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Thursday, February 7th, 2019
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| 11:00a |
Biologists answer fundamental question about cell size MIT biologists have discovered the answer to a fundamental biological question: Why are cells of a given type all the same size?
In humans, cell size can vary more than 100-fold, ranging from tiny red blood cells to large neurons. However, within each cell type, there is very little deviation from a standard size. In studies of yeast, MIT researchers grew cells to 10 times their normal size and found that their DNA could not keep up with the demands of producing enough protein to maintain normal cell functions.
Furthermore, the researchers found that this protein shortage leads the cells into a nondividing state known as senescence, suggesting a possible explanation for how cells become senescent as they age.
“There are so many hypotheses out there that try to explain why senescence happens, and I think this data provides a beautiful and simple explanation for senescence,” says Angelika Amon, the Kathleen and Curtis Marble Professor in Cancer Research in the Department of Biology and a member of the Koch Institute for Integrative Cancer Research.
Amon is the senior author of the study, which appears in the Feb. 7 online edition of Cell. Gabriel Neurohr, an MIT postdoc, is the lead author of the paper.
Excessive size
To explore why cell size is so tightly controlled, the researchers prevented yeast cells from dividing by modifying a gene critical for cell division, so that it could be turned off at a certain temperature. These cells continued to grow, but they could not divide and they did not replicate their DNA.
The researchers discovered that as the cells expanded, their DNA and their protein-building machinery could not keep pace with the needs of such a large cell. This failure to produce enough protein led to the dilution of the cytoplasm and disruption of cell division. The researchers believe that many other fundamental cell processes that rely on cellular molecules finding and interacting with each other may also be impaired when cells are too big.
“Theoretical models predict that diluting the cytoplasm will decrease reaction rates. Every chemical reaction would occur more slowly, and some threshold concentrations of certain proteins may not be reached, so certain reactions would never happen because the concentrations are lower,” Neurohr says.
The researchers showed that yeast cells with two sets of chromosomes were able to grow to twice the size of yeast cells with just one set of chromosomes before becoming senescent, suggesting that the amount of DNA in the cells is the limiting factor in the cells’ ability to grow.
Experiments with human cells yielded similar results: In a study of human fibroblast cells, the researchers found that forcing the cells to grow to excessive sizes (eight times their normal size) disrupted many functions, including cell division.
“It’s been clear for some time that cells do control their size, but it’s been unclear what the various physiological reasons are for why they do so,” says Jan Skotheim, an associate professor of biology at Stanford University, who was not involved in the research. “What’s nice about this work is it really shows how things go wrong when cells get too big.”
Age-related disease
Amon says excessive growth likely plays a major role in the development of senescence, which occurs in many types of mammalian cells and is thought to contribute to age-related organ dysfunction and chronic age-related diseases.
Senescent cells are often larger than younger cells, and this study, which showed that unchecked cell growth leads to senescence, offers a possible explanation for this observation. Human cells tend to grow slightly larger throughout their lifetimes, because every time a cell divides, it checks for DNA damage, and if any is found, division is halted while repairs are made. During each of these delays, the cell grows slightly larger.
“Over the lifetime of a cell, the more divisions you make, the higher your probability is of having that damage, and over time cells will get larger,” Amon says. “Eventually they get so large that they start diluting critical factors that are important for proliferation.”
A difficult question that remains unanswered is how different types of cells maintain the appropriate size for their cell type, which the researchers now hope to study further.
The research was funded, in part, by the National Institutes of Health, the Howard Hughes Medical Institute, the Paul F. Glenn Center for Biology of Aging Research at MIT, a National Science Foundation graduate research fellowship, the William Bowes Fellows program, and the Vilcek Foundation. | | 1:59p |
New pill can deliver insulin An MIT-led research team has developed a drug capsule that could be used to deliver oral doses of insulin, potentially replacing the injections that people with type 2 diabetes have to give themselves every day.
About the size of a blueberry, the capsule contains a small needle made of compressed insulin, which is injected after the capsule reaches the stomach. In tests in animals, the researchers showed that they could deliver enough insulin to lower blood sugar to levels comparable to those produced by injections given through skin. They also demonstrated that the device can be adapted to deliver other protein drugs.
“We are really hopeful that this new type of capsule could someday help diabetic patients and perhaps anyone who requires therapies that can now only be given by injection or infusion,” says Robert Langer, the David H. Koch Institute Professor, a member of MIT’s Koch Institute for Integrative Cancer Research, and one of the senior authors of the study.
Giovanni Traverso, an assistant professor at Brigham and Women’s Hospital, Harvard Medical School, and a visiting scientist in MIT’s Department of Mechanical Engineering, where he is starting as a faculty member in 2019, is also a senior author of the study. The first author of the paper, which appears in the Feb. 7 issue of Science, is MIT graduate student Alex Abramson. The research team also includes scientists from the pharmaceutical company Novo Nordisk.
