Don't shoot the messenger!

This week I am due to host a journal club.  A ritual which gives me great opportunity to make others feign interest in something that I am excited about.  This time around I have chosen to force them to read about a protein I have been interested in for some time called ‘p21’.  The paper I chose was recently published in the Journal of Biological Chemistry and for your info is titled ‘Reactive Oxygen Species and Mitochondrial Sensitivity to Oxidative Stress Determine Induction of Cancer Cell Death by p21’.  As exciting as this sounds, it may be easier to ignore the title, and I’ll try and explain a little bit about it.

Proteins such as p21 fit into what we like to call cell signalling pathways.  These pathways exist within single cells and act as a courier service for messages to be passed from one part of the cell to another.  This is much in the same way that your brain receives signals from the nervous system and sends signals back out to elicit a response.  Biologists have constructed these networks (made up of proteins) as a way of mapping how a message can be sent from the cell membrane to the nucleus and tell your DNA to express certain genes.

p21 is a very interesting protein because the gene that makes p21 is controlled by a very important protein called p53.  This protein is sometimes called the ‘guardian of the genome’ due to its role in protecting the cell from becoming cancerous.  Its job is to make sure that cell division and cell growth occur correctly and also acts as a suicide switch should the cell become damaged in a way that could lead to the formation of cancer.  Scientists have found that the gene producing p53 is mutated in over 50% of cancers.  The result of this is a cell may produce no p53 or produces a form of p53 which doesn’t function properly.  No more control of cell growth and no more preventing damaged cells from multiplying.

It has been known for some time that proteins such as p53 and p21 are involved in a wide range of messenger networks and are responsible for many diverse cellular functions.  What is now emerging is a better understanding of what makes these proteins do one thing and not another.  The paper above demonstrates some of that recent research and highlights how further understanding of how these proteins operate will lead to better treatments for cancer.

Induced Life: the Wonders of Stem Cells

Recently there was an amazing announcement in the world of stem cell research.  Scientists at Kyoto University in Japan managed to coax mouse derived stem cells to become viable eggs when transplanted into female mice.  The eggs were fertilised and embryos transplanted into foster mothers resulting in healthy, fertile offspring.  This is a major advancement in the science behind stem cell programming and fertility treatment.

The coolest part behind this work is understanding how to make stem cells develop into sex cells, or for that matter any other cell type.  This work comes out as Gurdon and Yamanaka receive the Nobel prize for work leading to the creation of stem cells from adult cells, a discovery that revolutionised science and our understanding of stem cells.  It’s a very complicated idea but I’ll try my best to explain it...

Gurdon and Yamanaka worked on the creation of what are called ‘induced pluripotent stem cells’ or iPS.  Pluripotent is the characteristic that stem cells have which means that they can go on to develop into any cell in your body (neurons, muscle, skin etc.).  The use of the word induced refers to the fact that these stem cells are created from a ‘mature’ adult cell that has already left its stem cell state.  The advantage of this is that it bypasses the ethics surrounding the use of embryonic stem cells derived from embryos.

So how do they do this?  

Very simply it is done by forcing the expression of genes which give stem cells their specific characteristics.  Amazingly, Yamanaka discovered that it only required expression of four key genes to create a stem cell.  These genes can be switched on by using a virus as a vector for carrying DNA sequences and inserting them into to the adult cell genome resulting in forced gene expression.

Picture taken from:http://www.rndsystems.com/cb_detail_objectname_cb09i2_induced_pluripotent_stem_cells.aspx

KLF4, SOX2, C-MyC, Nanog, Oct-3/4 and LIN-28 are genes that are forced to create iPS.

I know what you might be thinking; that’s seriously cool shit but how do you get from that to a fertile mouse conceived from a stem cell??

Well it’s easy (well not really) and simply involves nurturing stem cells with a cocktail of specific molecules that tell the stem cell what to do by activating certain genes at specific times.  Using this method scientists were able to produce a female sex cell from a stem cell which once fertilised was implanted into a donor mother and eventually was born as a healthy mouse.

You have to admit this kind of work is pretty amazing and Gurdon and co. much deserve the Nobel prize that they were awarded this year for without their groundbreaking work none of this science would be possible.

Nom Nom Nom Autophagy!

If you’re anything like me then you will be fascinated by autophagy.  It’s a process that cells go through to deal with starvation.  Much in the same way that humans as an organism would die without food, cells too, suffer the same fate unless they are kept happy with a constant supply of nutrients.  If we are hungry we eat.  If a cell is starved of glucose it doesn’t have the option of grabbing a Mars bar so instead has developed an intricate survival mechanism - Autophagy.

This process literally means ‘to self eat’ and in short involves break down of the less important components of the cell into the building blocks required to keep the cell alive.  Importantly this will include amino acids - the base unit of a protein - which allows synthesis of new proteins and cell survival.  As a survival mechanism it is not surprising that autophagy is linked to cancer.  What is more surprising (or perhaps not when you compare it to other processes linked to cancer) is that there is sufficient evidence to say that autophagy may be oncogenic (cause cancer) or tumour suppressive (prevent cancer) depending on many other interacting factors.  The link between autophagy and cell fate is currently a hot research topic and as our understanding of it improves it may become clear that autophagy can be used as a therapeutic target to tackle cancer.

