Ever Wondered How Alcohol Affects the Nervous System?

Not only in the UK, but all around the world, alcohol is enjoyed by many - drinking is indeed a popular pastime. However, when individuals over-indulge, it can lead to serious health problems including addition even though this is not very common. Nevertheless, in the UK, the NHS estimates that '9% of men and 4% of women show signs of alcohol dependence' (Source: DrinkAware). Over the decades, interest has increased around the effects of alcohol, not only on the physical but also on the mental state. In medicine, researchers will endeavour to find a physiological mechanism to a unexplained mental or behavioural phenomenon. A perfect example of this is the effect of various drugs, illegal and legal, on human behaviour. Quite a few of these substances cause imbalances in the amount of neurotransmitter released from pre-synaptic vesicles into the synaptic cleft in particular areas of the brain. In turn, the frequency of electrical impulses transmitted can fluctuate which can ultimately influence behaviour. To understand this better, it is beneficial to look back in history when the basic physiology and chemistry were uncovered.

Above: Scanning electron micrograph of neurotransmitter-containing vesicles (orange and blue) being released from a pre-synaptic neuron (Source: AnatomyBox)

Pre-1930s, there were noticeable disagreements between academics on how exactly neurons communicate their signals to one another. Was it electrical or was it chemical? It wasn't until 1936, when Sir Henry Dale and Otto Loewi received the Nobel Prize in Physiology or Medicine, that it became clear that these signals were indeed due to chemical transmission. This is possible through the action of neurotransmitters - chemicals which are released into the space between neuron, the synaptic cleft. Some scientists prior to this award did suggest that chemicals were involved, through observing the similarities in nerve stimulation in plants and animals (Source: NobelPrize.org) Loewi managed to illustrate the importance of these chemicals in an elegant way using experiments on frogs. His papers were published in 1921 - these showed that nerve impulses affected the heart using chemical transmission. Firstly, Loewi stimulated the vagus nerve fibres of an isolated frog's heart that had been connected on the other side to a ringer solution. Soon after this, he observed that the strength and frequency of the heartbeat decreased. The fluid remaining was used to surround another frog heart - the vagus nerves were not electrically stimulated. This time, the heart changed it's activity as if it had been electrically stimulated (Source: AnimalResearch.info) It seemed that the fluid has caused this change. Dale's discovery of the action of acteylcholine was inline with Loewi's results and so after subsequent years of research, Dale and Loewi were awarded the Nobel Prize in Physiology or Medicine. 

Chemical transmission is an important concept to understand when we consider how an impulse is able to transmit from neuron to neuron in the brain. It can be understood as a cascade of events beginning with the arrival of an action potential at the axon terminal of the pre-synaptic neuron. The depolarisation stimulates calcium ion channels to open, causing an influx of Ca²⁺ into the axon. This in turn stimulates vesicles filled with neurotransmitter to migrate to the end of the axon. The vesicles are then able to fuse with the lipid bi-layer membrane to release the neurotransmitter (e.g. acetylcholine) into the synaptic cleft. When these neurotransmitters bind to ligand-gated sodium channels on the post-synaptic neuron, this triggers another action potential to fire. To prevent constant firing of action potentials, a neurotransmitter such as acetylcholine is broken down by an enzyme (in this case, acetylcholinesterase), and the inactive products are reabsorbed by the pre-synaptic neuron through re-uptake transporters. These events will become important when we look at the effect of alcohol on the nervous system.

Above: Schematic diagram showing the transmission of an action potential  (Source: Biological Sciences Review Volume 26, Number 2).

Now, alcohol is one of the few substances than can cross what is referred to in anatomy as the blood-brain barrier (BBB). This is largely a fatty barrier than surrounds the blood vessels in the brain. In medical research, this barrier has been notoriously difficult to overcome when delivering drugs or attempting to treat an array of brain-related diseases, for example Alzheimer's. Until very recently, this has caused problems, however scientists have now found a way of delivering cancer-fighting drugs to targets by breaching the blood-brain barrier. A research team in Canada used 'tiny gas-filled bubbles, injected into the bloodstream of a patient, to punch temporary holes in the blood-brain barrier'. Following this, ultrasound was used to make the bubbles 'vibrate and push their way through, along with chemotherapy drugs' (Source: BBC) This has been a significant breakthrough - I encourage you to read more on the subject here.

The reason that alcohol is able to cross this barrier is that it is lipid soluble. Once alcohol crosses the barrier, it is able to affect the action of neurotransmitters. Before looking at how alcohol comes into play, it is useful to consider the different types of neurotransmitter that exist in the nervous system, and their different modes of action.

