Turned up to eleven: Fair and Balanced

Sunday, September 29, 2002

Remembrances (warning: may bore you to tears)
The comment about immunological differences reminds me of my graduate work, so if you will indulge me, here is a brief detour into that very, very boring (to most) realm. My graduate research was into the function of a set of exotoxins (that is, poisonous chemicals) produced by Staphylococcus aureus. In particular, the laboratory I worked in studied proteins called Superantigens. These proteins produce toxic effects by activating the immune system of the host animal in a dysfunctional manner. In a normal immune reaction, a T-cell might be highly specific toward a given antigen, and only ~1/10000 (0.01%) T-cells in the body might react to that particular stimulus. The response is thus tuned, so that only highly specific responses occur. A superantigen interferes with this by reacting with T-cells in a much less specific way, stimulating T-cells in a V-beta specific manner. In brief, there are three complementarity determining regions on the face of the T-cell receptor, and the V-beta (V stands for variable) chain is an important part of this determinant of T-cell receptor specificity. By specifically binding to this region, Superantigens are much more potent stimulants to the immune system. In particular, Toxic Shock Syndrome Toxin-1, one of the first superantigens discovered, is lethal when injected at a dose of 1 microgram in humans. However, in mice, superantigens are much less potent. Comparison of mice and rabbits as experimental models is instructive. Mice can withstand a dose of superantigen (usually Staphylococcal Enterotoxin B) much higher than rabbits. Research into this subject has shown that the responses are quite different, and that some of that difference is explained, not by the different structures in the immune systems themselves, but by differences in the microbial flora. This has been shown somewhat indirectly, by showing how the the different host animals respond to exposure to endotoxin, which is the outer cell membrane lipoprotein (mixture of fats and protein) of gram negative bacteria (like E. coli and Salmonella. It turns out that rabbit immune cells are largely tuned to the bacteria in their intestines, in contrast to other mammals (at least, that is what we know at this point). This may make them particularly sensitive to endotoxin. The reason this is important is that superantigens act to enhance the toxicity of endotoxin, in a mechanism that is as yet not well defined. It may turn out that the toxicity of superantigens is largely due to their "enhancement of endotoxin shock", rather than their specific effects on the immune system (or rather, as less direct consequence of this). An important note here, however, is that the actual structure of the immune system receptor, the immunoglobulin on the surface of the T-cell, is not the determinant. The main determinant of toxicity is not fully understood, but the nature of the microbial flora seems to be an important factor. There is also research that suggests that immune determinants play a role in specifying the bacteria in the gut, so the layers of complexity may continue to grow.

Chimps and Humans, pt II

"Robert Musil" has responded, and then responded again, to my original post. He has proposed some interesting notions, but ones that I think can be largely resolved by recourse to the fundamentals of molecular biology. Now, it seems to me that he is not well versed in the inner workings of molecular biology, which allows him to formulate some very interesting notions about evolution in particular. Nevertheless, I think that my explanation, all compliments aside, perhaps needs a bit of polishing. "Musil" states; (referring to my comments before about "junk" v. "non-junk" DNA similarity)

I think that the "best guess" of a good scientist is worth a lot, and deserves a lot of respect. I also think that a "best guess" is a guess. Further, the proposition that functionality can be expected to constrain genome structure is appealing, as is the corresponding thought that "junk" portions of the genome should be able to drift more.

Two points. 1). I was probably understating the case when I called it a "best guess". There have been many efforts to study human and ape genes, and all have borne out the very close relationship. 2). Functionality certainly constrains genome structure, in highly specific ways.

Moreover, there are plenty of examples of biological systems that serve the same function but seem to have very different structures. For example, the mouse immune system and the human immune system serve the same "function." But the differences betwen the mouse immune system and the human immune system have demolished more than a few immunological theories. It doesn't seem to me to be much of a stretch to ask whether those differences are reflected at the genome level. Of course, primates have more and deeper "functionality" in common than do rodents and humans.

