Thursday, February 23, 2006
Wednesday, February 22, 2006
Personally, it's once again plain ridiculous to get so upset over this sort of thing because it just makes people more curious. If nobody said anything about it, I doubt anyone would realise its existence except for the people that watch South Park, which is pretty much renowned for being offensive to just about everybody. Now, instead of a boycott they've just managed to stir up much more interest in the the cartoon. In fact, I have to concede that even I am more than a little curious as to what the show contains and may even watch it, when otherwise I wouldn't have bothered. With various calls to ban the cartoon as well, it once again raises the issue of where free speech should and should not be protected. In this case, although I'm 100% certain the cartoon is just a load of idiotic nonsense, I again support the TV company for sticking to their guns and displaying the cartoon anyway.
No matter how 'offended' something makes you, there is always a solution that actually works and that is even built in to every TV remote. It's called an "off" switch. Some people need to get more familiar with it.
Tuesday, February 21, 2006
You know, I find the very ideals surrounding holocaust denial to be generally reprehensible, especially with how much historical fact is frequently abused to various degrees. In this case however, I think the Austrian court has done the wrong thing. Simply because D. Irving has a particularly controversial and somewhat misguided view of history, however much it concerns the suffering of some six million people, he should not have been jailed for his views. Jailing him will simply make him out to be a martyr and goes against the sort of principles that 'democracy' supposedly stands for.
I'm beginning to wonder more and more if people think that free speech should go only as far as those you agree with. If that is what free speech is supposed to be, then it sounds somewhat more like a dictatorship of the majority rather than a true democracy. Just because someones views are repugnant/inflammatory doesn't automatically mean they should be jailed for it.
Also, Ocellated has some further comments that I thought were dead on.
Friday, February 17, 2006
In any event, while I have been resting off this delightful trip, it turns out that the 28th skeptics circle has been posed over at Unused and Probably Unusable. So if you've been itching to read some skeptical writing, I would certainly head on over there and indulge.
Thursday, February 16, 2006
Also, make sure you look at this comic currently doing the rounds at the moment. I have my Klingon costume ironed and ready for the coming reckoning, do you?
Wednesday, February 15, 2006
Like I said, I should have known this was probably still going on. I remember when I had chicken pox in first grade, and my cousin brought her three kids (who were my age--tangled family tree and long story) over to our house with the purpose of infecting them. It worked, and within a few days there were 6 of us spotted kids. But--this was in 1982, long before the introduction of the varicella vaccine here in the United States. Chickenpox "parties" were deemed a better alternative to potentially encountering the disease as an adult--when the frequency of serious complications is higher.I find it more than morbidly fascinating that anyone would deliberately hold 'parties' to spread an infectious disease. I can almost picture what the event must look like, with children performing the chicken dance while spitting in each-others mouths. Sadly, I got my various childhood diseases without much celebration let alone having my friends over to collect on my misery as well. That the practice apparently continues even today is a bit curious as well, although I suspect it might have something to do with parents misinterpreting the hygiene hypothesis. A vaccine is perfectly acceptable immune stimulation as a real 'virulent' organism is. This is because the same processes that make a vaccine work are the same that allow your immune system to destroy an invader to begin with.
This was quite the revelation as well:
So far, I've escaped with little more than a few scars on my forehead (I admit, I was a scratcher) and the ugliest childhood picture *ever*, since I decided to do some surgery on my bangs while I was pocked--resulting in about quarter-inch long, very crooked bangs. Did I mention I also had giant pink glasses and a few missing teeth at the time as well?Indeed, quite the image and I double/triple/quadruple dare Dr. Smith to post said picture. :D
A parliamentary select committee hearing has been told that inmates are more likely to reoffend if they have been involved in one rehabilitation programme.Looks like someone needs to re-think how these are run.
Tuesday, February 14, 2006
Today, unlike in the previous examples the threat of biological weapons is much greater, because technology has advanced to the point where we can simply design our own pathogens to be more effective weapons. Indeed, there has been a lot of concern over the potentials of newly altered biological weapons as potential WMDs (Weapons of Mass Destruction). The candidate list for organisms is also pretty long including such former greasts as smallpox as well as anthrax, plague, bacterial toxins like botulism, ebola and even influenza. As a result, being able to determine the hallmarks that would give away a potentially human designed organism could be essential in stopping it.
For example, an engineered strain of a virus could have entirely different functions compared to the normal wild-type. An organism that typically doesn't spread very easily person to person, could be engineered so that it is able to be aerosolised and spread through the air. This would greatly increase its ability to cause general havok by more rapidly spreading throughout the target population. The question that arises is how to determine if an organism is designed by human techniques, or if the pathogen is just another example of a newly emerged pathogen that has arisen by evolutionary processes.
This distinction is in fact fairly difficult to make in reality. Virulent microorganisms are highly capable of switching their genetic material around between one another by a process called Horizontal Gene Transfer (HGT). HGT involved numerous different mechanisms, but microorganisms are capable of simply grabbing DNA that is in the environment (say from other dead cells releasing it), circularised stretches of DNA often containing unique genes called plasmids, viruses can transfer genes from one organism to another (including between entirely different kingdoms) and even mobile stretches of DNA called transposons. A number of pathogens today, like several of the dreaded 'superbugs' that are found in hospitals such as MRSA (Methicillin Resistant Staphylococcus aureus) are the direct result of past HGT events.
So what sort of features would give away a pathogen that was designed by humans? Well this determination can only be made not by some irrelevant 'probability' calculation but by understanding the methods, motives and limitations that humans have when engineering new organisms.
