Bacteria can sense you're stressed!

Yep, they can! At least there seems to be a link between stress levels and infection.
One of the main hormones that is released in the body under stress is adrenaline. This helps bring about a Fight or Flight response, with effects such as an increase in heart rate, bronchodilation, and that unpleasant sensation of suddenly getting a dry mouth. These effects are due to adrenaline binding to receptors on different target cells (i.e. heart muscle cells, smooth muscle cells in the airways, or salivary glands) and triggering a signalling cascade within those cells, which initiates the responses seen.
Bacteria have been found to have adreceptors too (i.e. receptors that bind adrenaline). This means that invading bacteria should be able to detect adrenaline in the body as a response to stress. The question that poses itself now is: "How does adrenaline influence bacterial behaviour?" Unfortunately for us, they seem to love it! Bacteria use a method called Quorum Sensing to communicate to each other and assess their population density, as well as regulate the expression of virulence genes. It is thought that adrenaline is one of the hormones released by the human body that influences this mechanism by enhancing it and increases the bacteria's ability to replicate at the site of infection.
This is not only important in the field of medicine, where drugs developed to block adrenoceptors in bacteria may provide a way of combatting antibiotic resistance, one example of bacterial virulence, but also in the food industry, where the method of slaughter and animal keeping may play a role in increasing adrenaline levels in the muscle, which would make the meat more susceptable to bacterial colonisation.
This is just one of the many pathways that may be involved in the development of bacterial disease, and icreased susceptability to infection may well be due to the interplay and crosstalk between these pathways. But that's what makes it so fascinating!
So the next time your job gets you stressed or the kids are playing a bit too loudly, think about the bacteria that might be loving your high adrenaline levels ... on second thoughts - don't - that might make you even more stressed! :)

References:


http://www.pnas.org/content/100/15/8951.abstract?ijkey=6ccaada220c61e2c45a5c80d2cb7439e00291a50&keytype2=tf_ipsecsha

Use of Foetal Tissue Grafts in Treatment of Parkinson's

Research into Embryonic Stem cells has gone so far that foetal tissue has actually been implanted into Parkinson's patients' brains, the results however, have not been conclusive. The first studies that were conducted transplanting human foetal tissue were started in 1987 (1) and have been continued to this day. The type of implanted tissue has been varied to find the type of foetal tissue that would most efficiently survive in an adult brain as a Dopamine-secreting neuron. The foetal tissue is most often obtained through elective abortions, where mothers who want to have an abortion consent to the foetus being used in the study after abortion has taken place (2,3). I have not found a study that used surplus IVF embryos as tissue graft source.

When I heard of this the first time, I felt like something turned around inside me. I know the principle is similar to organ donation after a person has died. But an embryo cannot "consent" to its tissues being used for research or the treatment of another person's illness. The question that is even more important though is "Where does Human Life begin?" Does it begin at conception, which would be the most logical answer, or at somepoint later on? Maybe once a human form has begun to be visible? The potential to form each one of us was stored up in that single fertilized egg. I don't want to judge the women who have had abortions, no doubt their position is a very difficult one and I only hope to imagine some of the pressures that must be faced by them. I just want to remind us all of the immense value of a human life, be it contained in a fully developed human like you and me, or in an undeveloped human seen in a fertilized egg. 

Please feel free to comment - I would very much like to see your point of view!

