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Monday, August 8th, 2016
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| 12:00a |
Analyzing dynamic proteins Cell membranes are fluid, chaotic structures composed mainly of fatty molecules. Forming critical barriers between cells’ contents and their surroundings, these membranes also contain important proteins that allow cells to communicate with the outside world.
Such membrane-bound proteins are difficult to study because they change their structure when removed from membranes and therefore must be analyzed in place. Mei Hong, an MIT professor of chemistry who has spent much of her career studying membranes and the proteins embedded in them, embraces that complexity.
“You have to be willing to spend time measuring under conditions where the signals are not very pretty, but it tells you a lot. Those dynamics are something that a lot of people don’t quite want to deal with,” she says. “But it’s extremely important because so many drug targets are membrane proteins.”
Hong, who joined MIT’s faculty in 2014 as a tenured professor after 15 years at Iowa State University, has developed many novel techniques that use nuclear magnetic resonance (NMR) spectroscopy to reveal precise information about the structure of these complicated proteins.
“My lab’s goal is to really provide molecular insight, using NMR spectroscopy to answer a lot of structural, dynamic, and mechanistic questions,” she says.
Membrane dynamics
Hong grew up in China and attended Fudan University in Shanghai. Interested in both sciences and humanities, she began studying economics, a popular choice in China in the late 1980s. However, after a year of economics, Hong realized it wasn’t a good fit and switched to chemistry, which she found appealing because “it’s centrally positioned between physics and biology, so you can branch out in both directions,” she says.
She transferred to Mount Holyoke College in Massachusetts for her last two years of college, where she worked in a physical chemistry lab using laser spectroscopy, which uses high-energy laser pulses to study atoms and molecules over extremely short timescales.
From there, she went to the University of California at Berkeley to pursue a PhD in chemistry. She expected to continue studying laser spectroscopy, but near the end of a tour of Berkeley’s physical chemistry labs, she happened to visit a lab that focused on NMR spectroscopy. Though she had never used it before, NMR intrigued her.
“At the last stop, I decided to switch to NMR spectroscopy. It was a good decision,” Hong says. “A lot of students come to graduate school and do something that they have been exposed to before. It’s rare to do something completely different, but I thought the nuclear spin Hamiltonians in NMR seemed more interesting.”
For her PhD thesis, Hong used NMR to study how phospholipids, the major building blocks of membranes, take on their shapes. These molecules consist of fatty tails that face inward and protein heads that face outward. This research helped prepare her for her future work studying proteins embedded in cell membranes.
“It did lay a lot of groundwork for thinking later on about membrane proteins. You need to know the lipid membrane environment, their conformation, their dynamics, the feel for it,” she says.
After finishing her PhD, she came to MIT as a postdoc in chemistry professor Robert Griffin’s lab, where she developed techniques for measuring torsion angles in proteins, which help to reveal the structure of the proteins’ amino acid backbone. She then taught at the University of Massachusetts for a couple of years before going to Iowa State University.
New measurements
Over her career, Hong has developed several NMR techniques that allow her to better understand the structure of membrane-embedded proteins and other biological molecules. NMR, which uses the magnetic properties of atomic nuclei to reveal the structures of the molecules containing those nuclei, often relies on labeling the proteins of interest with an isotope of carbon known as carbon-13. Interactions between the carbon-13 atoms generate signals that allow scientists to interpret the proteins’ structure.
Early in Hong’s career, NMR researchers were labeling just a few carbon atoms per protein, which limited the information content of each measurement. Hong came up with a way to selectively label more of the carbon atoms — but not so many as to make the carbon-carbon interactions too numerous and difficult to interpret.
She also devised new ways to measure how deeply a protein is inserted into a membrane, to determine the orientation of a protein within a membrane, and to measure longer distances between atoms of a protein.
Among the proteins Hong has studied using these techniques is the influenza M2 protein, which forms a proton channel and is embedded in membrane that forms the influenza viral envelope. The influenza drugs amantadine and rimantadine interfere with the M2 protein, preventing the virus from infecting host cells.
