MIT: Study Furthers Radically New View of Gene Control


  • MIT researchers have developed a new model of gene control, in which the cellular machinery that transcribes DNA into RNA forms specialized droplets called condensates.

  • Image: Steven H. Lee

  • Along the genome, proteins form liquid-like droplets that appear to boost the expression of particular genes.

    In recent years, MIT scientists have developed a new model for how key genes are controlled that suggests the cellular machinery that transcribes DNA into RNA forms specialized droplets called condensates. These droplets occur only at certain sites on the genome, helping to determine which genes are expressed in different types of cells.

    In a new study that supports that model, researchers at MIT and the Whitehead Institute for Biomedical Research have discovered physical interactions between proteins and with DNA that help explain why these droplets, which stimulate the transcription of nearby genes, tend to cluster along specific stretches of DNA known as super enhancers. These enhancer regions do not encode proteins but instead regulate other genes.

    “This study provides a fundamentally important new approach to deciphering how the ‘dark matter’ in our genome functions in gene control,” says Richard Young, an MIT professor of biology and member of the Whitehead Institute.

    Young is one of the senior authors of the paper, along with Phillip Sharp, an MIT Institute Professor and member of MIT’s Koch Institute for Integrative Cancer Research; and Arup K. Chakraborty, the Robert T. Haslam Professor in Chemical Engineering, a professor of physics and chemistry, and a member of MIT’s Institute for Medical Engineering and Science and the Ragon Institute of MGH, MIT, and Harvard.

    Graduate student Krishna Shrinivas and postdoc Benjamin Sabari are the lead authors of the paper, which appears in Molecular Cell on Aug. 8.

    “A biochemical factory”

    Every cell in an organism has an identical genome, but cells such as neurons or heart cells express different subsets of those genes, allowing them to carry out their specialized functions. Previous research has shown that many of these genes are located near super enhancers, which bind to proteins called transcription factors that stimulate the copying of nearby genes into RNA.

    About three years ago, Sharp, Young, and Chakraborty joined forces to try to model the interactions that occur at enhancers.

    In a 2017 Cell paper, based on computational studies, they hypothesized that in these regions, transcription factors form droplets called phase-separated condensates. Similar to droplets of oil suspended in salad dressing, these condensates are collections of molecules that form distinct cellular compartments but have no membrane separating them from the rest of the cell.

    In a 2018 Science paper, the researchers showed that these dynamic droplets do form at super enhancer locations. Made of clusters of transcription factors and other molecules, these droplets attract enzymes such as RNA polymerases that are needed to copy DNA into messenger RNA, keeping gene transcription active at specific sites.

    “We had demonstrated that the transcription machinery forms liquid-like droplets at certain regulatory regions on our genome, however we didn’t fully understand how or why these dewdrops of biological molecules only seemed to condense around specific points on our genome,” Shrinivas says.

    As one possible explanation for that site specificity, the research team hypothesized that weak interactions between intrinsically disordered regions of transcription factors and other transcriptional molecules, along with specific interactions between transcription factors and particular DNA elements, might determine whether a condensate forms at a particular stretch of DNA. Biologists have traditionally focused on “lock-and-key” style interactions between rigidly structured protein segments to explain most cellular processes, but more recent evidence suggests that weak interactions between floppy protein regions also play an important role in cell activities.

    In this study, computational modeling and experimentation revealed that the cumulative force of these weak interactions conspire together with transcription factor-DNA interactions to determine whether a condensate of transcription factors will form at a particular site on the genome. Different cell types produce different transcription factors, which bind to different enhancers. When many transcription factors cluster around the same enhancers, weak interactions between the proteins are more likely to occur. Once a critical threshold concentration is reached, condensates form.

    “Creating these local high concentrations within the crowded environment of the cell enables the right material to be in the right place at the right time to carry out the multiple steps required to activate a gene,” Sabari says. “Our current study begins to tease apart how certain regions of the genome are capable of pulling off this trick.”

    These droplets form on a timescale of seconds to minutes, and they blink in and out of existence depending on a cell’s needs.

    “It’s an on-demand biochemical factory that cells can form and dissolve, as and when they need it,” Chakraborty says. “When certain signals happen at the right locus on a gene, the condensates form, which concentrates all of the transcription molecules. Transcription happens, and when the cells are done with that task, they get rid of them.”

