Tag Archives: cells

Researchers use engineered viruses to provide quantum-based enhancement of energy transport:MIT Research

Quantum physics meets genetic engineering

Researchers use engineered viruses to provide quantum-based enhancement of energy transport.

By David Chandler


 

CAMBRIDGE, Mass.–Nature has had billions of years to perfect photosynthesis, which directly or indirectly supports virtually all life on Earth. In that time, the process has achieved almost 100 percent efficiency in transporting the energy of sunlight from receptors to reaction centers where it can be harnessed — a performance vastly better than even the best solar cells.

One way plants achieve this efficiency is by making use of the exotic effects of quantum mechanics — effects sometimes known as “quantum weirdness.” These effects, which include the ability of a particle to exist in more than one place at a time, have now been used by engineers at MIT to achieve a significant efficiency boost in a light-harvesting system.

Surprisingly, the MIT researchers achieved this new approach to solar energy not with high-tech materials or microchips — but by using genetically engineered viruses.

This achievement in coupling quantum research and genetic manipulation, described this week in the journal Nature Materials, was the work of MIT professors Angela Belcher, an expert on engineering viruses to carry out energy-related tasks, and Seth Lloyd, an expert on quantum theory and its potential applications; research associate Heechul Park; and 14 collaborators at MIT and in Italy.

Lloyd, a professor of mechanical engineering, explains that in photosynthesis, a photon hits a receptor called a chromophore, which in turn produces an exciton — a quantum particle of energy. This exciton jumps from one chromophore to another until it reaches a reaction center, where that energy is harnessed to build the molecules that support life.

But the hopping pathway is random and inefficient unless it takes advantage of quantum effects that allow it, in effect, to take multiple pathways at once and select the best ones, behaving more like a wave than a particle.

This efficient movement of excitons has one key requirement: The chromophores have to be arranged just right, with exactly the right amount of space between them. This, Lloyd explains, is known as the “Quantum Goldilocks Effect.”

That’s where the virus comes in. By engineering a virus that Belcher has worked with for years, the team was able to get it to bond with multiple synthetic chromophores — or, in this case, organic dyes. The researchers were then able to produce many varieties of the virus, with slightly different spacings between those synthetic chromophores, and select the ones that performed best.

In the end, they were able to more than double excitons’ speed, increasing the distance they traveled before dissipating — a significant improvement in the efficiency of the process.

The project started from a chance meeting at a conference in Italy. Lloyd and Belcher, a professor of biological engineering, were reporting on different projects they had worked on, and began discussing the possibility of a project encompassing their very different expertise. Lloyd, whose work is mostly theoretical, pointed out that the viruses Belcher works with have the right length scales to potentially support quantum effects.

In 2008, Lloyd had published a paper demonstrating that photosynthetic organisms transmit light energy efficiently because of these quantum effects. When he saw Belcher’s report on her work with engineered viruses, he wondered if that might provide a way to artificially induce a similar effect, in an effort to approach nature’s efficiency.

“I had been talking about potential systems you could use to demonstrate this effect, and Angela said, ‘We’re already making those,’” Lloyd recalls. Eventually, after much analysis, “We came up with design principles to redesign how the virus is capturing light, and get it to this quantum regime.”

Within two weeks, Belcher’s team had created their first test version of the engineered virus. Many months of work then went into perfecting the receptors and the spacings.

Once the team engineered the viruses, they were able to use laser spectroscopy and dynamical modeling to watch the light-harvesting process in action, and to demonstrate that the new viruses were indeed making use of quantum coherence to enhance the transport of excitons.

“It was really fun,” Belcher says. “A group of us who spoke different [scientific] languages worked closely together, to both make this class of organisms, and analyze the data. That’s why I’m so excited by this.”

While this initial result is essentially a proof of concept rather than a practical system, it points the way toward an approach that could lead to inexpensive and efficient solar cells or light-driven catalysis, the team says. So far, the engineered viruses collect and transport energy from incoming light, but do not yet harness it to produce power (as in solar cells) or molecules (as in photosynthesis). But this could be done by adding a reaction center, where such processing takes place, to the end of the virus where the excitons end up.

