Monday, July 25th, 2016

Time	Event
11:00a	Imaging the brain at multiple size scales MIT researchers have developed a new technique for imaging brain tissue at multiple scales, allowing them to peer at molecules within cells or take a wider view of the long-range connections between neurons. This technique, known as magnified analysis of proteome (MAP), should help scientists in their ongoing efforts to chart the connectivity and functions of neurons in the human brain, says Kwanghun Chung, the Samuel A. Goldblith Assistant Professor in the Department of Chemical Engineering, and a member of MIT’s Institute for Medical Engineering and Science (IMES) and Picower Institute for Learning and Memory. “We use a chemical process to make the whole brain size-adjustable, while preserving pretty much everything. We preserve the proteome (the collection of proteins found in a biological sample), we preserve nanoscopic details, and we also preserve brain-wide connectivity,” says Chung, the senior author of a paper describing the method in the July 25 issue of Nature Biotechnology. The researchers also showed that the technique is applicable to other organs such as the heart, lungs, liver, and kidneys. The paper’s lead authors are postdoc Taeyun Ku, graduate student Justin Swaney, and visiting scholar Jeong-Yoon Park. Multiscale imaging The new MAP technique builds on a tissue transformation method known as CLARITY, which Chung developed as a postdoc at Stanford University. CLARITY preserves cells and molecules in brain tissue and makes them transparent so the molecules inside the cell can be imaged in 3-D. In the new study, Chung sought a way to image the brain at multiple scales, within the same tissue sample. “There is no effective technology that allows you to obtain this multilevel detail, from brain region connectivity all the way down to subcellular details, plus molecular information,” he says. To achieve that, the researchers developed a method to reversibly expand tissue samples in a way that preserves nearly all of the proteins within the cells. Those proteins can then be labeled with fluorescent molecules and imaged. The technique relies on flooding the brain tissue with acrylamide polymers, which can form a dense gel. In this case, the gel is 10 times denser than the one used for the CLARITY technique, which gives the sample much more stability. This stability allows the researchers to denature and dissociate the proteins inside the cells without destroying the structural integrity of the tissue sample. Before denaturing the proteins, the researchers attach them to the gel using formaldehyde, as Chung did in the CLARITY method. Once the proteins are attached and denatured, the gel expands the tissue sample to four or five times its original size. “It is reversible and you can do it many times,” Chung says. “You can then use off-the-shelf molecular markers like antibodies to label and visualize the distribution of all these preserved biomolecules.” There are hundreds of thousands of commercially available antibodies that can be used to fluorescently tag specific proteins. In this study, the researchers imaged neuronal structures such as axons and synapses by labeling proteins found in those structures, and they also labeled proteins that allow them to distinguish neurons from glial cells. “We can use these antibodies to visualize any target structures or molecules,” Chung says. “We can visualize different neuron types and their projections to see their connectivity. We can also visualize signaling molecules or functionally important proteins.” High resolution Once the tissue is expanded, the researchers can use any of several common microscopes to obtain images with a resolution as high as 60 nanometers — much better than the usual 200 to 250-nanometer limit of light microscopes, which are constrained by the wavelength of visible light. The researchers also demonstrated that this approach works with relatively large tissue samples, up to 2 millimeters thick. “This is, as far as I know, the first demonstration of super-resolution proteomic imaging of millimeter-scale samples,” Chung says. “This is an exciting advance for brain mapping, a technique that reveals the molecular and connectional architecture of the brain with unprecedented detail,” says Sebastian Seung, a professor of computer science at the Princeton Neuroscience Institute, who was not involved in the research. Currently, efforts to map the connections of the human brain rely on electron microscopy, but Chung and colleagues demonstrated that the higher-resolution MAP imaging technique can trace those connections more accurately. Chung’s lab is now working on speeding up the imaging and the image processing, which is challenging because there is so much data generated from imaging the expanded tissue samples. “It’s already easier than other techniques because the process is really simple and you can use off-the-shelf molecular markers, but we are trying to make it even simpler,” Chung says. (Comment on this)
