EL5 for vaccines and natural immunity

With the vaccine hesitancy being as prevalent as it is now, I think more than one of you have had someone in their immediate environment be vaccine-skeptical or at least vaccine-hesitant.

Here is an explanation that worked for someone from my family, helping them to transit from a “I don’t need it – I am healthy enough” mindset to “Ok, I am getting the vaccine ASAP”. In this particular case, the fact that they had several friends go to hospital due to COVID and in some cases be long-term incapacitate by COVID19 helped to raise awareness of how bad the disease can be, as well as underlying trust into my competence as well as a good will, with most of hesitation focused around “my natural immunity is already good” and “vaccines don’t work that well to start with”. Oh, and also the simplifications are pretty insane and I can hear immunologists and virologists scream for here, but it’s one of those “sacrifice precision for ease of understanding” cases.

So, the preamble being done, let’s get to the actual explanation:

“Your immune system works by learning what attacked you and takes time to react. Specifically, it looks for cells that explode and let their contents out (also called necrosis, as opposed to apoptosis-when the cell dies because it is programmed to by the organism) and starts looking for anything it would have not encountered before (or at least that it doesn’t encounter in the organism often) that is present in the contents of the exploded cell or around. When the immune system detects what is there, they start generating the antibodies and test all the cells in the organism to see if they contain the new dangerous compound (here it is particles of the virus). If the dangerous compound is present in the cells, the immune system orders “cleaner” cells to digest those cells and destroy them and everything they contain.

The problem is that the process starts only when there are first mass cell deaths (so the infection is well stated) and take several days to start and spin-up. During that time, the virus continue to propagate in the body.

So when the cleaning cells start digesting cells that have the virus in them, that’s a lot of cells. And some of them are very important and cannot be replaced – such as heart cells. Or some cells that can be regenerated, but if there are too much that die, you die as well (a good example are lung cells).

In case of the vaccine, you have proteins that are located on the outside of the virus that are injected, as well as an agent that will provoke the cells to explode and attract the immune system’s attention. So the immune system will detect the viral proteins “on the crime scene” and learn to find and destroy them on sight. But since there are not that many cells that are affected and are very easy to regenerate (muscle cells are among the easiest to regenerate – you actually regenerate a lot of them every day if you are exercising) and are not essential to life (given it’s a muscle of a hand and not heart/lungs/brain).

Once your immune system learnt to detect them, it will remember them for a long time and closely monitor your body to see if it can find the smallest traces of the particles it learned were dangerous, even before the first infected cell explodes. Your immune system will monitor your body even closer and longer for those particles if it finds those particles on a different “scene of crime’. That’s why we need a second dose of the vaccines.

So when the virus arrives, it is immediately detected and neutralized and cells it has the time to infect are destroyed before they explode and before the virus is able to replicate itself.

The reason we need to wait after a vaccine is that the immune system transits from a “I am currently responding to an attack” to a “I have responded to an attack and will remember what attacked me, so that the next time I can respond faster and better”. That process takes about 10-14 days, but 21 days leave a margin if the immune system doesn’t work all that great (for instance if the person is stressed).”

Now, as to the need to get vaccinated immediate, the argument went along the lines that with countries opening up, barriers for the virus propagation are going down and we are still very far from herd immunity, meaning your own vaccine is the only thing that will be protecting you, with everyone not yet vaccinated getting sweeped in the upcoming wave.

Reproducability in the High-throughtput and computational biology:

Just discovered about the  Potti scandal at Duke (primer for those who have never heard about it before from here: http://en.wikipedia.org/wiki/Anil_Potti)

Currently watching http://videolectures.net/cancerbioinformatics2010_baggerly_irrh/. Some of the extraordinary quotes (approximative though):

If, after a computational analysis, you give a biologist a single gene, unrelated to cancer until now, that correlates the increase of risk of cancer, it is most likely that you would hear something like “No, you’ve got stroma contamination over here: I’ve been studying this gene for years now and I perfectly know that it is completely uncorrelated with cancer”

If, after a computational analysis, you give a biologist a list of hundreds of genes, and you say: here is the genetic signature of cancer, it is most likely that he will just agree with you, because “yeah, this one seems to correlate with that one, so yeah, that makes sense”.

=> This is precisely why I am developping the information flow framework for drug discovery and clinical biology; to make biological sense from the lists of hundreds of perturbed genes.

Forensic Bioinformatics: Here is the raw data, here is the final results. Let’s try to figure out how we get from the raw data to the results, disregarding what they said they did in supdata.

=> Idea: use the chemotherapeutic drug against 60 cell lines pannel to determine specificity  and see if it correlates with the biological knowledge we have about those  cell lines

Let’s use metagenes!!! As matematicians, we know them as PCA, but well, let’s call them metagenes.

Their list and ours: you might see the pattern. Yes, the genes are IDs are off-set by 1.

So, we had a look at the software they were using and it’s documentation. if you want to read the docs, go to my website, because it was me who wrote it, since there were none!

Most of review commitees in biological journals are biologists, they will skip all the part related to the microarray analysis, jump to the results and see if the computational biology results are in agreement with wet lab results.


Murky waters of systems bilogy

I am currently trying to parse the Reactome.org owl database file into a format more suited for my needs. So far I have been experiencing some major difficulties, because of lack of rigor in organisation of classes in this ressource, at least in the biopax .owl export file.

First, obscure use of the “memberPhysicalEntity” attribute. Some of the proteins, complexes and smallMolecules are in fact whole classes of proteins, with functions often non-defined and metionned in the reactions. Which means I have to find them out by hand and use proxy objects (which are not real groups of proteins).

Second, mixture between:

  • Physical entities defined by a unique structure, for instance proteins as defined by a uniprot
  • Instantiated physical entities: the ones that contain a post-translation modification or are localized to a particular cellular compartment
  • Fragments of Physical entities, for instance alpha chains of different proteins
  • Collections of Fragments of physical entities, such as collection of all the alpha chains found within the database

Third, some redundancy in use of owl terms. For instance Catalysis, Control, TemplateReactionRegulation and Degradation are all used in a similar fashion, even if Catalysis is modulation of kinetic bareer in reaction and the other can actually completely perturbate  the reaction. What is the reason of redundancy of terms? It is not very clear…

Forth, lack of information essential for a class in the class description, aka “headless Horseman” problem:

  • Post-translational modifications on a protein, provided without location (i.e. somewhere) and without type (some modification).

Last, but not least, lots of “floating” compounds. There are about 6000 compounds (Proteins, Complexes or PhysicalEntities) that are pointed towards only by only one unique reaction. It means they participate to no other reaction and regulate no other reaction, except for only one. Which seems quite unrealistic to my eyes.

I have spend now about two weeks to get it all in order and I’ll try to publish the resulting cleaned file once I am done.

Linkage between eczema and low platelet count

Ever since my master course on advanced immunology by Nicole Harris at EPFL I had an impression that platelets have been playing an important role in the immune response but were still a completely under-explored domain. This impression where confirmed when I was working with Cedric Merlot on building a predictive systems biology method for predicting systemic drug effect based on multiple protein interaction. In fact, as a side-result our method suggested a strong linkage between platelets and serotonin and also pointed that it might be heavily with the rest of the immune response system.

While reading a paper on a completely unrelated subject I fall on a syndrome that looks like single-protein caused, but that links eczema and low platelet count. Now, that gets really interesting.

Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczemathrombocytopenia (low plateletcount), immune deficiency, and bloody diarrhea (secondary to the thrombocytopenia)