How Penicillin Works to Kill Bacteria

 
Bacterial cell walls are made of peptidoglycan [Bacteria Have Cell Walls]. In order to form a rigid structure, the polysaccharide chains (glycans) are linked together by peptide crosslinks. The first step in the formation of the crosslinks involves attachment of a short five residue peptide to the MurNAc sugar in the polysaccharide. This peptide ends in two D-Alanine (D-Ala) residues.

This peptide is further modified by attaching an additional peptide to the middle of the first one creating a branched structure. Finally the peptide of one of the polysaccharide molecules is attached to another to form the crosslink. The reaction is a transpeptidase reaction.

The mechanism is shown in the figure (Lee et al. 2003). The top structure (1) is a polysaccharideMurNAc-GlcNAc) with the first peptide already bound. Note that it ends in two D-Ala residues. The first step in the transpeptidase reaction involves binding of the enzyme (Enzyme-OH) to the D-Ala-D-Ala end of the chain. A reaction takes place in which one of the D-Alanine residues is released and the enzyme become attached to the end of the peptide (2).

In the second step, an adjacent peptidoglycan (purple) (3) with a branched structure is covalently linked to the first peptidoglycan forming a crosslink between the two polysaccharides.

Almost all bacteria have cell walls and they have transpeptidase enzymes that catalyze this reaction. The activity of this enzyme is inhibited by penicillins or β-lactams. Mondays Molecule #30 was Penicillin G, one of many different types of β-lactam that block cell wall formation and kill bacteria.

The mechanism of inhibition is well known. The β-lactam region of the drug resembles the D-Ala-D-Ala end of the peptide to which the transpeptidase enzyme binds. The structures are shown below.


A typical penicillin is shown at the top of the figure. The business part of the molecule is the β-lactam moiety and the "R" represents various groups that can be bound to create different penicillin drugs. The structure of D-Ala-D-Ala is shown below.

The structures of several different transpeptidases have been solved. The enzymes are usually called penicillin-binding proteins or PBP's. Most bacteria have several related versions of PDB genes but all of the enzymes are inhibited by β-lactams.

The figure shows the structure of penicillin-binding protein 1a (PBP1a) from Streptococcus pneumoniae with the bound drug in gray in the grove in the lower right corner of the enzyme (Contreras-Martel et al. 2006). This form of the enzyme is inactive because the drug binds very tightly to the active site and blocks the reaction. That's how penicillin works.

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Contreras-Martel, C., Job, V., Di Guilmi, A.M., Vernet, T., Dideberg, O. and Dessen, A. (2006) Crystal structure of penicillin-binding protein 1a (PBP1a) reveals a mutational hotspot implicated in beta-lactam resistance in Streptococcus pneumoniae. J. Mol. Biol. 355:684-96.


Lee, M., Hesek, D., Suvorov, M., Lee,W., Vakulenko, S. and Mobashery, S. (2003) A mechanism-based inhibitor targeting the DD-transpeptidase activity of bacterial penicillin-binding proteins. J. Am. Chem. Soc. 125:16322-16326.

Bacteria Have Cell Walls

 
Most species of bacteria have a cell wall. The rigid cell wall prevents the bacterial cell from expanding in solutions where the salt concentrations are lower than the salt concentration inside the cell. If it wasn't for the cell wall, bacteria wouldn't be able to live in fresh water or sea water.

Gram positive bacteria have a thick cell wall on the exterior that picks up the purple Gram stain (named after Hans Christian Gram). Gram negative bacteria, such as the E. coli cell shown in the figure, do not stain with the dye because the thinner cell wall lies between the inner and outer membranes.

The cell wall is made up of peptidoglycan, which, as the name implies, is a combination of polysaccharide (glycan) and peptides. The polysaccharide consists of alternating N-acetylglucosamine (GlcNac) and N-acetylmuramic (MurNAc) resides [see Glycoproteins].


During cell wall synthesis a short peptide of five amino acid residues is attached to the polysaccharide. The sequence of this peptide varies slightly from species to species. In some gram negative bacteria the sequence is L-alanine- D-isoglutamate- L-lysine- D-alanine- D-alanine. These short chains are linked to each other by another peptide consisting of five glycine residues. When the cross-links are formed, the terminal D-alanine residue is cleaved off so the final structure has only a single D-alanine at the end. (The significance of this cleavage will become apparent in subsequent postings.)


The completed peptidoglycan cell wall is extremely rigid because of the peptide crosslinks between the polysaccharide chains. In the figure above, the original peptide chain is colored blue and the second pentaglycine peptide is colored red. The right end of the red pentaglycine is covalently attached to the blue D-alanine residue at the bottom of an adjacent polysaccharide chain as shown in the cartoon in the upper right corner of the figure.

