The math of malaria: Drug resistance 'a numbers game' of competing parasites

"Computer models can sometimes give you insights that would be too difficult to get in a real-world setting," says Mary Bushman. She developed a malaria model for her PhD thesis, advised by Emory evolutionary biologist Jaap de Roode. (Ann Watson, Emory Photo/Video)

By Carol Clark

A new mathematical model for malaria shows how competition between parasite strains within a human host reduces the odds of drug resistance developing in a high-transmission setting. But if a drug-resistant strain does become established, that same competition drives the spread of resistance faster, under strong selection from antimalarial drug use.

“It’s basically a numbers game,” says Mary Bushman, who developed the model for her PhD thesis in Emory University’s Population Biology, Ecology and Evolution Graduate Program. “When you already have multiple strains of malaria within a population, and a drug-resistant strain comes along, it will usually go extinct simply because it’s a late-comer. Whichever strain is there first has the advantage.”

PLOS Biology published the findings, a computational framework that modeled a malaria epidemic across multiple scales: Transmission of parasites from mosquitos to humans, and the dynamics of parasites competing to infect blood cells while they also battle the immune system of a human host.

After creating the model, Bushman ran simulations tracking malaria in a population for roughly 14 years. The simulations included 400 theoretical people who were randomly bitten by 12,000 mosquitos that were infected with malaria parasites classified as either drug resistant or drug susceptible. Various levels of treatment with antimalarial drugs were also part of the simulations.

“Our model holds strong relevance for infectious diseases beyond malaria,” says Jaap de Roode, an evolutionary biologist at Emory and senior author of the paper. “We hope this research gives others a method to look at disease dynamics across scales of biological organisms to learn how drug resistance develops in a range of pathogens.”

The study’s authors also include Emory biologist Rustom Antia (a specialist in infectious disease modeling) and Venkatachalam Udhayakumar, a malaria expert from the Centers of Disease Control and Prevention’s Division of Parasitic Diseases and Malaria.

The researchers are now working to develop their specific model for malaria into a generalized software tool for infectious diseases. “Computer models can sometimes give you insights that would be too difficult to get in a real-world setting,” says Bushman, who is now a post-doctoral fellow in the Antia lab.

"The distinction between establishment and spread just jumped out of the data," Bushman says.

Malaria occurs in poor, tropical and subtropical areas of the world, although most of the global death toll consists of children from sub-Saharan Africa. People infected in this high-transmission area often have multiple strains of the parasite and, by the time they have reached adulthood, they have usually developed partial immunity.

“It’s a baffling disease,” Bushman says. “Malaria has been studied for more than 100 years, much longer than most diseases, but there is still a lot that we don’t understand about it."

Malaria is caused by several species of Plasmodium parasites that are transmitted to humans by mosquitos. Plasmodium falciparum, the most common malaria parasite on the continent of Africa, is the one responsible for the most malaria-related deaths globally.

P. falciparum has developed resistance to former first-line therapies chloroquine and sulfadoxine-pyrimethamine. Resistance has also emerged in Southeast Asia to the third and last available treatment, artemisinin combination therapy, or ACT.

One of the mysteries about malaria is why drug-resistant strains tend to emerge first in low-transmission areas, like Southeast Asia, and not appear until much later in Africa, where transmission is high.

Previous research led by de Roode and Bushman showed that when people are co-infected with drug-resistant and drug-sensitive strains of malaria, both strains are competitively suppressed.

For the current paper, the researchers wanted to get a more detailed understanding of these dynamics. Some evidence had shown that within-host competition could suppress resistance, while other studies showed that it could ramp resistance up.

“It was a little bit of a puzzle, why the findings were conflicting,” Bushman says.

The new model, driven by evidence for how malaria parasites work within the immune system and the blood cells they infect, provided a solution to the puzzle.

“Some previous models were based on the assumption that when you put two strains of malaria into a host, they split 50-50,” Bushman says. “But our model showed that the system is asymmetrical. When you put two strains in a host they virtually never split 50-50.”

The late-comer will usually go extinct, which explains why in high-transmission areas drug resistant strains are at a big disadvantage. But in low transmission areas, such as Southeast Asia, a drug resistant strain has a better chance of arriving first in a host and getting established.