    “A functional condensate has to be more than the sum of its parts, and how the protein and DNA components work together is something we don’t fully understand,” says Rohit Pappu, director of the Center for Science and Engineering of Living Systems at Washington University, who was not involved in the research. “This work gets us on the road to thinking about the interplay among protein-protein, protein-DNA, and possibly DNA-DNA interactions as determinants of the outputs of condensates.”

    A new view

    Weak cooperative interactions between proteins may also play an important role in evolution, the researchers proposed in a 2018 Proceedings of the National Academy of Sciences paper.

    The sequences of intrinsically disordered regions of transcription factors need to change only a little to evolve new types of specific functionality. In contrast, evolving new specific functions via “lock-and-key” interactions requires much more significant changes.

    “If you think about how biological systems have evolved, they have been able to respond to different conditions without creating new genes.

    We don’t have any more genes that a fruit fly, yet we’re much more complex in many of our functions,” Sharp says. “The incremental expanding and contracting of these intrinsically disordered domains could explain a large part of how that evolution happens.”

    Similar condensates appear to play a variety of other roles in biological systems, offering a new way to look at how the interior of a cell is organized.

    Instead of floating through the cytoplasm and randomly bumping into other molecules, proteins involved in processes such as relaying molecular signals may transiently form droplets that help them interact with the right partners.

    “This is a very exciting turn in the field of cell biology,” Sharp says. “It is a whole new way of looking at biological systems that is richer and more meaningful.”

    Some of the MIT researchers, led by Young, have helped form a company called Dewpoint Therapeutics to develop potential treatments for a wide variety of diseases by exploiting cellular condensates.

    There is emerging evidence that cancer cells use condensates to control sets of genes that promote cancer, and condensates have also been linked to neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and Huntington’s disease.

    The research was funded by the National Science Foundation, the National Institutes of Health, and the Koch Institute Support (core) Grant from the National Cancer Institute.

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    Scientists develop novel nano-vaccine for melanoma


    Melanoma in skin biopsy with H&E stain — this case may represent superficial spreading melanoma. Credit: Wikipedia/CC BY-SA 3.0

    Researchers at Tel Aviv University have developed a novel nano-vaccine for melanoma, the most aggressive type of skin cancer. Their innovative approach has so far proven effective in preventing the development of melanoma in mouse models and in treating primary tumors and metastases that result from melanoma.

    The focus of the research is on a nanoparticle that serves as the basis for the new vaccine. The study was led by Prof. Ronit Satchi-Fainaro, chair of the Department of Physiology and Pharmacology and head of the Laboratory for Cancer Research and Nanomedicine at TAU’s Sackler Faculty of Medicine, and Prof. Helena Florindo of the University of Lisbon while on sabbatical at the Satchi-Fainaro lab at TAU; it was conducted by Dr. Anna Scomparin of Prof. Satchi-Fainaro’s TAU lab, and postdoctoral fellow Dr. João Conniot. The results were published on August 5 in Nature Nanotechnology.

    Melanoma develops in the skin cells that produce melanin or skin pigment. “The war against cancer in general, and melanoma in particular, has advanced over the years through a variety of treatment modalities, such as chemotherapy, radiation therapy and immunotherapy; but the vaccine approach, which has proven so effective against various viral diseases, has not materialized yet against cancer,” says Prof. Satchi-Fainaro. “In our study, we have shown for the first time that it is possible to produce an effective nano-vaccine against melanoma and to sensitize the  to immunotherapies.”

    The researchers harnessed tiny particles, about 170 nanometers in size, made of a biodegradable polymer. Within each particle, they “packed” two peptides—short chains of amino acids, which are expressed in melanoma cells. They then injected the nanoparticles (or “nano-vaccines”) into a  bearing melanoma.

    “The nanoparticles acted just like known vaccines for viral-borne diseases,” Prof. Satchi-Fainaro explains. “They stimulated the immune system of the mice, and the immune cells learned to identify and attack cells containing the two peptides—that is, the melanoma cells. This meant that, from now on, the immune system of the immunized mice will attack melanoma cells if and when they appear in the body.”

    The researchers then examined the effectiveness of the vaccine under three different conditions.

    First, the vaccine proved to have prophylactic effects. The vaccine was injected into healthy mice, and an injection of melanoma  followed. “The result was that the mice did not get sick, meaning that the vaccine prevented the disease,” says Prof. Satchi-Fainaro.

    Second, the nanoparticle was used to treat a primary tumor: A combination of the innovative vaccine and immunotherapy treatments was tested on melanoma model mice. The synergistic treatment significantly delayed the progression of the disease and greatly extended the lives of all treated mice.

