South Asia ICEMR receives 7-year, $9.3M renewal from NIH

Pradipsinh Rathod, left, and Laura Chery, right. Dennis Wise/University of Washington

The National Institutes of Health has renewed a major grant that funds a University of Washington-led research center to understand malaria in India.

The initiative — Malaria Evolution in South Asia (MESA), first funded in 2010 — is one of 10 NIH-supported International Centers of Excellence for Malaria Research, or ICEMRs. The National Institute of Allergy and Infectious Diseases announced that it would provide $9.3 million in funds to the South Asia ICEMR over the next seven years, beginning July 1, 2017.

South Asia sits in the middle of the malaria corridor that cuts from Southeast Asia to Africa.

“India is a country of critical importance for understanding the spread of virulent malaria globally,” said Pradipsinh K. Rathod, a UW professor of chemistry and the director of the Malaria Evolution in South Asia ICEMR. “While most deaths caused by drug-resistant strains of malaria have occurred in Africa, most drug-resistant parasites arise first in Asia.”

Malaria in India remains underappreciated. The country has 1.3 billion people and more than 90% of the population live in areas where there is risk of malaria transmission. India had an estimated 13 million cases of malaria in 2015, according to the World Health Organization. Beyond that, the picture of malaria in India is one of diversity.

“There is enormous variation in the prevalence of malaria around the country — variation in levels of immunity and variation in the species of mosquitoes that spread the disease,” said Laura Chery, the South Asia ICEMR’s associate director. “Most importantly, there is unexpectedly high genetic diversity in malaria parasites that are circulating in India.”

In addition to researchers from the UW, the South Asia ICEMR also includes U.S. scientists from Harvard University, the Fred Hutchinson Cancer Research Center, the Center for Infectious Disease Research and Stanford University. But by far the largest contingent of researchers that make up the center’s efforts are the dozens of scientists, clinicians and field workers at sites across India.

“We have formed wonderful, productive partnerships with hospitals, clinics, government agencies and community members,” said Chery. “Together, we have learned to do advanced science on the ground at clinically important sites.”

Through partnerships with local hospitals and research institutes, the center currently works out of six sites across India. The locations capture the diversity of this massive country: Four sites are in eastern and northeastern India, where malaria is endemic and cases can reach as high as 50 to 100 per 1,000 people. Two other sites are on the west coast, where the prevalence of malaria can be relatively low — fewer than 1 case per 1,000 people. But these sites include urban hospitals that attract and treat large numbers of malaria patients, including migrants from other parts of the country.

“We believe that movement of people within the country can partly explain the complexity of malaria in India,” said Rathod. “However, we do not fully understand the basis for such variations.”

At each site, staff enroll patients to obtain malaria parasite samples, as well as information on each patient’s health history. From on-site laboratories in India, center staff and partners pursue a number of research projects: analyzing parasite samples for signs of drug resistance, understanding the basis for variations in disease presentation, sequencing parasite genomes and determining their genetic relatedness to one another, and testing how well different mosquito species take up various malaria strains.

In addition to setting up complex research infrastructure, in its first seven years the center has made some surprising conclusions about malaria in India. Parasites in India show more genetic diversity than parasites in the rest of the world combined, according to Rathod. As a consequence, some standard laboratory tests for drug resistance, developed elsewhere in the world, do not accurately predict whether Indian parasites will show drug resistance.

Drug resistance is a major concern in malaria. Chloroquine was once an effective drug to fight malaria. But a generation ago, malaria parasites began to evolve resistance to it, rendering it largely ineffective. Today, the drug artemisinin is considered the best treatment against malaria. But artemisinin-resistant strains of malaria already have been identified in Southeast Asia. The Indian government and the South Asia ICEMR are on the lookout for artemisinin resistance among patients in northeastern and eastern India. Beyond that, the South Asia ICEMR is looking for parasites that mutate at extraordinary rates, as seen in Southeast Asia.

“By getting a clearer picture of malaria in India, we’re ‘closing the gap’ on how this complex parasite behaves globally,” Rathod said.

