Biological systems, including cells, tissues and organs, can function properly only when their parts are working in harmony. These systems are often dauntingly complex: Inside a single cell, thousands of proteins interact with each other to determine how the cell will develop and respond to its environment.
Shown here are mouse intestinal epithelial cells. MIT and MGH researchers have modeled how such cells respond to tumor necrosis factor. Image: The Journal of Cell Biology
To understand this great complexity, a growing number of biologists and bioengineers are turning to computational models. This approach, known as systems biology, has been used successfully to model the behavior of cells grown in laboratory dishes. However, until now, no one has used it to model the behavior of cells inside a living animal.
In the March 22 online edition of the journal Science Signaling, researchers from MIT and Massachusetts General Hospital report that they have created a new computational model that describes how intestinal cells in mice respond to a natural chemical called tumor necrosis factor (TNF).
The work demonstrates that systems biology offers a way to get a handle on the complexity of living systems and raises the possibility that it could be used to model cancer and other complex diseases, says Douglas Lauffenburger, head of MIT's Department of Biological Engineering and a senior author of the paper.
"You're not likely to explain most diseases in terms of one genetic deficit or one molecular impairment," Lauffenburger says. "You need to understand how many molecular components, working in concert, give rise to how cells and tissues are formed — either properly or improperly."
Systems biology, a field that has grown dramatically in the past 10 years, focuses on analyzing how the components of a biological system interact to produce the behavior of that system — for example, the many proteins that interact with each other inside a cell to respond to hormones or other external stimuli.
"The beauty of systems biology is that it doesn't ignore the biological complexity of what's going on," says Kevin Haigis, an assistant professor of pathology at MGH and Harvard Medical School and a senior author of the Science Signaling paper.
"Biologists are trained to be reductionists," adds Haigis, who was a postdoctoral associate at MIT before moving to MGH. "I don't think people have failed to realize the complexity of how biology works, but people are accustomed to trying to reduce complexity to make things more understandable."
In contrast, the systems biology approach tries to capture that complexity through computer modeling of many variables. Inputs to the model might be the amounts of certain proteins found inside cells, and outputs would be the cells' resulting behaviors — for example, growing, committing suicide or secreting hormones.
While at MIT, Haigis worked in the lab of Tyler Jacks, director of the David H. Koch Institute for Integrative Cancer Research at MIT, studying the role of the cancer-causing gene Ras in the mouse colon. He teamed up with Lauffenburger and others to computationally model Ras' behavior in cell culture.
After Haigis moved to MGH, he and Lauffenburger decided to bring this computational approach to studying living animals because they believed that studies done in cultured cells could miss some of the critical factors that come into play in living systems, such as the location of a cell within a living tissue and the influence of cells that surround it.
In the new paper, the researchers tackled the complex interactions that produce inflammation in the mouse intestine. The intestine contains many types of cells, but they focused on epithelial cells (which line the intestinal tube) and their response to TNF.
Previous work has shown that TNF plays a central role in intestinal inflammation, and provokes one of two possible responses in the intestinal epithelial cells: cell death or cell proliferation. Chronic inflammation can lead to inflammatory bowel disease and potentially cancer.
In this study, the researchers got the data they needed to develop their computational model by treating normal mice with TNF, then determining whether the cells proliferated or died. They found that cell fate depended on the cells' location in the intestine — cells in the ileum proliferated, while those in the duodenum died.
The multi-faceted result would likely not have been seen in a lab dish. "In cell culture, you would have gotten one or the other," Lauffenburger says.
They also correlated the diverse outcomes with the activities of more than a dozen proteins found in the cells, allowing them to determine how the outcomes depended on quantitative combination of key signaling pathways, and furthermore, to predict how the outcomes would be affected by drug treatment. The researchers then tested the model's predictions in an additional cohort of mice, and found that they were accurate.
Jason Papin, assistant professor of biomedical engineering at the University of Virginia, says that the team's biggest accomplishment is demonstrating that systems biology modeling can be done in living animals (in vivo). "You always want to move to an in vivo setting, if possible, but it's technically more difficult," says Papin, who was not involved with this research.
The researchers are now trying to figure out in more detail what factors in the intestinal cells' environment influence the cells to behave the way they do. They are also studying how genetic mutations might alter the cells' responses.
They also plan to begin a study of neurological diseases such as Alzheimer's disease. Cancer is another disease that lends itself to this kind of modeling, says Jacks, who was not part of this study. Cancer is an extremely complicated disease that usually involves derangement of many cell signaling pathways involved in cell division, DNA repair and stress response.
"We expect that our ability to predict which targets, which drugs and which patients to bring together in the context of cancer treatment will require a deeper understanding of the complex signaling pathways that exist in cancer," says Jacks. "This approach will help us get there."
Caroline McCall | EurekAlert!
Transport of molecular motors into cilia
28.03.2017 | Aarhus University
Asian dust providing key nutrients for California's giant sequoias
28.03.2017 | University of California - Riverside
The Institute of Semiconductor Technology and the Institute of Physical and Theoretical Chemistry, both members of the Laboratory for Emerging Nanometrology (LENA), at Technische Universität Braunschweig are partners in a new European research project entitled ChipScope, which aims to develop a completely new and extremely small optical microscope capable of observing the interior of living cells in real time. A consortium of 7 partners from 5 countries will tackle this issue with very ambitious objectives during a four-year research program.
To demonstrate the usefulness of this new scientific tool, at the end of the project the developed chip-sized microscope will be used to observe in real-time...
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
28.03.2017 | Life Sciences
28.03.2017 | Information Technology
28.03.2017 | Physics and Astronomy