The new model also showed how once a drug-resistant strain becomes established in a high transmission area, it will spread much faster than it would in a low transmission area.

“The distinction between establishment and spread just jumped out of the data,” Bushman says. “Our model validated both sides of the argument — that within-host dynamics of competing parasites could both repress and accelerate the spread of resistance. The phenomena are occurring at different stages of the process so they both can happen.”

The results offer a new explanation for why chloroquine resistance arrived relatively late in Africa, appearing in Kenya and Tanzania in 1978, but then spread rapidly across the continent.

Related:
Mixed-strain malaria infections influence drug resistance
Zeroing in on 'super spreaders' and other hidden patterns of epidemics

Sensitivity to how others evaluate you emerges by 24 months

"Image management is fascinating to me because it's so important to being human," says Sara Valencia Botto, shown posing with a toddler.  The Emory graduate student published a study on how toddlers are attuned to image, along with psychology professor Philippe Rochat. (Kay Hinton, Emory Photo/Video)

By Carol Clark

Even before toddlers can form a complete sentence, they are attuned to how others may be judging them, finds a new study by psychologists at Emory University.

The journal Developmental Psychology is publishing the results, documenting that toddlers are sensitive to the opinions of others, and that they will modify their behavior accordingly when others are watching.

“We’ve shown that by the age of 24 months, children are not only aware that other people may be evaluating them, but that they will alter their behavior to seek a positive response,” says Sara Valencia Botto, an Emory PhD candidate and first author of the study.

While previous research has documented this behavior in four- to five-year-olds, the new study suggests that it may emerge much sooner, Botto says.

“There is something specifically human in the way that we’re sensitive to the gaze of others, and how systematic and strategic we are about controlling that gaze,” says Philippe Rochat, an Emory professor of psychology who specializes in childhood development and senior author of the study. “At the very bottom, our concern for image management and reputation is about the fear of rejection, one of the main engines of the human psyche.”

This concern for reputation manifests itself in everything from spending money on makeup and designer brands to checking how many “likes” a Facebook post garners.

“Image management is fascinating to me because it’s so important to being human,” Botto says. “Many people rate their fear of public speaking above their fear of dying. If we want to understand human nature, we need to understand when and how the foundation for caring about image emerges.”

The researchers conducted experiments involving 144 children between the ages of 14 and 24 months using a remotely controlled robot toy.

In one experiment, a researcher showed a toddler how to use the remote to operate the robot. The researcher then either watched the child with a neutral expression or turned away and pretended to read a magazine. When the child was being watched, he or she showed more inhibition when hitting the buttons on the remote than when the researcher was not watching.

In a second experiment, the researcher used two different remotes when demonstrating the toy to the child. While using the first remote, the researcher smiled and said, “Wow! Isn’t that great?” And when using the second remote, the researcher frowned and said “Uh-oh! Oops, oh no!” After inviting the child to play with the toy, the researcher once again either watched the child or turned to the magazine.

The children pressed the buttons on the remote associated with the positive response from the researcher significantly more while being watched. And they used the remote associated with the negative response more when not being watched.

During a third experiment, that served as a control, the researcher gave a neutral response of “Oh, wow!” when demonstrating how to use the two remotes. The children no longer chose one remote over the other depending on whether the researcher was watching them.

The control experiment showed that in the second experiment the children really did take into account the values expressed by the experimenter when interacting with the toy, and based on those values changed their behavior depending on whether they were being watched, Botto says.

A final experiment involved two researchers sitting next to one another and using one remote. One researcher smiled and gave a positive response, “Yay! The toy moved!” when pressing the remote. The second researcher frowned and said, “Yuck! The toy moved!” when pressing the same remote. The child was then invited to play with the toy while the two researchers alternated between either watching or turning their back to the child. Results showed that the children were much more likely to press the remote when the researcher who gave the positive response was watching.

“We were surprised by the flexibility of the children’s sensitivity to others and their reactions,” Botto says. “They could track one researcher’s values of two objects and two researchers’ values of one object. It reinforces the idea that children are usually smarter than we think.”

