Science, Theory, and Liberty

Update on structures

2010-11-23T12:42:00.001-08:00

First an update on the last one:
The structure of EF-Tu on the ribosome has now been solved with a non-hydrolyzable guanine nucleotide, in the true activated state. The metal ion that I guessed might be there is in fact not, but the ordered region of the effector loop is, in fact, ordered. This will hopefully lay to rest the idea that the elongation factors are activated by DISordering of their active site loops, which was always the biggest eyesore of all the models for their function so far. And the contacts with the ribosome are surprisingly simple, involving mainly just two histidines acting as a "ruler" to measure the orientation of the rRNA phosphate backbone. One is aligned in a phosphate-imidazole-water network vaguely reminiscent of the serine protease catalytic triad, explaining enhanced catalysis.

In addition, the number of G-protein coupled receptor structures has been steadily increasing. A friend asked me when I thought that solving new inactive GPCR structures would become boring, and while I'm sure this point will come sooner than anyone would predict at this time, we still have a ways to go. The family of seven-transmembrane receptors is very diverse, and there will no doubt be peculiarities to some of the more atypical members, like metabotropic glutamate receptors or even weirder ones like Frizzled. Yes, I know the last is not technically a GPCR, though it can be made into one quite easily by merely mutating loops, so I think of it as one. And that's not to mention the 100+ orphan receptors, whose ligand identification may be accelerated if we had structures.

A possible mechanism for elongation factors--finally?

2010-06-15T15:52:00.001-07:00

Like the last speculation, this one involves the ribosome. In particular, the two elongation factors that in bacteria are known as EF-Tu and EF-G. Like all GTPases, these proteins have a catalytic domain that resembles the Ras family of signaling molecules. Clearly, however, the details of the catalysis are distinct. In common with each other, both types of proteins have low catalytic activity on their own (though the quantitative meaning of "low" varies"), and need to be activated by binding to something else in order to achieve rapid catalysis.

In the case of Ras-like proteins, these partners are called GTPase-activating proteins, or GAPs, and they bind to a particular region of the proteins near the phosphates of the bound GTP. Their activity commonly (though not always) involves an arginine side chain that is inserted into the active site and presumably stabilizes the transition state. However, EF-Tu and EF-G are activated by interacting with a particular state of the ribosome. The sarcin-ricin loop, or SRL, of the large subunit occupies a position similar to GAPs in Ras-like GTPases, but in the available structures it makes few contacts to the protein. This is probably due to the fact that one part of the protein, the so-called Switch I segment, is disordered.

Some researchers have suggested that the disordering of this segment is what triggers catalysis, but I am very skeptical of that, largely for the simple reason that I've never seen another enzyme where catalysis is facilitated by decreasing the number or closeness of contacts to the substrate. In fact, the common scenario is the opposite, where loop or domain closures activate enzymes by making the contacts more extensive. I rather suspect that the disorder observed is due to the inability to actually form and trap the GTP-bound, activated form in the crystal. But in any case, the "arginine finger" mechanism, or similar, cannot operate, as there are no positively charged groups of any kind protruding from the SRL.

An intriguing (relatively) recent paper suggested that a GTPase involved in 30S ribosomal subunit assembly, YqeH, uses a potassium ion coordinated near the GTP phosphates to replace the arginine used by Ras. This was based on a previous structural demonstration that a related protein involved in tRNA modification uses this mechanism. Interestingly, both of these GTPases interact with folded RNA in one way or another, which raises the question of whether the elongation factors could similarly use a second metal ion (in addition to the Mg2+ common to all GTPases) to trigger catalysis upon interaction with the SRL. In fact, there is an acidic Asp residue in the P-loop region of both EFs near where this hypothetical cation would have to be.

However, a quick inspection of the structures of EF-Tu and EF-G bound to the ribosome shows that even at the modest resolution, a direct participation of the SRL in the coordination sphere of such an ion is essentially ruled out, at least in the approximate relative positioning of the molecules observed. Therefore, any role of the SRL in electrostatically recruiting a cation would need to be water-mediated. Alternatively, the Switch I region of GTP-bound EF-Tu contains a short helix whose dipole points very roughly toward the Asp in the P-loop, and realignment of this helix upon ribosome binding may provide a way to recruit a cation only upon proper juxtaposition of the two. As no structure exists of EF-G with the switch segments ordered, it is unknown whether this helix exists in that protein as well. It seems that even if a second cation is involved in the mechanism of elongation factors, it will be very difficult to obtain a structure with it present.

Kids and race

2010-05-18T13:21:00.001-07:00

A non-biochemistry post for a change--I'm sure most of you know about the study that shows how much racial bias children demonstrate when asked to judge pictures of people with different skin color. I wanted to respond to the following comment made by author Po Bronson:

"(Parents) want to give their kids this sort of post-racial future when they're very young and they're under the wrong conclusion that their kids are colorblind. ... It's in the absence of messages of tolerance that they will naturally ... develop these skin preferences."

I have to question the use of the word "naturally" here. It seems it is being used to really mean "even though their parents don't teach them to"--when in reality there are plenty of other sources they could pick up this prejudice from, especially other kids. Even young children appear not to be immune to the tendency to take cues from peers in terms of who is "good" and "bad", and be more likely to like a popular than an unpopular classmate.

The study does nothing to determine where these kids picked up their light skin preference, but it surely isn't some sort of simple effect of perceptual familiarity, as the black children showed it too. To call it "natural" is to make it look as though racial tolerance is this difficult thing to master, and that parents are solely to blame when it is lacking.

Fold.it

2010-03-04T21:06:00.000-08:00

Today I found an interesting site called Foldit, where you can download a program that lets you try folding a protein graphically. It differs from sites like Folding@home, which just draw on your computer's spare processor cycles, in that it actually hopes to use human intuition to help solve the protein folding problem, and compare it to the performance of computer algorithms on the same task. I downloaded it, and wanted to give my opinion on it.

First for the pros:
I am very happy (and pleasantly surprised) by the overall idea, that of finding humans who have unique mental capabilities that may be useful for solving real-world problems in biology. It often seems that the only kind of unusually gifted minds (whether you call them prodigies, savants, etc.) that most people know about, or at least care about, are "Rainman"-like human calculators, and then only as some kind of "freak show". I do believe there well could be people who have an intuitive sense of the forces stabilizing proteins, and could fold at least small proteins intuitively, just science never hears of them. And it's not just with this problem by any means. I think there are lots of optimization sort of problems in all areas of science and technology where certain humans could outperform computers--yet the dogma in the field is that there is no use in humans trying to do these tasks themselves.

