Tangled Bank

 



Tangled Bank #85 - The Reductionist's Tale has been posted on Migrations. There's a mechanical duck on the website.

Top 100 Science Sites

 
Here's a list of the top 100 science sites according to TOP100SCIENCE.COM. The links don't work since I just captured the image. You'll have to go to the TOP100SCIENCE website to visit the sites. The NCBI site is only listed at #14—that doesn't seem right.

I don't think there are any blogs in the top 100.



[Hat Tip: Phil Plait whose Bad Astronomy blog comes in at #377]

Nobel Laureates: Max Perutz and John Kendrew

 
 
The Nobel Prize in Chemistry 1962.

"for their studies of the structures of globular proteins"


Max Perutz (1914-2002) and John Kendrew (1917-1997) won the Nobel Prize in 1962 for solving the structures of hemoglobin (Perutz) and myoglobin (Kendrew). This is the same year that Watson, Crick, and Wilkins won for the structure of DNA [Nobel Laureates: Francis Crick, James Watson, and Maurice Wilkins]. Recall that Watson & Crick were working in the Perutz lab at the time of their discovery and Crick was actually working on the structure of hemoglobin as part of his Ph.D. thesis [The Story of DNA (Part 1)].

1962 was also the year that John Steinbeck won the prize for literature [see Nobel Laureates 1962].

The Presentation Speech was given by Professor G. Hägg, member of the Nobel Committee for Chemistry of the Royal Swedish Academy of Sciences. Those of you who weren't yet born in 1955 should make note of the fact that this work required an enormous number of calculations that were only made possible with the help of "a very large electronic computer." Many of my students are surprised to discover that biochemists have been working with computers for over fifty years. Most of them think that computers weren't invented until about 1990 when they were just babies.

Your Majesties, Your Royal Highnesses, Ladies and Gentlemen.

In the year 1869 the Swedish chemist Christian Wilhelm Blomstrand wrote, in his at that time remarkable book Die Chemie der Jetztzeit (Chemistry of Today):

"It is the important task of the chemist to reproduce faithfully in his own way the elaborate constructions which we call chemical compounds, in the erection of which the atoms serve as building stones, and to determine the number and relative positions of the points of attack at which any atom attaches itself to any other; in short, to determine the distribution of the atoms in space."

In other words, Blomstrand gives here as his goal the knowledge of how compounds are built up from atoms, i.e. knowledge of what is nowadays often called their "structure". Moreover, structure determination has been one of the biggest tasks of chemical research, and has been approached using many different techniques. For several reasons, the structure determination of carbon compounds, the so-called organic compounds, experienced an initial rapid development. At this stage the techniques were generally those of pure chemistry. One drew conclusions from the reactions of a compound, one studied its degradation products, and tried to synthesize it by combining simpler compounds. The structure thus arrived at, however, was in general rather schematic in character; it showed which atoms were bonded to a given atom, but gave no precise values for interatomic distances or interbond angles. However, for an up-to-date treatment of the chemical bond and in order to derive a correlation between structure and properties, these values are needed, and they can only be obtained using the techniques of physics.

The physical method which, more than any other, has contributed to our present-day knowledge of these mutual dispositions of the atoms is founded on the phenomenon which occurs when an X-ray beam meets a crystal. This phenomenon, called diffraction, results in the crystal sending out beams of X-rays in certain directions. These beams are described as reflections. The directions and intensities of such reflections depend on the type and distribution of the atoms within the crystal, and can therefore be used for structure determination. It is 50 years ago this year since Max von Laue discovered the diffraction of X-rays by crystals, a discovery for which he was awarded the 1914 Nobel Prize for Physics. This work opened up a whole new range of possibilities for studying both the nature of X-rays and the structure of compounds in the solid state. The initial application of structure determination was developed first and foremost by the two English scientists, Bragg father and son, and as early as 1915 they were rewarded with the Nobel Prize for Physics. The techniques have since been considerably refined, and it has been possible to solve more and more complicated structures. However, considerable difficulties were encountered as soon as any other than very simple structures were considered. There is no simple general way of progressing from experimental data to the structure of the compound under investigation. Moreover, the mathematical calculations are exceedingly time-consuming. However, by about the middle of the 1940's a point had been reached where it was becoming possible to carry out X-ray determinations of the structures of organic compounds which were so complicated that they defied all attempts using classical chemical methods.