Painting a scenario of a potential biological attack:
In this hypothetical scenario, patients manifesting signs of a rapid respiratory disease have been found in New York city with a nasty cough, quickly followed by a rapid scepticemia after a few days and almost inevitable death. Doctors observe to their horror that patients fail to respond to all front line antibiotics and the CDC (Centers for Disease Control) are rapidly called in to investigate. Their investigations simply confirm what health authorities already suspect, the disease in question is pneumonic plague caused by one of mankinds oldest enemies, Yersinia pestis. However, investigators are particularly worried by the complete unresponsiveness to the key antibiotics used to typically treat plague streptomycin, chloramphenicol and tetracycline. Most clinical strains of Y. pestis are nearly universally susceptible to antibiotics it raises a disturbing prospect: Is this a newly emerged and potentially epidemic quality kind of plague?
Even more agitating to investigators is another possibility that this is not a natural organism, but is instead the product of tampering by individuals attempting to utilise it as a weapon. Investigators have good reason to think this is a possibility, as in 2001 letters containing anthrax spores were distributed to several senators. Although only 5 people were killed and 13 infected, it was a pertinent reminder of the willingness and ability for potential terrorist organisations to employ biological agents. The source of these attacks is still unknown even to the present day and the perpetrator could still be at large. That investigators could be looking at a biological weapon with more on the way becomes a very real prospect.
The first step in combating the new strain after appropriate quarantine measures are taken, is to sequence the genome of Y. pestis strains collected from infected patients, as well as any extrachromosomal elements such as plasmids. Once done, investigators begin their analysis and their attention is immediately drawn to a large plasmid not normally associated with strains of plague found in America. Sequencing reveals the presence of a region of the plasmid with almost 4 different antibiotic resistance genes. Resistance plasmids are not particularly new in terms of Y. pestis, as highly multidrug resistant strains have already been found existing naturally in nature. Investigators analysing the strain immediately recognise something unusual, each of the genes is linked together by sequences exactly matching those recognised by restriction enzymes.
Restriction enzymes are the workhorses of clinical microbiology, biotechnology and genetics. Restriction enzymes are produced by bacteria to defend themselves from attacks from viruses called bacteriophages. By recognising specific repetitive sequences in the attacking viruses DNA, they prevent an infection by essentially chopping the viral genome into bits. One of the unusual properties of some of these enzymes is that when they 'cut' the target DNA they leave overhanging stretches of DNA. These overhangs can then be used to string together different genes that have been cut by the same restriction enzyme. Potentially as well, these enzymes could be used to string together antibiotic resistance genes and virulence factors needed to make a new biological weapon.
The investigators soon discover that this region of the plasmid containing the antibiotic genes are indeed linked by restriction enzymes, specifically using two that are very commonly available, EcoRI and BamHI. While this leads weight to the conclusion that the organism could have been designed by humans, it does not immediately indicate that this is the case. Genes for resistance have been used in biotechnology for numerous years, including in applications on plants and other transgenics including modified bacteria. In many cases, the antibiotic resistance genes are used as markers to select for bacteria that support the plasmid for replication purposes. After insertion into a plant or similar, the gene is useless for the plant but is still kept as a passenger into the environment.
As a result, it is theoretically possible that the genes on this plasmid are possibly derived from antibiotic markers used in standard genetic engineering. This could potentially explain the structure of this antibiotic group as a simple leftover from their previous application. Ruling this hypothesis out will require a deeper investigation into what antibiotic markers are commonly used in genetic engineering and particularly the question "how could Y pestis have aquired these genes?". Further, numerous important clues to the origin of this organism await to be found on the chromosome of this new strain and the plasmid it carries.
Anisimov A.P., L.E. Lindler and G.B. Pier (2004). Intraspecific diversity of Yersinia pestis. Clinical microbiology reviews, 434-464
Galimand M., A. Guiyoule, G. Gerbaud, B. Rasoamanana, S. Chanteau, E. Carniel and P. Courvalin (1997). Multidrug resistance in Yersinia pestis mediated by a transferable plasmid. The New England Journal of Medicine, 337:677-680.
Roberts R.J. (2005). How restriction enzymes became the workhorses of molecular biology. PNAS, 102:5905-5908.
Salyers A.A. and D.D. Whitt (2002). Bacterial Pathogenesis: A molecular approach 2nd edition. ASM press, Chapter 13:203-215.
Monday, February 13, 2006
Saturday, February 11, 2006
In its role in immunity, the ability to bind different peptides and recognise a wide range of different immunological insults would encourage diversity. In reality, the answer is not so obvious and the actual mechanisms that maintain MHC diversity are not properly understood. For example, although MHC regions between vertebrates have a similar structure being clustered together in single gene complexes, as comparisons between the gene regions that comprise the class I and class II MHCs in mammals and chickens reveal key differences. Mammalian MHCs have a lot more diversification among their loci while in chickens the B-complex codes for only two class I and two class II genes, of which only one of these genes is actually polymorphic.
Even with the different structures in other vertebrates, there is emerging support that MHC diversity is encouraged by an arms race against infectious parasites. Malaria in particular seems to be driving the diversification of different HLA class I and II haplotypes. Going back to chickens, there is strong evidence to associate the presence of certain class II MHC alleles with susceptibility to Mareks disease induced by a herpes virus, which causes a potentially lethal T-cell lymphoma. Similarly, studies conducted on mice indicate that mouse MHC haplotypes (H2 in this case) play important roles in determination of susceptibility to infection with Mycobacterium tuberculosis.