Ah, here is an interesting point. This is, in fact, the core of one of the deepest issues in Molecular Biology, the "structure-function" problem. We know, from years of experimentation, that, within the context of a cell, a given polynucleotide sequence (that is, the gene) gives rise, via several in themselves interesting processing steps, to a single, folded, functional protein (note: I oversimplify, slightly, but getting into alternative splicing would not improve the clarity of this post). A single, folded protein, moreover, has a single function or set of functions. So, given the gene sequence, it is possible in theory to predict the function(s) of a protein. This seems simple, but is in fact incredibly hard, and this single problem has been at the root of biochemistry and mol. bio. research for many years now. We now have very good methods for predicting the "secondary structure" of a polypeptide (there are 4 levels of protein structure), but "tertiary structure is only predicted, at this point, but analogy to known tertiary (often called 3-dimensional or "crystal") structures. But in all of this study, an interesting thing has been found. It appears that there are only a few dozen "folds", that is, general ways that proteins can form 3-dimensional structures. Of course, within each fold there are many variations, but essentially, these proteins of the same "fold" have similar overall shape. So, even though there are essentially limitless polypeptide sequences to choose from (20^n, where n is the length of the sequence), there are very few shapes that seem to work well.

Even more to the point, there are far fewer differences, in terms of the number of genes that vary, between us and, say, corn, than you might think. This is because there is a huge amount of genetic material devoted to "housekeeping" functions. For example, every cell in every organism that exists, or has ever existed, needs to use adenosine tri-phosphate (note to the pedants: very slight exaggeration here, but true in principle). In order to generate ATP, a proton gradient across a membrane has to form. This proton flow across the membrane provides energy to an enzyme that forms ATP. The basis for this process is the chemiosmotic principle, and the overall process is called "respiration". For the purposes of our discussion, the important issue here is that this process is essentially universal, in bacteria, corn, chimps and people. By some estimates, there are several thousand genes in every cell of human bodies that play these sorts of "housekeeping roles. A "simple way" to analyze this is to look at gene expression in different cell types in the body. Every brain, heart, skin, and immune cell contains a large set of genes that simply keep the cell functioning. These genes are a lot less amenable to change than genes for, say, eye color.

So where does this leave us?

But the differences betwen the mouse immune system and the human immune system have demolished more than a few immunological theories. It doesn't seem to me to be much of a stretch to ask whether those differences are reflected at the genome level. Of course, primates have more and deeper "functionality" in common than do rodents and humans.

I think Musil is overstating the case here. In fact, there are tremendous similarities between mouse and human immune systems. Can he name even one "theory" that was "demolished" by the differences? To be sure, there have been drugs tested on mice that didn't work in humans, but that is by no means the same thing. The reality is that the constituents have differences, but the overall function is very, very similar. The more we learn about how the immune system works in general, the better we can understand the observed differences in response.

I think the "mapping fallacy" comments are astute. Biologists do not use this sort of analysis to judge "similarity" in the way that people might judge the similarity of, say, two TV shows. The most important aspect of this, from a working biologist standpoint, is to understand the evolutionary relationship, and to refine our methods for understanding how speciation occurs. To that end, this sort of work is very important.

Thursday, September 26, 2002

Chimps and Humans
"Robert Musil" asks the burning question on everyone's mind;

Where prior studies suggest that 98.5% of the human genetic code can also be found in the chimp, a new study published in Proceedings of the National Academy of Sciences says the true overlap may be only 95%.
My confusion arises because I have never been able to determine from the popular media coverage (such as this linked article) if the "overlap" studies include comparisions of inactive genetic material. If the studies do include such comparisions, then why is it not possible that much of the active human code only overlaps with the inactive chimp code - and vice versa. Wouldn't that mean that a 95% (or 98.5%) "overlap" could be all but meaningless?

