Fishing for improved leukaemia treatments
6 October 2015
To enter this year’s MRC Max Perutz Science Writing Award, MRC-funded PhD students were asked to answer the question: ‘Why does my research matter?’ Here, Tomek Dobrzycki (a PhD student in Roger Patient’s lab) publishes his entry for the Award, in which he describes why zebrafish might hold the key to understanding how blood stem cells are formed.
Let’s take a journey back to Paris in 1963.
Although we could enjoy a croissant with President Charles de Gaulle or experience the last performances of superstar Édith Piaf, the highlight of our itinerary lies in the suburban commune of Villejuif.
Making our way to Institut Gustave-Roussy, we are about to witness the first case of using a bone marrow transplant to treat a person with leukaemia. Here, doctor Georges Mathé pioneered a therapy which has been helping people with blood cancer for decades.
The secret behind the success of the transplant lies within our skeleton. The inside of our bones, known as the bone marrow, houses specialised cells – stem cells.
To understand the uniqueness of stem cells, imagine a seed. The seed splits in half and one half develops into a fruit: an apple, a pear, a cherry… – various types, depending on the circumstances.
The other half, however, turns into the original seed and can split again. Stem cells are such seeds – one stem cell from our bone marrow, through such rounds of divisions, can generate millions of different blood cells, including red blood cells, white blood cells and platelets. These cells can give a patient a new, healthy blood system.
However, despite routine use, bone marrow transplants are yet to reach 100% success rate in curing leukaemias. The limitations come from the availability of stem cells that are fully compatible with the patient.
One way to improve the efficiency of the transplants would be to take healthy cells of the sick person, for example from their skin, and turn them into the stem cells. Scientists have used this approach to generate and maintain various stem cells. However, blood stem cells are much trickier – nobody has yet grown fully functional and transplantable blood stem cells in a dish.
We could tackle this issue if we fully understood how these cells are generated in the natural context of development. We know that a little human embryo which is only a month old already produces the blood stem cells and we know where they come from.
Generation of a stem cell is not a one-step process, though. It is rather a marathon run – which on average consists of more than 40,000 steps. Thinking of the process in molecular terms, we could attribute each of these steps to certain pieces of DNA in our cells, known as genes.
During development, the genes act together or one after another to form regulatory networks that ensure that each cell arises at the correct time and place. If one gene fails to complete the step it is responsible for, the marathon race of generating the blood stem cell may never be completed.
In my project at the MRC Molecular Haematology Unit at WIMM in Oxford I am investigating one of these players that ensure that a blood stem cell completes its multi-step marathon of programming. The gene that I study has an original name of Gata2.
To illustrate its importance, using the marathon analogy, Gata2 could be represented as food consumed for the race. If a runner eats too little, they will eventually become unable to take another step and fail to cross the finish line. However, if a runner is not cautious and eats too much, this may also have terrible effects on the running comfort and result in premature exit from the race.
Similarly, if a cell has too little or too much of Gata2, it will not complete the programme of becoming a blood stem cell. My research aims to discover why these levels have to be so precisely regulated.
For many reasons, this cannot be studied in human embryos. Luckily, we have a new star in the scientific field of blood development: the zebrafish. These tiny fish frequently lay many quickly developing eggs – they generate blood stem cells already after 24 hours of life! Thanks to this, we can learn a lot in a relatively short time.
The fish embryos are also transparent. If we make them fluorescent, we can observe the levels of important molecules, such as Gata2, in living animals.
But most importantly: all the human genes responsible for the thousands of steps on the journey of becoming the blood stem cells have their equivalents in zebrafish. Therefore, whatever we discover in the fish is likely to help us better understand how the bone marrow stem cells arise.
My work on Gata2 will probably reveal the mechanisms behind only a few, a few hundred tops, steps of the pathway. However, once combined efforts of scientists explain enough steps, we may be able to reenact the marathon race of development in a dish. Once we have done that, lives of many more leukaemia patients can be saved. And zebrafish will be one of the contributors.
Post edited by Roger Patient.