religion are the accommodationists. They are granting to religion (creationism) a privilege that they would never grant to astrologers, holocaust deniers, and advocates of quack medicine. I hope everyone agrees that the stupidity of those positions should be made clear to our students. Creationism doesn't deserve special treatment just because the basis of the silly belief is religious.

I agree with Dawkins that scientific societies like the Royal Society, the National Academies, AAAS, and even NCSE should not be promoting the false idea that science and religion are always compatible. I find it ironic that some of the same people who were most vehemently opposed to Michael Reiss are strangely silent when American societies jump into bed with religion.

Dawkins worries that forcing Micheal Reiss to resign "comes a little too close to a witch-hunt for my squeamish taste." Perhaps that's how Dawkins feels. Maybe I'm more squeamish than Richard Dawkins because I think it was a witch-hunt and I deplore the actions of some of my fellow scientists.

It will be interesting to see what happens when the witch-hunters turn their attention to the leading religious spokespersons for the National Academies and NCSE. Kenneth Miller, and Francis Collins might find themselves getting fewer speaking engagements. God only knows how they will react when they learn about Francisco Ayala. Ayala is a biologist who Chaired the National Academies Committee on Revising Science and Creationism. That's the group that published the accommodationist book Science, Evolution, and Creationism, a book that promotes the irrational Doctrine of Joint Belief.

According to a report from the University of California, Irvine, where Francisco Ayala is a Professor of Biology, he gave a lecture last May (2008) where he was asked an important question [Biology Professor Addresses Evolution and its Opponents].

When asked if religion should be removed from science courses, Ayala gave a surprising answer.

“Religion is not science, but the fact that science is compatible with religion is an important thing to state in science classes,” Ayala said.

Franscisco Ayala is not only a good biologist, he's also a Dominican priest former Dominican priest. Oops. Can you say "hypocrisy"?

I meant to imply that those who attacked Reiss are hypocrites. Where were they when the National Academies caved in to religion?

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1. John Wilkins addresses this same letter and weighs in against the "accommodationist" charge. Unfortunately, his posting [Dawkins on the nose again] isn't as good as most of what John writes. I'll give him the benefit of the doubt and assume he was under the weather when he wrote it.

Tangled Bank #114

 
The latest issue of Tangled Bank has been published on Sciene Made Cool [The Tangled Bank #114].

Welcome to the #114th edition of the Tangled Bank, a carnival of science bloggers where you’re guaranteed to learn something new and exciting. We’ll start in the classroom, the “traditional” place for learning, ....

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Send an email message to host@tangledbank.net if you want to submit an article to Tangled Bank. Be sure to include the words "Tangled Bank" in the subject line. Remember that this carnival only accepts one submission per week from each blogger.

Nobel Laureate: Otto Warburg

 


The Nobel Prize in Physiology or Medicine 1931.

"for his discovery of the nature and mode of action of the respiratory enzyme"

Otto Heinrich Warburg (1883 - 1970 ) received the Nobel Prize in Physiology or Medicine for his contributions to understanding cellular respiration. At the time he received the Nobel Prize, he was credited with discovering the "respiratory enzyme" and demonstrating that it required iron. The idea was that oxygen binds to iron during respiration in the same way that it binds to iron in hemoglobin. Here's how the discovery was described in the presentation speech on the Nobelprize.org website.

THEME:
Nobel Laureates

Definite proof that he was on the track of this well-hidden secret of Nature was obtained by the use of exact measurements of combustion in living cells or, as Warburg calls it, cell respiration. The quantitatively measured variations in the process of combustion under different conditions threw light on the nature of the respiratory ferment. Its tendency to enter into compounds with substances which combine with iron showed that it is itself an iron compound, and that its effects are due to iron.

We now know that this is incorrect. Warburg probably worked with cytochrome c which has a iron-containing heme group [Monday's Molecule #88] but cytochrome c does not bind oxygen. It is an intermediate in the oxidation-reduction pathway, contributing electrons to cytochrome c oxidase—the real oxygen binding enzyme. Cytochrome c oxidase does have an iron heme group that contributes to oxygen binding but copper atoms are also intimately involved.

This is a case where the Nobel Prize was awarded to the right person for the wrong reasons. Warburg made lots of contributions to biochemistry. He discovered flavin proteins and did seminal work on oxidation-reduction enzymes that use NAD⁺ as a cofactor. He also contributed significantly to our understanding of photosynthesis.

