Dr Payne, Zebrafish and DBA

Dr Elspeth Payne has very kindly agreed to write a short piece telling us a little about herself and her important DBA-related research.

  My name is Elspeth (Beth) Payne and I am a haematologist who trained in Glasgow, Oxford and London. I completed my haematology training in 2006 when I decided I would like to further my understanding of the science behind how blood diseases develop. I moved to the Dana-Farber Cancer Institute, part of Harvard Medical School in Boston, USA where I studied blood development and genes involved in leukaemia development under Professor A Thomas Look. I used zebrafish for my studies. These fish develop a blood system very similar to humans but it only takes them 5 days! They are also completely transparent so you can watch the blood cells developing in real time. I began working on a gene called RPS14 which is known to be involved in the development of a kind of pre-leukaemia. From here I started working on other ribosomal protein genes which as you know are mutated in Diamond–Blackfan Anaemia.  In particular I have been working on the effect of the amino acid Leucine on the development of blood in zebrafish that have lost RPS19 or RPS14.
I am now back in the UK and in July I was awarded an Intermediate Research Fellowship from the Wellcome Trust to start up my own research laboratory continuing some of my work on Diamond-Blackfan anaemia at University College London. I am also the recipient of the Wellcome-Beit prize as part of this fellowship.
Here are some links which summarise some of the research I have done and how I will be continuing this at UCL:

Lost in Translation

Genes are made up of DNA that we inherit from our parents. We have 2 copies of each gene, one from our mother and one from our father. Genes on their own cannot do anything, instead they provide a template, or ‘code’ to make protein. We call the process of making proteins “translation”. Mistakes in the gene code are called mutations. A mutation in a gene leads to abnormalities in the protein that that gene encodes.

You can think about this like letters and words in a book. The letters make up the words, the words make up sentences and sentences make up books. The letters are like the DNA coding letters. A specific sequence of letters makes up a word like a specific sequence of letters makes up an amino acid which are the building blocks of proteins. A specific sequence of words makes up a sentence, like a specific sequence of amino acids makes up a protein. Changing just one letter in a word can make a sentence that means something different or something that makes no sense at all, just like a mutation in a gene can disrupt the function of a protein.

For example:

  • The cat sat
  • The bat sat
  • The gat sat
  Most of you will be aware that mutations in genes that code for ribosomal proteins have been identified in patients with Diamond-Blackfan anaemia (DBA). The most common mutated ribosomal protein gene is called RPS19. Only one of the two copies of this gene is affected in patients with DBA. The other copy is completely normal. This means that patients with DBA only produce about half of the normal amount of RPS19 protein.

Ribosomal proteins are extremely important for every cell in the body. This is because they form part of the translation machinery (which is called a ribosome) that converts the DNA’s code into amino acids and then proteins. Because of this we think that one of the reasons for anaemia in DBA might be because some proteins are not being made properly. We think that blood cells are especially sensitive to reduced amounts of ribosomal proteins compared to other types of cells.

The first part of my research is to find out which proteins are made in DBA.  I am going to be using a very new method to determine this called “ribosome footprinting”. This method allows a very detailed assessment of which proteins are actively being made. Because most people with DBA are on treatment I will use a zebrafish with DBA instead. We will compare the proteins being made in the normal zebrafish and the DBA zebrafish and then then see if the same is true in DBA patients.

The second part of my research will use DBA zebrafish to test hundreds of new drugs to see if any of them can improve the zebrafish anaemia. We already know that zebrafish with half the normal level of RPS19 are anaemic. Therefore if we can find a drug that stops them from being anaemic this could be a new treatment for DBA. Zebrafish develop their blood system extremely rapidly so we can look at the effects of many drugs in hundreds of tiny zebrafish (less than 2mm long) at only 4 or 5 days after they are born. We already have an idea that this can work because we have tried giving DBA zebrafish the amino acid Leucine and this seems to improve their anaemia.

I believe that we will learn a lot from the zebrafish with DBA and I firmly believe that we can translate this into real treatments for real people with DBA.
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