Adult cells transformed into early-stage nerve cells, bypassing the pluripotent stem cell stage

A UW-Madison research group has converted skin cells from people and monkeys into a cell that can form a wide variety of nervous-system cells — without passing through the do-it-all stage called the induced pluripotent stem cell, or iPSC.

Bypassing the ultraflexible iPSC stage was a key advantage, says senior author Su-Chun Zhang, a professor of neuroscience and neurology. “IPSC cells can generate any cell type, which could be a problem for cell-based therapy to repair damage due to disease or injury in the nervous system.”

In particular, the absence of iPSC cells rules out the formation of tumors by pluripotent cells in the recipient, a major concern involving stem cell therapy.

A second advance comes from the virus that delivers genes to reprogram the adult skin cells into a different and more flexible form. Unlike other viruses used for this process, the Sendai virus does not become part of the cell’s genes.

Jianfeng Lu, Zhang’s postdoctoral research associate at the UW-Madison Waisman Center, removed skin cells from monkeys and people, and exposed them to Sendai virus for 24 hours. Lu then warmed the culture dish to kill the virus without harming the transforming cells. Thirteen days later, Lu was able to harvest a stem cell called an induced neural progenitor. After the progenitor was implanted into newborn mice, neural cells seemed to grow normally, without forming obvious defects or tumors, Zhang says.

Other researchers have bypassed the pluripotent stem cell stage while turning skin cells into neurons and other specialized cells, Zhang acknowledges, but the new research, just published in Cell Reports, had a different goal. “Our idea was to turn skin cells to neural progenitors, cells that can produce cells relating to the neural tissue. These progenitors can be propagated in large numbers.”

The research overcomes limitations of previous efforts, Zhang says. First, the Sendai virus, a kind of cold virus, is considered safe because it does not enter the cell’s DNA, and it is killed by heat within 24 hours. (This is quite similar to the fever that raises our temperature to remove cold virus.) Second, the neural progenitors have a greater ability to grow daughter cells for research or therapy. Third, the progenitor cells are already well along the path toward specialization, and cannot become, say, liver or muscle cells after implantation. Finally, the progenitors can produce many more specialized cells.

The neurons that grew from the progenitor had the markings of neurons found in the rear of the brain, and that specialization can also be helpful. “For therapeutic use, it is essential to use specific types of neural progenitors,” says Zhang. “We need region-specific and function-specific neuronal types for specific neurological diseases.”

Progenitor cells grown from the skin of ALS (Lou Gehrig’s disease) or spinal muscular atrophy patients can be transformed into various neural cells to model each disease and allow rapid drug screening, Zhang adds.

Eventually, the process could produce cells used to treat conditions like spinal cord injury and ALS.

"These transplantation experiments confirmed that the reprogrammed cells indeed belong to cells of the intended brain regions and the progenitors produced the three major classes of neural cells: neurons, astrocytes and oligodendrocytes," Zhang says. "This proof-of-principle study highlights the possibility to generate many specialized neural progenitors for specific neurological disorders."

ALS trial shows novel therapy is safe

An investigational treatment for an inherited form of Lou Gehrig’s disease has passed an early phase clinical trial for safety, researchers at Washington University School of Medicine in St. Louis and Massachusetts General Hospital report.

The researchers have shown that the therapy produced no serious side effects in patients with the disease, also known as amyotrophic lateral sclerosis (ALS). The phase 1 trial’s results, available online in Lancet Neurology, also demonstrate that the drug was successfully introduced into the central nervous system.

The treatment uses a technique that shuts off the mutated gene that causes the disease. This approach had never been tested against a condition that damages nerve cells in the brain and spinal cord.

“These results let us move forward in the development of this treatment and also suggest that it’s time to think about applying this same approach to other mutated genes that cause central nervous system disorders,” says lead author Timothy Miller, MD, PhD, assistant professor of neurology at Washington University. “These could include some forms of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and other conditions.”

ALS destroys nerves that control muscles, gradually leading to paralysis and death. For treatment of the disease, the sole FDA-approved medication, Riluzole, has only a marginal effect.

Most cases of ALS are sporadic, but about 10 percent are linked to inherited mutations. Scientists have identified changes in 10 genes that can cause ALS and are still looking for others.

The study focused on a form of ALS caused by mutations in a gene called SOD1, which account for 2 percent of all ALS cases. Researchers have found more than 100 mutations in the SOD1 gene that cause ALS.

