The National Institute for Computational Sciences

Measuring Forces in the Spleen

The Darter Supercomputer is Helping Researchers Understand the Biophysics of Red Blood Cells

[Image credit: © Kheng Ho Toh |]

The spleen, a small organ located behind the ribs on a person's left side, plays an important role in the human body's immune system, performing various protective functions but primarily serving as a mechanical blood filter that removes worn out and pathological red blood cells (RBCs) (erythrocytes). Using the Darter supercomputer at the National Institute for Computational Sciences, a team of researchers is modeling the biophysics of RBCs to understand their behavior in the spleen, with the aim of finding cures to diseases.

The project explores the critical RBC blood pressure highs and lows (gradients) required for healthy and pathological RBCs to pass through the small pores (inter-endothelial slits) in the spleen, says Principal Investigator Zhangli Peng of the University of Notre Dame.

Anemia and Malaria

Peng explains that the critical blood pressure for an RBC to pass the inter-endothelial slits is an important index with respect to a better understanding of a form of anemia (hereditary spherocytosis) and malaria—two diseases that are unrelated except for their association with RBCs and the spleen. He adds that the anemia is caused by a decrease in RBCs; and malaria is brought about by a parasite borne by mosquitoes.

"So, in the first scenario [hereditary spherocytosis anemia], we want more RBCs to pass all the way through the spleen; in the second [malaria], we want infected blood cells to be trapped there," Peng says. "Measuring forces in the spleen is difficult and cannot be studied systematically by experiments alone, so the use of numerical simulations becomes essential."

A Tailored Numerical Model

To enhance their efforts, Peng and his co-researchers in a prior project developed an RBC numerical model to use in their computer simulations. Peng explains that their model is based on a technique that involves a group of particles moving in continuous space for a distinct portion of time. The method, referred to as dissipative particle dynamics (DPD), employs particles that represent clusters of atoms rather than individual atoms. He says that due to what's called coarse graining, they are able to simulate large objects such as RBCs and the spleen for a relatively long time, while traditional molecular dynamics can simulate only small molecules for a few microseconds.

The RBC model the researchers fashioned is described in a 2013 paper published in the Proceedings of the National Academy of Science of the United States of America. The NICS-managed Kraken supercomputer (now decommissioned) provided support to the project.

The Significance of Surface Area

Using the DPD code built on an open-source software called LAMMPS (Large-scale Atomic/Molecular Massively Parallel Simulator) by Sandia National Laboratories, Peng says he and his co-researchers discovered that the surface area of RBCs plays an essential role in whether an RBC will pass the inter-endothelial slits. They found that a small reduction in RBC surface area (5 percent, for example) significantly increases the critical pressure necessary for RBCs to pass the spleen.

The form and behavior of an RBC, Peng explains, could, in certain respects, be considered analogous to a basketball. If air is added to a basketball, it becomes inflated and rigid; if the volume of air is decreased, the ball becomes much softer. Although an RBC is inflated with water rather than air, the principle is the same, he adds. Another important consideration in the dynamics, he notes, is the material of which the ball or the RBC consists, especially in terms of the membrane rigidity of the ball or the RBC.

Peng explains that the blood pressure gradient (BPG) of the spleen is more or less fixed and quantified as being about 1 pascal per micrometer. An RBC that's carrying a disease is more rigid than a healthy one, and under normal BPG, the increased membrane rigidity may prevent the cell from passing through, he adds.

Membrane rigidity is, however, not as important as another factor, Peng says: "We've found that the surface-area-to-volume ratio of RBCs is much more important than the membrane rigidity in determining the critical pressure. For example, in malaria the increased membrane rigidity may raise the critical pressure by 30 percent, but the decreased surface-area-to-volume ratio increases the critical pressure by 10 times."