Does Politics Influence When Scientific Papers Are Published?

 
I'm told that the American House of Representatives is considering a bill that will allow embryonic stem cell research. Matt Nisbet thinks that the recent publication of three papers on stem cell research [Reprogramming Somatic Cells] may have been timed to correspond with this debate in the US Congress [Understanding the political timing of stem cell studies]. Nisbet quotes from an article by Rick Weiss in the Washington Post [Darn Cells. Dividing Yet Again!]. Here's what Weiss says,

Thursday, June 7. After months of intense lobbying by scientists and patient advocacy groups, the House is ready to vote on legislation that would loosen President Bush's restrictions on the use of human embryos in stem cell research. But that very morning, the lead story in every major newspaper is about research just published in a British journal that shows stem cells can be made from ordinary skin cells.

The work was in mice, but the take-home message that suffuses Capitol Hill is that there is no need to experiment on embryos after all.

If that doesn't sound suspicious, consider this:

Monday, Jan. 8. After months of intense lobbying by scientists and patient advocacy groups, Congress is ready to vote on legislation that would loosen Bush's restrictions on stem cell research. But that very morning, newspapers are touting new research just published in a British journal suggesting that stem cells can be made from easily obtained placenta cells. No need for embryos after all!

Is there a plot afoot?

Lots of lobbyists, members of Congress and even a few scientists are starting to think so.

"It is ironic that every time we vote on this legislation, all of a sudden there is a major scientific discovery that basically says, 'You don't have to do stem cell research,' " Democratic Caucus Chairman Rahm Emanuel (Ill.) sputtered on the House floor on Thursday. "I find it very interesting that every time we bring this bill up there is a new scientific breakthrough," echoed Rep. Diana DeGette (D-Colo.), lead sponsor of the embryo access bill. Her emphasis on the word "interesting" clearly implies something more than mere interest.

"Convenient timing for those who oppose embryonic stem cell research, isn't it?" added University of Pennsylvania bioethicist Arthur Caplan in an online column. (The bill passed easily, but not with a margin large enough to override Bush's promised veto.)

Hmmm ... let's see if we can figure out what's going on here. Apparently there's some vast conspiracy afoot to keep the American ban on embryonic stem cell research in place. The idea is that scientists and the editors of Nature (for example) want to publish key papers about alternatives to embryonic stem cell research just when American politicians are about to vote on a bill to lift the ban.

The conspiracy makes several key assumptions. It assumes that the editors of the British journal Nature knew about the American bill back on May 22nd when they accepted the two papers. That's when the decision to publish on line for June 6th was taken (the two week delay between acceptance and online publication is typical). It assumes, therefore, that the acceptance date was juggled to meet the target date of June 6th—assuming that the editors even knew, or cared, about what was going on in Washington D.C. (USA). Presumably the acceptance date was delayed somewhat in order to fix the timing. One assumes that the group in Japan who published one of the papers had no problem with this delay and nor did the scientists in Boston. The papers were extremely important in a competitive field but, hey, anything can wait for American politics, right?

Harvard risk expert David Roepik and Temple mathematician John Allan Paulos are skeptical about the conspiracy theory with good reason. The whole idea is ludicrous but that doesn't stop Matt Nisbet from suggesting that it's true. Here's what Nisbet says,

Still, something more than just coincidence is likely to be going on here. Roepik and Paulos' arguments innocently assume that publication timing at science journals is random, without systematic bias. But journal editors, just like news organization editors and journalists, are subject to various biases, many of them stemming from the fact that they work within a profit-driven organization that has to keep up a subscriber base and play to their audience.

Peer-review is just one of the many filtering devices that scientific research goes through. Certainly many papers make it through peer-review based on technical grounds, but then editors at the elite journals, faced with limited space and the need to create drama and interest among subscribers and news organizations, apply more subjective criteria based on what they believe to be the "scientific newsworthiness" of the research. In other words, how much interest among the scientific community will these papers generate AND how much news attention?

Still, Nisbet isn't quite as paranoid and confused about the process as Rick Wiess. In the Washington Post article he says,

Then there is the question of motive. The Brits are competing against Americans in the stem cell field and are legally allowed to conduct studies on embryos. Might they be aiming to dominate the field by helping the conservative and religious forces that have so far restricted U.S. scientists' access to embryos?

Or might the journals be trying, as one stem cell expert opined on the condition of anonymity, to leverage their visibility by publishing stem cell articles just as Congress is voting on the topic?

Damn Brits. :-)

In fairness, Weiss includes a disclaimer from the editors of Nature,

"Nature has no hidden agenda in publishing these papers," said the journal's senior press officer, Ruth Francis, in an e-mail. The real goal was to get the papers out before a big stem cell conference in Australia next week, she said.

