Neuroscientists spot nature/nurture gene link

Neuroscientists at MIT's Picower Institute for Learning and Memory found that a previously unsuspected set of genes links nature and nurture during a crucial period of brain development

Nature--in the form of genes--and nurture--in the form of environmental influences--are fundamentally intertwined during this period.

"Our work points to how a disorder can be genetic and yet be dependent on the environment," said co-author Mriganka Sur, Sherman Fairchild Professor of Neuroscience at the Picower Institute and chair of MIT's brain and cognitive sciences department. "Many genes require activity to be expressed and make their assigned proteins. They alter their expression when activity is altered. Thus, we reveal an important mechanism of brain development that should open up a window into the mechanisms and treatment of brain disorders such as autism."

In the brain, some genes are only expressed, or turned on, in response to stimulus from the outside world. Like a panel of switches that turn lights on and off, genes that don't receive electricity don't "turn on" and express their particular proteins.

Sur and colleagues found a set of novel genes--including a calcium sensor called cardiac Troponin C, or cTropC--particularly sensitive to a critical period of development. The lack of proteins from these genes during a key phase of development could be one of the culprits in developing autism.

Researchers have long investigated the molecular mechanisms involved in monocular deprivation--when one eye is deprived of sight during a critical period of brain development, that eye becomes permanently blind, even after it is uncovered. This phenomenon is considered an important model for brain development because synapses for the covered eye--deprived of environmental stimulus, or what Sur calls "nurture"--shrivel up or get reassigned to other uses.

Sur and his colleagues looked at which genes are expressed, and which are not, when this phenomenon occurs. They hoped to pin down the correlation between nature--meaning the genes--and the external environment, or nurture. By identifying which genes are particularly apt to switch their expression patterns in response to "nurture," the researchers potentially narrowed down the ones that may be implicated in developmental disorders.

Researchers believe autism spectrum disorders are tied to brain changes that occur during critical periods of development. Different but overlapping critical periods are thought to exist for various cognitive functions affected in autism, such as language and social behaviors.

"Autism is a strongly genetic disorder: genes set up risk factors but by themselves simply make proteins," Sur said. "Genes work together with other influences. In the case of autism, these influences are unknown but could be molecules made by other genes or chemicals from the environment."

If scientists understood how genes changed in response to environmental influences during this crucial developmental period, they might be able to one day prevent or reverse the changes.

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Researchers make a point of explaining 'the wallpaper problem

Frustrated by tape that won't peel off the roll in a straight line? Angry at wallpaper that refuses to tear neatly off the wall?

A new study reveals why these efforts can be so aggravating. Wallpaper is not out to foil you--it's just obeying the laws of physics, according to a team of researchers from the Centre National de la Recherche Scientifique (CNRS) in Paris, the Universidad de Santiago, Chile, and MIT.

The report, published in the March 30 online issue of Nature Materials, sheds light on a phenomenon many people have experienced, which the researchers dubbed "the wallpaper problem."

"You want to redecorate your bedroom, so you yank down the wallpaper. You wish that the flap would tear all the way down to the floor, but it comes together in a triangle and you have to start all over again," said Pedro Reis, one of the authors of the paper and an applied mathematics instructor at MIT.

This pattern, where two cracks propagate toward each other and meet at a point, is extremely robust. It applies not only to wallpaper but other adhesives such as tape, as well as nonadhesive plastic sheets such as the shrink-wrap that envelops compact discs. It even extends to fruit: The skin on a tomato or a grape typically forms a triangle when peeled off.

"This has happened to everyone. it's frustrating," said Reis, who collaborated with Enrique Cerda and Eugenio Hamm of the Universidad de Santiago, Benoit Roman of CNRS and Michael LeBlanc of the University of Chicago.

The team found that those ubiquitous triangular tears arise from interactions between three inherent properties of adhesive materials: elasticity (stiffness), adhesive energy (how strongly the adhesive sticks to a surface) and fracture energy (how tough it is to rip).

The researchers developed a formulation that predicts the angle of the triangle formed, based on those three properties.

They also figured out just how those triangular tears arise. As the strip is pulled, energy builds up in the fold that forms where the tape is peeling from the surface. The tape can release that energy in two ways: by unpeeling from its surface and by becoming narrower, both of which it does.

In a possible industrial application, materials engineers could use this method to calculate one of the three key properties, if the other two are known. This could be particularly useful in microtechnologies, such as stretchable electronics, where the characterization of thin material properties is very difficult.

