Category Archives: Life Sciences

Complex Organic Molecules Discovered in Infant Star System

The new discovery hints that the building blocks of the chemistry of life are universal.


For the first time, astronomers have detected the presence of complex organic molecules, the building blocks of life, in a protoplanetary disc surrounding a young star. The discovery, made with the Atacama Large Millimeter/submillimeter Array (ALMA), reaffirms that the conditions that spawned the Earth and Sun are not unique in the Universe. The results are published in the 9 April 2015 issue of the journal Nature.

Artist impression of the protoplanetary disc surrounding the young star MWC 480. ALMA has detected the complex organic molecule methyl cyanide in the outer reaches of the disc in the region where comets are believed to form. This is another indication that complex organic chemistry, and potentially the conditions necessary for life, is universal. Credit: B. Saxton (NRAO/AUI/NSF)
Artist impression of the protoplanetary disc surrounding the young star MWC 480. ALMA has detected the complex organic molecule methyl cyanide in the outer reaches of the disc in the region where comets are believed to form. This is another indication that complex organic chemistry, and potentially the conditions necessary for life, is universal.
Credit:
B. Saxton (NRAO/AUI/NSF)

The new ALMA observations reveal that the protoplanetary disc surrounding the young star MWC 480 [1] contains large amounts of methyl cyanide (CH3CN), a complex carbon-based molecule. There is enough methyl cyanide around MWC 480 to fill all of Earth’s oceans.

Both this molecule and its simpler cousin hydrogen cyanide (HCN) were found in the cold outer reaches of the star’s newly formed disc, in a region that astronomers believe is analogous to the Kuiper Belt — the realm of icy planetesimals and comets in our own Solar System beyond Neptune.

Comets retain a pristine record of the early chemistry of the Solar System, from the period of planet formation. Comets and asteroids from the outer Solar System are thought to have seeded the young Earth with water and organic molecules, helping set the stage for the development of primordial life.

“Studies of comets and asteroids show that the solar nebula that spawned the Sun and planets was rich in water and complex organic compounds,” noted Karin Öberg, an astronomer with the Harvard-Smithsonian Center for Astrophysics in Cambridge, Massachusetts, USA, and lead author of the new paper.

“We now have even better evidence that this same chemistry exists elsewhere in the Universe, in regions that could form solar systems not unlike our own.” This is particularly intriguing, Öberg notes, since the molecules found in MWC 480 are also found in similar concentrations in the Solar System’s comets.

The star MWC 480, which is about twice the mass of the Sun, is located 455 light-years away in the Taurus star-forming region. Its surrounding disc is in the very early stages of development — having recently coalesced out of a cold, dark nebula of dust and gas. Studies with ALMA and other telescopes have yet to detect any obvious signs of planet formation in it, although higher resolution observations may reveal structures similar to HL Tauri, which is of a similar age.

Astronomers have known for some time that cold, dark interstellar clouds are very efficient factories for complex organic molecules — including a group of molecules known as cyanides. Cyanides, and most especially methyl cyanide, are important because they contain carbon–nitrogen bonds, which are essential for the formation of amino acids, the foundation of proteins and the building blocks of life.

Until now, it has remained unclear, however, if these same complex organic molecules commonly form and survive in the energetic environment of a newly forming solar system, where shocks and radiation can easily break chemical bonds.

By exploiting ALMA’s remarkable sensitivity [2] astronomers can see from the latest observations that these molecules not only survive, but flourish.

Importantly, the molecules ALMA detected are much more abundant than would be found in interstellar clouds. This tells astronomers that protoplanetary discs are very efficient at forming complex organic molecules and that they are able to form them on relatively short timescales [3].

As this system continues to evolve, astronomers speculate that it’s likely that the organic molecules safely locked away in comets and other icy bodies will be ferried to environments more nurturing to life.

“From the study of exoplanets, we know the Solar System isn’t unique in its number of planets or abundance of water,” concluded Öberg. “Now we know we’re not unique in organic chemistry. Once more, we have learnt that we’re not special. From a life in the Universe point of view, this is great news.”

Notes
[1] This star is only about one million years old. By comparison the Sun is more than four billion years old. The name MWC 480 refers to the Mount Wilson Catalog of B and A stars with bright hydrogen lines in their spectra.

[2] ALMA is able to detect the faint millimetre-wavelength radiation that is naturally emitted by molecules in space. For these most recent observations, the astronomers used only a portion of ALMA’s 66 antennas when the telescope was in its lower-resolution configuration. Further studies of this and other protoplanetary discs with ALMA’s full capabilities will reveal additional details about the chemical and structural evolution of stars and planets.

[3] This rapid formation is essential to outpace the forces that would otherwise break the molecules apart. Also, these molecules were detected in a relatively serene part of the disc, roughly 4.5 to 15 billion kilometres from the central star. Though very distant by Solar System standards, in MWC 480’s scaled-up dimensions, this would be squarely in the comet-forming zone.

Source: ESO

 

Stanford researchers solve the mystery of the dancing droplets

Years of research satisfy a graduate student’s curiosity about the molecular minuet he observed among drops of ordinary food coloring.