Many people believe that Warburg received a second Nobel Prize in 1944 for these other contributions but he was unable to accept it because Hitler declared that Germans, especially Jewish Germans, could not accept a foreign prize. The Nobel Committee has repeatedly declared that Warbug was not offered the prize in 1944 although he was considered a strong candidate. This declaration has not squelched the myth of two Nobel Prizes—a myth that is largely propagated on cancer websites (e.g., stopcancer.com). Warburg claimed that cancer was caused when cells switched from aerobic glycolysis to fermentation and this has made him a hero among the pseudoscience crowd. That's a tremendous disservice to one of the greatest biochemists who ever lived.

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How RNA Polymerase Binds to DNA

Most cells contain two forms of RNA polymerase. The "core" polymerase is the part that carries out transcription of a gene where the DNA sequence is copied to produce a single-stranded RNA molecule. The core polymerase binds DNA non-specifically as you might expect for a DNA binding protein that has to travel down a large number of different genes.

When transcription is terminated the core RNA polymerase is released. In order to start a new round of transcription, the core RNA polymerase has to be directed to bind at a promoter, defined as the specific DNA sequence where transcription is initiated. There are specific DNA binding factors that bind to promoters and to RNA polymerase. That's how they direct RNA polymerase to the place where transcription has to start. These factors bind first to core polymerase forming the second form of RNA polymerase called the holoenzyme.

The binding parameters of the E. coli core polymerase and the holoenzyme have been studied in detail. In E. coli cells there are several different versions of holoenzyme. Each one contains a different initiation factor that binds to a different series of promoters. The most common initiation factor is called σ⁷⁰ (sigma-70) and it binds to most of the promoters in the cell.

The steps in transcription initiation are shown in the figure. First, holoenzyme consisting of core polymerase + σ⁷⁰, binds non-specifically to any stretch of DNA. It then moves along the DNA in a one-dimensional search until it finds a promoter sequence. This is followed by a local unwinding of the DNA and synthesis of a short piece of DNA.

Subsequent steps (not shown) require the dissociation of the initiation factor (σ⁷⁰) and the formation of an elongation complex. RNA polymerase is then free to leave the promoter region and move down the gene making RNA.

THEME:
Transcription
The same kinds of parameters that we discussed yesterday are used to describe RNA polymerase binding [see DNA Binding Proteins and Repression of the lac Operon]. The core RNA polymerase by itself binds DNA non-specifically with an association, or binding, constant (K_a) of 10¹⁰ M^-1. This is very tight binding for a DNA binding protein. Once bound to DNA the core RNA polymerase dissociates very slowly (t_1/2 = 60 minutes).

The holoenzyme can also bind non-specifically. In this case the association constant is 5 × 10⁶ M^-1 and the complex dissociates rapidly (t_1/2 = 3 seconds). The holoenzyme binds specifically to promoter sequences with an association constant of 2 × 10¹¹ M^-1 and t_1/2 = 2 to 3 hours. Thus, the interaction of the initiation factor with core RNA polymerase has two effects: it decreases the affinity for random stretches of DNA and increases the affinity for the promoter sequence.

A typical E. coli cell contains about 5000 molecules of RNA polymerase. When the cells are growing rapidly, 2500 molecules will be bound to genes in transcription complexes. Another 1250 will be in initiation complexes of various sorts and most of the remaining RNA polymerase molecules (1200) will be bound to DNA non-specifically. Only a small number (~50) will be free in the cytoplasm.

Since the holoenzyme molecules are capable of initiating transcription on their own, a small number of the non-specifically bound molecules will accidentally transcribe short stretches of DNA. These spurious transcripts don't usually cause a problem since they are quite rare. Nevertheless, their presence means that much of the intergenic DNA in the E. coli genome is transcribed at one time or another.

Eukaryotic cells contain three different kinds of RNA polymerases [Eukaryotic RNA Polymerases]. Each one is much more complex that the bacterial enzymes but the principles of transcription initiation are the same.

In eukaryotes there are about a dozen general initiation factors for each of the different RNA polymerases. The ones for RNA polymerase II—the enzyme that transcribes protein-encoding genes—are called transcription factor IID (TFIID) etc. All of the factors are required for specific RNA polymerase binding at a promoter site and all of them associate with the core RNA polymerase to form a large holoenzyme complex. The eukaryotic general initiation factors do the same thing for eukaryotic core polymerase as the bacterial ones do for the bacterial RNA polymerase; they convert the complex to a specific DNA binding protein and lower its affinity for binding non-specifically.

As is the case in bacteria, a substantial number of holoenzyme complexes will be bound non-specifically to DNA at any one time. The proportion is much, much higher in mammalian cells because of the presence of so much junk DNA in the genome. This has the effect of soaking up a lot of holoenzyme complexes.

Since the holenzyme complexes, like those in bacteria, are capable of initiating basal levels of transcription, we should not be surprised to find spurious transciption in all parts of the genome. These transcript will be rare but they will come from any site where RNA polymerase holoenzme can bind.