“At the molecular level, these mutations affect the properties of the SOD1 protein in a variety of ways, but they all lead to ALS,” says Miller, who is director of the Christopher Wells Hobler Lab for ALS Research at the Hope Center for Neurological Disorders at Washington University.

Rather than try to understand how each mutation causes ALS, Miller and his colleagues focused on blocking production of the SOD1 protein using a technique called antisense therapy.

To make a protein, cells have to copy the protein-building instructions from the gene. Antisense therapy blocks the cell from using these copies, allowing researchers to selectively silence individual genes.

“Antisense therapy has been considered and tested for a variety of disorders over the past several decades,” Miller says. “For example, the FDA recently approved an antisense therapy called Kynamro for familial hypercholesterolemia, an inherited condition that increases cholesterol levels in the blood.”

Miller and colleagues at the University of California-San Diego devised an antisense drug for SOD1 and successfully tested it in an animal model of the disease.

Merit Cudkowicz, MD, chief of neurology at Massachusetts General Hospital, was co-PI of the phase I clinical safety trial described in the new paper. Clinicians at Barnes-Jewish Hospital, Massachusetts General Hospital, Johns Hopkins Hospital and the Methodist Neurological Institute in Houston gave antisense therapy or a placebo to 21 patients with SOD1-related ALS. Treatment consisted of spinal infusions that lasted 11 hours.

The scientists found no significant difference between side effects in the control and treatment groups. Headache and back pain, both of which are often associated with spinal infusion, were among the most common side effects.

Immediately after the injections, the researchers took spinal fluid samples. This let them confirm the antisense drug was circulating in the spinal fluid of patients who received the treatment.

To treat SOD1-related ALS in the upcoming phase II trial, researchers will need to increase the dosage of the antisense drug. As the dose rises, they will watch to ensure that the therapy does not cause harmful inflammation or other side effects as it lowers SOD1 protein levels.

“All the information that we have so far suggests lowering SOD1 will be safe,” Miller says. “In fact, completely disabling SOD1 in mice seems to have little to no effect. We think it will be OK in patients, but we won’t know for sure until we’ve conducted further trials.”

The therapy may one day be helpful in the more common, noninherited forms of ALS, some of which may be linked to problems with the SOD1 protein.

“Before we can consider using this same therapy for sporadic ALS, we need more evidence that SOD1 is a major contributor to these forms of the disorder,” Miller says. 

The trial was conducted with support from ISIS Pharmaceuticals, which co-owns a patent on the SOD1 antisense drug.

Fight Control: Researchers link individual neurons to regulation of aggressive behavior in flies

Scientists have long pondered the roots of aggression—and ways to temper it. Now, new research is beginning to illuminate the cellular-level circuitry responsible for modulating aggression in fruit flies, with the hope of someday translating the findings to humans.

Researchers at Harvard Medical School have identified two pairs of dopamine-producing neurons, also called dopaminergic neurons, and traced their aggression-modulating action to a common structure in the fly brain called the central complex, suggesting that important components of aggression-related behaviors may be processed there.

“This is the first research to identify single dopaminergic neurons that modulate a complex behavior—aggression—in fruit flies,” said Edward Kravitz, George Packer Berry Professor of Neurobiology at HMS and lead author of the study.

“We don’t know how complex this modulatory circuit is, but we now have a key element of it. If we eliminate or increase the function of that dopaminergic neuron, it affects the circuit of the brain responsible for controlling aggression,” Kravitz said.

The findings were published last week in PNAS.

Flies are an ideal animal model for neurological research because genetic methods allow scientists to manipulate neurons and simultaneously observe the resulting behaviors. Many fundamental nervous system mechanisms in flies are similar to those in humans. In fact, both flies and humans share the same neurohormones.

Dopamine is one such neurohormone, and across species it affects a range of behaviors, from learning and memory to motivation and movement. In humans, neurohormones are associated with conditions such as Parkinson’s disease and psychiatric disorders.

Dopaminergic neurons are found in small numbers in particular parts of nervous systems. In humans, there are about 200,000 to 400,000 of these neurons; in fruit flies there are about 100. While their numbers are few, these neurons influence a vast array of behaviors.

Kravitz, along with Olga Alekseyenko, a postdoctoral fellow in the Kravitz lab and first author on the paper, set out to discover how these few dopaminergic neurons can influence such a wide range of behaviors.

To do this, study co-first author, Yick-Bun Chan, HMS research associate in neurobiology, genetically engineered 200 lines of fruit flies. He then used them to target select dopaminergic neurons that could be activated or silenced while the flies engaged in various behaviors.