This opens the door to a couple of interesting issues. How do we determine how closely related two different organisms or species are, and how do we determine how much of the genome is "used"? Neither is a completely simple question to answer, but I will give it a shot. First, to the matter that Mr. Musil brings up. There are historical reasons for the 98.5% figure that has been commonly been used, but it has borne up under fairly intense scrutiny up till now. The initial studies used a technical analysis called a "CoT curve" (stands for concentration over time). This is also used to define the "complexity" of a genome, in a relative way. The method uses the biochemical tendency of DNA to reassociate after "melting" (heating to separate the two strands from one another), measuring the time it takes for double stranded DNA to re-form. Measuring the tendency of identical strands to reassociate gives a method for determining the amount of "junk DNA" in the chromosome. This is where the early understanding that most of the human genome was "junk" came from. As an aside, it may well turn out that that DNA is actually important, for some structural and regulatory reasons. The classic rehybridization experiment uses a method to tag the genomic DNA from one of the two organisms (say, a radioactive label), and then measures how much of the radiolabel sticks to an immobilized population of unlabelled DNA. There are lots of ways to think about doing this, and I am only giving you one. The point is that you can determine how strongly two pieces of DNA stick together, and this is a chemical way to determine how closely related they are.

In any event, the answer to Musil's query is "No, the comparison is not meaningless". That is, both the repeat DNA and the "useful" DNA seem to be very closely related. (there have been reports of even more closely related genome segments). The initial evidence for this very close relationship was based on DNA hybridization, as outlined above. Later studies, however, based on sequence analysis, bore out the hyb data. So what happened with this newest experiment?

(Incidentally, it is now thought that chimps are not our closest great ape relatives, that we are as closely related to bonobos)

Basically, the experimenter (on the faculty at Caltech, where I work), suggests that previous experimenters have underestimated the importance and prevalence of certain types of genetic change. We tend to think of mutation as being changes in the sequence at a single point (imaginatively called a point mutation), but there are other, perhaps more important ways to change the genetic code. Here are some examples:

Initial sequence: AGCTAGCTAGCT

Point mutant: AGCTAGGTAGCT

Deletion mutant: AGCTAG_TAGCT

Insertion mutant: AGCTAGCCTAGCT

The important thing to not in the latter two cases is that the insertion or deletion can be as long or short as you wish. It could be one base, 1000, up to an empirical limit on the order of a few hundred thousand bases (further investigations may turn up larger insertions). The insertion or deletion may be a result of recombination during DNA replication (someday, if you are very bad, I will explain this in excruciating detail), or as a result of insertion of foreign DNA such as a virus or transposon. Regardless, the end result is a serious disparity between the genomes being compared. So, Dr. Britten suggests, based on his analysis of a few million base pairs of the genomes of chimps and humans (about 0.1%), that we may be off in our estimate, and that it is probably closer to 95%. As far as Mr. Musil's concern goes, this study does not distinguish between "useful" DNA and "junk". The best guess, however, is that there isn't going to be a difference, but that, if anything, the functional genes are probably more similar, because they are constrained by their function. That is, the gene that encodes for hemoglobin is more restricted than an equal sized region that does not encode a gene, because what ever changes that hemoglobin gene, its essential function must be preserved. So, it is most likely that the "junk" DNA is not identical, with all the functional genes varying, but rather the other way around. In this sense, the very close similarity between our "junk" and chimp "junk" is further evidence of our close evolutionary pairing.

Wednesday, September 25, 2002

War and Gore (Al, not the other kind)
So, Al Gore gives a speech, and as Bob Somerby notes, all the cool kids want to know is, "Did he do this to gain a political advantage?" Aside from the insipid "mind reading" of the various pundits (Noonan and Kelly in particular), there has been a great deal of blogorrhea about whether or not he "lied", as many are so fond of saying (I am sure you can see where I am going here). Tim Noah has a pretty sharp rebuttal of the claim that Gore has changed his tune on "regime change", noting that he seems mostly concerned with whether attacking Saddam will disrupt the war on terror by alienating our Arab "allies", as well as Germany and France, who have been helping us capture Al Qaeda members around the world. This seems like a pretty good argument, if a bit complicated for our sound-bite infested news cycle. The "Crooowing" started relatively quickly, attempting to find some bit of "lying". The final result was this passage (via Jay Caruso)

Henry Hanks rules. He found the information I was looking for. Here again, is what Gore said the other day:

Now, back in 1991, I was one of a handful of Democrats in the United States Senate to vote in favor of the resolution endorsing the Persian Gulf War, and I felt betrayed by the first Bush administration's hasty departure from the battlefield even as Saddam began to renew his persecution of the Kurds in the north and the Shiites in the south, groups that we had, after all, encouraged to rise up against Saddam.

