Patients with sickle cell disease have mutant haemoglobin proteins that form deadly long, stiff fibres inside red blood cells. A research team led by University of Warwick researcher Dr Matthew Turner, propose a mathematical model in the 28 March online issue of PRL to explain the persistent stability of these deadly fibres. The theory suggests that an inherent “twistiness” in the strands that make up the fibres could be the key to their durability and possibly to new treatments. From the University of Warwick:
Researchers Say Deadly Twist Key To Sickle Cell Disease Date :31/03/2003
Type : Press Release
Patients with sickle cell disease have mutant haemoglobin proteins that form deadly long, stiff fibres inside red blood cells. A research team led by University of Warwick researcher Dr Matthew Turner, propose a mathematical model in the 28 March online issue of PRL to explain the persistent stability of these deadly fibres. The theory suggests that an inherent “twistiness” in the strands that make up the fibres could be the key to their durability and possibly to new treatments.
Red blood cells supply oxygen to the body using their cargo of haemoglobin, a protein that can capture and release oxygen. Haemoglobin molecules normally float freely in the cell, but sickle cell patients have a mutated, “sticky,” form of haemoglobin that tends to clump together into long fibres. The stiff fibres form a scaffolding that distorts the cells into their namesake “sickle” shape, so they jam up trying to pass through small blood vessels. The traffic jams deprive vital organs of oxygen, so patients end up with anaemia, jaundice, major organ damage, and many other maladies.
A sickle haemoglobin fibre can be made up of anywhere from 14 to more than 400 individual strands of haemoglobin molecules linked into long chains. Matthew Turner, of the University of Warwick in the UK, wondered why these strands tend to clump together into long, stiff, fibres rather than compact crystals, which would be less harmful. “A scaffolding made of the rigid fibres is much worse than a couple little sugar-cube-like crystals floating around,” Turner says. So he and his colleagues constructed a mathematical model.
The team’s equations start with the trade-offs that exist in any material as it tries to find the shape with the least overall stress. The forces at work include bending and stretching, and for haemoglobin strands, there is also a propensity to stick together. This stickiness would normally make a thick, compact crystal more stable than a thin fibre, Turner explains, because a crystal maximizes the contact area of the protein with itself. But for sickle haemoglobin, fibres are more stable. To favour fibres, the equations needed to include the fact that the individual strands of molecules are inherently “twisty.” They behave like the coiled wire that attaches a telephone to its handset, apparently because the molecules link up in a way that favours twisting. The strands wrap around one another like threads of rope to form the fibres. In their paper, the team shows that their model’s predictions for two of the mechanical properties of fibres agree with experiments.
Turner says that the model suggests a possible treatment for sickle cell disease. Gene therapy could introduce a haemoglobin mutant that formed less-twisty individual strands, and this “good mutant” might turn fibres into less harmful crystals. Simply introducing normal haemoglobin has been shown not to work, perhaps because the few normal haemoglobin molecules cannot eliminate the fibres.
Note for editors. The paper “Twisted protein aggregates and disease: the stability of sickle hemoglobin fibers M.S. Turner, R.W. Briehl, F.A. Ferrone, and R. Josephs is in Phys. Rev. Lett. 90, 128103 (print issue of 28 March 2003). Full paper at this link
For further information contact:
Dr Matthew S. Turner, Department of Physics
University of Warwick Tel: 024 76 522257
Email: [email protected]