“We did a lot of studies to figure out how drugs bind to it and what’s the drug-bound structure,” Hong says.
She is now also studying the structure and dynamics of virus fusion proteins, which are embedded in the viral envelope and help viruses to fuse to the cells they are infecting. “If you can inhibit these fusion proteins then you could stop the very first entry step, which makes them good drug targets,” she says. | | 10:59a |
Study finds brain connections key to reading A new study from MIT reveals that a brain region dedicated to reading has connections for that skill even before children learn to read.
By scanning the brains of children before and after they learned to read, the researchers found that they could predict the precise location where each child’s visual word form area (VWFA) would develop, based on the connections of that region to other parts of the brain.
Neuroscientists have long wondered why the brain has a region exclusively dedicated to reading — a skill that is unique to humans and only developed about 5,400 years ago, which is not enough time for evolution to have reshaped the brain for that specific task. The new study suggests that the VWFA, located in an area that receives visual input, has pre-existing connections to brain regions associated with language processing, making it ideally suited to become devoted to reading.
“Long-range connections that allow this region to talk to other areas of the brain seem to drive function,” says Zeynep Saygin, a postdoc at MIT’s McGovern Institute for Brain Research. “As far as we can tell, within this larger fusiform region of the brain, only the reading area has these particular sets of connections, and that’s how it’s distinguished from adjacent cortex.”
Saygin is the lead author of the study, which appears in the Aug. 8 issue of Nature Neuroscience. Nancy Kanwisher, the Walter A. Rosenblith Professor of Brain and Cognitive Sciences and a member of the McGovern Institute, is the paper’s senior author.
Specialized for reading
The brain’s cortex, where most cognitive functions occur, has areas specialized for reading as well as face recognition, language comprehension, and many other tasks. Neuroscientists have hypothesized that the locations of these functions may be determined by prewired connections to other parts of the brain, but they have had few good opportunities to test this hypothesis.
Reading presents a unique opportunity to study this question because it is not learned right away, giving scientists a chance to examine the brain region that will become the VWFA before children know how to read. This region, located in the fusiform gyrus, at the base of the brain, is responsible for recognizing strings of letters.
Children participating in the study were scanned twice — at 5 years of age, before learning to read, and at 8 years, after they learned to read. In the scans at age 8, the researchers precisely defined the VWFA for each child by using functional magnetic resonance imaging (fMRI) to measure brain activity as the children read. They also used a technique called diffusion-weighted imaging to trace the connections between the VWFA and other parts of the brain.
The researchers saw no indication from fMRI scans that the VWFA was responding to words at age 5. However, the region that would become the VWFA was already different from adjacent cortex in its connectivity patterns. These patterns were so distinctive that they could be used to accurately predict the precise location where each child’s VWFA would later develop.
Although the area that will become the VWFA does not respond preferentially to letters at age 5, Saygin says it is likely that the region is involved in some kind of high-level object recognition before it gets taken over for word recognition as a child learns to read. Still unknown is how and why the brain forms those connections early in life.
Pre-existing connections
Kanwisher and Saygin have found that the VWFA is connected to language regions of the brain in adults, but the new findings in children offer strong evidence that those connections exist before reading is learned, and are not the result of learning to read, according to Stanislas Dehaene, a professor and the chair of experimental cognitive psychology at the College de France, who wrote a commentary on the paper for Nature Neuroscience.
“To genuinely test the hypothesis that the VWFA owes its specialization to a pre-existing connectivity pattern, it was necessary to measure brain connectivity in children before they learned to read,” wrote Dehaene, who was not involved in the study. “Although many children, at the age of 5, did not have a VWFA yet, the connections that were already in place could be used to anticipate where the VWFA would appear once they learned to read.”
The MIT team now plans to study whether this kind of brain imaging could help identify children who are at risk of developing dyslexia and other reading difficulties.
“It’s really powerful to be able to predict functional development three years ahead of time,” Saygin says. “This could be a way to use neuroimaging to try to actually help individuals even before any problems occur.” | | 11:00a |
Neutrino search finds no evidence of “hidden” particle An exhaustive search for a ghostly subatomic particle called the sterile neutrino has come up empty, weakening the case for its existence.