With this link in mind it leaves the question as to the mechanisms that caused the divergence in the first place. As Piertney and Oliver detail (see Piertney S.B. and M.K. Oliver (2006). The evolutionary ecology of the major histocompatibility complex. Nature, 96:7-21 for more information on this topic) there are two main hypotheses that propose to explain this high diversification. The first is negative frequency-dependant selection, where new or rare alleles may be selected when organisms are exposed to a novel pathogen. Essentially, picture a group of animals that have just been exposed to a debilitating new organism such as ebola. Some isolated members of the population may have a MHC allele that makes them more resistant than others in the population. As the pathogen spreads, those with the resistant MHC allele are able to breed more successfully than those without it and the frequency of their respective MHC increases.
Over time however, the original epidemic starts to wane due to the increased amount of resistance the original pathogen begins to hit a brick wall. As it can no longer spread as easily, due to the build of immunity combined with resistance, selection would favour pathogens that are not recognised by this allele or alternatively the emergence of a new pathogen. Corresponding to the original situation, if other members had a slightly different MHC allele that rendered them resistant to this new pathogen the frequency of their MHC type will increase. After repeated rounds of assaults from new microbial challenges and this rise and fall of different alleles being favoured, inevitably leads to the distribution of multiple MHC types.
Alternatively, another explanation called the overdominance hypothesis proposes that MHC diversity arises from heterozygosity at the MHC loci. Essentially, because humans have two different copies at their MHC alleles that can produce a wider array of different peptide chains. This allows for the recognition of a larger number of potential microbial structures than an individual who was homozygous (two of the same MHC allele). As a result, individuals with the least overlap between the peptides they produce would be favoured and be able to respond to a wider array of different pathogens.
It is worth noting that these two processes of negative frequency-dependant selection and overdominance are unlikely to be mutually exclusive processes (teach the controversy!). Determining how these processes affected selection in the past is also very difficult, as natural populations tend to be of relatively small sizes and may be challenged by several pathogens at once. Of course, selection and maintenance of new MHC alleles may not simply be just from selection from parasitic relationships. Evidence also suggests that sexual selection may be equally as important in maintaining diversity in both humans and in animals.
Recalling that in part I, a proposed original function for a proto-MHC like molecule was as a mechanism to ensure that organisms maintained a more diverse gene pool. It turns out that MHC in current vertebrates may play a role in sexual selection. This was first observed in studies with mice, where females preferentially mated with males who were MHC-dissimilar to themselves and vice-versa. How mice (and possibly other animals including humans) determine how similar a potential mates MHC alleles are is probably complicated, but is theorised to be heavily dependant upon olfactory (smell) senses. This is because the makeup of MHC genes can affect the concentration of violatile acids that make produce odour in sweat and urine.
One clear example where MHC molecules were found to profoundly affect mate choice appeared in the Proceedings of the National Academy of Sciences (PNAS) last year. The paper by Milinsky et al (referenced below) investigated if the peptides produced by MHC of the three spined sticklebacks (Gasterosteus aculeatus) could interact with the animals olfactory senses. Their results give strong evidence that MHC molecules can influence sexual selection, as fish preferentially moved into water with peptides produced from different MHC and not into water demonstrating similar peptides that their own MHC would produce.
Over this three part series I have detailed only a very narrow range of the total research that has gone into the evolution of this critical system. From beginnings as a simple mechanism to prevent asexually producing organisms from reducing the diversity of their gene pools to a critical component in immunity, the modern MHC is an example of a complex system built from simpler precursors over evolutionary time. Clearly important in this system was the original whole genome duplications that gave rise to modern jawed vertebrates some 766 and 528 million years ago. These allowed for the duplicated genes to be co-opted and diversified to form the required systems for the modern MHC function. Additionally, selection pressures from parasites and even sexual selection continue to ensure that MHC genes remain highly diverse.
In all, there are still a great deal of unanswered questions surrounding both the origins of this system and how such large gene diversity was derived. Unfortunately, there may never be definitive answers to these questions, as many of the organisms that developed the first immunological novelties have long since gone extinct or modified their original systems. It is important however, to realise that scientists working on this field have provided numerous important insights into the mechanisms of evolution and how systems such as the immune system arose. Even more importantly, that researchers continue to publish giving us even greater insight and furthering our understanding, even if it may never be truly complete.
Messaoudi I., J.A. Guevara Patino, R. Dyall, J. LeMaoult and J. Nikolich-Zugich (2002). Direct link between mhc polymorphism, T-cell avidity and diversity in immune defence. Science, 298:1797-1800.
Milinski M., Siân Griffiths, K.M. Wegner, T.B.H. Reusch, A. Haas-Assenbaum, and T. Boehm (2005). Mate choice decisions of stickleback females predictably modified by MHC peptide ligands. PNAS, 102:4414-4418.
Pichugin A.V., S.N. Petrovskaya and A.S. Apt (2006). H2 complex controls CD4/CD8 ratio, recurrent responsiveness to repeated stimulations, and resistance to activationinduced apoptosis during T cell response to mycobacterial antigens. The society for leukocyte biology, 79:1-8.
Piertney S.B. and M.K. Oliver (2006). The evolutionary ecology of the major histocompatibility complex. Nature, 96:7-21.
Hill A.V. (1999). The immunogenetics of resistance to malaria. Proceedings of the Association of American Physicians, 111:272-277.