    Finally, the researchers validated their approach on tissues taken from patients with melanoma brain metastases. This suggested that the nano- can be used to treat brain metastases as well. Mouse models with late-stage melanoma brain metastases had already been established following excision of the primary melanoma lesion, mimicking the clinical setting. Research on image-guided surgery of primary melanoma using smart probes was published last year by Prof. Satchi-Fainaro’s lab.

    “Our research opens the door to a completely new approach—the —for effective treatment of , even in the most advanced stages of the disease,” concludes Prof. Satchi-Fainaro. “We believe that our platform may also be suitable for other types of cancer and that our work is a solid foundation for the development of other cancer nano-vaccines.”

    More information: Immunization with mannosylated nanovaccines and inhibition of the immune-suppressing microenvironment sensitizes melanoma to immune checkpoint modulators, Nature Nanotechnology(2019). DOI: 10.1038/s41565-019-0512-0 , https://nature.com/articles/s41565-019-0512-0

    Journal information: Nature Nanotechnology

    Provided by Tel Aviv University

    The Nano–Bio Interactions of Nanomedicines: ENMs – Understanding the Biochemical Driving Forces and Redox Reactions


    Engineered nanomaterials (ENMs) have been developed for imaging, drug delivery, diagnosis, and clinical therapeutic purposes because of their outstanding physicochemical characteristics.

    However, the function and ultimate efficiency of nanomedicines remain unsatisfactory for clinical application, mainly because of our insufficient understanding of nanomaterial/nanomedicine–biology (nano–bio) interactions.

    The nonequilibrated, complex, and heterogeneous nature of the biological milieu inevitably influences the dynamic bioidentity of nanoformulations at each site (i.e., the interfaces at different biological fluids (biofluids), environments, or biological structures) of nano–bio interactions.

    The continuous interplay between a nanomedicine and the biological molecules and structures in the biological environments can, for example, affect cellular uptake or completely alter the designed function of the nanomedicine.

    Accordingly, the weak and strong driving forces at the nano–bio interface may elicit structural reconformation, decrease bioactivity, and induce dysfunction of the nanomaterial and/or redox reactions with biological molecules, all of which may elicit unintended and unexpected biological outcomes.

    In contrast, these driving forces also can be manipulated to mitigate the toxicity of ENMs or improve the targeting abilities of ENMs.

    Therefore, a comprehensive understanding of the underlying mechanisms of nano–bio interactions is paramount for the intelligent design of safe and effective nanomedicines.

    In this Account, we summarize our recent progress in probing the nano–bio interaction of nanomedicines, focusing on the driving force and redox reaction at the nano–bio interface, which have been recognized as the main factors that regulate the functions and toxicities of nanomedicines.

    First, we provide insight into the driving force that shapes the boundary of different nano–bio interfaces (including proteins, cell membranes, and biofluids), for instance, hydrophobic, electrostatic, hydrogen bond, molecular recognition, metal-coordinate, and stereoselective interactions that influence the different nano–bio interactions at each contact site in the biological environment.

    The physicochemical properties of both the nanoparticle and the biomolecule are varied, causing structure recombination, dysfunction, and bioactivity loss of proteins; correspondingly, the surface properties, biological functions, intracellular uptake pathways, and fate of ENMs are also influenced.

    Second, with the help of these driving forces, four kinds of redox interactions with reactive oxygen species (ROS), antioxidant, sorbate, and the prosthetic group of oxidoreductases are utilized to regulate the intracellular redox equilibrium and construct synergetic nanomedicines for combating bacteria and cancers. Three kinds of electron-transfer mechanisms are involved in designing nanomedicines, including direct electron injection, sorbate-mediated, and irradiation-induced processes.

    Finally, we discuss the factors that influence the nano–bio interactions and propose corresponding strategies to manipulate the nano–bio interactions for advancing nanomedicine design. We expect our efforts in understanding the nano–bio interaction and the future development of this field will bring nanomedicine to human use more quickly.

    Researchers at Oregon State University reach Milestone in use of Nanoparticles to kill Cancer with Heat


    Abstract:
    Researchers at Oregon State University have developed an improved technique for using magnetic nanoclusters to kill hard-to-reach tumors.

     

    Magnetic nanoparticles – tiny pieces of matter as small as one-billionth of a meter – have shown anti-cancer promise for tumors easily accessible by syringe, allowing the particles to be injected directly into the cancerous growth.

    Once injected into the tumor, the nanoparticles are exposed to an alternating magnetic field, or AMF. This field causes the nanoparticles to reach temperatures in excess of 100 degrees Fahrenheit, which causes the cancer cells to die.