In 1937 Max Perutz performed some experiments in Cambridge to find out whether it might be possible to determine the structure of haemoglobin by X-ray diffraction, since no other method could be imagined for this purpose. Sir Lawrence Bragg, who tirelessly continued the work begun jointly with his father, in 1938 became the head of the Cavendish Laboratory in Cambridge. When he saw the results obtained by Perutz, he encouraged him to continue and has ever since lent a very efficient support. Haemoglobin belongs to the proteins which play such an enormous part in life processes, and which are a basic material in living organisms. Haemoglobin is a component of the red blood corpuscles. It contains iron which can take up oxygen in the lungs and later give it up to the body's other tissues. Haemoglobin is counted among the globular proteins, whose molecules are nearly spherical. It was chosen for the initial attempt, partly because it could develop good crystals, and partly because the haemoglobin molecule is quite small for a protein molecule. About ten years later, John Kendrew joined Perutz' research group, and the task allotted to him was to try to determine the structure of myoglobin. Myoglobin is another globular protein, closely related to haemoglobin, but with a molecule only a quarter as large. It is found in the muscles, and enables oxygen to be stored there. Particularly large amounts of myoglobin are found in the muscular tissues of whales and seals, which need to be able to store large quantities of oxygen when diving.

However, Perutz and Kendrew encountered considerable difficulties. In spite of exceptionally comprehensive work, the result was not forthcoming until 1953, when Perutz succeeded in incorporating heavy atoms, namely those of mercury, into definite positions in the haemoglobin molecule. By this means the diffraction pattern is altered to some extent, and the changes can be utilized in a more direct structure determination. The method was already known in principle, but Perutz applied it in a new way, and with great skill. Kendrew also succeeded, by an alternative method, in incorporating heavy atoms, generally mercury or gold, into the myoglobin molecule, and could subsequently proceed in an analogous manner.

A necessary condition for this technique is that the addition of the heavy atoms should not alter the positions of the other atoms of the molecule within the crystal. In this connection it is simply because of its enormous dimensions that the molecule remains practically unaltered. Bragg has rather aptly said that "the molecule takes no more notice of such an insignificant attachment than a maharaja's elephant would of the gold star painted on its forehead".

But even if the path was now open for a direct structure determination of haemoglobin and myoglobin, there was still an enormous amount of data to be processed. Myoglobin, the smaller of the two molecules, contains about 2,600 atoms, and the positions of most of these are now known. But for this purpose, Kendrew had to examine 110 crystals and measure the intensities of about 250,000 X-ray reflections. The calculations would not have been practicable if he had not had access to a very large electronic computer. The haemoglobin molecule is four times as large, and its structure is known less thoroughly. In both cases, however, Kendrew and Perutz are currently collecting and processing an even greater number of reflections in order to obtain a more detailed picture.

As a result of Kendrew's and Perutz' contributions it is thus becoming possible to see the principles behind the construction of globular proteins. The goal has been reached after twenty-five years' labour, and initially with only modest results. We therefore admire the two scientists not only for the ingenuity and skill with which they have carried out their work, but also for their patience and perseverance, which have overcome the difficulties which initially seemed insuperable. We now know that the structure of proteins can be determined, and it is certain that a number of new determinations will soon be carried out, perhaps chicfly following the lines which Perutz and Kendrew have indicated. It is fairly certain that the knowledge which will thus be gained of these substances which are so essential to living organisms will mean a big step forward in the understanding of life processes. It is thus abundantly clear that this year's prize-winners in chemistry have fulfilled the condition which Alfred Nobel laid down in his will, they have conferred the greatest benefit on mankind.

Doctor Kendrew and Doctor Perutz. One of you recently said that today's students of the living organism do indeed stand on the threshold of a new world. You have both contributed very efficiently to the opening of the door to this new world and you have been among the first to obtain a glimpse of it. Through your combined efforts there is now in view, as it has been stated by yourself, a firm basis for an understanding of the enormous complexities of structure, of biogenesis and of the functions of living organisms both in health and disease.

It is with great satisfaction, therefore, that the Royal Swedish Academy of Sciences has decided to award you this year's Nobel Prize for Chemistry for your brilliant achievement.

On behalf of the Academy I wish to extend to you our heartiest congratulations, and now ask you to receive from the hands of His Majesty the King the Nobel Prize for Chemistry for the year 1962.

The figures are taken from A Little Ancient History by Richard (Dick) Dickerson. The top figure shows the myoglobin/hemoglobin group outside the New Cavendish Laboratory in 1958. That's Maz Perutz in the white lab coat. The second picture is a remarkable photograph of two postdocs, Bror Strandberg (back) and Dick Dickerson (front) carrying the paper tapes for the myoglobin 2A data set. They are just outside the EDSAC II computing centre.

Hemoglobin

 
The following text is slightly modified from Horton et al. (2007) Principles of Biochemistry.