Neurotransmitters can either be excitatory (increases the likelihood of an action potential being fired on the post-synaptic neuron) or inhibitory (decreases the likelihood). Examples of excitatory neurotransmitters are glutamate, dopamine and acetylcholine. Glutamate is the most common kind of neurotransmitter in the brain and is thought to be involved in memory and learning. The well-known neurotransmitter dopamine is involved in the mechanisms of motivation and reward. It follows that many addictive drugs utilise the 'feel good' sensation that dopamine causes. And finally, acetylcholine is most commonly used in the contraction of involuntary muscle - it can be released at the site of a neuromuscular junction. A good example of an inhibitory neurotransmitter is gamma-amino butyric acid (GABA) - it's action is known to reduce stress. In fact, about a third of all brain synapses use GABA, and anti-anxiety drugs such as Valium enhance it's action. Another example of an inhibitory neurotransmitter is the amino acid glycine, however this is used mainly in the spinal cord, and is involved in about half of all synapses there, the rest using GABA. (Source: Principles of Anatomy and Physiology 13th edition - G.J. Tortora and B. Derrickson)

Above: The structure of common neurotransmitters (Source: CompoundChem). See source link for larger image.

Alcohol is widely known as a depressant drug. It is able to decrease excitatory action, and increase inhibitory action. Here, we can look at how alcohol affects the release of GABA. Ethanol increases the amount of GABA neurotransmitter released from pre-synaptic neuron in the brain, by increasing the likelihood that GABA containing vesicles fuse with the bi-layer membrane. To further induce an effect, ethanol encourages GABA to bind more easily to it's corresponding ligand-gated ion channels on the post-synaptic neuron. Subsequently, chloride ions flood into post-synaptic neuron cytoplasm, decreasing the chance that an action potential will fire. In parallel with this effect on GABA transmission, alcohol also affects the action of the excitatory neurotransmitter, glutamate. Ethanol decreases glutamate's excitatory activity, and this effect is quite dramatic considering that glutamate is used in 90% of synapses! (Source: Biological Sciences Review Volume 26, Number 2) The binding of glutamate to it's receptors on the post-synaptic neuron is blocked, thus an action potential cannot be triggered. Since glutamate is used in routes in the brain associated with learning and memory, it is common that people will suffer memory loss after a booze-fuelled night.

The imbalances between inhibitory and excitatory activity do explain the drowsiness, slow reactions and sometimes poor memory people have when drinking a significant amount of alcohol. However one observation we may have forgotten is that to many, drinking alcohol can make them feel good. From research, we know that the reward centre and the pathways associated with it are located in an area of the brain called the striatum. So far, there has been no clear link between alcohol and an effect on the action of the neurotransmitter dopamine. Recall that dopamine is involved in motivation and reward. Where is the link? Well, it is thought that the reward feedback system is usually 'kept in check by GABA inhibition. When this inhibition is suppressed, the reward system becomes more active'. Remember that alcohol does cause suppression of GABA inhibition as it encourages more GABA to bind to the post-synpatic neuron!

Above: Schematic of the brain showing the location of the striatum (yellow-orange region) (Source: Biological Sciences Review Volume 26, Number 2)

To conclude, we can see that in order to understand how alcohol can affect the nervous system, it is important to appreciate the biological cascade of events that occur during chemical transmission at the synapse. Although alcohol can be enjoyed in moderation, the public must be aware of the potential health complications associated, including liver disease, weight gain and sleep disruption. The incidence of liver disease particularly, is rising in the UK. Bear in mind that this disease not only affect adults, but also the young as well. Let us not forget also of the societal problems that can arise due to alcohol abuse, which include antisocial behaviour and violence in extreme cases.

Even today, alcohol still presents unsolved mysteries to researchers. However with continuous advances in technology, medicine, and neuroscience, how the brain is affected by substances is becoming clearer and clearer.


Additional credit: Oliver Freeman is a writer for the Biological Sciences Review and is also studying for a PhD in neuroscience.
 - Michelle Roberts, for her article published on the BBC website, 'Scientists breach brain barrier to treat sick patient'. Read more on the subject here.

Are You Getting the Right Match?

