Stronger treatments could cure Chagas disease

Researchers in the University of Georgia’s Center for Tropical and Emerging Global Diseases have found that a more intensive, less frequent drug regimen with currently available therapeutics could cure the infection that causes Chagas disease, a potentially life-threatening illness affecting up to 300,000 people in the United States.

Trypanosoma cruzi is a single-celled parasitic organism that causes Chagas disease. At least 6 million people are infected by T. cruzi, mostly in South America. Current drug therapies have been ineffective in completely clearing the infection and are associated with severe adverse side effects.

A single dose of benznidazole has been shown to be highly effective in killing more than 90% of parasites. However, after a CTEGD team found some of the parasites enter into a dormancy stage, the researchers hypothesized that an intermittent treatment schedule could be effective.

“In this system we can see what a single dose of drug does,” said Rick Tarleton, Regents’ Professor in UGA’s department of cellular biology. “Does it make sense to give a drug twice daily when the remaining dormant parasites are insensitive to it?”

The investigators found that giving as little as two-and-a-half times the typical daily dose of benznidazole, once per week for 30 weeks, completely cleared the infection, whereas giving the standard daily dose once a week for a longer period did not.

“Current human trials are only looking at giving lower doses over a shorter time period, which is the exact opposite of what we show works,” said Tarleton.

Since Tarleton’s team worked with a mouse model, how this change in treatment regimen will translate in humans is yet unknown, as are any potential side effects of the higher doses. Adverse reactions already are a problem with current treatments; the hope is that side effects from a less frequent dosage would be more tolerable.

Assessing the success of treatments in Chagas disease is a significant challenge. Tissue samples from infected organisms might not be representative of the entire organ or animal, since low numbers of persistent, dormant parasites can be difficult to detect. Therefore, Tarleton’s group used light sheet fluorescence microscopy to view intact whole organs from infected mice.

“With light sheet fluorescence microscopy, you have a broad view of potentially any tissue in the mouse that allows for dependable assessment of parasite load and persistence,” said Tarleton. “It gives you an incredible view of the infection.”

Using this technology, they learned something new about the dormant parasites: Some were still susceptible to drug treatment. This provides hope that new drug therapies could be developed to target these parasites.

“Discovery of new drugs should continue,” Tarleton said. “We still need better drugs.”

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Materials provided by University of Georgia. Original written by Donna Huber. Note: Content may be edited for style and length.

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Black soldier fly larvae as protein alternative for hungry humans

It may seem a little hard to swallow but the larvae of a waste-eating fly could become a new alternative protein source for humans, according to a University of Queensland scientist.

Professor Louw Hoffman said black soldier fly’s larvae, which was already utilised for animal feed, was a high quality protein.

“Just like meat, it contains all the nutrients humans need for health,” Professor Hoffman said.

“The larvae is richer in zinc and iron than lean meat, and its calcium content is as high as that of milk.”

“Their nutritional composition makes them an interesting contender as a meat alternative, and to date they have demonstrated their potential to partially replace meat in burger patties and Vienna sausages.”

Professor Hoffman said the United Nation’s Food and Agriculture Organization estimated that two billion people around the world already ate insects regularly as part of their diet.

“The biggest factor that prevents fly proteins being used in our food supply is Western consumer’s’ acceptance of insects as food,” he said.

“We will eat pea or oat milk, even lab-grown meats, but insects just aren’t on Western menus.”

Professor Hoffman has been studying the hurdles that need to be overcome before flies can directly enter the human food supply chain.

“There’s a lot of research that’s already been done on black soldier fly larvae as a feed for livestock, but we need to ensure we address safety issues before it can get legs as a human food,” he said.

“This includes understanding the different nutritional profiles of the fly at key stages of its growth, and the best ways to process the fly to preserve its nutritional value.

“While the fly can clean up toxic waste including heavy metals, it’s also recommended flies bred for human food be fed a clean source of organic waste.”

In addition to its nutrition profile, Professor Hoffman said there were strong environmental reasons for humans to eat fly larvae.

It’s estimated that less than half a hectare of black soldier fly larvae can produce more protein than cattle grazing on around 1200 hectares of cattle, or 52 hectares of soybeans.

“If you care about the environment, then you should consider and be willing to eat insect protein,” he said.