Scientists from MIT and the University of Wisconsin at Madison, along with 40 other institutions, report today in Physical Review Letters that after analyzing 20,000 neutrinos detected over the span of a year at the IceCube Neutrino Observatory at the South Pole, they were unable to observe any sign of sterile, or “hidden,” neutrinos.
Sterile neutrinos are hypothetical particles that may behave in ways that cannot be explained by the standard rules of physics. They are thought to have no interactions and thus to be completely “sterile” to physical matter — a quality that allows these particles to stream uninhibited and undetected through the universe. If they exist, scientists believe sterile neutrinos may be at the root of a number of cosmological mysteries, including dark matter, which makes up roughly one-third of the matter in the universe but somehow does not emit or reflect light.
While there have been hints of sterile neutrinos in recent years, scientists have yet to detect these particles directly, as they are incredibly elusive and are thought to interact only with gravity. Scientists hypothesize that sterile neutrinos should manifest themselves through the interactions of ordinary neutrinos — the second-most abundant particle in the universe, next to photons, that stream through every cell in our bodies, by the billions, without any effect.
These ghostly particles come in three “flavors,” or types: electron, muon, and tau neutrinos. Each flavor can transform into the other, in a phenomenon scientists call neutrino oscillation. If these ordinary neutrinos can also transform into a fourth flavor — the sterile neutrino — the total number of detectable neutrinos should dip, as sterile neutrinos are virtually invisible.
Scientists looked for such telltale dips using the IceCube Neutrino Observatory, a huge, cubic-kilometer particle detector buried deep under the ice at the South Pole. The detector consists of more than 5,000 light sensors, suspended from 86 strings that stretch down through the ice to the Antarctic floor, 2,450 meters deep — about the vertical distance of five Empire State Buildings.
While neutrinos cannot be observed directly, when they pass through ice, they produce electrically charged secondary particles that in turn emit light. Scientists can analyze the way in which IceCube’s sensors pick up this light, to determine the number of neutrinos and the angle at which they are passing through.
As they report in the new paper, the scientists, including MIT professor of physics Janet Conrad, postdoc Carlos Argüelles, graduate student Gabriel Collin, and former graduate student Ben Jones, collected and analyzed data over an entire year. Throughout 2011, the team detected 20,000 neutrinos.
“Every time IceCube sees one neutrino, there are a million other things next to it,” says Argüelles, who with the MIT team helped to process the data and develop the neutrino analysis. “We have to disentangle the one neutrino from all of this, and of those, we have to have a very good cleaning process to make certain they are real neutrinos. So it’s a very difficult thing.”
Once the researchers identified the neutrinos amid the noise, they counted them up, then organized them according to the energies at which they were detected. They then compared their results with a model that they developed, which predicts the number and energy of neutrinos they should see in the absence of sterile neutrinos. As it turns out, the neutrinos they did detect were an almost perfect match with their predictions, with no dips in the data that would indicate sterile neutrinos in the mix.
“We had a very good chance of seeing these particles, but they just weren’t there,” Collin says. “It’s made the case for sterile neutrinos weaker.”
This doesn’t necessarily mean the hypothesis of a fourth neutrino — and a completely new fundamental particle — is completely dead. The researchers compared their neutrino observations with theoretical predictions made by other scientists. From their observations, the team was able to rule out a number of possible scenarios that they determined, with 99 percent confidence, to be impossible. That is, if sterile neutrinos exist, they should not have the mass, energy, and other parameters that are proposed in these scenarios. However, the researchers were unable to exclude a small number of other predictions, based on their observations.
“We have identified where sterile neutrinos should not be, and we signaled a space where they can still survive,” Argüelles says. “We have five years more of data to analyze, which means we can do a better job in looking for this particle, and we are working hard on that.”