In the UK, there has been a big increase in the number of patients requiring transplants over the last decade or so. In fact, this pattern can be reflected worldwide. In order to understand why we need more donors to accommodate the continual increase in patients requiring transplantation of solid organs, its useful to know how we determine matches between donors and patients. "Solid" organs as you could infer, relate to organs that are in a solid state. Examples of these include the kidneys, pancreas, heart and lungs. It is widely accepted that it isn't easy to find compatibility between donor and recipient straight away - there must be biological compatibility of two types. The first is the well-known ABO blood group system. There are four different groups that an individual can fall into: A, B, AB, and O. Each group signifies the types of antigen present on the surface an erythrocyte, or red blood cell. Antigens are proteins on the plasma membrane of a cell, giving it its own 'identity'. This is essential in the multiple processes of the immune response, for example. A person identified with an 'A' type blood group has only 'A' type antigens on the cell surface membranes of red blood cells. However they will also have 'Anti-B' antibodies circulating in their blood plasma. The converse is true for those with a 'B' blood group. If someone were to have AB however, they would have both types of antigen on the cell surface membranes of red blood cells. Therefore no antibodies acting against these antigens would be circulating in their blood plasma. Now, those with type 'O' blood group are seen to be rarer than those with other blood groups, but it means as a donor you would be 'compatible' with any recipient of any blood type. For this blood type, no ABO antigens are present on the membranes of red blood cells, but the serum of these individuals will contain the 'Anti-A' and 'Anti-B' antibodies.

Chart showing the differences in cell type, antibodies and antigens present in individuals with different blood groups (Source: Wikipedia )

To illustrate this, let us consider a potential liver transplant between a donor with blood group O and recipient with blood group B. The donor has red blood cells with no ABO antigens, so when mixed with blood (and plasma) containing red blood cells with the B antigen and therefore 'Anti-A' antibodies, there will be no immune response. After all, the antibodies are not able to form an antigen-antibody complex.

Most people will be aware of the ABO blood group system; however there is another factor that always needs to be considered by doctors before carrying out any surgeries involving organ transplantation. This is what is known as the human leucocyte antigen (HLA) system. All cells known to contain nuclei in the body possess these protein complexes on their cell surface membranes. Therefore it is useful to know that red blood cells do not have these antigens as they have no nuclei, no genetic material encased. HLA types are inherited from both parents, and 'research has shown that the fewer the number of mismatches between donor and recipient HLA, the less likely it is that the organ will be rejected post-transplantation'. This is why it has become increasingly imperative for doctors to screen individuals for this type of antigen so that matches between patients and potential donors can be confirmed. A patients HLA type can be confirmed by a series of tests. The polymerase chain reaction (to create multiple copies of DNA) followed by gel electrophoresis (allows the scientist to visualise the result) being one of the more notable methods.

After the HLA type has been confirmed, the patient's serum is analysed to 'screen for the antibody profile'. Firstly, the serum is 'mixed with microbeads that have multiple HLAs on their surface'. This essentially serves to identify antibodies that are targeted at particular donor HLAs, using a fluorescent marker. This is needed as there is always a possibility that the recipient could have developed antibodies against a particular HLA in the past, whether it be pregnancy, previous transplants, or blood transfusions. These are known as 'sensitisation events'.

In addition to this, another test is carried out, involving mixing of recipient serum with donor cells. This is primarily to see if there is any immunological reaction to the donor cells, thus proving whether a donor is in fact compatible with the patient. The donor cells are those with nuclei, so scientists can test whether the HLAs of the donor form an antigen-antibody complex with antigens present in the patient's serum. 'Complement' molecules are also added which help to destroy cells (by lysis) that have their HLA antigens bound to patient antibodies. To see whether a reaction has occurred or not, a visualisation stain is applied, dead cells staining red, and live cells staining green.

Not only is it important to choose the right donor, but selecting viable organs for surgical use is also vital. Donors can either be living or deceased, but living donors 'are generally family members or close friends of the patient'. That isn't to say all are, of course, as altruistic donors are on the rise - these people are willing to donate an organ without knowing who will receive it in due course. Kidney donation is by far the most common transplantation from live donors. In fact, 'in the UK, 2732 out of 3740 transplants performed in 2011 were kidney transplants'. Donations from the deceased however can be divided into two sub-groups: those who are pronounced brain dead (DBD), or those with circulatory death (DCD). DCD is when the heart has completely stopped beating and thus there is no circulation flow throughout the body. DBD donors have organs 'kept alive' by a ventilator, with a constant blood supply in place.

A patient can be found to have their donated organs rejected by their own immune system at several possible stages after surgery:

Hyperacute: Rejection occurs immediately, even within a few minutes of transplantation. Surgeons would need to work quickly to remove the donor organ completely from the body. Nowadays, hyperacute rejection is very rare.

Accelerated acute: Rejection could happen within a few days to a week after surgery. The rejection may be due to the fact the patient has experienced a sensitisation event in the past, which produced the relevant antibodies.

Acute: Rejection occurs within the first 6 months of surgery, and is mainly due to a few mismatches in HLAs between the donor and the patient. This sort of rejection can be brought under control with certain immunosuppresant drugs that are specific to the recipient.

