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Developmental Biology - Blood

How Sickle Cells Form

Sickle cell formation based on millisecond bonds...


Vassiliy Lubchenko, associate professor of chemistry at the University of Houston (UH), reports on how a very brief molecular bond leads to formation of stiff hemaglobin filaments within blood cells.

The work is published in Nature Communications.

Droplets of liquid enriched by hemoglobin, form clusters inside red blood cells after two hemoglobin molecules form a bond - although a bond that only lasts about one thousandth of a second.
In patients with the inherited blood disorder sickle cell anemia, abnormal hemoglobin molecules link into stiff filaments inside red blood cells. These filaments distort the normally round blood cell shape into a 'sickle' shape, making it difficult for the cells to flow through blood vessels, causing the debilitating and painful disease.

Filaments begin as proteins congregated into tiny liquid droplets not much bigger than an atom, so small their measurements are counted in increments between microscopic and macroscopic, being called mesoscopic in size.
"Though relatively small in number, mesoscopic clusters pack a punch. They serve as essential nucleation, or growth centers, for things like sickle cell anemia fibers as well as in the formation of protein crystals.

Vassiliy Lubchenko PhD, Associate Professor, Departments of Chemistry and Physics, University of Houston, Houston, Texas, USA.

Droplets of hemoglobin are more crowded with protein than in any other cell in the body, explains Lubchenko. In an unexpected twist, these crowded areas also have the most molecules bound together into dimers or duos. "Dimers are key to formation of mesoscopic clusters," says Lubchenko, who suggests one way to prevent sickle cell disease is to prevent fiber clusters forming.

Same Mechanism, Different Substances

Lubchenko and researcher Ho Yin Chan's work implies their desire to deliberately induce uniform sized nanoparticle clusters in liquids and solids a useful tool in industry and nanotechnology. But also suggests another idea to Lubchenko.
"A tantalizing possibility suggesting precursors to living cells were not encased in membranes but instead, were more like these so called membrane-less organelles."

Vassilily Lubchenko PhD.

Mesoscopic entanglements may only last milliseconds, but appear to be the precursor chemistry to Ostwald ripening, the longer and greater molecular bonding that develops over millenium. In other words, their research touches on nothing less than one of the greatest mysteries in life.

Abstract
Solutions of proteins and other molecules exhibit puzzling, mesoscopically sized inclusions of a solute-rich liquid, well outside the region of stability of the solute-rich phase. This mesoscopic size is in conflict with existing views on heterophase fluctuations. Here we systematically work out a microscopic mechanism by which a metastable solute-rich phase can readily nucleate in a liquid solution. A requisite component of the mechanism is that the solute form long-lived complexes with itself or other molecules. After nucleated in this non-classical fashion, individual droplets grow until becoming mechanically unstable because of a concomitant drop in the internal pressure, the drop caused by the metastability of the solute-rich phase. The ensemble of the droplets is steady-state. In a freshly prepared solution, the ensemble is predicted to evolve in a way similar to the conventional Ostwald ripening, during which larger droplets grow at the expense of smaller droplets.

Authors
Ho Yin Chan and Vassiliy Lubchenko.

Data availability
The reported numerical data were obtained by numerical solution of algebraic and differential equations, as detailed in the article, using the commercially available mathematical software Matlab. When appropriate, the convergence of the solutions is described. All generated data are presented in the published article.


Acknowlegements
The authors thank Peter G. Vekilov and Peter G. Wolynes for many inspiring conversations. We gratefully acknowledge the support by the NSF Grant MCB-1518204 and the Welch Foundation Grant No. E-1765.


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Jul 3 2019   Fetal Timeline   Maternal Timeline   News  




Decreasing internal pressure within a cluster will result in mechanical instability. b) A graphical explanation of the mechanical instability and subsequent breaking up of a droplet as the pressure differential becomes negative. The flatter portions of the interface will cave first.
CREDIT Vassiliy Lubchenko.


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