Video credit: Diana Saville
Self-orientation
Several years ago, Traverso, Langer, and their colleagues developed a pill coated with many tiny needles that could be used to inject drugs into the lining of the stomach or the small intestine. For the new capsule, the researchers changed the design to have just one needle, allowing them to avoid injecting drugs into the interior of the stomach, where they would be broken down by stomach acids before having any effect.
The tip of the needle is made of nearly 100 percent compressed, freeze-dried insulin, using the same process used to form tablets of medicine. The shaft of the needle, which does not enter the stomach wall, is made from another biodegradable material.
Within the capsule, the needle is attached to a compressed spring that is held in place by a disk made of sugar. When the capsule is swallowed, water in the stomach dissolves the sugar disk, releasing the spring and injecting the needle into the stomach wall.
The stomach wall has no pain receptors, so the researchers believe that patients would not be able to feel the injection. To ensure that the drug is injected into the stomach wall, the researchers designed their system so that no matter how the capsule lands in the stomach, it can orient itself so the needle is in contact with the lining of the stomach.
“As soon as you take it, you want the system to self-right so that you can ensure contact with the tissue,” Traverso says.
The researchers drew their inspiration for the self-orientation feature from a tortoise known as the leopard tortoise. This tortoise, which is found in Africa, has a shell with a high, steep dome, allowing it to right itself if it rolls onto its back. The researchers used computer modeling to come up with a variant of this shape for their capsule, which allows it to reorient itself even in the dynamic environment of the stomach.
“What’s important is that we have the needle in contact with the tissue when it is injected,” Abramson says. “Also, if a person were to move around or the stomach were to growl, the device would not move from its preferred orientation.”
Once the tip of the needle is injected into the stomach wall, the insulin dissolves at a rate that can be controlled by the researchers as the capsule is prepared. In this study, it took about an hour for all of the insulin to be fully released into the bloodstream.
Easier for patients
In tests in pigs, the researchers showed that they could successfully deliver up to 300 micrograms of insulin. More recently, they have been able to increase the dose to 5 milligrams, which is comparable to the amount that a patient with type 2 diabetes would need to inject.
After the capsule releases its contents, it can pass harmlessly through the digestive system. The researchers found no adverse effects from the capsule, which is made from biodegradable polymer and stainless steel components.
Maria José Alonso, a professor of biopharmaceutics and pharmaceutical technology at the University of Santiago de Compostela in Spain, describes the new capsule as a “radically new technology” that could benefit many patients.
“We are not talking about incremental improvements in insulin absorption, which is what most researchers in the field have done so far. This is by far the most realistic and impactful breakthrough technology disclosed until now for oral peptide delivery,” says Alonso, who was not involved in the research.
The MIT team is now continuing to work with Novo Nordisk to further develop the technology and optimize the manufacturing process for the capsules. They believe this type of drug delivery could be useful for any protein drug that normally has to be injected, such as immunosuppressants used to treat rheumatoid arthritis or inflammatory bowel disease. It may also work for nucleic acids such as DNA and RNA.
“Our motivation is to make it easier for patients to take medication, particularly medications that require an injection,” Traverso says. “The classic one is insulin, but there are many others.”
The research was funded by Novo Nordisk, the National Institutes of Health, a National Science Foundation Graduate Research Fellowship, Brigham and Women’s Hospital, a Viking Olaf Bjork Research Scholarship, and the MIT Undergraduate Research Opportunities Program.
Other authors of the paper include Ester Caffarel-Salvador, Minsoo Khang, David Dellal, David Silverstein, Yuan Gao, Morten Revsgaard Frederiksen, Andreas Vegge, Frantisek Hubalek, Jorrit Water, Anders Friderichsen, Johannes Fels, Rikke Kaae Kirk, Cody Cleveland, Joy Collins, Siddartha Tamang, Alison Hayward, Tomas Landh, Stephen Buckley, Niclas Roxhed, and Ulrik Rahbek. | | 1:59p |
Unleashing perovskites’ potential for solar cells Perovskites — a broad category of compounds that share a certain crystal structure — have attracted a great deal of attention as potential new solar-cell materials because of their low cost, flexibility, and relatively easy manufacturing process. But much remains unknown about the details of their structure and the effects of substituting different metals or other elements within the material.
Conventional solar cells made of silicon must be processed at temperatures above 1,400 degrees Celsius, using expensive equipment that limits their potential for production scaleup. In contrast, perovskites can be processed in a liquid solution at temperatures as low as 100 degrees, using inexpensive equipment. What’s more, perovskites can be deposited on a variety of substrates, including flexible plastics, enabling a variety of new uses that would be impossible with thicker, stiffer silicon wafers.