BY TOM ABATE


A puzzling observation, pursued through hundreds of experiments, has led Stanford researchers to a simple yet profound discovery: Under certain circumstances, droplets of fluid will move like performers in a dance choreographed by molecular physics.

“These droplets sense one another, they move and interact, almost like living cells,” said Manu Prakash, an assistant professor of bioengineering and senior author of an article published in Nature.

The unexpected findings may prove useful in semiconductor manufacturing and self-cleaning solar panels, but what truly excites Prakash is that the discovery resulted from years of persistent effort to satisfy a scientific curiosity.

Video: Stanford researchers solve the mystery of the dancing droplets

The research began in 2009 when Nate Cira, then an undergraduate at the University of Wisconsin, was doing an unrelated experiment. In the course of that experiment Cira deposited several droplets of food coloring onto a sterilized glass slide and was astonished when they began to move.

Cira replicated and studied this phenomenon alone for two years until he became a graduate student at Stanford, where he shared this curious observation with Prakash. The professor soon became hooked by the puzzle, and recruited a third member to the team: Adrien Benusiglio, a postdoctoral scholar in the Prakash Lab.

Together they spent three years performing increasingly refined experiments to learn how these tiny droplets of food coloring sense one another and move. In living cells these processes of sensing and motility are known as chemotaxis.

“We’ve discovered how droplets can exhibit behaviors akin to artificial chemotaxis,” Prakash said.

As the Nature article explains, the critical fact was that food coloring is a two-component fluid. In such fluids, two different chemical compounds coexist while retaining separate molecular identities

The droplets in this experiment consisted of two molecular compounds found naturally in food coloring: water and propylene glycol.

The researchers discovered how the dynamic interactions of these two molecular components enabled inanimate droplets to mimic some of the behaviors of living cells.

Surface tension and evaporation

Essentially, the droplets danced because of a delicate balance between surface tension and evaporation.

Evaporation is easily understood. On the surface of any liquid, some molecules convert to a gaseous state and float away.

Surface tension is what causes liquids to bead up. It arises from how tightly the molecules in a liquid bind together.

Water evaporates more quickly than propylene glycol. Water also has a higher surface tension.  These differences create a tornado-like flow inside the droplets, which not only allows them to move but also allows a single droplet to sense its neighbors.

To understand the molecular forces involved, imagine shrinking down to size and diving inside a droplet.

There, water and propylene glycol molecules try to remain evenly distributed but differences in evaporation and surface tension create turmoil within the droplet.

On the curved dome of each droplet, water molecules become gaseous and float away faster than their evaporation-averse propylene glycol neighbors.

This evaporation happens more readily on the thin lower edges of the domed droplet, leaving excess of propylene glycol there. Meanwhile, the peak of the dome has a higher concentration of water.

The water at the top exerts its higher surface tension to pull the droplet tight so it doesn’t flatten out. This tugging causes a tumbling molecular motion inside the droplet. Thus surface tension gets the droplet ready to roll.

Evaporation determines the direction of that motion. Each droplet sends aloft gaseous molecules of water like a radially emanating signal announcing the exact location of any given droplet. The droplets converge where the signal is strongest.

So evaporation provided the sensing mechanism and surface tension the pull to move droplets together in what seemed to the eye to be a careful dance.

Rule for two-component fluids

The researchers experimented with varied proportions of water and propylene glycol. Droplets that were 1 percent propylene glycol (PG) to 99 percent water exhibited much the same behavior as droplets that were two-thirds PG to just one-third water.

Based on these experiments the paper describes a “universal rule” to identify any two-component fluids that will demonstrate sensing and motility.

Adding colors to the mixtures made it easier to tell how the droplets of different concentrations behaved and created some visually striking results.

In one experiment, a droplet with more propylene glycol seems to chase a droplet with more water. In actuality, the droplet with more water exerts a higher surface tension tug, pulling the propylene droplet along.

In another experiment, researchers showed how physically separated droplets could align themselves using ever-so-slight signals of evaporation.

In a third experiment they used Sharpie pens to draw black lines on glass slides. The lines changed the surface of the slide and created a series of catch basins. The researchers filled each basin with fluids of different concentrations to create a self-sorting mechanism. Droplets bounced from reservoir to reservoir until they sensed the fluid that matched their concentration and merged with that pool.

What started as a curiosity-driven project may also have many practical implications.

The deep physical understanding of two component fluids allows the researchers to predict which fluids and surfaces will show these unusual effects. The effect is present on a large number of common surfaces and can be replicated with a number of chemical compounds.

“If necessity is the mother of invention, then curiosity is the father,” Prakash observed.

Source: Stanford News

Ant-Man possible? Scientists shrink ants to study mechanisms that control DNA expression

By shrinking ants to sizes smaller than exist in nature, biologists present a useful model for understanding how environmental factors can influence DNA expression to create a range of outcomes.

This may not be exactly what the Marvel’s Ant-Man story has but still close enough to be amazing! 