More significantly, Weiss includes a comment from someone who seems to have hit the nail on the head,

To Ropeik, the Harvard risk expert, the fact that people are imputing anything more than sheer coincidence is "just more proof that inside the Beltway the thinking is so myopic. They see the whole world through their own lens, and are blinded" to common sense.

That sounds about right to me. If you live in Washington you start to think that the whole world revolves around the White House and Congress. It's easy to believe that everything has to be spun framed in order to influence American politicians—even the timing of publication of scientific papers by a prominent British journal.

Monday's Molecule #30

 
Today's molecule looks complicated but it has a very simple, and well-known, name. We need the correct common name and the long systematic (IUPAC) name.

As usual, there's a connection between Monday's molecule and this Wednesday's Nobel Laureate(s). This one is an obvious direct connection. Once you have identified the molecule the Nobel Laureate(s) are obvious.

The reward (free lunch) goes to the person who correctly identifies the exact molecule with the correct formal name and the Nobel Laureate(s). Previous free lunch winners are ineligible for one month from the time they first collected the prize. There are no ineligible candidates for this Wednesday's reward since recent winners have declined the prize on the grounds that they live in another country and can't make it for lunch on Thursday (a feeble excuse, in my opinion).

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

Was Bertrand Russell an Atheist or an Agnostic?

John Wilkins has posted an article on whether Bertrand Russell was an agnostic or an atheist [What is an Agnostic? by Bertrand Russell]. John links to an essay by Russell where he defines agnostic as,

An agnostic thinks it impossible to know the truth in matters such as God and the future life with which Christianity and other religions are concerned. Or, if not impossible, at least impossible at the present time.

This is a definition we can all agree on. I am an agnostic, as is John Wilkins and Richard Dawkins.

Bertrand Russell goes on to define atheist as,

An atheist, like a Christian, holds that we can know whether or not there is a God. The Christian holds that we can know there is a God; the atheist, that we can know there is not.

This is not correct. There are many people who have decided not to believe in Gods and they live their lives as if there were no Gods. However, they do not maintain that the nonexistence of Gods is known for certain. They believe that that it's impossible to prove a negative. These people call themselves atheists and they think that this is true to the original root meaning of the word ("not a theist"). Many of us are atheists and agnostics.

Russell knows that there is a difference between the philosophical concept of being unable to prove a negative and the practical, day-to-day, behavior of believers and non-believers. In another essay (Am I An Atheist Or An Agnostic?) he says,

Here there comes a practical question which has often troubled me. Whenever I go into a foreign country or a prison or any similar place they always ask me what is my religion.

I never know whether I should say "Agnostic" or whether I should say "Atheist". It is a very difficult question and I daresay that some of you have been troubled by it. As a philosopher, if I were speaking to a purely philosophic audience I should say that I ought to describe myself as an Agnostic, because I do not think that there is a conclusive argument by which one prove that there is not a God.

On the other hand, if I am to convey the right impression to the ordinary man in the street I think I ought to say that I am an Atheist, because when I say that I cannot prove that there is not a God, I ought to add equally that I cannot prove that there are not the Homeric gods.

None of us would seriously consider the possibility that all the gods of homer really exist, and yet if you were to set to work to give a logical demonstration that Zeus, Hera, Poseidon, and the rest of them did not exist you would find it an awful job. You could not get such proof.

Therefore, in regard to the Olympic gods, speaking to a purely philosophical audience, I would say that I am an Agnostic. But speaking popularly, I think that all of us would say in regard to those gods that we were Atheists. In regard to the Christian God, I should, I think, take exactly the same line.

There is exactly the same degree of possibility and likelihood of the existence of the Christian God as there is of the existence of the Homeric God. I cannot prove that either the Christian God or the Homeric gods do not exist, but I do not think that their existence is an alternative that is sufficiently probable to be worth serious consideration. Therefore, I suppose that that on these documents that they submit to me on these occasions I ought to say "Atheist", although it has been a very difficult problem, and sometimes I have said one and sometimes the other without any clear principle by which to go.

When one admits that nothing is certain one must, I think, also admit that some things are much more nearly certain than others. It is much more nearly certain that we are assembled here tonight than it is that this or that political party is in the right. Certainly there are degrees of certainty, and one should be very careful to emphasize that fact, because otherwise one is landed in an utter skepticism, and complete skepticism would, of course, be totally barren and completely useless.

Bertrand Russell was not a Christian as the essays in his book, Why I Am Not a Christian demonstrated. Some of these essays lead to a famous court case in 1940 where Russell was declared unfit to teach at City College because his moral views were too permissive.

Above all, Russell was a rationalist who opposed superstition. His views on religion, written back in 1927, still sound familiar today.