And here is what he said in 1991:

"I want to state this clearly, President Bush should not be blamed for Saddam Hussein's survival to this point. There was throughout the war a clear consensus that the United States should not include the conquest of Iraq among its objectives. On the contrary, it was universally accepted that our objective was to push Iraq out of Kuwait, and it was further understood that when this was accomplished, combat should stop."

He can't even tell the truth about something like this, and we're supposed to take seriously the criticism he has leveled at the President?

Pretty damning, right? He clearly was not that upset in 1991, and now he is claiming that he was. Leaving aside the equally poor memories of Bush (Harken, Rangers) and Cheney (Halliburton selling to Iraq), is this pair of quotations fair? Fortunately for Gore's supporters, Hesiod is on the case. A full reading of Gore's April 1991speech, from which the above quote was ripped, brings some context.

"In my opinion, Madam President, and...

I want to state this clearly, President Bush should not be blamed for Saddam Hussein's survival to this point. There was throughout the war a clear consensus that the United States should not include the conquest of Iraq among its objectives. On the contrary, it was universally accepted that our objective was to push Iraq out of Kuwait, and it was further understood that when this was accomplished, combat should stop.

That is also why, after it became apparent that Iraqi forces were being routed, pressure mounted rapidly here and abroad to proclaim a cease-fire.

If it was a mistake to believe that Saddam Hussein would be a prompt political casualty of the war, as the debacle it turned out to be for Iraq, that his rule would end shortly after the defeat of his armies, then that was a mistake widely shared throughout our country.

But only the President could speak on behalf of the United States to suggest that Saddam Hussein ought to be overthrown, and only the President could decide on behalf of the United States to permit the use of Iraqi combat helicopters to suppress rebellion, in clear violation of the understanding of the conditions agreed to at Safwan. The President's appeal was, therefore, arguably a factor in stirring up rebellion.

The President's decision not to ground the Iraqi combat helicopters conferred an important, perhaps decisive, advantage to Saddam Hussein in overcoming rebellion and then in generating the mass, panicked flight with which we are now confronted.

There have been published reports that the United States took other steps to encourage rebellion. I do not know whether that is the case or not. We should know.

Certainly, I am prepared to accept that the President, as an individual, is as shocked and angered at what is happening before our eyes as any American. I believe, however, his initial refusal to act was the result of a conviction he has held and continues to hold about basic American interests in this situation."

This sort of makes it sound like Gore was pretty upset at GHWB, dontcha think? Like maybe that we should have supported the rebellion in Iraq by the Kurds and Shiites that we instigated to some degree, instead of allowing Saddam to put that rebellion down. We had, at that time, total control of the airspace over Iraq. If we had said "No helicopters", that probably would have been it. Now, I wouldn't be surprised if there were good reasons for GHWB's decision, such as pressure from neighboring Arab states, and possibly even Israel, to keep from falling to pieces. Just as an example, it was surmised that the Shiite population of Iraq (~60%, mostly in the south, I believe), might wish to join Iran's theocracy, destabilizing the political balance between Egypt, Saudi Arabia, Syria, and Iran (I am probably oversimplifying). Also, the Turkish opposition to a Kurdish separatist movement may have (almost certainly did) play a role. Nevertheless, it seems to me that Gore can hardly be called a "liar" in this context. He certainly does seem to have been upset that Saddam was not removed from power.

Friday, September 20, 2002

Asthma, Clean kids, and you
What follows is a comment I tried to leave at Gene Expression with respect to this very short post by Razib.