For the 2017-2024 cycle, other South Asia ICEMR project leaders are Neena Valecha, director of the National Institute of Malaria Research in India, and Manoj Duraisingh at Harvard University. Additional U.S.-based senior contributors are Joseph Smith at the Center for Infectious Disease Research, Shripad Tuljapurkar at Stanford University and James Kublin and Holly Janes at the Fred Hutchinson Cancer Research Center. Additional India-based senior contributors are Anup Anvikar at National Institute of Malaria Research; Subrata Baidya at Agartala Government Medical College; D.R. Bhattacharrya and P.K. Mohapatra at Regional Medical Research Centre, NE Region; Edwin Gomes at Goa Medical College & Hospital; Sanjeeb Kakati at Assam Medical College; Ashwani Kumar at National Institute of Malaria Research, Goa Field Unit; Sanjib Mohanty and A.K. Singh at Ispat General Hospital; and Swati Patankar at Indian Institute of Technology Bombay.

For more information about Professor Rathod and his research, please visit his faculty page or the NIH NIAID South Asia ICEMR website.

Story by James Urton, UW News. Additional coverage in the July 2017 Perspectives Newsletter from the College of Arts & Sciences.

 

Recent work by David Ginger and coworkers published in Nature Materials

Recent work by Professor David Ginger and colleagues was published online on June 19 in Nature Materials. The research was also highlighted in a News & Views article.

Lead author Rajiv Giridharagopal, left, and co-author Lucas Flagg standing next to an atomic force microscope. Dane deQuilettes

The Ginger group, in collaboration with Professor Christine Luscombe (Materials Science & Engineering) and the Clean Energy Institute, has discovered the basic design principles for constructing polymers that can transport both electrons and ions. This is a critical step toward making polymer-based devices at the interface of biology and electronics, such as improved biosensors and bioelectronics implants.

“Most of our technology relies on electronic currents, but biology transduces signals with ions, which are charged atoms or molecules,” said David Ginger, Alvin L. and Verla R. Kwiram Endowed Professor of Chemistry and chief scientist at the UW’s Clean Energy Institute. “If you want to interface electronics and biology, you need a material that effectively communicates across those two realms.”

UW researchers directly measured a thin film made of a single type of conjugated polymer—a conducting plastic—as it interacted with ions and electrons. They show how variations in the polymer layout yielded rigid and non-rigid regions of the film, and that these regions could accommodate electrons or ions—but not both equally. The softer, non-rigid areas were poor electron conductors but could subtly swell to take in ions, while the opposite was true for rigid regions.

The Luscombe group made new P3HT films that had different levels of rigidity based on variations in polymer arrangement. Tests conducted by the Ginger group showed a clear correlation between polymer arrangement and electrochemical properties. The less rigid and more amorphous polymer layouts yielded films that could swell to let in ions, but were poor conductors of electrons. More crystalline polymer arrangements yielded more rigid films that could easily conduct electrons.

Their results demonstrate how critical the polymer synthesis and layout process is to the film’s electronic and ionic conductance properties. Their findings may even point the way forward in creating polymer devices that can balance the demands of electronic transport and ion transport.

“The implication of these findings is that you could conceivably embed a crystalline material—which could transport electrons—within a material that is more amorphous and could transport ions,” said Ginger. “Imagine that you could harness the best of both worlds, so that you could have a material that is able to effectively transport electrons and swell with ion uptake—and then couple the two with one another.”

See the UW News article for expanded coverage.

To learn more about Professor Ginger and his research, please visit his faculty page and research group website.

To learn more about Professor Luscombe and her research, please visit her faculty page and research group website.

To learn more about the UW Clean Energy Institute, please visit the CEI website.

 

Recent work by Anne McCoy and coworkers published in Science

McCoy 2015 editWater conducts electricity, but the process by which this familiar fluid passes along positive charges has puzzled scientists for decades.

But in a paper published in the Dec. 2 issue of the journal Science, an international team of researchers has finally caught water in the act — showing how water molecules pass along excess charges and, in the process, conduct electricity.

“This fundamental process in chemistry and biology has eluded a firm explanation,” said co-author Anne McCoy, professor of chemistry. “And now we have the missing piece that gives us the bigger picture: how protons essentially ‘move’ through water.”

The team was led by Mark Johnson, senior author and a professor at Yale University. For over a decade, Johnson, McCoy and two co-authors — Professors Kenneth Jordan at the University of Pittsburgh and Knut Asmis at Leipzig University — have collaborated to understand how molecules in complex arrangements pass along charged particles.

Read the full UW News story here. To learn more about Professor McCoy and her research, visit her faculty page and research group website.

