Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New theorem helps reveal tuberculosis' secret

23.02.2016

Team led by Rice University develops approach to uncover missing connections in biochemical networks

A new methodology developed by researchers at Rice and Rutgers universities could help scientists understand how and why a biochemical network doesn't always perform as expected. To test the approach, they analyzed the stress response of bacteria that cause tuberculosis and predicted novel interactions.


Upon infection with Mycobacterium tuberculosis bacilli (labeled in red), macrophages (nuclei stained blue) accumulate lipid droplets (green). The network controlling the expression of an enzyme that is central to bacterial metabolic switching to lipids as nutrients during infection is the topic of a new paper by researchers at Rice and Rutgers universities.

Credit: Emma Rey-Jurado/Public Health Research Institute

The results are described in a PLOS Computational Biology paper published today.

"Over the last several decades, bioscientists have generated a vast amount of information on biochemical networks, a collection of reactions that occur inside living cells," said principal investigator Oleg Igoshin, a Rice associate professor of bioengineering.

"We are beginning to understand how these networks control the dynamics of a biological response, that is, the precise nature of how a concentration of biomolecules changes with time," he said. "But to date, only a few general rules that relate the dynamical responses with the structure of the underlying networks have been formulated. Our theorem provides another such rule and therefore can be widely applicable."

The theorem uses approaches from control theory, an interdisciplinary branch of engineering and mathematics that deals with the behavior of dynamical systems that have inputs. The theorem formulates a condition for an underlying biochemical network to display non-monotonic dynamics in response to a monotonic trigger. For instance, it would explain the expression of a gene that first speeds up, then slows down and returns to normal. (Monotonic responses always increase or always decrease; non-monotonic responses increase and then decrease, or vice-versa.)

The theorem states that a non-monotonic response is only possible if the system's output receives conflicting messages from the input, such that one branch of the pathway activates it and another one deactivates it.

If a non-monotonic response is observed in a system that appears to be missing such conflicting paths, it would imply that some biochemical interactions remain undiscovered, Igoshin said.

"What we do is figure out the mechanism for a dynamic phenomenon that people have observed but can't explain and that seems to be inconsistent with the current state of knowledge," he said.

The theorem was formulated and proven in collaboration with Eduardo Sontag, a distinguished professor in the Department of Mathematics and Center for Quantitative Biology at Rutgers. Sontag focuses on general principles derived from feedback control analysis of cell signaling pathways and genetic networks.

The researchers applied their theory to explain how Mycobacterium tuberculosis responds to stresses that mimic those the immune system uses to fight the pathogen. Igoshin said M. tuberculosis is a master in surviving such stresses. Instead of dying, they become dormant Trojan horses that future conditions may reactivate.

According to the World Health Organization, a third of the world's population is infected by the tuberculosis bacteria, though the disease kills only a fraction of those infected.

"The good thing is that 95 percent of infected people don't have symptoms," said Joao Ascensao, a Rice senior majoring in bioengineering and first author of the paper. "The bad thing is you can't kill the bacteria. And then if you get immunodeficiency, due to HIV, starvation or other things, you're out of luck because the disease will reactivate."

Ascensao said M. tuberculosis is hard to grow and work with in a molecular biology setting. "A generation of E. coli takes 20 minutes to grow, but for M. tuberculosis, a generation takes from 24 hours to over 100 hours when it goes latent," he said. "So even though we have this really sparse data, the theory allowed us to uncover what's happening behind the scenes."

The study was motivated by a 2010 publication by Marila Gennaro, a professor of Medicine in the Public Health Research Institute at Rutgers, and Pratik Datta, a research scientist in her lab, who are also co-authors of the new paper. Their results showed that as M. tuberculosis gradually runs out of oxygen, the expression of some genes would suddenly rise and then fall back. They characterized the biochemical network that controls the expression of these non-monotonic genes, but the mechanism of the dynamical response was not understood.

"It didn't make sense to me intuitively," Igoshin said. "At first I couldn't prove it mathematically, but then Sontag's theorem allowed us to conclude that some biochemical interactions were missing in the underlying network."

Ascensao and Baris Hancioglu, then a postdoc in Igoshin's lab and now a bioinformatics specialist at Ohio State University, built computer models and ran simulations of oxygen-starved M. tuberculosis. Their results suggested a few possible solutions that were tested in the follow-up experiments by Gennaro's group.

Eventually the simulations predicted a new interaction that could explain the dynamics of the glyoxylate shunt genes that control the metabolic transition network known to be important to the bacteria's virulence.