In vertebrates, O₂ is bound to molecules of hemoglobin for transport in red blood cells, or erythrocytes. Viewed under a microscope, a mature mammalian erythrocyte is a biconcave disk that lacks a nucleus or other internal membrane-enclosed compartments (right). A typical human erythrocyte is filled with
approximately 3 × 10⁸ hemoglobin molecules.

Hemoglobin is more complex than myoglobin because it is a multisubunit protein. In adult mammals, hemoglobin contains two different globin subunits called α-globin and β-globin. Hemoglobin is an α₂β₂ tetramer, which indicates that it contains two α chains and two β chains. Each of these globin subunits is similar in structure and sequence to myoglobin, reflecting their evolution from a common ancestral globin gene in primitive chordates.


Each of the four globin chains contains a heme prosthetic group identical to that found in myoglobin. The α and β chains face each other across a central cavity (above). The tertiary structure of each of the four chains is almost identical to that of myoglobin (left). The α chain has seven helices, and the β chain has eight. (Two short α helices found in β-globin and myoglobin are fused into one larger one in α-globin.) Hemoglobin, however, is not simply a tetramer of myoglobin molecules. Each α chain interacts extensively with a β chain, so hemoglobin is actually a dimer of αβ subunits. The presence of multiple subunits is responsible for oxygen-binding properties that are not possible with single-chain myoglobin.

The structure of hemoglobin was solved by Max Perutz [Nobel Laureates].



©Laurence A. Moran and Pearson Prentice Hall 2007

Myoglobin

 
Myoglobin is the simplest type of oxygen carrying molecule in vertebrates. It consists of a single polypeptide chain bound to a heme group. The example shown on the left is sperm whale myoglobin. It shows the heme group edge on (gray) bound to a molecule of oxygen (red balls in the middle of the heme group on the right). The other oxygens, left and top, are part of the heme molecule.

The oxygen is bound to the iron atom at the center of the heme group. In the absence of oxygen this iron atom interacts with the side chains of two histidine residues in the myoglobin polypeptide chain. When oxygen binds it forms a bridge between one of the histidine residues (His-64) and the iron atom in the heme group.

Although the oxygen molecule is tightly bound in this configuration it is still capable of being released under the right conditions. Those conditions can be found inside cells that have become depleted in oxygen. Myoglobin is usually found in muscle cells in vertebrates where it plays a role in storing oxygen. The structure of myoglobin was determined by John Kendrew [Nobel Laureates].

Myoglobin is a member of a large family of globins. They include hemoglobin and similar oxygen carrying molecules in bacteria, plants, and other animals. The myoglobins have evolved from ancestral globins to specialize in oxygen storage inside cells.

©Laurence A. Moran and Pearson Prentice Hall 2007

Heme Groups

 
Monday's Molecule #37 is the heme group found in myoglobin and hemoglobin. The heme group consists of a ring structure, called a tetrapyrrole ring system, complexed to a central iron atom. There are many different kinds of these tetrapyrrole structures in cells. They are distinguished by slight changes in the chemistry of the ring system. This particular structure (left) is called protoporphyrin IX. The structure was originally determined by Hans Fischer [Nobel Laureate: Hans Fischer],

The red color of blood is due to the presence of the heme group, which absorbs visible light. Note that the pyrrole rings are linked by methene bridges (-CH=) to create a conjugated double bond system where electrons can be shared all across the ring. Not only does this mean that these rings can absorb photons, it also means that they can accommodate additional electrons without too much trouble.

This is why there are many heme proteins that are involved in oxidation-reduction reactions (reactions that transfer electrons from one substrate to another). For example, cytochrome c has a similar kind of heme group (right). Cytochrome c is a major player in membrane associated electron transport systems in bacteria and mitochondria and in photosynthesis.

Heme type molecules are always tightly bound to proteins. Such molecules are called prosthetic groups and there are two types. The heme in hemoglobin is bound by many weak interactions such as hydrogen bonds and van der Waals interactions. The heme in cytochrome c is an example of a covalently bound prosthetic group. It is attached to its protein by bonds between the edge of the porphyrin ring and cysteine (Cys) side chains in the protein.

Chlorophyll (left) is another type of tetrapyrrole ring molecule but it differs from most others because the central chelated metal ion is magnesium (Mg) instead of iron. Chlorophyll molecules absorb light very efficiently and that's why they play such an important role in photosynthesis. Photosynthesizing organisms—bacteria, algae, plants—have dozens (or hundreds) of chlorohyll molecules packed in their membranes.


©Laurence A. Moran and Pearson Prentice Hall 2007

Physicians Are "Science Professionals"

 
At least that's what the IDiots say [Medical Doctors a Fast Growing Segment of Darwin Doubting Science Professionals].