In the modern world of the internet, I think the time has very much come for people who know or suspect they have such unique talents to network with each other, and share both ideas and life experiences. Whether it is to actually figure out how to use those skills in the real world, or just to relate to the feeling of alienation that arises when one feels his/her thinking style is not accepted by others, this is a definite niche for a social networking site. In fact, it was exactly this type of group I was looking for when I stumbled across Foldit. In case you're wondering, I did not find any such groups, so I will probably be starting one in the not too distant future

But back to Foldit, I quickly realized there are many things that make it less than ideal, both as a way to discover hidden talent and as a means of solving the folding problem:
1) Lack of transparency:
When one looks at the ranking system for users, it becomes clear that the judgment criterion is not similarity to some known native structure, but score by a Rosetta-type scoring function. The specific function used, however, is obscure. If this were just some video game, I could see the makers wanting to keep the exact scoring system secret, in order to not make the game too easy. However, if this is even pretending to be science, then a very open disclosure of the nature of the problem is in order, even if the scoring function is very realistic. One might worry that using a real native structure as the reference would allow cheating by those who know the structure--but CASP has found a logical way around this, by using unpublished structures.
2) Manipulation is unwieldy:
The only way to fold a protein is to bend the backbone by dragging it from one point, and then the rest follows in a "springy" fashion. There's no good way to "tweak" individual residues. Also, there should be some sort of way to specify helix formation and beta-sheet pairing on some global level, and then build these elements as "ideal" units that can then be bent to allow packing.
3) Side chain handling is weird:
Side chains do not have full mobility, they "spring" only to common rotamers that are reasonably clash-free. While this can be useful, especially for beginners, as it prevents really bad things like sticking a methionine through the "hole" in a benzene ring, it also means that it is not possible to stretch a side chain to form, e.g., a hydrogen bond, and then allow the structure to relax with this already made. That goes for everything, in fact--while interactive molecular mechanics is way cool, it's very good to be able to turn OFF the force field, to allow getting out of local minima. Especially when the mechanics is not "real" molecular mechanics. Also, Asp/Asn and Glu/Gln are impossible to tell apart, and the "flip" of Asn/Gln amides is invisible. This is not great for folding, and downright awful for ligand modeling (see below).
4) Ligands are included, but almost definitely not well:
A few of the tutorial levels involve moving a non-protein ligand into position. This was probably introduced to allow enzyme/receptor design. However, one must wonder what kind of force field is used to describe protein-ligand interactions. The whole idea of Rosetta is very "globalist", and for something like ligand recognition, which could be dominated by precise hydrogen bonding and stacking geometries, it is unlikely that this program does it justice. Add to that the insistence that every side chain be in a common rotamer at all times, and it is not even possible to move them into ligand-centric positions. So, the utility of this feature is questionable, in my opinion.

So the conclusion is, two thumbs up for the effort to give human intuition a chance to hack away at real scientific problems. But, this program may well do a rather poor job at this, as well as in predicting structures. It was rather easy to get within the top five scores for some proteins, and yet I did not feel as if I was actually creating good-looking structures. Most likely, the top scorers will be those who can best get around the awkwardness of being stuck in local minima by the limited controls. And if you want to test your ability to predict structures for your own sake (as opposed to impressing others), maybe downloading old CASP targets is a better bet.

Just a crazy idea (warning, technical)

2010-01-14T14:22:00.000-08:00

This is officially the first time I actually say something "serious" about science on this blog. I don't know if there are any who will read this who will have the knowledge to even understand this, but I mainly want to record this somewhere in the off case that it turns out to be correct.

Anyway, I have had a long-standing interest in the ribosome, and recently I read a structural paper in Cell reporting the structure of the ribosome in complex with a ribonuclease called RelE. This is a heck of a weird RNase, as it cuts messenger RNA as it is being translated, in the middle of a codon that's about to be read.

The authors show very convincingly that the RNA is NOT cleaved between the first and second nucleotides of the codon, but that it is cleaved between the second and third nucleotide. In the structure, this site lines up with a site on RelE that corresponds to the active site in a number of related RNases, and that's all well and good.

On the other hand, there's a small (or maybe big) problem here. All possible catalytic residues are more than 5 Angstroms from the scissile bond in both ribosomes, except maybe for Arg 81, which is mutated to Ala. In fact, there is not a single contact made to this phosphate. Furthermore, the 2' -OH nucleophile is positioned in a stereochemically awkward manner, that would require a large rotation of the phosphate to allow attack opposite the 5' -OH leaving group (See Figure 4B in the paper). In contrast, in the related nuclease (Fig. 4A), if you take the phosphate oxygen near the catalytic His 92 as the leaving group mimic, the 2' -OH of the guanine is a nice 180 degrees from it. While a rotation is certainly not impossible, and may be hindered here by the 2' O-methyl modification of the adenine, it seems it would require a significant movement of the guanine ribose.

What is most intriguing, though, is that in one ribosome the next phosphate, the one separating the current A-site codon from the next, appears better poised for attack. Not only would the required rotation of the phosphate be only about 60 degrees, rather than 120 degrees for the preceding phosphate, but this could be well accommodated without much movement of either ribose. In addition, if the 2' -OH were not methylated, it would probably move to hydrogen bond with the N3 of C 1054. Finally, the residue Arg 56 is both near the 2' -OH and the leaving group.

This immediately suggests that there may have been a primordial ribozyme-like activity in which C 1054 activated the 2' -OH of the third nucleotide for attack on its phosphate, and was assisted by some group playing the role of Arg 56, both helping activate the nucleophile and promote leaving group departure. In fact, when I had viewed the pre-cleavage state structure before reading the biochemical evidence for the scissile bond being in the other position, and not being familiar with other RNases, I just assumed that this was the scissile phosphate in the modern RelA.

In turn, this prompted the (maybe crazy) idea that possibly such an activity remains even today, and when the mRNA is cleaved after the third base, this makes the third base (i.e., the G) more mobile, allowing it to better align to be cut again at the site identified by the authors. While such a complicated cascade "violates" Occam's razor, its advantage would be that it provides a way to guard against excessive activity of a potentially toxic enzyme like RelA, particularly if the first cut were reversible.

