Posts Tagged ‘science’

Laboratory animals such as mice are an important part of chemical safety tests, say researchers

by Jeff Tollefson

The US Environmental Protection Agency (EPA) is trying to sharply reduce its use of animals in toxicity tests. Many scientists and environmentalists say the move is premature and could undermine chemical regulation.

In a memo to staff, EPA administrator Andrew Wheeler said that the agency would make use of “cutting-edge, ethically sound science” that does not rely on animal testing.

Wheeler signed a directive on 10 September that commits the EPA to reduce its funding request for animal studies by 30% by 2025, and to phase them out entirely by 2035. After 2035, any tests or funds for studies involving animals such as mice would require the approval of the EPA administrator. The plan, which will affect research by EPA scientists and industry, has been in the works for more than a year. Agency officials have said that the shift away from animal experiments won’t limit chemical regulation or reduce public safety.

Wheeler also said that EPA had awarded US$4.25 million in grants to universities for research into alternative toxicity testing methods. The grant recipients are Johns Hopkins University in Baltimore, Maryland; Vanderbilt University in Nashville, Tennessee; Oregon State University in Corvallis; and the University of California, Riverside.

“I don’t think anyone would be saddened by reducing animal research,” says Laura Vandenberg, an environmental health scientist at the University of Massachusetts Amherst. But she fears that the EPA is effectively tying its own hands.

Uncertain outcomes

Scientists can and do use advanced screening tools to study the potential effects of chemicals at the cellular and biochemical level, Vandenberg says. But to regulate a chemical, the EPA must show that there are adverse effects in living organisms, she says. “There is no adverse effect in a Petri dish.”

And just because researchers don’t see negative effects of chemicals on cells in the lab, it doesn’t mean that they aren’t there, Vandenberg adds. “We are going to get caught in a position where we won’t really be able to regulate chemicals in the US.”

The Humane Society of the United States, an animal-advocacy group in Washington DC, praised the EPA’s decision. “We applaud the agency and urge industry and other stakeholders to continue this momentum and move away from animal testing,” said chief executive officer Kitty Block in a statement.

Not everyone is so sanguine about EPA’s decision. The move represents an “unholy alliance” between the chemical industry and animal-rights groups that are pushing to halt animal tests, says Jennifer Sass, a senior scientist at the Natural Resources Defense Council, an environmental advocacy group in New York City.

Sass says that the EPA has reduced its reliance on animal testing in certain areas. For instance, tests to see whether a chemical is corrosive to the skin can now be done on skin that is grown in a Petri dish. But without tests on animals such as mice or rabbits, the only way for companies to study chemical interactions in the body is to use computer models, she says. And those models are often proprietary, which makes it hard to assess their accuracy.

“A chemical goes into a black box, and out comes an answer that is very hard for people to understand and independently review,” Sass says.


Nourianz is the first adenosine A2A receptor antagonist approved for use in Parkinson Disease

By Brian Park

The Food and Drug Administration (FDA) has approved Nourianz (istradefylline; Kyowa Kirin) tablets as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson disease (PD) experiencing “off” episodes.

Nourianz is an oral selective adenosine A2A receptor antagonist and non-dopaminergic pharmacologic option. Adenosine A2A receptors are found in the basal ganglia of the brain where degeneration or abnormality is noted in PD; the basal ganglia are involved in motor control.

The approval was based on data from four 12-week, randomized, placebo-controlled clinical trials that evaluated the efficacy and safety of Nourianz in 1143 patients with PD taking a stable dose of levodopa/carbidopa with or without other PD medications.

Results from all 4 studies have demonstrated a statistically significant decrease from baseline in daily “off” time in patients treated with Nourianz compared with placebo. Regarding safety, the most common treatment-emergent adverse reactions were dyskinesia, dizziness, constipation, nausea, hallucination, and insomnia.