Religion is based, I think, primarily and mainly upon fear It is partly the terror of the unknown and partly, as I have said, the wish to feel that you have a kind of elder brother who will stand by you in all your troubles and disputes. Fear is the basis of the whole thing—fear of the mysterious, fear of defeat, fear of death. Fear is the parent of cruelty, and therefore it is no wonder if cruelty and religion have gone hand in hand. It is because fear is at the basis of these two things. In this world we can now begin a little to understand things, and a little to master them by the help of science, which has forced its way step by step against the Christian religion, against the churches, and against the opposition of all the old precepts.

Science can help us get over this craven fear in which mankind has lived for so many generations. Science can teach us, and I think our own hearts can teach us, no longer to look around for imaginary supports, to longer to invent allies in the sky, but rather to look to our own efforts here below to make this world a fit place to live in, instead of the sort of place that the churches in all these centuries have made it.

The Ethics of Stem Cell Research

 
Arthur Caplan is the director of the Center for Bioethics at the University of Pennsylvania. He was written an article on the MSNBC website that addresses the new work on reprogramming cells to produce totipotent stem cells [Does stem cell advance provide an ethical out?].

He claims that the new work will not replace conventional creation of embryonic stem cell lines using embryos because the new procedure has only been shown to work in mice and because it involves retrovirus vectors. This may be true, although Rudi Jaenisch seems to be more optimistic [see Reprogramming Somatic Cells].

I'm interested in another part of Caplan's essay where he says,

As much as critics of this field of research would like to have you believe that human embryos in dishes are people, that moral argument is not compelling.

Human embryos in dishes are not people or even potential people. They are, at best, possible potential people.

Frozen embryos in infertility clinics face a fate of certain destruction anyway. The moral case against using them, or cloned embryos, which have almost zero chance of becoming people, is no less compelling because progress has been made in another area of research.

The existence of a new way to perhaps make embryonic-like stem cells is not enough to make frozen embryos and cloned embryos off-limits for American scientists or for research relying on federal funds.

Those in favor of human embryonic stem cell research, and that is the majority of Americans according most polls, including one done by CNN just last month, do not have to change their minds about the morality of such research even when another avenue for creating embryonic-like cells is found in mice.

What Caplan fears is that those who are opposed to destroying embryos will use this new work to reinforce their opinion that a ban must be enforced. This is almost certainly correct but there's little that he can do to change their minds.

What puzzles me is that Caplan argues the case that these embryos are not humans—in fact they are not even "possible potential" humans. This seems to be typical of the sort of debate that passes for ethics these days. I don't get it.

For those of us who are pro-abortion the argument makes no sense at all. We are already committed to the concept that real potential humans can be destroyed so the destruction of earlier stages poses no problem whatsoever. We simply don't care to debate whether embryos at the pre-blastula stage are human or not since the decision has no bearing on whether they should be destroyed.

For those who oppose abortion, and the destruction of embryos, the declaration that they are not even "possible potential" humans rings hollow. For them, the issue is not going to be settled by scientists. If it were, it would not be an "ethical" issue at all but a simple scientific problem. For many of them the facts are quite obvious. God created man and woman to make babies and any direct interference in that process is an attempt to disrupt the process that God intended.

This is a group who distrust scientists from the get-go. The idea that they are going to allow men in white lab coats to poke at human embryos just in order to advance their careers is a non-starter. Remember, most of this group doesn't even believe in evolution or a 4.5 billion year old Earth. Why should they believe what scientists have to say about embryos?

So what's the point of making the argument about the "humanness" of embryos, especially from someone who is director of bioethics at a major university? Who is he trying to convince, George Bush? Where are Mooney and Nisbet when we need them? Caplan needs a lesson on spin framing.

I have recently discovered that there are many moral realists in philosophy departments. This group believes that there is an underlying "truth" behind every ethical problem and it is the goal of ethical reasoning to discover this "truth." I wonder what the "truth" is about destroying embryos in order to create stem cells? I would have thought that the definition of moral truth depends on your cultural/religious background but I'm told that this "ethical relativism" is very much a minority position among philosophers.

[Hat Tip: Shalini at Scientia Natura: Stem cell breakthrough]

Still Banned From Uncommon Descent

 
Poor old DaveScott. Like GilDodgen he's very confused about the evolution of topoisomerases [A Dynamic Fitness Landscape]. He posted the same video they've been confused about for several months and asked if someone could explain it to him. I tried to post a comment to help him out since he really needs it. I linked to my earlier posting [A State of Extreme Cognitive Dissonance].

My comment never got published on the blog. I guess like most IDiots he doesn't want my help.

Reprogramming Somatic Cells

 
There were three papers published this week that showed how to reprogram somatic cells so they could act like embryonic stem cells (Maherali et al., 2007; Okita et al., 2007; Wernig et al., 2007). The trick is to introduce genes for four different transcription factors into the somatic cells (e.g., skin cells). When the four transcription factors (Oct4, Sox2, c-Myc, and Klf4) are made they turn on genes in the somatic cell that cause it to reprogram and become competent to differentiate into any other type of cell, including germ cells.

