Research could lead to treatments for Alzheimer's, Parkinson's,
Fluorescent micrograph (scale bar: 10 micrometers) shows yeast cells (red) with septin (green), which enables the budding of daughter cells. MIT researchers have found septin also helps neurons sprout the branch-like protrusions used to communicate with other neurons. Image / Philippsen Lab, Biozentrum B
In a finding that may lead to potential new treatments for diseases such as Alzheimer's and Parkinson's, researchers at the Picower Institute for Learning and Memory at MIT report an unexpected role in the brain for a well-known protein.
A study by Morgan H. Sheng, Menicon Professor of Neuroscience and a Howard Hughes Medical Institute investigator, and colleagues appearing in the Oct. 23 issue of Current Biology shows that the same protein that enables a yeast cell to bud into two daughter cells also helps neurons sprout the branch-like protrusions used to communicate with other neurons.
The work revolves around septins--proteins known since the 1970s to play an essential function in the process through which the cytoplasm of a single yeast cell divides. "In yeast, septin is localized exactly at the neck between the yeast mother cell and the bud or emerging daughter cell," Sheng said. "Amazingly, we found septin protein localized at the base of the neck of neuronal dendritic spines and at the branchpoint of dendritic branches."
Nine of the 14 septins found in mammals are found in the brain. One of them, Sept7, appears the most, but its role was unclear. Septins form long filaments and act as scaffolds, recruiting other proteins into their assigned roles of builders of the cell infrastructure.
While neurons don't divide, they do form protrusions that eventually elongate into dendritic branches. Dendrites, from the Greek word for "tree," conduct electrical stimulation from other neurons to the cell body of the neuron from which the dendrites project.
Electrical stimulation is transmitted via synapses, which are located at various points along the dendritic branches. Dendrites play a critical role in receiving these synaptic inputs. "Because dendritic spines are important for synaptic function and memory formation, understanding of septins may help to prevent the loss of spines and synapses that accompanies many neurodegenerative diseases," said co-author Tomoko Tada, a postdoctoral associate in the Picower Institute. "Septin could be a potential target protein to treat these diseases."
Moreover, in the cultured hippocampal neurons the researchers used in the study, septin was essential for normal branching and spine formation. An abundance of septin made dendrites grow and proliferate while a dearth of septin made them small and malformed.
"Boosting septin expression and function would enhance the stability of spines and synapses, and therefore be good for cognitive functions such as learning and memory," Sheng said. His laboratory is now exploring ways to prevent septin degradation and loss.
In addition to Sheng and Tada, authors are MIT affiliates Alyson Simonetta and Matthew Batterton; Makoto Kinoshita of Kyoto University Graduate School of Medicine; and Picower postdoctoral associate Dieter Edbauer.
This work is supported by the National Institutes of Health and the RIKEN-MIT Neuroscience Research Center
New research at MIT has revealed for the first time the role of bone's atomistic structure in a toughening mechanism that incorporates two theories previously proposed by researchers eager to understand the secret behind the material's lightweight strength.
Past experimental studies have revealed a number of different mechanisms at different scales of focus, rather than a single theory. The combination mechanism uncovered by the MIT researchers allows for the sacrifice of a small piece of the bone in order to save the whole, helps explain why bone tolerates small cracks, and seems to be adapted specifically to accommodate bone's need for continuous rebuilding from the inside out.
"The newly discovered molecular mechanism unifies controversial attempts of explaining sources of the toughness of bone, because it illustrates that two of the earlier explanations play key roles at the atomistic scale," said the study's author, Esther and Harold E. Edgerton Professor Markus Buehler of MIT's Department of Civil and Environmental Engineering.
"It's quite possible that each scale of bone--from the molecular on up--has its own toughening mechanism," said Buehler. "This hierarchical distribution of toughening may be critical to explaining the intriguing properties of bone and laying the foundation for new materials design that includes the nanostructure as a specific design variable."
Unlike synthetic building materials, which tend to be homogenous throughout, bone is heterogeneous living tissue whose cells undergo constant change. Scientists have classified bone's basic structure into a hierarchy of seven levels of increasing scale. Level 1 bone consists of bone's two primary components: chalk-like hydroxyapatite and collagen fibrils, which are strands of tough, chewy proteins. Level 2 bone comprises a merging of these two into mineralized collagen fibrils that are much stronger than the collagen fibrils alone. The hierarchical structure continues in this way through increasingly larger combinations of the two basic materials until reaching level 7, or whole bone.
Buehler scaled down his model to the atomistic level, to see how the molecules fit together--and equally important for materials scientists and engineers--how and when they break apart. More precisely, he looked at how the chemical bonds within and between molecules respond to force. Last year, he analyzed for the first time the characteristic staggered molecular structure of collagen fibrils, the precursor to level 1 bone.
In his newer research, he studied the molecular structure of the mineralized collagen fibrils that make up level 2 bone, hoping to find the mechanism behind bone's strength, which is considerable for such a lightweight, porous material.
At the molecular level, the mineralized collagen fibrils are made up of strings of alternating collagen molecules and consistently sized hydroxyapatite crystals. These strings are "stacked" together in a staggered fashion such that the crystals appear in stair-step configurations. Weak bonds form between the crystals and molecules in the strings and between the strings.