Unfortunately, only the 5' fragment was isolated. If two successive cuts were made, this fragment would be the same, but the 3' fragment would be one nucleotide shorter, and a free 2'-3' cyclic GMP would be formed. This may be totally off, but on the other hand the thought was too striking not to write down somewhere.

The Swine Flu Song

2009-04-29T23:45:00.000-07:00

I haven't posted on here in a long time, but I just saw this and got an idea that I wanted to share with the world.

A San Francisco man named Stephan Zielinski, who is NOT a biochemist, decided to turn the sequence of swine flu hemagglutinin into a song.

Someone totally needs to take his algorithm and incorporate it into a plugin for one of the structure viewers like Chimera. Then, artists can create audiovisual works in which not only is a protein "played" musically, but the side chain of each amino acid flashes in the 3-D structure simultaneously with its respective sound. In this way, a linear piece of music is made to correspond with a path through 3-D space... How mindblowing.

Membrane protein structures--part 3

2008-07-09T14:55:00.000-07:00

I haven't posted here for a long time, so I decided to summarize a little of membrane structural biology over the last few months.

By far the most exciting advancements have occurred in the field of GPCRs. The Stevens group at The Scripps Research Institute (who also published the adrenoceptor structure mentioned a few posts ago) published a new structure of the same receptor, but with a different antagonist (3D4S). In this structure, a cholesterol molecule was observed in a slightly different location from in the previous one, which led to the discovery of a putative cholesterol recognition motif. Also, Schertler and colleagues at the MRC laboratory in Cambridge solved the structure of the turkey beta1 adrenoceptor with yet a third antagonist (2VT4).

One might think that with the first structures of "real" pharmacologically relevant GPCRs being solved, the relevance of rhodopsin, the previously prototypical member of the superfamily, might be on the way out. However, this is most definitely not a conclusion to jump to automatically, as a recent structure (3CAP) from Park et. al. demonstrates. This is the structure of opsin, which is rhodopsin without the covalently attached light-absorbing molecule retinal. Many of the helices show a change in conformation relative to rhodopsin, and based on some biochemical data showing constitutive activity in opsin, the authors propose that this structure may represent the long-sought active state of the receptor. This structure shows changes of a significantly greater magnitude from dark state rhodopsin than any other structure previously proposed to be activated, and this makes me more inclined to believe that it could actually be active. In fact, I am guessing the shift observed in opsin may be TOO large to represent normal activation, and may represent a partial unfolding of the receptor due to complete loss of the stabilizing effect of retinal. Though much less notable, for the sake of completeness I will add that a structure of squid rhodopsin has also been published (2Z73).

As for ion channels, a bacterial homologue of the Cys-loop superfamily, to which nicotinic and GABA(A) receptors in animals belong, has been solved (2VL0). The ligand of this receptor is unknown, and the low homology with other Cys-loop receptors along with the mediocre resolution mean that this structure will most likely not be useful for modeling studies. Also, this is not recent, but the structure of the acid-sensing channel ASIC1 (2QTS) provides insight into a new fold of ion channel. The most intriguing property of this structure is the fact that the homotrimeric channels show each monomer to be in a different conformation, with some of the differences being large (almost 10 Angstroms). This may be an artifact of the crystal structure, but if not, this would be an unprecedented finding.

In the area of transporters, not that much has happened, although there is a structure of a sodium-galactose transporter by a group at UCLA due to be released soon. Intriguingly, this transporter is related to LeuT, despite a lack of sequence similarity aside from conservation of a few glycines at proposed hinge regions. The fact that this transporter is in the inward-facing conformation, as opposed to LeuT, which was in the outward-facing conformation, should provide insight into the transport mechanism.

Transmembrane pump structure

2007-12-20T22:22:00.000-08:00

We are clearly now fully in the era of the membrane protein crystal structure--it's clear that even being in the greasy environment of the cell membrane isn't going to protect proteins much longer from the X-ray beams of determined structural biologists. This time, the structure is of the sodium potassium pump, also known as the Na+/K+ ATPase, which sets up the sodium and potassium gradients necessary for numerous cellular functions, from simple maintenance of osmotic balance to uptake of nutrients and nerve impulse transmission. Pharmacologically speaking, this protein is also the target of the simultaneously highly toxic and medically useful cardiac glycosides.

I am not nearly as surprised at the publication of this structure as I was at the adrenoceptor structure mentioned in my last post, or the structure of the amino acid transporter LeuT mentioned on here over a year ago, since multiple structures of a functionally very similar ion pump, namely the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase, had been published years ago (interestingly, some newer structures of this Ca2+ ATPase were just released as well).

I skimmed through the paper in which the Na+/K+ ATPase structure is described, and curiously the authors make absolutely no mention of the cardiac glycoside binding site, despite the fact that there is a clearly visible pocket among the amino acid side chains known to be involved in the binding of these inhibitors. Maybe, a discussion of this site was omitted either due to the modest resolution (3.5 A), and/or because the K+ occupied form of the protein, which is (assumed to be) mimicked by the rubidium ions in the crystal structure, is known to have a lower affinity for cardiac glycosides than the unoccupied form. It seems to me that groups like Qiu et. al. were very much on the right track, though.

Shout it from the rooftops...

2007-10-26T02:47:00.000-07:00

... a new G-protein coupled receptor (GPCR) has been crystallized!!! This one is actually pharmacology relevant, and closely homologous to the targets of many clinically important drugs. Namely, it's the beta2 adrenoceptor, bound to the partial inverse agonist ("beta blocker") carazolol. Immediately following a publication of the structure of the receptor complexed with carazolol and an antibody at modest (3.4 A in the plane of the membrane, 3.7 A along an axis normal to this plane) resolution in Nature, Brian Kobilka and colleagues published a high (2.4 A) resolution structure obtained by insertion of T4 lysozyme into the third intracellular loop, which yielded better-diffracting crystals. Congratulations to the Kobilka lab!

Those who have any kind of interest in structure-based drug design will most undoubtedly know how big this news is without me spouting all kinds of hype, and most others probably don't care anyway, so I won't give a long explanation. If you would like some more introduction, Keith Robison at Omics!, Omics! has a post on this. Any pharmacology or structural biology bloggers who actually read this should feel free to link here, write their own post if they think mine sucks, or of course can link directly to the articles as I have done.

