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Tag: immune system

Atlantic Cod Are Not Your Average Fish

Another month, another paper, and like with last month’s, I picked another genetics paper, this time covering an interesting quirk of immunology.

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This month’s paper from Nature talks about a species of fish that has made it to the dinner plates of many: the Atlantic Cod (Gadus morhua). The researchers applied shotgun sequencing techniques to look at the DNA of the Atlantic Cod. What they found about the Atlantic Cod’s immune system was very puzzling: animals with vertebra (so that includes fish, birds, reptiles, mammals, including humans!) tend to rely on proteins called Major Histocompatibility Complex (MHC) to trigger our adaptive immune systems. There tend to be two kinds of MHC proteins, conveniently called MHC I and MHC II:

    • MHC I is found on almost every cell in the body – they act like a snapshot X-ray of sorts for your cells, revealing what’s going on inside. If a cell has been infected by an intracellular pathogen like a virus, the MHC I complexes on the cell will reveal abnormal proteins (an abnormal snapshot X-ray), triggering an immune response to destroy the cell.
    • MHC II is found only on special cells called antigen-presenting cells. These cells are like advance scouts for your immune system – they roam your body searching for signs of infection. When they find it, they reveal these telltale abnormal proteins to the immune system, triggering an immune response to clear the infection.

The genome of the Atlantic cod, however, seemed to be completely lacking in genes for MHC II! In fact, when the researchers used computational methods to see how the Atlantic cod’s genome aligned with another fish species, the Stickleback (Gasterosteus aculeatus), it looked as if someone had simply cut the MHCII genes (highlighted in yellow) out! (see Supplemental Figure 17 below)

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Yet, despite not having MHC II, Atlantic cod do not appear to suffer any serious susceptibility to disease. How could this be if they’re lacking one entire arm of their disease detection?One possible answer: they seemed to have compensated for their lack of MHC II by beefing up on MHC I! By looking at the RNA (the “working copy” of the DNA that is edited and used to create proteins) from Atlantic cod, the researchers were able to see a diverse range of MHC I complexes, which you can see in how wide the “family tree” of MHCs in Atlantic cod is relative to other species (see figure 3B, below).

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Of course, that’s just a working theory – the researchers also found evidence of other adaptations on the part of Atlantic cod. The key question the authors don’t answer, presumably because they are fish genetics guys rather than fish immunologists, is how these adaptations work? Is it really an increase in MHC I diversity that helps the Atlantic cod compensate for the lack of MHC II? That sort of functional analysis rather than a purely genetic one would be very interesting to see.

The paper is definitely a testament to the interesting sorts of questions and investigations that genetic analysis can reveal and give a nice tantalizing clue to how alternative immune systems might work.

(Image credit – Atlantic Cod) (All figures from paper)

Paper: Star et al, “The Genome Sequence of Atlantic Cod Reveals a Unique Immune System.” Nature (Aug 2011). doi:10.1038/nature10342

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Of Mice and Cocaine

Yes, I know. I’m crazy late with the last of 2010’s paper-a-month blog entries (not to mention, given the list of 2011 resolutions, I also need to produce one more for this month), but better late than never!

This month’s paper was a bit of a curiosity to me (which will hopefully be clear soon). It was published in Molecular Therapy and caught my eye as the researchers claimed to be able to produce a cocaine vaccine which actually works!

Mammalian immune systems don’t usually respond to chemicals which aren’t related to a bacteria/virus/fungus (that’s one of the reasons that, provided you don’t have a food allergy/sensitivity, your body doesn’t start randomly attacking all the “foreign” food that you eat). Now the idea of tricking a mammal’s immune system to attack poisons and drugs isn’t new –various groups have tried chemically linking molecules of an addictive drug like cocaine to molecules that your body’s immune system will recognize (like cholera toxin and tetanus toxin) – but to get a high enough immune response which lasts for enough time to be potentially useful has been relatively out of reach.

This month’s paper did two interesting things. First, they attached a molecule which looks like cocaine directly to inactivated viruses. Secondly, they actually gauged how well these vaccines worked in live mice!

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Figure 1a (above) shows, at a high-level, what the researchers did to create their vaccine. On the left is GNC, a molecule which looks very similar to cocaine. On the right is an overview of Adenovirus structure. By chemically linking the two, the researchers were able to create what they called dAd5GNC which they could then inject into mice in much the same way that people are vaccinated today. The theory being that the presence of a real virus would attract the attention of the immune system and the GNC would get the immune system to make antibodies which bind and attack cocaine.

So, did it work? The researchers were able to use an assay which measures antibody production to gauge if the right antibodies were being created (impressively, they were able to show high antibody levels even 13 weeks out) – but the real test is in whether or not it actually does anything in live animals. In figure 2d (below), the researchers took mice which were injected with saline (a negative control) and those who were injected with dAd5GNC (the vaccine) and, four weeks later, injected them with radioactively labeled cocaine (so that you can easily track and measure it). They then compared the amount of cocaine that was in the brain and the amount that stayed in the mouse’s bloodstream. As you can see, while the amount of cocaine reaching the brain in vaccinated mice was lower than in mice injected only with saline, but the amount of cocaine in the bloodstream was much higher – suggesting that the vaccine was successful in creating cocaine antibodies which would bind cocaine molecules and keep them from entering the brain.

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But does that translate into actual behavior? This is one of the most interesting experiments I’ve seen (although, as I’m not a mousework expert, I’m not sure how clinically relevant), but in a nutshell, what the researchers did was take the two groups of mice, inject them with cocaine (or saline as a negative control), and see if the mice acted high by running around more. Think I’m kidding? They even showed diagrams of mouse activity (Figure 3a, below) – without looking at the labels, see if you can guess which mice are the frantic/high ones:

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The paper has some numerical charts, but suffice to say the above figure was definitely one of those “pictures worth a thousand words”.

A very cool experiment – but I was definitely left me with a few questions. Foremost of all, it had always been my understanding that immune responses, even where the body has already been immunized, take place over the course of hours or days. That’s fast enough to stop you from catching measles or the same cold twice, but injected cocaine? It’s fast and there are a ton of cocaine molecules. The mice in the experiment above were literally injected with cocaine and observed for 10-30 minutes immediately afterwards. Maybe I’ve misunderstood how cocaine works or how the immune system works, but that is an open question which leaves me a little wary.

The second is the issue around the relative amounts of cocaine in the brain and the blood. I understand that measuring radioactive counts like the researchers did here is an imperfect science, but I’m confused how the vaccine produced such a huge difference in the amount of cocaine in the bloodstream but a much less dramatic difference in the brain, yet still produced a very striking difference in behavior. That last point could simply be explained by how sensitive the brain is to cocaine, but these two questions collectively leave me a little puzzled.

(Figures from paper)

Paper: Hicks et al., “Cocaine Analog Coupled to Disrupted Adenovirus: A Vaccine Strategy to Evoke High-titer Immunity Against Addictive Drugs.” Molecular Therapy (Jan 2010) – doi: 10.1038/mt.2010.280

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