This research was funded, in part, by the National Science Foundation. | | 11:00a |
Toward practical quantum computers Quantum computers are largely hypothetical devices that could perform some calculations much more rapidly than conventional computers can. Instead of the bits of classical computation, which can represent 0 or 1, quantum computers consist of quantum bits, or qubits, which can, in some sense, represent 0 and 1 simultaneously.
Although quantum systems with as many as 12 qubits have been demonstrated in the lab, building quantum computers complex enough to perform useful computations will require miniaturizing qubit technology, much the way the miniaturization of transistors enabled modern computers.
Trapped ions are probably the most widely studied qubit technology, but they’ve historically required a large and complex hardware apparatus. In today’s Nature Nanotechnology, researchers from MIT and MIT Lincoln Laboratory report an important step toward practical quantum computers, with a paper describing a prototype chip that can trap ions in an electric field and, with built-in optics, direct laser light toward each of them.
“If you look at the traditional assembly, it’s a barrel that has a vacuum inside it, and inside that is this cage that’s trapping the ions. Then there’s basically an entire laboratory of external optics that are guiding the laser beams to the assembly of ions,” says Rajeev Ram, an MIT professor of electrical engineering and one of the senior authors on the paper. “Our vision is to take that external laboratory and miniaturize much of it onto a chip.”
Caged in
The Quantum Information and Integrated Nanosystems group at Lincoln Laboratory was one of several research groups already working to develop simpler, smaller ion traps known as surface traps. A standard ion trap looks like a tiny cage, whose bars are electrodes that produce an electric field. Ions line up in the center of the cage, parallel to the bars. A surface trap, by contrast, is a chip with electrodes embedded in its surface. The ions hover 50 micrometers above the electrodes.
Cage traps are intrinsically limited in size, but surface traps could, in principle, be extended indefinitely. With current technology, they would still have to be held in a vacuum chamber, but they would allow many more qubits to be crammed inside.
“We believe that surface traps are a key technology to enable these systems to scale to the very large number of ions that will be required for large-scale quantum computing,” says Jeremy Sage, who together with John Chiaverini leads Lincoln Laboratory’s trapped-ion quantum-information-processing project. “These cage traps work very well, but they really only work for maybe 10 to 20 ions, and they basically max out around there.”
Performing a quantum computation, however, requires precisely controlling the energy state of every qubit independently, and trapped-ion qubits are controlled with laser beams. In a surface trap, the ions are only about 5 micrometers apart. Hitting a single ion with an external laser, without affecting its neighbors, is incredibly difficult; only a few groups had previously attempted it, and their techniques weren’t practical for large-scale systems.
Getting onboard
That’s where Ram’s group comes in. Ram and Karan Mehta, an MIT graduate student in electrical engineering and first author on the new paper, designed and built a suite of on-chip optical components that can channel laser light toward individual ions. Sage, Chiaverini, and their Lincoln Lab colleagues Colin Bruzewicz and Robert McConnell retooled their surface trap to accommodate the integrated optics without compromising its performance. Together, both groups designed and executed the experiments to test the new system.
“Typically, for surface electrode traps, the laser beam is coming from an optical table and entering this system, so there’s always this concern about the beam vibrating or moving,” Ram says. “With photonic integration, you’re not concerned about beam-pointing stability, because it’s all on the same chip that the electrodes are on. So now everything is registered against each other, and it’s stable.”
The researchers’ new chip is built on a quartz substrate. On top of the quartz is a network of silicon nitride “waveguides,” which route laser light across the chip. Above the waveguides is a layer of glass, and on top of that are the niobium electrodes. Beneath the holes in the electrodes, the waveguides break into a series of sequential ridges, a “diffraction grating” precisely engineered to direct light up through the holes and concentrate it into a beam narrow enough that it will target a single ion, 50 micrometers above the surface of the chip.
Prospects
With the prototype chip, the researchers were evaluating the performance of the diffraction gratings and the ion traps, but there was no mechanism for varying the amount of light delivered to each ion. In ongoing work, the researchers are investigating the addition of light modulators to the diffraction gratings, so that different qubits can simultaneously receive light of different, time-varying intensities. That would make programming the qubits more efficient, which is vital in a practical quantum information system, since the number of quantum operations the system can perform is limited by the “coherence time” of the qubits.
