Taking DRACOnian measures against viruses

When Alexander Fleming shamelessly took credit for a drug produced by the penicillium bread mould, our fight against bacteria completely changed. Even now, bacterial diseases are nowhere near the threat they were before that discovery. But today, we are seemingly having to put up with emerging viruses. Every year, we have to put up with entirely new strains of flu. There is nothing we can do about the viruses that cause the common cold. There are various antivirals out there, but they are specific for specific diseases, like flu, or HIV.
Generally, it’s been fairly difficult to make anti-viral drugs. Often, a lot of the problem comes from the way viruses work. When they are outside the cell, they don’t have any active metabolic processes that can be targeted by drugs. And when they are inside the host cells, the metabolic processes they’re mostly using are ours. So it’s very hard to target the viruses without attacking the host. Compared to bacteria, viruses present a very small target. 
Could a paper published in PLOS One called  “Broad Spectrum Anti-viral Therapeutics” represent a penicillin moment for viruses ? A trailblazer that can transform our relationship with viruses ? To work this out, let’s take a good long look at what these anti-viral therapeutics are, and what they do.  To do that, we have to talk about DRACO.

Are we talking about the DRACO from Harry Potter, or the dragon voiced by Sean Connery in Dragonheart ?

Whilst I compliment you on your knowledge of pop culture, you are wrong on both counts. DRACO is a handy acronym that stands for Double-stranded Ribonucleic acid Activated Caspase Oligomizer. DRACO is the drug that is being purported to extinguish all of those nasty viruses. To understand how it works, we need to take a look at how some of our most pernicious viruses work.
You may have heard about DNA, and how it’s genetic code is a blueprint for life. Your genome is encoded in your DNA. The nucleus of your cell holds all of the DNA, and acts like a library for your genetic code. When your cell needs a specific genetic code to make a certain protein, the nucleus makes an RNA copy of the appropriate gene and sends it out into the rest of the cell, where it can be used to construct a protein.
The goal of a virus is to enter a cell, and to hijack this process to make more viruses. Usually at some point, the virus will attempt to substitute it’s own genetic code for that of the host cell, tricking the host cell to make more viruses ^[1].
However, some viruses can store their genetic code using RNA only. Whilst RNA is less stable than the DNA, it means that these viruses can go straight to the cell machinery that translate RNA into protein, and get ahead with making virus based proteins.

End of Hiatus

A couple of months ago, for reasons too irritating to get into, my internet got cut off, which made blogging nearly impossible. But then again, I needed to focus on writing up my thesis.  That didn't go exactly as well as I planned.....

It turns out, wasting time and procrastinating can occur even in the absence of the internet. As you can tell, internet access is no longer a problem, and so once again I can procrastinate by researching and writing posts for this blog ! Expect more posts soon.

#Microtwjc Why FRET about Biosensors ?

The latest paper for #microtwjc focuses on finding a new way to sense metabolites inside of living bacteria.  Bacteria need to regulate their nutrient intake, because like people, they don't want to get too fat or thin. 

If there isn't enough nutrient in the environment, they need to conserve what they have, and if more appears, they need to consume it as efficiently as possible, but if they did that all the time, it could cause them problems.

Microbial Phylomon- Salmonella enterica

To get everyone in the mood for #microtwjc tonight, I give you the microbial phylomon card for Salmonella enterica.

Previous Microbial phylomon posts can be found below:
http://defectivebrain.fieldofscience.com/2011/08/more-microbial-phylomon.html
http://defectivebrain.fieldofscience.com/2011/09/even-more-microbial-phylomon.html
http://defectivebrain.fieldofscience.com/2011/12/when-phylomon-fall-from-sky.html
http://defectivebrain.fieldofscience.com/2011/08/microbial-phylomon.html
http://defectivebrain.fieldofscience.com/2011/10/microbial-phylomon-it-came-from-beneath.html
http://defectivebrain.fieldofscience.com/2011/08/microbial-phylomon-and-friends.html

#Microtwjc A Salmonella of Doubt ?

The microbiology twitter journal club beckons, and it is now time to wade through the latest paper, on Salmonella, and how to spot different subtypes of this bacteria. This allows us to get a look at the recent evolutionary history of the bacteria, and to track new subtypes as they arise. In the past, the ways these new subtypes were tracked and analysed through serotyping. 

#microtwjc Do Electric Guts Dream of Android Burgers ? part 2

In part 1 of this post, I briefly described the key piece of equipment used in this study- the TIM2 machine, designed to model the large intestine.

