Jennifer Smith Is Going to Meet Stéphane Dion

 
You remember Jennifer Smith, don't you? She lives in Milton, Ontario. That's the place made famous by PZ Myers 'cause he stopped for a few days to get his car fixed.

Well, it turns out that Jennifer went to a town hall meeting with her MP, the newly Liberalized Garth Turner. During the meeting she so impressed her MP that he invited her to meet with our future Prime Minister next week [All Politics Are Local]. (That's Dion in the picture, with his dog Kyoto.)

Hey, Jennifer, ask him if he'll increase reseach funding when we elect him next Fall.

The Low-Fat Diet Flunks Another Test

 
The title comes from an article by John Tierney on his blog [Tierney Lab: Putting Ideas in Science to the Test].

It's not really news. Low-fat diets have been challenged for years. There is good evidence that the Atkins diet really works for some people and it's healthy. Tierny gives us a quotation from a recent New York Times article that reported on a massive study recently completed.

The largest study ever to ask whether a low-fat diet reduces the risk of getting cancer or heart disease has found that the diet has no effect.

The $415 million federal study involved nearly 49,000 women ages 50 to 79 who were followed for eight years. In the end, those assigned to a low-fat diet had the same rates of breast cancer, colon cancer, heart attacks and strokes as those who ate whatever they pleased, researchers are reporting today.

‘’These studies are revolutionary,'’ said Dr. Jules Hirsch, physician in chief emeritus at Rockefeller University in New York City, who has spent a lifetime studying the effects of diets on weight and health. ‘’They should put a stop to this era of thinking that we have all the information we need to change the whole national diet and make everybody healthy.'’

All studies on human diets and nutrition are suspect, in my opinion. It's just the nature of the game. There are always contradictory results.

I'm not going to say that fat is never bad for you. What I say is that you should be skeptical about all claims concerning diet and health. They all need to be taken with a grain of salt (and a pound of steak ). Whenever you hear someone claiming to have all the answers you can dismiss them without a second thought. Nobody has the answers in this field, and that includes Professors, scientists, and physicians.

Intelligent Design Creationism and the History of Life

 
Denyse O'Leary repeats a common criticism of evolution over on Post-Darwinist [Response to student: Darwinian evolution not random?/ ID is God of the Gaps?].

On the face of it, Darwinian evolution is highly improbable or impossible on mathematical grounds. I mean that the history of complex life on earth (600 mya?) does not likely give us the resources we need for the random mutations. Once the Big Bang theory made it possible to establish an age for the universe (approx 13 bya) and the Earth (approx 4 bya), Darwinism was certain to come under attack.

600 million years is more than enough time for complex single-celled organisms to evolve mechanisms of associating to form complex multicellular organisms. This probability argument is just fancy hand-waving designed to impress the uninformed. (The fact that it's also made by the uninformed is ironic, but not surprising.)

But the real hypocrisy of the intelligent design creationist (IDC) community is in not coming up with a better explanation. Here's your big chance, Denyse. Why not give us a thumbnail sketch of how intelligent design creationism explains the fossil record of animals over the past 600 million years? While you're at it, you might throw in a brief description of how IDC accounts for the genetic data. You know, the genetic data that shows a perfectly reasonable rate of random mutations?

None of the IDiots have ever done this. They rant and rave about how improbable evolution is but they never give us an alternative that explains the facts. Why is that?

I'll make it real easy for you, Denyse. You don't have to explain everything. I'll be quite satisfied if the intelligent design creationists can give me their version of shark evolution. You can start with the separation of bony fish from cartilagenous fish about 450 million years ago. How did God do this? Why did He do it?

You can explain the appearance of Orthacanthus about 250 million years ago and why they look so similar to the species that lived a few million years earlier. Then you can tell us why God waited until 155 million years ago before creating the lamnoids that gave rise to modern looking sharks like the big white shark. Along the way, we eagerly await your explanation for why so many of those species are no longer with us. Did God get angry with them or does he just discard them as useless junk whenever He gets around to updating the latest model?

Here's a cladogram to help you out. When can we expect a response?

Science Blogging and Podcasts

 
Hsien Hsien Lei at Genetics & Health is experimenting with podcasts. She's figured out how to put a podcast on her blog. This is impressive. I haven't been able to do it ... yet.

See the result at Genetics and Health Podcast - Reflecting On My Role. I'm looking forward to more podcasts and to seeing how the experiment plays out.