References:

(1) Lindval O, Björklund A (2004): "Cell Therapy in Parkinson's Disease" in The American Society for Experimental NeuroTherapeutics 1(4): 382-393 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC534947/

(2) Kordower J H, Freeman T B, Snow B J, Vingerhoets F J G, Mufson E J, Sanberg P R, Hauser R A, Smith D A, Nauert G M, Perl D P, Olanow C W (1995): "Neuropathological Evidence of Graft Survival and Striatal Reinnervation after the Transplantation of Fetal Mesencephalic Tissue in a Patient with Parkinson's Disease" in The New England Journal of Medicine 332: 1118-1124 
http://www.nejm.org/doi/full/10.1056/NEJM199504273321702#ref16=&t=articleMethods

(3) Strömberg I, Almqvist P, Bygdeman M, Finger TE, Gerhardt G, Granholm A, Mahalik TJ, Seiger A, Olson L, Hoffer B (1989): "Human Fetal  Mesencephalic Tissue Grafted to Dopamine-Denervated Striatum of Athymic Rats: Light- and Electron-Microscopical Histochemistry and in viva Chronoamperometric Studies" in The Journal of Neuroscience 9(2): 614-624 

http://www.jneurosci.org/content/9/2/614.full.pdf

Calcium Signalling - truly marvelous!

I am currently revising for my upcoming exams and one of the topics we have covered this semester is Calcium Signalling. Calcium is a metal ion that is essential for the correct functioning of a huge range of cellular processes.
Maybe the most well-known of these is its importance for muscle function. In this case, Calcium binds to a molecule called troponin, leading to the movement of protein fibres called myosin and actin, creating a contraction of the muscle cell.
Calcium at high levels in the cell is toxic however, as it readily binds phosphate to create nonsoluble Calciumphosphate, the main constituent of kidney stones. So how does the cell generate levels of Calcium that are high enough to initiate the response it needs without endangering itself?
This is where a collection of clever mechansims come into play: The cell's Calcium-control Toolkit, so to speak. There are molecules called Buffering Proteins that bind and effectively mop up any Calcium they come across. Another type of molecule involved is the Plasma Membrane (i.e. Cell Membrane) Calcium ATPase (or pump). This uses energy to pump Calcium out of the cell. Another such pump, the SERCA, pumps Calcium from the cytoplasm (the inner environment of the cell) into the ER or SR (these are a type of organelle, i.e. membrane-bound compartment, found in any normal cell and specifically in muscle cells, respectively), where the Calcium is stored.
These two organelles play an important role in the control of Calcium Signalling. When a certain type of hormone binds onto a receptor on the cell surface, a signalling cascade (involving the Phosphoinositol pathway) takes place that releases the molecule IP3. And tata tata - the ER (i.e. the afore mentioned organelle that stores Calcium) has a receptor for IP3! Binding triggers the release of the stored Calcium. Now comes the really clever part: some signalling pathways rely on large Calcium waves sweeping through the cell, instead of only local increases in Calcium. Once Calcium has been released by the ER, that Calcium itself can then initiate further release from the ER, which can initiate further release, which initiates further release, which ... you get the picture. It's awesome! :) Once the cell realises there is much too much Calcium in the cell, the release stops and the Toolkit come into play again to decrease the Calcium level to resting state.
This Calcium wave is central to the fertilization of an egg cell: once the first sperm enters the egg, a Calcium wave like this is triggered and the increase in Calcium across the whole cell initiates the formation of a protective protein envelope around the fertilized egg, preventing any more sperm from entering. It also starts off the fertilized egg on the route of development! Isn't it amazing that each one of us started developing from a single fertilized egg cell into who we are today because of this amazing mechanism involving a humble metal ion???!!

References


Berridge MJ, Lipp P, Bootman MD (2000): "The Versality and Universality of Calcium Signalling", Nat Rev Mol Cell Bio 1: 11-21

Chromatin and Cancer

Proteins are the things in our cells that make it happen. Proteins come in all shapes and forms, some work as monomers, some as huge multi-subunit complexes. They are important for catalysing a whole range of different reactions that are essential for the cell's survival and its effect on the cells around it, which in turn can have systemic implications depending on the tissue the cell is found in.
So you can imagine that protein synthesis must be a tightly controlled process and that mistakes can result in disease, one of which is cancer - the uncontrolled proliferation of cells to form a tumour.

