Zika virus 'a game-changer' for mosquito-borne diseases

The Aedes aegypti mosquito, which transmits Zika, as well as the dengue and chikungunya viruses. “Mosquito control is not considered ‘sexy’ science, like developing a new drug or a vaccine,” says Emory disease ecologist Uriel Kitron, “but more attention and resources need to be devoted to it.”

By Carol Clark

The Zika virus, unlike other mosquito-borne viruses such as dengue, is relatively unknown and unstudied. That is set to change since Zika, now spreading through Latin America and the Caribbean, has been associated with an alarming rise in babies born in Brazil with abnormally small heads and brain defects – a condition called microcephaly.

“This is a huge public health emergency and horrible on many levels,” says Uriel Kitron, chair of Emory’s Department of Environmental Sciences and an expert in vector-borne diseases, which are transmitted by mosquitoes, ticks or other organisms. “The microcephaly cases are a personal tragedy for the families whose babies are affected. They will need much care and support, some of them for decades. The costs to the public health system will be enormous, and Brazil was already experiencing an economic crisis.”

For the past several years, Kitron has collaborated with Brazilian scientists and health officials to study the dengue virus, which is spread by the same mosquito species, Aedes aegypti, as Zika. The focus of that collaboration is now shifting to Zika. Kitron will return to Salvador, the capital of the Brazilian state of Bahia, in February to support the country’s research strategies and control efforts for the outbreak.

“Dengue is a very serious disease, but it doesn’t usually kill people,” Kitron says. “Zika is a game-changer. It appears that this virus may pass through a woman’s placenta and impact her unborn child. That’s about as scary as it gets.”

Since the Zika outbreak began in northeastern Brazil last spring, an estimated 500,000 to 1.5 million people have been infected. The resulting illness only lasts a few days. The symptoms, including a rash, joint pains, inflammation of the eyes and fever, tend to be less debilitating than those of dengue. As many as 80 percent of infected people may be asymptomatic.

It was not until months after Zika cases showed up in Brazil that a spike in microcephaly births was tied to women infected during pregnancy. More than 3,500 microcephaly cases have been reported since October in Brazil, compared to around 150 cases in 2014.

While Zika’s connection to microcephaly has yet to be definitively proven, the presence of the virus has been found in the bodies of five of the newborns that died with the condition and in the placentas of two women who miscarried babies with microcephaly.

The Centers for Disease Control and Prevention has warned pregnant women not to travel unnecessarily to more than a dozen countries currently experiencing an outbreak of Zika virus, as well as Puerto Rico. The governments of Brazil, El Salvador and Columbia, meanwhile, are urging women to delay any plans of pregnancy.

“People are worried that Zika may also have other, more subtle, effects on fetuses besides microcephaly,” Kitron says. “We just don’t know that much about Zika. It has not been studied extensively in the lab and field data is also limited.”

So far, the few known cases of Zika in the U.S. mainland are linked to people who had traveled abroad and were likely infected by mosquitos elsewhere. If Zika follows the same patters as dengue fever, however, states like Texas, Florida and Hawaii could experience small outbreaks transmitted by mosquitoes during the summer months.

The Zika virus is named after an isolated forest in Uganda where it was discovered in a monkey in 1947. Only a handful of human cases were known until 2007 when it popped up in the Yap Islands of the southwestern Pacific Ocean, sickening thousands of people. In 2013 Zika appeared in French Polynesia and the following year in other islands of the South Pacific.

Although Zika outbreaks have coincided with a slightly increased rate of Gillian-Barre’s Syndrome, none of the previous outbreaks were associated with a spike in microcephaly births.

The Brazilian Zika outbreak, first identified in May, is the largest ever. The cases are centered in the northeastern states of Paraiba, Pernambuco and Bahia. Zika quickly spread in the region, since the population had never been exposed to the virus, making it highly susceptible. Given the high rate of infection, herd immunity may delay future outbreaks for several years, Kitron says.

Zika cases were initially confused with chikungunya, another virus transmitted by the Aedes aegypti mosquito that was introduced to Brazil and other parts of Latin America and the Caribbean in 2014.

Zika, chikungunya and dengue viruses are all now circulating in Brazil. They cause similar symptoms, complicating clinical identification during outbreaks. And no treatments or vaccines exist for any of the three viruses, making mosquito control vital.

“Mosquito control is not considered ‘sexy’ science, like developing a new drug or a vaccine,” Kitron says, “but more attention and resources need to be devoted to it.”

Aedes aegypti are like “the roaches” of the mosquito world, perfectly adapted to living with humans, especially in urban environments, says Gonzalo Vazquez-Prokopec, another disease ecologist in Emory’s Department of Environmental Sciences who studies vector-borne diseases.