UPDATE: I'm going to try and embed a podcast. Here's the Nature podcast from March 1, 2007 (I hope).


powered by ODEO

CBC

Canada .... hmmmm

 
You have to watch it right to the end ..... I don't know whether to laugh or cry (it's pretty funny).



[Hat Tip: Canadian Cynic]

Fairy Rings

 
I look at the botany photo of the day every day. This is a service provided by the Botanical Gardens at the University of British Columbia and I really appreciate their attempt to wean us away from animals.

Usually the photographs are spectacular closeup images taken with cameras that are much more expensive than mine. But yesteday's picture was from Google Earth! It shows 100 year old fairy rings near Kensington Palace in central London. The rings are probably caused by Marasmius oreades. Find out how a little fungus can make rings visible from so high.

Innocent Man Released from Jail

 
Mahmoud Jaballah is called a "terrorism suspect." He has been in jail for five years but he's never been found guilty of anything. That means he's an innocent man according to my sense of justice and he'll remain innocent until proven guilty.

Yesterday he learned that he will soon be released. Today's Toronto Star has the story [Terror suspect ordered freed].

Toronto terrorism suspect Mahmoud Jaballah will be released on strict bail conditions after more than five years in jail without charges, despite government protests he remains a danger to Canada.

His release comes on the heels of last month's Supreme Court ruling that struck down an immigration law as unconstitutional and deals another blow to the government's handling of security cases involving non-citizens.

Yeast Mitochondria

 
There's a paper in this month's issue of Developmental Cell that uses the technique of electron tomography to examine the fine structure of a yeast cell. This technique involves slicing the cell into many thin sections then taking electron micrographs of each section and reconstructing a three-dimensional model of the cell.

The species is the fission yeast Schizosaccharomyces pombe and the results are spectacular. The image on the left was part of the Bio News Net press release.

The emphasis in the paper is on the organization of microtubules. Those are the thin green lines runing down the length of the cell. It turns out that many of the vesicles and mitochondria are associated with these microtubules. Here's the abstract of the paper ..

Polarized cells, such as neuronal, epithelial, and fungal cells, all display a specialized organization of their microtubules (MTs). The interphase MT cytoskeleton of the rod-shaped fission yeast, Schizosaccharomyces pombe, has been extensively described by fluorescence microscopy. Here, we describe a large-scale, electron tomography investigation of S. pombe, including a 3D reconstruction of a complete eukaryotic cell volume at sufficient resolution to show both how many MTs there are in a bundle and their detailed architecture. Most cytoplasmic MTs are open at one end and capped at the other, providing evidence about their polarity. Electron-dense bridges between the MTs themselves and between MTs and the nuclear envelope were frequently observed. Finally, we have investigated structure/function relationships between MTs and both mitochondria and vesicles. Our analysis shows that electron tomography of well-preserved cells is ideally suited for describing fine ultrastructural details that were not visible with previous techniques.

One of the most interesting things about this paper is that it illustrates the structure of mitochondria. Look at the picture on the right from their paper. The gold things are mitochondria and they appear to be stuck to microtubules. Individual mitochondria are shown in the inserts in order to illustrate the convoluted and branching structures of those that are associated with microtubules. (The one labelled "G" is not stuck to microtubules.)

Most people don't realize that mitochondria are so complicated. Furthermore, the structures are dynamic—they can change significantly in the space of minutes.

Höög, J.L., Schwartz, C., Noon, A.T., O'Toole, E.T., Mastronarde, D.N., McIntosh, J.R., and Antony, C. (2007) Organization of Interphase Microtubules in Fission Yeast Analyzed by Electron Tomography. Developmental Cell 12: 349-361.

James Randi and Richard Dawkins

 
It's a shame when you get two smart people like this on the same stage and all you get are banalities. The audience must have been very disappointed.

Nobel Laureate: Paul Hermann Müller

 
The Nobel Prize in Physiology or Medicine 1948.

"for his discovery of the high efficiency of DDT as a contact poison against several arthropods"


Paul Hermann Müller won the Nobel Prize in 1948 for is discovery that DDT was an effective insect poison [see Monday's Molecule #16 and DDT Blocks the Voltage-Gated Sodium Channel]. Müller was looking for a contact poison that would protect plants from insects. He extended the work of others who discovered compounds that could be applied to wool to prevent them from being ruined by moths. These compounds resembled DDT but they were not as effective. Müller's approach is described in the presentation speech ...

Paul Müller went his own way and tried to find insecticides for plant protection. In so doing he arrived at the conclusion that for this purpose a contact insecticide was best suited.