Chronic: Rejection could even occur after 6 months from the point of surgery and mainly due to repeated episodes of acute rejection. This is the main problem facing patients with transplants - some patients will be required to take immunosuppresive drugs for the vast duration of their life.


With a population as ethnically diverse as the UK, it has become increasingly difficult for those of minor ethnic origins to receive the right matches for organ donation, although overall there is a big gap between the numbers requiring transplants and willing donors.Those of Black and Asian origin have been known to have 'uncommon HLA types'. Many countries, such as Spain, Belgium, France and the USA have implemented an 'opt-out' scheme nationwide. This means it is presumed you give consent for your organs to be donated, unless you state otherwise. In the UK, the public's view may be changing on whether we should carry on with our current system in order to meet the piling demand for organs across all ages, all backgrounds, and all ethnicities.


Credit to Steven Jervis, clinical scientist at the Manchester Transplantation Laboratory who wrote for the Biological Sciences Review (Volume 24, Number 1)

The Small Guys That Help Regulate Protein Synthesis

If you have an interest in cellular biology, the chances are you've come across the different types of nucleic acids that are used to code for proteins and control certain activities of the cell. However, what might be new to you is the existence of MicroRNA or miRNA, in its common notation. Essentially these are regular strands of RNA but very small - in fact a regular sized RNA molecule may be around 100 times longer than the average length miRNA. As miRNA are single stranded, the molecules tend to quite flexible, in contrast to the well known rigid DNA double helix molecule. Originally, scientists tended to believe that in eukaryotic cells at least, there were only two types of RNA: ribosomal RNA and messenger RNA. At first, miRNA were seen to be RNA that were too insignificant to have any real function, they were considered free clumps of nucleotides in short.

Now the importance of miRNA molecules has been realised, thanks to cutting edge research on a particular type of nematode worm - specifically Caenorhabditis elegans. In 1993, the first miRNA identified was named lin-4. What scientists found is that somehow, these minute molecules prevent the development of the larvae. 

After these baby steps into this field of research, the year 2000 saw the discovery of the miRNA molecule let-7. This was found to 'regulate development in C.elegans'. What was more significant however, was that this molecule could be found in all animal and plant cells. But what do we mean by 'regulate development'? This particular miRNA molecule is found to be responsible for controlling aspects of the cell cycle and cell differentiation. But healthy functioning cells doesn't rely on a single miRNA molecule - many different molecules working together ensure cellular processes go on as intended.

But how do miRNA's work?

In an average human cell, over 1000 different miRNA molecules can be found. Each of these specific strands seek to target a particular RNA molecule. With over 60% of RNA molecules being targeted by miRNAs, it could be said that controlling protein synthesis is a very organised and vast operation. What is important to note, is that miRNA molecules are encoded by genes, a lot like proteins in fact. It follows that these genes are present in the cell's DNA.

To synthesise miRNA, firstly one long strand of specially structured RNA is manufactured from miRNA genes. These could be considered the precursors of miRNA (Pri-miRNA) and are subsequently lysed by enzymes and transported from the nucleus, into the cytoplasm. Any two different  miRNAs can align through regular RNA-RNA hydrogen bonded base-pairing. However in some parts, there may be some non-complementary base pairing which would lead to bulges from the molecule. Using specific enzymes, the hydrogen bonds can be broken to leave two separate miRNA molecules which can go on to target their designated RNA molecule.

Due to inconsistencies in base pairing with an mRNA molecule, miRNAs have been found to inhibit protein synthesis by preventing the ribosome translating the RNA molecule. But another way miRNA's function is that they can achieve complete complementary base pairing with an mRNA molecule. Specific degrading enzymes can then recognise this situation and destroy the miRNA-mRNA complex, preventing the protein ever being synthesised.

(Two examples of pri-miRNA - sequences in red represent 'mature' miRNA. Notice there are bulges where there is no complementary base pairing - WIkipedia - microRNA)

Extended research has shown that 'malfunction of miRNAs is implicated in some liver diseases, diseases of the nervous system, cardiovascular disease, cancer and obesity'. One example given in the September issue of the Biological Sciences Review is miRNAs affecting normal nervous function. Individuals with mental retardation sometimes have whats called "fragile X syndrome", where as implied, the X chromosome tends to break easily. In association with this, it has been found that in the nerve cells of these individuals, miRNA molecules have prevented the synthesis of an essential protein by binding with mRNA.

Even miRNA has been believed to be the culprit in some cancers. It isn't always bad that an miRNA molecule binds to RNA - some miRNAs suppress tumour growth whilst others promote it.