"Researchers found that the hypoxic (oxygen-starved) signal would lead bacteria to switch from one type of food to a different type of food," Igoshin said. "They used to eat sugars, but they'd start eating the fat accumulated inside of infected macrophages, a type of immune cell. It looks like this switch might be associated with going from an active bacterium to a latent, dormant bacterium that's stable and doesn't cause any symptoms."

The researchers argued that the stress-induced activation of adaptive metabolic pathways involving glyoxylate genes is transient, increasing only until there's enough of the protein present to achieve stability. "If these hypotheses are correct," they wrote, "drugs blocking negative interactions responsible for non-monotonic dynamics could in principle destabilize transitions to latency or trigger reactivation."

###

The research was supported by the National Institutes of Health. The researchers used the National Science Foundation-supported supercomputing resources administered by Rice's Ken Kennedy Institute for Information Technology.

David Ruth
713-348-6327
david@rice.edu

Mike Williams
713-348-6728
mikewilliams@rice.edu

Read the open-access paper at http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1004741

This news release can be found online at http://news.rice.edu/2016/02/22/new-theorem-helps-reveal-tuberculosis-secret-2/

Follow Rice News and Media Relations via Twitter @RiceUNews

Related Materials:

Oleg Igoshin Research Group: http://igoshin.rice.edu

Rice Department of Bioengineering: http://bioe.rice.edu

Images for download:

http://news.rice.edu/files/2016/02/0222_TB-1-WEB-2com3pq.jpg

Rice senior Joao Ascensao, left, and bioengineer Oleg Igoshin led a team to reveal hidden details about gene-expression dynamics using the bacteria that causes tuberculosis as a test model. (Credit: Jeff Fitlow/Rice University)

http://news.rice.edu/files/2016/02/0222_TB-3-WEB-2jy0567.jpg

Upon infection with Mycobacterium tuberculosis bacilli (labeled in red), macrophages (nuclei stained blue) accumulate lipid droplets (green). The network controlling the expression of an enzyme that is central to bacterial metabolic switching to lipids as nutrients during infection is the topic of a new paper by researchers at Rice and Rutgers universities. (Credit: Emma Rey-Jurado/Public Health Research Institute)

Media Contact

David Ruth
david@rice.edu
713-348-6327

 @RiceUNews

http://news.rice.edu 

David Ruth | EurekAlert!

More articles from Life Sciences:

nachricht Nonstop Tranport of Cargo in Nanomachines
20.11.2018 | Max-Planck-Institut für molekulare Zellbiologie und Genetik

nachricht Researchers find social cultures in chimpanzees
20.11.2018 | Universität Leipzig

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Nonstop Tranport of Cargo in Nanomachines

Max Planck researchers revel the nano-structure of molecular trains and the reason for smooth transport in cellular antennas.

Moving around, sensing the extracellular environment, and signaling to other cells are important for a cell to function properly. Responsible for those tasks...

Im Focus: UNH scientists help provide first-ever views of elusive energy explosion

Researchers at the University of New Hampshire have captured a difficult-to-view singular event involving "magnetic reconnection"--the process by which sparse particles and energy around Earth collide producing a quick but mighty explosion--in the Earth's magnetotail, the magnetic environment that trails behind the planet.

Magnetic reconnection has remained a bit of a mystery to scientists. They know it exists and have documented the effects that the energy explosions can...

Im Focus: A Chip with Blood Vessels

Biochips have been developed at TU Wien (Vienna), on which tissue can be produced and examined. This allows supplying the tissue with different substances in a very controlled way.

Cultivating human cells in the Petri dish is not a big challenge today. Producing artificial tissue, however, permeated by fine blood vessels, is a much more...

Im Focus: A Leap Into Quantum Technology

Faster and secure data communication: This is the goal of a new joint project involving physicists from the University of Würzburg. The German Federal Ministry of Education and Research funds the project with 14.8 million euro.

In our digital world data security and secure communication are becoming more and more important. Quantum communication is a promising approach to achieve...

Im Focus: Research icebreaker Polarstern begins the Antarctic season

What does it look like below the ice shelf of the calved massive iceberg A68?

On Saturday, 10 November 2018, the research icebreaker Polarstern will leave its homeport of Bremerhaven, bound for Cape Town, South Africa.

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Optical Coherence Tomography: German-Japanese Research Alliance hosted Medical Imaging Conference

19.11.2018 | Event News

“3rd Conference on Laser Polishing – LaP 2018” Attracts International Experts and Users

09.11.2018 | Event News

On the brain’s ability to find the right direction

06.11.2018 | Event News

 
Latest News

Nonstop Tranport of Cargo in Nanomachines

20.11.2018 | Life Sciences

Researchers find social cultures in chimpanzees

20.11.2018 | Life Sciences

When AI and optoelectronics meet: Researchers take control of light properties

20.11.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>