The idea of sicklesense is to provide a forum where the results of contemporary research into sickle cell disease can be made available, and where viewers can comment on and discuss the relevance of the findings. I will try and enliven the science with some additional facts, figures, thoughts and observations about sickle cell along the way.
Many of you will take hydroxycarbamide and some will derive considerable symptomatic benefit from this drug, but it is not a cure. Crises still occur and patients remain anaemic and jaundiced and, whats more, the response to treatment is varies greatly between patients. Why is that? Well Martin Steinberg, from Boston and his colleagues provide an elegant answer in the most recent edition of Blood.
Hydroxycarbamide works, at least partially, by increasing the amount of foetal haemoglobin (Hb F) inside red blood cells. Steinberg calculates that there needs to be at least 10pg of Hb F inside at least 70% of all the red cells if there is to be a dramatic and consistent reduction in sickling and all it’s consequences Unfortunately, although many patients who take hydroxycarbamide will manage to increase their Hb F level to 20 or 25% of their total haemoglobin, the Hb F is not evenly distributed among their red cells, some red cells may contain a lot, but the majority will contain much less than the critical 10pg/cell allowing sickling to continue unchecked. Steinberg makes the point that hydroxycarbamide will never be the sole answer because increasing the dose, to try and achieve sufficient concentrations of Hb F in a majority of red cells, would result in unacceptable toxicity from the drug. What is needed are other drugs, perhaps taken in combination with hydroxycarbamide, which will increase the Hb F in a pancellular distribution, that is to say, in all the individuals red cells.
Now in mice, who have been genetically engineered so that they have sickle cell disease, a drug which inactivates a particular gene (BCL11A), does result in a pancellular increase in Hb F at concentrations >10pg/red cell, the therapeutic target that Steinberg has identified. Whether the same would happen in humans is as yet unknown, but watch this space!
Fetal haemoglobin in sickle cell anaemia: a glass half full? Martin Steinberg, David Chui, George Dover, Paola Sebastiani & Abdulrahman Alsultan Blood. 2014;123(4):481-485.
And to finish, a history lesson.
Dr Africanus Horton was probably the first doctor to publish a description, in the medical literature, of sickle cell disease. In his medical magnum opus, published in London in 1874, “The Diseases of Tropical Climates and Their Treatment” he noted the association between recurrent episodes of pain, fever and anaemia and recognized that these attacks were more frequent in the rainy season. He did not look down a microscope and did not see the abnormal, sickled red cells characteristic of the condition, nor did he name it, that came later, but he may have been the first to describe the typical clinical manifestations of the disease.
Africanus Horton was born James Beale Horton in 1835, in the village of Gloucester, outside Freetown, Sierra Leone. He was the only one of eight siblings to survive childhood. His parents were freed, Igbo slaves, rescued by the Royal Navy on the notorious Middle Passage and landed in Freetown, far away from their homeland in SE Nigeria. Freetown had been established in 1792 by John Clarkson, an abolitionist from Nova Scotia, Canada, specifically as a haven for freed slaves, and during the 19th century thousands of African Americans, West Indians and Africans made their way there, some with the help of the Sierra Leone Company, to start a new life.
Africanus was an exceptional boy and must have been spotted early on as a student of unusual talents. Aged 15 years his family moved to Freetown itself were he was initially educated by the Church Missionary Society and subsequently attended the Fourah Bay Institute.
Founded in 1827, this was the first new university in West Africa since the slow decline of Timbuktu after their defeat in 1591 by an invading Moroccan army. It had been intended that Africanus would pursue a career in the church as an Anglican missionary, but in the early 1850’s The British War Office was looking for bright boys (it would have to be boys!) to train as doctors and Africanus was awarded a scholarship in 1853, together with two others, Samuel Campbell and William Davies, to study medicine in the UK. He trained at Kings College Hospital, in South London, and then at the University of Edinburgh, qualifying with an MD in 1859, only the second African to qualify in medicine from a British medical school. What, I wonder, did he make of the cold and rain of Edinburgh? It was whilst a medical student that he took the name Africanus, an expression of pride in his ancestry and possibly of defiance in the face of prejudice. He is remembered by a plaque in Buccleugh Place in central Edinburgh.
After qualifying Africanus was commissioned into the British Army as an Assistant-Staff Sergeant and served throughout West Africa, in The Gambia, Ghana and Nigeria, seeing active service in the Ashanti wars of 1863 and 1873 and rising to the rank of Surgeon Major before he retired from army life in 1879, after 20 years aged 38.
His interests were wide and varied; in addition to medicine and science he was an early African Nationalist, countering prejudice with a seminal work, published in London in 1868, “West African Countries and Peoples; a Vindication of the African Races”, which put forward novel ideas for the development of self government in West Africa; and he was also a banker, gold mining entrepreneur and philanthropist, giving much of his wealth for the advancement of scientific training in West Africa. Africanus died suddenly in Freetown in 1883, aged only 48 years, and was forgotten for some eighty years, until the rise of the independence movements in the 1960’s when he was lauded as an early champion of African independence.