Now, researchers have been able to decipher a key aspect of the behavior of perovskites made with different formulations: With certain additives there is a kind of “sweet spot” where greater amounts will enhance performance and beyond which further amounts begin to degrade it. The findings are detailed this week in the journal Science, in a paper by former MIT postdoc Juan-Pablo Correa-Baena, MIT professors Tonio Buonassisi and Moungi Bawendi, and 18 others at MIT, the University of California at San Diego, and other institutions.
Perovskites are a family of compounds that share a three-part crystal structure. Each part can be made from any of a number of different elements or compounds — leading to a very broad range of possible formulations. Buonassisi compares designing a new perovskite to ordering from a menu, picking one (or more) from each of column A, column B, and (by convention) column X. “You can mix and match,” he says, but until now all the variations could only be studied by trial and error, since researchers had no basic understanding of what was going on in the material.
In previous research by a team from the Swiss École Polytechnique Fédérale de Lausanne, in which Correa-Baena participated, had found that adding certain alkali metals to the perovskite mix could improve the material’s efficiency at converting solar energy to electricity, from about 19 percent to about 22 percent. But at the time there was no explanation for this improvement, and no understanding of exactly what these metals were doing inside the compound. “Very little was known about how the microstructure affects the performance,” Buonassisi says.
Now, detailed mapping using high-resolution synchrotron nano-X-ray fluorescence measurements, which can probe the material with a beam just one-thousandth the width of a hair, has revealed the details of the process, with potential clues for how to improve the material’s performance even further.
It turns out that adding these alkali metals, such as cesium or rubidium, to the perovskite compound helps some of the other constituents to mix together more smoothly. As the team describes it, these additives help to “homogenize” the mixture, making it conduct electricity more easily and thus improving its efficiency as a solar cell. But, they found, that only works up to a certain point. Beyond a certain concentration, these added metals clump together, forming regions that interfere with the material’s conductivity and partly counteract the initial advantage. In between, for any given formulation of these complex compounds, is the sweet spot that provides the best performance, they found.
“It’s a big finding,” says Correa-Baena, who in January became an assistant professor of materials science and engineering at Georgia Tech. What the researchers found, after about three years of work at MIT and with collaborators at UCSD, was “what happens when you add those alkali metals, and why the performance improves.” They were able to directly observe the changes in the composition of the material, and reveal, among other things, these countervailing effects of homogenizing and clumping.
“The idea is that, based on these findings, we now know we should be looking into similar systems, in terms of adding alkali metals or other metals,” or varying other parts of the recipe, Correa-Baena says. While perovskites can have major benefits over conventional silicon solar cells, especially in terms of the low cost of setting up factories to produce them, they still require further work to boost their overall efficiency and improve their longevity, which lags significantly behind that of silicon cells.
Although the researchers have clarified the structural changes that take place in the perovskite material when adding different metals, and the resulting changes in performance, “we still don’t understand the chemistry behind this,” Correa-Baena says. That’s the subject of ongoing research by the team. The theoretical maximum efficiency of these perovskite solar cells is about 31 percent, according to Correa-Baena, and the best performance to date is around 23 percent, so there remains a significant margin for potential improvement.
Although it may take years for perovskites to realize their full potential, at least two companies are already in the process of setting up production lines, and they expect to begin selling their first modules within the next year or so. Some of these are small, transparent and colorful solar cells designed to be integrated into a building’s façade. “It’s already happening,” Correa-Baena says, “but there’s still work to do in making these more durable.”
Once issues of large-scale manufacturability, efficiency, and durability are addressed, Buonassisi says, perovskites could become a major player in the renewable energy industry. “If they succeed in making sustainable, high-efficiency modules while preserving the low cost of the manufacturing, that could be game-changing,” he says. “It could allow expansion of solar power much faster than we’ve seen.”
Perovskite solar cells “are now primary candidates for commercialization. Thus, providing deeper insights, as done in this work, contributes to future development,” says Michael Saliba, a senior researcher on the physics of soft matter at the University of Fribourg, Switzerland, who was not involved in this research.
Saliba adds, “This is great work that is shedding light on some of the most investigated materials. The use of synchrotron-based, novel techniques in combination with novel material engineering is of the highest quality, and is deserving of appearing in such a high-ranking journal.” He adds that work in this field “is rapidly progressing. Thus, having more detailed knowledge will be important for addressing future engineering challenges.”
The study, which included researchers at Purdue University and Argonne National Laboratory, in addition to those at MIT and UCSD, was supported by the U.S. Department of Energy, the National Science Foundation, the Skolkovo Institute of Science and Technology, and the California Energy Commission. | | 11:59p |
New technique pinpoints milestones in the evolution of bacteria Bacteria have evolved all manner of adaptations to live in every habitat on Earth. But unlike plants and animals, which can be preserved as fossils, bacteria have left behind little physical evidence of their evolution, making it difficult for scientists to determine exactly when different groups of bacteria evolved.
