What’s New in Research: March 2016
Expansion Mini-Microscopy: High Quality Magnification on the Cheap
Researchers from Brigham and Women’s Hospital (BWH) and MIT have combined an innovative microscopy technique with a methodology for building inexpensive mini-microscopes, allowing them to capture images at a resolution that, until now, has only been possible with benchtop microscopes that are orders of magnitude higher in cost. Details about the hybrid technique, known as Expansion Mini-Microscopy (ExMM), are published this week in Scientific Reports.
The new work takes advantage of an expansion microscopy method recently developed by a group led by Edward Boyden, PhD, of the MIT Media Lab and McGovern Institute, and colleagues that uses a swellable gel to physically grow a specimen up to approximately 4.5 times its original dimensions. Bioengineers from BWH led by Ali Khademhosseini, PhD, director of the Biomaterials Innovation Research Center have recently built mini-microscopes from a webcam and off-the-shelf components, including fluorescence capacity with adjustable magnifications that cost as low as a few to a few tens of dollars per piece. However, the resolution of the images available using these mini-microscopes has been limited. Now, by integrating this approach with physical expansion of the samples, researchers have achieved a resolution comparable to the resolution previously attainable only by conventional benchtop microscopes.
As a proof of concept, the team put ExMM to the test by magnifying bacteria. They see wide-ranging applications for their technique, including use in developing countries for point-of-care diagnosis.
“We anticipate that our ExMM technology is likely to find widespread applications in low-cost, high-resolution imaging of biological and medical samples, potentially replacing the benchtop microscope in many cases where portability is a priority, such as in research and health care scenarios in undeveloped countries or remote places,” said Khademhosseini.
“The beauty of the ExMM technology lies in its simplicity—by combining physical and optical magnifications, high performance is achievable at a low cost. It’s a ‘best of both worlds’ technology, in a way, utilizing the best features of inexpensive chemicals and inexpensive optics,” said Boyden.
“The further advancement of the technology, through the development of cheap and simple ExMM detection kits and the algorithms associated with imaging processing, will allow streamlined sample preparation, imaging and analysis,” said co-first author, Shrike Zhang, PhD, of BWH’s Biomedical Division. Jae-Byum Chang, PhD, of the Boyden lab at MIT is also a co-first author of the study.
Paper cited: Zhang YS et al., “Hybrid Microscopy: Enabling Inexpensive High-Performance Imaging through Combined Physical and Optical Magnifications” Scientific Reports DOI: 10.1038/srep22691
Key Molecule in Microcalcification Formation Identified
The build-up of calcium mineral in blood vessels and heart valves – known as cardiovascular calcification – is a major contributor to cardiovascular diseases, whose burden on global health continues to increase as the population ages. A BWH research team, led by Elena Aikawa, MD, PhD, and the first author on the publication, Claudia Goettsch, PhD, investigated the molecular mechanism of microcalcification formation – a characteristic of unstable atherosclerotic plaques that are a major cause of heart attacks. The team identified sortilin as a key regulator of this calcification process. This sorting receptor operates independently of healthy bone mineralization, making modulating sortilin activity a promising therapeutic intervention strategy. The researchers’ results are published in the Journal of Clinical Investigation.
Their pre-clinical study found that sortilin regulates the trafficking and loading of an essential calcification enzyme into extracellular vesicles, thereby controlling the earliest sub-cellular events in microcalcification formation.
Previous genetic studies have detected an association between genetic differences potentially associated with the SORT1 gene and coronary artery calcification. This new work provides a biological mechanism that could explain this association.
“Our study unraveled a sortilin-mediated pathway and provides mechanistic insight into the formation of dangerous vascular microcalcification,” said Aikawa. “This can potentially lead to the development of anti-calcification therapies aimed at blocking sortilin pathways.”
Google Glass Meets Organs-On-Chips
BWH investigators have developed hardware and software to remotely monitor and control devices that mimic the human physiological system. Devices known as organs-on-chips allow researchers to test drug compounds and predict physiological responses with high accuracy in a laboratory setting. But monitoring the results of such experiments from a conventional desktop computer has several limitations, especially when results must be monitored over the course of hours, days or even weeks.
Google Glass, one of the newest forms of wearable technology, offers researchers a hands-free and flexible monitoring system. To make Google Glass work for their purposes, Zhang et al. custom developed hardware and software that takes advantage of voice control command (“ok glass”) and other features in order to not only monitor but also remotely control their liver- and heart-on-a-chip systems. Using valves remotely activated by the Glass, the team introduced pharmaceutical compounds on liver organoids and collected the results. Their results appear this week in Scientific Reports.
“We believe such a platform has widespread applications in biomedicine, and may be further expanded to health care settings where remote monitoring and control could make things safer and more efficient,” said senior author Ali Khademhosseini, PhD, Director of the Biomaterials Innovation Research Center at BWH.
“This may be of particular importance in cases where experimental conditions threaten human life – such as work involving highly pathogenic bacteria or viruses or radioactive compounds,” said leading author, Shrike Zhang, PhD, also of BWH’s Biomedical Division.