“Istradefylline is an Adenosine A2A receptor antagonist, and is a novel non-dopaminergic pharmacologic approach to treating OFF episodes for people living with PD,” said Dr Stuart Isaacson, MD, Parkinson’s Disease and Movement Disorders Center of Boca Raton, Florida. “Based on data from four clinical studies, istradefylline taken as an adjunct to levodopa significantly improved OFF time and demonstrated a well-tolerated safety profile. Istradefylline represents an important new treatment option for patients with Parkinson’s disease who experience ‘OFF’ episodes.”

The FDA had accepted the resubmitted NDA for Nourianz in April 2019 after previously rejecting the submission in 2008 due to concerns over efficacy findings.

For more information visit

FDA Approves New Adjunct Treatment for Parkinson Disease

Scientists from Harvard University’s Dana-Farber Cancer Institute have found evidence that a chemical derived from cannabis may be capable of extending the life expectancy for those with pancreatic cancer.

Pancreatic cancer makes up just 3 percent of all cancers in America. But with a one-year survival rate of just 20 percent (and five-year survival rate of less than 8), it’s predicted to be the second leading cause of cancer-related death by 2020.

Headlines about the illness, as a result, tend to be discouraging. But this month scientists from Harvard University’s Dana-Farber Cancer Institute have released some much-needed good news. In their study, published in the journal Frontiers of Oncology on July 23, the researchers revealed that a chemical found in cannabis has demonstrated “significant therapy potential” in treatment of pancreatic cancer.

The specific drug, called FBL-03G, is a derivative of a cannabis “flavonoid” — the name for a naturally-occurring compound found in plants, vegetables and fruits which, among other purposes, provides their vibrant color. Flavonoids from cannabis were discovered by a London researcher named Marilyn Barrett in 1986, and were later found to have anti-inflammatory benefits.

But while scientists long suspected that cannabis flavonoids may have therapeutic potential, the fact that they make up just 0.14 percent of the plant meant that researchers would need entire fields of it to be grown in order to extract large enough quantities. That changed recently when scientists found a way to genetically engineer cannabis flavonoids — making it possible to investigate their benefits.

Enter the researchers at Dana-Farber, who decided to take the therapeutic potential of one of these flavonoids, FBL-03G, and test it on one of the deadliest cancers through a lab experiment. The results, according to Wilfred Ngwa, PhD, an assistant professor at Harvard and one of the study’s researcher, were “major.”

“The most significant conclusion is that tumor-targeted delivery of flavonoids, derived from cannabis, enabled both local and metastatic tumor cell kill, significantly increasing survival from pancreatic cancer,” Ngwa tells Yahoo Lifestyle. “This has major significance, given that pancreatic cancer is particularly refractory to current therapies.”

Ngwa says that the study is the first to demonstrate the potential new treatment for pancreatic cancer. But on top of successfully killing those cells, the scientist found FBL-03G capable of attacking other cancer cells — which was startling even to them. “We were quite surprised that the drug could inhibit the growth of cancer cells in other parts of the body, representing metastasis, that were not targeted by the treatment,” says Ngwa. “This suggests that the immune system is involved as well, and we are currently investigating this mechanism.”

The significance of that, says Ngwa, is that, because pancreatic cancer is often diagnosed in later stages, once it has spread, and the flavonoids seem to be capable of killing other cancer cells, it may mean the life expectancy of those with the condition could increase.

“If successfully translated clinically, this will have major impact in treatment of pancreatic cancer,” says Ngwa.

The next step for the Harvard researchers is to complete ongoing pre-clinical studies, which Ngwa hopes will be completed by the end of 2020. That could set the stage for testing the new treatment in humans, opening up a new window of hope for a group long in need of it.

Frank Keutsch, Zhen Dai and David Keith (left to right) in Keutsch’s laboratory at Harvard University.

Zhen Dai holds up a small glass tube coated with a white powder: calcium carbonate, a ubiquitous compound used in everything from paper and cement to toothpaste and cake mixes. Plop a tablet of it into water, and the result is a fizzy antacid that calms the stomach. The question for Dai, a doctoral candidate at Harvard University in Cambridge, Massachusetts, and her colleagues is whether this innocuous substance could also help humanity to relieve the ultimate case of indigestion: global warming caused by greenhouse-gas pollution.