Friday, February 10, 2006
As stated in part I, as a general rule there are two main classes of MHC that are important in aquired immunity in vertebrates namely class I and class II. For simplicity, I'm going to restrict the discussion to the MHC class I complex for the remainder of this post. MHC class I molecules load peptides that have been processed by intracellular proteases and present them on the surface of cells. This process occurs in nearly every cell in the body, with the exceptions of sperm cells and some neurons. As MHC class I molecules load peptides that have been derived from the proteins produced by the host and those produced by potential invaders such as viruses, this makes them critical in immune function for tolerisation of the effector cells that initiate immune responses.
The proteins involved in MHC class I presentation, called the endogenous pathway as it occurs in cells is shown in diagram 1 below, adapted from Danchin E. et al, the major histocompatibility complex origins (full sized image recommended!).
Here the process can clearly be seen starting with the processing of endogenous antigen by a cellular proteasome. This enzyme slices the protein up into a series of small peptide bits, that can then be processed further and fed into the endoplasmic reticulum (ER in the diagram) by the Transporter associated with Antigen Processing or TAP1 and TAP2. Inside the endoplasmic reticulum, the two MHC class I heavy chains are assembled with the help of proteins called molecular chaperones. These chaperones help to stabilise the protein while it is being assembled and prevent it from falling to pieces. Calnexin (Cnx in the diagram) is the classical chaperone involved early on with others following during the process. Once assembled, the peptides transported through into the ER are complexed with the MHC class I and then the entire assembly of the class I MHC+peptide are secreted onto the surface of the cell.
Overall this seems pretty complicated and it raises questions as to how such a complicated system arose to begin with. As with many questions in biology, the answers lie in the study of the past and the evolutionary history that all organisms share. The origin of this system can be traced back to two large duplication events in the genomes of two classes of organisms: the first during the split some 766 million years ago between the jawless fish such as lampreys and jawed fishes, which later gave rise to higher vertebrates (including us!). This first duplication event is not thought to have given rise to the adaptive immune system, instead a second duplication event some 528 million years ago in the last common ancestor of jawed vertebrates is likely to be where this system arose.
So what makes these large scale duplications so important when it comes to the evolution of the immune system? At least initially in most cases the duplicate is just performing the function of the original gene without much of a change in function, but due to the lesser impact of selection on the duplicate it is prone to building up mutations. In many cases, rather than perform a new function the gene is simply obliterated by the accumulation of mutations that render it inactive. Alternatively, the duplicate may be functional and diverge to freely take on a new function later down the line.
Even more dramatic is an event where an entire organisms genome becomes duplicated doubling the chromosome number. These large increases in genomic content (or ploidy) are actually fairly common in plants and fungi. Once these sorts of duplications occur, the spare genes are free to mutate and particularly can be "co-opted" or have their functions altered for their use in other systems. Generally, a protein can be co-opted without a 'shift' meaning the duplicated genes function is retained without much of an alteration. Alternatively, the gene can have its function altered (co-option with shift) and do something that it normally didn't do or even have a new function added.
Predictably, many of the genes that now function in the endogenous pathway for MHC class I presentation have their roots from these ancestral duplicated genes. For example, at the start of the entire pathway is a large multi-subunit protein called the proteasome. This enzyme is responsible for the chopping up of endogenous antigens into peptides suitable for loading into MHC class I molecules. It turns out that similar proteasomes in organisms such as the fruit fly Drosophila melanogasta and in yeast produce peptides that are similar to those loaded onto MHC molecules. It is probably quite likely that such a proteasome is an example of a protein that has been co-opted for a new function without a substantial shift in biochemical behaviour.
Conveniently, phylogenetic studies (Clark M.S. et al) conducted on the three main catalytic proteins in the immunoproteasome, PSMB8, PSMB9 and PSMB10 replace the functionally similar ones in the normal proteasome PSMB5, PSMB6 and PSMB7. This indicates they have arisen from a duplication of three similar ancestral proteins after the seperation of the jawed and jawless vertebrate lineages. As would be expected, both the cellular proteasome and the immunoproteasome produce peptides that can be loaded onto MHC molecules. The original more ancestral like catalytic unit (PSMB5, PSMB6 and PSMB7) has more or less been co-opted without any alteration in behaviour. Additionally, in the immunoproteasome the PSMB8, PSMB9 and PSMB10 subunits have mutated and become more specialised, producing more specific peptides for loading onto MHC.
Another example of a protein co-opted for use in the endogenous pathway for MHC expression are proteins called molecular chaperones. Calnexin, which is involved with the complete assembly of the final MHC complex by stablising the two heavy chain is already present in eukaryotic cells. In its specific case, the gene has been duplicated twice with calnexin maintaining its original function and the duplicate calmegin, has been completely altered in function for a role in the function of sperm. This example again emphasises the importance that duplications followed by co-option and mutation of the spare gene play in the evolution of complex systems.
The TAP1/TAP2 transporters that are responsible for moving peptides into the endoplasmic reticulum are also the result of ancestral gene duplications. Three genes involved in peptide transport, TAP1/TAP2 and another protein ABCB9, belong to the adenosine triphosphate-binding cassette (ABC) family. These proteins are again all related from a single common ancestral gene that was duplicated and diversified sometime after the jawed/jawless vertebrate split. In evidence of this, phylogenetic studies have found orthologs of ABCB9 in the lamprey genome but not for TAP1 or TAP2.