Paper cited: Zhang et al. “Google Glass-Directed Monitoring and Control of Microfluidic Biosensors and Actuators” Scientific Reports DOI: 10.1038/srep22237
Global Trends in Vaccine Discovery
In an analysis of global trends in vaccine research, Aaron Kesselheim, MD, JD, MPH, and Thomas Hwang of the Division of Pharmacoepidemiology and Pharmacoeconomics found that new vaccine production increased by 3-5 percentage points at all clinical testing stages over the past two decades. According to the World Health Organization (WHO), vaccines prevent approximately 2-3 million deaths per year, yet many serious infectious diseases like HIV and malaria still lack effective vaccines. Not only are vaccines a widely cost-effective treatment, they also indirectly benefit economic and social issues like cognitive development and labor productivity. The researchers hope their results will inform ongoing policy making in promoting and incentivizing vaccine discovery. Their findings are published in Health Affairs.
Hwang and Kesselheim collated information from Informa’s Pharmaprojects database, which tracks the progress of investigational products. The researchers noted that small- and medium-size companies accounted for nearly twice as many new vaccine trials as large companies, which dominate late-stage trials. The authors recommend that policymakers foster new vaccine development by targeting incentives to smaller companies with such tools as prizes or public-private partnerships that lower upfront costs.
“As key stakeholders aim to meet ambitious goals for vaccine discovery and delivery, there is renewed urgency in evaluating how various policy mechanisms could accelerate vaccine innovation and increase the range of diseases that can be prevented or treated by vaccines,” said the authors.
Paper cited: Hwang and Kesselheim. “Vaccine Pipeline Has Grown During The Past Two Decades With More Early-Stage Trials From Small And Medium-Size Companies.” Health Affairs. DOI: 10.1377/hlthaff.2015.1073.
Human Rights Failings in the Ebola Pandemic
After more than 28,000 cases of Ebola were reported between 2013 and 2015, a BWH-led team of researchers sought a more thorough understanding of the forces fueling the pandemic. Paul Farmer, MD, PhD, chief of BWH’s Division of Global Health Equity and co-founder of Partners In Health (PIH), and his colleagues highlight human rights failings as a major contributor to the rapid re-emergence of Ebola. This contrasts with analyses that emphasize biomedical and cultural causes (such as poor quality of care and flawed health services). In their recent paper, Farmer and his colleagues explain these inequalities with a biosocial approach: a way of thinking that they argue has not yet received enough attention in this context. Their paper is published in the Health and Human Rights Journal.
A biosocial approach provides an analysis of disease transmission with a critical social and political context. The researchers conducted systematic observations of hospitals and community care centers in West Africa and interviewed four Ebola survivors from Kono District in Sierra Leone. They incorporated their ethnographic data into accounts of the region’s political, economic, social and ecological climate. The researchers attributed the many preventable deaths to more ingrained and overarching factors, such as the poverty that drives over-extraction of resources and the exploitative government inherited from colonialism.
“An historically grounded, biosocial approach can foster a change towards a more reflexive understanding of outbreak responses in general, one that provides a corrective lens for biomedical tunnel vision,” said the authors.
Paper cited: Richardson ET et al. “Biosocial Approaches to the 2013-2016 Ebola Pandemic.” Health and Human Rights Journal, online available at http://www.hhrjournal.org/2015/12/biosocial-approaches-to-the-2013-2016-ebola-pandemic/
A Promising Target for Glioblastoma Therapies
BWH investigators have found that a microRNA present in all glioblastoma tumors may be a promising target for the development of therapies to treat this aggressive form of brain cancer. Their findings are published in EMBO Molecular Medicine.
Glioblastoma (GBM) is the most aggressive primary brain cancer, with a median survival time of 14 months after diagnosis. Unfortunately, very few drugs are approved for treating GBM, and those that have any success tend to be highly toxic with a significant tumor recurrence rate. GBM is particularly difficult to treat, since many mutations and epigenetic alterations make the disease unique in each patient. Researchers have recently identified high levels of microRNA-10b (miR-10b) as a defining trait of all GBM tumors, potentially providing a rare opportunity for a universal treatment approach. In a BWH-led pre-clinical study, investigators explored miR-10b’s role in the disease’s progression and their results indicate that miR-10b is a promising candidate for the development of targeted GBM therapies.
The researchers used mouse models to study how miR-10b helps cancer stem cells survive and whether targeting this microRNA could reduce tumor growth without harming healthy neuroglial cells. The team found that treatment with an inhibitor of miR-10b slowed growth and progression of GBM in mouse models of the disease without systemic toxic effects.
“This work demonstrates the feasibility of therapeutic miRNA targeting for GBM,” said Anna Krichevsky, PhD, of BWH’s Ann Romney Center for Neurologic Diseases. “Our preclinical results may point the way to a new and safe strategy for GBM treatment for all subtypes of GBM.”