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Bibliography

Bustamante,C., Guthold,M., Zhu,X., and Yang,G. (1999) Facilitated target location on DNA by individual Escherichia coli RNA polymerase molecules observed with the scanning force microscope operating in liquid. J. Biol. Chem. 274, 16665-16668.
Goodrich,J.A., Cutler,G., and Tjian,R. (1996) Contacts in context: promoter specificity and macromolecular interactions in transcription. Cell 84, 825-830.
Koleske,A.J. and Young,R.A. (1995) The RNA polymerase II holoenzyme and its implications for gene regulation. Trends Biochem. Sci. 20, 113-116.
Myer,V.E. and Young,R.A. (1998) RNA polymerase II holoenzymes and subcomplexes. J. Biol. Chem. 273, 27757-27760.
Ossipow,V., Tassan,J.P., Nigg,E.A., and Schibler,U. (1995) A mammalian RNA polymerase II holoenzyme containing all components required for promoter-specific transcription initiation. Cell 83, 137-146.
Pan,G., Aso,T., and Greenblatt,J. (1997) Interaction of elongation factors TFIIS and elongin A with a human RNA polymerase II holoenzyme capable of promoter-specific initiation and responsive to transcriptional activators. J. Biol. Chem. 272, 24563-24571.
Ricchetti,M., Metzger,W., and Heumann,H. (1988) One-Dimensional Diffusion of Escherichia-Coli Dna-Dependent Rna-Polymerase - A Mechanism to Facilitate Promoter Location. Proceedings of the National Academy of Sciences of the United States of America 85, 4610-4614.
Shimamoto,N. (1999) One-dimensional diffusion of proteins along DNA. Its biological and chemical significance revealed by single-molecule measurements. J. Biol. Chem. 274, 15293-15296.
Singer,P. and Wu,C.W. (1987) Promoter search by Escherichia coli RNA polymerase on a circular DNA template. J. Biol. Chem. 262, 14178-14189.
Singer,P.T. and Wu,C.W. (1988) Kinetics of promoter search by Escherichia coli RNA polymerase. Effects of monovalent and divalent cations and temperature. J. Biol. Chem. 263, 4208-4214.
von Hippel,P.H. (2007) From "simple" DNA-protein interactions to the macromolecular machines of gene expression. Annual Review of Biophysics and Biomolecular Structure 36, 79-105.
von Hippel,P.H. and Berg,O.G. (1989) Facilitated target location in biological systems. J. Biol. Chem. 264, 675-678.

Genetics and Race

 
John Hawks has some interesting things to say about genetics and race based on a New York Times article about David Goldstein. The article can be found at: A Dissenting Voice as the Genome Is Sifted to Fight Disease, and the Hawks' posting is at: David Goldstein profile.

Scientists are discovering more and more genetic differences between human races and this is starting to cause some problems as described in the New York Times article ...

Another pursuit that interests him, one of high promise for reconstructing human evolutionary history, is that of discovering which genes bear the mark of recent natural selection. When a new version of a gene becomes more common, it leaves a pattern of changes that geneticists can detect with various statistical tests. Many of these selected genes reflect new diets or defenses against disease or adaptations to new climates. But they tend to differ from one race to another because each human population, after the dispersal from Africa some 50,000 years ago, has had to adapt to different circumstances.

This newish finding has raised fears that other, more significant differences might emerge among races, spurring a resurrection of racist doctrines. “There is a part of the scientific community which is trying to make this work off limits, and that I think is hugely counterproductive,” Dr. Goldstein said.

John Hawks is an expert in these kinds of studies so it's interesting to read his comments. Note that there's no disagreement over the facts; races are genetically different. I disagree with Hawks and Goldstein on the cause of some of this variation. In my opinion they are placing too much emphasis on selection as the cause of variation between species and not enough emphasis on chance. Differences in ABO blood type frequencies, for example, are probably not due to selection.

At the end of his posting Hawks mentions a quotation from Theodosius Dobzhansky. This is a quotation that everyone should keep in mind as they enter the debate. You can find out more by reading a 2006 posting about Dobzhansky on continuing human evolution. Here's the actual Dobzhansky quotation from that posting ...

The chief reasons why so many people are loath to admit the genetic variability of socially and culturally significant traits are two. First, human equality is stubbornly confused with identity, and diversity with inequality, as though to be entitled to an equality of opportunity, people would have to be identical twins. Human diversity is not incompatible with equality. Secondly, it is futile to look for one-to-one correspondence between cultural forms and genetic traits. Cultural forms are not determined by genes, but their emergence and maintenance are made possible by the genetically conditioned human diversity

Let me sound a note of caution to those who wish to comment. The fact that humans races might be genetically different says absolutely nothing at all about equality and racism. For this thread only, I will delete any comments where the author is confused about this distinction. This is a discussion about science and whether some scientific investigations should be censored because they might be misinterpreted.