The structures are not available from the PDB yet, and I haven't even examined the figures in the paper with the high resolution structure yet (beyond the new Kobilka lab front page graphic, which I just stumbled upon)--I want to see how much I can predict before I actually view the structure in detail. Nevertheless, once they are, I (and undoubtedly dozens of others) will be creating new models of other adrenoceptor complexes, as well as of other receptors in the amine subfamily. It is almost certain that these will be substantially more correct than the previous rhodopsin-based models, however illuminating the latter have been (and what I know about the new structure seems to say that they were not THAT far off).

...Whew! I haven't blogged in over five months, but I just had to say something about this. After a week that started with the southern California wildfires (I didn't have to evacuate, but I was close enough to see the smoke, and the campus has been closed), I receive notice of this. If someone had asked me last week to make a bet, I would have said I would have finished grad school before a drug-bound GPCR structure was published ( I just started this fall--note also that my area of grad study has nothing to do with GPCRs, crystallography, or pharmacology--this is just a personal area of interest). On the other hand, the structure of LeuT a little over two years ago totally caught me off guard too. I guess we're finally coming into the era of the membrane protein crystal structure. Any guesses as to when the first GPCR agonist complex structure will be published?

A little puzzle

2007-05-17T01:53:00.000-07:00

Here's something for whoever reads this blog to try and figure out. Below I have posted what I have tried to make look like an excerpt from a story (it actually isn't from any story). The "plot" is a little disjointed at times I will admit, but there is something "special" about this piece of writing, and that something has to do with the 30 underlined phrases. As a small hint, as I bet many people will think along these lines, the phrases do NOT unscramble to spell something--at least not that I intended. I specifically tried to use a lot of phrases that were unlikely to occur in normal text and/or used rare words--there are many other phrases of the same type I could have used that make sense by themselves, but that wouldn't have been as much of a challenge. I wonder if anyone will leave a guess in the comments.

On to the "excerpt":

"Where shall we direct our forces, at Colombo, in the Niagara provincial territory?"

"It's that or Segovia".

"It doesn't really matter", Davis interjected. "As of now we lack the technology to swiftly encircle the territory. If we attempt our mission like this, word of our approach is certain to reach them in no time, and our attack is sure to be thwarted."

"But in order to make any difference we would need to increase our maneuverability by a thousandfold. Even with state-of-the-art vehicles running on specially nanoformulated fuel, and ultra-multiplexed communication transponders to coordinate the whole process, I don't know if we could do it."

"A thousandfold is veneer compared to the solid gains in speed we could obtain with the necessary equipment. Meanwhile, you simply must put your energy into fourth gear and hope for the best. I'll send a request to our technology acquisition officials through the overnet to notify them that we are in need of an expanded arsenal.

"In terms of increasing energy reserves, what ever happened to the work of Dr. Ramirez? Do you remember what he did when he was still working for Phytovance? I was thinking about that the other day".

"He studied the prospect of using a novel biochemical mechanism, found in the chloroplasts of vacuolate cells in the newly discovered tropical Ephemerides fern, to store chemical energy at an unprecedented density."

"But how much energy could be stored in each single one of his devices, a picojoule?"

"That's possible, but considering how lightweight and compact the microscopic fuel cells he invented are, the discovery could still lead to some immensely profitable patents. It beats our current bio fuels by a decent margin. Just think if you could hold a device in your hand that would supply your average home with electricity for several days. However, I remember hearing allegations that he stole the idea from some other researcher, one who was lesser known in the field."

"Well, the fact that his research into exotic plants was funded using corporate money is a warning. Men do things under the money-moon that they would be wise enough not to under the daylight of pure intellectual discovery."

"Do you know where he lives now?"

"I believe down in Newport, at least that's what I heard from one of my friends who ran into him at a biodevices conference ".

"Hot as a candlewick, Newport is these days. It seems everyone is trying to start up their businesses in the area. In the western part of the city, at least two thirds of the population is parvenu."

* * * *

Egan Morris was flying back to the headquarters of the technological division when the overnet transmission reached him, watching the scenery through a window to take his mind off the stress of the many requests for assistance he had received that day: a heavy volume accumulated in only a little over an hour. The shallow water near the coastline formed a straight turquoise stripe. The spectacular mountain ranges down below stretched as far as the eye could see, and from this height they seemed almost stationary, serpentine valleys filling the gaps between them. As Morris's gaze fell upon them, he was reminded of a poem he had read many years ago:

In December, I on powdery snow-blanketed slopes will gaze
During Christmas and all of it's cheer
I go skiing while I enjoy all the days
'Til the starting of a brand new year

As February a religiosity brings
I do existential thoughts contemplate
Of of majesty and most wondrous things
Hoping springtime will not start too late

In March I meander through valleys and hills
The color of Isfahan granite
I've been lots of places for sure, but this still
Must be one of the best on the planet
My Connecticut

* * * *

Meanwhile, Lawrence Hamford was relaxing in front of the television. An injury sustained from a previous encounter with the enemy had left him with a badly infected cut on his left thigh. He still had not returned to his former condition, but it was nothing that a few days of streptomycin, hearty meals, and rest couldn't take care of. His wife was in the kitchen with their son Ryan, preparing some lunch. Ryan had just finished making himself some eggs.

"What kind are those?", she asked him.
"This is scramble, ma" he replied, the words muddled by the half-eaten piece of bread he held in his mouth.

Hamford got up from his seat and walked into the bathroom to inspect his wound in the mirror. The mirror was small and mounted above a scrappy vanity, one that looked like it had been constructed out of leftover pieces of wood sitting in someone's garage. There were more important things to think about, though, than home improvements.

"So, so calendar, have you got anything for me today", he said mentally to himself as he looked at the calendar on the wall of his kitchen as he walked by.

* * * *

By now the soldiers were in the process of marching across a desert plain. As the their heavy-duty boots impacted the ground, they made a rhythmic plodding sound: "EEFB EFFB FAFB FUFB, EEFB EFFB FAFB FUFB..."

It wasn't long before they encountered the first enemy troops, led by General Williamson. As men opened fire, the thunderous, digitally amplified voice of the General rang out over the plain:
"Philistines and feathered fowl, of war and by my words, to Styx is where you all will go!". General Williamson was a military Bacchus; he responded with such excessive celebration and revelry to the massacre of his opponents armies and to the leveling of their major cities that even his allies were disgusted.

The many roles of the brain cannabinoid pathway

2007-04-20T18:05:00.000-07:00

Now on a more celebratory note: In honor of 4/20, I will post a brief review of the multifaceted activity of the central cannabinoid receptor, CB1, which is expressed in the brain. The peripheral receptor, CB2, also has interesting roles, especially in regulating the immune system, though for the sake of brevity I will omit those here.

