Microscopes allow researchers to peer into tiny cells and tissues by making the objects appear larger. However, visualizing extremely tiny cellular structures requires specialized microscopes that are very expensive, and even the most advanced microscopes are limited in how much they can magnify objects. Using a paradigm-shifting technique called expansion microscopy (ExM), Pioneer and Transformative Research Awardee Dr. Edward Boyden is taking the novel approach of actually making the samples themselves larger. Using a material commonly found in baby diapers, Dr. Boyden and colleagues at the Massachusetts Institute of Technology (MIT) are able to expand tissues to about 4.5 times their normal size, enabling visualization of tiny cellular structures and proteins with ordinary microscopes. This material, called sodium acrylate, holds proteins in place while it swells in the presence of water, resulting in minimal distortion of the sample’s structure. Using ExM, researchers could image a 3-dimensional slice of brain tissue and could zoom in to see the tiny synapse where neurons communicate with each other. By eliminating the need for costly, specialized equipment, ExM has the potential to enable many more scientists to examine structures otherwise unobservable in the cell.
(Photo: Dr. Edward Boyden presenting ExM at the Common Fund's High Risk, High Reward Research Symposium in December 2014)
Listen to Dr. Boyden’s talk at the Common Fund’s High Risk, High Reward Research Symposium (starts at 1 hour, 33 minutes)
Read the press release from MIT
Chen F, Tillberg PW, and Boyden ES. Expansion Microscopy. Science, Jan 2014, DOI: 10.1126/science.1260088.
Using a newly developed technology, a research team led by Dr. Kim Lewis of Northeastern University in Boston has discovered 25 new antibiotics, with one in particular very promising for potential future use to treat an array of difficult to treat human infections including MRSA (Methicillin-resistant Staphylococcus aureus), which in 2013 alone caused 480,000 infections. The Transformative Research Award was created specifically to support exceptionally innovative and/or unconventional research projects that have the potential to create or overturn fundamental paradigms. Although inherently risky, projects also have high potential to create breakthroughs that have the ability to change the landscape of a scientific area. (Photo: Slava Epstein/Northeastern University)
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Two NIH Common Fund High Risk-High Reward Awardees were named as winners of The Brain Prize for 2013, which is awarded by the Grete Lundbeck European Brain Research Foundation. Americans, Karl Deisseroth, a 2005 Pioneer Awardee, and 2012 Transformative Research Awardee, and Edward S. Boyden, a 2007 New Innovator, and 2012 Transformative Research Awardee and four European scientists were awarded the 2013 prize for their contributions to the development of “optogenetics.” Optogenetics is a technique that merges the fields of optics and genetics using light to specifically control the activity of genetically selected neurons. This revolutionary technique has allowed scientists to begin to gain a better understanding of the way circuits of neurons carry out complex functions. This technique has broad application potential in research from studying fundamental activities, such as memory formation and breathing, to more complex disorders and diseases, such as addiction, psychiatric disorders, and Alzheimer’s disease.
The Brain Prize, the world’s largest brain research prize, is awarded to scientists who have made an outstanding contribution to European brain research, and is awarded to scientists who have conducted research in Europe, or to scientists who have conducted research in collaboration with European scientists.
A major challenge to researchers studying the brain has been the inability to study a fully intact brain, from both the global and microscopic perspectives. For example, researchers might want to examine the way a chemical interacts with brain cells, or neurons, both in the context individual neurons and of long neural circuits across the entire brain. Previously, researchers had to choose either to study a fully intact brain, which involves a lengthy sample preparation process and potential structural dissimilarities compared to the original organ, or to study small sections of the brain where one can examine fine molecular and cellular interactions without knowledge of the original complex structure of the neural circuit and structure of the intact brain. Dr. Karl Deisseroth, a 2012 Transformative Research Awardee from Stanford University and his colleagues, have combined tools from the fields of chemical engineering, computational optics, and molecular genetics to develop a new technology to solve this problem by transforming a fully intact mouse brain into a completely clear gel-based brain with all structural and molecular integrity intact. This new technology, named Clear Lipid-exchanged Anatomically Rigid Imaging/immunostaining-compatible Tissue hYdrogel (CLARITY) replaces lipids, or fats, which make the brain appear white outside of the body, and help form the structural basis for the brain, with a clear gel-like material that binds to cells, proteins, DNA, RNA, and other small molecules in the brain. The result is a completely clear brain with a gel-like consistency that maintains the same molecular and cellular relationships and structure as the original brain.