The idea is simple: spray a bunch of particles into the stratosphere, and they will cool the planet by reflecting some of the Sun’s rays back into space. Scientists have already witnessed the principle in action. When Mount Pinatubo erupted in the Philippines in 1991, it injected an estimated 20 million tonnes of sulfur dioxide into the stratosphere — the atmospheric layer that stretches from about 10 to 50 kilometres above Earth’s surface. The eruption created a haze of sulfate particles that cooled the planet by around 0.5 °C. For about 18 months, Earth’s average temperature returned to what it was before the arrival of the steam engine.

The idea that humans might turn down Earth’s thermostat by similar, artificial means is several decades old. It fits into a broader class of planet-cooling schemes known as geoengineering that have long generated intense debate and, in some cases, fear.

Researchers have largely restricted their work on such tactics to computer models. Among the concerns is that dimming the Sun could backfire, or at least strongly disadvantage some areas of the world by, for example, robbing crops of sunlight and shifting rain patterns.

But as emissions continue to rise and climate projections remain dire, conversations about geoengineering research are starting to gain more traction among scientists, policymakers and some environmentalists. That’s because many researchers have come to the alarming conclusion that the only way to prevent the severe impacts of global warming will be either to suck massive amounts of carbon dioxide out of the atmosphere or to cool the planet artificially. Or, perhaps more likely, both.

If all goes as planned, the Harvard team will be the first in the world to move solar geoengineering out of the lab and into the stratosphere, with a project called the Stratospheric Controlled Perturbation Experiment (SCoPEx). The first phase — a US$3-million test involving two flights of a steerable balloon 20 kilometres above the southwest United States — could launch as early as the first half of 2019. Once in place, the experiment would release small plumes of calcium carbonate, each of around 100 grams, roughly equivalent to the amount found in an average bottle of off-the-shelf antacid. The balloon would then turn around to observe how the particles disperse.

The test itself is extremely modest. Dai, whose doctoral work over the past four years has involved building a tabletop device to simulate and measure chemical reactions in the stratosphere in advance of the experiment, does not stress about concerns over such research. “I’m studying a chemical substance,” she says. “It’s not like it’s a nuclear bomb.”

Nevertheless, the experiment will be the first to fly under the banner of solar geoengineering. And so it is under intense scrutiny, including from some environmental groups, who say such efforts are a dangerous distraction from addressing the only permanent solution to climate change: reducing greenhouse-gas emissions. The scientific outcome of SCoPEx doesn’t really matter, says Jim Thomas, co-executive director of the ETC Group, an environmental advocacy organization in Val-David, near Montreal, Canada, that opposes geoengineering: “This is as much an experiment in changing social norms and crossing a line as it is a science experiment.”

Aware of this attention, the team is moving slowly and is working to set up clear oversight for the experiment, in the form of an external advisory committee to review the project. Some say that such a framework, which could pave the way for future experiments, is even more important than the results of this one test. “SCoPEx is the first out of the gate, and it is triggering an important conversation about what independent guidance, advice and oversight should look like,” says Peter Frumhoff, chief climate scientist at the Union of Concerned Scientists in Cambridge, Massachusetts, and a member of an independent panel that has been charged with selecting the head of the advisory committee. “Getting it done right is far more important than getting it done quickly.”

Joining forces
In many ways, the stratosphere is an ideal place to try to make the atmosphere more reflective. Small particles injected there can spread around the globe and stay aloft for two years or more. If placed strategically and regularly in both hemispheres, they could create a relatively uniform blanket that would shield the entire planet (see ‘Global intervention’). The process does not have to be wildly expensive; in a report last month, the Intergovernmental Panel on Climate Change suggested that a fleet of high-flying aircraft could deposit enough sulfur to offset roughly 1.5 °C of warming for around $1 billion to $10 billion per year1.