I developed asthma after I came to the United States. This article rehashes the idea that excessive hygiene is causing the increase in asthma rates. I'm not too convinced though, seems like it's more correlation than causation.
(here is the link to the article in the NYT)

That is what the hygiene hypothesis suggests. The suggestion is that environmental exposure induces a state of tolerance in the immune system. Basically, immune cells, in particular B-cells, produce specific responses to antigens, i.e. foreign substances in or on body surfaces. During the maturation of the B-cell, a process called isotype switching is responsible for directing what sort of immune response is attached to each foreign object. In particular, in B-cells, there are four main types of "isotype", called IgM (for immunoglobulin M), IgG, IgA, and IgE. IgM is the "immature" type, present on the surface of the B-cell after it has been produced in the bone marrow and is either circulating in the blood, or resident in the spleen or lymph nodes. IgM is also the first type that circulates in the blood when the B-cell matures into a plasma cell after specific stimulation by an antigen. When the isotype switch occurs (this is one of the few types of non-germline genetic rearrangements known), the B-cell produces one of the other three types.

The switch seems to depend on a number of factors, but is transduced through signals received at the cell surface, and is thus dependent, to large extent, on where in the body the cell resides. IgA is part of the immune response in mucosal layers (the GI tract, for example), IgE is responsible for the histamine response (allergies and asthma are "misfires" of this response), and IgG is responsible for humoral immunity in the bloodstream and tissue. So the propensity to switch to IgE antibodies in response to harmless antigens such as pollens and dust is the root of allergy, and by extension, asthma. This seems to be connected to when in the course of development people are first exposed to these antigens. The hygiene hypothesis implies that early exposure induces tolerance, rather than activation. This is quite complex, but it might be good for me as a refresher in some of the broader concepts of immunology, so I may delve deeper in a future post.

Of course, there is still much to understand about why this occurs, and whether or not being kept too clean is really the reason is open to debate.

I was wrong
Impossible, you say? Well, thankfully, the previous post turned out to be mere paranoia, rather than dreadful insight!
In other news, I am quite pleased about the recent arrests in the war on terror. The med students in Florida thing was a bad scene, and hopefully, it will get sorted out without too much harm done (they should be let back into the med school program they were starting). I will be getting back to the science stuff soon, mainly because I find that I am simply not knowledgeable enough about poli sci etc to make a useful comment. Check any of the links at the left for more insightful comments.

Thursday, September 05, 2002

Distant Early Warning??
Many will recall that in the days prior to 9/11, there was an assassination attempt (successful) on the leader of the Northern Alliance in Afghanistan. In retrospect, it seems to have been an effort to destroy a potential adversary to OBL, and hinder an attempt by the US to retaliate against the Taliban and Al Qaeda. Obviously, it failed, but I find it hard not to notice the parallel between what happened then (assassination of pro-Western leader in Afghanistan) and what almost happened today to Hamid Karzai. Coupled with this very worrying story about a possible break-in at Dugway Proving Grounds in Utah, where a lot of high grade chemical and biological munitions are thought to be stored, and I could start to worry. I have been very critical of our government recently, but I sure as hell hope they are a lot more competent than I have been giving them credit for, and I hope that they prove my criticisms wrong. I also dearly hope I am wrong about all of these coincidences (I didn't even mention the Al Qaeda connected car bomb in Afghanistan, or the huge car bomb that failed to detonate in Israel).

Did I mention that I really hope I am wrong?

A more succint, eloquent statement of my rant

Not by me, of course! Check out Matthew Yglesias on the state of the war on terror. This, IMO, should be how the Dems approach this subject.

Wednesday, September 04, 2002

Back to science stuff
Now that I got that out of my system, I want to comment (gently!) on Charlie Murtaugh's bloggage about "Homeland Insecurity". I read an excerpt of that article, and agree with his assessment of Scheier's analysis, but I wanted to comment on the immune system analogy. Charlie says "I'm sure there's an evolutionary expert out there who will shoot me down, but I strongly suspect that we owe both aspects of our lifestyle to our flexible immune system."