Now MIT scientists have devised a reliable way to determine when certain groups of bacteria appeared in the evolutionary record. The technique could be used to identify when significant changes occurred in the evolution of bacteria, and to reveal details about the primitive environments that drove such changes in the first place.
In a paper published online Jan. 28 in the journal BMC Evolutionary Biology, the researchers report using the technique to determine that, around 450 to 350 million years ago, during the Paleozoic Era, several major groups of soil bacteria acquired a specific gene from fungi that allowed them to break down chitin — a fibrous material found in the cell walls of fungi and in the exoskeletons of arthropods — and use its products to grow.
This evolutionary adaptation in bacteria may have been driven by a significant shift in the environment. Around the same time, arthropods such as early spiders, insects, and centipedes, were moving from the oceans onto land. As these terrestrial arthropods spread and diversified, they left behind chitin, creating richer soil environments and a new opportunity for bacteria — particularly those that acquired the chitinase gene — to thrive.
“Before this period, you would have had soils, but it might have looked like the dry valleys of Antarctica,” says Gregory Fournier, the Cecil and Ida Green Assistant Professor of Geobiology in MIT’s Department of Earth, Atmospheric, and Planetary Sciences. “With animals living in soils for the first time, that provided new opportunities for microbes to take advantage and diversify.”
Fournier says that, by tracing certain genes such as chitinase in bacteria, scientists can gain new insight into the early history of animals and the environments in which they lived.
“Microbes contain in their genomes a shadow history of animal life that we can use to fill gaps in our understanding of not only microbes, but also of the early history of animals,” Fournier says.
The paper’s authors include lead author Danielle Gruen PhD ’18, now a postdoc at the National Institutes of Health, and former postdoc Joanna Wolfe, now a research scientist at Harvard University.
Missing fossils
Without a fossil record, scientists have used other techniques to lay out bacteria’s “tree of life” — a map of genetic relationships, showing many branches and splits as bacteria have evolved into hundreds of thousands of species through time. Scientists have established such maps by analyzing and comparing the gene sequences of existing bacteria.
Using a “molecular clock” approach, they can estimate the rates at which certain genetic mutations may have occurred, and calculate the time at which two species may have diverged.
“But that can only tell you relative time, and there’s a huge uncertainty associated with these estimates,” Fournier says. “We have to anchor this tree somehow to the geological record, to absolute time.”
The team found they could use fossils from an entirely different organism to anchor the time at which certain groups of bacteria evolved. While in the vast majority of cases, genes are passed down through generations, from parent to offspring, every so often, a gene can hop from one organism to another, via a virus or through the environment, in a process known as horizontal gene transfer. The same genetic sequence, therefore, can appear in two organisms that otherwise would have entirely different genetic histories.
Fournier and his colleagues reasoned that if they could identify a common gene between bacteria and an entirely different organism — one with a clear fossil record — they might be able to pin bacteria’s evolution to the point at which this gene was transferred from the fossil-dated organism, to bacteria.
Splitting trees
They looked through the genome sequences of thousands of organisms and identified a single gene, chitinase, that appeared in several major bacterial groups, as well as in most species of fungi, which have a well-established fossil record.
They then used algorithms to produce a tree of all the different species with the chitinase genes, showing the relationships between species based on mutations in their genomes. Next, they employed a molecular clock approach to determine the relative times at which each species of bacteria containing chitinase branched from its respective ancestor. They repeated this same process for fungi.
The researchers traced chitinase in fungi to the point at which it most resembled the gene when it first appeared in bacteria, and reasoned that that must have been when fungi transferred the gene to bacteria. They then used fungi’s fossil record to pinpoint the time at which transfer likely occurred.
They found that, following the subsequent transfer of this gene across several groups of bacteria, three major groups of soil bacteria containing the chitinase gene all diversified around 450 to 350 million years ago. This rapid burst of microbe diversity was likely in response to a similar diversification of land animals, and specifically, chitin-producing arthropods, which occurred around this same period, as the fossil record shows.
“This result supports [the idea] that microbial groups tend to acquire genes for using resources as soon as they are available in the environment,” Fournier notes. “In principle, this approach can therefore be used to date many more groups of microbes, using the transfer of other genes that use other resources.”
Fournier is now developing an automated pipeline for detecting useful gene transfers between bacteria and other organisms, from huge amounts of gene data. For instance, he is looking at microbial genes responsible for breaking down collagen, a compound that is produced only in animals, and is found in soft body tissues.
“If we have a shadow history in the microbes of genes that eat soft body tissue, we could maybe reconstruct the early history of soft body tissues, which don’t preserve well in the fossil record,” Fournier says.
This research was supported, in part, by the National Science Foundation and the Simons Foundation. |
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