For those who do not know, cannabinoid receptors are activated by a set of endogenous signaling molecules known as endocannabinoids, in addition to the marijuana compound THC and various synthetic molecules of multiple structural classes. The endocannabinoids are nearly all esters and amides of unsaturated fatty acids, and the most important are anandamide (arachidonyl ethanolamide) and 2-arachidonylglycerol.

First, probably one of the least surprising roles of CB1 is to control appetite. This has led to the development of CB1 antagonists, most notably rimonabant, as anti-obesity drugs.

In addition, the CB1 receptor is involved in suppressing the release of several neurotransmitters, including glutamate, GABA, acetylcholine, and norepinephrine. It appears that there is a close functional interconnection between the CB1 receptor and the mu opioid receptor, which binds opioid peptides such as endorphins and enkephalins in addition to opium alkaloids like morphine, in the regulation of neurotransmitter release.

The CB1 receptor has been found to reduce seizure-type activity in the brain, as shown here in the hippocampus. One possible mechanism that probably contributes to this effect is a reduction in the synchrony of neuronal firing, decreasing the probability of large spikes of electrical activity. Amnestic at Gene Expression gave a good explanation of this phenomenon a while back. On the flip side, this decreased synchronization may underlie the inhibition of memory by cannabinoids.

CB1 has also shown roles in neurogenesis (differentiation of stem cells to form neurons) as well as differentiation of neurons and astroglia. This points to an overall effect of CB1 activation to stimulate "building up" of the neural network in the brain.

Finally, on a completely different note, the CB1 receptor has shown a role in implantation of the blastocyst (a very early stage of embryonic development) in the uterus. In order for proper implantation to occur, the development of the blastocyst to the point where it is competent to implant, and the development of the uterus to the point where it is prepared to receive the blastocyst, must be synchronized. The blastocyst expresses the CB1 receptor, and the uterus expresses the enzymes necessary to synthesize the endocannabinoid anandamide. It was found that the effect of anandamide on the blastocyst was highly concentration-dependent, with promotion of implantation competence at low concentration and inhibition at high concentration, both of these being mediated by CB1.

Reflections on Virginia Tech

2007-04-20T18:01:00.000-07:00

I would like to say a few things regarding the massacre at Virginia Tech.

First, I think the "blame war" going on now around the incident is very counterproductive. As terrible as this incident was, it is still an isolated occurrence and I don't believe it can be attributed primarily to a general failure in the university, our society, or any other cause outside the specific life circumstances of the shooter.

While Virginia Tech could clearly have been more prompt in alerting students to the news of the dormitory shooting, it is understandable that school officials expected that to be an isolated incident. You can't expect someone to have predicted that the happenings at the residence hall were only the tip of an iceberg. The same goes for the strange plays Cho Seung-Hui wrote for English class. I'm sure there are many students with a macabre imagination who never go on to commit any crimes in the real world. While it certainly would have been kind of students in the class to ask Cho if something was bothering him, and in fact he was offered counseling, I doubt paranoia would have been justified. Finally, on the subject of gun control, he would have probably been able to obtain those weapons no matter how rigorous a background check was, since he (presumably) had no criminal record. Reason has a good article explaining how probably neither ultra-strict or ultra-loose gun control is the answer.

I don't believe that the true blame lies with anyone other than Cho Seung-Hui himself. His shooting was directed at random people, the majority of whom must not have wronged him in any way, so any idea that he was "getting even" is not fitting here, no matter how much he had been made to suffer previously.

However, while I do not "fault" them, I do believe that some circumstances in Cho's surroundings, including his bullying, had some role to play in him becoming angry enough to murder 33 people. It is also sad that he was provided no opportunity for releasing his anger before it built up to such a level. For many more reasons than just the possiblity of creating a murderer, I think we should all think carefully before labeling people "losers" or considering them less valuable just because they don't fit in socially. There is so much more to a person's worth.

I strongly hope that this incident will not lead to increased negative stereotyping of loners, misfits, people who act "strange" but nonviolent, etc. This can only make the problem worse, by making these people less likely to open up and seek help in addressing injustices they have faced. I also hope that more peaceful but weird-acting people will not start to be forced into psychiatric settings in an attempt to "catch the next school shooter". Psychiatry is already used as a means of denying rights to supposedly "crazy" people, though thankfully this is rare due to laws making involuntary treatment very difficult. I would like to see it stay that rare.

An unlikely prank

2007-04-16T23:26:00.000-07:00

This one via Reason Magazine:

In April 2006, TSA officials at Minneapolis-St. Paul International Airport played a prank on a woman and her boyfriend, who were returning from a spring break trip to Mexico. As one of the woman's bags went through the scanner as she was passing through security during her stopover, an alarm went off. The officials took out a souvenir picture and started discussing it, saying "That's it, call police." As more TSA officials surrounded her, she was so scared that she had an asthma attack before being notified that it was an April fools joke. She is still upset about the incident a year later.

Somehow I never would have thought those guys would have been able to get away with pulling a "false alarm" prank like that, in an age where everyone is so paranoid about security that even an obviously joking comment about carrying a bomb triggers a reaction of anxious hysteria. On the other hand, maybe those TSA officials were under so much pressure to maintain an unbroken state of stern vigilance that they needed to use a prank as a way to let off some steam.

Algorithms that could use some re-working (Part 2)

2007-04-08T11:05:00.000-07:00

Having seen this site, I looked up some of the other sites created by one of its creators (Geoff Peters). One particularly interesting one is the Baby Name Guesser, where you type in someone's first name and the program does some Google searches to try and figure out if it's a boy or a girl.

I typed in a bunch of names of people I've met or got off the Internet, specifically trying to make the names as difficult as possible, and I would say it had about a 70% success rate, which is good
seeing as I couldn't have guessed many of the names it got right. The performance was by far the worst for Asian names, as might be expected.

The funny part, though, was when I looked under the 100 most masculine and most feminine names. The 30th most masculine name, according to the software, is "Aargh!", which supposedly is a boy's name 552 times as often as it is a girl's name. I can't imagine anyone except a pirate naming his son "Aargh!" (Just imagine saying things like "Aargh! How was school today?").

In the comments section, one user said that at one time the 5th most popular girl's name was Jackson (it's not anymore). The site also gives what it thinks are famous people with each name, and for "Jackson" it listed "Jackson Street Juice Bar" and "Jackson Daily News"!

