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Sickle Cell Anemia - From African Myth to Modern Therapy

Before its first description in western medicine in the year 1910, Sickle cell anaemia was referred by different names in different African tribes. One such reference was the term “Ogbanjes” which means children who come and go. The affected families had death-themed family names which would imply that they would die sooner than the other families.

A recent study which involved genome analysis of around 3000 patients revealed that the disease is likely to have originated from a child in West Africa around 7300 years back. There is also a theory stating that these mutations occurred on an evolutionary basis to protect oneself from malaria (falciparum infection).  

In 1904, a young man named Walter Clement Noel from the island of Grenada (West Indies) came to Chicago to study at the school of dentistry. He went to Dr James B. Herrick with complaints of pain episodes, and symptoms of anaemia. Herrick was a cardiologist and not too interested in Noel’s case so he assigned a resident, Dr Ernest Irons to the case. Irons examined Noel’s blood under the microscope and saw red blood cells he described as “having the shape of a sickle”. When Herrick saw this in the chart, he became interested because he saw that this might be a new, unknown disease. He subsequently published a paper in one of the medical journals in the year 1910 where he used the term “sickle shaped cells”

 
This is the first report of Sickle cell anaemia by Dr Herrick

This is the first report of Sickle cell anaemia by Dr Herrick

 

Once Herrick made his discovery, the Pandora’s box was opened and scientists all over took interest in this new phenomenon. But, despite all the buzz about this weird deformation of the red blood cells, it took twelve years for Dr. V. R. Mason to coin the term Sickle Cell Anemia

Now while doctors knew that such an entity existed they did not understand how the disease worked. No one precisely understood the reason for rapid death of such cells. Nor did medical professionals really understand how it caused joint pain. In 1929, Hahn and Gillespie observed that the sickling was more prominent and severe in conditions of hypoxia and low pH. This gave researchers a foothold to further understand how sickling occurs. 

Now the conditions under which 'sickling' happened were somewhat clear. Yet, how the physical sickling process occurred still remained a question. In 1940, a medical student from John’s Hopkins medical school demonstrated that the change in the RBC shape was due to the changes in hemoglobin at low oxygen concentrations. 

So wait. Why doesn’t sickling of RBC occur in all cells in everyone? We all have hemoglobin right? 

In 1951, Linus Pauling and his colleague,Harvey Itano demonstrated, with protein electrophoresis, that the sickle cell haemoglobin was structurally different from normal haemoglobin. This made it more likely to sickle. 

This was the first time in history where a cause of a disease was attributed to abnormal chemical structure of a protein. Linus Pauling was awarded Nobel prize in Chemistry for his work in chemical bonding. 

So a Nobel Prize and forty years of research later, we came to know that there were abnormally structured hemoglobin at fault for this disease. But what was wrong with it? In 1956, Vernon Ingram and Hunt sequenced the haemoglobin structure and reported the change of an amino acid at the 6th position from glutamic acid to valine which helped them predict the mutation as well.

In 1977, finally the genetic locus of the sickle cell trait was elucidated by Gilbert and Sanger. This was the first genetic disorder whose molecular basis was known although a lot of genetic disorders were described earlier.

Six decades after its discovery, there was still no cure in sight for this disease. In 1984, a miracle happened and like so many things in medicine, luck played a huge role. An eight year old girl, who had leukaemia and sickle cell anemia was given a bone marrow transplant for the leukaemia. As she followed up with doctors, the noticed that there was no longer any sign of the leukaemia and there was no sign of sickling either! 

Since then, hydroxyurea has been recognised as a drug that can be used to treat sickle cell anemia and penicillin is used to prevent pneumococcal sepsis in Sickle cell anaemia patients because they have poor splenic functions. Gene therapy using viral vectors is the cutting edge treatment for patients suffering from this hemoglobin bending disease. Recently, CRISPR Cas9 system, a gene editing tool has been employed successfully in animal studies to prevent the cessation of HbF production at 6 months of life, thereby making HbF available in adult life and thus preventing sickling.

The story of sickle cell anemia, its discovery, understanding and cure, tells us one thing - that perseverance in medicine will always give answers. It’s the little ray of hope for us fighting so many battles against so many diseases.