Systematically he tried hundreds of synthesized organic substances on flies in a type of Peet-Grady chamber. An article by the Englishmen Chattaway and Muir, gave him the idea of testing combinations with the CCl3 groups, and this then finally led to the realization that dichloro-diphenyl-trichloro-methylmethane acted as a contact insecticide on Colorado beetles, flies and many other insect species under test. He determined its extraordinary persistence, and simultaneously developed the various methods of application such as solutions, emulsions and dusts.

In trials under natural conditions Müller was able to confirm the long persistent contact action on flies, Colorado beetles and gnats (Culex).

Subsequent work revealed that DDT was effective against a wide variety of insects and was harmless to mammals. Among the insects that were killed by DDT were lice, the carriers of thyphoid, and malaria mosquitos.

At the time, Müller was working for the J.R. Geigy Dye-Factory Co. in Basel Switzerland and he had given samples of DDT to the Swiss Army for testing. The results demonstrated that insect borne diseases could be controlled by DDT.

At that time, the Allied Armies of the West were struggling with severe medical problems. A series of diseases transmittable by insects, diseases such as typhus, malaria and sandfly fever claimed a large number of victims and interfered with the conduct of the War. The Swiss, who had recognized the great importance of DDT, secretly shipped a small quantity of the material to the United States; in December of 1942 the American Research Council for Insectology in Orlando (Florida) undertook a large series of trials which fully confirmed the Swiss findings. The war situation demanded speedy action. DDT was manufactured on a vast scale whilst a series of experiments determined methods of application. Particularly energetic was General Fox, Physician-in-Chief to the American forces.

In October of 1943 a heavy outbreak of typhus occurred in Naples and the customary relief measures proved totally inadequate. General Fox thereupon introduced DDT treatment with total exclusion of the old, slow methods of treatment. As a result, 1,300,000 people were treated in January 1944 and in a period of three weeks the typhus epidemic was completely mastered. Thus, for the first time in history a typhus outbreak was brought under control in winter. DDT had passed its ordeal by fire with flying colours.

By the late 1950's it became apparent that extensive use of DDT to control insects leads to its accumulation in the environment. This, in turn, leads to its concentration in the tissues of some animals, such as fish. The long term build up of DDT causes illness and death and it was finally banned in most countries in the 1970's.

Alcoholics Anonymous: 12 Steps

 
This month's reader's Digest has a couple of articles on Alcoholics Anonymous. The gist of the articles is that the famous 12 steps really don't work all that well. Apparently, there's no data to support the claim that Alcoholics Anonymous is successful at getting people to stop drinking.

I had no idea what these 12 steps were until they were published in the articles I read yesterday. For those of you who don't know, here they are [Alcoholics Anonymous]. I'm not surprised that this isn't a magic bullet but I am surprised at how religious AA must be. They must think that most alcoholics are Christians.

THE TWELVE STEPS
OF ALCOHOLICS ANONYMOUS

1. We admitted we were powerless over alcohol ﾗ that our lives had become unmanageable.
2. Came to believe that a Power greater than ourselves could restore us to sanity.
3. Made a decision to turn our will and our lives over to the care of God as we understood Him.
4. Made a searching and fearless moral inventory of ourselves.
5. Admitted to God, to ourselves and to another human being the exact nature of our wrongs.
6. Were entirely ready to have God remove all these defects of character.
7. Humbly asked Him to remove our shortcomings.
8. Made a list of all persons we had harmed and became willing to make amends to them all.
9. Made direct amends to such people wherever possible, except when to do so would injure them or others.
10. Continued to take personal inventory and when we were wrong promptly admitted it.
11. Sought through prayer and meditation to improve our conscious contact with God, as we understood Him, praying only for knowledge of His will for us and the power to carry that out.
12. Having had a spiritual awakening as the result of these steps, we tried to carry this message to alcoholics, and to practice these principles in all our affairs.

Atheists: Get Out of the USA!

 
From my [confined] space comes this copy of a letter to the editor. I don't know which paper it appeared in.

Let me know if I can help out. I can arrange temporary residence in Canada and help you find a good job. I'll teach you how to speak Canadian and how to go about cancelling your health insurance. I can even put you in touch with someone who will buy all your guns.

I'll even treat you a curling broom and a Toronto Maple Leafs sweater to help you get adjusted as quickly as possible. Do you like poutine?