BY BJORN CAREY


In the pages of Marvel comic books, Ant-Man manipulates fictional subatomic particles in order to shrink and fight crime as one of Earth’s mightiest heroes.

In real life, a team of biologists has now achieved similar shrinking results by manipulating ants’ DNA. The work won’t produce any superpowers, but it presents a useful model for understanding how environmental factors can influence DNA expression to create a range of outcomes in a population.

The work is published online in the journal Nature Communications. Sebastian Alvarado, a postdoctoral fellow at Stanford, conducted the research as a graduate student at McGill University, working alongside fellow graduate student Rajendhran Rajakumar, and professors Ehab Abouheif and Moshe Szyf, all of McGill.

 

Video : Stanford researcher explains the science behind Ant-Man

The experiment was designed as a means to study variation in quantitative traits. These are individual qualities, such as height or body weight, that can naturally vary across a defined range in a population. This variation is usually driven by the degree that environmental or other factors influence the expression of a particular gene, which makes ants an excellent test model.

In an ant colony, queens, workers and soldiers share similar genetics. But early in ant development, social, nutritional and chemical cues cause some genes to be more active, ultimately creating a wide range of body sizes, each specialized to a different task in the colony.

Many of these changes are controlled by DNA methylation, a process in which molecules are added to sections of DNA sequences. These additions affect how the DNA is interpreted and expressed, thus influencing an organism’s development or behavior.

“A lot of growth and development and sizing mechanisms that exist across the animal kingdom are found to be regulated by the same DNA methylation processes,” Alvarado said.

In the experiment, Alvarado and his colleagues at McGill exposed ant larvae to drugs that either increased or decreased the amount of DNA methylation. In doing so, they created ants that were larger within a caste and even significantly smaller than what exists in a natural population.

They then traced this size change to a specific growth factor gene, and found that across the population, varying degrees of DNA methylation to that gene directly corresponded to body size. A 20 percent modification in DNA methylation yielded a 20 percent change in body size, for example.

“This helps explain at a molecular level how continuums exist between two very discrete variables,” said Alvarado, who is now a member of biology Professor Russell Fernald’s lab at Stanford. “We can now look at diversity within a population by considering what expressions exist in between these variables and the actual molecular mechanism that controls that difference.”

Drawing a stronger connection between how environment and genetic factors influence DNA expression, Alvarado said, could have payoff in mapping the genetic basis of diseases and understanding evolutionary changes.

Source: Stanford News


 

Magnetic brain stimulation:New technique could lead to long-lasting localized stimulation of brain tissue without external connections.

By David Chandler


CAMBRIDGE, Mass–Researchers at MIT have developed a method to stimulate brain tissue using external magnetic fields and injected magnetic nanoparticles — a technique allowing direct stimulation of neurons, which could be an effective treatment for a variety of neurological diseases, without the need for implants or external connections.

The research, conducted by Polina Anikeeva, an assistant professor of materials science and engineering, graduate student Ritchie Chen, and three others, has been published in the journal Science.

Previous efforts to stimulate the brain using pulses of electricity have proven effective in reducing or eliminating tremors associated with Parkinson’s disease, but the treatment has remained a last resort because it requires highly invasive implanted wires that connect to a power source outside the brain.

“In the future, our technique may provide an implant-free means to provide brain stimulation and mapping,” Anikeeva says.

In their study, the team injected magnetic iron oxide particles just 22 nanometers in diameter into the brain. When exposed to an external alternating magnetic field — which can penetrate deep inside biological tissues — these particles rapidly heat up.

The resulting local temperature increase can then lead to neural activation by triggering heat-sensitive capsaicin receptors — the same proteins that the body uses to detect both actual heat and the “heat” of spicy foods. (Capsaicin is the chemical that gives hot peppers their searing taste.) Anikeeva’s team used viral gene delivery to induce the sensitivity to heat in selected neurons in the brain.

The particles, which have virtually no interaction with biological tissues except when heated, tend to remain where they’re placed, allowing for long-term treatment without the need for further invasive procedures.

“The nanoparticles integrate into the tissue and remain largely intact,” Anikeeva says. “Then, that region can be stimulated at will by externally applying an alternating magnetic field. The goal for us was to figure out whether we could deliver stimuli to the nervous system in a wireless and noninvasive way.”

The new work has proven that the approach is feasible, but much work remains to turn this proof-of-concept into a practical method for brain research or clinical treatment.

The use of magnetic fields and injected particles has been an active area of cancer research; the thought is that this approach could destroy cancer cells by heating them. “The new technique is derived, in part, from that research,” Anikeeva says. “By calibrating the delivered thermal dosage, we can excite neurons without killing them. The magnetic nanoparticles also have been used for decades as contrast agents in MRI scans, so they are considered relatively safe in the human body.”

The team developed ways to make the particles with precisely controlled sizes and shapes, in order to maximize their interaction with the applied alternating magnetic field. They also developed devices to deliver the applied magnetic field: Existing devices for cancer treatment — intended to produce much more intense heating — were far too big and energy-inefficient for this application.