11:00a	Patch that delivers drug, gene, and light-based therapy to tumor sites shows promising results Approximately one in 20 people will develop colorectal cancer in their lifetime, making it the third-most prevalent form of the disease in the U.S. In Europe, it is the second-most common form of cancer. The most widely used first line of treatment is surgery, but this can result in incomplete removal of the tumor. Cancer cells can be left behind, potentially leading to recurrence and increased risk of metastasis. Indeed, while many patients remain cancer-free for months or even years after surgery, tumors are known to recur in up to 50 percent of cases. Conventional therapies used to prevent tumors recurring after surgery do not sufficiently differentiate between healthy and cancerous cells, leading to serious side effects. In a paper published today in the journal Nature Materials, researchers at MIT describe an adhesive patch that can stick to the tumor site, either before or after surgery, to deliver a triple-combination of drug, gene, and photo (light-based) therapy. Releasing this triple combination therapy locally, at the tumor site, may increase the efficacy of the treatment, according to Natalie Artzi, a principal research scientist at MIT’s Institute for Medical Engineering and Science (IMES) and an assistant professor of medicine at Brigham and Women’s Hospital, who led the research. The general approach to cancer treatment today is the use of systemic, or whole-body, therapies such as chemotherapy drugs. But the lack of specificity of anticancer drugs means they produce undesired side effects when systemically administered. What’s more, only a small portion of the drug reaches the tumor site itself, meaning the primary tumor is not treated as effectively as it should be. Indeed, recent research in mice has found that only 0.7 percent of nanoparticles administered systemically actually found their way to the target tumor. “This means that we are treating both the source of the cancer — the tumor — and the metastases resulting from that source, in a suboptimal manner,” Artzi says. “That is what prompted us to think a little bit differently, to look at how we can leverage advancements in materials science, and in particular nanotechnology, to treat the primary tumor in a local and sustained manner.” The researchers have developed a triple-therapy hydrogel patch, which can be used to treat tumors locally. This is particularly effective as it can treat not only the tumor itself but any cells left at the site after surgery, preventing the cancer from recurring or metastasizing in the future. Firstly, the patch contains gold nanorods, which heat up when near-infrared radiation is applied to the local area. This is used to thermally ablate, or destroy, the tumor. These nanorods are also equipped with a chemotherapy drug, which is released when they are heated, to target the tumor and its surrounding cells. Finally, gold nanospheres that do not heat up in response to the near-infrared radiation are used to deliver RNA, or gene therapy to the site, in order to silence an important oncogene in colorectal cancer. Oncogenes are genes that can cause healthy cells to transform into tumor cells. The researchers envision that a clinician could remove the tumor, and then apply the patch to the inner surface of the colon, to ensure that no cells that are likely to cause cancer recurrence remain at the site. As the patch degrades, it will gradually release the various therapies. The patch can also serve as a neoadjuvant, a therapy designed to shrink tumors prior to their resection, Artzi says. When the researchers tested the treatment in mice, they found that in 40 percent of cases where the patch was not applied after tumor removal, the cancer returned. But when the patch was applied after surgery, the treatment resulted in complete remission. Indeed, even when the tumor was not removed, the triple-combination therapy alone was enough to destroy it. The technology is an extraordinary and unprecedented synergy of three concurrent modalities of treatment, according to Mauro Ferrari, president and CEO of the Houston Methodist Research Institute, who was not involved in the research. “What is particularly intriguing is that by delivering the treatment locally, multimodal therapy may be better than systemic therapy, at least in certain clinical situations,” Ferrari says. Unlike existing colorectal cancer surgery, this treatment can also be applied in a minimally invasive manner. In the next phase of their work, the researchers hope to move to experiments in larger models, in order to use colonoscopy equipment not only for cancer diagnosis but also to inject the patch to the site of a tumor, when detected. “This administration modality would enable, at least in early-stage cancer patients, the avoidance of open field surgery and colon resection,” Artzi says. “Local application of the triple therapy could thus improve patients’ quality of life and therapeutic outcome.” Artzi is joined on the paper by João Conde, Nuria Oliva, and Yi Zhang, of IMES. Conde is also at Queen Mary University in London. (Comment on this)
11:00a	New lithium-oxygen battery greatly improves energy efficiency, longevity Lithium-air batteries are considered highly promising technologies for electric cars and portable electronic devices because of their potential for delivering a high energy output in proportion to their weight. But such batteries have some pretty serious drawbacks: They waste much of the injected energy as heat and degrade relatively quickly. They also require expensive extra components to pump oxygen gas in and out, in an open-cell configuration that is very different from conventional sealed batteries.  