When pressure is applied to the fabric-like fibrils, some of the weak bonds between the collagen molecules and crystals break, creating small gaps or stretched areas in the fibrils. This stretching spreads the pressure over a broader area, and in effect, protects other, stronger bonds within the collagen molecule itself, which might break outright if all the pressure were focused on them. The stretching also lets the tiny crystals shift position in response to the force, rather than shatter, which would be the likely response of a larger crystal.
Previously, some researchers suggested that the fundamental key to bone's toughness is the "molecular slip" mechanism that allows weak bonds to break and "stretch" the fabric without destroying it. Others have cited the characteristic length of bone's hydroxyapatite crystals (a few nanometers) as an explanation for bone's toughness; the crystals are too small to break easily.
At the atomistic scale, Buehler sees the interplay of both these mechanisms. This suggests that competing explanations may be correct; bone relies on different toughening mechanisms at different scales.
Buehler also discovered something very notable about bone's ability to tolerate gaps in the stretched fibril fabric. These gaps are of the same magnitude--several hundred micrometers--as the basic multicellular units or BMUs associated with bone's remodeling. BMUs are a combination of cells that work together like a small boring tool that eats away old bone at one end and replaces it at the other, forming small crack-like cavities in between as it works its way through the tissue.
Thus, the mechanism responsible for bone's strength at the molecular scale also explains how bone can remain so strong--even though it contains those many tiny cracks required for its renewal.
This could prove very useful information to civil engineers, who have always used materials like steel that gain strength through density. Nature, however, creates strength in bone by taking advantage of the gaps, which themselves are made possible by the material's hierarchical structure.
"Engineers typically over-dimension structures in order to make them robust. Nature creates robustness by hierarchical structures," said Buehler.
This work was funded by a National Science Foundation CAREER award and a grant from the Army Research Office.
Photo / Donna Coveney
MIT Professor Markus Buehler has helped reveal why bones are so tough. The object on the screen is a triple helical tropocollagen molecule, a fundamental building block of bone. Next to the molecule are nanosized hydroxyapatite chalk-like crystals. In his work he simulates the behavior of the composite of tropocollagen and hydroxyapatite during deformation. Enlarge image
CONTACT
Elizabeth A. Thomson MIT News Office Phone: 617-258-5402 E-mail: thomson@mit.edu
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Markus Buehler - MIT Department of Civil and Environmental Engineering
Residents of Italy's capital will glimpse the future of urban mapmaking next month with the launch of "Wiki City Rome," a project developed at the Massachusetts Institute of Technology that uses data from cellphones and other wireless technology to illustrate the city's pulse in real time.
The project will debut Sept. 8 during Rome's "Notte Bianca" or white night, an all-night festival of events across the capital city. During that night, anyone with an Internet connection will be able to see a unique map of the Italian capital that shows the movements of crowds, event locations, the whereabouts of well-known Roman personalities, and the real-time position of city buses and trains.
The map will also be broadcast on a big-screen display in one of Rome's main squares in the city center, giving Romans real-time feedback on the human dynamics in their immediate surroundings.
Wiki City Rome stems from MIT's SENSEable City Laboratory, an initiative directed by Carlo Ratti that studies the impact of new technologies on cities. The project builds on the work of "Real Time Rome," presented during the 2006 Venice Architecture Biennale, the prestigious biannual exhibition of contemporary art.
Organizers say Wiki City Rome raises the intriguing prospect of a map drawn on the basis of dynamic elements of which the map itself is an active part. According to researcher Francesco Calabrese of SENSEable City Lab, a person could consult the map to find the most crowded place in Rome to drink an aperitivo - and then identify the least congested route by which to reach it.
"Rome's Notte Bianca is all about the city, the people and the events, and Wiki City Rome will give Romans a new awareness of how they move within their city in response to this exceptional pulse of activities," said researcher Kristian Kloeckl, a SENSEable City Lab member who is also working on the project.
"How do people react towards this new perspective on their own city while they are determining the city's very own dynamic? How does having access to real-time data in the context of possible action alter the process of decision-making in how to go about different activities?" Kloeckl asked. "These are among the questions we may be able to answer."
By looking at a city using a "real-time control system" as a working analogy, the Wiki City project studies tools that enable people to become prime actors themselves in improving the efficiency of urban systems. In coming years, the Wiki City project will develop as an open platform where anybody can download and upload data that are location and time sensitive.
"By deploying developments of the 'Web 2.0' and the 'Semantic Web,' Wiki City can be a significant leap forward towards a pervasive 'internet of things' to support human action and interaction," said Carlo Ratti.
Ratti's team obtains its data anonymously from cell phones, GPS devices on buses and taxis, and other wireless mobile devices. Data are made anonymous and aggregated from the beginning, so there are no implications for individual privacy.
Partnering with the SENSEable City Lab on Wiki City Rome are SEAT Pagine Gialle, Telecom Italia, Telespazio, the Rome public transportation authority ATAC, La Repubblica, and Trenitalia.
In addition to Kloeckl, Calabrese and Ratti, members of the Wiki City Rome team include Assaf Biderman, Bernd Resch, and Fabien Girardin
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