Gene Genie #17

 

The 17th edition of Gene Genie has just been published on Gene Sherpas [Gene Genie #17 and 10,000 visitors].

If you don't know about Gene Sherpas then this is your chance to check it out. The blog is run by Steve Murphy, a physician with a very special interest.

I am the founder of a Personalized Medicine practice (likely the first private practice of its kind). In addition I am the Clinical Genetics Fellow at Yale University until 2010. Now not under contract and that's why I am posting and running my practice. I also am developing a modern medical genetics curriculum for residents and other physicians. On this blog I am educating the public and hopefully some physicians about the field of genetics and personalized medicine.

A former student of mine shares these interests. He tells me that physicians don't get much education in genetics while in medical school and as a result they aren't up to speed when it comes to understanding the genetics of various diseases.

Another former student of mine is a genetic counselor. This is a growing field of professionals who can advise patients (and doctors) about human genetics.

Linnaeus 2007

 
This year marks the 300th anniversary of the birth of Carl Linnaeus. There will be celebrations all around the would but Sweden is leading the way [Linnaeus 2007].

Linnaeus' Life and Achievements

Carl Linnaeus is the most well-known Swedish scientist, both internationally and in Sweden. He has left traces in many ways: there are places that bear his name, there are locations on the Moon that have been named after him, he is depicted on Swedish banknotes, and "Linnea" is a popular first name for girls in Sweden. Carl Linnaeus placed his stamp on a complete era of scientific history - the Linnaean era. The Linnaean era is characterised by an ambition to catalogue, organise and give names to the whole natural world.

Mapping Nature

Linnaeus is probably best known as a botanist, and for his sexual system. His scientific achievements, however, also extend into the mineral world and zoology, in addition to botany. He was curious about the complete natural world, and wanted to map the whole of nature. This mapping has given us the naming convention known as the "binary nomenclature", that Linnaeus introduced. Linnaeus published a number of rule-books on which the system was based, and the system, after some initial resistance, has come not only to dominate natural history, but also to influence other scientific fields. Linnaeus clarifies language, he bases his science on a rigid terminology, formulates the concept of species and sets the broad dimensions of natural history. Humans in his system, for example, are known as Homo sapiens and they are primates in the class of mammals, Mammalia, - all of these are names and concepts that Linnaeus coined.

The Linnaean Conceptual Structure

The Linnaean conceptual structure has become popular both within the academic world and among hobbyists. The concept has spread throughout the world, initially by those known as the "Linnaean apostles", a group of disciples who reached farther afield throughout the world than any Swedes had previously reached. Their deaths in far-flung places carry a hint of heroism, they died for the sake of science. The continued influence of Linnaeus has stimulated scientific journeys, cataloguing and strange destinies, but it has also had a more calm interaction with nature at many places across the globe, with its placid nature of collection and systematic thought. Linnaeus creativity and sense of curiosity has left traces not only in science but also in literature and in other fields of culture.

Skagit Valley Provincial Park

 
Today's Botany Photo of the Day is a picture of the forest in Skagit Valley Provincial Park in Southern British Columbia on the USA border.

The little thumbnail on the left doesn't do justice to the photograph. You need to see the whole thing. Isn't it beautiful?

The Spandrels of San Marco and the Panglossian Paradigm

This week's citation classic on The Evilutionary Biologist is "The Spandrels of San Marco and the Panglossian Paradigm: A Critique of the Adaptationist Programme" by S.J. Gould and R.C. Lewontin [This Week's Citation Classic].

This is John Dennehy's best choice by far. It's a classic paper and everyone interested in evolution must read it carefully. Whether you agree with Gould & Lewontin or not, you can't participate in the debate unless you've read and understand this paper. I'm pleased that John appreciates it, although I'm a little upset over some of the things he says about Gould. Clearly, he needs some remedial indoctrination re-education ....

[There's a link to an online version of the paper from John's article so nobody has any excuse not to read it.]

Are You as Smart as a Third Year University Student? Q5

 
Question 1
Question 2
Question 3
Question 4
The standard Gibbs free energy change for the aldolase reaction in the direction of cleavage is +28 kJ mol-1. What does this tell you about the properties of this reaction in yeast cells that are actively producing ATP via glycolysis?

         a)  flux through this particular reaction will be
                in the direction of gluconeogenesis
         b)  the activity of this enzyme must be regulated
         c)  there must be another enzyme in yeast that bypasses this reaction
         d)  this is the rate limiting reaction in glycolysis
         e)  the concentration of FBP will be very much higher than
                the concentration of G3P

Are You as Smart as a Third Year University Student? Q4

 
Question 1
Question 2
Question 3The open-chain form of fructose 1,6-bisphosphate is shown as the substrate for the aldolase reaction. Why?

         a)  the open-chain form is more abundant inside the cell
         b)  cyclic molecules destabilize the transition state
         c)  the product of the previous reaction in glycolysis
               is the open-chain form
         d)  the open-chain form is thermodynamically more stable
               and this contributes to the positive standard Gibbs free
               change for the reaction
         e)  the active site of the enzyme can’t accommodate the
                furanose or pyranose forms

The Aldolase Reaction and the Steady State

 
On banning the word "spontaneous" to describe biochemical reactions.Aldolase is an enzyme that's important in gluconeogenesis and glycolysis. I'm discussing it because RPM is describing his work on aldolase genes in Drosophila melanogaster [Aldolase in Gluconeogenesis & Glycolysis].