Recent work by David Masiello and coworkers published in Nature Photonics

masiello_nature-photonics_squareRecent work by Associate Professor David Masiello and colleagues was highlighted in a November 7 article in Nature Photonics. The research was also highlighted in Chemical & Engineering News and in a News & Views feature article in Nature Photonics.

Measurement of the two distinct components—scattering and absorption—of a single nanoscale object’s optical extinction provides fundamentally important and complementary information on how that object processes light: either scattering it back to the far-field or converting it into internal excitation. Today, various techniques exist to measure the scattering from individual nanoscale objects, all relying on the detection of scattered photons in regions of zero background. Measuring their absorption, however, is much more complicated due to the fundamental inability to detect extremely small reductions in transmission over statistical fluctuations in the number of photons. This means that the spectroscopic signature of the vast majority of molecules—specifically, those that are transformed into dark states through photoreactions—is difficult to access.

To overcome this challenge, researchers in the Masiello group and the Goldsmith group at the University of Wisconsin–Madison devised a new experimental route to measure the absorption spectra of individual, nonemissive nanoscale objects by photothermal contrast in an optical microresonator cavity.

Photothermal spectroscopies function by inferring an object’s absorption from the localized temperature increase and resulting refractive index inhomogeneity produced by the excited object’s nonradiative decay. In their work, the team coupled individual plasmonic nanorods to an ultrahigh-quality optical microresonator cavity and succeeded in determining the nanorod’s absorption spectrum by monitoring the temperature-dependent attometer shifts in the resonance frequency of microresonator’s whispering gallery modes. These exceedingly small but detectable resonance shifts correspond to temperature increases of ~100 nK (measured at room temperature!), making their absorption spectrometer simultaneously one of the world’s best thermometers. Suprisingly, the nanorod’s absorption spectrum revealed a dense array of sharp Fano interferences arising from its interaction with the whispering gallery modes of the microresonator, allowing the team to deeply explore the hybridization of plasmonic and photonic cavity modes.

This collaborative effort brought together the creativity and talents of several graduate students and postdocs in multiple departments between the two institutions. The results were achieved following years of hard work involving both theorists and experimentalists. Future directions will explore the feasibility of this system to serve as a platform for studying quantum physics at room temperature.

To learn more about Professor Masiello and his research, visit his faculty page and research group website.

Nature Methods cover article details refined, accessible technique for expansion microscopy

dividing_finalCongratulations to Assistant Professor Joshua Vaughan and his UW co-workers, whose recent work was featured on the cover of Nature Methods. Their report details the development of a simplified method to “inflate” cellular structures for use in an imaging technique known as expansion microscopy.

Efforts to improve the resolution of cellular structures typically focus on addressing the limitations of microscope hardware. With expansion microscopy, higher resolution is achieved through physical alteration of the specimen. By linking swellable polymers to customized fluorophores, researchers can physically expand the specimen to enable super-resolution microscopy with a conventional laboratory microscope.

As noted in the journal, Vaughan and co-workers have “developed and characterized new methods for linking fluorophores to the polymer that now enable expansion microscopy with conventional fluorescently labeled antibodies and fluorescent proteins.” By simplifying the procedure and expanding fluorophore options, they came up with separate approaches to provide high resolution imaging of individual cells and of tissue slices. In addition to facilitating a range of biological studies, these refinements broadly expand access to the technique, enabling researchers to use a variety of conventional fluorophores and ordinary laboratory microscopes to achieve high resolution cellular imaging.

More information about this work can be found in Nature Methods and in the UW News press release.

For more information about Professor Vaughan and his research, please visit his faculty page and research group website.

Recent work by Jesse Zalatan featured on the cover of Cell

Assistant Professor Jesse Zalatan and co-workers at the UCSF have developed a method to encode complex, synthetic transcriptional regulatory programs using the CRISPR-Cas system. Natural biological systems can switch between different functional or developmental states depending on the particular set of genes being expressed, and the ability to synthetically control gene expression has important implications as both a research tool and as a means to engineer novel cell-based therapeutics and devices.

Zalatan and coworkers designed CRISPR-Cas RNA scaffold molecules that specify both a DNA target and the function to execute at the target, so that sets of RNA scaffolds can be used to generate a synthetic, multigene transcriptional program in eukaryotic cells in which some genes are activated and others are repressed. These types of programs can be used to reprogram complex reaction networks in biological systems, such as metabolic pathways or signaling cascades.