I don't really have any suggestions on how to improve this program, because I don't really knpw how it works (other than that it looks for a set of key phrases), and because this problem is much harder than the song identification.

Algorithms that could use some re-working (Part 1)

2007-04-08T10:34:00.000-07:00

A few months ago I found out about a website called SongTapper.com, where people can go to try to find the title and artist of a song just from the rhythm. You tap each syllable of the lyrics on the space bar, and the program tries to guess the song. I would say it worked for about 10-15% of the songs I tried.

Curious about how the site was SUPPOSED to work, I decided to look up the algorithm used by SongTapper. It is a surprisingly simple one, and one that immediately suggests why it performs so poorly. This is how it goes (see "How does it work?" on this page):

1) The sequence of taps is (logically) first converted to a list of time spacings between taps.

2) Next(and this is the iffiest part), the time intervals are re-scaled to normalize the average time to a preset value. In other words, whether you are tapping "Break Ya Neck" by Busta Rhymes or "Come Away With Me" by Norah Jones, the average time interval between syllables as used in any computations is the same. The tempo information that is lost in this step would potentially be able to eliminate a greater number of incorrect matches than any other piece of data derived from the tap sequence.

3)The following step is to translate the sequence of N normalized time intervals into a text string of N-1 characters, with each character indicating whether a given time interval is about the same as, significantly longer than, or significantly shorter than the preceding one, with "significantly" determined by some cutoff. So, for instance, in the fragment "Jin(1)gle(1) Bells,(2) jin(1)gle(1) all(1) the(0) way", the numbers I have stuck in there indicate that most of the gaps seem about of the same length, except the one separating the two lines, which is longer, and the one between "the" and "way", which seems shorter. The program's representation of this would thus be "sudssd", where s=same, u=up (in other words, longer), and d=down (shorter).

4)This string is then matched using a previous algorithm, which I know nothing about, to the database to find the best song. So not only does this method not consider the overall tempo of the piece, it also is oblivious to how much the durations vary. Is one duration 5 times as long as the previous, or just 50% greater?

This algorithm was apparently enough to be able to discriminate among a set of 30 children's songs, but those songs have a more or less similar tempo and tend to have distinctive, well-delineated melodic sequences. For a database of hundreds of more complex songs, the space of possible rhythms is covered more densely and it apparently doesn't work so well (I can't believe I'm THAT bad of a tapper). In fact, over time it gets worse--the first time it was able to get "Hit The Road, Jack", but when I re-tested it today before mentioning it as a working example here, it didn't anymore. In fact, it wasn't able to identify ANY song I tapped today.

I'm sure there are many better algorithms out there that don't throw out so much information. In particular, having been exposed somewhat to the field of bioinformatics, I wouldn't be surprised if some of the approaches used for biological sequence alignment would be of use here. The sets of durations could be compared directly, with some sort of penalty proportional to the difference in the tapping time interval and the time interval stored in the database. Allowing a number of "gaps" (i.e. missing syllables) in either sequence of durations, in which the two durations on either side of the gap would be summed to make a single long duration, would make the program more error-tolerant.

Ecstasy through serotonin

2007-03-23T17:35:00.000-07:00

It has long been known that the recreational amphetamine derivative MDMA (3,4-methylenedioxymethamphetamine, "Ecstasy") causes a massive release of the neurotransmitter serotonin within the brain, unlike most other psychoactive substances of similar structure, which release predominantly dopamine and norepinephrine. It has also been assumed that this effect of MDMA on serotonin is responsible for the unique psychopharmacology of the compound, which is known as an "entactogen" effect.

On the other hand, given the widely assumed role of dopamine as a "pleasure transmitter", it could be suggested that possibly the euphoria produced by MDMA is entirely due to the dopamine released by the drug. This would agree with the pharmacological profiles of neurotransmitter reuptake inhibitors, with drugs that inhibit dopamine reuptake (such as cocaine and methylphenidate) having euphoric effects, and those that only appreciably inhibit the reuptake of norepinephrine, serotonin, or both (like most antidepressants) showing no such effects in the vast majority of the population.

The release of all three neurotransmitters relies on the ability of MDMA to bind as a substrate to the corresponding reuptake transporters, which normally function to actively pump released neurotransmitter out of the synapse. This interaction allows the neurotransmitters to pass backwards through the transporters into the synapse. In a new experiment, Trigo et. al. allowed mice with the serotonin transporter knocked out (SERT-KO) to self-administer MDMA, and found that in fact these animals would not choose to receive the drug. This indicates that the serotonin transporter is indispensible for the reinforcing effect of MDMA.

I would have liked to see a corresponding experiment with dopamine transporter (DAT) knockout mice, as the involvement of SERT does not preclude a simultaneous role for DAT. The only study involving MDMA and DAT-KO mice that I can find assessed hyperactivity and repetitive movements, and found that the baseline hyperactivity of these mice was reduced by MDMA.

In terms of the neurochemistry of reward processes, the results of this experiment support the idea that reward is not mediated solely by dopamine. The more mechanistic insight is that blocking reuptake of a neurotransmitter and reversing its transport are not necessarily functionally equivalent with regard to reward signaling, even though they both increase the level of the transmitter in the synapse. If they were, then given that inhibition of serotonin reuptake by SERT is not reinforcing, serotonin release should not be either.

The latest on microRNAs

2007-02-27T01:25:00.000-08:00

(from Gene Expression)

In the latest new development in the hot field of gene regulation by non-coding RNA molecules, researchers at the Wistar institute found that microRNAs can be edited after synthesis in such a way that only a single nucleotide is changed, but yet the targeting specificity for gene regulation can be completely changed. This is another example of a seemingly universal rule I see emerging from biology, namely that every possible level of regulatory complexity, from genes all the way to proteins, is used in some instance.

Convergent imprinting

2007-02-27T01:18:00.000-08:00

There has been a lot of talk within the last decade or so about so-called epigenetic phenomena, in which the chemical structure of either DNA or the proteins with which it is associated are modified without changing the actual sequence of the DNA bases. Epigenetic alterations of the genome have the potential to transmit information from one generation to the next without the actual underlying genes needing to mutate, allowing faster adaptation.