Fructose 1,6-bisphosphate aldolase ("aldolase") catalyzes the reaction shown below where two 3-carbon compounds are joined to produce a 6-carbon fructose molecule.


The mechanism of aldolase is described in Pushing Electrons. What I want to discuss here is the fact that this reaction is reversible. It has to operate equally efficiently in either direction.

The direction shown is part of gluconeogenesis: the synthesis of glucose. The standard Gibbs free energy change for this reaction is -28 kJ mol^-1 (ΔG°′ = -28 kJ mol^-1). This may not mean a lot to most of you but it indicates that under standard conditions the reaction gives off a lot of energy. Very negative values are associated with release of energy and energy release is favored over uptake of energy.

In terms of old fashioned biochemistry, we would have said that the reaction was spontaneous in the direction shown. In other words, the enzyme will be more likely to synthesize fructose 1,6-bisphosphate (F1,6P) than to break it down.

This perspective is very misleading since inside the cell the reaction can easily flow in either direction depending only on small changes in the concentrations of substrates and products. In the new way of looking at metabolism we no longer talk about reactions being spontaneous and we no longer use the standard Gibbs free energy changes (ΔG°′) as indicators of direction. This change in teaching was stimulated, in part, by the difficulties in explaining how the aldolase reaction could catalyze breakdown of fructose 1,6-bisphosphate to dihydroxyacetone (DAP) phosphate and glyceraldehyde 3-phosphate (G3P) in the face of a standard Gibbs free energy change that was very positive. (The value for the reverse reaction is +28 kJ mol^-1.) Those kind of reactions weren't supposed to happen in the old textbooks and it suggested that glycolysis is impossible.

Here's how we think about it today. What the standard Gibbs free energy change tells us is that under standard conditions the reaction will proceed to the right until equilibrium is reached. The standard conditions are 1M concentrations of all the substrates and products.

When enough of the substrates are converted to product the reaction will start to flow in the opposite direction until eventually an equilibrium is reached where the rate of synthesis of fructose 1,6-bisphosphate equals the rate of its breakdown. At this point the real (as opposed to standard) Gibbs free energy change will be 0 (zero). There will be no overall tendency for the reaction to flow in one direction or the other. The concentrations of substrates and products at this point will be the equilibrium values. I hope it's clear that at equilibrium the concentration of fructose 1,6-bisphosphate will be much higher than the concentrations of dihydroxyacetone and glyceraldehyde 3-phosphate. We can illustrate this in a cartoon that represents the concentrations as blobs of various sizes.


The standard Gibbs free energy change doesn't tell us whether a reaction will be spontaneous or not. Instead, it simply tells us the final concentrations of substrates and products at equilibrium. (You can calculate this using simple equations that you learn in introductory chemistry courses.) The equilibrium concentrations are the concentrations found inside the cell since almost all reactions operate at Gibbs free energy values close to zero. In other words, most biochemical reactions are near-equilibrium reactions with steady-state concentrations close to the equilibrium values.

The concentrations of the substrates and product of the aldolae reaction look like the blob cartoon shown above. If the cell is making glucose then there will be a steady trickle of substrates flowing into the reaction and this increases the substrate concentration (little blobs) a little bit so that more of it is converted to fructose 1,6-bisphosphate (F1,6P) (big blob) in order to restore the equilibrium.

Conversely, if the cell is breaking down glucose then the concentration of fructose 1,6bisphosphate will increase above the equilibrium, steady-state value and more of it will be broken down to the 3-carbon compounds. This will happen in spite of the fact that there is already a lot more F1,6-P inside the cell than G3P and DAP.

This explains why the central reactions of the gluconeogenesis/glycolysis pathways can catalyze reactions in either direction and can swich quickly from one direction to another. The key is that the steady-state concentrations inside the cell are far from the standard concentrations.

Aldolase in Gluconeogenesis & Glycolysis

RPM at evolgen has started a series of articles on publishing original research on blogs. He's going to tell us about the aldolase genes in Drosophila melangogaster. I'm sure he's going to be explaining some interesting studies about the evolution of the two aldolase genes so I urge you to pay attention. Here are the three postings so far.