The next step toward making this a practical technology for clinical use in humans “is to understand better how our method works through neural recordings and behavioral experiments, and assess whether there are any other side effects to tissues in the affected area,” Anikeeva says.

In addition to Anikeeva and Chen, the research team also included postdoc Gabriela Romero, graduate student Michael Christiansen, and undergraduate Alan Mohr. The work was funded by the Defense Advanced Research Projects Agency, MIT’s McGovern Institute for Brain Research, and the National Science Foundation.

The rise and fall of cognitive skills:Neuroscientists find that different parts of the brain work best at different ages.

By Anne Trafton


CAMBRIDGE, Mass–Scientists have long known that our ability to think quickly and recall information, also known as fluid intelligence, peaks around age 20 and then begins a slow decline. However, more recent findings, including a new study from neuroscientists at MIT and Massachusetts General Hospital (MGH), suggest that the real picture is much more complex.

The study, which appears in the XX issue of the journal Psychological Science, finds that different components of fluid intelligence peak at different ages, some as late as age 40.

“At any given age, you’re getting better at some things, you’re getting worse at some other things, and you’re at a plateau at some other things. There’s probably not one age at which you’re peak on most things, much less all of them,” says Joshua Hartshorne, a postdoc in MIT’s Department of Brain and Cognitive Sciences and one of the paper’s authors.

“It paints a different picture of the way we change over the lifespan than psychology and neuroscience have traditionally painted,” adds Laura Germine, a postdoc in psychiatric and neurodevelopmental genetics at MGH and the paper’s other author.

Measuring peaks

Until now, it has been difficult to study how cognitive skills change over time because of the challenge of getting large numbers of people older than college students and younger than 65 to come to a psychology laboratory to participate in experiments. Hartshorne and Germine were able to take a broader look at aging and cognition because they have been running large-scale experiments on the Internet, where people of any age can become research subjects.

Their web sites, gameswithwords.org and testmybrain.org, feature cognitive tests designed to be completed in just a few minutes. Through these sites, the researchers have accumulated data from nearly 3 million people in the past several years.

In 2011, Germine published a study showing that the ability to recognize faces improves until the early 30s before gradually starting to decline. This finding did not fit into the theory that fluid intelligence peaks in late adolescence. Around the same time, Hartshorne found that subjects’ performance on a visual short-term memory task also peaked in the early 30s.

Intrigued by these results, the researchers, then graduate students at Harvard University, decided that they needed to explore a different source of data, in case some aspect of collecting data on the Internet was skewing the results. They dug out sets of data, collected decades ago, on adult performance at different ages on the Weschler Adult Intelligence Scale, which is used to measure IQ, and the Weschler Memory Scale. Together, these tests measure about 30 different subsets of intelligence, such as digit memorization, visual search, and assembling puzzles.

Hartshorne and Germine developed a new way to analyze the data that allowed them to compare the age peaks for each task. “We were mapping when these cognitive abilities were peaking, and we saw there was no single peak for all abilities. The peaks were all over the place,” Hartshorne says. “This was the smoking gun.”

However, the dataset was not as large as the researchers would have liked, so they decided to test several of the same cognitive skills with their larger pools of Internet study participants. For the Internet study, the researchers chose four tasks that peaked at different ages, based on the data from the Weschler tests. They also included a test of the ability to perceive others’ emotional state, which is not measured by the Weschler tests.

The researchers gathered data from nearly 50,000 subjects and found a very clear picture showing that each cognitive skill they were testing peaked at a different age. For example, raw speed in processing information appears to peak around age 18 or 19, then immediately starts to decline. Meanwhile, short-term memory continues to improve until around age 25, when it levels off and then begins to drop around age 35.

For the ability to evaluate other people’s emotional states, the peak occurred much later, in the 40s or 50s.

More work will be needed to reveal why each of these skills peaks at different times, the researchers say. However, previous studies have hinted that genetic changes or changes in brain structure may play a role.

“If you go into the data on gene expression or brain structure at different ages, you see these lifespan patterns that we don’t know what to make of. The brain seems to continue to change in dynamic ways through early adulthood and middle age,” Germine says. “The question is: What does it mean? How does it map onto the way you function in the world, or the way you think, or the way you change as you age?”

Accumulated intelligence

The researchers also included a vocabulary test, which serves as a measure of what is known as crystallized intelligence — the accumulation of facts and knowledge. These results confirmed that crystallized intelligence peaks later in life, as previously believed, but the researchers also found something unexpected: While data from the Weschler IQ tests suggested that vocabulary peaks in the late 40s, the new data showed a later peak, in the late 60s or early 70s.

The researchers believe this may be a result of better education, more people having jobs that require a lot of reading, and more opportunities for intellectual stimulation for older people.

Hartshorne and Germine are now gathering more data from their websites and have added new cognitive tasks designed to evaluate social and emotional intelligence, language skills, and executive function. They are also working on making their data public so that other researchers can access it and perform other types of studies and analyses.