But a new variation of the battery chemistry, which could be used in a conventional, fully sealed battery, promises similar theoretical performance as lithium-air batteries, while overcoming all of these drawbacks. The new battery concept, called a nanolithia cathode battery, is described in the journal Nature Energy in a paper by Ju Li, the Battelle Energy Alliance Professor of Nuclear Science and Engineering at MIT; postdoc Zhi Zhu; and five others at MIT, Argonne National Laboratory, and Peking University in China. One of the shortcomings of lithium-air batteries, Li explains, is the mismatch between the voltages involved in charging and discharging the batteries. The batteries’ output voltage is more than 1.2 volts lower than the voltage used to charge them, which represents a significant power loss incurred in each charging cycle. “You waste 30 percent of the electrical energy as heat in charging. … It can actually burn if you charge it too fast,” he says. Staying solid Conventional lithium-air batteries draw in oxygen from the outside air to drive a chemical reaction with the battery’s lithium during the discharging cycle, and this oxygen is then released again to the atmosphere during the reverse reaction in the charging cycle. In the new variant, the same kind of electrochemical reactions take place between lithium and oxygen during charging and discharging, but they take place without ever letting the oxygen revert to a gaseous form. Instead, the oxygen stays inside the solid and transforms directly between its three redox states, while bound in the form of three different solid chemical compounds, Li2O, Li2O2, and LiO2, which are mixed together in the form of a glass. This reduces the voltage loss by a factor of five, from 1.2 volts to 0.24 volts, so only 8 percent of the electrical energy is turned to heat. “This means faster charging for cars, as heat removal from the battery pack is less of a safety concern, as well as energy efficiency benefits,” Li says. This approach helps overcome another issue with lithium-air batteries: As the chemical reaction involved in charging and discharging converts oxygen between gaseous and solid forms, the material goes through huge volume changes that can disrupt electrical conduction paths in the structure, severely limiting its lifetime. The secret to the new formulation is creating minuscule particles, at the nanometer scale (billionths of a meter), which contain both the lithium and the oxygen in the form of a glass, confined tightly within a matrix of cobalt oxide. The researchers refer to these particles as nanolithia. In this form, the transitions between LiO2, Li2O2, and Li2O can take place entirely inside the solid material, he says. The nanolithia particles would normally be very unstable, so the researchers embedded them within the cobalt oxide matrix, a sponge-like material with pores just a few nanometers across. The matrix stabilizes the particles and also acts as a catalyst for their transformations. Conventional lithium-air batteries, Li explains, are “really lithium-dry oxygen batteries, because they really can’t handle moisture or carbon dioxide,” so these have to be carefully scrubbed from the incoming air that feeds the batteries. “You need large auxiliary systems to remove the carbon dioxide and water, and it’s very hard to do this.” But the new battery, which never needs to draw in any outside air, circumvents this issue. No overcharging The new battery is also inherently protected from overcharging, the team says, because the chemical reaction in this case is naturally self-limiting — when overcharged, the reaction shifts to a different form that prevents further activity. “With a typical battery, if you overcharge it, it can cause irreversible structural damage or even explode,” Li says. But with the nanolithia battery, “we have overcharged the battery for 15 days, to a hundred times its capacity, but there was no damage at all.” In cycling tests, a lab version of the new battery was put through 120 charging-discharging cycles, and showed less than a 2 percent loss of capacity, indicating that such batteries could have a long useful lifetime. And because such batteries could be installed and operated just like conventional solid lithium-ion batteries, without any of the auxiliary components needed for a lithium-air battery, they could be easily adapted to existing installations or conventional battery pack designs for cars, electronics, or even grid-scale power storage. Because these “solid oxygen” cathodes are much lighter than conventional lithium-ion battery cathodes, the new design could store as much as double the amount of energy for a given cathode weight, the team says. And with further refinement of the design, Li says, the new batteries could ultimately double that capacity again. All of this is accomplished without adding any expensive components or materials, according to Li. The carbonate they use as the liquid electrolyte in this battery “is the cheapest kind” of electrolyte, he says. And the cobalt oxide component weighs less than 50 percent of the nanolithia component. Overall, the new battery system is “very scalable, cheap, and much safer” than lithium-air batteries, Li says. The team expects to move from this lab-scale proof of concept to a practical prototype within about a year. “This is a foundational breakthrough, which may shift the paradigm of oxygen-based batteries,” says Xiulei Ji, an assistant professor of chemistry at Oregon State University, who was not involved in this work. “In this system, commercial carbonate-based electrolyte works very well with solvated superoxide shuttles, which is quite impressive and may have to do with the lack of any gaseous O2 in this sealed system. All active masses of the cathode throughout cycling are solid, which presents not only large energy density but compatibility with the current battery manufacturing infrastructure.” The research team included MIT research scientists Akihiro Kushima and Zongyou Yin; Lu Qi of Peking University; and Khalil Amine and Jun Lu of Argonne National Laboratory in Illinois. The work was supported by the National Science Foundation and the U.S. Department of Energy. (Comment on this)

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