“As far as I know, this is the first serious attempt to integrate optical waveguides in the same chip as an ion trap, which is a very significant step forward on the path to scaling up ion-trap quantum information processors [QIP] to the sort of size which will ultimately contain the number of qubits necessary for doing useful QIP,” says David Lucas, a professor of physics at Oxford University. “Trapped-ion qubits are well-known for being able to achieve record-breaking coherence times and very precise operations on small numbers of qubits. Arguably, the most important area in which progress needs to be made is technologies which will enable the systems to be scaled up to larger numbers of qubits. This is exactly the need being addressed so impressively by this research.”
“Of course, it's important to appreciate that this is a first demonstration,” Lucas adds. “But there are good prospects for believing that the technology can be improved substantially. As a first step, it's a wonderful piece of work.” | | 3:00p |
Research by MIT undergrad helps crack chemical mystery When Martin McLaughlin ’15 arrived at MIT as a freshman in the fall of 2011, he had a plan in mind. McLaughlin wanted to work in the lab of Catherine Drennan, an MIT professor of biology and chemistry, and Howard Hughes Medical Institute (HHMI) investigator, who uses X-ray crystallography to study proteins.
And so McLaughlin, with Drennan’s approval, started doing research in addition to taking a normal course load, as part of MIT’s Undergraduate Research Opportunities Program (UROP). The project he focused on was challenging: figuring out precisely how an enzyme called lipoyl synthase (LipA) acts as a catalyst in reactions that produce lipoic acid. Our metabolisms need lipoic acid to convert food into energy, but the process through which it is naturally produced has been unclear.
Specifically, McLaughlin, as part of a larger research team featuring scientists from MIT and Penn State University, was trying to understand one thing above all. LipA inserts sulfur into the reaction that produces lipoic acid. But where does the sulfur come from in the first place?
Now McLaughlin’s work has produced a notable answer, in a paper published today. LipA, in an unusual chemical arrangement, removes the sulfur from an iron-sulfur cluster that it already contains. In effect, LipA “cannibalizes” itself to catalyze the reaction that produces lipoic acid.
“The enzyme is actually cannibalizing its own cluster, pulling it out and putting in sulfur,” Drennan explains. “The definition of a catalyst is that it’s not being consumed. So this goes against all the fundamentals really, that the enzyme would just destroy itself.” Yet that is what the results show.
The finding could have long-term applications in medicine and agriculture, and is also generally significant within biochemistry research, since solving the LipA mystery suggests a means by which other enzymes use sulfur in similar settings.
“It just wasn’t understood how nature inserts sulfur into unactivated carbon centers,” says Squire Booker, a professor of chemistry and of biochemistry and molecular biology at Penn State, and an HHMI investigator, whose own research group made essential contributions to the finding. Booker, who as it happens received his PhD from MIT in 1994, adds: “We knew how the process takes place for incorporation of oxygen, for example. But we didn’t know how the sulfur goes in, and we didn’t know what the source of the sulfur was.”
The new paper, “Crystallographic snapshots of sulfur insertion by lipoyl synthase,” is being published today in the Proceedings of the National Academies of Science (PNAS). The authors are McLaughlin; Nicholas D. Lanz, a graduate student at Penn State; Peter J. Goldman, a former Drennan lab graduate student; Kyung-Hoon Lee, a researcher in Booker’s lab; Booker; and Drennan.
Arrive at MIT on Thursday; start research on Monday
Remarkably, McLaughlin’s work on LipA predates his time at MIT. McLaughlin was a student at State College High School in State College, Pennsylvania, and already interested in science, when he decided to see if he could volunteer in a lab at nearby Penn State. Before long, McLaughlin had connected with Booker, who was amenable to showing high school students the research ropes.
“Squire said, ‘Sure, you can work in my lab,’” McLaughlin recounts. “So we met and he told me I’d be setting up crystallization trials in an anaerobic chamber. I had no idea what that meant.”