The research was supported by the Italian energy company Eni through the MIT Energy Initiative. In addition to MIT postdocs Nimrod Heldman and Patrick Rebentrost, the team included researchers at the University of Florence, the University of Perugia, and Eni.

Source:MIT News Office

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

Microscopic “walkers” find their way across cell surfaces

Technology could provide a way to deliver probes or drugs to cell structures without outside guidance.

By David Chandler


 

CAMBRIDGE, Mass–Nature has developed a wide variety of methods for guiding particular cells, enzymes, and molecules to specific structures inside the body: White blood cells can find their way to the site of an infection, while scar-forming cells migrate to the site of a wound. But finding ways of guiding artificial materials within the body has proven more difficult.

Now a team of researchers at MIT led by Alfredo Alexander-Katz, the Walter Henry Gale Associate Professor of Materials Science and Engineering, has demonstrated a new target-finding mechanism. The new system allows microscopic devices to autonomously find their way to areas of a cell surface, for example, just by detecting an increase in surface friction in places where more cell receptors are concentrated.

The finding is described this week in a paper in the journal Physical Review Letters, written by Alexander-Katz, graduate student Joshua Steimel, and postdoc Juan Aragones.

“The idea was to find out if we could create a synthetic, active system that could sense gradients in biological receptors,” Alexander-Katz explains. “Currently, we don’t know of anything that can do that.”

Cells have a way of locating areas that bear a specific kind of chemical signature — a process called chemotaxis. That’s the method used by white blood cells, for example, to locate regions where pathogens are attacking body cells.

“Our system is very simple,” Alexander-Katz says — similar to the way in which bacteria locate nutrients they need. The system, without guidance, samples areas on a surface and migrates toward those where friction is greater — which also correspond to areas where receptors are concentrated.

The system uses a pair of linked particles with magnetic properties. In the presence of a magnetic field, the paired particles begin to tumble across a surface, with first one particle and then the other making contact — in effect, “walking” across the surface.

So far, the work has been carried out on a model cell surface, on a functionalized microscope slide, but the effect should work similarly with living cells, Alexander-Katz says. The team’s goal now is to demonstrate the ability of the microscopic walkers to find their way toward concentrations of receptors in actual living tissue.

The method could potentially have a variety of applications, Alexander-Katz says. For example, it could be developed as a method of locating tumor cells within the body by identifying their surface texture, perhaps in combination with other characteristics.

Such magnetic microwalkers, he adds, could be unleashed to locate areas of interest on various kinds of surfaces, based solely on differences in friction. The particles naturally migrate toward high-friction regions, where they could then be induced to interact with a surface by active molecules attached to them.

“It’s a very versatile system,” Alexander-Katz says, that can be functionalized by attaching other kinds of receptors or binding agents to affect or monitor the target area in different ways.

The next step is to test the approach in more complex settings. The initial work was done with flat surfaces; the team now aims to conduct studies in complex 3-D settings to make sure the process works effectively in situations that more closely resemble a real cellular environment.

The research was supported by the U.S. Department of Energy, the MIT Energy Initiative, and the Chang family.

Should scientists handle retractions differently?

Study: Retracted papers needlessly stigmatize and jeopardize solid research in related fields.

By Peter Dizikes


CAMBRIDGE, Mass. – It is one of the highest-profile cases of scientific fraud in memory: In 2005, South Korean researcher Woo-Suk Hwang and colleagues made international news by claiming that they had produced embryonic stem cells from a cloned human embryo using nuclear transfer. But within a year, the work had been debunked, soon followed by findings of fraud. South Korea put a moratorium on stem-cell research funding. Some scientists abandoned or reduced their work in the field.

But the case is not so simple: By 2007, other stem-cell researchers had found that the debunked research contained a few solid findings amid the false claims. While prior stem-cell findings remained intact, it took time to rebuild support for the field.

Now a study by MIT scholars quantifies the fallout for scientists whose fields suffer high-profile retractions, with a twist: Even valid older research, when cited in a retracted study, loses credibility — especially if the retracted paper involves malfeasance. The fallout from a retraction does not land solely on the scientists who are at fault, but on people in the field more broadly.