Most of the solar geoengineering research so far has focused on sulfur dioxide, the same substance released by Mount Pinatubo. But sulfur might not be the best candidate. In addition to cooling the planet, the aerosols generated in that eruption sped up the rate at which chlorofluorocarbons deplete the ozone layer, which shields the planet from the Sun’s harmful ultraviolet radiation. Sulfate aerosols are also warmed by the Sun, enough to potentially affect the movement of moisture and even alter the jet stream. “There are all of these downstream effects that we don’t fully understand,” says Frank Keutsch, an atmospheric chemist at Harvard and SCoPEx’s principal investigator.

The SCoPEx team’s initial stratospheric experiments will focus on calcium carbonate, which is expected to absorb less heat than sulfates and to have less impact on ozone. But textbook answers — and even Dai’s tabletop device — can’t capture the full picture. “We actually don’t know what it would do, because it doesn’t exist in the stratosphere,” Keutsch says. “That sets up a red flag.”

SCoPEx aims to gather real-world data to sort this out. The experiment began as a partnership between atmospheric chemist James Anderson of Harvard and experimental physicist David Keith, who moved to the university in 2011. Keith has been investigating a variety of geoengineering options off and on for more than 25 years. In 2009, while at the University of Calgary in Canada, he founded the company Carbon Engineering, in Squamish, which is working to commercialize technology to remove carbon dioxide from the atmosphere. After joining Harvard, Keith used research funding he had received from Microsoft co-founder Bill Gates, to begin planning the experiment.

Keutsch, who got involved later, is not a climate scientist and is at best a reluctant geoengineer. But he worries about where humanity is heading, and what that means for his children’s future. When he saw Keith talk about the SCoPEx idea at a conference after starting at Harvard in 2015, he says his initial reaction was that the idea was “totally insane”. Then he decided it was time to engage. “I asked myself, an atmospheric chemist, what can I do?” He joined forces with Keith and Anderson, and has since taken the lead on the experimental work.

An eye on the sky
Already, SCoPEx has moved farther along than earlier solar geoengineering efforts. The UK Stratospheric Particle Injection for Climate Engineering experiment, which sought to spray water 1 kilometre into the atmosphere, was cancelled in 2012 in part because scientists had applied for patents on an apparatus that could ultimately affect every human on the planet. (Keith says there will be no patents on any technologies involved in the SCoPEx project.) And US researchers with the Marine Cloud Brightening Project, which aims to spray saltwater droplets into the lower atmosphere to increase the reflectivity of ocean clouds, have been trying to raise money for the project for nearly a decade.

Although SCoPEx could be the first solar geoengineering experiment to fly, Keith says other projects that have not branded themselves as such have already provided useful data. In 2011, for example, the Eastern Pacific Emitted Aerosol Cloud Experiment pumped smoke into the lower atmosphere to mimic pollution from ships, which can cause clouds to brighten by capturing more water vapour. The test was used to study the effect on marine clouds, but the results had a direct bearing on geoengineering science: the brighter clouds produced a cooling effect 50 times greater than the warming effect of the carbon emissions from the researchers’ ship2.

Keith says that the Harvard team has yet to encounter public protests or any direct opposition — aside from the occasional conspiracy theorist. The challenge facing researchers, he says, stems more from a fear among science-funding agencies that investing in geoengineering will lead to protests by environmentalists.

To help advance the field, Keith set a goal in 2016 of raising $20 million to support a formal research programme that would cover not just the experimental work, but also research into modelling, governance and ethics. He has raised around $12 million so far, mostly from philanthropic sources such as Gates; the pot provides funding to dozens of people, largely on a part-time basis.

Keith and Keutsch also want an external advisory committee to review SCoPEx before it flies. The committee, which is still to be selected, will report to the dean of engineering and the vice-provost for research at Harvard. “We see this as part of a process to build broader support for research on this topic,” Keith says.

Keutsch is looking forward to having the guidance of an external group, and hopes that it can provide clarity on how tests such as his should proceed. “This is a much more politically challenging experiment than I had anticipated,” he says. “I was a little naive.”

