Our Latest Paper is Out in Nature Genetics – What’s the Big Deal?


Merlin Crossley, Lab Head


Our Latest Paper is Out in Nature Genetics – What’s the Big Deal?


This week we went through the proofs of our latest paper, which is perhaps our most significant work yet. Gabbie led this project, together with Beeke, who is now working in the home of CRISPR in University of California Berkeley. Lu also played a major role providing a critical new technique and Manan did the bioinformatics. Past lab members like Alister, initiated the project, Jon helped with bioinformatics again and Richard, Kate and I oversaw it all over a period of about seven years. To do the proofs we ticked back and forth across the world at all hours of the day electronically and now the paper has been published in Nature Genetics. A News and Views commentary can be found here.

It’s a big deal for us because that is a top journal and I’ll now explain why the science is important.

We study the globin genes, that encode haemoglobin which carries oxygen around your body. Some people have mutations in these genes and suffer from sickle cell anaemia or thalassaemia. Sickle cell relates to one particular point mutation that interferes with the haemoglobin protein and causes red blood cells to adopt a sickled shape. The other conditions are often known as thalassaemia – as they were first identified in the Mediterranean and the Greek for sea is Thalassa. Hundreds of different mutations have been found to affect the globin genes and it is estimated that as much as 7% of the world’s population carry such a mutation.

Why so many?

Because it’s good to have a mutation in one of your chromosomes in the globin genes, provided the other chromosome is OK. The mutation will slightly alter your blood and that makes it harder for the malaria parasite to thrive. This means that wherever malaria has been a problem one finds people with mutations in their globin genes. Of course, it’s not that people want to have the mutation, but that the mutations have arisen by chance and natural selection has ensured their proliferation in the population. So one finds people affected by this condition in the Mediterranean, Africa, the Middle East, India, Southern China, Southeast Asia, South America and the disease is also found in African American populations.

As I’ve said, having a mutation on one chromosome is OK but if you inherit two mutations – one from your mother and the other from your father – you’ll have no normal globin genes and that is a big problem. Depending on how severely the mutation disables haemoglobin you may need life long blood transfusions and special iron chelation therapy to extract iron from old red blood cells.

But nature also provides some hints at a solution. A few people with mutations in their globin genes seem to be fine. It’s been discovered this is because another gene – a special foetal globin gene that is busy in utero and allows babies to absorb oxygen from their mother’s blood – continues to be active throughout life in a few people. In the rest of us that gene is silenced after birth.

The mutations that reawaken the foetal globin gene reside in the gene’s control region – the promoter – just upstream of the coding region. Some of these mutations were first described by Francis Collins back in the late 1980s. But no one had figured out how these mutations allowed foetal globin to stay on.

Our paper shows that the various mutations disrupt the binding sites for one or the other known foetal globin repressor protein – BCL11A or ZBTB7A. These are two DNA-binding proteins that have been implicated in foetal globin gene silencing. BCL11A was found via Genome Wide Associate Studies (GWAS) and we discovered ZBTB7A as a result of noticing the mutations knocked it off the DNA of the foetal globin gene and we published that with our collaborators in Harvard last year in Science. This year we’ve gone on to publish the whole story.

To us this represents the end of the beginning of research aimed at turning on the foetal globin gene to treat sickle cell anaemia and thalassaemia. Introducing these mutations or mutations like them into blood stem cells really could cure these diseases. One can’t readily do gene therapy across all of the developing world but if CRISPR can be injected into the blood and manages to edit the gene in enough stem cells, then that might well represent a viable treatment option.

I know those are still big ‘ifs’ but I’m reasonably excited by this prospect. Over the years I’ve repeatedly heard that we are on the verge of a breakthrough and that gene therapy would cure this condition or that – even baldness. I’m still waiting. But this time I’m waiting optimistically. CRISPR is good at making deletions – that’s all one has to do here – to delete the control region – and CRISPR seems good at editing blood cells.

The question is whether one get enough of it into a patient or whether one needs to take the cells out and then transplant them back in.

Time will tell.




Want to know more? Read on here


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