Confocal image of MCF-7 (human breast cancer cells) treated with the chemotherapeutic agent etoposide.  Stained with acridine orange the green shows where the dye has stained the nucleus and the red is where the cell is starting to 'digest' parts of itself in small capsules called autophagasomes.  (courtesy of me and Aston University)

I have been involved in breast cancer research for the past 4 years.  Treatment for the most common types of breast cancer have been very successful and helped to not only extend lives but also ‘cure’ breast cancer sufferers.  A major issue currently facing cancer researchers is the development of resistance to chemotherapy regimes that can result in a tumour growing back or treatments becoming ineffective in certain patients.  It is not fully understood how this occurs but a variety of genetic and epigenetic changes have been attributed to the evolution of tumours carrying drug resistance cells.  Darwinian theory would naturally select for these resistance cells following the selective pressure of an anti-cancer therapy and could give rise to a resistant tumour.  This phenomenon is fascinating and I would recommend reading more about it to any reader who has an underling interest in cancer biology.

So how does this all link to autophagy? Well quite simply, Autophagy has been shown to be a direct cause of drug resistance in cancer cells.  By helping the cell to survive under times of extreme stress, such as being bombarded with a nasty chemotherapeutic agent, the probability of survival-elite clones taking over a tumour population is increased dramatically.  Recent research proposes autophagy inhibitors may be a way to reverse or impair drug resistance in cancer but because of the complex cellular network controlling autophagy, it is not yet known how effective they may be clinically.  This is a major area of current cancer research and expect some exciting breakthroughs to take place soon.

Space Freefall and Boiling Blood

News coverage of Felix Baumgartner and his crazy idea to be the first person to break the sound barrier by free falling 23 miles from THE EDGE OF SPACE always seems to mention that should he fail...his skin will boil.  Well this sounds incredibly dangerous and as a curious scientist I wanted to find out more about his jump and the risks involved.

For his jump, Felix will wear  pressure suit manufactured by David Clark Co., the makers of suits worn by astronauts and high altitude pilots.  The biggest risk seems to come from Felix ripping his suit as he makes the jump.  He would be exposed to the harshest of conditions; 120,000 feet up, -23 degrees celsius and an air pressure of 1LB per square inch.  The lack of oxygen and low temperatures could cause lethal bubbles to form in his bodily fluids.

This phenomenon caused by exposure to near vacuum is known as the Armstrong Limit and represents the altitude at which atmospheric pressure reaches 0.0618 atmosphere units.  At this altitude water boils at around 37°C due to the direct relationship between saturation temperature and saturation pressure.  In simpler terms, at normal pressure (say in London) water boils at 100°C because this is the temperature that saturates how much thermal energy the liquid water can take on before boiling or turning into a gas.  In comparison, at low pressure (say at the top of Mt. Everest) the same water will boil at 71°C.  So if Felix rips his suit he will be exposed to pressures so low that the water in his body will begin to boil...not ideal.

It sounds like the makings of an 80's horror film death but exposure to vacuum is not as damaging as it sounds.  The containing effect of your skin and circulatory system protects your blood from boiling.  No instant freeze as heat does not dissipate that rapidly from the body.  Loss of consciousness occurs only after sufficient oxygen deprivation from the brain.  NASA reported that in 1965 a test subject was accidentally exposed to near vacuum and simply went unconscious after 14 seconds.  He regained consciousness after re-pressurisation to around 15,000 feet and reported that the last thing he remembers is the water on his tongue beginning to boil.

Lance Armstrong - Fallen Hero

After years of accusations, allegations and ‘did he, didn’t he?’, the USADA has finally laid to rest Lance Armstrong, the USPS team and one of sporting’s most impressive achievements.

The evidence compiled by the USADA was enough to force Armstrong to give up his long-term battle to silence his opponents in August 2012.  The 1,000 page report released by the USADA yesterday is a heavy blow to Armstrong as it portrays him as not only a dope cheat but also as a bully and aggressive team leader whom personally ran ‘the most sophisticated, professionalised and successful doping programme the sport has ever seen’.

The doping regime instilled by USPS was tactical, planned and intelligent.  They timed their use of EPO - a glycoprotein hormone that regulates red blood cell production - in order to avoid detection.  Before a drug test riders would also have a saline transfusion to manipulate their red blood cell concentration.  Effective detection methods were not available until after 2000 and even then they were only useable within a small time frame.    Lance would have already won the 1999 Tour de France and set himself on route to cycling history.

Personally I am gutted that Armstrong is not the cycling legend that he was made out to be.  He was a sporting a hero of mine for his 7 Tour de France victories, coming back after battling cancer.  I am in no doubt that the majority of top level riders in his era would have been doping and so am also in no doubt that Armstrong is still the greatest cyclist of all time.  However, I am disappointed that he bullied teammates into doping, as this changes my perception of his character and the values I thought he embodied.  Armstrong was one of my sporting heroes.  Emphasis on was.