Possibly the most compelling evidence for the evolution of the MHC from ancestral duplication events followed by co-option of the newly derived genes comes from the genomic structure of the MHC regions. The clustering of genes involved in the MHC pathways, the the previously mentioned MHC I, MHC II and MHC III regions maps similarly to a primitive 'proto-MHC' like region in amphioxus. Most interestingly, it was discovered through these analyses that the MHC class I region genes were translocated fairly recently from the ancestral location in the mammalian lineage, which is not the norm in other jawed invertebrates. This discovery led to the hypothesis that the ancestral proto-MHC like region has existed before the split between protosomes and deuterosomes some 800 million years ago. Considering the bloc duplications of the MHC region, scientists were able to determine that this hypothesis was correct. A proto-MHC region has been present in the common ancestor of protosomes and deuterosomes, giving more clues as to the origins of the vertebrate immune system.
Although this post has ended up a little long, the details given here are only scratching the surface of the large and fascinating field of research surrounding the origins of the immune system. In summary, the current MHC region is the product of multiple duplication events in several proteins localised around a pro-MHC like region existing since the protosome/deuterosome split. Additionally, many of the genes critical for immune function have been duplicated from other ancestral genes and then co-opted for new functions involving immunity. The concluding part of this series tommorow will further examine the environmental selection factors that maintain such an unusally diverse range of MHC alleles.
Danchin E.G., V. Vitiello, A. Vienne, O. Richard, P. Gouret, M.F. McDermott and P. Pontarotti (2004). The major histocompatibility complex origins. Immunological reviews, 198:216-232.
Danchin E.G., L. Abi-Rachel, A. Gilles and P. Pontarroti (2003). Conservation of the MHC region throughout evolution. Immunogenetics, 55:141-148.
Phylogenetic analysis of the proteasome subunits.
Clark M.S., P. Pontarroti, A. Gilles, A. Kelly and G. Elgar (2000). Identification and characterisation of a beta proteasome subunit cluster in the Japanese pufferfish (Fugu rubripes). The Journal of Immunology, 165:4446-4452.
Papers and a good textbook article on gene duplications
McLysaght A., K. Hokamp and K.H. Wolfe (2002). Extensive genomic duplication during early chordate evolution. Nature Genetics, 31:200-204
Gu X., Y. Wang and J. Gu (2002). Age distrubution of human gene families shows significant roles of both large- and small-scale duplications in vertebrate evolution. Nature Genetics, 31:205-209
Alberts B., A. Johnson, J. Lewis, M. Raff, K. Roberts and P. Walter (2002). Molecular Biology of the Cell 4th edition. Garland Science Taylor and Francis Group, pages 40-41;459-462.
Thursday, February 09, 2006
The immune system of vertebrates is basically responsible for organising molecular weapons that destroy pathogens attempting to attack the host. This process is exceedingly complicated and starts with the recognition of invading organisms by cells such as dendritic cells and macrophages. On the surface of these sentries are molecules that recognise PAMPs (Pathogen Associated Molecular Patterns), which include structures such as bacterial LPS (Lipopolysaccharide) and peptidoglycan (a bacterial cell wall structure). These sentries can then pick the invader up and degrade it intracellularly to present the invader to other cells. Alternatively, most other cells in the body can recognise pathogens as intracellular organisms like viruses proteins are degraded. These are then presented on the surface of the cell for the immune system to survey.
Importantly this raises the question of how the immune system recognises what is ultimately a friendly cell and one that is infected. After all, when the immune system gets it wrong and attacks self tissue things quickly spire out of control. To solve this dilemma, cells of the immune system are 'trained' as to what is friendly and what isn't by special molecules called the major histocompatibility complex or MHC. These molecules are what macrophages and dendritic cells mount the peptides they produce on after degrading invaders. Similarly, cells that have degraded viral proteins or similar also display the chopped up protein on MHC on the surface of the cell for the immune system to survey. Additionally, they also display chopped up proteins that have been produced by friendly cells and these are critical in 'tolerising' the immune system so it knows what friendly proteins should look like. Although this is important as well, I won't be discussing this particular part of the immune system in this post so we'll leave that particular story as is for the moment.
There are two general classes of these MHC molecules that are important in the immune system performing the same sort of function. The first is MHC class I that is produced by all cells with the exception of sperm and certain neurons. This is the MHC molecule that mounts proteins that have been degraded by cells generally and displays both microbial and 'self' antigens. As it's responsible for sensing what is happening inside a cell these molecules are mostly involved in cell mediated immune response against intracellular parasites. A second class of MHC, conveniently called class II, is produced by the aforementioned macrophages and dentritic cells upon degrading invaders they have found.
With this critical function in immunity it raises interesting questions as to how the MHC came to evolve and then become incorporated into a proto-immune system. The first obvious question that needs to be considered is what the original function of the proto-MHC molecules were. As it turns out, some clues as to the origin of the MHC is revealed in some of the simplest chordates alive today. In a paper in Nature(1), Anthony W. De Tomaso et al, investigated a primitive chordate called Botryllus schlosseri, which has an unusual mechanism for ensuring sexual diversity. These animals produce a small tadpole like larvae that moves around eventually settling to form an immotile colony.
Although seemingly unexceptional, when two seperate colonies of this organism meet they can have a widely different reaction. In one particular scenario the colonies may fuse together, while in another they reject the other colony and remain unfused. This results from the fact these colonies form structures at their periphery called ampullae, which are sites where a kind of MHC like molecule interacts with the other colony they have encountered. The molecule, called FuHC (Fusion/Histocompatibility) has hundreds of different alleles, similar to that of vertebrate MHC molecules and if similar to the other colonies FuHC alleles causes the ampullae fuse so the colonies share a single blood supply. If the FuHC alleles are not in common, then the ampullae go into a 'rejection' mode, destroying themselves preventing vascular fusion.