The new process, allows researchers to fluorescently tag small molecules and specific cell types to visualize individual molecular interactions as well as entire cellular networks in 3-D providing insight at both the molecular and whole system level which previously was not possible. CLARITY can be used by researchers to observe fine details of brains from animals and human patients with symptomatic neurological diseases without losing the larger-scale whole system perspective, potentially leading to new insights into diseases that affect the brain.
- Read more about this exciting new technology and watch videos of mouse brains transformed using CLARITY in the NIH Press Release here
- Read about this exciting new technology in the NIH Director’s Blog here
- Read the New York Times Article here
Chung K, Wallace J, Kim S-Y, Kalyanasundaram S, Andalman AS, Davidson TJ, Mirzabekov JJ, Zalocusky KA, Mattis J, Denisin AK, Pak S, Bernstein H, Ramakrishnan C, Grosenick L, Gradinaru V, Deisseroth K. Structural and molecular interrogation of intact biological systems. Nature, April 10, 2012. DOI: 10.1038/Nature12107.
Drs. Kang Zhang and Sheng Ding, funded in part by the NIH Director’s Transformative R01 (T-R01) Award program, have unlocked the key to transforming human embryonic stem cells (hESCs) into a type of precursor cell that can be produced in large quantities and has the potential to become many different types of brain cells. Their findings, published in the May 17, 2011 issue of Proceedings of the National Academy of Sciences, represent a huge leap forward in stem cell science. hESCs, with their ability to become any cell type in the human body, hold great potential for repairing or replacing damaged tissues. However, a number of obstacles have prevented hESCs from fulfilling this promise. Scientists have faced challenges finding the right method to change hESCs into more specialized precursor cells, which can self-renew to produce large quantities of cells while also retaining the ability to become many different cell types within a specific tissue. Additionally, hESCs can cause the formation of tumors, which prohibits their use for therapeutic purposes. Drs. Zhang, Ding, and colleagues used a novel combination of small molecules to induce hESCs to become primitive neuronal stem cells (pNSCs), a cell type that can be directed to make many different types of neurons, or brain cells. Unlike hESCs, pNSCs did not induce tumor formation when injected into mice, which opens the door for potential therapeutic use. The researchers coaxed the pNSCs to form the types of neurons damaged by Parkinson’s disease and Lou Gehrig’s disease (amyotrophic lateral sclerosis; ALS), and suggest that pNSCs could be used to make many other types of neurons as well. This same method could be modified to direct hESCs to make other types of stem cells that could then be used to make heart, pancreas, or other tissue types. Future studies will need to examine how these cells could be used to treat a variety of human diseases.
Li W, Sun W, Zhang Y, Wei W, Ambasudhan R, Xia P, Talantova M, Lin T, Kim J, Wang X, Kim WR, Lipton SA, Zhag K, and Ding S. Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by small molecules inhibitors. Proceedings of the National Academy of Sciences, 2011 May 17; 108(20): 8299-8304. PMID: 21525408.
Dr. Miguel A. Nicolelis at Duke University and Dr. J. Keith Joung at Massachusetts General Hospital and Harvard Medical School received “duals honors” through the Common Fund’ High-Risk Research program in FY 2010: an NIH Director’s Transformative TR01 award and Pioneer Award. Dr. Nicolelis is using his T-R01 Award to study dorsal spinal column stimulation as a novel alternative treatment of Parkinson's disease. Dr. Joung is identifying and applying new technologies that use molecular regulators to regenerate specific components of the nervous system and treat neurodegenerative diseases with his TR01 award.