Cancer is a disease that is caused by many different defects, some of which can be inherited or induced by environmental influences, such as an unhealthy lifestyle or exposure to carcinogenic substances. In many cases, cancers are multifactorial, i.e. many different factors come together to predispose a person to cancer and finally to initiate tumorigenesis. 

In order to control growth and division, a cell has a number of intricate mechanisms in place that make sure the cell only divides after its DNA has been correctly replicated, and that the environmental conditions are favourable for growth. Mutations in genes that code for proteins involved in these processes can lead to cancer, as the controlling elements are taken away and the cell undergoes multiple rounds of replication unchecked.

A group of genes identified as having a central role in the prevention of cancer, are the tumour suppressor genes. These code for proteins that in some way provide a check in the cell's replication machinery to stop progression from normal cell growth to uncontrolled proliferation. An example of this is p53, also known as the "guardian of the genome" because of its central role in many crucial processes overseeing cell survival and cancer prevention. 

Therefore, cancers can be formed due to mutations in these proteins, but in general, tumorigenesis can often occur due to the synergic effect of many different factors. In the last few years, it has become apparent that chromatin remodelling may play an important role in initiating cancer and determining tumour progression (1). 

Chromatin is a structure made up of individual proteins called histones that coats DNA in such a way as to condense it in the cell nucleus and can control gene transcription by for example obstructing or opening up binding sites for proteins involved in the inititation of transcription on the DNA template. This remodelling of chromatin is performed by special proteins termed "ATP-dependent remodelling complexes". 

One example is the SWI/SNF complex, which is found in many eukaryotic cells, including yeast, fly and human cells. This is an example of a large mutli-subunit protein that is made up of an ATPase subunit (the molecular motor of the complex), three core subunits and a range of accessory subunits. The ATPase contains a Bromodomain, a region of the protein that recognises a certain chemical group on the histones in chromatin (an acetyl-group), and therefore, once the histone has been modified to display this chemical group (i.e. has been acetylated), SWI/SNF binding to the chromatin can be stabilised via interactions between the Bromodomain and the acetyl-group on the chromatin (2). Now this is the cool bit: SWI/SNF moves along the DNA (this is why it needs the ATPase, i.e. the molecular motor - it needs energy to move and this is supplied in the form of ATP) and changes the position of the chromatin subunits (called nucleosomes - these are made up of 8 histone proteins) so as to leave a part of the DNA uncovered and accessible to other proteins that can then bind and start transcribing the DNA to make a copy of the gene of interest that can be sent outside the nucleus and then used to make a new protein. 

What has all of this got to do with cancer? Well, researchers have found that in a number of cases, cancerous cells have SWI/SNF complexes that are not normal. For example, they may be missing one of their subunits (as is the case in many Malignant Rhabdoid Tumours, where the core subunit SNF5 is defective (1)), or they may have a different combination of subunits that changes their function slightly and makes them more able to contribute to tumour formation (1). 

Abnormal SWI/SNF could for example fail to uncover the right part of DNA needed for a tumour suppressor gene to be transcribed and therefore help break down the cell's protective mechanisms against cancer formation. 

As you can see, it is hard to remain within one area when looking at the body and how mechanisms are affected in disease to bring about an abnormal state, because the mechanisms all work together to make up an intricate network of interactions. Like in a chain, if one of the links breaks, the whole chain opens up and is broken. The same is true for many disease states and the challenge is to find the "weak link", so as to be able to target it in some way in a hope of curing the disease.

References:

(1) Weissman B, Knudsen K E (2009), "Hijacking the Chromatin Remodeling Machinery: Impact of SWI/SNF Pertubations in Cancer", Cancer Research 69 (21): 8223-8230

(2) Hassan A H, Prochasson P, Neely K E, Galasinski S C, Chandy M, Carrozza M J, Workman J L (2002), "Function and Selectivity of Bromodomains in Anchoring Chromatin-Modifying Complexes to Promoter Nucleosomes", Cell 111: 369-379