“We took the existing theories that were out there and showed that they’re all wrong. The question now is: What is the right one? To get to that answer, we’re going to need to run a lot more studies and collect a lot more data,” Hartshorne says.

The research was funded by the National Institutes of Health, the National Science Foundation, and a National Defense Science and Engineering Graduate Fellowship.

Source: MIT News Office

Rotating night shift work can be hazardous to your health

Possible increase in cardiovascular disease and lung cancer mortality observed in nurses working rotating night shifts, according to report in the American Journal of Preventive Medicine

ELSEVIER HEALTH SCIENCES


Night shift work has been consistently associated with higher risk for cardiovascular disease (CVD) and cancer. In 2007 the World Health Organization classified night shift work as a probable carcinogen due to circadian disruption. In a study in the current issue of the American Journal of Preventive Medicine, researchers found that women working rotating night shifts for five or more years appeared to have a modest increase in all-cause and CVD mortality and those working 15 or more years of rotating night shift work appeared to have a modest increase in lung cancer mortality. These results add to prior evidence of a potentially detrimental effect of rotating night shift work on health and longevity.

Sleep and the circadian system play an important role in cardiovascular health and antitumor activity. There is substantial biological evidence that night shift work enhances the development of cancer and CVD, and contributes to higher mortality.

An international team of researchers investigated possible links between rotating night shift work and all-cause, CVD, and cancer mortality in a study of almost 75,000 registered U.S. nurses. Using data from the Nurses’ Health Study (NHS), the authors analyzed 22 years of follow-up and found that working rotating night shifts for more than five years was associated with an increase in all-cause and CVD mortality. Mortality from all causes appeared to be 11% higher for women with 6-14 or ?15 years of rotating night shift work. CVD mortality appeared to be 19% and 23% higher for those groups, respectively. There was no association between rotating shift work and any cancer mortality, except for lung cancer in those who worked shift work for 15 or more years (25% higher risk).

The NHS, which is based at Brigham and Women’s Hospital, began in 1976, with 121,700 U.S. female nurses aged 30-55 years, who have been followed up with biennial questionnaires. Night shift information was collected in 1988, at which time 85,197 nurses responded. After excluding women with pre-existing CVD or other than non-melanoma skin cancer, 74,862 women were included in this analysis. Defining rotating shift work as working at least three nights per month in addition to days or evenings in that month, respondents were asked how many years they had worked in this way. The prespecified categories were never, 1-2, 3-5, 6-9, 10-14, 15-19, 20-29, and ?30 years.

According to Eva S. Schernhammer, MD, DrPH, currently Associate Professor of Medicine, Harvard Medical School, and Associate Epidemiologist, Department of Medicine, Brigham and Women’s Hospital, Boston, this study “is one of the largest prospective cohort studies worldwide with a high proportion of rotating night shift workers and long follow-up time. A single occupation (nursing) provides more internal validity than a range of different occupational groups, where the association between shift work and disease outcomes could be confounded by occupational differences.”

Comparing this work with previous studies, she continues, “These results add to prior evidence of a potentially detrimental relation of rotating night shift work and health and longevity…To derive practical implications for shift workers and their health, the role of duration and intensity of rotating night shift work and the interplay of shift schedules with individual traits (e.g., chronotype) warrant further exploration.”

Source: American Journal of Preventive Medicine via EurekAlert

Musashi proteins, stained red, appear in the cell cytoplasm, outside the nucleus. At right, the cell nucleus is stained blue.
Image Credit: Yarden Katz/MIT

Proteins drive cancer cells to change states

When RNA-binding proteins are turned on, cancer cells get locked in a proliferative state.

 By Anne Trafton


 

A new study from MIT implicates a family of RNA-binding proteins in the regulation of cancer, particularly in a subtype of breast cancer. These proteins, known as Musashi proteins, can force cells into a state associated with increased proliferation.

Biologists have previously found that this kind of transformation, which often occurs in cancer cells as well as during embryonic development, is controlled by transcription factors — proteins that turn genes on and off. However, the new MIT research reveals that RNA-binding proteins also play an important role. Human cells have about 500 different RNA-binding proteins, which influence gene expression by regulating messenger RNA, the molecule that carries DNA’s instructions to the rest of the cell.

“Recent discoveries show that there’s a lot of RNA-processing that happens in human cells and mammalian cells in general,” says Yarden Katz, a recent MIT PhD recipient and one of the lead authors of the new paper. “RNA is processed at several points within the cell, and this gives opportunities for RNA-binding proteins to regulate RNA at each point. We’re very interested in trying to understand this unexplored class of RNA-binding proteins and how they regulate cell-state transitions.”

Feifei Li of China Agricultural University is also a lead author of the paper, which appears in the journal eLife on Dec. 15. Senior authors of the paper are MIT biology professors Christopher Burge and Rudolf Jaenisch, and Zhengquan Yu of China Agricultural University.

Controlling cell states

Until this study, scientists knew very little about the functions of Musashi proteins. These RNA-binding proteins have traditionally been used to identify neural stem cells, in which they are very abundant. They have also been found in tumors, including in glioblastoma, a very aggressive form of brain cancer.