The team detected two pairs of dopaminergic neurons that affected aggressive behavior in the flies. Interestingly, aggression was increased in the flies either by augmenting the function of these cells or by deactivating them.

In fruit flies, males fight for territory and form stable hierarchical relationships. Using previous observations and analysis of more than 20,000 interactions in fly fights, the team established quantitative measures of aggressive behavior, such as lunging, that allowed them to compare aggression levels in different fly attacks.

“When we turned off the pairs of dopaminergic neurons, the flies fought with more lunging; when we turned them on, they also fought at higher intensity levels. Apparently normal levels of aggression require a precise amount of dopamine released at a specific time and place in the nervous system. These results suggest that these neurons ordinarily hold aggression in check,” said Alekseyenko.

Also significant was the finding that while the two sets of dopaminergic neurons modulated aggression, they did not influence other behaviors.

The first pair of neurons are found in the PPM3 cluster of neurons in the fly brain and the second are within the T1 cluster. Both pairs innervate different parts of the central complex, an important structure in the fly brain.

“We already knew that dopamine receptors are present in the central complex, but we didn’t know which dopamine neurons connected to the receptors or what behaviors those neurons affected,” said Alekseyenko.

“Now we know that two pairs of aggression-mediating dopaminergic neurons terminate in different regions of the central complex, and we know that those regions have different types of dopamine receptors. Our study shows that aggression is one of the behaviors coordinated in these regions of the brain, but we still don’t fully understand the process,” he said.

In a third group of flies, a neuron pair that projected into a different part of the brain was identified. These neurons affected locomotion and sleep, but did not influence aggression.

Kravitz said the next phase of the research will be to use genetic tools to allow his team to identify the subsequent steps in the brain circuitry—which neurons are pre- and post-synaptic to the T1 and PPM3 neurons and how that affects neuronal network function.

The goal will be to establish fundamental principles for how dopaminergic neurons work in the fruit fly system, with the hope that the research will one day translate to how these neurons work in higher species. This may ultimately aid in the development of new dopamine-targeted medications for humans.

“We can now relate these two pairs of neurons specifically to one behavior, and that is aggression,” Kravitz said. “That means we have one piece of the puzzle.”

Researchers untangle molecular pathology of giant axonal neuropathy

Giant axonal neuropathy (GAN) is a rare genetic disorder that causes central and peripheral nervous system dysfunction. GAN is known to be caused by mutations in the gigaxonin gene and is characterized by tangling and aggregation of neural projections, but the mechanistic link between the genetic mutation and the effects on neurons is unclear. In this issue of the Journal of Clinical Investigation, Robert Goldman and colleagues at Northwestern University uncover how mutations in gigaxonin contribute to neural aggregation.They demonstrated that gigaxonin regulates the degradation of neurofilament proteins, which help to guide outgrowth and morphology of neural projections. Loss of gigaxonin in either GAN patient cells or transgenic mice increased levels of neurofilament proteins, causing tangling and aggregation of neural projections. Importantly, expression of gigaxonin allowed for clearance of neurofilament proteins in neurons. These findings demonstrate that mutations in gigaxonin cause accumulation of neurofilament proteins and shed light on the molecular pathology of GAN.

Spring cleaning in your brain: U-M stem cell research shows how important it is

Deep inside your brain, a legion of stem cells lies ready to turn into new brain and nerve cells whenever and wherever you need them most. While they wait, they keep themselves in a state of perpetual readiness – poised to become any type of nerve cell you might need as your cells age or get damaged.

Now, new research from scientists at the University of Michigan Medical School reveals a key way they do this: through a type of internal “spring cleaning” that both clears out garbage within the cells, and keeps them in their stem-cell state.

In a paper published online in Nature Neuroscience, the U-M team shows that a particular protein, called FIP200, governs this cleaning process in neural stem cells in mice. Without FIP200, these crucial stem cells suffer damage from their own waste products — and their ability to turn into other types of cells diminishes.

It is the first time that this cellular self-cleaning process, called autophagy, has been shown to be important to neural stem cells.

The findings may help explain why aging brains and nervous systems are more prone to disease or permanent damage, as a slowing rate of self-cleaning autophagy hampers the body’s ability to deploy stem cells to replace damaged or diseased cells. If the findings translate from mice to humans, the research could open up new avenues to prevention or treatment of neurological conditions.

