Platelet blood cells, like many other cells in the body, have a biological clock that determines their lifespan. Now scientists have shown that this clock is set by an unruly protein that tries to kill the cell, and another which holds it back. Manipulating these proteins could greatly increase the lifespan of platelet stocks used in transfusions.
Life is about constant, ongoing death. To cope with the stresses of living, the majority of our body parts are constantly replacing themselves, generating fresh cells to replace dead and dying ones. This turnover is tightly controlled by genes that set a sort of biological clock, governing the lifespan of each cell.
These clocks are set to different lifespans, based on a cell’s role in the body. Among the various cells in our blood alone, clocks can range from days to years.
For example, ‘memory B lymphocytes’ survive for decades for they grant us the ability to resist infections we’ve already experienced, like chicken pox or measles.
Platelets (right), on the other hand, are responsible for clotting and healing, and they are used up much more quickly. They are created by blood stem cells and circulate around the body only to be destroyed about 10 days later in the liver and the spleen.
Clearly, some sort of clock governs the life and death of platelets, ensuring that we always have just the right number. Now, Kylie Mason and colleagues from the Walter and Eliza Hall Institute of Medical Research have worked out that this clock is set by two proteins.
The first, Bak, is unruly and belligerent, constantly looking to cause trouble. If Bak had its way, it would trigger a biochemical chain reaction that kills the platelet.
Fortunately, another protein, Bcl-xL, plays the part of the even-tempered friend constantly holding Bak back. But over time, Bcl-xL gets tired and starts to degrade, and crucially, it has less stamina than Bak and wears out earlier.
This might not be a problem in other cells that could generate new Bcl-xL from their own DNA. But platelets have no nucleus and thus, no DNA. That option is closed to them. When they are birthed from stem cells, they are given a fixed lifetime supply of Bcl-xL.
Without a fresh supply, the platelet’s complement of Bcl-xL starts to fail, and over time more and more Bak is unleashed. Once a threshold level is reached, the cell’s fate is sealed. It dies.
Mason found that mice with faulty mutant versions of Bcl-xL suffer from thrombocytopenia, a disease caused by a lack of platelets. Without its restraining influence, Bak is let loose and kills too many platelets before the blood stem cells can replenish the supply.
Mason’s discovery has practical implications for the thousands of people every year who require platelet transfusions. Transfusions are needed for people who have diseases ranging from thrombocytopenia to cancer.
The chemotherapies used to fight cancer can often disable the blood stem cells within bone marrow. As a result, cancer patients often have low platelet levels and if this goes untreated, they are at risk of serious bleeding.
Most donated tissues would be kept on ice to prolong their shelf-life. But for platelets, this wouldn’t work. For reasons not fully understood, cold transfused platelets are recognised as intruders by a host’s immune system and are destroyed.
So platelets must be stored at room temperature and there, they are very unstable. At 37 degrees Celsius, platelets survive for just five days, half their lifespan in the human body.
The killing action of Bak explains why stored platelets are so unstable. Outside of the human body, Bak is stable at room temperature, while Bcl-xL levels rapidly decline, speeding up the platelets’ death clock.
Mason’s work suggests that chemicals which preserve Bcl-xL can double the lifespan of stored platelets. They could even lead to new treatments for people with diseases like thrombocytopenia.
The next step however, is to find out if other blood cells, particularly red blood cells which also lack their own DNA, have similar ticking death clocks.
Reference: Mason, Carpinelli, Fletcher, Collinge, Hilton, Ellis, Kelly, Ekert, Metcalf, Roberts, Huang & Kile. 2007. Programmed anuclear cell death delimits platelet life span. Cell 128: 1173-1186.
More posts on medical discoveries:
Round peg, square hole – why our bird flu drugs are a fluke
Neutralising anthrax – moving closer to a cure
The secret of drug-resistant bubonic plague
Drugs that work against each other could fight resistant germs
Sneaking medicines past the brain’s defences