“Normally they’re marking stem and progenitor cells, but they get turned on in cancers. That was intriguing to us because it suggested they might impose a more undifferentiated state on cancer cells,” Katz says.

To study this possibility, Katz manipulated the levels of Musashi proteins in neural stem cells and measured the effects on other genes. He found that genes affected by Musashi proteins were related to the epithelial-to-mesenchymal transition (EMT), a process by which cells lose their ability to stick together and begin invading other tissues.

EMT has been shown to be important in breast cancer, prompting the team to look into Musashi proteins in cancers of non-neural tissue. They found that Musashi proteins are most highly expressed in a type of breast tumors called luminal B tumors, which are not metastatic but are aggressive and fast-growing.

When the researchers knocked down Musashi proteins in breast cancer cells grown in the lab, the cells were forced out of the epithelial state. Also, if the proteins were artificially boosted in mesenchymal cells, the cells transitioned to an epithelial state. This suggests that Musashi proteins are responsible for maintaining cancer cells in a proliferative, epithelial state.

“These proteins seem to really be regulating this cell-state transition, which we know from other studies is very important, especially in breast cancer,” Katz says.

Musashi proteins, stained red, appear in the cell cytoplasm, outside the nucleus. At right, the cell nucleus is stained blue. Image Credit: Yarden Katz/MIT
Musashi proteins, stained red, appear in the cell cytoplasm, outside the nucleus. At right, the cell nucleus is stained blue.
Image Credit: Yarden Katz , MIT

 

The researchers found that Musashi proteins repress a gene called Jagged1, which in turn regulates the Notch signaling pathway. Notch signaling promotes cell division in neurons during embryonic development and also plays a major role in cancer.

When Jagged1 is repressed, cells are locked in an epithelial state and are much less motile. The researchers found that Musashi proteins also repress Jagged1 during normal mammary-gland development, not just in cancer. When these proteins were overexpressed in normal mammary glands, cells were less able to undergo the type of healthy EMT required for mammary tissue development.

Brenton Graveley, a professor of genetics and developmental biology at the University of Connecticut, says he was surprised to see how much influence Musashi proteins can have by controlling a relatively small number of genes in a cell. “Musashi proteins have been known to be interesting for many years, but until now nobody has really figured out exactly what they’re doing, especially on a genome-wide scale,” he says.

The researchers are now trying to figure out how Musashi proteins, which are normally turned off after embryonic development, get turned back on in cancer cells. “We’ve studied what this protein does, but we know very little about how it’s regulated,” Katz says.

He says it is too early to know if the Musashi proteins might make good targets for cancer drugs, but they could make a good diagnostic marker for what state a cancer cell is in. “It’s more about understanding the cell states of cancer at this stage, and diagnosing them, rather than treating them,” he says.

The research was funded by the National Institutes of Health.

Source : MIT News Office

New way to turn genes on

Technique allows rapid, large-scale studies of gene function.

By Anne Trafton


CAMBRIDGE, MA — Using a gene-editing system originally developed to delete specific genes, MIT researchers have now shown that they can reliably turn on any gene of their choosing in living cells.

This new application for the CRISPR/Cas9 gene-editing system should allow scientists to more easily determine the function of individual genes, according to Feng Zhang, the W.M. Keck Career Development Professor in Biomedical Engineering in MIT’s Departments of Brain and Cognitive Sciences and Biological Engineering, and a member of the Broad Institute and MIT’s McGovern Institute for Brain Research.

This approach also enables rapid functional screens of the entire genome, allowing scientists to identify genes involved in particular diseases. In a study published in the Dec. 10 online edition of Nature, Zhang and colleagues identified several genes that help melanoma cells become resistant to a cancer drug.

Silvana Konermann, a graduate student in Zhang’s lab, and Mark Brigham, a McGovern Institute postdoc, are the paper’s lead authors.

A new function for CRISPR

The CRISPR system relies on cellular machinery that bacteria use to defend themselves from viral infection. Researchers have previously harnessed this cellular system to create gene-editing complexes that include a DNA-cutting enzyme called Cas9 bound to a short RNA guide strand that is programmed to bind to a specific genome sequence, telling Cas9 where to make its cut.

In the past two years, scientists have developed Cas9 as a tool for turning genes off or replacing them with a different version. In the new study, Zhang and colleagues engineered the Cas9 system to turn genes on, rather than knock them out.

Scientists have tried to do this before using proteins that are individually engineered to target DNA at specific sites. However, these proteins are  difficult to work with. “If you use the older generation of tools, getting the technology to do what you actually want is a project on its own,” Konermann says. “It takes a lot of time and is also quite expensive.”

There have also been attempts to use CRISPR to turn on genes by inactivating the part of the Cas9 enzyme that cuts DNA and linking Cas9 to pieces of proteins called activation domains. These domains recruit the cellular machinery necessary to begin reading copying RNA from DNA, a process known as transcription.