I won't shoot down that assertion, because I think it is true, to a great extent (leaving aside the many other things that play into our lifestyle). Dr. Murtaugh contrasts vertebrates adaptive immunity with the innate immunity that invertabrates possess, suggesting that this may explain the shorter lifespan of insects, and their smaller size. I have to disagree here. 1) there are some fairly large invertebrates, just not insects (outside scary dinosaur movies, that is). You have to look in the ocean, though, because gravity gets in the way (think squid and octopus). Land based invertebrates, insects in particular, utilize an "exoskeleton" to allow for structural integrity; this holds their innards in, and holds their shape. Insects, therefore, have to go through a metabolically costly process of molting to develop (the stages are called instars, I believe). This combination of factors leads to the size limitations (for flying insects, the costs of flight also probably are important). Another thing to remember is that bigger is not necessarily better; factors such as body heat maintenance, predator prey relations, cost of reproduction (ranging from exposure to predation when copulating or raising young to the sheer physical cost of brooding) may play a role in keeping an organism small. Plus, insects have been around a very long time, and have thus developed to fit their particular niche very well, in some sense.

Thus, I would probably take the converse argument to Charles, and suggest that the adaptive immunity that vertebrates utilize is not useful to a small, short-lived, chitinous exoskeleton bearing insect, and thus confers no advantage over the cheap but effective innate system. Incidentally, humans and vertebrates have an extensive innate immune system themselves, which provides a strong first line of defense against infection while the adaptive system is, well, adapting. Evolution does not follow any one path, but rather organisms diverge into different survival and reproduction strategies. For large, endoskeletal vertebrates that have offspring in very small numbers and are slow to mature, a comprehensive immunity to unpredictable disease is a viable survival strategy. Conversely, evolving for rapid maturation, large broods, and short generation times obviates the need for this level of protection against infection.

Tuesday, September 03, 2002

War, what is it good for? (good question!)

I am going to rant and vent a bit now, so those of you who come here for reasoned, well informed, calm opinions can go elsewhere for a while. I am pissed off, and I am going to use my platform to reach my dozen of readers and let them know about it!

What the f*ck is going on.

It is now almost a year since 9/11, and what have we done? The time of memorializing, contextualizing, mourning the loss is upon us again. Wouldn't it be nice if some small change in the ways of the world had occured in this year since the moment "everything changed"? Lets review; Islamist nutjob arranges to crash planes into buildings, devastates us. We fight back by...what? Searching people for tweezers, apparently. Yes, we did fight a "war" in Afghanistan, and succeeded in toppling a weak extremist regime that was harboring terrorists. Unfortunately, we failed to capture or kill those terrorists. Instead, we apparently stood around with our hands in our collective pants while they went and hid in the mountains, or fled to Pakistan. WTF? Shouldn't capturing or killing Bin Laden have been priority A-1**** for a while after 9/11? What in the world could be more important than that? Oh, right, steel tariffs and farm subsidies, making sure no grandma got on a plane with tweezers or a stick of gum wrapped in foil that could be used as a weapon! Also, lets make sure that we protect the rights of gun owners by not checking the records of gun sales, but we won't worry about protecting people against snooping into what they read (by the way, there is a reason the 1st amendment comes 1st, and the 48% of you who think it is too protective of our rights should go move to Saudi Arabia, where they have dispensed with all this silly talk of "rights")

Now, we come to about a year later, and where do we stand in the war on terror? Is Osama behind bars, or in pieces in some Afghan cave? Well, we don't know about the latter, but he sure as hell isn't the former! In a year, the most feared, hegemonic, powerful nation has managed to avoid capturing any major players in Al Qaeda (the guy they have at Guantanamo seems not to have been too high up, from what I understand). Mullah Omar and Osama are off somewhere playing checkers, for all we know. Meanwhile, Dubya and co. seem to have decided that we don't really need to pursue that silly attempt at Justice, and instead should go after the guy who is willing to stand still (Saddam).

Here is my proposal, and I hope some people will take me up on it. Everytime a member of Dubya's administration gets on TV, radio, or gives a speech about going to war in Iraq, someone should start chanting "Where's Osama", and keep it up until they get thrown out of the building. Every columnist in the country should write an op-ed every week, entitled "How close are we to capturing Osama?". NOTHING, with the exception of the very preservation of our country, should be more important than finding that bastard. To do any less is to insult the memory of everyone who died nearly a year ago.