Biology Behind: Sickle Cell Disease

Greetings everybody!

Congratulations you have got through the week and it is now officially Friday! To all those students out there who have started your exam season good luck! I am sure you guys heard all about the edexcel biology question asking you to explain the link between sickle cell and malaria. May be a bit to late, but lets get it all out in the open!

Sickle Cell Disease is a heritable disease that affects the blood. Sufferers of this disease experience a symptom known as crises, a period of acute pain that varies in longevity from a few hours to days. Sickle Cell Disease is also twinned to the onset of other conditions such as anaemia, leg ulcers, jaundice, kidney damage, high blood pressures along with increased susceptibility to infections and stroke. In 2010 302,800 children were born with this crippling disease, two thirds of these children residing in Africa. By 2050, this number is predicted to rise by 25%.  Sickle cell is a growing problem in a region that is poorly prepared to deal with the increased burden on their health services.

Development of this disease all comes down to whether or not an individual inherits a gene that has a minor genetic change, otherwise known as a mutation. The mutation itself is tiny, a substitution of one amino acid for another on the gene that codes for the haemoglobin protein. How does something so small have such a large impact? Lets use the analogy of building a house. Before your house is built you have a blueprint, this blueprint details every dimension of your dream house (your DNA strand). You do not pick up on it but within that blueprint one of the measurements have been taken very wrong (the switch of glutamic acid with valine). When your dream house is completed it has a completely different shape to what you wanted (sickle shaped blood cells).

Lets get into the details of this disease. The mutation in the haemoglobin gene results in the shape of our red blood cells to change from a flexible disc shape to a rigid sickle appearance. Unlike healthy haemoglobin, 'sickled' haemoglobin binds to oxygen once and when released, sickled haemoglobin bind to one another forming rigid rods. These rigid rods then reshape the disc shaped red blood cell into a narrow crescent.

Changing the shape of red blood cells is not where it stops. Sickle blood cells also become very sticky! This increased stickiness allow them to stick to one another and form blockages in narrow blood vessels. These blockages starve tissues and organs of much needed oxygen. Additional complications such as those previously mentioned are thought to be caused by alterations of our bodies pain receptors to enhance the discomfort as well as shorter life spans for our red blood cells.

Exploring that malaria and sickle cell link

Sickle cell disease cases are typically found in areas with hot climates such as Africa. Interestingly this is where the vector for Malaria transmission is also found- the Anopheles Mosquito. Evidence suggests that such geographic concentrations of sickle cell cases may have arisen from a preference for the sickle cell trait. 
Sickle cell is a recessive disease, therefore you would need two sickle traits in order to have the disease. However, those who inherit only one sickle trait are technically carriers - those with the trait but remain healthy. Have a look below at the image showing the rules of inheritance for this disease.

Carriers are practically malaria resistant. Plasmodium (malaria causing parasite) is transferred from an infected Anopheles mosquito and once in our bodies hijacks a ride in our red blood cells, during the trip they feed of our cells haemoglobin. One theory on how carriers confer malarial resistance could be down to small changes in their blood, such as slightly higher carbon monoxide levels or possibly how the oxygen interacts with sickle haemoglobin. This combination diminishes carriers as suitable hosts for the malaria parasite. Such resistance may be selected for by women or men who will pass this resistance onto their children. 


Symptom based approach:

Medications such as penicillin and folic acid can treat the infection and stimulate the production of red blood cells in young children. The main drug on the market is hydroxycarbamide, it reduces the frequency and severity of crises.

Development of treatment has been slow for this disease based on lack of pharmaceutical investments. In 2010, Don Abraham a chemist at the Virginia Commonwealth University focused his efforts on synthesising a drug with anti sickle effects. Interestingly, he found a promising compound in food products that offered a gateway into preventing the sickiling of cells in caramel, roasted coffee beans and dark beer!

Isolation of specific compounds within these anti sickling food agents led to the development of Aes-103. In early clinical trial stages, it was found those on the trial drug experienced a significant reduction in pain.

Additional drug developments are focusing on making sickled red blood cells less sticky. On further examination it was found that sickled cells caused white blood cells, platelets and cells on the lining of the blood vessel to stick to one another. Such blockages are diagnosed as vaso-occlusive crises. Pain originating from such blockages can lead to hospitalisation and permeant organ damage.

Two approaches are taken to reduce these from of crises. One, synthesise a drug that will bind to the surface of sickle blood cells preventing them from blocking narrow blood vessels. Or, target a specific group of proteins that we know when activated cause cells on the blood vessel to bind to white blood cells. This group of proteins are known as selectins, and such a drug to ensure they remain unactivated was under trial in 2014, called Rivipansel. Clinical trials of this drug reduced the time spent in hospitals, the longevity of crises events and decreased the need for Opoid medication by 83%.

Tackling the gene responsible:

Such approaches are centred around the term 'gene therapy' or genetic manipulation. It involves the insertion of a functional gene in to the patients DNA, or, by editing the faulty gene within the patient. Such methods have the highest success rates in disorders resulting from a single gene mutation- like Sickle Cell. Two approaches can be taken.

First of, the conventional gene therapy this process involves healthy gene insertion. It all starts by modifying a harmful virus to insert the healthy gene into the patient own cells, these modified cells are then transplanted back into the patient. Alternatively, gene editing cal be used. In simple terms this is the equivalent of a 'cut and paste' on a molecular scale. This fixes the problem by correcting the mistake found in a specific set of stem cells known as haemotopoietic stem cells. This guys give rise to the two type of blood cell.

Alright guys,
Thats all for this week.
Over and out.

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