Hawks doesn't allow comments on his blog. This is such an interesting topic that I thought I'd mention it here to get some feedback.

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[Image Credit: The image is obviously the cover of Scientific American from December 2003. This is one of the most blatant examples of political correctness ever published in a prestigious journal and it's one more example of the decline of Scientific American. It doesn't take much to recognize that the faces on the cover are identical except for skin color. As if that's all there is to human populations.]

DNA Binding Proteins

Proteins that bind to DNA can be divided into two groups: those that bind to a specific DNA sequence and those that bind non-specifically. Proteins in the latter category include those required for DNA replication, repair, and recombination, as well as packaging proteins like the histones.

Proteins that bind to specific DNA sequences are often activators or repressors involved in regulating gene expression. These are proteins that interact with a short, well-defined, nucleotide sequence found near the start site for transcription. The purpose of this posting is to review some of the basic characteristics of such proteins using lac repressor as a well studied example.

The figure below shows the structure of a lac repressor dimer bound to DNA.


The rate and strength of binding of lac repressor to DNA has been the subject of many papers over the course of several decades. Lac repressor binds tightly to a specific DNA sequence at the beginning of the lac operon. When it is bound to DNA it prevents, or represses, transcription of the operon.

Now, here's the important point: all specific DNA binding proteins also bind DNA non-specifically. In many cases it's part of the search mechanism for the specific binding site. In the case of lac repressor, for example, the protein binds to any old place on the DNA molecule and slides along the DNA searching for a specific binding sequence. After sliding for a second or so it falls off and re-binds to another part of the DNA molecule.

Once the repressor finds its specific binding site it remains bound for about twenty minutes. In biochemical terms we say that it's bound half-life is 20 minutes. The strength of binding is described by an equilibrium binding constant (K_B) that reflects the ratio of free repressor to bound repressor. For lac repressor the binding constant is one of the highest measured for any DNA binding protein (= 10¹³ M^-1). What this means is that lac repressor binds very tightly to its specific binding site.

The equilibrium binding constant for non-specific binding is only 4 × 10⁴ M^-1. Thus, repressor binds nearly one billion (10⁹) times more strongly to its specific binding site than to any old stretch of DNA. That's very impressive. In fact, it's one of the largest differences known for any DNA binding protein. When bound non-specifically the half-life is measured in seconds. It falls off (dissociates) rapidly.

These measurements have interesting consequences. There are about ten repressor molecules in each cell (E. coli). At any given time one of them will almost certainly be at its binding site near the lac operon but the other nine will be bound to DNA somewhere else. There are millions of places where the repressor can bind non-specifically but only one where it can bind specifically.¹

Some of these non-specific binding sites will, by chance, resemble the sequence of the specific binding site so lac repressor will linger longer at those sites than at sites that are completely unrelated to the specific binding sites. The point is that even for a highly specific DNA binding protein like lac repressor, most of the protein is bound to other sites most of the time.

For lac repressor, this fundamental property doesn't have serious consequences but for activators it's a different story. An activator is a protein that binds near a gene and recruits RNA polymerase to the site where it can begin transcription. Since most activators will be bound to random DNA sequences most of the time, the chances of accidentally recruiting RNA polymerase to begin a spurious transcript are quite high. From what we know about basic biochemistry, we expect that random spurious transcription should be quite common.

Tomorrow we'll look at RNA polymerase binding in the presence and absence of a specific DNA binding activator.

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1. The specific binding sites are called operators. There are actually three different operator sequences to which lac repressor can bind but that doesn't make much different for the point I trying to make.

Random Genetic Drift Simulator

 
Here's a nice Java applet from Kent Holsinger at the University of Connecticut [Genetic Drift]. Thanks to Pascal for the link.

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It's the Leader, Stupid

 
Canada is in the middle of a federal election and the Liberal Party under Stéphane Dion is going to lose a lot of seats. The losses may even be enough to give our current Prime Minister, Stephen Harper of the Conservative Party, a majority.

This is not an election about the economy. It's not about Canada's foreign policy. It's not about the environment and the carbon tax of the Liberal party. It's not about health care and it's not about education.

It's about leadership. Stéphane Dion does not inspire confidence and a lot of Liberal supporters, including me, can't bring themselves to vote for him. We want him to resign as soon as possible and we're willing to vote for someone else in order to make sure that Dion gets the message.

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