The experiments were performed in mice and they are based on the work of Takahashi and Yamanaka (2006). The interesting thing about this experiment is that it achieves a goal that most scientists expected; namely, the ability to reprogram cells by changing the pattern of gene expression. This goal was achieved less than two years after Science magazine asked two so-called "fundamental" questions in their July 2005 issue [SCIENCE Questions: How Does a Single Somatic Cell Become a Whole Plant? and SCIENCE Questions: How Can a Skin Cell Become a Nerve Cell?]. What it reveals is that the editors of Science were out of touch with the scientific community. These were not significant questions. The solution was known it was just a matter of finding out which transcription factors were required.

Here's a short video where Rudi Jaenisch explains the significance of his work. I think it represents good science communication from a scientist. What do you think?

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Maherali, N., Sridharan, R., Xie, W., Utikal, J., Eminli, S., Arnold, K., Stadtfeld, M., Yachechko, R., Tchieu, J., Jaenisch, R., Plath, K. and Hochedlinger, K. (2007) Directly Reprogrammed Fibroblasts Show Global Epigenetic Remodeling and Widespread Tissue Contribution. Cell: Stem Cell 1: 55-70.

Okita, K., Ichisaka, T. and Yamanaka, S. (2007) Generation of germline-competent induced pluripotent stem cells. Nature advance online publication 6 June 2007 | doi:10.1038/nature05934

Takahashi, K. and Yamanaka, S. (2007) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676.

Wernig, M., Meissner, A., Foreman, R., Brambrink, T., Ku, M., Hochedlinger, K., Bernstein, B.E. and Jaenisch, R. (2007) In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature advance online publication 6 June 2007 |doi:10.1038/nature05944

[Hat Tip: Alex Palazzo for the video [Rudy Jaenisch on Stem Cells] and for alerting us in advance to watch for exciting news]

USA TODAY/Gallup Poll on Evolution

 
Check out the USA Today website for information on the latest poll [USA TODAY/Gallup Poll results].

Let's look at the result of two questions on Creationism and Evolution.

23. Next, we'd like to ask about your views on two different explanations for the origin and development of life on earth. Do you think -- [ITEMS ROTATED] -- is -- [ROTATED: definitely true, probably true, probably false, (or) definitely false]?

A. Evolution, that is, the idea that human beings developed over millions of years from less advanced forms of life

B. Creationism, that is, the idea that God created human beings pretty much in their present form at one time within the last 10,000 years

The interesting thing about these results is that only 18% think that evolution is a fact and only 15% believe that a 6000 year old Earth is definitely false. That's pretty frightening if you think about it.

But here's something even more puzzling.

24. How familiar would you say you are with each of the following explanations about the origin and development of life on earth -- very familiar, somewhat familiar, not too familiar, or not at all familiar? How about -- [ITEMS ROTATED]?

A. Evolution

Almost everyone (82%) thinks they understand evolution well enough to have an opinion. They're almost certainly wrong.

It shows us where we need to start. We need to get out the message that evolution is a scientific fact and that evolutionary theory is complicated enough that it requires some study in order to get the basic concepts down pat. Before we can teach we have to convince people that they need to learn.

I wonder how many of the people who think that evolution is true actually understand it?

I Knew It: There Can Be More than One Solution to a Sudoku Puzzle!

 
A recent article by Agnes M. Herzberg and M. Ram Murty in the Notices of the American Mathematical Society confirms what many of us have known for years: there's more than one way to solve a Sudoku puzzle. Unfortunately, most of them are still wrong [Sudoku Squares and Chromatic Polynomials].

However—and here's the encouraging part—there are sometimes more than one right answer. The puzzle shown on the right is an example. Try it. (Answer below.)

There are two different ways to fill in the blank cells. Both of them are valid solutions.

I've always thought that the Sudoku puzzles were more like logic puzzles than mathematical puzzles and the article confirms that impression. The puzzles can be solved using colors instead of numbers. Here's what the authors say about the popularity of these puzzles.

It is interesting to note that the Sudoku puzzle is extremely popular for a variety of reasons. First,it is sufficiently difficult to pose a serious mental challenge for anyone attempting to do the puzzle. Secondly, simply by scanning rows and columns, it is easy to enter the “missing colors”, and this gives the solver some encouragement to persist. The novice is usually stumped after some time. However, the puzzle can be systematically solved by keeping track of the unused colors in each row, in each column, and in each sub-grid. A simple process of elimination often leads one to complete the puzzle. Some of the puzzles classified under the “fiendish” category involve a slightly more refined version of this elimination process, but the general strategy is the same. One could argue that the Sudoku puzzle develops logical skills necessary for mathematical thought.