The Adhesion Force Between Layers

A basketball and an RBC are also similar in assembly, Peng explains, in that both have material layers when inflated and remain bound together as a composite. He says simulations on Darter are enabling him and his co-researchers to see how the oil membrane on the outside of the cell (lipid bilayer) and the network of proteins on the inside of the cell (cytoskeleton) maintain their bond.

"We want to study the adhesion force that exists in all directions between these two layers," Peng says. "If the deformation of the RBCs is too large, then the two layers may detach from each other in a process akin to delamination. The detachment will lead to partial loss of the lipid bilayer and reduction of the total surface area. This will further make the RBC more spherical and less deformable and reduce its chance of passing the spleen in its following lifetime."

Such research, he notes, would be expensive and infeasible without high-performance computing resources with very efficient concurrent problem solving (parallelization) capabilities.

Support from Kraken and Darter

Peng and his co-researchers typically employed 35,000 computer processor cores for six hours at a time on Kraken and are now doing so on Darter (under Extreme Science and Engineering Discovery Environment [XSEDE] project number TG-MCB130124). And as of this writing, they have used 1,365,522.15 service units on Darter, Peng says.

"With the powerful computers such as Kraken and Darter, we are able to model the biophysics of a living cell with all the cytoskeletal proteins considered," he says. "The molecular interactions between the lipid bilayer and the cytoskeleton in an RBC were predicted. We found that the surface-area loss of the RBCs plays a much more important role than the membrane rigidity change for RBCs to pass the spleen, so we will focus on the surface-area loss in our future direction. The results may inspire some drug targeting on the RBC surface area for fighting anemia."

In an earlier paper published in Cellular Microbiology, Peng found by numerical simulations that the mature sexual malaria-infected RBCs (male and female gametocytes) can pass the inter-endothelial slits in the spleen due to their lower membrane rigidity and slender shape. After malaria parasites infect a patient, they go through several asexual stages during the first 48 hours, and then a small percentage of asexual parasites will convert to male and female gametocytes in several days. Peng explains that only the sexual gametocytes can transmit to mosquitoes and then to other people, while asexual malaria parasites cannot. Thus, to eradicate malaria, the transmission of gametocytes to people must be prevented.

Based on the finding published in Cellular Microbiology, Peng is collaborating with a branch of the pharmaceutical company Novartis to test a drug on manipulating the membrane rigidity and shape of mature sexual malaria-infected RBCs (gametocytes) to prevent their transmission to mosquitoes and other people.

Insight into Metastasis

Peng says his current research project will pave the way for the study of a cell's journey through the inter-endothelial cells in the blood vessel walls, which takes place in the spreading of cancer from one organ to another (metastasis) and the exiting of white blood cells from the smallest blood vessels in the body (capillaries) into the organs, which occurs as part of the body's immune response to pathogens.

Related Paper in Progress

Igor V. Pivkin, Zhangli Peng, George Em Karniadakis, Ming Dao, and Subra Suresh. Sequestration dynamics of red blood cells in the human spleen. In preparation for submission to Proceedings of the National Academy of Sciences of the U.S.A.

Scott Gibson, science writer, NICS

Article posting date: 15 July 2014

About JICS and NICS: The Joint Institute for Computational Sciences (JICS) was established by the University of Tennessee and Oak Ridge National Laboratory (ORNL) to advance scientific discovery and state-of-the-art engineering, and to further knowledge of computational modeling and simulation. JICS realizes its vision by taking full advantage of petascale-and-beyond computers housed at ORNL and by educating a new generation of scientists and engineers well versed in the application of computational modeling and simulation for solving the most challenging scientific and engineering problems. JICS runs the National Institute for Computational Sciences (NICS), which had the distinction of deploying and managing the Kraken supercomputer. NICS is a leading academic supercomputing center and a major partner in the National Science Foundation's eXtreme Science and Engineering Discovery Environment, known as XSEDE. In November 2012, JICS sited the Beacon system, which set a record for power efficiency and captured the number one position on the Green500 list of the most energy-efficient computers.