Botto is continuing to lead the research in the Rochat lab for her PhD thesis. She is now developing experiments for children as young as 12 months to see if the sensitivity to being evaluated by others emerges even earlier than the current study documents.

And she is following the 14- to 24-month-old children involved in the published study, to see if the individual differences they showed in the experiments are maintained as they turn four and five. The researchers are measuring social and cognitive factors that may have predictive power for individual differences — such as language ability, temperament and a child’s ability to pick up on social norms and to understand that people can have beliefs different from their own.

“Ultimately, we hope to determine exactly when children begin to be sensitive to others’ evaluations and the social and cognitive factors that are necessary for that sensitivity to emerge,” Botto says.

Such basic research may translate into helping people in a clinical environment who are at the extremes of the spectrum of such sensitivity, she adds.

“It’s normal and necessary to a certain extent to care about our image with others,” Botto says. “But some people care so much that they suffer from social anxiety, while others care so little that it is not optimal in a society where cooperation is essential.”

The American Psychological Association contributed to this report. 

Related:
Babies have logical reasoning before age one, study finds
Babies' spatial reasoning predicts later math skills

Students develop personal cooling device to help cope with climate change

The Vimband was developed by Emory undergraduates Ryan James, Jesse Rosen-Gooding and Hieren Helmn, in the hopes of winning the Hult Prize.

A trio of Emory students is on a globe-trotting million-dollar quest this summer to address one of the world’s most urgent challenges — helping people find physical comfort in the face of climate change.

One answer, they believe, might be the “Vimband,” their idea for a personal temperature-regulation device that could be worn to cool the body in extremely hot weather or warm individuals enduring severely cold temperatures.

Amid scientific reports that global temperatures are climbing, direct body cooling could go far in providing personal relief, especially for populations living in increasingly hot climates, says Ryan James, a sophomore from Highland, Maryland, majoring in business and computer science, who convened a team of Emory students eager to pose a solution to the problem.

“World-wide, the use of air-conditioning is expected to nearly triple by 2050, and with detrimental environmental effects, that isn’t a sustainable solution,” James says. “There needs to be an alternative.”

So instead of controlling the temperatures of large buildings or residences, the Emory team set their sights on a smaller, more efficient target — the individual. Together, they’ve created a prototype for a rechargeable device that essentially functions as a small, personalized heating and cooling unit. The compact box may be worn around the wrist, neck or head — pulse points on the human body near major arteries that play a critical role in regulating body temperature.

Click here to read more about the Vimband, and the students' quest to win the the Hult Prize, an annual business innovation challenge open to students around the world.

The search for secrets of ancient remedies

Cassandra Quave is a world leader in the field of medical ethnobotany — studying how indigenous people used plants in their healing practices to identify promising candidates for modern drugs.

Cassandra Quave (it rhymes with “wave”) is an assistant professor in Emory’s Center for the Study of Human Health and in the School of Medicine’s Department of Dermatology. She is also a member of the Emory Antibiotic Resistance Center.

The Florida native looks at home in the sweltering heat of South Georgia, standing behind a pick-up truck parked on a dirt road that winds through a longleaf pine forest. She tilts a straw cowboy hat back from her face and waves off a flurry of gnats. Her utility belt bristles with shears and a hunting knife. The unfolded gate of the truck bed serves as her desk, as she wrangles a leafy vine of passionflower into a wooden plant press.

 “The Cherokee pounded the roots of passionflower into a poultice to draw out pus from wounds, boils and abscesses,” Quave says. “Everywhere I look in this ecosystem I see plants that have a history of medicinal use by native peoples. The resin of the pine trees all around us, the fronds from the ferns beneath them and the roots of those beautiful yellow flowers over there — black-eyed Susans — were all used to treat wounds and sores.”

Read more here about Quave's field work this summer, and the undergraduates who helped her collect plants of importance to Native Americans.

Neuroscientists team with engineers to explore how the brain controls movement

The labs of Georgia Tech's Muhannad Bakir (far left) and Emory's Samuel Sober (far right) combined forces for the project. The work will be led by post-doctoral fellows in their labs, Georgia Tech's Muneeb Zia (center left) and Emory's Bryce Chung (center right). Photos by Ann Watson, Emory Photo/Video.

