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 Modern genetic sequencing tools give clearer picture of how corals are related
17.08.2017 | University of Washington

nachricht The irresistible fragrance of dying vinegar flies
16.08.2017 | Max-Planck-Institut für chemische Ökologie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

Gold shines through properties of nano biosensors

17.08.2017 | Physics and Astronomy

Greenland ice flow likely to speed up: New data assert glaciers move over sediment, which gets more slippery as it gets wetter

17.08.2017 | Earth Sciences

Mars 2020 mission to use smart methods to seek signs of past life

17.08.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>