In a related review article just published online in the journal Autophagy, the lead U-M scientist and colleagues from around the world discuss the growing evidence that autophagy is crucial to many types of tissue stem cells and embryonic stem cells as well as cancer stem cells.

As stem cell-based treatments continue to develop, the authors say, it will be increasingly important to understand the role of autophagy in preserving stem cells’ health and ability to become different types of cells.

“The process of generating new neurons from neural stem cells, and the importance of that process, is pretty well understood, but the mechanism at the molecular level has not been clear,” says Jun-Lin Guan, Ph.D., the senior author of the FIP200 paper and the organizing author of the autophagy and stem cells review article. “Here, we show that autophagy is crucial for maintenance of neural stem cells and differentiation, and show the mechanism by which it happens.”

Through autophagy, he says, neural stem cells can regulate levels of reactive oxygen species – sometimes known as free radicals – that can build up in the low-oxygen environment of the brain regions where neural stem cells reside. Abnormally higher levels of ROS can cause neural stem cells to start differentiating.

Guan is a professor in the Molecular Medicine & Genetics division of the U-M Department of Internal Medicine, and in the Department of Cell & Developmental Biology.

A long path to discovery

The new discovery, made after 15 years of research with funding from the National Institutes of Health, shows the importance of investment in lab science – and the role of serendipity in research.

Guan has been studying the role of FIP200 — whose full name is focal adhesion kinase family interacting protein of 200 kD – in cellular biology for more than a decade. Though he and his team knew it was important to cellular activity, they didn’t have a particular disease connection in mind. Together with colleagues in Japan, they did demonstrate its importance to autophagy – a process whose importance to disease research continues to grow as scientists learn more about it.

Several years ago, Guan’s team stumbled upon clues that FIP200 might be important in neural stem cells when studying an entirely different phenomenon. They were using FIP200-less mice as comparisons in a study, when an observant postdoctoral fellow noticed that the mice experienced rapid shrinkage of the brain regions where neural stem cells reside.

“That effect was more interesting than what we were actually intending to study,” says Guan, as it suggested that without FIP200, something was causing damage to the home of neural stem cells that normally replace nerve cells during injury or aging.

In 2010, they worked with other U-M scientists to show FIP200’s importance to another type of stem cell, those that generate blood cells. In that case, deleting the gene that encodes FIP200 leads to an increased proliferation and ultimate depletion of such cells, called hematopoietic stem cells.

But with neural stem cells, they report in the new paper, deleting the FIP200 gene led neural stem cells to die and ROS levels to rise. Only by giving the mice the antioxidant n-acetylcysteine could the scientists counteract the effects.

“It’s clear that autophagy is going to be important in various types of stem cells,” says Guan, pointing to the new paper in Autophagy that lays out what’s currently known about the process in hematopoietic, neural, cancer, cardiac and mesenchymal (bone and connective tissue) stem cells.

Guan’s own research is now exploring the downstream effects of defects in neural stem cell autophagy – for instance, how communication between neural stem cells and their niches suffers. The team is also looking at the role of autophagy in breast cancer stem cells, because of intriguing findings about the impact of FIP200 deletion on the activity of the p53 tumor suppressor gene, which is important in breast and other types of cancer. In addition, they will study the importance of p53 and p62, another key protein component for autophagy, to neural stem cell self-renewal and differentiation, in relation to FIP200.

Study finds that hot and cold senses interact

A study from the University of North Carolina School of Medicine offers new insights into how the nervous system processes hot and cold temperatures. The research led by neuroscientist Mark J. Zylka, PhD, associate professor of cell biology and physiology, found an interaction between the neural circuits that detect hot and cold stimuli: cold perception is enhanced when nerve circuitry for heat is inactivated.

“This discovery has implications for how we perceive hot and cold temperatures and for why people with certain forms of chronic pain, such as neuropathic pain, or pain arising as  direct consequence of a nervous system injury or disease, experience heightened responses to cold temperatures,” says Zylka, a member of the UNC Neuroscience Center.

The study also has implications for why a promising new class of pain relief drugs known as TRPV1 antagonists (they block a neuron receptor protein) cause many patients to shiver and “feel cold” prior to the onset of hyperthermia, an abnormally elevated body temperature. Enhanced cold followed by hyperthermia is a major side effect that has limited the use of these drugs in patients with chronic pain associated with multiple sclerosis, cancer, and osteoarthritis.

Zylka’s research sheds new light on how the neural circuits that regulate temperature sensation bring about these responses, and could suggest ways of reducing such side-effects associated with TRPV1 antagonists and related drugs.