Vazquez-Prokopec specializes in spatial analysis of disease transmission patterns and has several research projects for dengue fever ongoing in Latin America. He is traveling to the Brazilian capital of Brasilia in February to assist the country’s vector control team as they continue to battle the outbreak through mosquito control.

While mosquitoes that carry malaria only feed during the evening, the Aedes aegypti feeds almost exclusively on humans and bites primarily during the daytime.

“Killing mosquitoes is labor-intensive and expensive if you do it well, and it can be difficult to get funding for it,” Vazquez-Prokopec says. “Now we have three viruses – dengue, chikungunya and Zika – being spread by Aedes aegypti, so that greatly increases the cost-effectiveness of doing high-quality, thorough mosquito control.”

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Cells talk to their neighbors before making a move

Cells trade information with adjoining cells and, like the telephone game, the original message becomes garbled the further it travels down the line.

By Carol Clark

To decide whether and where to move in the body, cells must read chemical signals in their environment. Individual cells do not act alone during this process, two new studies on mouse mammary tissue show. Instead, the cells make decisions collectively after exchanging information about the chemical messages they are receiving.

“Cells talk to nearby cells and compare notes before they make a move,” says Ilya Nemenman, a theoretical biophysicist at Emory University and a co-author of both studies, published by the Proceedings of the National Academy of Sciences (PNAS). The co-authors also include scientists from Johns Hopkins, Yale and Purdue.

The researchers discovered that the cell communication process works similarly to a message relay in the telephone game. “Each cell only talks to its neighbor,” Nemenman explains. “A cell in position one only talks to a cell in position two. So position one needs to communicate with position two in order to get information from the cell in position three.”

And like the telephone game – where a line of people whisper a message to the person next to them – the original message starts to become distorted as it travels down the line. The researchers found that, for the cells in their experiments, the message begins to get garbled after passing through about four cells, by a factor of about three.

“We built a mathematical model for this linear relay of cellular information and derived a formula for its best possible accuracy,” Nemenman says. “Directed cell migration is important in processes from cancer to the development of organs and tissues. Other researchers can apply our model beyond the mouse mammary gland and analyze similar phenomena in a wide variety of healthy and diseased systems.”

Since at least the 1970s, and pivotal work by Howard Berg and Ed Purcell, scientists have been trying to understand in detail how cells decide to take an action based on chemical cues. Every cell in a body has the same genome but they can do different things and go in different directions because they measure different chemical signals in their environment. Those chemical signals are made up of molecules that randomly move around.

“Cells can sense not just the precise concentration of a chemical signal, but concentration differences,” Nemenman says. “That’s very important because in order to know which direction to move, a cell has to know in which direction the concentration of the chemical signal is higher. Cells sense this gradient and it gives them a reference for the direction in which to move and grow.”

Berg and Purcell understood the best possible margin of error – the detection limit – for such gradient sensing. During the subsequent 30 years, researchers have established that many different cells, in many different organisms, work at this detection limit. Living cells can sense chemicals better than any man-made device.

It was not known, however, that cells can sense signals and make movement decisions collectively.

“Previous research has typically focused on cultured cells,” Nemenman says. “And when you culture cells, the first thing to go away is cell-to-cell interaction. The cells are no longer a functioning tissue, but a culture of individual cells, so it’s difficult to study many collective effects.”

The first PNAS paper drew from three-dimensional micro-fluidic techniques from the Yale University lab of Andre Levchenko, a biomedical engineer who studies how cells navigate; research on mouse mammary tissue at the Johns Hopkins lab of Andrew Ewald, a biologist focused on the cellular mechanisms of cancer; and the quantification methods of Nemenman, who studies the physics of biological systems, and Andrew Mugler, a former post-doctoral fellow in Nemenman’s lab at Emory who now has his own research group at Purdue.

The 3D micro fluidics allowed the researchers to experiment with functional organoids, or clumps of cells. The method does not disrupt the interaction of the cells. The results showed that epidermal growth factor, or EGF, is the signal that these cells track, and that the cells were not making decisions about which way to move as individuals, but collectively.

“The clumps of cells, working collectively, could detect insanely small differences in concentration gradients – such as 498 molecules of EGF versus 502 molecules – on different sides of one cell,” Nemenman says. “That accuracy is way better than the best possible margin of error determined by Berg and Purcell of about plus or minus 20. Even at these small concentration gradients, the organoids start reshaping and moving toward the higher concentration. These cells are not just optimal gradient detectors. They seem super optimal, defying the laws of nature.”

Collective cell communication boosts their detection accuracy, turning a line of about four cells into a single, super-accurate measurement unit.

In the second PNAS paper, Nemenman, Mugler and Levchenko looked at the limits to the cells’ precision of collective gradient sensing not just spatially, but over time. “We hypothesized that if the cells kept on communicating with one another over hours or days, and kept on accumulating information, that might expand the accuracy further than four cells across,” Nemenman says. “Surprisingly, however, this was not the case. We found that there is always a limit of how far information can travel without being garbled in these cellular systems.”

