Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Many bodies prompt stem cells to change

17.06.2014

Rice University scientists apply new theory to learn how and why cells differentiate

How does a stem cell decide what path to take? In a way, it’s up to the wisdom of the crowd.


An overview of the stem cell gene network gives a sense of the complex process involved in cell differentiation, as transcription factors and protein complexes influence and loop back upon each other. Rice University researchers found that stem cell differentiation can be defined as a many-body problem as they developed a theoretical system to analyze large gene networks. (Credit: Bin Zhang/Rice University)

The DNA in a pluripotent stem cell is bombarded with waves of proteins whose ebb and flow nudge the cell toward becoming blood, bone, skin or organs. A new theory by scientists at Rice University shows the cell’s journey is neither a simple step-by-step process nor all random.

Theoretical biologist Peter Wolynes and postdoctoral fellow Bin Zhang set out to create a mathematical tool to analyze large, realistic gene networks. As a bonus, their open-access study to be published this week by the Proceedings of the National Academy of Sciences helped them understand that the process by which stem cells differentiate is a many-body problem.

... more about:
»DNA »energy »function »genes »stem cells »transition

“Many-body” refers to physical systems that involve interactions between large numbers of particles. Scientists assume these many bodies conspire to have a function in every system, but the “problem” is figuring out just what that function is. In the new work, these bodies consist not only of the thousands of proteins expressed by embryonic stem cells but also DNA binding sites that lead to feedback loops and other “attractors” that prompt the cell to move from one steady state to the next until it reaches a final configuration.

To test their tool, the researchers looked at the roles of eight key proteins and how they rise and fall in number, bind and unbind to DNA and degrade during stem cell differentiation. Though the interactions may not always follow a precise path, their general pattern inevitably leads to the desired result for the same reason a strand of amino acids will inevitably fold into the proper protein: because the landscape dictates that it be so.

Wolynes called the new work a “stylized,” simplified model meant to give a general but accurate overview of how cell networks function. It’s based on a theory he formed in 2003 with Masaki Sasai of Nagoya University but now takes into account the fact that not one but many genes can be responsible for even a single decision in a cellular process.

“This is what Bin figured out, that one could generalize our 2003 model to be much more realistic about how several different proteins bind to DNA in order to turn it on or off,” Wolynes said.

A rigorous theoretical approach to determine the transition pathways and rates between steady states was also important, Zhang said. “This is crucial for understanding the mechanism of how stem cell differentiation occurs,” he said.

Wolynes said that because the stem cell is stochastic — that is, its fate is not pre-determined — “we had to ask why a gene doesn’t constantly flip randomly from one state to another state. This paper for the first time describes how we can, for a pretty complicated circuit, figure out there are only certain periods during which the flipping can occur, following a well-defined transition pathway.”

In previous models of gene networks, “Instead of focusing on proteins actually binding to DNA, they just say, ‘Well, there’s a certain high level of this protein or low level of that protein,’” Wolynes said. “At first, that sounds easier to study because you can measure how much protein you’ve got. But you don’t always know if it is bound. It has become increasingly clear that the rate of protein binding to DNA plays an important role in gene expression, particularly in eukaryotic systems.”

The notion that many-body effects even existed began in 1942 when British scientist C.H. Waddington established the idea of an epigenetic landscape for stem cells as a way to describe why pluripotent cells in embryos are destined to turn into bone, muscle and all the other parts of the body – but don’t turn back. Waddington compared the cells’ paths to marbles rolling to the bottom of a valley.

That concept rang true to Wolynes. His energy landscape theory has become key to understanding protein folding, although that theory sees the landscape as a funnel rather than a valley. “Waddington said that as a cell develops into an embryo and beyond, it becomes many different kinds of cells,” Wolynes said. “Those cells might branch off and differentiate further, but they don’t typically go back to the original state and start over.

“His analogy – the idea of falling down through a valley – kicked around for a long time, but it was hard to make it mathematically precise. In his time, they didn’t know about DNA,” Wolynes said.

In both energy and epigenetic landscapes, Wolynes said, the steady state at the bottom is an attractor. “It means wherever you start from, you end up attracted to that same place,” he said. “In genetic networks, things like steadily oscillating patterns can also be considered attractors.”

Once biologists began to understand genetic switches in DNA, the whole picture became more complicated, he said. “The landscape now has to incorporate the active parts of DNA that are trying to decide whether to turn this gene on or that gene off. In the ’50s, we learned how genes made decisions on the basis of their production of proteins. These proteins then act back on the same genes in a kind of feedback loop.”

The loops allow genes to remain active for far longer than it would take a protein simply to bind or unbind to a section of DNA. In the researchers’ equations, the loops become attractors that help regulate transformation of the cell and can be mapped onto the many-body landscape.