Reis, who now works in MIT's Applied Mathematics Laboratory, and his collaborators at CNRS and Universidad de Santiago got the idea for the project after noticing consistent tearing patterns in plastic sheets such as the plastic wrapping of CDs.

The researchers tried controlled experimental versions of the same process in their lab and got the same results. "This shape is really robust, so there must be something fundamental going on that gives rise to these shapes," Reis said.

However, the shapes formed by tearing nonadhesive sheets proved difficult to study because they are not perfect triangles, and without adhesion, the physics of the problem is more complicated. Instead, the researchers turned their attention to adhesives, which do form perfect triangles when torn.

The triangular shapes can also be seen in the work of French artist Jacques Villeglé. His art consists of posters taken from the streets of Paris and other French cities, complete with the same sort of rips that the researchers studied. One of the posters may be featured on the cover of Nature Materials to illustrate the team's paper.

Torn posters, tape and tomato skins may seem like strange research topics for physicists and applied mathematicians, but it's perfectly normal to Reis and his colleagues, who draw inspiration from an array of everyday objects.

Such real-world applications are not only fun to study, but "we can really learn things that will be useful for industry and help us understand the everyday world around us. It is also a great way to motivate students to be interested in science," Reis said.

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Voting for more than just either-or

Traditional voting systems only allow people to make a single choice -- a limitation many voters find frustrating, particularly when there is a crowded field of candidates as there was early in the current presidential nominating cycle.

But it doesn't have to be that way.

Alternative voting systems, which allow people to rank their preferences in order instead of simply picking one, have been known for centuries, but have been devilishly difficult to implement and often result in a very slow tallying of results. One example is the system used in the Iowa caucuses, in which supporters of candidates who fail to reach a certain threshold in the first round can then move on to their second choices, and so on until a clear winner emerges.

A new computer software system developed by MIT researchers promises to make such ranking systems just as easy as traditional voting -- and to give results that leave more people satisfied. The system is about to get its first mass-market trial with the cable music network MTV.

Benjamin Mako Hill, while he was a graduate student in the MIT Media Lab's Computing Culture group, created a system called Selectricity, which has been online as a free service since last fall and is about to unveil an upgraded version with more options. With this software, any user can go to the website (www.selectricity.org) and set up a "Quickvote" in just a few seconds, and users anywhere who have access to the Internet can then cast their votes, providing an instant tally.

There's even an ultra-simple version that works through cellphones using basic text messaging. The system is so simple that hundreds of people have been using it for decisions as simple and immediate as where to go for dinner or when to hold a meeting.

But the system is also sophisticated enough to handle real elections, at least on a small scale. In February, a beta version of the new, improved software was used by a national student organization to elect their first board of directors -- and the way that election turned out was a dramatic confirmation of the value of the new system.

Each of 16 campus chapters of the group Students for Free Culture got an equal vote to select five members of their governing board from among a slate of 13 candidates. But as it turned out, the result would have been very different had they used a traditional voting system.

Hill, now a research fellow at MIT's new Center for Future Civic Media, says "the first place winner in plurality didn't even make it into the top five" using the more sophisticated preferential voting system, in which each chapter was able to rank all of the candidates in order of preference. That candidate, who would have been the winner in an ordinary election, "was ranked first more than any other candidate" -- four first-place votes out of 16 -- but "he was very polarizing and was ranked near-last on most of the other ballots," Hill explains. So in a traditional vote, the vast majority of the voters would have been very unhappy with the outcome.

Instead, with the Selectricity preferential voting system -- which allows the results to be scored using any of a variety of different known mathematical systems for selecting winners -- "the first-place winner using the Schulze/Condorcet (and most of the other methods) had only two first-place votes, but was in the top three or four on almost every ballot," Hill says. "It ended up being a real example of the power of preferential elections," leaving a majority of voters satisfied.

Selectricity users can pick which selection method to use when they set up a ballot, but once votes are cast the website also allows users the option of analyzing the results using several alternative methods, so that the outcomes can be compared.

