The 2007 Nobel Prize in Physiology or Medicine

 
The winners of the 2007 Nobel Prize in Physiology or Medicine were just announced this morning. This year's prize goes to Mario R. Capecchi, Martin J. Evans and Oliver Smithies for their work on "principles for introducing specific gene modifications in mice by the use of embryonic stem cells."

This is a bit of a surprise. These were not names that came up regularly in Nobel Prize Gossip. Many people, including me, thought that there would be a specific award for stem cells before anyone got the prize for exploiting stem cells. This doesn't mean that todays winners aren't worthy. I doubt that anyone will question the award to Oliver Smithies, for example. I don't know as much about Capecchi and Evans.

See Press release for a complete description of the work of Capecchi, Evans, and Smithies. Here's the summary ...

This year's Nobel Laureates have made a series of ground-breaking discoveries concerning embryonic stem cells and DNA recombination in mammals. Their discoveries led to the creation of an immensely powerful technology referred to as gene targeting in mice. It is now being applied to virtually all areas of biomedicine – from basic research to the development of new therapies.

Gene targeting is often used to inactivate single genes. Such gene "knockout" experiments have elucidated the roles of numerous genes in embryonic development, adult physiology, aging and disease. To date, more than ten thousand mouse genes (approximately half of the genes in the mammalian genome) have been knocked out. Ongoing international efforts will make "knockout mice" for all genes available within the near future.

With gene targeting it is now possible to produce almost any type of DNA modification in the mouse genome, allowing scientists to establish the roles of individual genes in health and disease. Gene targeting has already produced more than five hundred different mouse models of human disorders, including cardiovascular and neuro-degenerative diseases, diabetes and cancer.

---

[Photo Credit: GETTY, Time magazine]

Junk in your Genome: LINEs

Scientists first began to get a glimpse of the organization of mammalian genomes about 40 years ago when they looked at the overall complexity using hydridization technology. It soon became apparent that most of the genome was made up of short stretches of DNA that were repeated thousands of times. One major component of this repetitive DNA was about 6000 bp in length. These sequences were called Long Interspersed Elements or LINEs. The other component was much shorter, about 300 bp. These were called Short Interspersed Elements or SINEs.

We now know that LINEs are a form of retrotransposon. The major human LINE is called L1 and it has two open reading frames (ORF's) that are similar to the gag and pol genes of typical retrotransposons [Retrotransposons].


The LINE sequence (blue, above) is organized like a typical gene with a 5′ untranslated region (5′ UTR) and a 3′ untranslated region (3′ UTR). There are two open reading frames (ORF) encoding an RNA binding protein, a reverse transcriptase, and an endonuclease similar to the retrovirus integrase. Like most transposons, L1 is flanked by a short repeated section of genomic DNA.

The role of the RNA binding protein has not been fully worked out but the roles of the reverse transcriptase and endonuclease proteins are known. When the L1 sequences is transcribed, it can be copied into double-stranded DNA and this copy can be integrated into the genome at a site cleaved by the endonuclease.

The copy-integration scheme is shown in the figure on the left from Current Genetics: junk DNA - repetitive sequences.

The net effect of this mechanism is to spread a copy of L1 to another part of the genome. Thus, L1 is a typical selfish DNA transposon.

The human genome contains about 500,000 copies of L1 but the vast majority are fragments of various sizes. Most of the fragments are missing the 5′ end and they presumably arose when the copying mechanism failed to completely copy the L1 mRNA from the 3′ end. About 10,000 copies are full length (6000 bp) and of these 80-100 are known to be "active." Active L1s have intact ORFs and they are regularly transcribed.

About 17% of your genome is composed of L1 LINEs and fragments. It is one of the major sources of junk DNA in your genome.

The important point to remember is that the active L1 LINEs are constantly producing reverse transcriptase in human cells. This enzyme can copy any available RNA into double-stranded DNA. It is responsible for most of the pseudogenes that litter our genome contributing to the mass of functionless DNA known as junk.

Atheists Spreading the Word

 
On Friday evening there was a 20 minute segment about atheism on CBC's The National. The National is the main evening news program on CBC. The segment is broken up into three YouTube videos (below).

I think it's a pretty good introduction to atheism and I can't imagine that it would have made the evening news a few years ago. No matter what anyone says, the evidence that Dawkins, Harris, et al. have moved this debate into the public realm seems overwhelming. I just don't understand those who think that the "militant" atheists are hurting the cause.

Look for Justin Trottier of the Centre for Inquiry. He's at the beginning of the third video. If you live in Toronto you should come out to our meetings at the centre [Standing Room Only]. It's just a block south of the campus. If you're a student you should join the University of Toronto Secular Alliance. We have many exciting events planned for this year. Watch for "Café Inquiry" coming this winter.

Tea might pose fluoride risk

 
Here's an example of bad science journalism from the latest edition of New Scientist [Tea might pose fluoride risk].

Tea might pose fluoride risk

Tea drinkers beware. Too much of the wrong kind can add significantly to the amount of fluoride you consume, with the tea in just four cups supplying up to one-third of the maximum safe daily amount.

You have to read further in the article to see that it refers to a study done in Sri Lanka where the drinking water contains high levels of fluoride.

In some parts of Sri Lanka drinking water contains up to five times the maximum fluoride recommended by the World Health Organization, and some 98 per cent of people are affected by fluorosis.

The study shows that local tea grown in Sri Lanka contains fluoride so when you make tea with the water containing excess fluoride you get an increased dose of fluoride. Even if you make the local tea with distilled water you still get excessive doses of fluoride with just four cups of this tea.

All this is explained in the article but the headline and the opening paragraph are very misleading. It's only certain kinds of tea that might cause a problem and it's not at all clear whether people in other countries can even buy this tea. It almost seems as though the person who wrote this article was deliberately trying to to scare people in order to attract readers. That's not acceptable science journalism.

---

[Photo Credit: Harvesting tea leaves in Malaysia from Encyclopedia Brintannica]

Psychic Arrested in Calgary

 
A psychic who defrauded someone of $220,000 US ($218,000 CDN) was recently arrested in Calgary. I'm not going to give you the details. You'll have to hop on over to Mike's Weekly Skeptic Rant to find out.

Fortunately, Mike makes it a bit easy to guess the right answer when he proposes this multiple choice question.

So there's this "psychic" who reads palms, gives advice, sees the future; she is on the run from police. The cops are hot on her trail. Does she:

a) use her psychic powers to see where the cops are and how they'll approach?

b) influence the "universe" by putting her desires out there to be realized?

c) go downstairs and sit at the kitchen table with a delicious Hot Pocket and a pistol to await her bullet-ridden showdown with Johnny Lawdog? or

d) realize that her "powers" are non-existent and hide in the closet under some blankets?

Mike also has a useful suggestion for what to do with all the money, assuming it's recovered. Should it all be returned to the "victim"?

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.

---

[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?

---

[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.

---

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