    But for some cancer types such as prostate cancer, or the ovarian cancer used in the Oregon State study, direct injection is difficult. In those types of cases, a “systemic” delivery method – intravenous injection, or injection into the abdominal cavity – would be easier and more effective.

    The challenge for researchers has been finding the right kind of nanoparticles – ones that, when administered systemically in clinically appropriate doses, accumulate in the tumor well enough to allow the AMF to heat cancer cells to death.

    Olena Taratula and Oleh Taratula of the OSU College of Pharmacy tackled the problem by developing nanoclusters, multiatom collections of nanoparticles, with enhanced heating efficiency. The nanoclusters are hexagon-shaped iron oxide nanoparticles doped with cobalt and manganese and loaded into biodegradable nanocarriers.

    Findings were published in ACS Nano.

    “There had been many attempts to develop nanoparticles that could be administered systemically in safe doses and still allow for hot enough temperatures inside the tumor,” said Olena Taratula, associate professor of pharmaceutical sciences. “Our new nanoplatform is a milestone for treating difficult-to-access tumors with magnetic hyperthermia. This is a proof of concept, and the nanoclusters could potentially be optimized for even greater heating efficiency.”

    The nanoclusters’ ability to reach therapeutically relevant temperatures in tumors following a single, low-dose IV injection opens the door to exploiting the full potential of magnetic hyperthermia in treating cancer, either by itself or with other therapies, she added.

    “It’s already been shown that magnetic hyperthermia at moderate temperatures increases the susceptibility of cancer cells to chemotherapy, radiation and immunotherapy,” Taratula said.

    The mouse model in this research involved animals receiving IV nanocluster injections after ovarian tumors had been grafted underneath their skin.

    “To advance this technology, future studies need to use orthotopic animal models – models where deep-seated tumors are studied in the location they would actually occur in the body,” she said. “In addition, to minimize the heating of healthy tissue, current AMF systems need to be optimized, or new ones developed.”

    The National Institutes of Health, the OSU College of Pharmacy and Najran University of Saudi Arabia supported this research.

    Also collaborating were OSU electrical engineering professor Pallavi Dhagat, postdoctoral scholars Xiaoning Li and Canan Schumann of the College of Pharmacy, pharmacy graduate students Hassan Albarqi, Fahad Sabei and Abraham Moses, engineering graduate student Mikkel Hansen, and pre-pharmacy undergrads Tetiana Korzun and Leon Wong.

    Copyright © Oregon State University

    Looking at Nanotechnology in Biotechnology


    For some time, the difference between a biotechnology company and a pharmaceutical company was straightforward.

    A biotechnology focused on developing drugs with a biological basis. Pharmaceutical companies focused on drugs with a chemical basis.

    It was sort of an artificial distinction, and is even more so now because pharmaceutical companies haven’t excluded biologics from their portfolios.

    At one time there were even distinctions in the definitions related to small molecules versus large molecules, but those are largely in the dustbin of biopharma vocabulary. It’s one reason why “biopharma” itself is a useful word to bridge the two, and really, biotech and pharma are largely interchangeable.

    Nanotechnology Versus Biotechnology

    But what about nanotechnology? Is that biotechnology?

    The answer to that seems to be … yes and no.

    Nanotechnology typically refers to technology that is less than 100 nanometers in size. Although not horribly useful for differentiating things on the microscopic—or smaller—scale, there are 25,400,000 nanometers in an inch. So … small. Really small.

    Wouldn’t that refer to many drugs? Yes, probably.

    But nanotechnology typicallyrefers to tech made of manmade and inorganic materials in that size range. Again, the key word is “typically.”

    There is overlap.  Liji Thomas, writing for Azo Nano, says, “Nanobiotechnology deals with technology which incorporates nanomolecules into biological systems, or which miniaturizes biotechnology solutions to nanometer size to achieve greater reach and efficacy….

    Bionanotechnology, on the other hand, deals with new nanostructures that are created for synthetic applications, the difference being that these are based upon biomolecules.”

    Clear? Probably not. Here are some examples of biotechnology companies utilizing nanotechnology, along with whatever tools they need to develop their compounds.

    PEEL Therapeutics. PEEL Therapeutics is a small biotech company, largely in stealth mode, founded by Joshua Schiffman, an associate professor of Pediatrics at the University of Utah and Avi Schroeder, an assistant professor of chemical engineering at the Technion-Israel Institute of Technology. 