In this scenario, FuHC is acting as a mechanism not for immunity but for maintaining a more diverse range of genes among Botryllus schlosseri. When two colonies of Botryllus schlosseri fuse very often one of the colonies gametic expression becomes the norm and the other fails to be able to spread its genes. Naturally, the effect on the organisms would be to lower the amount of diversity in their gene pool if this occured more often. The FuHC system as a result plays an interesting role in maintaining the diversity of the organisms gene pool and preventing them all from reducing the diversity of their gene pool. Perhaps most tantalising, is the possibility of discovering potential effector cells similiar in function with vertebrate Natural Killer (NK) cells that are responsible for the destruction of cells at the ampullae that do not match.
Although the FuHC story gives an interesting insight into the possible origins of the MHC in vertebrates, it's unlikely to be a direct homologue. This is due to the fact FuHC is structurally different to the vertebrate MHC, in that its immunoglobulin domains do not directly correspond. In any event, this molecule gives key insight into the possible functions of a proto-MHC molecule that are still shared today.
The discovery of the MHC was one of those numerous 'fortuitous' things in science, where looking for the solution to one problem led to the discovery of something entirely different. These molecules were discovered while looking for the mechanisms that determined graft rejection, as it turned out individuals with different MHC molecules to the graft would end up having their immune system attack it. This is because the hosts immune system sees the grafts MHC molecules (among other things) as non-self and goes on the attack. Genetic mapping revealed that these genes were all clustered in the same genetic context with three general regions (The MHC I region, the MHC II region and the MHC III region, which is ironically in the middle of the MHC I and MHC II regions).
So in this scenario I have (hopefully) shed some light on the possibly origins of the vertebrate MHC from a simple molecule that serves to differentiate cells to aid in sexual diversification. Tommorow, we shall continue investigating the wealth of evidence for the evolution of these molecules, with an important discussion as to the mechanisms that acted to produce the human immune system: namely gene duplication and a process called co-option. Additionally, I'll also discuss the means that selection acts to keep the genetic diversity of MHC in humans so unusually high.
De Tomaso A.W., S.V. Nyholm, K.J. Palmeri, K.J. Ishizuka, W.B. Ludington, K. Mitchel and I.L. Weissman (2005). Isolation and characterization of a protochordate histocompatibility locus. Nature, 438:454-459.
Also used (extensively used in tommorows post):
Danchin E., V. Vitiello, A. Vienne, O. Richard, P. Gouret, M.F. McDermott and P. Pontarotti (2004). The major histocompatibility complex origins. Immunological reviews, 198:216-232.
Piertney S.B. and M.K. Oliver (2006). The evolutionary ecology of the major histocompatibility complex. Heredity, 96:7-21.
Wednesday, February 08, 2006
I guess this is some sort of 'win'.
Alas, science is a communal enterprise, and it is the community of scientists which decides which claims are refuted, and which stand. They do so mostly by voting with their own hands, so to speak: scientists will choose to use in their daily work, to formulate new hypotheses, to design experiments and to pursue intellectually, those claims they think are valid, and ignore those that are not. In this respect, the contrast between the vibrant field of evolutionary biology, with its continuous stream of publications and its numerous applications (in biotechnology, genomics, medicine, etc), and ID, which by Behe’s own admission has generated close to nothing in terms of scientific output of any kind (including non-peer-reviewed works), could not be starker and more damning.Exactly. Behe believes that so long as he remains 'unconvinced' that the evidence for the immune system evolving (for example) is insufficient, then by some sort of almost divine edict it somehow becomes the responsibility for other scientists to prove him wrong. Science does not progress by claiming the moon is made of cheese then demanding NASA prove you incorrect. Instead, you need to prove there is cheese to begin with and then the responsibility of coming up with a better explanation falls on your detractors.
Tuesday, February 07, 2006
1) Although the opinion’s phrasing makes it seem to come from my mouth, the remark about the studies being “not good enough” was the cross-examining attorney’s, not mine.Really? Is that really the case Dr. Behe? You seem to have a very short memory for certain statements that you've made.
From the trial transcripts, we have Behe saying:
Oh dear, looks like Dr. Behe is remembering the events of his own testimony at the trial rather differently than what actually happened. Much like how the 'peer review' of his book, Darwins Black Box was different than what he understood. In any event he does indeed imply they are 'not good enough'' and yet:
Q. You were asked some questions about the immunity system, and Mr. Rothschild gave you some books and articles and piled some papers on top of you. Do you remember that?
A. I do remember that, yes.
Q. And you claim that you didn't find these examples all that persuasive, correct?
A. That's right.
2) I was given no chance to read them, and at the time considered the dumping of a stack of papers and books on the witness stand to be just a stunt, simply bad courtroom theater. Yet the Court treats it seriously.This seems to be a direct contradiction of terms. Dr. Behe, did you find them 'unpersuasive' or had you not bothered reading them to know to begin with? If you hadn't read them, how are you to determine they are not persuasive, which is certainly interpretable as 'not good enough' unless you are already entering with the idea nobody could disprove your pet notion of IC?
It's amazing how Behe thinks he can get away with claiming he found that the papers were not persuasive without ever having read them to begin with. This is aside from the fact Behe should be reading and keeping up with the literature to begin with. To vindicate his claims about the irreducible complexity of the immune system, surely Behe should be keeping up with the very subject area he is claiming to be 'researching'. Evidentally, Behes ignorance about the actual evidence present says infinitely more about his 'scholarship' and dedication to doing proper science more than anything else.