Who knew? I suppose we shouldn't be surprised if they think an M.D. degree makes you a "science professional." After all, these are some of the same people who think the Earth is only 10,000 years old.

UPDATE: Turns out that many of these medical doctors are actually dentists [Dentists Against Darwin]. Sheesh!

Your View of Evolution

 
The poll for August asks you to identify the person who comes closest to representing your view of evolution. Check out the left hand margin.

70% of Sandwalk Readers are Atheists

 
According to the latest poll (see left hand margin) 70% of Sandwalk readers are atheists (PZ would be proud.). 12% are agnostics—I guess Wilkins and Catshark figured out how to vote multiple times. Only 14% are believers. I wish there were more believers, it would make for more lively discussions.

Six of you are uncertain. Why?

Another Bad Review of The Edge of Evolution

PZ Myers draws attention to another review of Michael Behe's new book The Edge of Evolution [Behe gets another thumbs-down]. This review is published in the July issue Discover magazine [The Simplistic Manifesto]. The author is Cory S. Powell.

I disagree with PZ. This is not a good review. Actually, it's a very bad review. Like many of the published reviews of The Edge of Evolution the author seems to have been reading a far different book than the one I read. Powell says,

To reach this conclusion, Behe makes a number of invalid assumptions about how molecules evolve and interact. He alleges that, because many functional adaptations require multiple changes in proteins, two or more mutations must occur together at the same time in the same gene and only rarely can several mutations "sequentially add to each other to improve an organism’s chances of survival." But in fact natural selection does work on transitional forms, as molecules and traits evolve stepwise. Stepwise evolution has been well documented; one good instance of this is the emergence of color vision. Mutations add up little by little, leading to major changes to proteins over time.

The essence of Behe's argument is not that it's impossible to evolve a double mutation if each one is beneficial. The whole point of the book is that stepwise evolution requires that each step is beneficial. The evidence, according to Behe, shows that many cases involving double mutations involve intermediates that are disadvantagous. Thus, the double mutant had to arise in a single step and this is highly unlikely.

Behe isn't always as clear as he should be but he does make it perfectly clear that he accepts the mechanism that Powell describes. Thus, Powells' criticism is inappropriate and this makes it a bad review. Apparently Powell didn't read the section on the evolution of antifreeze proteins in fish (pp. 77-81) where Behe describes each of the many steps that lead to the modern antifreeze proteins.

Each step would have given the fish some protection against freezing water. Thus, Behe concludes,

Even though we haven't directly observed it, the scenario seems pretty convincing as an example of Darwinian evolution by natural selection. It's convincing because each of the steps is tiny&mdash'no bigger than the step that yielded the sickle cell mutation n humans—and each step is an improvement.

The Discovery review points out that complex combinations of mutations can arise in a stepwise manner by standard Darwinian mechanisms. It implies that Behe never thought of this in his book but that's total nonsense. Of course he did. Behe doesn't deny that phenotypes requiring multiple steps can be produced by random mutations, as long as each step is beneficial. The essence of his argument is that it's impossible to generate phenotypes that require multiple random mutations if the intermediates aren't beneficial.

I'm not arguing that Behe is correct. In fact, I'm preparing a series of postings that will challenge some of his ideas. What I'm objecting to is the mischaracterization of Behe's arguments in many of the published reviews. If you're going to criticize Behe then challenge the argument he makes in the book; namely, that most stepwise pathways are impossible because the intermediates are less fit than their parents.

Powell makes another common mistake in his review. He says,

Behe makes another big, related error in the way he interprets how proteins work together. He contends that for even three proteins to evolve in a cooperative association is wildly improbable, "beyond the edge of evolution." Within a protein, five or six amino acids (components of proteins) need to change simultaneously for it to bond with another protein, according to Behe. From this he concludes that it is impossible for proteins’ interaction to evolve, again requiring life to have been programmed for success from the start. Plenty of evidence contradicts this assertion, however. Many proteins within cells interact with other proteins in ways in which only two or three amino acids are critical for binding.

Behe admits that you may only need three or four selected changes in order to generate a new binding site (p. 114). He agrees that the evolution of a single binding site is within reach of evolution but the simultaneous generation of two binding sites is beyond the edge of evolution because the probabilities are so low. The point is that there are many complexes that require the interaction of several different proteins and the intermediates—where only two proteins interact—are not beneficial. Refuting Behe's real arguments requires a little more effort than the superficial criticism of arguments that Behe is not making.