Analyzing the coupled dynamics of all these chemical reactions in a cell could be done by brute force, he said, but the computational cost would be enormous. So the Rice team decided to take a big-picture approach based on Wolynes’ earlier work. It so happened that the resulting theoretical models of embryonic stem cells matched nicely with what experimentalists had seen in their studies.

For example, the models explained the fluctuations experimentalists had observed in the expression of a master regulator, a protein called nanog, and its important role in maintaining a cell’s pluripotency. Stem cells move from one steady state to the next on their journeys; in their calculations, they found a much higher level of nanog gene expression in what they called SC1, the basic stem cell, than in SC2, a stem cell that had moved to the second steady state. This matched what experiments had measured, the researchers said.

“This is still just a beginning,” Wolynes said. “We’re looking at embryonic stem cells now, but someday we want to treat the complete developmental program of organisms with hundreds of genes. We can see how these mathematics can scale up to that regime.”

Wolynes is the Bullard-Welch Foundation Professor of Science and a professor of chemistry and a senior scientist with the Center for Theoretical Biological Physics (CTBP) at Rice.

The D.R. Bullard-Welch Chair at Rice University and the National Science Foundation (NSF)-sponsored CTBP, supported the research. The researchers utilized the Data Analysis and Visualization Cyberinfrastructure supercomputer supported by the NSF and administered by Rice’s Ken Kennedy Institute for Information Technology.

David Ruth | Eurek Alert!
Further information:
http://news.rice.edu/2014/06/16/many-bodies-prompt-stem-cells-to-change/

Further reports about: DNA energy function genes stem cells transition

More articles from Life Sciences:

nachricht Great apes communicate cooperatively
25.05.2016 | Max-Planck-Institut für Ornithologie

nachricht Rice study decodes genetic circuitry for bacterial spore formation
24.05.2016 | Rice University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Computational high-throughput screening finds hard magnets containing less rare earth elements

Permanent magnets are very important for technologies of the future like electromobility and renewable energy, and rare earth elements (REE) are necessary for their manufacture. The Fraunhofer Institute for Mechanics of Materials IWM in Freiburg, Germany, has now succeeded in identifying promising approaches and materials for new permanent magnets through use of an in-house simulation process based on high-throughput screening (HTS). The team was able to improve magnetic properties this way and at the same time replaced REE with elements that are less expensive and readily available. The results were published in the online technical journal “Scientific Reports”.

The starting point for IWM researchers Wolfgang Körner, Georg Krugel, and Christian Elsässer was a neodymium-iron-nitrogen compound based on a type of...

Im Focus: Atomic precision: technologies for the next-but-one generation of microchips

In the Beyond EUV project, the Fraunhofer Institutes for Laser Technology ILT in Aachen and for Applied Optics and Precision Engineering IOF in Jena are developing key technologies for the manufacture of a new generation of microchips using EUV radiation at a wavelength of 6.7 nm. The resulting structures are barely thicker than single atoms, and they make it possible to produce extremely integrated circuits for such items as wearables or mind-controlled prosthetic limbs.

In 1965 Gordon Moore formulated the law that came to be named after him, which states that the complexity of integrated circuits doubles every one to two...

Im Focus: Researchers demonstrate size quantization of Dirac fermions in graphene

Characterization of high-quality material reveals important details relevant to next generation nanoelectronic devices

Quantum mechanics is the field of physics governing the behavior of things on atomic scales, where things work very differently from our everyday world.

Im Focus: Graphene: A quantum of current

When current comes in discrete packages: Viennese scientists unravel the quantum properties of the carbon material graphene

In 2010 the Nobel Prize in physics was awarded for the discovery of the exceptional material graphene, which consists of a single layer of carbon atoms...

Im Focus: Transparent - Flexible - Printable: Key technologies for tomorrow’s displays

The trend-forward world of display technology relies on innovative materials and novel approaches to steadily advance the visual experience, for example through higher pixel densities, better contrast, larger formats or user-friendler design. Fraunhofer ISC’s newly developed materials for optics and electronics now broaden the application potential of next generation displays. Learn about lower cost-effective wet-chemical printing procedures and the new materials at the Fraunhofer ISC booth # 1021 in North Hall D during the SID International Symposium on Information Display held from 22 to 27 May 2016 at San Francisco’s Moscone Center.

Economical processing

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Networking 4.0: International Laser Technology Congress AKL’16 Shows New Ways of Cooperations

24.05.2016 | Event News

Challenges of rural labor markets

20.05.2016 | Event News

International expert meeting “Health Business Connect” in France

19.05.2016 | Event News

 
Latest News

LZH shows the potential of the laser for industrial manufacturing at the LASYS 2016

25.05.2016 | Trade Fair News

Great apes communicate cooperatively

25.05.2016 | Life Sciences

Thermo-Optical Measuring method (TOM) could save several million tons of CO2 in coal-fired plants

25.05.2016 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>