At present, it may be difficult to see how miRNAs can be used to treat disease, but I believe there is no doubt that it could one day be widely use to diagnose them. Cancers are a good example. It has been observed that particular concentrations of a miRNA can correlate with different rates of growth of malignant tumours. From miRNA analysis, it may be possible for doctors to predict the best treatment options for patients.

However this does't mean treatment isn't possible! According to Professor Sheila Graham of the University of Glasgow, new research has revealed the potential of "miRNA sponges" in cells. These are non-functioning RNA molecules that "mop up" specific miRNA molecules so that they can't interrupt the synthesis of essential proteins.



Credit to Professor Sheila Graham for her article 'MicroRNAs - small players in big diseases' published in the Biological Sciences Review (Volume 27, Number 1).

Fat!

One of the major health issues facing our world, the western world especially, is obesity. In fact, it is estimated that there are over 1.4 billion people overweight with over 500 million obese. These figures are expect to rise. In 1971, it was estimated that in North America, 14.5% of the population were obese. Now, the figure is over double at 30.9%. These figures were taken from the Biological Sciences Review article 'Lifestyle and Cardiovascular Disease', Volume 26, Number 2. Britain, despite it's small land mass, is considered the second 'fattest' country in the world - in reference to it's people that is. It is not only to do with the fact our country is now becoming overcrowded, our very habits, morals, behaviour and eating patterns have contributed to a dramatic increase in cases of obesity in the last couple of decades. To many people, carbohydrates contribute to the base of a diet. However in many cases an imbalance of this food group inevitably leads to weight gain and the formation of excess fat (adipose) tissue. How does this mechanism work? Well, central to this question is respiration, adipocytes (fat cells) and of course the different types of fat. Here, I want to explain how a weight gain is achieved, even right down to the molecular level.

Firstly, we need to understand that the molecule glucose makes up the vast majority of carbohydrate-based foods. Glucose is essential to our well being, in particular being vital to the function of our nervous system and our muscular system. It's uptake by our many billions of cells initiate the start of the production of the 'energy' molecule ATP, or Adenosine Triphosphate. It is a continuous process, however once our cells are content with the amount of glucose needed to produce ATP, glucose is transported and stored in various tissues of the body.

Adipocytes

Usually, glucose can be converted into glycogen via glycogenesis for "short-term" storage in muscles and the liver. Glycogen can be easily hydrolysed back into glucose for ease of access to body cells and tissues. However alternatively, glucose can be stored as part of fat molecules called triglycerides. These molecules comprise of a glycerol backbone with three attached hydrocarbon chains. These chains were originally carboxylic acids, better known as fatty acids - they take part in a condensation reaction to release three water molecules in forming a triglyceride. The main site in the body in which we would find triglycerides is in adipocytes. However triglycerides can also be utilised by muscle cells in the release of energy if needed. Fats are generally considered a second source of energy after carbohydrates. As well as the storage of glucose, triglycerides can also be formed from the digestion of fatty foods into the base components glycerol and fatty acids before subsequent absorption.

So how exactly is fat managed?

Well, to start with there are two different kinds of adipocytes, white and brown. It is important to distinguish between these two cell types as they have very contrasting roles. When fat is said to be 'stored', it is held within the white adipocytes of the body. When these cells are content with the amount of glucose needed to carry out respiration to yield the maximum number of ATP's, excess glucose is converted into fat here. The receptor that recognises this and promotes the storage of fat is called PPARγ. Conversely, brown adipocytes are considered extremely 'energy ineffecient', "burning" up triglycerides and storing very little, if any, of them. The result is that much heat is produced, a consequence of the many mitochondria this cell has. In fact, it has the most of any cell in the human body. This was once considered a survival mechanism for newborn infants as they had brown adipocytes in large numbers - the heat generated helps to protect the child from comparatively cold conditions to the womb. New research has found that adults posses these exact same cell types, 'roughly 60g in the neck region'. These cells adjust their calorie-burni ctivity in accordance with food intake and external temperature just to name a couple.

Now here is the intriguing part. Recent experiments in mice have shown that an increase in brown adipocytes 'help protect against diet-induced obesity and type 2 diabetes by preventing the build-up of triglycerides in other cell types, such as those in the liver and muscle'.

So what are the potentials of brown adipocytes?

In my view, adipocytes quite fasdcinate me now I've read a lot more into the subject. In cellular respiration, glucose is commonly processed through a series of step-by-step exothermic reactions. However in brown adipocytes, the stage that normally produces the largest number of ATP's is halted. It is known as oxidative phosphorylation. This means rather than using the energy released form the exothermic reactions to produce ATP, it is dissipated as heat energy - usually regardedas very inefficient!

