Dawkin’s “extended phenotype”, an extension or a revolution?

Posted by: Issa Abu-Dayyeh

The extended phenotype, a relatively longer and a more difficult reading than Dawkin’s “The selfish gene”, is in my opinion a book worth the reading effort for several reasons:

1-Although a big portion of the book was dedicated to rebuttal critics that showered Dawkins with accusations of being a genetic determinist and a reductionist (Based on his views in the Selfish gene), Dawkin’s replies to those criticisms are pretty logical and organised. In fact, Dawkins almost did not have to retract any of the claims he made 6 years before “the extended phenotype” was written.

2-The rest of the book sets to establish a new vision on the extent to which a gene can act.

Many of us would agree that an organisms’ behaviour is selected to maximize the success of the replication of the genes residing inside this organism. As tempting as this statement might be, this vision definitely pictures the body as the gene’s prison. It is the boundary, the wall,the farthest limit upon which a gene can act.

Dawkins suggests in “the extended phenotype” that the action of genes goes way beyond their ability to produce proteins for the bodies they reside in. In fact, genes can have effects on inaminate objects (such as the type of house an animal would build) or on other living beings. An example given by Dawkins is a trematode that lives in snails. This trematode codes for proteins that drive the snail to produce thicker shells than ususal. This provides greater protection for the trematode while diverting the snail’s energy from practices that could benefit the snail but not the trematode such as: reproduction. The author goes on and on giving examples of how genes can act at a distance!

But how influential is this extended phenotype argument? After reading the book, my initial thought was that it is really no revolution! This is simply an extension of our vision of how far genes should be seen to go. On a deeper thought, I believe this book is revolutionary from a different perspective. First, it places more emphasis on the interactions of genes (regardless of the organism that carries them) on the overall evolution of complex traits and the natural selection they undergo. The principle also explains how a parasite can alter the host’s behaviour to its advantage (therefore suggesting what was formerly thought as mal-adaptation of a host gene as good adaptation of the parasite gene), and how some parasites can end up as symbionts and ultimately interested in increasing the reproductive success of the host and, soon, very difficult to even be seen as  parasites (ex: the mitochondria and chloroplast endosymbiont theory).

This book simply modifies a vision: from behaviour maximizing the success of the genes inside the organism to behaviour maximizing the success of genes that code for that specific behaviour, no matter in whose body those genes are found. This definition reorganizes the genetic vision in a way highly compatible with dawkins’ selfish gene view of evolution and natural selection. Is he right about the extended phenotype or is he wrong? I think most of us would agree it is a logical extension of what we perceive as a direct effect of a gene, but what really matters is that it is different… and a different view is sometimes what we need to reevaluate our current vision and devise new experiments to expand our knowledge. Not to mention the importance of such a vision on the mathematics of genetic contributions to phenotypes. In a nutshell, this is a book worth reading!

MHC I and MHC II, simple and clear, once and for all!

posted by: Issa Abu-Dayyeh

Every couple of months I ultimately get into a discussion about the role of MHC class I and II in the activation of immune functions. What drives their transcription/translation, what cells produce them, how are the peptides found and loaded on them; these are many questions that do not seem to go in the long-term memory section of my brain as well as many others.

Here I decided -once and for all- to summarize the dogmas in the aspects mentioned previously.

MHC class I are molecules produced by all nucleated cells, their production is augmented by IFN-alpha, IFN-beta, IFN-gamma, and TNF-alpha. They are loaded with peptides that result from proteasome-mediated degradation of proteins found in the cytosol, they are transported to be expressed on the surface of cells, and MHC I molecules bound to foreign peptides activate CD8+ T cells by binding to their TCR.

In other words, these MHC molecules keep the internal contents of molecules in check. This is consistent with the fact that such a mechanism is very useful against cancer cells and cells infected with viruses that are actively producing their proteins inside the cells.

On the other hand, MHC class II molecules are produced by antigen presenting cells of the immune system: mainly dendritic cells, macrophages, and B cells. Their production is primarily driven by IFN-gamma (and not the other interferons), they are loaded with peptides that are generated by peptidases found inside phagolysosomes, and upon their translocation to the cell surface, they activate CD4+ T cells.

Two main comments come to my mind upon writing those “facts”:

1- It is impressive how those two MHC types seem to complement each other’s function. MHC I screens for internal “problems”: viruses, cancer, and other antigens that are hiding inside cells away from immune detection, while MHC class II are directed against obvious intruders that go inside the cells by phagocytosis (or any surface detection mechanism ex: TLR) such as:  bacteria and parasites. Together, those two molecules work hand in hand in keeping the organism as alert as possible to all sorts of invaders.

2-Although it is interesting per se that interferons and other pro-inflammatory cytokines upregulate the production of those molecules, it is even more interesting to see that molecules such as IFN-gamma which is not typically involved in counter-acting viral infections can upregulate MHC type I molecules. To me, this suggests that an invasion of the immune system by viruses must somehow lead to the production of danger signals recognized by IFN-gamma producing cells (or their activators) and ultimately leads to a response against those viruses through MHC I upregulation (Future work in the field will be the judge!)

In the end, it is as if the immune system is on “code red” and asks each cell to rapidly disply its ID card to the immune police….Normal cells will show the good ID and pass, suspicious cells will display a “wanted” ID and are destined to be eliminated.

Isn’t it amaizing???

We know Nirtic Oxide is produced when SHP-1 is absent, but why??

Posted by: Issa Abu-Dayyeh

The exact role played by the protein tyrosine phosphatase (SHP-1) in the negative regulation of macrophage functions has been an active area of research for many years. In fact, SHP-1 deficient mice are hyper-inflammatory. They lose their hair “for God’s sake” due to exaggerated inflammatory responses in the skin area! (hence their name motheaten). But what does this tell us? It tells us a lot of pathways are simply “on fire”. To dissect every single pathway controlled by this PTP is a humongous job, and the best approach in my opinion is to try to focus, and dissect a pathway at a time and a function at a time. So, what did we attempt to do in our most recent publication (Blanchette, J. et al.) in Immunology (2008)?

The paper explores the signaling pathways that seem to be major contributors to NO production in SHP-1 deficient macrophages. NO production is driven by a gene known as iNOS whose expression is driven by several transcription factors, most importantly: Nf-kB, STAT, and AP-1. One of those transcription factors “AP-1” is activated by a MAP kinase called JNK.

This work utilizes inhibitors of many of these members to see which of them will be able to suppress that excess NO production observed in SHP-1 deficient macrophages in an effort to understand how SHP-1 causes this increased NO production.

To save you the dull experimental details…Results showed that the exaggerated NO production in SHP-1-/- macrophages seems to be due to an increased JNK/AP-1 and not NF-kB activity.

And so what? some people might ask!

Well…I agree a finding like this might not find a cure to leishmaniasis. Nevertheless, bearing in mind that NF-kB translocation is increased in the absence of SHP-1, this paper then suggests something rather important. This increased NF-kB activity is not contributing to iNOS transcription. What is it doing then? and how can iNOS be differentially regulated? These are questions that await answers. (If somebody has answers, I will be glad to hear from them).

This work simply broadens our knowledge about where SHP-1 exerts its effects, and by knowing how, we can probably try to eventually revert some of those actions during the course of a Leishmania infection and help find an effective drug against leishmaniasis that is not as toxic as the ones available nowadays…

A block added to the wall. that is how I see it.

If you are interested in viewing the paper, please visit it here