Publishing Original Research on Blogs - Part 1
Publishing Original Research on Blogs - Part 2
Publishing Original Research on Blogs - Part 3

I hope he won't mind if I describe some of the biochemistry of the aldolase catalyzed reaction and the pathways where aldolase is involved. I don't think RPM is going to do any more than what he briefly described in Part 2.

The first point I want to make is that aldolase is a type of enzyme that forms and cleaves carbon-carbon bonds. There are many different types of aldolases with different substrates and products. The most common of these enzymes is fructose 1,6-bisphosphate aldolase. Because it's so common it is often just called "aldolase." All of the the other aldolases must be specified in order to avoid confusion.


There are two different kinds of aldolases (i.e., the fructose 1,6-bisphosphate kinds). Class I enzymes (left, above) are only found in plants and animals. Class II enzymes (right, above) are usually found in bacteria, protists, and fungi. Many species of plants and animals have both types of enzyme. The two different types of aldolase are completely unrelated. They have different structures and sequences even though they catalyze the same reaction. I think the two Drosophila aldolase genes that RPM is discussing both encode Class I aldolases.

Aldolase is one of the most important enzymes in the pathway known as gluconeogenesis (glucose biosynthesis). In this pathway two molecules of the 3-carbon compound pyruvate [Pyruvate] are eventually converted to one molecule of the 6-carbon compound glucose. The gluconeogenesis pathway reads from bottom to top in the figure on the left.

One of the key steps in this pathway is the joining of two 3-carbon molecules to make a single 6-carbon molecule. That's the step catalyzed by aldolase. The substrates are glyceraldehyde 3-phosphate and dihydroxyacetone phosphate and the product is fructose 1,6-bisphosphate.

All species can synthesize glucose 6-phosphate using this pathway. It is clearly one of the most ancient pathways in cells. Early on in the history of life—once glucose molecules began to accumulate in the biosphere—there was a need to convert them back to pyruvate and recover the energy that had been used to synthesize glucose in the first place. In most species this pathway was the Entner-Douderoff pathway, a pathway related to the pentose phosphate pathway. It involves another type of aldolase called KDPG aldolase that joins glyceraldehyde 3-phosphate directly to pyruvate.

Somewhat later, new enzymes arose that could get around the difficult steps in gluconeogeneis. These are shown as separated red arrows in the figure. This new pathway is called glycolysis and it represents a more direct "reversal" of gluconeogenesis. All eukaryotes, and most bacteria have the glycolysis pathway. They are capable of converting glucose to pyruvate using a few specialized enzymes and most of the same enzymes used in gluconeogenesis. Notice that the enzymes, substrates and products of the core part of the pathway (from fructose 1,6-bisphosphate to phosphoenolpyruvate) are identical in glycolysis and gluconeogenesis (parallel red and blue arrows). What this means is that flux in this part of the pathway can flow in either direction depending on the state of the cell. This includes the aldolase reaction.

Gluconeogenesis is usually more important than glycolysis. In order to appreciate this, think about plants. They make all of their glucose from carbon dioxide so the only glucose that can be broken down is the glucose that the plants make themselves. It follows that more glucose is synthesized than is broken down by glycolysis. This is true of bacteria, protists and fungi.

The situation in animals is a little different since glucose is an important food source. It's possible that the overall flux in this pathway favors glucose breakdown although even in animals there is considerable glucose synthesis going on.

The bottom line is that aldolase is mainly required for gluconeogenesis and only in animals, and some specialized species (like yeast), is glycolysis more important. In older biochemistry textbooks the emphasis was on glycolysis and not gluconeogenesis. This is because the more classical biochemistry tended to focus on mammalian fuel metabolism (rat liver biochemistry) where glycolysis was important and glucoenogenesis was not. The mammal-centric form of teaching ignored the evolutionary history of metabolism and it's importance in other species.

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[Figure credits: The structure of the class I aldolase is from PDB 2ALD. The class II structure is from PDB 1ZEN]

Norway Is Not a Christian Nation

 
Recent poll results for Norway give this breakdown when it comes to religious beliefs.

• 29 percent believe in a god or deity
• 23 percent believe in a higher power without being certain of what
• 26 percent don't believe in God or higher powers
• 22 percent have doubts

No matter how you slice it, Norway is not a Christian nation.

So, how does this lack of firm religious belief translate into Norwegian society? Are Norwegians immoral, warmongering, and poverty-stricken? Here's a letter to the Montgomery Advertiser that answers that question [Norway flourishes as secular nation].

And what has secularism done to Norway? The Global Peace Index rates Norway the most peaceful country in the world. The Human Development Index, a comparative measure of life expectancy, literacy, education and standard of living, has ranked Norway No. 1 every year for the last five years.