The five methods currently included are:

• A traditional simple plurality method: whoever gets the most first-place votes wins.
• The "Approval" method, devised in the 1970s, in which people can vote "for" as many candidates as they like -- one vote per candidate -- to indicate which ones would be acceptable, and then all the votes for each candidate are simply added up and the person with the most votes wins.
• The Borda count, first proposed in 1770, which awards weighted numbers to each candidate depending on the ranking voters give them (such as 1 for a first-place vote, 2 for second, etc.) and then these numbers are totaled to determine the winner.
• The Condorcet method, devised in 1299 and refined in the 18th century, in which each candidate is compared one at a time with each of the others to see which one was preferred over the other by the most people, and then the one who wins the most of these pairings is the winner.
• The Schulze methode, a refinement of Condorcet devised in 1997, which uses a complex mathematical formula to compare each candidate's rankings with each of the others.

MTV, which provided Hill with a $30,000 grant for the project last year as a winner of its mtvU "Digital Incubator" competition, is planning to use Selectricity to allow viewers to vote for their preferences among a selection of music videos to be presented in a new program that will be airing in the next few weeks. Details are still being worked out with the network, Hill says.

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On a 'roll': MIT researchers devise new cell-sorting system

Capitalizing on a cell's ability to roll along a surface, MIT researchers have developed a simple, inexpensive system to sort different kinds of cells--a process that could result in low-cost tools to test for diseases such as cancer, even in remote locations.

Rohit Karnik, an MIT assistant professor of mechanical engineering and lead author of a paper on the new finding appearing last week in the journal Nano Letters, said the cell-sorting method was minimally invasive and highly innovative.

"It's a new discovery," he said. "Nobody has ever done anything like this before."

The method relies on the way cells sometimes interact with a surface (such as the wall of a blood vessel) by rolling along it. In the new device, a surface is coated with lines of a material that interacts with the cells, making it seem sticky to specific types of cells. The sticky lines are oriented diagonally to the flow of cell-containing fluid passing over the surface, so as certain kinds of cells respond to the coating they are nudged to one side, allowing them to be separated out.

Cancer cells, for example, can be separated from normal cells by this method, which could ultimately lead to a simple device for cancer screening. Stem cells also exhibit the same kind of selective response, so such devices could eventually be used in research labs to concentrate these cells for further study.

Normally, it takes an array of lab equipment and several separate steps to achieve this kind of separation of cells. This can make such methods impractical for widespread screening of blood samples in the field, especially in remote areas. "Our system is tailor-made for analysis of blood," Karnik said. In addition, some kinds of cells, including stem cells, are very sensitive to external conditions, so this system could allow them to be concentrated with much less damage than with conventional multistage lab techniques.

"If you're out in the field and you want to diagnose something, you don't want to have to do several steps," Karnik said. With the new system, "you can sort cells in a very simple way, without processing."

Now that the basic principle has been harnessed in the lab, Karnik estimates it may take up to two years to develop into a standard device that could be used for laboratory research purposes. Because of the need for extensive testing, development of a device for clinical use could take between five and 10 years, he estimated.

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Shell shock

An MIT materials scientist's research on sea snails has helped transform battery technology and may end the era when cell phones die if they're dropped and PDAs must be replaced if they get dunked in the tub.

Thanks to those sea snails and a eureka moment, Angela Belcher, Germeshausen Professor of Materials Science and Engineering and Biological Engineering, is developing smart nano-materials--hybrids of organic and inorganic components--beginning with a rechargeable, biologically based battery that looks like plastic food wrap.

Belcher's eureka moment occurred 10 years ago; it arose from her long, delighted fascination with abalone, the sea snail, and from her willingness to ask a wide-open question, "What if?"

Holding up an abalone shell before a visitor, Belcher describes the moment when the two threads--persistent interest and sudden insight--came together, forming the basis of her current research, which spans inorganic chemistry, materials chemistry, biochemistry, molecular biology and electrical engineering.

A seventh-generation Texan, Belcher began studying abalone when she entered the University of California, Santa Barbara, as a graduate student. (Abalone cling to California's coastal rocks.) Intrigued since childhood by pearls and pearl-making mollusks, she was impressed by the abalone's shell: it's 98 percent calcium carbonate--what we call chalk, only 3,000 times stronger.

"The abalone makes this amazing material out of a common mineral," she says.

As a doctoral student at Santa Barbara, Belcher had an office with an ocean view. Working on her dissertation, a study of how the abalone produces both its rough outer shell and its opalescent interior simultaneously, she could see whales and dolphins in the Pacific.

On the wall opposite her desk hung a huge periodic table.