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Materials provided by University of Queensland. Note: Content may be edited for style and length.

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Study helps explain why motivation to learn declines with age

As people age, they often lose their motivation to learn new things or engage in everyday activities. In a study of mice, MIT neuroscientists have now identified a brain circuit that is critical for maintaining this kind of motivation.

This circuit is particularly important for learning to make decisions that require evaluating the cost and reward that come with a particular action. The researchers showed that they could boost older mice’s motivation to engage in this type of learning by reactivating this circuit, and they could also decrease motivation by suppressing the circuit.

“As we age, it’s harder to have a get-up-and-go attitude toward things,” says Ann Graybiel, an Institute Professor at MIT and member of the McGovern Institute for Brain Research. “This get-up-and-go, or engagement, is important for our social well-being and for learning — it’s tough to learn if you aren’t attending and engaged.”

Graybiel is the senior author of the study, which appears today in Cell. The paper’s lead authors are Alexander Friedman, a former MIT research scientist who is now an assistant professor at the University of Texas at El Paso, and Emily Hueske, an MIT research scientist.

Evaluating cost and benefit

The striatum is part of the basal ganglia — a collection of brain centers linked to habit formation, control of voluntary movement, emotion, and addiction. For several decades, Graybiel’s lab has been studying clusters of cells called striosomes, which are distributed throughout the striatum. Graybiel discovered striosomes many years ago, but their function had remained mysterious, in part because they are so small and deep within the brain that it is difficult to image them with functional magnetic resonance imaging (fMRI).

In recent years, Friedman, Graybiel, and colleagues including MIT research fellow Ken-ichi Amemori have discovered that striosomes play an important role in a type of decision-making known as approach-avoidance conflict. These decisions involve choosing whether to take the good with the bad — or to avoid both — when given options that have both positive and negative elements. An example of this kind of decision is having to choose whether to take a job that pays more but forces a move away from family and friends. Such decisions often provoke great anxiety.

In a related study, Graybiel’s lab found that striosomes connect to cells of the substantia nigra, one of the brain’s major dopamine-producing centers. These studies led the researchers to hypothesize that striosomes may be acting as a gatekeeper that absorbs sensory and emotional information coming from the cortex and integrates it to produce a decision on how to act. These actions can then be invigorated by the dopamine-producing cells.

The researchers later discovered that chronic stress has a major impact on this circuit and on this kind of emotional decision-making. In a 2017 study performed in rats and mice, they showed that stressed animals were far more likely to choose high-risk, high-payoff options, but that they could block this effect by manipulating the circuit.

In the new Cell study, the researchers set out to investigate what happens in striosomes as mice learn how to make these kinds of decisions. To do that, they measured and analyzed the activity of striosomes as mice learned to choose between positive and negative outcomes.

During the experiments, the mice heard two different tones, one of which was accompanied by a reward (sugar water), and another that was paired with a mildly aversive stimulus (bright light). The mice gradually learned that if they licked a spout more when they heard the first tone, they would get more of the sugar water, and if they licked less during the second, the light would not be as bright.

Learning to perform this kind of task requires assigning value to each cost and each reward. The researchers found that as the mice learned the task, striosomes showed higher activity than other parts of the striatum, and that this activity correlated with the mice’s behavioral responses to both of the tones. This suggests that striosomes could be critical for assigning subjective value to a particular outcome.

“In order to survive, in order to do whatever you are doing, you constantly need to be able to learn. You need to learn what is good for you, and what is bad for you,” Friedman says.

“A person, or this case a mouse, may value a reward so highly that the risk of experiencing a possible cost is overwhelmed, while another may wish to avoid the cost to the exclusion of all rewards. And these may result in reward-driven learning in some and cost-driven learning in others,” Hueske says.

The researchers found that inhibitory neurons that relay signals from the prefrontal cortex help striosomes to enhance their signal-to-noise ratio, which helps to generate the strong signals that are seen when the mice evaluate a high-cost or high-reward option.

Loss of motivation

Next, the researchers found that in older mice (between 13 and 21 months, roughly equivalent to people in their 60s and older), the mice’s engagement in learning this type of cost-benefit analysis went down. At the same time, their striosomal activity declined compared to that of younger mice. The researchers found a similar loss of motivation in a mouse model of Huntington’s disease, a neurodegenerative disorder that affects the striatum and its striosomes.