As the new paper contends, “scientific misconduct and mistakes, as signaled to the scientific community through retractions, cause a relative decline in the vitality of neighboring intellectual fields.” This spillover effect, which includes a 6 percent decline in citations relative to similar, unaffected papers, suggests that scientists would benefit by trying to describe the nature of each retraction in more detail.

“A well-functioning, transparent retraction process is actually part and parcel of the scientific system,” says Pierre Azoulay, an economist at the MIT Sloan School of Management, and a co-author of the new study. “We need a system where … journals help the readers spell out the reasons for the retractions, and help the scientific community parse the implications for the forward movement of science.”

Identifying the “stigma story”

The paper, “Retractions,” is published in the Review of Economics and Statistics, a peer-reviewed economics journal. The authors are Azoulay, the Sloan Distinguished Associate Professor of Management; Fiona Murray, the Alvin J. Siteman Professor of Entrepreneurship, associate dean for innovation at MIT Sloan, and co-director of MIT’s Innovation Initiative; Joshua Krieger, a doctoral student at MIT Sloan; and Jeffrey Furman, an economist at Boston University.

Murray and Furman were co-authors of an influential 2012 paper that studied the circumstances in which retractions occur. The new paper, Azoulay notes, is different in that it spotlights “the consequences of retractions, not their antecedents.”

The current study focuses on the life sciences. The researchers examined the effects of more than 1,000 retractions of papers published between 1973 and 2007, and retracted by 2009. They also used the PubMed Related Citations Algorithm to help define the research fields relevant to those retracted papers.

Given those definitions of research fields, the researchers then examined the effect of retractions on intellectually related work. One group of 60,000 papers that they examined experienced the 6 percent decline in citation rates after retractions occurred in the same fields. To establish that fact, the researchers compared the citation trajectories of those papers with a control group of 110,000 papers that were published in the same journals. The data and method draw on work Azoulay has compiled and refined while developing numerous other analyses of citation rates in scientific literature.

But within these numbers lie another story: The citation rates for related papers that are still valid drop more precipitously when papers citing them are retracted for reasons of fraud or other misconduct, as opposed to, say, a laboratory mistake.

“Most of the declines in citations and funding we see are driven by fraud cases,” Krieger notes. “When an honest mistake happens, the related field doesn’t experience this big decline.”

Conversely, this means that, given two equally valid sets of past research, legitimate research cited in a paper later retracted for fraud will be more harshly punished.

Further evidence for the “stigma story,” as Krieger calls it, is that academic papers and nonacademic papers from firms tend to shun retracted papers at similar rates — but papers from commercial firms do not avoid citing older, still-valid related papers to the same extent as academic researchers. This could mean there is an unfounded flight away from those related papers in academic research.

“Our evidence pointing to the stigma story implies that funding agencies and investigators should be more cautious when deciding to abandon a field after a case of research misconduct,” Krieger adds. “We need to be careful in separating what we’ve learned about the field’s scientific status from our strong reactions to the disgrace of misconduct and fraud.”

Limits to knowledge

As Azoulay and his colleagues acknowledge, there are limits to their study. It’s possible that citations in fields affected by fraud logically should decline more than those marred by honest mistakes, because scientists may rightfully conclude that research areas containing outright fraud are further away from yielding productive results.

“Maybe … fraud retractions and error retractions are different in ways that are correlated for the potential for follow-on research,” Azoulay says.

The researchers tried to account for that in their study, by looking at the number of citations garnered by retracted articles prior to the discovery of problems, then correlating that with the impact on related papers. But the numbers do not show an underlying structural reason why retractions for fraud, as opposed to unintentional mistakes, should generate a larger impact on related prior research.

The researchers have a couple of specific policy suggestions to limit unwarranted damage to the accretion of scientific knowledge. For instance, journals that retract articles should offer detailed explanations of why those papers are no longer valid. It would not be hard, they suggest, to develop a basic system of categories of retractions.

“By lumping together honest mistakes and misconduct, we’re undermining the smooth functioning of the retraction system,” Azoulay says.

Source: MIT News Office