The research was selected by the journal Neuron as cover story for the April 10, 2013 print edition and was available in the April 4, 2013 advanced online edition.

This new study used cutting edge cell ablation technology to delete the nerve circuit that encodes heat and some forms of itch while preserving the circuitry that sense cold temperatures. This manipulation results in animals  that were practically “blind” to heat, meaning they could no longer detect hot temperatures, Zylka explains. “Just like removing heat from a room makes us feel cold (such as with an air conditioner), removing the circuit that animals use to sense heat made them hypersensitive to cold. Physiological studies indicated that these distinct circuits regulate one another in the spinal cord.”

TRPV1 is a receptor for heat and is found in the primary sensory nerve circuit that Zylka studied. TRPV1 antagonists make patients temporarily blind to heat, which Zylka speculates is analogous to what happened when his lab deleted the animals’ circuit that detects heat: cold hypersensitivity.

Zylka emphasizes that future studies will be needed to confirm that TRPV1 antagonists affect cold responses in a manner similar to what his lab found with nerve circuit deletion.

Researchers Develop New System to Study Trigger of Cell Death in Nervous System

Researchers at the University of Arkansas have developed a new model system to study a receptor protein that controls cell death in both humans and fruit flies, a discovery that could lead to a better understanding of neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

Michael Lehmann, an associate professor of biological sciences, uses fruit fly genetics to study the receptor — N-methyl-D-aspartate receptor, known as the NMDA receptor — that triggers programmed cell death in the human nervous system.

With an aging population, neurodegenerative diseases have become a major public health concern, Lehmann said.

“Whenever brain cells die as a result of neurodegenerative disease, or as a consequence of injuries caused by stroke, exposure to alcohol or neurotoxins, this receptor is involved,” he said. “So it’s very important to understand how it functions and how it may be possible to influence it.”

When larvae of Drosophila melanogaster, a common fruit fly, grow from the larval stage into adults, they shed most of their former organs and grow new ones. About 1 ½ years ago, researchers in Lehmann’s laboratory discovered that the NMDA receptor is required for cell death in the system that they had used for several years to study basic mechanisms of programmed cell death in fruit flies.

“Our model system for studying programmed cell death is the salivary glands in the fly larvae, which are comparatively large organs that completely disappear during metamorphosis,” he said. “Disposal of this tissue by programmed cell death provides us with a very nice system to study the genes that are required for the process. We can use it to identify genes that are required for programmed cell death in humans, as well.”

The National Institutes of Health has awarded Lehmann a three-year, $260,530 grant to support the study.

Brandy Ree, a doctoral student in the interdisciplinary graduate program in cell and molecular biology, worked with Lehmann to use a combination of biochemistry and fruit fly genetics in an attempt to define the pathway that leads from activation of the receptor to the cell’s eventual death.

“We developed a new system to study the receptor outside the nervous system in a normal developmental context,” Lehmann said. “Many of the different components involved in cell death are known in this system. There are more than 30,000 publications about this receptor, but there is still very little known about how the receptor causes cell death. We just have to connect the dots and fit the receptor into the pathway to find out how exactly it contributes to the cell’s death.”

A mid-career investigator in the Center for Protein Structure and Function at the University of Arkansas, Lehmann has studied programmed cell death in Drosophila melanogaster for more than a decade.

In 2007, Lehmann’s research group discovered an important mechanism that regulates the destruction of larval fruit fly salivary glands that could point the way to understanding programmed cell death in the human immune system. They published their findings in the Journal of Cell Biology.

(Image: BD Biosciences)

How herpesvirus invades nervous system

Northwestern Medicine scientists have identified a component of the herpesvirus that “hijacks” machinery inside human cells, allowing the virus to rapidly and successfully invade the nervous system upon initial exposure.

Led by Gregory Smith, associate professor in immunology and microbiology at Northwestern University Feinberg School of Medicine, researchers found that viral protein 1-2, or VP1/2, allows the herpesvirus to interact with cellular motors, known as dynein. Once the protein has overtaken this motor, the virus can speed along intercellular highways, or microtubules, to move unobstructed from the tips of nerves in skin to the nuclei of neurons within the nervous system.

This is the first time researchers have shown a viral protein directly engaging and subverting the cellular motor; most other viruses passively hitch a ride into the nervous system.

