Back to blood’s beginning
In her commended 2016 Max Perutz Science Writing Award article, PhD student Edie Crosse, from the MRC Centre for Regenerative Medicine, describes her research aiming to generate healthy stem cells from patients to treat leukaemia.
Blood, both vital and sinister, is tied so closely to our ideas of what it is to be human, warm and alive.
Throughout history people have felt connected to their families, tribes and countrymen imagining that the same blood flows through their veins – as if more than just cells but spirit is circulated. Nordic people often allude to their Viking blood making them hardier and stoic; the ancient Mayans believed blood was given by the Gods to bestow them with life, and frequently gave ritualistic blood-letting ceremonies to return it to them.
These cultural perceptions of blood are perhaps why the word leukaemia is so evocative – as if the essence of the afflicted person has been polluted. Blood cancer. The UK alone saw 9,300 new cases in 2013 and on average 13 deaths each day. There is clearly important work to be done and my PhD plays a part in that.
Leukaemia arises from the blood stem cells which reside in the bone marrow. In normal healthy conditions these stem cells, termed haematopoietic stem cells (HSCs), divide to either create a new version of themselves or to generate cells of the blood and immune system. In leukaemia, a genetic change causes uncontrolled proliferation of one of the blood cell types, disrupting the balance of the blood dynamics and resulting in increased susceptibility to infection as well as reduced ability to clot and heal wounds and bruises. The effects are devastating.
Current treatment sees patients receiving chemotherapy and/or radiotherapy to kill the cancerous cells. They are then transplanted with HSCs deriving from the bone marrow either harvested from themselves at an earlier stage or from a donor. These cells have the amazing ability to find their way from the blood vessels to the bone marrow of the recipient, set up camp there and start a production line of all the cells of blood and immune system.
But it is a far from perfect solution. Transplants deriving from the patient’s own cells may contain contaminating cancerous cells and remission is a frequent occurrence. Cells from the patient would recognise donor transplanted cells as foreign and vice versa prompting a two-way immune attack. This means immunosuppressive drugs are required in a patient whose immune system has already been nearly wiped out from the radiation and chemotherapy. The result is an extremely sick patient at high risk of further disease and infection and mortality rates remain high.
This is where my PhD project comes in. What if it were possible to generate an unlimited source of healthy HSCs from the patient’s own cells thus avoiding the immunosuppressive drugs that weaken the patient so much? Nobel Prize winning techniques have shown it’s possible to turn back the time on cells, reprogramming them to a powerful stem cell state capable of generating any cell type in the body simply by altering the expression of a few critical genes. If we could then direct these cells to become an HSC, scan and correct them for cancer causing abnormalities, we’ve got ourselves some transplantable, patient-specific stem cells.
Simple right? In practice, in order to reprogram these cells you have to understand in great detail how these cells are generated naturally in the body. This involves an extraordinarily complex network of signals, spanning from the far-ranging down to communication between neighbouring cells. This lets the cell know that it is in the right place at the right time and it changes its identity into that of a blood stem cell. Some of these critical signals are known but they have not been sufficient to make the perfect HSC in the lab.
This process first occurs early in embryonic development, so it is this time that we study so meticulously in our lab group. We know the region in the embryo where HSCs first arise, in the central blood vessel, and we know the type of cell that they morph from. It is my job to screen this region for signals that are likely to turn them into HSCs. This takes a bit of detective work. Certain clues, such as changes in cell shape, indicate a cell changing into an HSC. This transition involves different genes being switched on or off so comparison of differences between shape-changing cells and their unchanging neighbours may reveal critical signals that were previously unknown.
The very first HSCs are extremely rare but we are constantly whittling down the population of cells in which we know they reside. It is not too far a distant notion in which we crack the code of their identity. Then it’s a short hop to generating them for clinical use and using them to treat leukaemia as well as other blood disorders. So perhaps as well as giving people back their health we can give them back their spirit.