SCoPEx faces technical challenges, too. It must spray particles of the right size: the team calculates that those with a diameter of about 0.5 micrometres should disperse and reflect sunlight well. The balloon must also be able to reverse its course in the thin air so that it can pass through its own wake. Assuming the team is able to find the calcium carbonate plume — and there is no guarantee that they can — SCoPEx needs instruments that can analyse the particles and, it is hoped, carry samples back to Earth.

“It’s going to be a hard experiment, and it may not work,” says David Fahey, an atmospheric scientist at the National Oceanic and Atmospheric Administration in Boulder, Colorado. In the hope that it will, Fahey’s team has provided SCoPEx with a lightweight instrument that can reliably measure the size and number of particles that are released. The balloon will also be equipped with a laser device that can monitor the plume from afar. Other equipment that could collect information on the level of moisture and ozone in the stratosphere could fly on the balloon as well.

Up to the stratosphere
Keutsch and Keith are still working out some of the technical details. Plans with one balloon company fell through, so they are now working with a second. And an independent team of engineers in California is working on options for the sprayer. To simplify things, the SCoPEx group plans to fly the balloon during the spring or autumn, when stratospheric winds shift direction and — for a brief period — calm down, which will make it easier to track the plume.

For all of these reasons, Keutsch characterizes the first flight as an engineering test, mainly intended to demonstrate that everything works as it should. The team is ready to spray calcium carbonate particles, but could instead use salt water to test the sprayer if the advisory committee objects.

Keith still thinks that sulfate aerosols might ultimately be the best choice for solar geoengineering, if only because there has been more research about their impact. He says that the possibility of sulfates enhancing ozone depletion should become less of a concern in the future, as efforts to restore the ozone layer through pollutant reductions continue. Nevertheless, his main hope is to establish an experimental programme in which scientists can explore different aspects of solar geoengineering.

There are a lot of outstanding questions. Some researchers have suggested that solar geoengineering could alter precipitation patterns and even lead to more droughts in some regions. Others warn that one of the possible benefits of solar geoengineering — maintaining crop yields by protecting them from heat stress — might not come to pass. In a study published in August, researchers found that yields of maize (corn), soya, rice and wheat3 fell after two volcanic eruptions, Mount Pinatubo in 1991 and El Chichón in Mexico in 1982, dimmed the skies. Such reductions could be enough to cancel out any potential gains in the future.

Keith says the science so far suggests that the benefits could well outweigh the potential negative consequences, particularly compared with a world in which warming goes unchecked. The commonly cited drawback is that shielding the Sun doesn’t affect emissions, so greenhouse-gas levels would continue to rise and the ocean would grow even more acidic. But he suggests that solar geoengineering could reduce the amount of carbon that would otherwise end up in the atmosphere, including by minimizing the loss of permafrost, promoting forest growth and reducing the need to cool buildings. In an as-yet-unpublished analysis of precipitation and temperature extremes using a high-resolution climate model, Keith and others found that nearly all regions of the world would benefit from a moderate solar geoengineering programme. “Despite all of the concerns, we can’t find any areas that would be definitely worse off,” he says. “If solar geoengineering is as good as what is shown in these models, it would be crazy not to take it seriously.”

There is still widespread uncertainty about the state of the science and the assumptions in the models — including the idea that humanity could come together to establish, maintain and then eventually dismantle a well-designed geoengineering programme while tackling the underlying problem of emissions. Still, prominent organizations, including the UK Royal Society and the US National Academies of Sciences, Engineering, and Medicine, have called for more research. In October, the academies launched a project that will attempt to provide a blueprint for such a programme.

Some organizations are already trying to promote discussions among policymakers and government officials at the international level. The Solar Radiation Management Governance Initiative is holding workshops across the global south, for instance. And Janos Pasztor, who handled climate issues under former UN secretary-general Ban Ki-moon, has been talking to high-level government officials around the world in his role as head of the Carnegie Climate Geoengineering Governance Initiative, a non-profit organization based in New York. “Governments need to engage in this discussion and to understand these issues,” Pasztor says. “They need to understand the risks — not just the risks of doing it, but also the risks of not understanding and not knowing.”