    Schiffman was doing work on a tumor suppressor gene, p53, which shows up at very high numbers in elephants. Elephants have significantly lower rates of cancer than humans, who normally have two normal copies of p53. Humans with a disease called Li-Fraumeni Syndrome, have only one, and they have a 100 percent change of getting cancer, or very close to it.

    What PEEL is attempting to do is build a synthetic version of p53 and insert them into a novel drug delivery system using nanotechnology. “Peel,” by the way, is the phonetic spelling of the Hebrew word for elephants. eP53 has been successfully encapsulated in nanoparticles, and at least in petri dishes, has demonstrated proof of concept. Elephants are not being experimented upon.

    Exicure. Based in Skokie, Illinois, Exicure (formerly known as AuraSense) is a clinical stage biotechnology company that’s working on a new class of immunomodulatory and gene regulating drugs that uses proprietary three-dimensional, spherical nucleic acid architecture.

    The SNA technology came out of the laboratory of Chad Mirkin at the Northwestern University International Institute for Nanotechnology.

    The company has received financing from the likes of Microsoft’s Bill Gates, Aonfounder Pat Ryan, David Walt, co-founder of Illumina, and Boon Hwee Koh, director of Agilent Technologies. 

    The technology platform is complex, but it is essentially various single and double-stranded nucleic acids stuck on the outside of a nanosphere.

    They are able to easily penetrate cells, which then trigger immune responses.

    SpyBiotech. Headquartered in Oxford, UK, SpyBiotech focuses on the so-called “super glue” that combines two parts of the bacteria that causes strep throat. It was spun out of Oxford University, and was based on research performed by its Department of Biochemistry and the Jenner Institute. When the bacteria that cause step throat are separated, they are attracted to each other and attempt to reattach.

    The company is working to use this principle to develop vaccines that, instead of using virus-causing bacteria, will bind onto viral infections.

    One of the bacteria that can cause strep throat, impetigo and other infections, Streptococcus pyogenes, is often shortened to Spy, hence the name of the company. When Spy is split into a peptide (SpyTag) and its protein partner (SpyCatcher), they are attracted to each other. The researchers isolated the “glue” that creates the attraction, and believe it can be used to bond vaccines together.

    The company has backing from GV,formerly Google Ventures, the venture fund backed by Alphabet/Google.

    One of the company’s founders is Mark Howarth, professor of Protein Nanotechnology at the University of Oxford. The fact that he’s working on protein nanotechnology undercuts a traditional definition of nanotechnology as not using biological materials. On his website, Howarth notes that SpyTag and SpyCatcher “is the strongest protein interaction yet measured and is being applied around the world for diverse areas of basic research and biotechnology. We are extending this new class of protein interaction, to create novel possibilities for synthetic biology.”

    Ultimately, when researchers are developing drugs, they are using whatever tools are necessary to find effective treatments for diseases. Biotechnology may more accurately be thought of as a set of tools and a philosophical approach to solving biological problems, compared to pharmaceuticals, and nanotechnology is yet another tool.

    In the wider world of drug discovery and development, there is also increasing use of artificial intelligence, data science and computational algorithms as well. And who knows what will be used tomorrow.

    Army research may be used to treat cancer, Heal combat wounds


    RESEARCH TRIANGLE PARK, N.C. — Army research is the first to develop computational models using a microbiology procedure that may be used to improve novel cancer treatments and treat combat wounds.

    Using the technique, known as electroporation, an electrical field is applied to cells in order to increase the permeability of the cell membrane, allowing chemicals, drugs, or DNA to be introduced into the cell.

    For example, electro-chemotherapy is a cutting-edge cancer treatment that uses electroporation as a means to deliver chemotherapy into cancerous cells.

    The research, funded by the U.S. Army and conducted by researchers at University of California, Santa Barbara and Université de Bordeaux, France, has developed a computational approach for parallel simulations that models the complex bioelectrical interaction at the tissue scale.

    Previously, most research has been conducted on individual cells, and each cell behaves according to certain rules.

    “When you consider a large number of them together, the aggregate exhibits novel coherent behaviors,” said Pouria Mistani, a researcher at UCSB. “It is this emergent phenomenon that is crucial for developing effective theories at the tissue-scale — novel behaviors that emerge from the coupling of many individual elements.”

    This new research, published in the Journal of Computational Physics, is funded by the U.S. Combat Capabilities Development Command’s Army Research Lab, the Army’s corporate research laboratory known as ARL, through its Army Research Office.