How many of you are hooked?

A Warning to Our American Guests

 
Canadian Cynic has just alerted me to a problem that could get my American friends in big trouble when they come for my daughter's wedding in a few weeks [ You keep using that word "democracy" ...]. The problem is explained by Ed Brayton over on Dispatches from the Culture Wars [No Cuban Cigars Abroad Too?].

You see, the American government is very, very afraid of Fidel Castro. They're certain that he is about to subvert Americans and turn them all into (gasp!) socialists. In order to prevent any contamination, all Americans are forbidden to visit Cuba or to buy any Cuban products. This does not only apply in the USA but in other countries as well.

Yep, that means Canada. Americans can't smoke Cuban cigars in Canada and they can't drink Cuban rum either. So be careful my friends. Your government may throw you in jail if you don't specify non-Cuban rum at the bar. (I'll never tell.) Many of the Canadian guests will have vacationed in Cuba last winter. You better not talk to them.

Here's the specific regulation copied from Ed's blog.

The question is often asked whether United States citizens or permanent resident aliens of the United States may legally purchase Cuban origin goods, including tobacco and alcohol products, in a third country for personal use outside the United States. The answer is no. The Regulations prohibit persons subject to the jurisdiction of the United States from purchasing, transporting, importing, or otherwise dealing in or engaging in any transactions with respect to any merchandise outside the United States if such merchandise (1) is of Cuban origin; or (2) is or has been located in or transported from or through Cuba; or (3) is made or derived in whole or in part of any article which is the growth, produce or manufacture of Cuba. Thus, in the case of cigars, the prohibition extends to cigars manufactured in Cuba and sold in a third country and to cigars manufactured in a third country from tobacco grown in Cuba.

Atheist Books Are Bestsellers

 
Publishers Weekly has an article on books about atheism [Believe It or Not]. They report on the number of copies of these books that have been sold. Here's the summary complied by Friendly Atheist [How Well Are the Atheist Books Selling?].

• The God Delusion by Richard Dawkins: 282,000 copies sold
• The End of Faith by Sam Harris: 250,000 copies sold (says this article)
• Letter to a Christian Nation by Sam Harris: 123,000 copies sold
• God is Not Great by Christopher Hitchens: 58,000 copies sold
• Breaking the Spell by Daniel Dennett: 52,000 copies sold
• God: The Failed Hypothesis by Victor Stenger: 60,000 copies shipped

These are impressive numbers, especially since the soft cover editions aren't out yet.

In case you're thinking about trying to make a living writing books like these, consider that the author gets about $2 per book. There are considerable expenses that need to be covered by that royalty payment so, in most cases, the net income isn't enough to induce you to quit your day job.

Charles Darwin Was a Gradualist

 
Punctuated Equilibria refer to patterns of evolution characterized by long periods of stasis interrupted by shorter periods of evolutionary change. The changes are associated with speciation events where a new, changed, species splits off from the parental, unchanged, species. This is speciation by cladogenesis (splitting) as opposed to anagenesis, where a single species changes gradually into something different without splitting.

Stephen Jay Gould wrote a massive book on macroevolutionary theory that featured punctuated equilibria and its consequences such as species sorting. The original book was called The Structure of Evolutionary Theory. It's 1433 large pages long. Few people have read the entire thing. I am one.

Recently, the publishers of The Structure of Evolutionary Theory (Belknap Press of Harvard University Press) have brought out a new book by Stephen Jay Gould—a remarkable achievement since Gould died in 2002. As it turns out, the new book Punctuated Equilibrium, is just chapter nine of the large book; a 279 page chapter called Punctuated Equilibrium and the Validation of Macroevolutionary Theory. PZ Myers reviewed this book for New Scientist a few weeks ago [Punctuated Equilibrium by Stephen Jay Gould].

One of the significant impacts of Punctuated Equilibrium is the emphasis on episodic change rather than the gradualism that was so commonly believed to be the main pattern in evolution. Eldredge and Gould explain why gradualism was such a prominent part of evolutionary theory before punctuated equilibrium came along. Gould has extended that explanation in Structure and in numerous essays.

Gould points out that Charles Darwin was a firm believer in gradualism. Indeed, it was an essential component of Darwin's defense of evolution and his promotion of natural selection. Darwin's gradualism arose from his commitment to the uniformitarianism of Lyell and his emphasis on the vast age of the Earth. According to Gould there are several different meanings of gradualism but the one that conflicts with punctuated equilibria is the idea that change must be gradual at geological scales.

This is why Darwin said that nature does not proceed by leaps and it's why Darwin postulated that gaps in the fossil record were due to lack of data.