For more information about Professor Zalatan and his research, please visit his faculty page and research group website.

Boydston research group has back-to-back papers highlighted in C&E News

boydstonResearch by Assistant Professor AJ Boydston and his group has been featured in two recent articles in the American Chemical Society’s Chemical & Engineering News. An article in the December 18, 2014 issue highlights his research on polymers that change color when stretched (http://cen.acs.org/articles/92/web/2014/12/3-D-Printed-Polymer-Devices.html). Just one month later, an article in the January 19, 2015 issue summarized the Boydston group’s research on a metal-free route to prepare polymers (http://cen.acs.org/articles/93/i3/Radical-Polymer-Approach.html).

For more information about Professor Boydston and his research program, please visit his faculty page and research group website.

UW researchers uncover the molecular basis of the heartbeat

Stoll HCNconformationchange editAssistant Professor Stefan Stoll (Chemistry), Professor William Zagotta (Physiology & Biophysics), and co-workers have used double electron-electron resonance (DEER) spectroscopy to determine the structural origins of the regulatory function of cyclic adenosine monophosphate (cAMP) on an important ion channel. Their work reveals that binding of the cAMP induces a large structural change in the intracellular part of the channel. The ion channel studied, a hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channel, is critical to the function of heart, as it is part of the heart’s natural pacemaker. The HCN channel is crucial in regulating the heartbeat: binding of cAMP to HCN increases of the heart rate. This work, reported in the Proceedings of the National Academy of Sciences, could form the basis for better drug design for disorders of electrical signaling in the heart. (A movie showing a model of the structural change can be downloaded in Quicktime format from: http://felix.chem.washington.edu/HCN_DEER_movie.mov.)

To learn more about Professor Stoll and his research, please visit his faculty page and research group website.

To learn more about Professor Zagotta and his research, please visit his faculty page.

Department ranks 10th nationally for research spending

nsf_smallOne measure of the scale and strength of chemistry research programs is success in the allocation of competitively awarded grant and contract funds in support of research. The Department of Chemistry at the University of Washington has in recent years been among the leaders nationally by this measure. According to the most recent (2012) National Science Foundation Survey of Higher Education Research and Development, the University of Washington Department of Chemistry is ranked 10th nationally for overall research and development spending in chemistry, appearing just below the Department of Chemistry at the Massachusetts Institute of Technology for total expenditures. In terms of federally-funded research and development spending, the Department of Chemistry ranks 8th nationally.

Date related to the survey can be found at http://www.nsf.gov/statistics/herd/.

Multi-disciplinary approach to understanding Botulinum toxin

RonetalFigResearch Associate Professor Werner Kaminsky contributed to a research project recently highlighted in Nature. With the catch phrase “BOTOX paralyses zebrafish muscles and blocks fin regeneration”, Nature highlighted a publication on the effect of Botulinum toxin on bone regeneration,[i] tested on small fish, whose fins were cut-off (under sedation), then regrown while testing different amounts of medications administrated to the fish’s dorsolateral trunk and the base of the tail fin prior to surgery.[ii] Nature summed up the findings with “muscle paralysis (was) similar to that seen in mammals and humans in that it was focal, dose-dependent and short-lasting.” and “BTx treatment had a negative impact on bone formation during fin regeneration.” The work involved a truly diverse multi-discipline co-operation between members of three departments on the UW campus: Orthopaedics and Sports Medicine, Pharmacology, and Chemistry. The regenerating zebrafish tail fin often provides a compelling model for therapeutic studies. However, a major hurdle to such efforts is the lack of quantitative modalities for bone mineralization analysis. Kaminsky contributed his patented microscopy technology to determine bone mineralization with a custom built automated polarized light microscope to sequentially acquire images under a stepwise rotating polarizer. This enabled birefringence to be decoupled from transmittance and orientation, allowing for quantitative analysis.

 

[i]http://onlinelibrary.wiley.com/doi/10.1002/jbmr.2274/abstract;jsessionid=DF9492DBD18E5943C72A2F63D73A2816.f03t04

[ii]http://www.nature.com/bonekey/knowledgeenvironment/2014/140806/bonekey201463/full/bonekey201463.html