By Carol Clark

Scientists have made remarkable advances into recording the electrical activity that the nervous system uses to control complex skills, leading to insights into how the nervous system directs an animal’s behavior.

“We can record the electrical activity of a single neuron, and large groups of neurons, as animals learn and perform skilled behaviors,” says Samuel Sober, an associate professor of biology at Emory University who studies the brain and nervous system. “What’s missing,” he adds, “is the technology to precisely record the electrical signals of the muscles that ultimately control that movement.”

The Sober lab is now developing that technology through a collaboration with the lab of Muhannad Bakir, a professor in Georgia Tech’s School of Electrical and Computer Engineering. The researchers recently received a $200,000 Technological Innovations in Neuroscience Award from the McKnight Foundation to create a device that can record electrical action potentials, or “spikes” within muscles of songbirds and rodents. The technology will be used to help understand the neural control of many different skilled behaviors to potentially gain insights into neurological disorders that affect motor control.

“Our device will be the first that lets you record populations of spikes from all of the muscles involved in controlling a complex behavior,” Sober says. “This technique will offer unprecedented access to the neural signals that control muscles, allowing previously impossible investigations into how the brain controls the body.”

“By combining expertise in the life sciences at Emory with the engineering expertise of Georgia Tech, we are able to enter new scientific territory,” Bakir says. “The ultimate goal is to make discoveries that improve the quality of life of people.”

A prototype of the proposed device has 16 electrodes that can record data from a single muscle. The McKnight Award will allow the researchers to scale up to a device with more than 1,000 electrodes that can record from 10 or more muscles.

The Sober lab previously developed a prototype device — electrodes attached to flexible wires — to measure electrical activity in a breathing muscle used by Bengalese finches to sing. The way birds control their song has a lot in common with human speech, both in how it is learned early in life and how it is produced in adulthood. The neural pathways for birdsong are also well known, and restricted to that one activity, making birds a good model system for studying nervous system function.

“In experiments using our prototype, we discovered that, just like in brain cells, precise spike timing patterns in muscle cells are critical for controlling behavior — in this case breathing,” Sober says. 

The prototype device, however, is basic. Its 16 electrodes can only record activity from a single muscle — not the entire ensemble of muscles involved in birdsong. In order to gain a fuller picture of how neural signals control movement, neuroscientists need a much more sophisticated device.

The McKnight funding allowed Sober to team up with Bakir. Their goal is to create a micro-scale electromyography (EMG) sensor array, containing more than 1,000 electrodes, to record single-cellular data across many muscles.

The engineering challenges are formidable. The arrays need to be flexible enough to fit the shape of small muscles used in fine motor skills, and to change shape as the muscles contract. The entire device must also be tiny enough not to impede the movement of a small animal.

“Our first step is to build a flexible substrate on the micro-scale that can support high-density electrodes,” Bakir says. “And we will need to use microchips that work in parallel with 1,000 electrodes, and then attach them to that substrate.”

To meet that challenge, the Bakir lab will create a 3D integrated circuit. “Essentially, it’s building a miniature skyscraper of electrical circuits stacked vertically atop one another,” Bakir says. This vertical design will allow the researchers to minimize the size of the flexible substrate.

“To our knowledge, no one has done what we are trying to do in this project,” Bakir says. “That makes it more difficult, but also exciting because we are entering new space.”

The Sober lab will use the new device to expand its songbird vocalization studies. And it will explore how the nervous system controls the muscles involved when a mouse performs skilled movements with its forelimbs.

An early version of the technology will also be shared with collaborators of the Sober lab at three different universities. These collaborators will further test the arrays, while also gathering data across more species.

“We know so little about how the brain organizes skilled behaviors,” Sober says. “Once we perfect this technology, we will make it available to researchers in this field around the world, to advance knowledge as rapidly as possible.”

The mission of the McKnight Foundation’s Technological Innovations in Neuroscience Award, as described on its website, is “to bring science closer to the day when diseases of the brain and behavior can be accurately diagnosed, prevented and treated.”

Related:
Singing in the brain: Songbirds sing like humans
Dopamine key to vocal learning, songbird study finds