    “Mathematical research enables us to study the bioelectric effects of cells in order to develop new anti-cancer strategies,” said Dr. Joseph Myers, Army Research Office mathematical sciences division chief.

    “This new research will enable more accurate and capable virtual experiments of the evolution and treatment of cells, cancerous or healthy, in response to a variety of candidate drugs.”

    Researchers said a crucial element in making this possible is the development of advanced computational algorithms.

    “There is quite a lot of mathematics that goes into the design of algorithms that can consider tens of thousands well-resolved cells,” said Frederic Gibou, a faculty member in the Department of Mechanical Engineering and Computer Science at UCSB.

    Another potential application is accelerating combat wound healing using electric pulsation.

    “It’s an exciting, but mainly unexplored area that stems from a deeper discussion at the frontier of developmental biology, namely how electricity influences morphogenesis,” — or the biological process that causes an organism to develop its shape — Gibou said. “In wound healing, the goal is to externally manipulate electric cues to guide cells to grow faster in the wounded region and accelerate the healing process.”

    The common factor among these applications is their bioelectric physical nature. In recent years, it has been established that the bioelectric nature of living organisms plays a pivotal role in the development of their form and growth.

    To understand bioelectric phenomena, Gibou’s group considered computer experiments on multicellular spheroids in 3-D. Spheroids are aggregates of a few tens of thousands of cells that are used in biology because of their structural and functional similarity with tumors.

    “We started from the phenomenological cell-scale model that was developed in the research group of our colleague, Clair Poignard, at the Université de Bordeaux, France, with whom we have collaborated for several years,” Gibou said.

    This model, which describes the evolution of transmembrane potential on an isolated cell, has been compared and validated with the response of a single cell in experiments.

    “From there, we developed the first computational framework that is able to consider a cell aggregate of tens of thousands of cells and to simulate their interactions,” he said. “The end goal is to develop an effective tissue-scale theory for electroporation.”

    One of the main reasons for the absence of an effective theory at the tissue scale is the lack of data, according to Gibou and Mistani. Specifically, the missing data in the case of electroporation is the time evolution of the transmembrane potential of each individual cell in a tissue environment. Experiments are not able to make those measurements, they said.

    “Currently, experimental limitations prevent the development of an effective tissue-level electroporation theory,” Mistani said. “Our work has developed a computational approach that can simulate the response of individual cells in a spheroid to an electric field as well as their mutual interactions.”

    Each cell behaves according to certain rules. 

    “But when you consider a large number of them together, the aggregate exhibits novel coherent behaviors,” Mistani said. “It is this emergent phenomenon that is crucial for developing effective theories at the tissue-scale — novel behaviors that emerge from the coupling of many individual elements.”

    The effects of electroporation used in cancer treatment, for example, depend on many factors, such as the strength of the electric field, its pulse and frequency.

    “This work could bring an effective theory that helps understand the tissue response to these parameters and thus optimize such treatments,” Mistani said. “Before our work, the largest existing simulations of cell aggregate electroporation only considered about one hundred cells in 3-D, or were limited to 2-D simulations. Those simulations either ignored the real 3-D nature of spheroids or considered too few cells for tissue-scale emergent behaviors to manifest.”

    The researchers are currently mining this unique dataset to develop an effective tissue-scale theory of cell aggregate electroporation.

    _______________________________________

    The CCDC Army Research Laboratory (ARL) is an element of the U.S. Army Combat Capabilities Development Command. As the Army’s corporate research laboratory, ARL discovers, innovates and transitions science and technology to ensure dominant strategic land power. Through collaboration across the command’s core technical competencies, CCDC leads in the discovery, development and delivery of the technology-based capabilities required to make Soldiers more effective to win our Nation’s wars and come home safely. CCDC is a major subordinate command of the U.S. Army Futures Command.

    ____________________________

    Israeli scientists ‘print’ world’s first 3D heart with human tissue | The Jerusalem post


    A team of Tel Aviv University researchers revealed the heart, which was made using a patient’s own cells and biological materials.
    — Read on m.jpost.com/HEALTH-SCIENCE/Israeli-scientists-print-first-3D-heart-586902/amp

    Rutgers University – Alzheimer’s may be linked to defective brain cells spreading disease


    Rutgers scientists say neurodegenerative diseases like Alzheimer’s and Parkinson’s may be linked to defective brain cells disposing toxic proteins that make neighboring cells sick

    In a study published in Nature, Monica Driscoll, distinguished professor of molecular biology and biochemistry, School of Arts and Sciences, and her team, found that while healthy neurons should be able to sort out and and rid brain cells of toxic proteins and damaged cell structures without causing problems, laboratory findings indicate that it does not always occur.