Powell continues,

Such simple binding sites can arise frequently in proteins. And such interactions form the networks that regulate all sorts of physiological processes in cells and organisms. Cell biologists and biochemists are increasingly finding that, in truth, protein interactions and networks are easy to evolve. Behe should know this—but he has a long history of alleging evolutionary impossibilities and ignoring the scientific literature.

Powell is completely missing the point here. Behe does not deny that such complexes exist, nor does he deny that they evolved in the sense that they arose in organisms whose ancestors didn't have them. Once the mutations occurred, they became fixed in the population by natural selection. Furthermore, Behe does not deny that these networks are "easy to evolve." In fact, they are so "easy to evolve" that they cannot be explained by natural selection acting on random mutations as "Darwinism" requires. Thus, mutations cannot be random.

You don't refute Behe by pointing to examples of evolution by common descent or natural selection; this includes evolution of protein complexes. That's not the point. The point is that "Darwinian" evolution, according to Behe, must require small steps where each step is beneficial and this cannot be demonstrated. Indeed, in many cases the intermediates will likely be detrimental. The conclusion is that multiple mutations have to occur simultaneously as in some drug resistance. For most populations the probability of this happening by random mutation is very small. The fact that it happened is evidence of directed mutation, or so Behe thinks.

In order to show that Behe is wrong you have to demonstrate that his understanding of evolution (i.e., "Darwinism") is wrong and this has led him to false conclusions about probabilities. Many reviewers have failed to do this, possibly because they accept Behe's version of Darwinism.

You can read Michael Behe's responses to his reviewers on the Amazon.com site [Michael Behe's Amazon Blog]. I think it's fair to say that Behe makes some good points (and many bad ones) when he accuses his reviewers of misrepresentation.

Virtual Toronto

 
Here's a site that combines an interactive map of Toronto with images from selected streets [Toronto Virtual City]. The photograph (left) shows the entrance to my building on the University of Toronto campus. The view is looking north from College St.

The satellite view is about two years old. It was taken when the new building was still under construction so the street level image doesn't match the satellite view.

Hmmm ... that reminds me. How come we don't see any more postings where we have to identify a university campus? I forgot which blog that was on.

[Hat Tip: Monado]

Gene Genie #12

 


Gene Genie #12 has been posted at My Biotech Life [Gene Genie #12 aka The Dozen].

The image is from the article on snpedia [WikiPedia Meets Genetics]. Read about how you can access the personal genome of Jim Watson and Craig Ventor.

Monday's Molecule #37

 
Today's molecule looks complicated but it has a very simple name. The short common name of this molecule is not sufficient—you have to supply the correct biochemical name that distinguishes this molecule from similar ones found inside all cells. You're more than welcome to supply the complete IUPAC name if you know it.

There's an indirect connection between this Monday's Molecule and Wednesday's Nobel Laureate(s).

The reward (free lunch) goes to the person who correctly identifies the molecule and the Nobel Laureate(s). Previous free lunch winners are ineligible for one month from the time they first collected the prize. There's only one (Marc) ineligible candidates for this Wednesday's reward since many recent winners haven't collected their prize. The prize is a free lunch at the Faculty Club.

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

Canadian Dinosaur Coins

 
The Royal Canadian Mint has dinosaur coins for sale. Here's a picture of the first one. It shows a fossil Parasaurolophus, a crested, duck-billed species from Alberta.

Future coins will depict Triceratops (2009); Tyrannosaurus rex (2009); and Dromaeosaurus (2010). The face value of the coins is $4 (CDN)—that's currently about $3.80 in US currency but it will be about $4.60 by the time the last coin is issued unless the US dollar stops falling. (Getting out of Iraq would help.)

Only 20,000 coins are being minted. The finish on the "fossil" image is impossible to reproduce exactly so each coin will be slightly different in tone and color. You can buy them for $39.95 (CDN).

How many people know what "D.G. Regina" stands for? (Hint: it's not an atheist slogan.)

The OUT Campaign

 
RichardDawkin.net has started something called the The OUT Campaign. The goal is to encourage all non-believers (atheists) to come out of the closet and make their rejection of religious superstition known. You're supposed to use the red "A" as a symbol to declare that you are an atheist. Several bloggers have put it on their website.

I do not believe in God. I am an atheist. However, the fact that I don't believe in something is often the only thing I have in common with other atheists. It seems a bit silly to form a club based only on what you don't believe in. It would be like having a club for everyone who doesn't believe in Bigfoot, or Santa Claus.

So, while I am happy to announce my preference for rationalism over superstition and proud to be an atheist. I won't be joining any organization based on a negative. I am a proud member of Skeptics Canada and The Centre for Inquiry, Toronto because they stand for something positive.

[Hat Tip: PZ Myers]