However, these efforts have been unable to consistently turn on gene transcription. Zhang and his colleagues, Osamu Nureki and Hiroshi Nishimasu at the University of Tokyo, decided to overhaul the CRISPR-Cas9 system based on an analysis they published earlier this year of the structure formed when Cas9 binds to the guide RNA and its target DNA. “Based on knowing its 3-D shape, we can think about how to rationally improve the system,” Zhang says.

In previous efforts, scientists had tried to attach the activation domains to either end of the Cas9 protein, with limited success. From their structural studies, the MIT team realized that two small loops of the RNA guide poke out from the Cas9 complex and could be better points of attachment because they allow the activation domains to have more flexibility in recruiting transcription machinery.

Using their revamped system, the researchers activated about a dozen genes that had proven difficult or impossible to turn on using the previous generation of Cas9 activators. Each gene showed at least a twofold boost in transcription, and for many genes, the researchers found multiple orders of magnitude increase in activation.

Genome-scale activation screening

Once the researchers had shown that the system was effective at activating genes, they created a library of 70,290 guide RNAs targeting all of the more than 20,000 genes in the human genome.

They screened this library to identify genes that confer resistance to a melanoma drug called PLX-4720. This drug worksDrugs of this type work well in patients whose melanoma cells have a mutation in the BRAF gene, but cancer cells that survive the treatment can grow into new tumors, allowing the cancer to recur.

To discover the genes that help cells become resistant, the researchers delivered CRISPR components to a large population of melanoma cells grown in the lab, with each cell receiving a different guide RNA targeting a different gene. After treating the cells with PLX-4720, they identified several genes that helped the cells to survive — some previously known to be involved in drug resistance, as well as several novel targets.

Studies like this could help researchers discover new cancer drugs that prevent tumors from becoming resistant.

“You could start with a drug that targets the mutated BRAF along with combination therapy that targets genes that allow the cell to survive. If you target both of them at the same time, you could likely prevent the cells from developing resistance mechanisms that enable further growth despite drug treatment,” Konermann says.

Scientists have tried to do large-scale screens like this by delivering single genes carried by viruses, but that does not work with all genes.

Zhang’s lab also plans to use this technique to screen for genes that, when activated, could correct the effects of autism or neurodegenerative diseases such as Alzheimer’s. He also plans to make the necessary reagents available to academic labs that want to use them, through the Addgene repository.

The research was funded by the National Institute of Mental Health; the National Institute of Neurological Disorders and Stroke; the Keck, Searle Scholars, Klingenstein, Vallee, and Simons foundations; and Bob Metcalfe.

Sourse: MIT News

The harlequin filefish can disguise its smell. Image: Tane Sinclair-Taylor

You are what you eat – if you’re a coral reef fish

In a world first study researchers have found a coral-eating fish that disguises its smell to hide from predators.

“For many animals vision is less important than their sense of smell,” says study lead author Dr Rohan Brooker from the ARC Centre of Excellence for Coral Reef Studies (Coral CoE) at James Cook University.

“Because predators often rely on odors to find their prey, even visually camouflaged animals may stick out like a sore thumb if they smell strongly of ‘food’.” Dr Brooker says.

The research, published in the journal Proceedings of the Royal Society B, found that the harlequin filefish changed its smell to match the coral it ate.

“By feeding on corals, the harlequin filefish ends up smelling enough like its food that predators have a hard time distinguishing it from the surrounding coral habitat,” Dr Brooker says.

The harlequin filefish can disguise its smell. Image: Tane Sinclair-Taylor
The harlequin filefish can disguise its smell. Image: Tane Sinclair-Taylor

Study co-author, Professor Philip Munday from the Coral CoE says the ability to chemically camouflage itself is a great advantage for the fish.

“The harlequin filefish shelters among the branches of coral colonies at night, where not only does it look like a coral branch, it also smells like one, enabling it to remain undetected by nocturnal predators.”

Professor Doug Chivers from the University of Saskatchewan, who is also a co-author, agrees.

“A finely-tuned combination of visual and chemical camouflage may be an effective anti-predator strategy that helps the fish to avoid being eaten,” Professor Chivers says.
Not only does the filefish confuse its predators, it matches the odour of the coral so closely that small crabs, which lived on coral branches, couldn’t distinguish it from coral.

Professor Munday says it’s a remarkable example of how closely animals can be adapted to their habitats.

“However, the filefishes’ cover is blown if it shelters in a different species of coral than the one it has been eating. Then, the predators can distinguish it presence and track it down,” Professor Munday says.

The ability to chemically ‘blend in’ occurs in some plant-eating invertebrates, but this is the first time this type of camouflage has been found in higher order animals, such as fish.

“This is very exciting because it opens the possibility of a wide range of different animals also using similar mechanisms, right under our noses,” Dr Brooker says.

Paper

You are what you eat: diet-induced chemical crypsis in a coral-feeding fish by Rohan Brooker, Philip Munday, Doug Chivers and Geoffrey Jones is published in the journal Proceedings of the Royal Society B.