Do Electric Guts Dream of Android Burgers? Part 1 #microtwjc

The next paper for #microtwjc raises some interesting questions about what effects probiotics have on the gut. If you want to study the gut, and the bacteria within it, there are a number of little problems. For instance, many of the bacteria in the gut are anaerobes, and will shrivel up the moment they get exposed to air. It is thought that the distribution of different bacteria varies throughout the gut, so just taking faecal samples won't cut it. 
So what can you do? There are animal models, where you can try and sample the bacteria in different areas of the intestine after dissection, or perhaps use techniques like bioluminescence to look at bacteria directly within the digestive tract. I remember hearing someone pitch a project to use magnetic resonance spectroscopy (using some fancy MRI technology) to analyse bacterial metabolites within the guts of human volunteers.
There is another way that researchers can try and work out what's happening in the gut. Through the creation of an artificial gut.
Consider for a second that in simple terms, your gut is basically a fancy bioreactor. It is a vessel in which enzymes, bile and bacteria all get mixed together to help you digest your food. So what if we tried to create this system artificially, and what would reveal about digestion
 Minekus et al (published in 1999) developed the system, where they essentially created an artificial model of the large intestine, which over the last ten years has been developed to the one seen in the week 6 #microtwjc paper.
So how does this machine replicate the way that the Large Intestine works ?

• Peristalsis- Your gut moves food around through squeezing it's walls and pushing the food along. The inside of this machine has a series of flexible walled tubes, which have water pumped along the outside of them. The pumping of the water passing through the system causes periodic compressions to be transferred through the system, mirroring the peristaltic movement seen in actual human guts.
• Temperature: The water passing through the gut is heated to body temperature, which is 37 °C.
• Bile: Bile performs a number of functions, such as introducing a number of salts which act to emulsify fats. Another function it performs is neutralising gut acid, and keeping the pH of the large intestine stable. To ensure that the pH of the electric version of this system is stable,  pH sensors were present to control the infusion of sodium hydroxide, preventing it from getting too acidic.
• Absorption: The main function of the gut is to absorb nutrients, such as short chain fatty acids. To replicate this, fibre membranes placed at strategic points along the machine allow for small molecules to pass through them. These are hooked up to pumps an pressure sensors to ensure that the pressure within the system remains constant. 
•  Metabolites: In the human large intestine, partially digested food comes in from the small intestine. To replicate the present of this food, metabolites are added into this system, and because of the way the absorption works (via osmosis) the action of that system also acts to keep the metabolite levels within the gut fairly constant.
• Anaerobic- It is generally thought that the human gut is mostly colonised by anaerobic bacteria*. So air was prevented from entering the system by flushing it with gaseous nitrogen.

This is the basis for the TIM2 system. Now, anyone can easily see that it isn't a perfect model for the gut. With any model, physical or computational, there are limitations. What you get is based off of your assumptions when creating it, and if you forget those, then you can be lead badly astray.
So the question is is it useful?

The only way to determine this is to validate the model.
In the initial paper, they found that the system absorbed short chain fatty acids, and maintained pH fairly well with "standard" fermenter flora and allowed them to survive in the system.
Also "Three successive experiments were carried out using fecal inocula from three diff€erent methane-excreting volunteers". They did not mention whether these people were chosen on the basis of their methane excretion. They looked at how well the faecal flora survived in the large intestine.
So from this first paper, they showed that this model of the gut could keep bacteria from the human gut alive, and that this system could absorb short chain fatty acids.


The point I would like to make about this model system is that yes, it does have limitations. It is not a perfect representation of the human gut.  Even though we can't extrapolate findings with this equipment directly into humans, we can still put this machine to good use. It can be use to grow bacteria with different nutrients, and furthermore elucidate some of the more complex relationships between them within the human large intestine. 
It is with that in mind that I shall look at the actual #microtwjc paper in part 2 of this post.


  Minekus, M., Smeets-Peeters, M., Bernalier, A., Marol-Bonnin, S., Havenaar, R., Marteau, P., Alric, M., Fonty, G. & Huis in't Veld, J.H.J. (1999). A computer-controlled system to simulate conditions of the large intestine with peristaltic mixing, water absorption and absorption of fermentation products, Applied Microbiology and Biotechnology, 53 (1) 114. DOI: 10.1007/s002530051622

Part 2 is up here

* I should point out right now that I am not entirely certain whether the mammalian gut is entirely an anaerobic environment. For instance, I pointed out a study using bioluminescence to study bacteria as they invaded the gut. The bioluminescence reaction shown there requires oxygen to be present in order to function. So this indicates strongly that there is oxygen in the mammalian gut, but again, this conflicts with what is known about most of the microbiota present, which tend to shrivel and die at the mere mention of that element.