DDT Blocks the Voltage-Gated Sodium Channel

 
Monday's Molecule #16 is 1,1,1-trichloro-2,2 bis(p-chlorophenyl) ethane, better known as DDT. DDT is a powerful insecticide. It binds to the voltage-gated sodium channel and locks it in the open state. Prolonged influx of sodium ions causes the nerves to fire repeatedly and this causes death of the insect.

The reason DDT is so powerful is due to its specificity. It binds to insect channel proteins but not to those of other animals (or plants, fungi, protists, and bacteria). Thus, it is an effective insecticide used to fight malaria and other insect borne diseases.

Unfortunately, even though DDT is not immediatly toxic to other animals it does have one disadvantage: it is extremely stable—its biological half-life is about eight years. Furthermore, DDT is stored in fatty tissues and its buildup in birds and fish resulted in considerable loss of these species. That, coupled with the evolution of DDT resistant insects, led to a ban of DDT in most countries by the 1970's.

Rachel Carson is largely credited with launching the environmental movement in 1962 with the publication of Silent Spring. The title refers to a world without birds. While I was writing this up I did a quick survey of the graduate students in the nearby labs and none of them had ever heard of Rachel Carson. Not only that, neither had several of my colleagues. I feel old.

One of the main targets of Silent Spring was DDT. By the time the book was published it was estimated that DDT had saved the lives of millions of people through prevention of malaria and thyphoid but it's effectiveness was much diminished. That's why the ban was not as controversial as it might have been.

Let's look at the biochemistry of DDT. We have already learned about the simple voltage-gated potassium channel. The Na⁺ (sodium) channel is closely related to the K⁺ channel protein. Recall that the K⁺ channel consists of four identical subunits surrounding a central hole through which K⁺ ions enter the cell.

The Na⁺ channel protein is much larger than the K⁺ channel subunit because it consists of four of the smaller subunits fused into a single polypeptide chain. The tolopology of the Na⁺ channel protein is shown below.

Each of the domains (I-IV) corresponds to a single subunit of the K⁺ channel. Like the K⁺ channel, the four domains of the Na⁺ channel protein are arranged around a central tunnel through which sodium ions enter the cell. The S5 and S6 helices line the tunnel.

The toplogy diagram above shows the locations of mutations conferring resistance to DDT and similar drugs. Each one represents mutants identified in resistant houseflies, fruit flies, mosquitos, or moths. The important mutations are substitutions at the 932 position normally occupied by leucine (L932) and at the 929 position normally occupied by threonine (T929) (blue dots). For example, the substition of isoleucine for threonine at 929 (T929I) confers almost complete resistance to DDT.

Incidently, the methionine at 918 (M918) is what confers sensitivity to DDT in the insect voltage-gated Na⁺ channel. Other animlas have a different amino acid at this position and they are not sensitive to DDT.

O'Reilly et al. (2006) modeled the structure of the Na⁺ channel using the known structures of the K⁺ channel proteins. This is necessary because the Na⁺ channel has not been crystallized. It's an excellent way to get a structure when you know that two proteins are homologous (descended from a common ancestor).

From the model, the authors were able to focus on the probable site of DDT binding based on the known mutations to resistance. In this case, they looked at the interface between helix S5 in Domain II and nearby helices S6 from Domain II (IIS6) and S6 from Domain III (IIIS6), which packs against IIS5 in the structure. They tried docking various insecticides in this region and came up with a good fit in all cases. The DDT binding site is shown below.

Note that the side chains of T929 and L932 interact directly with DDT. These are the sites of mutations to high levels of resistance. It looks like changes to these amino acids prevent binding of DDT and that's the basis of resistance.

The S4-S5 linker helix is shown in yellow in this figure. Recall that this is the helix that responds to membrane potential by reorienting to a more vertical position. This, in turn, shifts the S5 and S6 helices to more vertical postions and closes the channel. In the presence of DDT the S5 and S6 helices are effectively cross-linked and they cannot shift to a position where they move closer together. This prevents closing of the channel. DDT locks the channel in the open conformation leading to a continual influx of Na⁺, uncontrolled firing of the nerve, and eventual death.

O'Reilly, Andrias O., Khambay, Bhupinder P. S., Williamson, Martin S., Field, Linda M., Wallace, B. A., and Davies, T. G. Emyr (2006) Modelling insecticide-binding sites in the voltage-gated sodium channel. Biochem. J. (2006) 396:255–263.