PZ Myers noted this in his review when he said,

Gould and Eldredge proposed punctuated equilibrium as a paleontologist's view of the history of life: they were describing the paleontological data available at the time pointing out that there was no geological evidence to support Charles Darwin's belief that species evolved gradually. Time has shown them to be correct, and their observations are now accepted by most biologists as a accurate account of evolutionary history.

Now, PZ is no dummy. He's been around the blogosphere and newsgroups long enough to know that calling Darwin a gradualist is like waving a red flag in front of a bull. There's a large group of Darwin apologists out there who will do anything to prove that Charles Darwin was right about everything, even if is has to be proved retrospectively (i.e., somehow we didn't notice that Darwin believed in punctuated equilibrium until 1972).

The first salvo was fired in the letters column in this week's issue of New Scientist. Wayne Bagguley writes,

I am shocked that someone as knowledgeable as P.Z. Myers is promoting the age-old myth about "Charles Darwin's belief that species evolved gradually" without periods of stasis. In On the Origin of Species Darwin wrote "Although each species must have passed through numerous transitional stages, it is probable that the periods, during which each underwent modifications, though many and long as measured by years, have been short in comparison with the periods which each remained in an unchanged condition. These causes, taken conjointly, will to a large extent explain why—though we do not find many links—we do not find interminable varieties connecting together all extinct and existing forms by the finest graduated steps."

Stephen Jay Gould is no dummy. As an expert on Darwin and the history of biology you can be sure that he's heard these complaints before. You can be certain that Gould has addressed them numerous times.

The longest, and best, defense of Darwin's gradualism can be found in chapter 2 of Structure. This is a 76 page chapter titled "The Essence of Darwinism and the Basis of Modern Orthodoxy." I'm sure PZ Myers has read this chapter and that's why he said what he said. Gould makes the point that,

SInce Darwin prevails as the patron saint of our profession, and since everyone wants such a preeminant authority on their side, a lamentable tradition has arisen for appropriating single Darwinian statements as defenses for particular views that either bear no relation to Darwin's own concerns, or that even confute the general tenor of his work.... I raise this point here because abuse of selective quotation has been particularly notable in discussion of Darwin's views on gradualism. Of course Darwin acknowledged great variation in rates of change, and even episodes of rapidity that might be labelled catastrophic (at least on a local scale); for how could such an excellent naturalist deny nature's multifariousness on such a key issue as the character of change itself? But these occasional statements do not make Darwin the godfather of punctuated equilibrium ....

You'll have to read Gould's chapter to see the case he makes because it's much too involved to summarize here. I do note one pithy comment to the effect that,

I will not play 'duelling quotations' with 'citation grazers,' though a full tabulation of relative frequencies could easily bury their claims under a mountain of statements.

He then proceeds to tabulate dozens of quotations that demonstrate Darwin's gradualism!

Natural Foods Contain Lots of "Carcinogens"

 
Bruce Ames was a Professor in the Department of Biochemistry & Molecular Biology at the University of California, Berkeley (USA). This is one of the leading departments of biochemistry in the entire world. Bruce Ames is currently a senior scientist at the Children's Hospital Oakland Research Institute (CHORI) in Oakland, California (USA).

Ames developed the Ames test, a biological test to detect chemicals that are mutagenic. He has published dozens of papers on mutagens and mutagenesis and dozens of papers on human health and nutrition.

The Ames test is used to create a database of possible cancer-causing chemicals. One of the important issues is the question of where these potential carcinogens can be found. Is it only synthetic compounds that pose a danger? Is it true that "natural" products are much safer? This is the issue that John Tierney raises in his New York Times article [see Did Rachel Carson Get It Right?]. Tierney elaborates on his website where he refers to the work of Bruce Ames [see Synthetic v. Natural Pesticides].

The answer is pretty clear, even though it is not widely appreciated. There are plenty of chemicals in natural products that test positive in the Ames test and test positive in tests for cancer using rodents. Since we eat far more natural products that synthetic products, it follows that we are far more likely to get cancer from eating "healthy" foods than from eating at a fast food restaurant.

Here's the abstract from a classic paper by Ames and Lois Swirsky Gold from 1998.