When the researchers used genetically targeted drugs to boost activity in the striosomes, they found that the mice became more engaged in performance of the task. Conversely, suppressing striosomal activity led to disengagement.

In addition to normal age-related decline, many mental health disorders can skew the ability to evaluate the costs and rewards of an action, from anxiety and depression to conditions such as PTSD. For example, a depressed person may undervalue potentially rewarding experiences, while someone suffering from addiction may overvalue drugs but undervalue things like their job or their family.

The researchers are now working on possible drug treatments that could stimulate this circuit, and they suggest that training patients to enhance activity in this circuit through biofeedback could offer another potential way to improve their cost-benefit evaluations.

“If you could pinpoint a mechanism which is underlying the subjective evaluation of reward and cost, and use a modern technique that could manipulate it, either psychiatrically or with biofeedback, patients may be able to activate their circuits correctly,” Friedman says.

The research was funded by the CHDI Foundation, the Saks Kavanaugh Foundation, the National Institutes of Health, the Nancy Lurie Marks Family Foundation, the Bachmann-Strauss Dystonia and Parkinson’s Foundation, the William N. and Bernice E. Bumpus Foundation, the Simons Center for the Social Brain, the Kristin R. Pressman and Jessica J. Pourian ’13 Fund, Michael Stiefel, and Robert Buxton.

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Scientists map structure of potent antibody against coronavirus

Scientists at Fred Hutchinson Cancer Research Center in Seattle have shown that a potent antibody from a COVID-19 survivor interferes with a key feature on the surface of the coronavirus’s distinctive spikes and induces critical pieces of those spikes to break off in the process.

The antibody — a tiny, Y-shaped protein that is one of the body’s premier weapons against pathogens including viruses — was isolated by the Fred Hutch team from a blood sample received from a Washington state patient in the early days of the pandemic.

The team led by Drs. Leo Stamatatos, Andrew McGuire and Marie Pancera previously reported that, among dozens of different antibodies generated naturally by the patient, this one — dubbed CV30 — was 530 times more potent than any of its competitors.

Using tools derived from high-energy physics, Hutch structural biologist Pancera and her postdoctoral fellow Dr. Nicholas Hurlburt have now mapped the molecular structure of CV30. They and their colleagues published their results online today in the journal Nature Communications.

The product of their research is a set of computer-generated 3D images that look to the untrained eye as an unruly mass of noodles. But to scientists they show the precise shapes of proteins comprising critical surface structures of antibodies, the coronavirus spike and the spike’s binding site on human cells. The models depict how these structures can fit together like pieces of a 3D puzzle.

“Our study shows that this antibody neutralizes the virus with two mechanisms. One is that it overlaps the virus’s target site on human cells, the other is that it induces shedding or dissociation of part of the spike from the rest,” Pancera said.

On the surface of the complex structure of the antibody is a spot on the tips of each of its floppy, Y-shaped arms. This infinitesimally small patch of molecules can neatly stretch across a spot on the coronavirus spike, a site that otherwise works like a grappling hook to grab onto a docking site on human cells.

The target for those hooks is the ACE2 receptor, a protein found on the surfaces of cells that line human lung tissues and blood vessels. But if CV30 antibodies cover those hooks, the coronavirus cannot dock easily with the ACE2 receptor. Its ability to infect cells is blunted.

This very effective antibody not only jams the business end of the coronavirus spike, it apparently causes a section of that spike, known as S1, to shear off. Hutch researcher McGuire and his laboratory team performed an experiment showing that, in the presence of this antibody, there is reduction of antibody binding over time, suggesting the S1 section was shed from the spike surface.

The S1 protein plays a crucial role in helping the coronavirus to enter cells. Research indicates that after the spike makes initial contact with the ACE2 receptor, the S1 protein swings like a gate to help the virus fuse with the captured cell surface and slip inside. Once within a cell, the virus hijacks components of its gene and protein-making machinery to make multiple copies of itself that are ultimately released to infect other target cells.

The incredibly small size of antibodies is difficult to comprehend. These proteins are so small they would appear to swarm like mosquitos around a virus whose structure can only be seen using the most powerful of microscopes. The tiny molecular features Pancera’s team focused on the tips of the antibody protein are measured in nanometers — billionths of a meter.