Norway has the second highest GDP per capita in the world, an unemployment rate below 2 percent, and average hourly wages among the world's highest.

Hmmm ... now that can't be right, can it?

How does secular Norway stack up against true Christian nations like the USA and South Africa?

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[Hat Tip: RichardDawkins.net]

Alert! There's a Federal Election Coming in Canada!

 
Garth Turner, the blogging MP, posted this cool pirate flag icon on his website [The Turner Report]. (PZ will be jealous.) It's a reference to a comment by Stephen Harper, Canada's (soon to be ex-)Prime Minister) that the Liberal Party should make up their minds whether to "fish or cut bait" when it comes to supporting his minority government.

It's worth reading what Turner has to say even if it's only to get some idea of what it takes to run a credible election campaign. He estimates that it costs $90,000 in his Halton riding.

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[Hat Tip: Jennifer Smith at Runesmith's Canadian Content (Pirates of Sixteen Mile Creek).]

Posting Comments on PLoS One

 
Okay that's it for me. This isn't worth the trouble.

I tried posting a response on the thread "Is "prokaryotic" an outdated term?" over on PloS One and after getting bumped around to several different webpages I finally ended up with what looked like a response form. I typed in an extremely erudite and well-reasoned response that would have blown everyone out of the water then hit the "Post" button. (There's no "Preview" option on PLoS One. This is highly discriminatory—it works against people like me who need to proofread everything before posting.)

The result of trying to post a comment is the error message shown below. I can close the error window and hit "Post" again but this produces an endless cycle of error messages.


I'm not an complete idiot when it comes to using computers. I'm not going to waste any more time trying to post comments on the PLoS Website.

Is "Prokaryote" a Useful Term?

 
Coturnix (Bora Zivkovic) is the Online Community Manager at PLoS-ONE (Public Library of Science). Part of his job is to get people to post comments on the PLoS websites. [New in Science Publishing, etc.]

So when Bora suggested we get involved in a debate on "Is "prokaryotic" an outdated term?" I hopped on over to the PLoS website and read the comments. I discovered that you have to register on PLoS in order to comment so I went ahead and did that and posted a response to the question.

I don't like registering on websites, it's a painful process, especially in this case 'cause you have to answer a lot of questions. It took me about ten minutes to figure out what to do and to convince the program to let me register even though I didn't want to receive email spam from PLoS. I also had to make up a user ID—Larry_Moran, in this case—because, apparently your name isn't good enough. This is not a very open process.

Theme

The Three Domain Hypothesis
Anyway, the question is important. If you think the Three Domain Hypothesis is well established, then you believe there are two non-eukaryotic domains (Bacteria, Archaea). Furthermore, the eukaryotes cluster with the Archaea according to this hypothesis. Thus, the word "prokaryote" encompasses a paraphyletic group and becomes useless.

But we wouldn't be having this discussion if the Three Domain Hypothesis is incorrect. In that case, the root of the tree might well be a split between eukaryotes and prokaryotes. The point is that the discussion about usefulness of "prokaryote" is really a debate about the validity of the Three Domain Hypothesis and we shouldn't forget that. It's wrong to assume that your side has won that debate and then start to solidify your apparent victory by defining your opponent's point of view out of existence!

Phone this Hotline for Technical Support

 

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[Hat Tip: Canadian Cynic]

You Will Be Assimilated!

 
Canada's ongoing attempt to subvert American culture has been noted by Tegumi Bopsulai, FCD (not his real name). He sends this photograph of a Tim Horton's in Geneva, New York. It's not the one that's farthest south—that distinction goes to the Timmy's in Jamestown NY, as far as I know.

Does anyone have any other evidence of Canada's success? I believe the assimilation is more successful in states like New York than in California. I don't think we're even trying in Texas.

Happy 50th Birthday!

 
50 years ago today we were treated to the continuous "beep-beep" of the first artificial Earth satellite. Sputnik ("traveling companion") was launched by the Soviet Union on October 4, 1957. [Listen to it here.]

It was an exciting time. I remember the thrill of realizing that the space age had truly begun and like many others I tried, unsuccessfully, to find Sputnik in my telescope.

For some, the launch was a traumatic event for another reason. It signaled to the entire world that the Soviet Union was a technologically advanced country. Many interpreted this to mean that science (not technology) education in the Soviet Union was ahead of that in the West. This was not an unreasonable assumption, as it turns out, but not because of Sputnick.

Some improvements in science education were made and, according to popular belief, our students in the West rapidly caught up with those in other countries, only to fall behind again in the 1980's. The truth is certainly more complicated.

Does anyone know of a reliable study of science education in various countries over the past 50 years? What was the real effect of Sputnik in the short term and in the long term?

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[Photo credit: Astronomy Picture of the Day for October 4, 2007.]

[See Bad Astronomy for more information and links about Sputnik I.