How do you fix broken blood?

Congenital Dyserythropoietic Anaemia (CDA) is a rare disease that causes insufficient production of red blood cells. This means that the body is unable to carry enough oxygen around to its vital organs, resulting in dizziness, chest pain, tiredness and shortness of breath. In severe cases, patients are dependent on regular blood transfusions for life. In a subset of these patients, the underlying cause of how this disease is passed down from generation to generation remains elusive – but two grants recently award to scientists working in Veronica Buckle’s lab in the MRC MHU hope to help solve this problem. Bryony Graham explains more.

Imagine if your life was dependent on someone else’s blood.

That’s what people with inherited forms of anaemia (defective red blood cell production) are faced with. They regularly spend hours hooked up to a drip whilst a couple of pints of someone else’s blood trickles gradually into their system.

Maybe you think this doesn’t sound so bad; you get a day off work, you can have a nap whilst it’s happening – what’s the problem?

The problem is iron. Ever noticed the slightly metallic taste that you get if you ever lick a cut on your finger? That’s because iron is found inside every single one of your red blood cells, and the presence of that metal is critical for the ability of your cells to do their job and carry oxygen around your body.

Iron is so critical to our survival that we have evolved not only to absorb iron very efficiently, but we are also completely unable to get rid of it from our bodies.

If someone requires regular blood transfusions to compensate for their own lack of functional blood cells, the iron in the transfused red blood cells eventually builds up in their body and inevitably leads to excess iron accumulation in their system, ultimately leading to liver and heart failure.

Understanding the underlying cause of inherited anaemias such as CDA is therefore absolutely fundamental to developing new and effective treatments that avoid blood transfusions and all the issues associated with them, and this critical need is recognized in two independent grants recently awarded to scientists at the WIMM to do just that.

The DNA sequence inside your cells is partitioned into sections called genes, and it is known that patients with one of the three known forms of CDA, CDA type I (CDA-1) can have changes or mutations in at least two different genes – but it isn’t fully understood what all these changes are, where they are within the gene, or how they affect its function.

To add to the complexity of the matter, some patients don’t have mutations in these two key genes at all, and yet they still suffer from CDA-1 – so what causes the disease in these individuals? The answer could lie in the ‘junk’ DNA that sits between genes, which isn’t usually examined when doctors look at the DNA of patients with inherited diseases like CDA – but so far, nobody has had the time, funding or resources to check.

Until now.

Chris Babbs, working in Veronica Buckle’s lab in the MRC Molecular Haematology Unit, was awarded funding by Action Medical Research for Children and the Henry Smith Charity to investigate exactly what and where the changes to the DNA are in patients with CDA-1, using patients from a rare anaemia clinic set up at the nearby Oxford University Hospitals NHS Trust by Dr Noémi Roy.

This invaluable resource gives Chris access to many patient samples, which is critical for detecting subtle, and usually infrequent, changes to the DNA that causes anaemia in these individuals.

As well as identifying these tiny changes to the DNA in patients with CDA-1, Chris will then generate cells in the lab that carry the same mutations and coax the modified cells to form blood in a petri dish.

By watching these cells as they grow and mature into red blood cells, he will then try to identify how and what goes wrong during the development of cells that carry the same mutations from patients with CDA-1, and therefore try and understand better what causes anaemia in people who suffer from the disease.

In addition, Dr Noémi Roy was also awarded a Starter Grant for Clinical Lecturers by the Academy of Medical Sciences to try and understand the effect that the changes Chris is looking at might have on the body as a whole.

By examining what happens when these genes are removed in experimental systems designed to mimic the disease in a laboratory environment, she hopes to try and understand better how CDA develops, which could hopefully lead to better and more effective treatments for this rare but devastating disease.

Although by definition rare diseases like CDA affect less than 1:2000 people, there are over 6000 diseases classified in this way, collectively affecting around 30 million citizens throughout the EU. Elucidating the underlying cause of these diseases often leads to fundamental breakthroughs in our understanding of how the body works, and so grants like those awarded to Noémi and Chris potentially have far-reaching implications for our knowledge of how the blood works, and how to fix it when it doesn’t.

If you or anyone you know is affected by CDA or any other type of inherited anaemia, please visit the Congential Anaemia Network website.

You can read an original research article by Chris Babbs on some of the mutations which can cause CDA-I (a subtype of CDA) here.

Post edited by Chris Babbs, Noemi Roy and Veronica Buckle.