Two recent papers offer possible solutions to the seemingly perennial blood shortage, while a third suggests ways to help patients whose blood clots too easily.
In the March 23 Cell, researchers show that the classical apoptotic protein Bcl-xL and Bak determine the lifespan of platelets - the nucleus-lacking blood cell type that controls clotting - a finding that could point up ways to lengthen platelet lifespan. Meanwhile, in the early online edition of Nature Biotechnology, researchers show how to make type O "universal donor" blood from other types.
"A platelet is destined to die from the moment it is born," Cell paper senior author Benjamin Kile told BioWorld Today. That, of course, is true of every living thing - but the platelet is definitely headed for the cliffs faster, and more inexorably, than most other living things. "The only thing keeping it alive is Bcl-xL. As the amount of Bcl-xL decreases with time, the platelet gets closer and closer to the edge, until finally, there isn't enough Bcl-xL to restrain the pro-death protein Bak, and apoptosis is initiated - leading to a predetermined lifespan of roughly five days."
In nucleated cells, too, Bak and Bcl-xL are involved in an intricate relationship to control cell survival and death. But, Kile said, "platelets can't make any more Bcl-xL to stave off death - they are carrying a time bomb they can't defuse.
"It had been shown previously that if you removed the nucleus from a cell, you can still make it undergo apoptosis - but no one had ever demonstrated that a naturally anucleate cell undergoes apoptosis as part of its normal life," added Kile, who is laboratory head in the Division of Molecular Medicine at the Walter & Eliza Hall Institute of Medical Research in Parkville, Australia.
Likewise, "people had shown previously that various aspects of platelet behavior resemble apoptosis, and that various pieces of the apoptotic machinery are present in them - but no one had ever linked it to the control of lifespan in vivo."
Kile and his colleague conducted a genomewide mutation screen in mice to search for the genetic causes of thrombocytopenia, or excessive bleeding.
Their search uncovered two such mouse strains, both with mutations in Bcl-xL. Mice specifically engineered to lack Bcl-xL also were deficient in platelets. Blocking Bcl-xL reduced platelets' lifespan and caused mice to become platelet deficient, while eliminating Bak corrected those defects and increased platelet lifespan.
At the basic science level, the authors noted that "It will be interesting to examine whether other cells lacking a nucleus, such as erythrocytes, are controlled by similar mechanisms" - which highlights that fact that two major cell types of the blood system have no nucleus. Kile distinguished between anucleate platelets, which never have a nucleus to begin with, and enucleate red blood cells, which get rid of theirs during development.
"Is it chance that both these components of blood have no nucleus? It's an open question," he said. "Lower organisms like fish don't have platelets; they have 'thrombocytes' - nucleated cells that perform the function of platelets. This suggests that higher organisms have evolved from there to the point of having platelets for some reason."
But as for what that reason might be, "we don't know," he said.
In the clinic, the discovery could enable platelet lifespan to be tweaked artificially. Kile said he hopes "that these findings will one day have a major impact on the blood shortage - we are actively engaged in screening for compounds that can inhibit platelet apoptosis during blood bank storage. One of our major goals is to develop such molecules so that platelet lifespan can be extended during storage, thereby alleviating the pressure on supply. The team is now actively pursuing a drug development program aimed at manipulating this switch in order to prolong the lifespan of blood bank platelets, increasing their availability to patients receiving cancer treatment and others in danger of serious bleeding."
Another paper, published in Nature Biotechnology's April 1 edition, describes how to make red blood cells universally suitable for transplantation: by turning them into group O. Blood comes in the basic types A, B, AB and O, depending on the presence or absence of certain antigens on the surface of red blood cells. While it has been possible to turn type B blood into type O using antigen-snipping enzymes, the process has never been practical at an industrial scale.
In their Nature Biotechnology paper, the authors "went fishing through 2,500 fungal and bacterial isolates for more suitable enzymes," scientists from the University of Bristol and the University of British Columbia wrote in an accompanying News and Views article. "The upshot of their work is the production of novel recombinant glycosidases. . . . After a 60-minute incubation with the appropriate enzyme, whole units (200 ml) of A1, A2, B and A1B red cells expressed neither A nor B antigens, as determined by FDA-licensed blood grouping reagents."
Since the Bcl-xL /Bak interaction described by Kile and his colleagues in Cell is a homeostatic one, the other direction - preventing clotting - might also be a possible therapeutic avenue. In another recent paper, published in the April 2 early online edition of the Proceedings of the National Academy of Sciences, scientists report another possible avenue toward preventing clotting. They show that extracellular RNA is a cofactor for inducing blood clotting. Large RNA molecules, but not DNA, functioned as a co-factor to induce a clotting response after cell damage. The researchers hypothesize that their findings open up possibilities for patients at risk of blood clotting, and may provide a mechanistic explanation for why cancer patients have such an elevated risk of clots.