Together, the two papers offer a detailed model for collective cellular gradient sensing, verified by experiments in mouse mammary organoids. The collective model expands the classic Berg-Purcell results for the best accuracy of an individual cell, which stood for almost forty years. The new formula quantifies the additional advantages and limitations on the accuracy coming from the cells working collectively.

 “Our findings are not just intellectually important. They provide new ways to study many normal and abnormal developmental processes,” Nemenman says.

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Singing in the brain: Songbirds sing like humans

"In terms of vocal control, the bird brain appears as complicated and wonderful as the human brain," says biologist Samuel Sober, shown in his lab with a pair of zebra finches. (Photo by Ofer Tchernichovski.)

By Carol Clark

A songbirds’ vocal muscles work like those of human speakers and singers, finds a study published in the Journal of Neuroscience. The research on Bengalese finches showed that each of their vocal muscles can change its function to help produce different parameters of sounds, in a manner similar to that of a trained opera singer.

“Our research suggests that producing really complex song relies on the ability of the songbirds’ brains to direct complicated changes in combinations of muscles,” says Samuel Sober, a biologist at Emory University and lead author of the study. “In terms of vocal control, the bird brain appears as complicated and wonderful as the human brain.”

Pitch, for example, is important to songbird vocalization, but there is no single muscle devoted to controlling it. “They don’t just contract one muscle to change pitch,” Sober says. “They have to activate a lot of different muscles in concert, and these changes are different for different vocalizations. Depending on what syllable the bird is singing, a particular muscle might increase pitch or decrease pitch.”

Previous research has revealed some of the vocal mechanisms within the human “voice box,” or larynx. The larynx houses the vocal cords and an array of muscles that help control pitch, amplitude and timbre.

Instead of a larynx, birds have a vocal organ called the syrinx, which holds their vocal cords deeper in their bodies. While humans have one set of vocal cords, a songbird has two sets, enabling it to produce two different sounds simultaneously, in harmony with itself.

“Lots of studies look at brain activity and how it relates to behaviors, but muscles are what translates the brain’s output into behavior,” Sober says. “We wanted to understand the physics and biomechanics of what a songbird’s muscles are doing while singing.”

The researchers devised a method involving electromyography (EMG) to measure how the neural activity of the birds activates the production of a particular sound through the flexing of a particular vocal muscle.

The results showed the complex redundancy of the songbird’s vocal muscles. “It tells us how complicated the neural computations are to control this really beautiful behavior,” Sober says, adding that songbirds have a network of brain regions that non-songbirds do not.

The study was co-authored by Kyle Srivastava, a graduate student of the Emory and Georgia Tech Biomedical Engineering Doctoral Program, and Coen Elemans, a biologist from the University of Southern Denmark and a former visiting professor at Emory, funded by the Emory Institute for Quantitative Theory and Methods and the National Institutes of Health.

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Climate-smart agriculture still lags after Paris

Nitrous fertilizer usage in agriculture generates emissions of nitrous oxide — one of the least-known, yet important, greenhouse gases.

Eri Saikawa, Emory assistant professor of Environmental Sciences, led a delegation of Emory students to the recent United Nations climate talks in Paris (COP21). An expert on greenhouse gas emissions, Saikawa wrote an opinion piece at the conclusion of the talks for The Conversation. Following is an excerpt of her article:

"Although the COP included initiatives targeting air pollution, climate and health all at once, there was a lack of comprehensive strategy for the interlinked effects of climate and agriculture at the summit.

"Agriculture contributes 10%-12% of global anthropogenic greenhouse gas (GHG) emissions, and it has altered all of the three important greenhouse gases linked to terrestrial sources: CO2, CH4 and nitrous oxide (N2O). The flip side is that there is a significant potential in agriculture for reducing these biogenic sources of greenhouse gases.

"The agricultural sector is also important because we need to pay more attention to nitrous oxide – possibly the least-known important GHG. N2O is not just a GHG; it also depletes the ozone layer in the stratosphere.

"The Montreal Protocol, which was ratified in 1989, has been effective at reducing greenhouse gases that are also ozone-depleting substances (Velders et al, 2006). However, N2O is not included in the Montreal Protocol, and its emissions are sharply rising.

"The concentrations of N2O in the atmosphere are increasing rapidly and we find that there is a statistically significant increase in emissions from the agricultural sector in Asia, including China and India. This makes sense, as the nitrogen fertilizer usage in these countries is the largest and the third-largest in the world and is only increasing."

Read the whole article in The Conversation.

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Study shows how algal toxin damages sea lions' brains and behavior

Neuroscientist Peter Cook with one of the sea lions that served as a control during the study. (Photos courtesy of the Marine Mammal Center.)