"This protein not only grabs the wheel, it steps on the gas," says Smith. "Overtaking the cellular motor to invade the nervous system is a complicated accomplishment that most viruses are incapable of achieving. Yet the herpesvirus uses one protein, no others required, to transport its genetic information over long distances without stopping."

Herpesvirus is widespread in humans and affects more than 90 percent of adults in the United States. It is associated with several types of recurring diseases, including cold sores, genital herpes, chicken pox, and shingles. The virus can live dormant in humans for a lifetime, and most infected people do not know they are disease carriers. The virus can occasionally turn deadly, resulting in encephalitis in some.

Until now, scientists knew that herpesviruses travel quickly to reach neurons located deep inside the body, but the mechanism by which they advance remained a mystery.

Smith’s team conducted a variety of experiments with VP1/2 to demonstrate its important role in transporting the virus, including artificial activation and genetic mutation of the protein. The team studied the herpesvirus in animals, and also in human and animal cells in culture under high-resolution microscopy. In one experiment, scientists mutated the virus with a slower form of the protein dyed red, and raced it against a healthy virus dyed green. They observed that the healthy virus outran the mutated version down nerves to the neuron body to insert DNA and establish infection.

"Remarkably, this viral protein can be artificially activated, and in these conditions it zips around within cells in the absence of any virus. It is striking to watch," Smith says.

He says that understanding how the viruses move within people, especially from the skin to the nervous system, can help better prevent the virus from spreading.

Additionally, Smith says, “By learning how the virus infects our nervous system, we can mimic this process to treat unrelated neurologic diseases. Even now, laboratories are working on how to use herpesviruses to deliver genes into the nervous system and kill cancer cells.”

Smith’s team will next work to better understand how the protein functions. He notes that many researchers use viruses to learn how neurons are connected to the brain.

"Some of our mutants will advance brain mapping studies by resolving these connections more clearly than was previously possible," he says.

New urgency in battle against ‘bound legs’ disease

The harm done by konzo – a disease overshadowed by the war and drought it tends to accompany – goes beyond its devastating physical effects to impair children’s memory, problem solving and other cognitive functions.

Even children without physical symptoms of konzo appear to lose cognitive ability when exposed to the toxin that causes the disease, researchers report in the journal Pediatrics.

“That’s what’s especially alarming,” said lead author Michael Boivin, a Michigan State University associate professor of psychiatry and of neurology and ophthalmology. “We found subtle effects that haven’t been picked up before. These kids aren’t out of the woods, even if they don’t have the disease.”

Konzo means “bound legs” in the African Yaka language, a reference to how its victims walk with feet bent inward after the disease strips away motor control in their lower limbs. Its onset is rapid, and the damage is permanent.

People contract konzo by consuming poorly processed bitter cassava, a drought-resistant staple food in much of sub-Saharan Africa. Typically, the plant’s tuber is soaked for a few days, then dried in the sun and ground into flour – a process that degrades naturally occurring cyanide.

“As long as they do that, the food’s pretty safe,” said Boivin, who began studying konzo in 1990 as a Fulbright researcher in the Democratic Republic of Congo. “But in times of war, famine, displacement and hardship, people take shortcuts. If they’re subsisting on poorly processed cassava and they don’t have other sources of protein, it can cause permanent damage to the nervous system.

“Konzo doesn’t make many headlines because it usually follows other geopolitical aspects of human suffering,” he added. “Still, there are potentially tens of millions of kids at risk throughout central and western Africa. The public health scope is huge.”

To find out if the disease affects cognitive function, Boivin and colleagues from Oregon Health and Science University turned to the war-torn Congo. They randomly selected 123 children with konzo and 87 neighboring children who showed no signs of the disease but whose blood and urine samples indicated elevated levels of the toxin.

Using cognitive tests, the researchers found that children with konzo had a much harder time using working memory to solve problems and organize visual and spatial information.

They also found that konzo and non-konzo children from the outbreak area showed poor working memory and impaired fine-motor skills when compared to a reference group of children from a part of the region unaffected by the disease.

Konzo’s subtler impacts might seem minor compared to its striking physical symptoms, but Boivin noted that the cognitive damage is similar to that caused by chronic low-grade exposures to other toxic substances such as lead.

Scientists eventually may be able to prevent such damage by creating nontoxic cassava varieties and introducing other resilient crops to affected regions, Boivin said. Meanwhile, public health education programs are under way to help stop outbreaks.

“For now,” he said, “if we could just avoid the worst of it – the full-blown konzo disease that has such devastating effects for children and families – that’s a good start.”