Scientists have spent years of research trying to suggest new methods to combat the ever-pressing problem of obesity. Novel resserach into a particluar protein found in adipocytes called sirtuin has sparked a glimmer of hope. Sirtuin has been found to be associated with 'calorfic restriction' where life expectancy has increased with decreasing the number of calories in the diet gradually over a prolonged period of time. As sirtuin is commonly found in metabolising brown fat cells, there may be potential for sirtuin to be stimulated in white fat cells in combating weight gain. The experiments that scientists carried out confimred that with an increased presence of sirtuin, white fat cells started to show some of the characteristsc of brown fat cells, i.e. genes were becoming switched on that were analogous to brown fat cells. Parallel to this, other genes in the white fat cells were becoming switched off, again the same ones that are switched off in normal brown fat cells.

This phenomenal "growing" effect of white fat cells has significant potential. It is down to the protein sirtuin, how this works requires a little more understanding. Sirtuin is found to bind to the PPARγ receptor and modifies it. This receptor is found on the nucleus of white adipocytes. Therefore this receptor doesn't resume in normal function - instead it 'activates a transcription factor called Prdm16 that stwiches on a set of genes necessary for using up chemical energy to produce heat'.

Another plus side of the 'browning' of white adipocytes is that, in diabetic mice, their responsiveness  to insulin increased.

Is it all too good to be true? Well, not exactly. You see, sirtuin is found in many different types of cell throughout the body, not just adipocytes. This would imply that adjusting concentrations of sirtuin will have additional, even unwanted effects to the body. These problems will need to be investigated further by researchers in the future.


Credit to Joseph Robertson, who writes for the Biological Sciences Review (Volume 26, Number 2), for his article "Fighting the Flab" which was published.

Understanding Congenital Heart Disease

The heart is undoubtedly to many one of the most essential organs of the body, supplying all major tissues with oxygen and glucose which allows body cells to respire - to generate ATP. However what is also very important is how the heart develops during pregnancy, and how effective it is as an organ. Unfortunately children are sometimes born with congenital heart defects which means the heart's duty to pump blood around the body sufficiently can become compromised. These conditions are considered relatively rare which means for scientists, students, doctors and specialists, heart development has become a very interesting topic of study. Since the heart is considered a relatively complex organ, giving rise to our double circulatory system, rare conditions help scientists to appreciate it's development. More crucially, it may trigger the development of new treatments for these defects. An article in the Biological Sciences Review helped me understand what exactly we mean by congenital heart disease.

To start with, an interesting statistic you may want to bear in mind is that 'between 1% and 5% of the human population are born with structural or functional problems with their hearts'. You may consider this a small percentage, but this equates to a very large quantity. But a statistic isn't always representative - many congenital heart defects in infants aren't detected which means the actual percentage could be higher. What is even more interesting, is that congenital heart disease is the 'most common non-infectious cause of child death'.

The tree main types of congenital heart disease which you would want to know about are:

• Septation defects: This is where there is an error is the separation of different parts (chambers) of the heart
• Unilateral blocks: Defects referring to the heart valves
• Routing abnormalities: Erros in connecting chambers of the heart with the correct major blood vessel or even failure in connection at all. 

How does the mammalian heart form? First of all, it's important to appreciate how blood is pumped around the body in a fully developed heart. Here I've included an animation which shows how this is achieved. Notice the valves are incredibly important in monitoring how blood flows and it's volumes whilst in the four chambers. Credit is given to The Children's Hospital of Philadelphia for this animation.

As the heart is the first organ required of an embryo, it develops quite early, starting as a 'crescent-shaped structure at about 2 weeks of gestation'. From this, a straight tube structure takes form which leads onto a Y-shape tube due to a join which forms at it's centre. What is amazing is that even at this stage of development, the heart continues to beat 'as early as day 22 of gestation'.

The next phase of development includes determining the positions of different parts of the heart. Chambers need to be positioned in the correct places relative to each other. This is what is known as "cardiac looping", and involves the heart muscle to bend in a very particular manner which is controlled by genes. This stage of heart formation is crucial as malformations can lead to routing problems when blood vessels may fail to attach to the various chambers of the heart.

After this stage, chambers need to be formed. At around 6-8 weeks into pregnancy, atria and ventricles become separated from each other as different areas of heart tissue become distinguished. At this point, valves are also formed in conjunction with the chambers. You may have heard of a 'hole in the heart', when someone has a hole through their atrial septum. This condition can arise at this stage of development. What is intriguing is that despite this seemingly worrying condition, problems don't seem to arise until adulthood (it is asymptomatic). It is the most common congenital heart defect diagnosed in adulthood. Of course it would be better that this was diagnosed sooner, however as mentioned many heart defects go unnoticed during early childhood.