Yet structural biologists equipped with the right tools can now build accurate 3D images of these proteins, deduce how parts of these structures fit like puzzle pieces, and even animate their interactions.

Fred Hutch structural biologists developed 3D images of an antibody fished from the blood of an early COVID-19 survivor that efficiently neutralized the coronavirus.

Dr. Nicholas Hurlburt, who helped develop the images, narrates this short video showing how that antibody interacts with the notorious spikes of the coronavirus, blocking their ability to bind to a receptor on human cells that otherwise presents a doorway to infection.

Key to building models of these nanoscale proteins is the use of X-ray crystallography. Structural biologists determine the shapes of proteins by illuminating frozen, crystalized samples of these molecules with extremely powerful X-rays. The most powerful X-rays come from a gigantic instrument known as a synchrotron light source. Born from atom-smashing experiments dating back to the 1930s, a synchrotron is a ring of massively powerful magnets that are used to accelerate a stream of electrons around a circular track at close to the speed of light. Synchrotrons are so costly that only governments can build and operate them. There are only 40 of them in the world.

Pancera’s work used the Advanced Photon Source, a synchrotron at Argonne National Laboratory near Chicago, which is run by the University of Chicago and the U.S. Department of Energy. Argonne’s ring is 1,200 feet in diameter and sits on an 80-acre site.

As the electrons whiz around the synchrotron ring, they give off enormously powerful X-rays — far brighter than the sun but delivered in flashes of beams smaller than a pinpoint.

Structural biologists from around the world rely on these brilliant X-ray beamlines to illuminate frozen crystals of proteins. They reveal their structure in the way these bright beams are bent as they pass though the molecules. It takes powerful computers to translate the data readout from these synchrotron experiments into the images of proteins that are eventually completed by structural biologists.

The Fred Hutch team’s work on CV30 builds on that of other structural biologists who are studying a growing family of potent neutralizing antibodies against the coronavirus. The goal of most coronavirus vaccine candidates is to stimulate and train the immune system to make similar neutralizing antibodies, which can recognize the virus as an invader and stop COVID-19 infections before they can take hold.

Neutralizing antibodies from the blood of recovered COVID-19 patients may also be infused into infected patients — an experimental approach known as convalescent plasma therapy. The donated plasma contains a wide variety of different antibodies of varying potency. Although once thought promising, recent studies have cast doubt on its effectiveness.

However, pharmaceutical companies are experimenting with combinations of potent neutralizing antibodies that can be grown in a laboratory. These “monoclonal antibody cocktails” can be produced at industrial scale for delivery by infusion to infected patients or given as prophylactic drugs to prevent infection. After coming down with COVID-19, President Trump received an experimental monoclonal antibody drug being tested in clinical trials by the biotech company Regeneron, and he attributes his apparently quick recovery to the advanced medical treatment he received.

The Fred Hutch research team holds out hope that the protein they discovered, CV30, may prove to be useful in the prevention or treatment of COVID-19. To find out, this antibody, along with other candidate proteins their team is studying, need to be tested preclinically and then in human trials.

“It is too early to tell how good they might be,” Pancera said.

This work was supported by donations to the Fred Hutch COVID-19 Research Fund.

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Healthcare as a climate solution

Although the link may not be obvious, healthcare and climate change — two issues that pose major challenges around the world — are in fact more connected than society may realize. So say researchers, who are increasingly proving this to be true.

Case in point: A new study by UC Santa Barbara’s Andy MacDonald found that improving healthcare in rural Indonesia reduced incentives for illegal logging in a nearby national park, averting millions of dollars’ worth of atmospheric carbon emissions.

The analysis, published in the Proceedings of the National Academy of Sciences, finds that deforestation in the national park declined 70% in the 10 years after an affordable health clinic opened in the area. This equates to more than $65 million worth of avoided carbon emissions when translated to the European carbon market, the study reports.

“The results illustrate a strong link between human health and conservation in tropical forests in the developing world,” said MacDonald, an assistant researcher at the Earth Research Institute who coauthored the study with UC Santa Barbara’s David Lopez-Carr and colleagues at Stanford University, North Carolina State University Raleigh, Oregon Health and Science University, Natural Capital Advisors, and two NGOs involved in the intervention.

