Computer modeling reveals hidden conversations within cells

September 15, 2005

University of California, San Diego biochemists have developed a computer program that helps explain a long-standing mystery: how the same proteins can play different roles in a wide range of cellular processes, including those leading to immune responses and cancer.

Prior to the UCSD team's findings, which are published in the September 16 issue of the journal Science, many scientists expressed doubts that a computational approach could represent the intricate mechanisms through which cells respond to outside signals. However, the researchers report that their computer model accurately predicts particular behaviors of living cells. They also believe that the model has important practical applications, including guiding the design of better treatments for cancer and other diseases that involve failures in cell communication

"Our computational approach revealed how the same set of proteins produce physiologically different outputs in response to only subtly different inputs," explained Alexander Hoffmann, an assistant professor of chemistry and biochemistry, who led the team. "This is the first step toward developing drugs that interfere with one of the pathological functions of the proteins, but leave the healthy functions intact. For example, many current cancer drugs dramatically reduce immune function. Computer modeling should make it possible to design anti-cancer drugs that do not weaken patients' immune systems."

The computer model comprises 70 equations to account for the behavior of five proteins and three RNA molecules in the "NF-kappaB signaling pathway," which regulates genes involved in cancer, inflammation, immune function and cell death. Each equation takes into account a different parameter, such as how quickly a protein is synthesized, or how quickly it is degraded.

The researchers chose the NF-kappaB proteins because there is a wide body of prior research that they were able to draw on to set the initial parameters in the model. As they were developing the model, they repeatedly tested and refined it by comparing the model's predictions with the results of experiments with living cells.

"The beauty of this kind of interdisciplinary work is the almost circular way the model's predictions drive the design of new experiments, and the how results of those experiments can be fed back into the model to improve it," said Shannon Werner, a graduate student in chemistry and biochemistry, who did the experimental work described in the paper.

Once the model consistently predicted the behavior of living cells in a variety of experimental conditions, the researchers used the model to infer what was going on inside cells in much greater detail than would be possible through laboratory experiments alone.

The model revealed why two natural chemicals have opposite physiological effects. When exposed to one of the chemicals, the proteins create positive feedback that lengthens the amount of time they are active. When exposed to the other chemical, they initiate negative feedback, which shuts them down rapidly.

"The prevailing view has been that proteins are either on or off like a light switch, but that didn't explain how activating the same proteins with different chemicals could have opposing effects on cells," explained Hoffmann. "Our model shows that, analogous to how a telephone transmits an infinite number of different signals along a single wire, it is the timing of the proteins' activity that allows them to exert intricate control over the behavior of a cell. The computer model reveals the hidden conversations in the cell's wiring."

The researchers attribute their success in developing the computer model, despite criticism that the computational approach would require too many simplifications to accurately model cell communication, to the diverse expertise they brought together.

"Developing a computer model is both science and art," said Derren Barken, a graduate student in bioinformatics and experienced software engineer, who programmed the model. "It requires intuition built up over time, but it also requires someone like Alex, who can critically evaluate the scientific literature to decide what parameters need to be included in the model, and someone like Shannon who can take the predictions of the model and design experiments to test them in the laboratory."
-end-
The study was supported by the National Institutes of Health, the National Science Foundation and the UC Academic Senate.

University of California - San Diego

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.