Botulism and Tetanus Toxins

Botox, the miraculous wrinkle eraser known for paralyzing faces of the rich and famous, turns out to be a toxin closely related to Tetanus neurotoxin, known for causing the less sought after "Lock Jaw"(warning: disturbing images).

Why is this interesting? Well botulism neurotoxin (Botox / BoNT) causes paralysis, but tetanus neurotoxin (TeTx) causes the exact opposite - over contraction of opposing muscles. Hmm... how does that work?

TeTx and BoNT are virulence factors released by the bacteria Clostridium tetani, and Clostridium botulinum respectively. As their names might suggest, both of these toxins attack neurons (hence neurotoxins). Now for the technical talk - how do these toxins do their thing?

Let's start with BoNT:

Getting into the neuron -
BoNT consists of two subunits, A and B. The B subunit attaches to a receptor on the membrane surface of the presynaptic neuron (the one that is sending the signal). Once attached, BoNT is endocytosed into the cell (basically it is in a little bubble inside the cell). The B subunit then creates a pore in the membrane of that bubble, allowing subunit A to enter the cell. BoNT is now in the cell and ready to do it's damage.

Doing Damage - Signals sent from neuron to neuron require a release of "neurotransmitters," or signalling proteins, into the synaptic cleft (the area between the presynaptic and postsynaptic neurons). These signalling proteins are made in the main body of the neuron, the soma, where RNA is translated into protein. They are then packaged into vessicles (kinda like the bubble mentioned earlier), and transported down the axon to the presynaptic terminal (where BoNT is). Normally, the vessicle would then dock with the cell membrane via "SNARE" proteins and release it's contents into the synaptic cleft where they could signal the postsynaptic neuron to propagate the signal. BoNT basically cut's up certain "SNARE" proteins, preventing vesicles from being able to dock and release their transmitters. No SNARE --> No docking --> No release of transmitter --> No propagation of signal --> paralysis!

Now for TeTx:
TeTx works in pretty much the exact same way except for it chews up SNAREs that are present in inhibitory neurons. Inhibitory neurons function to relax the opposing muscle of the muscle that is being signaled to contract. So, in the case of the jaw, both the muscle that closes the jaw and the muscle the opens the jaw are simultaneously contracting. The reason your jaw locks shut when this happens is that the muscles that close your jaw are much stronger than the muscles that open.

There you have it! Two toxins that do essentially the same thing, but with drastically different results.

Now for a few cool facts:

• 1 gram of crystallin BoNT could kill more than 10,000 adults
• Babies shouldn't eat honey because honey often contains botulinium spores found in the wild. Botulinium spores are not a problem for adults because we have a mature intestinal flora (lots of bacteria that outcompete the botulinium spores allowing them to pass through our system without germinating and colonizing)
• Both of these bacteria are anaerobic (meaning they grow in conditions without oxygen). Rusty nails happen to have rough surfaces allowing for exclusion of oxygen, so rusty nails happen to be a good location for bacteria like tetanus to grow. Tetanus has nothing to do with rust, it just happens that rusty nails allow for a good environment for the bacteria to grow, and a way for the bacteria to be transmitted into humans (don't step on that rusty nail!).

That's all for now!

Staphylococcus aureus and Antibiotic Resistance

Does MRSA ring a bell? Yeah, Methicillin-Resistant Staphylococcus Aureus, known for causing nasty infections in hospitals around the country. Well, If you ever wanted to know where MRSA may have developed it's methicillin resistance, read the following:

Bacteria Subsisting on Antibiotics (The full article is no longer freely available. This link will take you to the free abstract.)

So, an "antibiotic resistome" eh? My favorite line, "We cultured clonal bacterial isolates from 11 diverse soils (table S2) that were capable of using one of 18 different antibiotics as their sole carbon source." Wow! Not only were bacteria found to be merely resistant to antibiotics, they were found to be using them as their SOLE energy source! That's what I call specialization!

The relatively recent development of antibiotic resistance in strains of Staph might lead one to wonder, considering the relatively little time humans have been using antibiotics in medicine, how have bacteria been able to adapt so quickly to our treatments to become so resistant in only a matter of decades? Though bacteria do reproduce quickly allowing for accelerated evolution, random mutations seem like an unlikely culprit for how fast Staph has been able to adapt to our treatments. Then how did it happen? One possible answer is in this paper. The problem is thinking in such a human centric manner. Ultimately, resistance mechanisms did have to evolve at some point in time, but these resistance genes did not likely evolve in the past hundred years.

Think about where we got our first antibiotics - from fungi, molds, plants! Bacteria have been evolving alongside all of these hosts for far more than thousands of years. So, how did Staph, a human pathogen, manage to get the resistance gene from a bacteria that colonizes on fungi? Horizontal Gene Transfer (HGT). Hence, the concept of the "antibiotic resistome," an environmental reservoir of antibiotic resistance. From this reservoir, bacteria can essentially share genes that they have evolved through co-evolution with another species of bacteria.

Put simply, bacteria can share certain defenses. Staph can pick up what it needs to survive our "advanced" treatments by just picking up the defenses another species of bacteria has used to survive these antibiotics for thousands of years.

Anyhow... I thought that was interesting.

"...enabling same-sex couples to have their own genetic offspring."

A must read article from Nature...

New Sources of Sex Cells

A little background for those who might need it - so, some scientists set out to determine the differences between pluripotent cells (stem cells, a.k.a. cool cells that can differentiate into any type of tissue) and differentiated cells (like a skin cell). Turns out that if you transfect (insert genes via a virus) 4 specific genes into a differentiated cell you can "induce pluripotency" to form an induced pluripotent stem (iPS) cell. In other words, you can make what looks and acts like a stem cell from almost any cell... woah. They did this in 2006 with mice cells and then again in 2007 with human cells.

Two important notes -

1. Though iPS cells have a gene expression profile that is very similar to embryonic stem cells, they are NOT exactly the same. So, there is some concern that these cells might not differentiate in an expected manner, or may become cancerous (freaky mutant petri dish babies!!!!!), and so on.

2. The current method of gene introduction, transfection, is known to cause some problems (this is why they stopped gene therapy experiments). The problem is achieving site-specific integration of those 4 special genes. If one of those genes happens to, say, integrate into a tumor suppressor gene, thus knocking out that gene, voila! you have a potentially cancerous cell. hmmm... problems. Well, needless to say, scientists have been working on developing new techniques of gene introduction (some completely new and some just special forms of transfection) and I have been told by one of my professors that "the near future looks promising."

So, obviously there are some interesting ethical discussions to be had... Perhaps another time. I need to get some sleep.

[Important note: I am not an expert on this field. In fact, I haven't even finished my B.S., so if I have any details wrong, which is probably the case, please feel free to enlighten me.]