It meant McLaughlin would be using a biology “glove box” — putting on gloves and reaching into a small, oxygen-free box to try to crystallize proteins. That is, researchers put proteins in solutions which evaporate, and under certain circumstances the proteins will crystallize in a way that allows them to be further analyzed.
“My job was to set up all of these crystallization experiments,” says McLaughlin. “I got lucky and got crystals for a few of those proteins, and one of them was lipoyl synthase.”
“Martin really was somebody very different,” Booker says. “He was aggressive, in a good way, incredibly motivated. He was so excited about science. Within a week, he said, ‘I’m going to need a key to the lab.’”
By the time he graduated from high school, McLaughlin had become proficient in doing the lab work, and had also gotten accepted to MIT. Booker and Drennan were already collaborating on the project, so Booker, acting as a catalyst, suggested to McLaughlin he could work on the sulfur problem with Drennan at MIT.
“Martin emailed me that he’s coming to MIT for undergrad, and asked if he could work in my research group,” Drennan recalls. “And I said ‘Absolutely.’ He said, ‘Well, okay, I might need a little time to settle into MIT.’ So I’m thinking sophomore year, or something. Then he said, ‘I arrive on Thursday, I unpack on Friday. Could I wait until the following Monday to start in the lab?’ Which is a week before classes start. He shows up in the lab apologizing for how long it took him to arrive.”
In the meantime, an important advance had been made by Nicholas Lanz, a Penn State graduate student, who found that in certain circumstances, molecules containing carbon form a bond with iron-sulfur clusters in such a way that an iron atom disappears — leaving an “extra” sulfur atom available for another reaction. In a sense, this showed that the conditions for the chemical cannibalization existed.
“For us, this was an important discovery, because it showed that the iron-sulfur cluster actually can be cannibalized in the reaction,” Booker says. “We saw it.”
Lanz prepared a version of this molecule and turned it over to McLaughlin, who then crystallized it and was able to perform the analysis of the structures and mechanisms showing that LipA, a bit counterintuitively, was indeed using its own sulfur atoms to help produce lipoic acid.
“Crystallography is a little unusual in that it’s very difficult to tell if you’re going to get any interesting results until you get them,” McLaughlin says. “You spend months or years working on getting a single crystal. I always hoped it would work, but I definitely wouldn’t say I knew it would work. It was an interesting enough system that I was willing to spend years on it, if that’s what was needed.”
Notably, when McLaughlin started at MIT, Drennan adds, her lab workers had been trying to get high-quality crystals of LipA for many years. “My graduate students had all but given up, and then Martin arrived,” she says.
No boring conversations allowed
The researchers emphasize that there are still many things about LipA that must be studied further — including how the iron-sulfur clusters get rebuilt after being cannibalized. That said, there are many potential applications that could come from understanding the natural production of lipoic acid.
“Lipoic acid is an incredibly important cofactor,” Booker says. “You can’t have aerobic life without lipoic acid.”
A synthetic version of lipoic acid is currently manufactured and used as a medical supplement in some countries, to combat diabetes, among other conditions. But it is also possible to envision drugs that target the reaction in order to stop multiple diseases, including some cancers and tuberculosis. (The molecule used in the research came from a tuberculosis bacterium, in fact.) Lipoic acid is also a livestock feed supplement manufactured in a “costly multistep synthesis,” the researchers point out in the paper, which could become simplified.
For now, the researchers are pleased to have made the current advance, and McLaughlin — who is now a doctoral student at the University of Illinois — emphasizes his good fortune in having been in the middle of the LipA story.
“I’m so grateful to Squire and to Cathy,” McLaughlin says. “They let a high school and undergraduate student work on some of their coolest projects. Both of those labs are great places to become a scientist.” And, he adds: “MIT is a very intellectually rich environment. It’s very difficult to have a boring conversation at MIT.”
The research was supported by the National Institutes of Health, the National Science Foundation, the Meryl and Stewart Robertson UROP Fund, the MIT Energy Initiative, and the DeFlorez Endowment Fund. The work was also based on research supported by the National Institute of General Medical Sciences, and the U.S. Department of Energy. |
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