Source : ARC Centre of Excellence Coral Reef Studies

Electrical and computer engineering Professor Barry Van Veen wears an electrode net used to monitor brain activity via EEG signals. His research could help untangle what happens in the brain during sleep and dreaming.

Photo Credit: Nick Berard/UW-Madison

Stanford scientists seek to map origins of mental illness and develop noninvasive treatment

An interdisciplinary team of scientists has convened to map the origins of mental illnesses in the brain and develop noninvasive technologies to treat the conditions. The collaboration could lead to improved treatments for depression, anxiety and post-traumatic stress disorder.

BY AMY ADAMS


Over the years imaging technologies have revealed a lot about what’s happening in our brains, including which parts are active in people with conditions like depression, anxiety or post-traumatic stress disorder. But here’s the secret Amit Etkin wants the world to know about those tantalizing images: they show the result of a brain state, not what caused it.

This is important because until we know how groups of neurons, called circuits, are causing these conditions – not just which are active later – scientists will never be able to treat them in a targeted way.

“You see things activated in brain images but you can’t tell just by watching what is cause and what is effect,” said Amit Etkin, an assistant professor of psychiatry and behavioral sciences. Etkin is co-leader of a new interdisciplinary initiative to understand what brain circuits underlie mental health conditions and then direct noninvasive treatments to those locations.

“Right now, if a patient with a mental illness goes to see their doctor they would likely be given a medication that goes all over the brain and body,” Etkin said. “While medications can work well, they do so for only a portion of people and often only partially.” Medications don’t specifically act on the brain circuits critically affected in that illness or individual.

The Big Idea: treat roots of mental illness

The new initiative, called NeuroCircuit, has the goal of finding the brain circuits that are responsible for mental health conditions and then developing ways of remotely stimulating those circuits and, the team hopes, potentially treating those conditions.

The initiative is part of the Stanford Neurosciences Institute‘s Big Ideas, which bring together teams of researchers from across disciplines to solve major problems in neuroscience and society. Stephen Baccus, an associate professor of neurobiology who co-leads the initiative with Etkin, said that what makes NeuroCircuit a big idea is the merging of teams trying to map circuits responsible for mental health conditions and teams developing new technologies to remotely access those circuits.

“Many psychiatric disorders, especially disorders of mood, probably involve malfunction within specific brain circuits that regulate emotion and motivation, yet our current pharmaceutical treatments affect circuits all over the brain,” said William Newsome, director of the Stanford Neurosciences Institute. “The ultimate goal of NeuroCircuit is more precise treatments, with minimal side effects, for specific psychiatric disorders.”

“The connection between the people who develop the technology and carry out research with the clinical goal, that’s what’s really come out of the Big Ideas,” Baccus said.

Brain control

Etkin has been working with a technology called transcranial magnetic stimulation, or TMS, to map and remotely stimulate parts of the brain. The device, which looks like a pair of doughnuts on a stick, generates a strong magnetic current that stimulates circuits near the surface of the brain.

TMS is currently used as a way of treating depression and anxiety, but Etkin said the brain regions being targeted are the ones available to TMS, not necessarily the ones most likely to treat a person’s condition. They are also not personalized for the individual.

Pairing TMS with another technology that shows which brain regions are active, Etkin and his team can stimulate one part of the brain with TMS and look for a reaction elsewhere. These studies can eventually help map the relationships between brain circuits and identify the circuits that underlie mental health conditions.

In parallel, the team is working to improve TMS to make it more useful as a therapy. TMS currently only reaches the surface of the brain and is not very focused. The goal is to improve the technology so that it can reach structures deeper in the brain in a more targeted way. “Right now they are hitting the only accessible target,” he said. “The parts we really want to hit for depression, anxiety or PTSD are likely deeper in the brain.”

Technology of the future

In parallel with the TMS work, Baccus and a team of engineers, radiologists and physiologists have been developing a way of using ultrasound to stimulate the brain. Ultrasound is widely used to image the body, most famously for producing images of developing babies in the womb. But in recent years scientists have learned that at the right frequency and focus, ultrasound can also stimulate nerves to fire.

In his lab, Baccus has been using ultrasound to stimulate nerve cells of the retina – the light-sensing structure at the back of the eye – as part of an effort to develop a prosthetic retina. He is also teaming up with colleagues to understand how ultrasound might be triggering that stimulation. It appears to compress the nerve cells in a way that could lead to activation, but the connection is far from clear.

Other members of the team are modifying existing ultrasound technology to direct it deep within the brain at a frequency that can stimulate nerves without harming them. If the team is successful, ultrasound could be a more targeted and focused tool than TMS for remotely stimulating circuits that underlie mental health conditions.

The group has been working together for about five years, and in 2012 got funding from Bio-X NeuroVentures, which eventually gave rise to the Stanford Neurosciences Institute, to pursue this technology. Baccus said that before merging with Etkin’s team they had been focusing on the technology without specific brain diseases in mind. “This merger really gives a target and a focus to the technology,” he said.

Etkin and Baccus said that if they are successful, they hope to have both a better understanding of how the brain functions and new tools for treating disabling mental health conditions.

Source: Stanford News