The idea that synthetic chemicals such as DDT are major contributors to human cancer has been inspired, in part, by Rachel Carson's passionate book, Silent Spring. This chapter discusses evidence showing why this is not true. We also review research on the causes of cancer, and show why much cancer is preventable. Epidemiological evidence indicates several factors likely to have a major effect on reducing rates of cancer: reduction of smoking, increased consumption of fruits and vegetables, and control of infections. Other factors are avoidance of intense sun exposure, increases in physical activity, and reduction of alcohol consumption and possibly red meat. Already, risks of many forms of cancer can be reduced and the potential for further reductions is great. If lung cancer (which is primarily due to smoking) is excluded, cancer death rates are decreasing in the United States for all other cancers combined. Pollution appears to account for less than 1% of human cancer; yet public concern and resource allocation for chemical pollution are very high, in good part because of the use of animal cancer tests in cancer risk assessment. Animal cancer tests, which are done at the maximum tolerated dose (MTD), are being misinterpreted to mean that low doses of synthetic chemicals and industrial pollutants are relevant to human cancer. About half of the chemicals tested, whether synthetic or natural, are carcinogenic to rodents at these high doses. A plausible explanation for the high frequency of positive results is that testing at the MTD frequently can cause chronic cell killing and consequent cell replacement, a risk factor for cancer that can be limited to high doses. Ignoring this greatly exaggerates risks. Scientists must determine mechanisms of carcinogenesis for each substance and revise acceptable dose levels as understanding advances. The vast bulk of chemicals ingested by humans is natural. For example, 99.99% of the pesticides we eat are naturally present in plants to ward off insects and other predators. Half of these natural pesticides tested at the MTD are rodent carcinogens. Reducing exposure to the 0.01% that are synthetic will not reduce cancer rates. On the contrary, although fruits and vegetables contain a wide variety of naturally-occurring chemicals that are rodent carcinogens, inadequate consumption of fruits and vegetables doubles the human cancer risk for most types of cancer. Making them more expensive by reducing synthetic pesticide use will increase cancer. Humans also ingest large numbers of natural chemicals from cooking food. Over a thousand chemicals have been reported in roasted coffee: more than half of those tested (19/28) are rodent carcinogens. There are more rodent carcinogens in a single cup of coffee than potentially carcinogenic pesticide residues in the average American diet in a year, and there are still a thousand chemicals left to test in roasted coffee. This does not mean that coffee is dangerous but rather that animal cancer tests and worst-case risk assessment, build in enormous safety factors and should not be considered true risks. The reason humans can eat the tremendous variety of natural chemical "rodent carcinogens" is that humans, like other animals, are extremely well protected by many general defense enzymes, most of which are inducible (i.e., whenever a defense enzyme is in use, more of it is made). Since the defense enzymes are equally effective against natural and synthetic chemicals one does not expect, nor does one find, a general difference between synthetic and natural chemicals in ability to cause cancer in high-dose rodent tests. The idea that there is an epidemic of human cancer caused by synthetic industrial chemicals is false. In addition, there is a steady rise in life expectancy in the developed countries. Linear extrapolation from the maximum tolerated dose in rodents to low level exposure in humans has led to grossly exaggerated mortality forecasts.

Ames, B.N. and Gold, L.S. (1998) The causes and prevention of cancer: the role of environment. Biotherapy 11:205-20.

Did Rachel Carson Get It Right?

 
Rachel Carson is widely credited with kick starting the environmentalist movement following publication of Silent Spring back in 1962. She pointed out the dangers of widespread use of DDT and promoted the idea that synthetic chemicals can cause cancer.

Many scientists take issue with the "facts" in her book and they believe that she may have done more harm than good. If you care about scientific accuracy then you must be skeptical about her claims, even if you admire her goals.

Carson was born on May 27, 1907 and last month marked the 100th anniversary of her birth.

For a summary of where she went wrong you might as well start with a recent New York Times article by John Tierney [Fateful Voice of a Generation Still Drowns Out Real Science]. Tierney outlines the case very well and he has attracted a lot of attention by not pulling his punches.

For Rachel Carson admirers, it has not been a silent spring. They’ve been celebrating the centennial of her birthday with paeans to her saintliness. A new generation is reading her book in school — and mostly learning the wrong lesson from it.

This is the kind of science journalism that I admire but, as you might imagine, Tierney has come under fierce attack from those people who value superstition over rationalism. Tierney has attempted to deal with those attacks on his website [Synthetic v. Natural Pesticides].

There are many issues here but one of the most interesting is whether the essence of Carson's claim is accurate. Is it true that a large percentage of cancers is caused by synthetic chemicals in the environment? That certainly seems to be the general perception both inside and outside the scientific community.

Does this controversy remind you of the framing debate? It's clear that Rachel Carson used very effective framing in advocating her opposition to chemicals in the environment. The metaphor of a "Silent Spring" being only one of many examples. At the time there may have been many scientists who agreed with her about the dangers of DDT and, by extension, many other synthetic chemicals.

However, it's clear that there were also scientists who disagreed, as John Tierney points out in his New York Times piece. The problem is that once scientists start down the framing pathway they open a Pandora's Box that's very hard to close. I think that scientists have to be very, very, careful about abandoning objectivity and skepticism in order to push a political agenda. Once they jump on the bandwagon it's very hard to jump off if the scientific evidence fails to support the agenda. And that hurts the credibility of science.