Joni Mitchell Sings About DDT

 
Here's part of the lyrics from Big Yellow Taxi. I don't know about the rest of you but I'd much rather watch and listen to Joni Mitchell than Al Gore or David Suzuki. You may not recognize the song until you hear her sing it.

They took all the trees
Put 'em in a tree museum
And they charged the people
A dollar and a half just to see 'em

Don't it always seem to go
That you don't know what you've got
Till it's gone
They paved paradise
And put up a parking lot

Hey farmer farmer
Put away that DDT now
Give me spots on my apples
But leave me the birds and the bees
Please!

Voltage-Gated Ion Channels

 
Cells have to import and export ions in order to survive. Since ions are charged molecules, they do not pass through the cell membrane. This means they have to be transported by proteins that are embedded in the membrane.

There are many different kinds of transporters. Some of them use up energy to move ions across the membrane by a process called active transport. Some of them simply open a channel and allow ions to pass through. Let's look at some channel proteins.

A typical channel protein consists of several subunits arranged around a central hole that permits passage of ions. In this case we'll be dealing with ion channel proteins that allow movement of Na⁺ (sodium) or K⁺ (potassium) ions from the outside of the cell (top) to the cytoplasm (bottom). The part of the protein that spans the membrane is usually an α helical region. In fact, there are usually several α helices in a channel protein.

The flow of ions must be regulated, so these channel proteins must be capable of opening and closing to allow or restrict the flow of Na⁺ or K⁺. This is why they're called gated channels. There are several ways of controlling the gate. We are going to be discussing mechanisms that respond to the membrane potential—the difference in charge on either side of the membrane. For example, the wave of membrane depolarization that occurs as a nerve impulse, or action potential, moves along the axon of a nerve cell.

These channel proteins are called voltage-gated ion channels.

The simplest kind of voltage-gated ion channels are the K⁺ (potassium) channels found in bacteria and in eukaryotes. The role of potassium channels is to allow influx of potassium if the concentration inside the cell drops below some minimal value. Normally the concentration of K⁺ in the cytoplasm is about 100 times greater than the concentration outside the cell because K⁺ ions are actively transported into the cell as Na⁺ ions are pumped out. The concentration of Na⁺ outside the cell is about 10 times higher than the inside concentration.

From time to time, these concentrations are perturbed (e.g., during the firing of a nerve impulse) and the sodium and potassium channels will open to restore the resting state concentrations. The gates in the ion channels will only open for 1 millisecond but this is enough to allow entry of thousands of ions per channel.

The structures of several bacterial K⁺ channels are known and recently the structure of the homologous channel from rat was solved. The structures are very similar. Let's look at the rat voltage-gated K⁺ channel (Longe et al. 2005a; Long et al. 2005b).

The complete channel consists of four identical subunits colored red, green, yellow, and blue in the figure on the left. The crystallized protein has an additional β subunit at the bottom attached to the T1 cytoplasmic domain but I've removed it in order to simplify the description. The β subunit contains an oxidoreductase activity that's coupled to the influx of potassium.

If you look at the structure of the single red subunit you can see that it consists of a bundle of four transmembrane α helices labelled S1-S4 on the left and two others (S5 and S6) on the top right. The S5 and S6 helices are the ones that form the central channel when the four subunits come together. This is most easily seen in the top view at the bottom of the figure. The black dot in the middle represent a K⁺ ion about to pass through the channel.

The structure shown is the open conformation that allows passage of ions. The closed conformation was modeled from the known structure of the bacterial channels and experimental data that implicated the S4-S5 linker helix in the gating process. You can see this linker helix in the figure above. It joins the S1-S4 bundle to the S5, S6 bundle. It is not one of the transmembrane helices. The results are shown below.

In the closed conformation, the S4-S5 helix responds to changes in the membrane potential by twisting from a horizontal position to a slightly more vertical position. This causes the S5 and S6 transmembrane helices to also adopt a more vertical orientation. Since the same conformational change occurs in all four subunits, the net effect is to make the entire protein more narrow and this closes the channel in the middle of the protein. The switch between the open and closed conformations is extremely rapid and it is very sensitive to changes in the membrane potential.

Long, Stephen B., Campbell, Ernest B., MacKinnon, Roderick (2005a) Crystal Structure of a Mammalian Voltage-Dependent Shaker Family K+ Channel. Science 309:897-903.

Long, Stephen B., Campbell, Ernest B., MacKinnon, Roderick (2005b) Voltage Sensor of Kv1.2: Structural Basis of Electromechanical Coupling. Science 309:903-908.