Then he comes out with this:
I said in my testimony that the studies may have been fine as far as they went, but that they certainly did not present detailed, rigorous explanations for the evolution of the immune system by random mutation and natural selection — if they had, that knowledge would be reflected in more recent studies that I had had a chance to read (see below).Bear in mind that Behe has admitted that he has never read them to begin with so how would he know? He very obviously fails to keep up with the current literature on the evolution of the immune system, so it's quite clear that he wouldn't know about these studies even if they appeared.
4) This is the most blatant example of the Court’s simply accepting the Plaintiffs’ say-so on the state of the science and disregarding the opinions of the defendants’ experts. I strongly suspect the Court did not itself read the “fifty eight peer-reviewed publications, nine books, and several immunology textbook chapters about the evolution of the immune system” and determine from its own expertise that they demonstrated Darwinian claims. How can the Court declare that a stack of publications shows anything at all if the defense expert disputes it and the Court has not itself read and understood them?The point is Behe that you are the one making the claim that the immune system is IC, not the court and not the plantiffs. It should be up to you to maintain your own level of knowledge by actually bothering to read what other scientists write, in peer reviewed journals no less and not in popular books like Behes empty box. The fact is, that there has been a wealth of research on the immune system and the collective whole of the papers published gives us a picture of how the immune system evolved. It would be very hard to find a single paper that explained everything we know all from one experiment, but what we know is indeed in numerous papers that are published every year.
This response merely shows Behes contempt for following the actual research being produced by actual scientists. Perhaps Behe can demonstrate where he, or any ID advocate has ever bothered doing an experiment to prove the immune system is irreducibly complex? His response merely reinforces the courts points rather than serves as any form of 'refutation'. If Behe doesn't want to make himself at least familiar with research in the areas he makes claims for, he has no right calling himself a 'scientist'.
Dr. Behe needs to realise that science is not about making a claim and having everyone disprove what you think. Science is about proposing a testable hypothesis and then assembling positive evidence (or for that matter disproving the original hypothesis) that demonstrates your idea is correct. Rather than being a 'court stunt' as Behe derides the presentation of actual research articles (the irony of that can be left for the reader to determine) it demonstrates that breadth and depth of research into the evolution of the immune system. That Behe fails to do any research of his own, in other words assembling positive evidence for his claims, demonstrates the lack of any real science behind his claims very sufficiently.
Monday, February 06, 2006
Saturday, February 04, 2006
The genetically modified chicken crossed the road to contaminate the non-GM chickens on the other side of the road with genetically modified DNA. This has created a “superchicken” that can cross roads at will without ever being hit by a truck.Interestingly enough, it seems that greenpeace have still failed to update their website with the more recent information surrounding the 'infiltration' of genetically engineered maize genes into the wild type. It seems sensationalist claims are much better arguments than presenting 'facts' in this scenario.
Oh dear, this certainly quite horrible indeed! Though I can't recall how 'Faust' would actually manage to 'glorify' Satan, considering the horrible price that the character Faust pays for selling his soul. It's certainly not a pleasant opera but glorifying 'Satan' is far from the point of it. Speaking of, let's have a look at the actual tape in question.
"Any adult with common sense would not think that video was appropriate for a young person to see. I'm not sure it's appropriate for a high school student," Robby Warner said after two of her children saw the video.
Another parent, Casey Goodwin, said, "I think it glorifies Satan in some way."
Tresa Waggoner showed approximately 250 first-, second- and third-graders at Bennett Elementary portions of a 33-year-old series titled "Who's Afraid of Opera" a few weeks ago.
World famous Joan Sutherland and her three delightful puppet friends bring to life two great operas - Faust and Rigoletto in a special way that the whole family is sure to enjoy. Sutherland introduces her puppet audience to the story behind each opera and then performs their highlights in complete costume with elaborate sets. At key moments the Dame returns to her puppets to reveal more about the opera's plot. As Maguerite in Faust, Sutherland falls in love with someone who sold his soul for eternal youth and pleasure. In Rigoletto as Gilda, she is in love with the flirtatious and corrupt Duke of Mantua to the despair of her father, the court jester. Who says opera can't be enjoyed by kids?Well, I'm glad to see that puppets have been continuing their time honored tradition of distorting childrens minds and leading them to Satan. Of course, I can't quite say what is supposed to be so offensive about a video starring puppets that is meant as an introduction to opera for children. Maybe it was the final climactic scene where the puppets engorged themselves on a Satanic high and had a blood orgy*. As for the teacher in question?
Once again the refusal of a certain 'group' to open their minds and at least examine the source material involved results in everyone ending up miserable. At least the children seemed to end up getting something out of it.
Waggoner, who is in her first year teaching vocal music in Bennett, said she doesn't expect to stay in town.
"I know I'm not accepted here, that I'm not welcome here by the parents," she said. "It's a very uncomfortable position."
"The biggest travesty is the childrens' education." When initially asked what they knew about the opera, she said, her students said, "fat women screaming," "people yelling in Viking hats," and "I hate it." After seeing the Faust video, "they got excited by opera, but now they associate it with a four letter word," Waggoner said.Hmmm, well Satan is 'five' letters so I'm not quite sure if her twisting the children to devil worship has exactly bore out.
*May or may not have happened in the video.
Friday, February 03, 2006
No one believes that Judge Jones' decision, even if it's replicated in courtrooms across the country, is going to stop the campaign against materialism and for a God-centered worldview. But it surely must be seen as a catastrophic defeat for the notion of intelligent design, and no single institution is so identified with it, and has more of its financial and intellectual resources tied up in it, than the Discovery Institute of Seattle. Maybe the group can regroup and make a comeback, but for now, the mighty wedge is irreparably blunted.And the rest of the article is well worth reading.
