Computer Model could Help Test New Sickle Cell Drugs

A team of Brown University researchers has developed a new computer model that simulates the way red blood cells become misshapen by sickle cell disease. The model, described in a paper published in Science Advances, could be useful in the preclinical evaluation of drugs aimed at preventing the sickling process.

"There are currently only two drugs approved by the FDA for treating sickle cell disease, and they don't work for everyone," said Lu Lu, a Ph.D. student in the Division of Applied Mathematics at Brown and the study's co-lead author. "We wanted to build a model that considers the entire sickling process and could be used to quickly and inexpensively pre-screen new drug candidates."

Sickle cell disease is a genetic disorder that affects millions of people worldwide. The disorder causes red blood cells, which are normally soft and round, to become stiff, sticky and sickle-shaped (a bit like a crescent moon). The irregularly shaped cells get stuck in blood vessels, causing pain, swelling, strokes and other complications.

At the cellular level, sickle cell disease affects hemoglobin, a protein in red blood cells responsible for transporting oxygen. When oxygen-deprived, sickle cell hemoglobin clumps together inside the cell. The clumps then form long polymer fibers that push against the cell wall, stiffening the cells and forcing them out of shape.

George Karniadakis, a professor of applied mathematics at Brown and senior author of the new research, has worked for years to better understand the disorder. Most recently, he's worked with Lu and He Li, a research professor at Brown, to create detailed biophysical models of each stage of the sickling process, including a model of red blood cell function called OpenRBC and a supercomputer model of sickle cell fiber formation.

This new model combines and simplifies the previous models to create a single kinetic model of the entire sickling process. Using information gleaned from the detailed supercomputer models, the researchers were able to build a simplified version that captures all the important dynamics of the sickling process, yet can be run on a laptop.

To validate the model, the researchers showed that it could reproduce the outcomes of prior experiments in the lab and in people.

Because the dynamics of the sickling process can vary depending upon where in the body it's happening, researchers designed the model to simulate sickling process in different organs. For example, because oxygen plays a key role in the process, sickling unfolds very differently in oxygen-rich areas like the lungs compared to more oxygen-poor areas like the kidneys. The model allows users to input parameters specific to the organ they're hoping to simulate. That same flexibility also enables to model to be run for individual patients who may have more or less severe versions of the disorder.

To test the potential effectiveness of drugs, the model allows users to input the mode of action by which a drug is presumed to work, information is often gathered during preliminary lab studies. For example, if a drug is designed to boost the amount of healthy hemoglobin in red blood cells, that information can be used by the model to generate the effect on a large population of patient-specific or organ-specific red blood cells.

"Sometimes a drug can be designed to work on one parameter, but ends up having a different effects on other parameters," Karniadakis said. "The model can tell if those effects are synergistic or whether they may negate each other. So the model can give us an idea of the overall effect of the drug."

The researchers are hopeful the model could be useful in identifying promising drug candidates.

"Clinical drug trials are very expensive and the vast majority of them are unsuccessful," Karniadakis said. "The hope here is that we can do in silico trials to screen potential medications before proceeding to a clinical trial."

Lu Lu, Zhen Li, He Li, Xuejin Li, Peter G Vekilov, George Em Karniadakis.
Quantitative prediction of erythrocyte sickling for the development of advanced sickle cell therapies.
Science Advances, Vol. 5, no. 8. doi: 10.1126/sciadv.aax3905.

Most Popular Now

Using Artificial Intelligence to Predict…

Thyroid nodules are small lumps that form within the thyroid gland and are quite common in the general population, with a prevalence as high as 67%. The great majority of...

NHS Health Tech Team of the Year Named

A pioneering NHS trust has been recognised at the 2019 HTN Awards for its innovative work using InterSystems technology to help enhance care for hundreds of thousands of patients. North...

Philips and Klinikum Stuttgart Hospital …

Royal Philips (NYSE:PHG, AEX:PHIA), a global leader in health technology, and German Klinikum Stuttgart hospital, the largest provider in the region, announced they have signed a comprehensive 10-year innovation partnership...

Personalised and Powerful: UK to Lead Ne…

The UK will be transformed into a global hub for radiotherapy research, pioneering the use of the latest techniques such as FLASH radiotherapy and artificial intelligence, with a new £56...

Innovations for Tomorrow's Healthcare - …

18 - 21 November 2019, Düsseldorf, Germany. Groundbreaking innovations shape tomorrow's medical progress. At this year's MEDICA, visitors can find out what these exemplary innovations will be like in the here...

SilverCloud Health Marks World Mental He…

More than 300,000 people suffering with mental health disorders such as anxiety and depression have now been treated through innovative digital therapy programmes developed as a result of a partnership...

Siemens Healthineers Launches ACUSON Red…

Siemens Healthineers has launched the ACUSON Redwood, a new ultrasound system built on the company's new platform architecture and features advanced applications for greater clinical confidence, AI-powered tools for smart...

AI Predicts which Pre-Malignant Breast L…

New research at Case Western Reserve University could help better determine which patients diagnosed with the pre-malignant breast cancer commonly as stage 0 are likely to progress to invasive breast...

Nuance and Microsoft Partner to Transfor…

Nuance Communications Inc. and Microsoft Corp. have joined forces to help transform healthcare delivery for a more sustainable future. Together, the companies will accelerate the delivery of ambient clinical intelligence...

MEDICA 2019 + COMPAMED 2019 Bring in ove…

18 - 21 November 2019, Düsseldorf, Germany. More dynamic, more digital and more networked than ever: the medical industry is taking strides into the future. If you want to be in...

Telehealth Effectively Diagnoses / Manag…

A recent study of 368 pregnant mothers, led by Bettina Cuneo, MD, director of perinatal cardiology and fetal cardiac telemedicine at Children's Hospital Colorado, found that fetal congenital heart disease...

Siemens Healthineers Closes ECG Manageme…

Siemens Healthineers AG has completed the acquisition of a majority stake in ECG Management Consultants, a leading U.S. healthcare advisory firm, with an effective date of November 1, 2019. The...