In mammals, there is a process known as genetic imprinting, which changes the function of genes based on their parent of origin. Anyone with a basic background in the genetics has learned that in sexually reproducing organisms (both animals and plants), half of the DNA in each organism comes from the male parent and half from the female parent, such that each gene has two copies. For most genes, both of these copies are active, so that the observed phenotype is determined by the dominant or recessive properties of the maternal and paternal alleles. However, a fraction of mammalian genes are only expressed if they came from the father and another fraction are only expressed if they came from the mother. The copies that are not expressed therefore have no effect on any of the traits of the offspring. Interestingly, a similar phenomenon has been shown to occur in plants.

Since any evolutionary lineage connecting mammals and plants passes through many ancestor species whose current forms lack imprinting, the development of imprinting in plants and mammals strongly suggests convergent evolution. This recent paper summarizes the great many similarities that have been found in the mechanism of imprinting in these two sets of life forms, including the roles of DNA methylation, histone modification, and chromatin remodeling. Many of the enzymes that create and maintain the parent-specific markers responsible for imprinting in fact are related in animals and plants, indicating that similar machinery got recruited to carry out the process in both.

One question that has generated quite some speculation is why imprinting would have evolved to begin with. At first glance, it seems like imprinting would have been strongly disfavored. If both maternal and paternal alleles of a gene are expressed, then a mutation in one can often be at least partially compensated for by the other, "good" copy, and so automatic silencing of one allele by imprinting would be expected to significantly reduce the ability of the organism to handle mutations. The well-known explanations proposed for the origin of imprinting all involve some form of genetic conflict, driven by the asymmetric involvement of the two parents in early embryonic development. The evolutionary biologist David Haig in particular has done a fair amount of theoretical work on the possible driving forces for the development of imprinting, and interested readers may look up some of his articles if they wish to read more.

A case of the wrong hand

2007-02-27T01:04:00.000-08:00

A perfect example of the danger of blindly trusting the output of computers, as well as the self-correcting nature of science, was provided by the lab of Geoffrey Chang. The work here concerned the crystal structures of several transporters in the cell membranes of bacteria. One, called MsbA, is a member of the class of proteins called ABC transporters because of the part of their structure known as the "ATP-binding cassette" that is involved in providing the energy for transport. MsbA is involved in transporting lipids from one side of the membrane to the other, but it is related to proteins involved in drug resistance, including a protein in cancer cells that enables them to pump out chemotherapy drugs.

Given the difficulty of determining the structures of membrane proteins, Chang's structure of MsbA was seen as a great success. However, major doubt was cast on his results when the structure of another ABC transporter called Sav1866 was determined. Sav1866 is a true multidrug resistance pump, and thus represented a step toward understanding the more pharmacologically relevant members of the ABC transporter family. The problem was, the structure of Sav1866 looked very different from Chang's MsbA structure. In particular, the two halves of the transporter were much more intertwined in Sav1866, such that there was a large twist in the overall structure and that the bundles of helices on each side of the central pore consisted of elements from both halves, rather than a single half as reported for MsbA (see the article with new structure here).

It turns out that the source of the discrepancy is something very simple and totally unintentional. Chang's group used a homemade program to analyze the data, and an error in this program caused two columns of numbers to be swapped. This in turn inverted the coordinate axes (made the structure the wrong hand, as crystallographers call it). This is apparently an easy mistake, but one that is guaranteed to totally ruin a structure. Since the structure was in the low enough resolution range where modeling the atoms into the observed electron density takes some guesswork, the group was still able to build a reasonable model even though the structure was backwards. You can see a figure showing the effect of the reversal in this news article from Science.

Unfortunately, the group used the same data analysis program to analyze another structure, of a bacterial multidrug resistance transporter from a totally different family called EmrE. Once again, they were able to build a satisfactory structure in terms of chemical bonds into their backwards electron density (though I must say I smelled a rat the moment I first saw the structure, due to the fact that the side-chain packing was far worse than anything I'd seen in comparable resolution structures. I cannot comment about MsbA because if I ever saw that one it was too long ago for me to remember what it looked like). All in all, this mistake resulted in the retraction of five scientific papers.

Several researchers have commented on the fact that there were reasons to doubt the proposed sructure of EmrE due to discrepancies with other experimental results. The major lesson here is to double-check all computer output to make sure it is reasonable, both from the standpoint of expected side chain conformations and biochemical data on the protein of interest. While some inferences from biochemical data also can be flawed (i.e. data on residues responsible for substrate binding to enzymes have been shown to sometimes identify residues far from the active site even in good structures), there are cases in which it is worthwhile at least to go over a proposed crystal structure with a fine-toothed comb to make sure everything is reasonable.

Systems biology network maps

2007-02-27T00:52:00.000-08:00

I am in the process of visiting graduate schools now, and I wish to do research in the area of systems biology. For those who don't know what this area is about, it is the study of biological systems as collections of interacting components, which can exhibit complex behavior that is the result of these interactions as opposed to the function of any one component or chemical reaction. This is in contrast to most of the previous work in molecular biology and biochemistry, which typically isolated single enzymes, receptors, or protein complexes and attempted to assign them specific roles in the physiology of the cell ("transcription factor X mediates the response of the cell to low glucose" or "the interaction between proteins Y and Z ensures that translation of the messenger RNA occurs at the correct place and time within the cell").

In order to be able to understand the types of behavior that result from the interactions (phosphorylation, transcriptional upregulation, synthesis of a regulatory small molecule) of proteins, it is necessary to have some idea of how they are linked up in the first place. This brings me to my biggest reservation about going into systems biology (or biology in general for that matter)--even with the tremendous strides made in genome sequencing, microarray technology, techniques for visualizing protein targeting in the cell, etc., there are still many gaps in our current "wiring diagrams" of most cellular pathways. As someone interested in theory, if you are working with one of these pathways that contains such gaps, your predictions will often be incorrect no matter how flawless your ability to predict function from connectivity.

I have done some searching and seem to have found some of the largest "chunks" of wiring that have been mapped out thus far. I would like to briefly mention a few key articles here for anyone who wishes to look these up. Note that this is not meant to be an in-depth summary of the current state of systems biology: there is a lot of work that has been done to characterize lots of smaller interaction networks, though I am going for big diagrams here and nothing else.

Papers by Shen-Orr et. al. (2002) and Balazsi et. al. (2005) investigated the transcriptional regulatory network in E. coli. One article describes the frequency of occurrence of various motifs (clusters of components wired together in a specific way), whereas the other introduces the idea of an "origon", the set of network nodes downstream of a single input.

Lee et. al (2002) reported the connectivity of the transcriptional regulatory network in S. cerevisiae and surveyed the types of motifs present.