However this isn't always a bad thing, not in foetuses that is. Foetuses contain specialised structures in their heart which aid development which adults do not possess. The foramen oval is in fact 'a small gap through which blood passes from the right atrium into the left atrium'. Why is this? A foetus is supplied blood which is oxygenated from the placenta, from the mother. Therefore if this blood were to pass through it's lungs it would render them useless as the blood is already oxygenated. This means in a foetus, the right atrium receives oxygenated blood which can then be passed into the left atrium and then the left ventricle to be pumped to the rest of the body. This gap normally closes shortly after birth, however if this fails this is an alternative way a 'hole in the heart' can remain. Surgery is usually used to treat the condition.

How can we treat heart defects? In order to pursue a treatment, we must start with extensive and long-lasting research into the genes and signalling pathways used in heart development. Scientists have started to examine heart defects that have been induced by specific mutations in genetic code, in DNA. As a single gene codes for the production of a single polypeptide, a change in phenotype can be deduced from a change in the genetic sequence, or genotype.

Scientists have introduced a method of identifying what processes regulate heart formation - this is called mutant screening. There are two possible ways of carrying out this method:

1. 'Forward genetics' - Individuals are studied for a particular characteristic, or phenotype. Then their genetic sequences are analysed in the hope of identifying the gene responsible for a particular abnormality. 
2. 'Reverse genetics' - This is considered the converse approach, where the effect of a known gene on a characteristic is investigated. In mice, this could involve deliberately inducing a mutation (using a mutagen such as ENU*) or removing a gene to see whether this causes a change in development. Removing a gene means no longer synthesising a particular protein, so this is useful when looking at how the heart develops without that protein present. 

*ENU = N-ethyl-N-nitrosourea (causes a point mutation)

An example of this which is stated in the article is that of the gene Nkx2.5 in mice. The removal of this in mice caused faulty development. However when looking at mutations of this gene in humans, it correlated with atrial septal (hole in heart) defects in families. Another example is that the loss of protein TBX1 encoded by a certain gene leads to certain congenital heart defects in humans. 

The potential of genetic screening for heart defects is fast advancing. It has allowed us to screen embryos for diseases and in the future could mean correcting abnormalities during pregnancy.

Max Brödel inspired anatomical drawing of the heart, showing ventricular and atrial chambers.

Credit is given to Katherine Powell who writes for the Biological Sciences Review (Volume 26, Number 1) for her published article . 

The Ongoing Pursuit For Stem Cell Medicine

In recent times, attention has been drawn to a particular area of biological science involving the use of stem cells. In biology, these are a type of undifferentiated cells which are capable of being multipotent or even pluripotent (embryonic stem cells only). This truly remarkable characteristic has intrigued and ultimately inspired scientists to develop techniques that can be applied to the medical field.

However we must appreciate that there are two types of stem cell. Adult and embryonic. Embryonic stem cells are derived from a 'small hollow ball of cells' called a blastocyst. This is one of the immediate results of fertilisation. What scientists are interested in is the inner cell mass - these cells are undifferentiated but more importantly they are pluripotent. This means that they have the capacity to develop into any type of cell in the body. Conversely, adult stem cells are considered multipotent, meaning they have the capability to develop into one type of cell however the variety is limited. In the human body, the most common extraction point for adult stem cells is bone marrow (although many other tissues and organs are known to produce stem cells, including the brain, heart and skin). Interestingly, foetuses have also been found to have stem cells.

Some adult stem cells such as fibroblasts can actually be reprogrammed genetically for them to 'behave like embryonic stem cells'. These are known as induced pluripotent stem cells.

Another fascinating property of stem cells is that during asymmetric division, two daughter cells are produced with contrasting characteristics. One cell is the result of self-renewal, whilst the other the result of differentiation. This explains how our body is able to heal and repair itself - any type of cell can be made available to any site where it is needed. This ability for these cells to replicate themselves and differentiate is a marvel of genetics. So how is this controlled? An engaging article in a Biological Sciences Review magazine gave me an insight.

Differentiation of stem cells is dependent on 'changing the expression of the self-renewal and pluripotency control genes'. Scientists have carefully monitored which genes switch on or off during differentiation for a variety of cell types. The result is, we can identity which genes control differentiation for a vast array of cell types. An example given is that for the production of cartilage cells (chondroctyes), adult stem cells need to 'express high levels of the gene SOX-9. This gene encourages the expression of a different gene called COL2A1 as a consequence. As genes code for polypeptides, it follows that COL2A1 codes for the production of the type-2 collagen protein. Cartilage largely comprises of this protein.