By Carol Clark

A study of wild California sea lions provides the first neurobiological evidence for how a naturally occurring algal toxin affects both the brains and behavior of the animals, leading to significant deficits in spatial memory. The journal Science is publishing the findings, showing how domoic acid damages the sea lions’ hippocampus and disrupts an important neural network.

“We were able to correlate the extent of the hippocampal damage to specific behavioral impairments relevant to the animals’ survival in the wild,” says lead author Peter Cook, a post-doctoral fellow in the Center for Neuropolicy at Emory University. Cook conducted the sea lion research while a graduate student at the University of California, Santa Cruz, and he is continuing to expand on it at Emory.

“Our research provides a way to model the behavioral and biological effects of this toxin in a large-brain mammal,” Cook says. “Better understanding of these effects may also help us identify subtle effects in humans that may be at risk.”

Although cases of fatal human domoic acid poisoning are rare, due to careful monitoring of fisheries, it is unclear if there are effects that go undetected in communities that eat unmonitored seafood.

"Sea lions are like sentinels of ocean health," Cook says, "because when they are in distress, they will almost always swim to shore."

Warming oceans and agricultural runoff may be two factors contributing to an increase in harmful algae blooms, including the planktonic algae Pseudo-nitzschia. The algae produces domoic acid, a potent neurotoxin. During large blooms, the acid can become concentrated in the tissues of shellfish and in fish that feed on the algae. Sea birds and marine mammals that consume these marine organisms can then become poisoned.

Whales and dolphins are also likely impacted by domoic acid, Cook says, although they are more difficult to study than sea lions. “Sea lions are like sentinels of ocean health,” he says, “because when they are in distress, they will almost always swim to shore. We can measure their neurobiology in ways that we can’t in other animals that may also be in distress.”

Wildlife suffering from domoic acid toxicity can display a range of odd behaviors, including seizures, lethargy, disorientation, excessive friendliness or aggressiveness. The condition is often fatal.

Poisoned birds spawned a film.

In 1961, Monterey Bay summer resident Alfred Hitchcock was captivated by reports of frenzied sooty shearwaters. It was a mystery why flocks of the birds were seen regurgitating anchovies, flying into objects and dying in the streets. The incident inspired one of Hitchcock’s most famous films, “The Birds.”

Scientists did not connect domoic acid toxicity to strange behavior by wildlife in the region until the 1990s, when masses of brown pelicans became disoriented and died.

This year, the west coast experienced a massive algae bloom, the largest ever recorded. It extended from Southern California to Alaska, prompting numerous closures of shellfish fisheries.

Large algae blooms attract large schools of fish that feed on them, such as anchovies and sardines. That, in turn, attracts the sea lions. “They are opportunistic feeders and they like to gorge themselves when they have the chance,” Cook says.

Prior research has characterized some of the clinical effects of domoic acid poisoning, but Cook wanted to assess the behavioral effects in wild animals and measure the correlation between the biological changes.

During a three-year period, the research team studied 30 California sea lions undergoing veterinary care and rehabilitation at the Marine Mammal Center in Sausalito. The study included animals with and without symptoms of brain damage caused by exposure to domoic acid.

The sea lions underwent behavioral tests to assess their spatial memory and brain imaging (MRI). The results documented impaired performance on short- and long-term spatial memory tasks in animals with lesions on the right side of the hippocampus. The lesions appear similar to those seen in humans with medial temporal lobe epilepsy.

While acute poisoning can cause seizures and disorientation in sea lions, brain lesions develop over time, likely as a result of the chronic epileptic condition caused by one or more exposures to the toxin, Cook says. “We don’t know how heavy the exposure needs to be, or how often repeated, to cause this kind of brain damage, and we don’t know the effects of repeated low-dose exposure.”

The team also used functional MRI to look at the effects of domoic acid exposure on important brain networks. They found that sea lions with symptoms of toxic exposure had greatly reduced connectivity between the hippocampus and the thalamus, a pathway known to be essential for the formation of episodic memory – memories of events and experiences.

“This is the first evidence of changes to brain networks in exposed sea lions, and suggests that these animals may be suffering a broad disruption of memory, not just spatial memory deficits,” Cook says.

The sea lion study provides rare experimental evidence linking a naturally occurring neurotoxic effect to behavioral impairment in a wild animal. “Nature was doing the dosing. Our study was a natural experiment, giving it ecological validity,” Cook says. “Animals are complicated and they live in complicated environments that are changing really fast in ways that can have a negative impact on a wide range of species.”

Co-authors of the study also include researchers from the University of California, Davis, AnimalScan Advanced Veterinary Imaging, Pennington Biomedical Research Center; the Marine Mammal Center and the Shedd Aquarium. The work was funded by the National Science Foundation and the Lucile Packard Foundation.

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