Oda et.al (2005) reported what they believed to be a comprehensive map of the epidermal growth factor receptor signaling pathway.

Oda and Kitano (2006) described a signaling map of the Toll-like receptor network, which is involved in innate recognition of pathogens by the immune system.

Farkas et. al (2006) reported the presence of subnetworks in the S. cerevisiae transcriptional regulatory network that appear to be involved in the integration of multiple stimuli.

Week of Science make-up

2007-02-27T00:47:00.000-08:00

My participation in the Week of Science was interrupted by my circumstances surrounding my traveling to interview at Princeton's graduate school, and by the time I got back it had ended over a week before. Disappointed by my inability to contribute more than two posts to the Week of Science, I decided to make up by making four posts with detailed scientific content content in one day. Here they are:

More on torcetrapib, and protein modeling

2007-02-12T19:56:00.000-08:00

While there is much speculation about the reason for the poor results with torcetrapib, if in fact the probelm is due to an off-target effect (i.e. interaction with a protein target other than CETP), then design of new molecules with different chemical structures targeting CETP will be of interest. Also, torcetrapib's stabilization of the CETP/HDL complex may be responsible for some effects in addition to transfer inhibition that may be unwanted (see here for more info). In order to avoid this stabilization, it would be useful to know its structural basis.

Since the crystal of CETP has recently been published, I have decided to model the interaction of torcetrapib with CETP. I have several possible binding modes that I am looking at, though I haven't picked one out definitively, and none of them agree with the experimental data (i.e. all of them involve the competitive binding of torcetrapib to one of the lipid-binding sites in the tunnel, or to a region that overlaps several of these sites).

Although some bloggers (particularly Derek Lowe at In The Pipeline) have raised concerns about the applicability of theoretical models to drug design and pharmacology, I find trying to predict the ways in which small molecules bind to proteins too interesting NOT to do it, even if in the end it proves to be less useful than some would hope. For a while I have had the interest in competing with other people interested in protein structure in trying to predict the binding modes of small molecules, and in real life I don't know enough individuals who share my interest to be able to make this a reality.

I thought that with the notoriety that torcetrapib has achieved, along with the growing segment of the blogosphere devoted to pharmacology, this may be my chance to get some people interested, so if anyone wants to also try predicting the structure of this complex let me know. Then, if someone solves the structure of the complex (which I suspect might be quite soon, given that the protein has already been crystallized and these inhibitors have received such great attention) then we can check the quality of our models.

Structural data in the aftermath of Pfizer's pfailure

2007-02-09T14:09:00.000-08:00

By now I'm sure a lot of you have heard about the disappointing results of Pfizer's Phase III clinical trial of torcetrapib. The reason that it didn't work as expected is still a topic of debate, and is complicated by the fact that torcetrapib was never given alone but only with an existing drug of the statin class. If you want more information about the drug discovery debate surrounding this, Derek Lowe over at In The Pipeline has some info.

This drug was intended to raise HDL (the "good cholesterol") and lower VLDL ("bad cholesterol"), by inhibiting cholesteryl ester transfer protein (CETP). The function of CETP is like a shuttle that can dock to either a HDL or VLDL particle and freely exchange the lipids it has bound to it with those inside the particle. The binding and release of lipids by CETP is nonspecific and is able to occur with both cholesteryl esters and triglycerides, though the concentration differences between the different types of lipoproteins cause net transfer of cholesteryl esters to VLDL and triglycerides to HDL.

Within a little over a month of the disappointing clinical trials, the crystal structure of CETP in complex with four lipid substrates was reported (in fact by scientists at Pfizer as well). The structure revealed that the protein is shaped kind of like a crescent moon (they call it a "boomerang") with a long tunnel inside of it. The tunnel connects two openings in the concave face of the crescent, each of which is plugged by a molecule of phospholipid whose tails are buried inside the tunnel and whose charged head groups stick out toward the aqueous solution. The remaining volume inside the tunnel is occupied by two cholesteryl ester (CE) molecules, and the hydrophobic portions of the four lipids make numerous contacts with each other as well as with the side chains lining the tunnel. One of the openings of the tunnel is partially covered by a helix having one hydrophobic face and one hydrophilic face.

The authors propose that exchange of lipids by CETP involves movement through the channel, such that a lipid exits through one opening while another lipid enters through the other end, keeping the tunnel occupied at all times. Both CE binding sites could also bind triglycerides, allowing them to be exchanged for the CE. In order for transfer to occur, the openings must be "unplugged" by the movement of the two phospholipids into the lipoprotein once it has bound to the concave face of CETP. The radius of curvature of the concave face of the crescent is just right to encircle part of a HDL particle, allowing a tight association of both openings with the lipoprotein surface, though association with the larger LDL requires flexing of secondary structure elements to straighten the CETP. The helix that caps one of the openings presumably assists in formation of a hydrophobic bridge between the core of the lipoprotein and the tunnel.

Back in December 2005, scientists at Pfizer published some data on the mechanism of action of torcetrapib, showing that it stabilizes the CETP-HDL complex. This could be explained in numerous ways, including trapping a particular conformation by stabilizing a fixed shape of the tunnel upon binding, interfering with the capping of the openings with phospholipids, etc. The much more puzzling finding is that, in their experiments, neither CE nor phospholipid (PL) binding to CETP was affected by torcetrapib. CETP that they showed was occupied by torcetrapib still bound ~1.4 molecules of CE and ~1.7 molecules of PL per CETP. In order to explain this, one would have to assume that torcetrapib does not occupy any of the four observed lipid binding sites in the tunnel. If it occupied a CE site, then CE could at most bind 1:1, and if it occupied a PL site, PL could at most bind 1:1. If it partially occupied two of the sites, then binding of both would be reduced. The only lipid whose binding appeared to be reduced by torcetrapib was triglyceride, though any site in the tunnel that binds triglyceride should also be involved in binding one of the other lipids (as demonstrated by the crystal structure). More on this in my next post...

Introduction

2007-02-09T14:02:00.000-08:00

This is a continuation of my old blog, The Libertarian Scientist. I will in general keep the same format, but since I find that I blog more about science than about libertarian ideas, my new blog title has the "science" moved before the "liberty".

This week one of my favorite blogs, Gene Expression, is doing a "just science" week together with a few others, where all posts are about pure science. I'm sort of participating too, which means I'll be starting out by presenting some of my thoughts about some things in the scientific news.