The Indonesian clinic accepts barter as payment and gives discounts to villages based on community-wide reductions in logging. Given its success, it could provide a blueprint for preserving the world’s biodiverse carbon sinks while reducing poverty and illness.

“This innovative model has clear global health implications,” said coauthor Michele Barry, senior associate dean of global health at Stanford and director of the Center for Innovation in Global Health. “Health and climate can and should be addressed in unison, and done in coordination with and respect for local communities.”

Every second, more than 100 trees disappear from tropical forests around the world. These forests, some of the world’s most important carbon reservoirs, are crucial to slowing climate change and mass extinction.

The current paradigm for conserving tropical forests — establishing protected areas — often excludes and disenfranchises local communities. This failure to address people’s needs can lead communities with few economic alternatives to illegally log and convert the land. Lack of access to high-quality, affordable healthcare can compound the problem by perpetuating cycles of poor health and expanding out-of-pocket costs.

With this in mind, the nonprofit organizations Alam Sehat Lestari and Health In Harmony in 2007 established a healthcare clinic adjacent to Gunung Palung National Park in West Kalimantan, Indonesia, with the support of the local government. The clinic was able to serve thousands of patients by accepting a range of alternative payments, such as tree seedlings, handicrafts and labor — an approach that was created in collaboration with the communities themselves.

Through agreements with most of the region’s district leaders, the clinic also provided discounts to villages that could show evidence of reductions in illegal logging. Between 1985 and 2001, this region had lost 60% of its forest to this activity. In addition to affordable health care, the intervention provided training in sustainable, organic agriculture and a chainsaw buyback program.

Researchers worked with the two non-profits to analyze more than 10 years of the clinic’s patient health records, coupled with satellite observations of forest cover over that time. “Private foundations funded the interventions, but it’s innovative new programs at Stanford and the University of California that are funding the research,” MacDonald said.

The medical care led to a significant decline in a range of diseases such as malaria, tuberculosis and diabetes. At the same time, satellite images of the national park showed a 70% reduction in deforestation, compared to forest loss at control sites, an amount equivalent to more than 6,770 acres of rainforest.

“We didn’t know what to expect when we started evaluating the program’s health and conservation impacts, but we were continually amazed that the data suggested such a strong link between improvements in healthcare access and tropical forest conservation,” said lead author Isabel Jones, who recently earned her doctorate in biology at Stanford. Looking more closely at community-level logging rates, the researchers found that the greatest drop-offs in logging occurred adjacent to villages with the highest rates of clinic usage.

A global blueprint

“This is a case study of how to design, implement and evaluate a planetary health intervention that addresses human health and the health of rainforests on which our health depends,” said coauthor Susanne Sokolow, a senior research scientist at Stanford.

Globally, about 35% of protected areas are traditionally owned, managed, used or occupied by Indigenous and local communities. Yet the perspective and guidance of Indigenous peoples and local communities are rarely considered in the design of conservation and climate mitigation programs. By contrast, the Indonesian clinic’s success grew out of the early and continued input of local communities who identified the mechanisms driving health and environmental problems as well as possible solutions.

Such holistic approaches can have greater long-term effects by preserving and restoring the ecosystem services that protect human health. These include natural filtering processes that reduce the risk of waterborne diseases and shade-providing forest canopies that reduce ground temperature and heat-related illnesses.

“The data support two important conclusions: human health is integral to the conservation of nature and vice versa, and we need to listen to the guidance of rainforest communities who know best how to live in balance with their forests,” said Monica Nirmala, the executive director of the clinic from 2014 to 2018 and current board member of Health In Harmony.

The clinic in West Kalimantan is still active, and the researchers are currently working on a follow-up project to see whether it and similar interventions in Indonesia have alleviated some of the shock from COVID-19 both on human health and deforestation.

“We would expect illegal logging activity to respond to changes in timber market prices or loss of income associated with COVID-19,” MacDonald said. “We want to know whether the interventions buffered communities against these effects, as well as whether they increased the communities’ resilience in terms of health and wellbeing.

“Health in Harmony is also expanding to Madagascar and Brazil,” he added, “and we want to be able to robustly evaluate the impacts of their interventions there.”

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