Lyme disease, first described by Allen Steere in 1975 after an outbreak of arthritis in children living near Lyme, Connecticut. In the short term it was discovered that Lyme disease causes some fairly nasty flu-like symptoms, a rash and sometimes neurological problems including meningitis. Over time, the disease starts to manifest itself as delibilitating joint pain later progressing to a form of arthritis. As it turns out, this disease was caused by a spirochate bacterium called Borrelia burgdorferi that was spread by deer ticks. Later, patients claiming to have suffered an infection with the organism had symptoms similar to chronic fatigue syndrome, although Steere disagreed that there was any association (leading to the "Lyme Scandal").
Although antibiotics are very effective such as oral amoxycillin if caught early, the treatment for more chronic manifestations is far from pleasant. Essentially, this involves the injection of several antibiotics intravenously into the body over several weeks to eliminate the organism. Eventually, one of the major drug companies, GalaxoSmithKline produced a vaccine using a structure on the outer structure of the bacterium called OspA. Unfortunately, speculation that quickly spread among the public that the vaccine may be associated with autoimmune disorders put an end to the vaccine. While these claims were never substantiated by the FDA or the CDC, they still put an end to the vaccine which was widthdrawn from the market.
Now another company, Baxter vaccines based in Austria has decided to have another crack at producing a vaccine against lyme disease. In this particular case, they have used a vaccine again based on the OspA protein, essentially re-releasing the previously failed GalaxoSmithKline vaccine with one key modification: The removal of a small protein sequence. This short protein attached to OspA was the one at the center of a large debate over the possibility of the original vaccine causing an autoimmune disorder. It was hypothesised that because this short protein resembled that of another human protein, it might cause the immune system to make a 'mistake' and attack self proteins. This process, known as 'molecular mimicry' was assumed to be the cause of the later arthritis that manifests after an infection with Borrelia burgdorefi.
Over time however, no study has demonstrated that the molecular mimicry hypothesis surrounding OspA is correct and that a wide range of protein sequences can activate the immune cells involved and with widely different sequences, dealing heavy damage to the molecular mimicry hypothesis. Even so, the new vaccine will lack the particular protein sequence of the original in order to avoid public controversy.
The development of a vaccine surrounding lyme disease tells an interesting story about how misguided public opinion can often be the death of a vaccine. Although not widely spread, the concern over side effects (real or imagined) often paints a more pressing picture in the publics mind rather than the actual infectious organism in question. In many respects, this is merely the symptom of a society that has benefitted from the widespread use of vaccines and antibiotics that have wiped out most common infectious diseases already. The lessons learned from the failed introduction to lyme disease could also be applied to other cases, including the recent introduction of MeNZB to New Zealand.
Wednesday, February 01, 2006
In the study, they examined actinomyces soil-dwelling spore forming bacteria such as Steptomyces against a wide range of antibiotics, 21 in total, including vancomycin and synthetic antibiotics such as ciprofloxacin. In total, a library of 480 strains was constructed and then screened for their resistance against the 21 antibiotics they had assembled. Although screened at high concentrations of each antibiotic, a disturbingly large number of bacteria were resistant and many even able to enzymatically destroy the antibiotics in question. Most of the bacteria were resistant to 6-8 different antibiotics and two strains were resistant to 15(!) of the 21 antibiotics tested.
Possibly the most disturbing finding of the paper was just how poorly some new medically important antibiotics performed against these isolates. Daptomycin, which is hoped to be a new front line drug for use on multi-drug resistant pathogens like MRSA, was found to be utterly ineffective against all strains with a whopping 80% being able to inactivate the drug. This is pretty significant because it indicates that resistance to some of our newer front line drugs are already out there and could potentially be passed to pathogens. Additionally, many other antibiotics that aren't even commonly encountered by soil microbes appeared to have resistance determinants already, such as fluoroquinolones and of course synthetic antibiotics like ciprofloxacin.
An interesting result from my perspective concerned the antibiotic rifampicin. Rifampicin is important in the treatment of mycobacterial infections and typically resistance only shows up through several point mutations in the targets RNA polymerase beta sub-unit. This study demonstrated that several of these soil microbes could actually break the antibiotic down completely and didn't require said point mutations. This could probably lend weight to the concept that mycobacteria in general don't tend to aquire resistance (or other genes for that matter) through horizontal gene transfer terribly often.
Overall, the findings of the paper show two incredibly disturbing trends. The first is just how much range of antibiotics soil bacteria can resist, and the wide array of mechanisms and mutations they have for doing so. The second is that many of the antibiotics we have used for years have high amounts of innate resistance in the soil microbiota and worse still, many new 'up and coming' antibiotics already face the threat of high resistance genes in the environment. Although the study didn't demonstrate how much of these determinants can spread between soil bacteria and clinically important organisms, such a large reservoir cannot be ignored as it is potentially an extremely high risk. Finally, the study was highly limited to only what bacteria could be grown in the lab and actually underestimates the actual amount of resistance present in the environment.
It's fairly clear from these sorts of findings that antibiotic use has to be heavily conserved and selection for the development or aquisition of resistance genes has to be carefully monitored. These genes are already out there in the environment and doing highly irresponsible things like feeding our antibiotics willy nilly to farm animals, is going to set up a time bomb for processes like horizontal gene transfer to work on.
I'm now more comfortable with the argument that the FSM generally focuses its satire enough on its intended "creation science" targets for reasonable devout people to take its point without offense. Properly used, it can do a lot of good.Well, Ramen to that.