When adult stem cells are used in medicine, scientists tend to use induced pluripotent stem cells (see above) as their diversity for differentiation is a significant advantage. However for medical applications in the body, sometimes we require the aid of biomaterials to supplement the use of implanted stem cells.  The example used in this article is treatment of back pain due to a slipped disc. The pain is caused by an indentation into the spinal cord by a disc, causing a compression. Intevertebral disc cells are produced by stem cells in a lab, which can them be cultured and left to proliferate. One approach to treating the condition is to 'seed' the cells into a synthetic hydrogel. This compound exists as a gel at body temperature, it is also thermosensitive. This gel can then be 'injected into the damaged disc, where it would form a gel and act like a shock absorber, similar to a natural disc'.

The potential of stem cells in medical application is exciting and promising with continuous ongoing research. Diseases such as Alzheimer's and muscular dystrophy could one day be in combat with emerging stem cell treatments to improve the lives of those who endure the pain of these conditions.


Credit to Dr Stephen Richardson, lecturer in cell tissue engineering at the University of Manchester who wrote for the Biological Sciences Review (Volume 26, Number 4)

Organ Transplant Increase Globally

With organ transplantation becoming increasingly in demand, it seems as though steadily the healthcare services of the world are steadily reaching that demand. According to the BBC, 4655 organ transplants were carried out between 2013 and 2014. In fact this is a 10% increase on the interval of the previous year which is interesting to note. But what is more important is that over many years, the numbers have only increased.

This is very encouraging with this rate of progress however many patients are still left over extended periods of time without an organ transplant available.

However how many of us are actually organ donors? The short answer is 20 million registered. The major problem today is the inability for families to give consent of their deceased loved ones to be organ donors after death. The families decision can therefore override the decision made by the loved ones to become organ donors. This could explain the fact that 3 people a day die because organs aren't simply available for transplant, according to NHS Blood and Transplant Data.

I must agree that the decision of the family must be taken into consideration, however it must be the duty of the donor to inform their family of their decision. Ensuring the whole family has made an informed decision is imperative so that their is less risk of organs becoming unavailable 'at the last minute'.

Nevertheless, living donors are equally as important, if not more so. 'Just over 1000' transplants were possible with living donors.

The bottom line question that is asked in this article is "If we would accept an organ for ourselves or would want someone we love to be saved by a transplant shouldn't we be willing to donate one too?".


In fact while we are on the subject, I would like to elaborate on the idea of organ transplantation and consent. In February, I received my quarterly copy of the Biological Sciences Review. I remember there being an interesting column on how consent for organ donation has changed over the past decade or so, with specific insight into the work of the Human Tissue Authority (HTA).

The HTA was set up in 2005, following events where sometimes hospitals 'retained human organs and tissues without consent'. Therefore the subsequent purpose of the HTA was 'to ensure that valid consent is in place for the removal, storage an use of human tissue and organs'. Living matter that was catered for by the HTA ranges from the very small to the large, cells to organ systems.

In 2012, the HTA decided to take on responsibility not just to ensure consent, but ensure that if organs were retained, they would be preserved for their quality. Also making sure the organs were safe for transplantation.

Another important duty of the HTA is to regulates the actions of 'all organisations that remove, store and use tissues and organs for research, medical truing, post-mortem examination, education and training, and display in public'.

In addition to handing organs and tissues from dead donors, the HTA also has responsibility for the viability of all organs and bone marrow tissue from living donors.

I really like the idea of having a HTA as it reassures the public of the safety and viability of organs when organ transplantation is needed. It acts like a 'watchdog' by inspecting organisations that store, remove and use human tissue. By licensing these organisations, hospitals, and the public will know of the quality of the organs that will be used for transplantation.

Another positive aspect I feel that will emerge from this is increased confidence in organ donation. The HTA 'hopes more people will donate their tissues for scientific and medical research…for transplants…fore medical education and training.'

What astonishes me the most is that according to this article, in the year 2011-2012, 'the HTA approved 1214 living organ donations…the vast majority (96%) were kidneys'. It seems that kidney transplantation, living kidney transplantation is very much in demand. Only the remainder were donated liver lobes.

But who receives the donation? In fact 9 out of 10 donations were for the family members. Converesly there were 39 "altruistic" donations, were the donor wishes there organ to be directed to the patient in the hospital with the most clinical need.

In truth, I have endless appreciation for the donors that give up part of their own body, to help others, sometimes others that they even don't know. No knowledge of family history, personality, causes of the health issue…nothing. It is the ultimate selfless act.


Credit to Alan Clamp, current Chief Executive of the HTA, who wrote for the Biological Sciences Review (Volume 26, Number 3)

Additional credit to Nick Triggle of the BBC whose article can be found here