    These findings, Driscoll said, could have major implications for neurological disease in humans and possibly be the way that disease can spread in the brain.

    “Normally the process of throwing out this trash would be a good thing,” said Driscoll. “But we think with neurodegenerative diseases like Alzheimer’s and Parkinson’s there might be a mismanagement of this very important process that is supposed to protect neurons but, instead, is doing harm to neighbor cells.”

    Driscoll said scientists have understood how the process of eliminating toxic cellular substances works internally within the cell, comparing it to a garbage disposal getting rid of waste, but they did not know how cells released the garbage externally.

    “What we found out could be compared to a person collecting trash and putting it outside for garbage day,” said Driscoll. “They actively select and sort the trash from the good stuff, but if it’s not picked up, the garbage can cause real problems.”

    Working with the transparent roundworm, known as the C. elegans, which are similar in molecular form, function and genetics to those of humans, Driscoll and her team discovered that the worms — which have a lifespan of about three weeks — had an external garbage removal mechanism and were disposing these toxic proteins outside the cell as well.

    Ilija Melentijevic, a graduate student in Driscoll’s laboratory and the lead author of the study, realized what was occurring when he observed a small cloud-like, bright blob forming outside of the cell in some of the worms. Over two years, he counted and monitored their production and degradation in single still images until finally he caught one in mid-formation.

    “They were very dynamic,” said Melentijevic, an undergraduate student at the time who spent three nights in the lab taking photos of the process viewed through a microscope every 15 minutes. “You couldn’t see them often, and when they did occur, they were gone the next day.”

    Research using roundworms has provided scientists with important information on aging, which would be difficult to conduct in people and other organisms that have long life spans.

    In the newly published study, the Rutgers team found that roundworms engineered to produce human disease proteins associated with Huntington’s disease and Alzheimer’s, threw out more trash consisting of these neurodegenerative toxic materials.

    While neighboring cells degraded some of the material, more distant cells scavenged other portions of the diseased proteins.

    “These finding are significant,” said Driscoll. The work in the little worm may open the door to much needed approaches to addressing neurodegeneration and diseases like Alzheimer’s and Parkinson’s.”

    Story Source:

    Materials provided by Rutgers University. Original written by Robin Lally. Note: Content may be edited for style and length.


    Journal Reference:

    1. Ilija Melentijevic, Marton L. Toth, Meghan L. Arnold, Ryan J. Guasp, Girish Harinath, Ken C. Nguyen, Daniel Taub, J. Alex Parker, Christian Neri, Christopher V. Gabel, David H. Hall, Monica Driscoll. C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress. Nature, 2017; DOI: 10.1038/nature21362

    Cite This Page:

    Rutgers University. “Alzheimer’s may be linked to defective brain cells spreading disease: Study finds toxic proteins doing harm to neighboring neurons.” ScienceDaily. ScienceDaily, 10 February 2017. <www.sciencedaily.com/releases/2017/02/170210131016.htm>.

    New Cancer Research – Converting Cancer Cells to Fat Cells to Stop Cancer’s Spread


    A method for fooling breast cancer cells into fat cells has been discovered by researchers from the University of Basel.

    The team were able to transform EMT-derived breast cancer cells into fat cells in a mouse model of the disease – preventing the formation of metastases. The proof-of-concept study was published in the journal Cancer Cell. 

    Malignant cells can rapidly respond and adapt to changing microenvironmental conditions, by reactivating a cellular process called epithelial-mesenchymal transition (EMT), enabling them to alter their molecular properties and transdifferentiate into a different type of cell (cellular plasticity).

    Senior author of the study Gerhard Christofori, professor of biochemistry at the University of Basel, commented in a recent press release: “The breast cancer cells that underwent an EMT not only differentiated into fat cells, but also completely stopped proliferating.”

    “As far as we can tell from long-term culture experiments, the cancer cells-turned-fat cells remain fat cells and do not revert back to breast cancer cells,” he explained.

    Epithelial-mesenchymal transition and cancer 

    Cancer cells can exploit EMT – a process that is usually associated with the development of organs during embryogenesis – in order to migrate away from the primary tumor and form secondary metastases. Cellular plasticity is linked to cancer survival, invasion, tumor heterogeneity and resistance to both chemo and targeted therapies. In addition, EMT and the inverse process termed mesenchymal-epithelial transition (MET) both play a role in a cancer cell’s ability to metastasize.