"Suddenly, I wondered, what if we could assemble materials like the abalone does--but not be limited to one element? What if we could bond protein to other elements in the periodic table and grow new materials?" she says.

Belcher recalls she stood on her desk to get closer to the chart of 110 elements, and that she felt like running down the hall in excitement.

"It seemed so logical and easy. Shells had been self-assembling, manufacturing amazing materials for 500 million years," she says.

Belcher received her PhD in 1997 and came to MIT in 2002. She won a MacArthur "Genius" award in 2004 and was named Researcher of the Year by Scientific American in 2006.

Her eureka moment has launched a new chapter in bio-engineering; it has led to the development of smart new nano-materials, essential to advances in optics and electronics.

With MIT colleagues Paula Hammond, Bayer Professor of Chemical Engineering, and Yet-Ming Chiang, professor of materials science and engineering, Belcher grew the first biologically based, nano-scale rechargeable battery--the one that may end short-lived cell phones.

Belcher's MIT battery is comprised of a virus she and her colleagues engineered to latch itself to cobalt oxide. It does look like a clear film. Transparent, efficient, it could one day be poured onto the object it's powering, like a coat of energizing paint.

Fabricating viral films, Belcher says, may provide new pathways for organizing molecules to help create electronic, optical and magnetic materials.

And she keeps studying the ancient abalone for clues to those new pathways. She keeps a cache of abalone shells on her MIT desk.

"It builds exquisite materials. It's a very nice animal, " vegetarian Belcher notes, offering a shell to a guest.

(In her research, Belcher is careful to avoid harming or killing her subjects, who live in abalone condominiums. To get samples of their secretions to study, she inserts glass slides beneath their shells, rather than endanger them.)

Belcher still enjoys heady moments like the one in her oceanfront office, when delight makes her feel like running down the hall outside her lab in Building 16.

But her work at MIT is driven by a different question than the one that arose when she stood on her desk, scanning the periodic table, abalone shell in hand.

"Back then, I asked, 'What if? Wouldn't it be interesting if?'" she says. "Now, the questions are more like, 'What's the most efficient, useful material we could make?'"

Ultra-tiny computer chips, fuel cells, "smart" nanocrystal sensors--anything is possible with hybrid materials, she says.

"Abalone shells are self-assembling. What if we could make a material that is self-re-assembling? What if iPods and Blackberrys could genetically mend their own cracks? These devices get dropped; they break; what material can we make so they fix themselves?"

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MIT researchers demonstrate protective role of microRNA

Snippets of genetic material that have been linked to cancer also play a critical role in normal embryonic development in mice, according to a new paper from MIT cancer biologists.

The work, reported in the March 7 issue of Cell, shows that a family of microRNAs--short strands of genetic material--protect mouse cells during development and allow them to grow normally. But that protective role could backfire: The researchers theorize that when these microRNAs become overactive, they can help keep alive cancer cells that should otherwise die--providing another reason to target microRNAs as a treatment for cancer.

Discovered only a decade ago, microRNAs bind to messenger RNAs (mRNAs), preventing them from delivering protein assembly instructions, thereby inhibiting gene expression. The details of how microRNAs act are not yet fully understood.

"The scientific community is busy trying to understand what specific biological functions these microRNAs affect," said Andrea Ventura, lead author of the paper and postdoctoral associate in the Koch Institute for Integrative Cancer Research at MIT (formerly known as the Center for Cancer Research).

Ventura--who works in the laboratory of Tyler Jacks, director of the Koch Institute--and her colleagues studied the function of a family of microRNAs known as the miR-17~92 cluster.

Previous research has shown that the miR-17~92 cluster is overactive in some cancers, especially those of the lungs and B cells.

To better understand these microRNAs' role in cancer, the researchers decided to study their normal function. Knocking out microRNA genes and observing the effects can offer clues into how microRNA helps promote cancer when overexpressed.

They found that when miR-17~92 was knocked out in mice, the animals died soon after birth, apparently because their lungs were too small. Also, their B cells, a type of immune cell, died in an early stage of cell development.

This suggests that miR-17~92 is critical to the normal development of lung cells and B cells. In B cells, these microRNAs are likely acting to promote cell survival by suppressing a gene that induces cell death, said Ventura.

"Understanding why these things are happening provides important insight into how microRNAs affect tumorigenesis," he said.

The researchers theorize that when miR-17~92 becomes overactive in cancer cells, it allows cells that should undergo programmed cell death to survive.

Blocking microRNAs that have become overactive holds promise as a potential cancer treatment. Research is now being done on molecules that prevent microRNAs from binding to their target mRNA.

More work needs to be done to make these inhibitors into stable and deliverable drugs, but Ventura said it's possible it could be done in the near future.

The exact genes targeted by miR-17~92 are not known, but one strong suspect is a gene called Bim, which promotes cell death. However, a single microRNA can have many targets, so it's likely there are other genes involved.

The researchers also studied the effects of knocking out two other microRNA clusters that are closely related to miR-17~92 but located elsewhere in the genome.

They found that if the other two microRNA clusters are knocked out but miR-17~92 remains intact, the mice develop normally. However, if miR-17~92 and one of these similar clusters are removed, the mice die before birth, suggesting there is some kind of synergistic effect between these microRNA families.

Other MIT authors of the paper are Amanda Young, graduate student in biology; Monte Winslow, postdoctoral fellow in the Center for Cancer Research (CCR); Laura Lintault, staff affiliate in the CCR; Alex Meissner, faculty member at the Broad Institute of MIT and Harvard; Jamie Newman, graduate student in biology; Denise Crowley, staff affiliate at the CCR; Rudolf Jaenisch, professor of biology and member of the Whitehead Institute for Biomedical Research; Phillip Sharp, MIT Institute Professor; and Jacks, who is also a professor of biology.

The research was funded by the National Institutes of Health and the National Cancer Institute.

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MIT develops energy-efficient microchip

Researchers at MIT and Texas Instruments have unveiled a new chip design for portable electronics that can be up to 10 times more energy-efficient than present technology. The design could lead to cell phones, implantable medical devices and sensors that last far longer when running from a battery.

The innovative design will be presented Feb. 5 at the International Solid-State Circuits Conference in San Francisco by Joyce Kwong, a graduate student in MIT's Department of Electrical Engineering and Computer Science (EECS).

Kwong carried out the project with MIT colleagues Anantha Chandrakasan, the Joseph F. and Nancy P. Keithley Professor of Electrical Engineering, and EECS graduate students Yogesh Ramadass and Naveen Verma. Their Texas Instruments (TI) collaborators are Markus Koesler, Korbinian Huber and Hans Moormann. The team demonstrated the ultra-low-power design techniques on TI's MSP430, a widely used microcontroller. The work was conducted at the MIT Microsystems Technology Laboratories, which Chandrakasan directs.

The key to the improvement in energy efficiency was to find ways of making the circuits on the chip work at a voltage level much lower than usual, Chandrakasan explains. While most current chips operate at around one volt, the new design works at just 0.3 volts.

Reducing the operating voltage, however, is not as simple as it might sound, because existing microchips have been optimized for many years to operate at the higher standard-voltage level. “Memory and logic circuits have to be redesigned to operate at very low power supply voltages,” Chandrakasan says.

One key to the new design, he says, was to build a high-efficiency DC-to-DC converter-which reduces the voltage to the lower level-right on the same chip, reducing the number of separate components. The redesigned memory and logic, along with the DC-to-DC converter, are all integrated to realize a complete system-on-a-chip solution.

One of the biggest problems the team had to overcome was the variability that occurs in typical chip manufacturing. At lower voltage levels, variations and imperfections in the silicon chip become more problematic. “Designing the chip to minimize its vulnerability to such variations is a big part of our strategy,” Chandrakasan says.

So far the new chip is a proof of concept. Commercial applications could become available “in five years, maybe even sooner, in a number of exciting areas,” Chandrakasan says. For example, portable and implantable medical devices, portable communications devices and networking devices could be based on such chips, and thus have greatly increased operating times. There may also be a variety of military applications in the production of tiny, self-contained sensor networks that could be dispersed in a battlefield.

In some applications, such as implantable medical devices, the goal is to make the power requirements so low that they could be powered by “ambient energy,” Chandrakasan says-using the body's own heat or movement to provide all the needed power. In addition, the technology could be suitable for body area networks or wirelessly enabled body sensor networks.

“Together, TI and MIT have pioneered many advances that lower power in electronic devices, and we are proud to be part of this revolutionary, world-class university research,” said Dr. Dennis Buss, chief scientist at Texas Instruments. “These design techniques show great potential for TI future low-power integrated circuit products and applications including wireless terminals, battery-operated instrumentation, sensor networks and medical electronics.”

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