    Using mouse models of both murine and human breast cancer the team investigated whether they could therapeutically target cancer cells during the process of EMT – whilst the cells are in a highly plastic state. When the mice were administered Rosiglitazone in combination with MEK inhibitors it provoked the transformation of the cancer cells into post-mitotic and functional adipocytes (fat cells). In addition, primary tumor growth was suppressed and metastasis was prevented. 

    Cancer cells marked in green and a fat cell marked in red on the surface of a tumor (left). After treatment (right), three former cancer cells have been converted into fat cells. The combined marking in green and red causes them to appear dark yellow. Credit: University of Basel, Department of Biomedicine

    Christofori highlights the two major findings in the study: 

    “Firstly, we demonstrate that breast cancer cells that undergo an EMT and thus become malignant, metastatic and therapy-resistant, exhibit a high degree of stemness, also referred to as plasticity. It is thus possible to convert these malignant cells into other cell types, as shown here by a conversion to adipocytes.”

    “Secondly, the conversion of malignant breast cancer cells into adipocytes not only changes their differentiation status but also represses their invasive properties and thus metastasis formation and their proliferation. Note that adipocytes do not proliferate anymore, they are called ‘post-mitotic’, hence the therapeutic effect.”

    Since both drugs used in the preclinical study were FDA-approved the team are hopeful that it may be possible to translate this therapeutic approach to the clinic. 

    “Since in patients this approach could only be tested in combination with conventional chemotherapy, the next steps will be to assess in mouse models of breast cancer whether and how this trans-differentiation therapy approach synergizes with conventional chemotherapy. In addition, we will test whether the approach is also applicable to other cancer types. These studies will be continued in our laboratories in the near future.”

    Journal Reference: Ronen et al. Gain Fat–Lose Metastasis: Converting Invasive Breast Cancer Cells into Adipocytes Inhibits Cancer Metastasis. Cancer Cell. (2019). Available at: https://www.cell.com/cancer-cell/fulltext/S1535-6108(18)30573-7&nbsp;

    Gerhard Christofori was speaking to Laura Elizabeth Lansdowne, Science Writer for Technology Networks

    NEW NANOTECH DRIVES HEALING BY “TALKING” TO WOUNDS


    A Time To Heal

    Researchers from Imperial College London have created a new molecule that can “talk” to the cells in the area near injured tissues to encourage wound healing.

    “This intelligent healing is useful during every phase of the healing process, has the potential to increase the body’s chance to recover, and has far-reaching uses on many different types of wounds,” lead researcher Ben Almquist said in a news release.

    Setting A TrAP

    The Imperial team describes the wound-healing molecules, which it calls traction force-activated payloads (TrAPs), in a study published Monday in the journal Advanced Materials.

    The first step to creating TrAPs was folding segments of DNA into aptamers, which are three-dimensional shapes that latch tightly to proteins. The researchers then added a “handle” to one end of the aptamer.

    As cells navigated the area near a wound during lab testing, they would pull on this handle, causing the aptamer to open and release proteins that encouraged wound healing. By changing the handle, the researchers found they could control which cells activated the TrAPs.

    According to Almquist, “TrAPs provide a flexible method of actively communicating with wounds, as well as key instructions when and where they are needed.”

    To The Clinic

    It can take a long time for research to move from the laboratory to the clinical trial stage, but the TrAPs team might be able to speed along the path. That’s because aptamers are already used for drug delivery, meaning they’re already considered safe for human use.

    TrAPs are also fairly straightforward to create, meaning it wouldn’t be difficult to scale the technology to industrial levels. According to the researchers’ paper, doctors could then deliver the TrAPs via anything from collagen sponges to polyacrylamide gels. So if future testing goes well, the molecules could soon change how we heal a variety of wounds.

    READ MORE: New Material Could ‘Drive Wound Healing’ Using the Body’s Inbuilt Healing System [Imperial College London]

    More on aptamers: New Nanobots Kill Cancerous Tumors by Cutting off Their Blood Supply

    Story Source:

    Materials provided by Imperial College London. Original written by Caroline Brogan. Note: Content may be edited for style and length.


    Journal Reference:

    1. Anna Stejskalová, Nuria Oliva, Frances J. England, Benjamin D. Almquist. Biologically Inspired, Cell‐Selective Release of Aptamer‐Trapped Growth Factors by Traction Forces. Advanced Materials, 2018 DOI: 10.1002/adma.201806380