One concern is that governments might one day panic over the consequences of global warming and rush forward with a haphazard solar-geoengineering programme, a distinct possibility given that the costs are cheap enough that many countries, and perhaps even a few individuals, could probably afford to go it alone. These and other questions arose earlier this month in Quito, Ecuador, at the annual summit of the Montreal Protocol, which governs chemicals that damage the stratospheric ozone layer. Several countries called for a scientific assessment of the potential effects that solar geoengineering could have on the ozone layer, and on the stratosphere more broadly.

If the world gets serious about geoengineering, Fahey says that there are plenty of sophisticated experiments that researchers could do using satellites and high-flying aircraft. But for now, he says, SCoPEx will be valuable — if only because it pushes the conversation forward. “Not talking about geoengineering is the greatest mistake we can make right now.”

Nature 563, 613-615 (2018)

doi: 10.1038/d41586-018-07533-4

By Michael Marshall

Blobs of simple carbon-based compounds could have been the precursors to the first living cells. A new study suggests that such droplets could have formed quickly and easily on the young Earth.

“We were able to find these interesting microdroplet structures that could be synthesised from prebiotically available resources,” says Tony Jia of the Tokyo Institute of Technology in Japan. “Maybe they weren’t the direct precursors to modern cells, but perhaps they could have had some effect or had a role in the emergence of initial life.”

All modern cells are surrounded by an outer wall called a membrane, which is made of long chain-like molecules called lipids. Given the ubiquity of these membranes, many researchers studying how life began have made simple membrane-lined spheres, which they say could mimic the first simple cells.

The droplets Jia and his colleagues made are different. “They don’t have an outer layer,” says Jia. “In that sense they’re membrane-less.”

The first cells?
The team made them from simple chemicals called alpha-hydroxy acids. These are made by the same processes that create amino acids, suggesting they were present on the early Earth, says team member Kuhan Chandru of the National University of Malaysia. “You can find them in meteorites as well.” He showed in 2018 that alpha-hydroxy acids link up to form complex molecules at a wide range of temperatures.

In the new study, the team simply dissolved the acids in water, then left them to dry out at 80 °C for a week – mimicking the conditions near a hot volcanic pond.

The acids turned into a thick jelly, because they had again formed complex molecules. When the researchers added water, the jelly formed hundreds of droplets a few micrometres across. Further experiments showed that crucial biological molecules, including protein and RNA, could enter the droplets and still perform their functions.

Cells without walls
Membrane-less droplets were a key element of the first popular hypothesis for life’s origin, which was set out by Russian biologist Alexander Oparin in the 1920s. However, the idea fell out of favour when it emerged that all cells have membranes.

The idea is now being re-assessed, says Kate Adamala of the University of Minnesota in Minneapolis. She suspects that life went through a “membrane-less stage” and that membranes only arose later.

Both droplets and membrane-based cells are a container for life’s components. This is crucial, says Adamala, because it keeps all the parts together, creating an individual organism from what would otherwise be a mess of chemicals.

But membranes are such good barriers that the first cells would have struggled to get food in and waste out, Adamala argues. So at the very beginning, membrane-less droplets would be better. “You don’t have to be shut off from the environment, because those droplets are permeable and you can have things diffusing in and out of them.”

Journal reference: PNAS, DOI: 10.1073/pnas.1902336116

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A mouse exploring one of the custom hologram generators used in the experiments at Stanford. By stimulating particular neurons, scientists were able to make engineered mice see visual patterns that weren’t there.

By Carl Zimmer

In a laboratory at the Stanford University School of Medicine, the mice are seeing things. And it’s not because they’ve been given drugs.

With new laser technology, scientists have triggered specific hallucinations in mice by switching on a few neurons with beams of light. The researchers reported the results on Thursday in the journal Science.

The technique promises to provide clues to how the billions of neurons in the brain make sense of the environment. Eventually the research also may lead to new treatments for psychological disorders, including uncontrollable hallucinations.

“This is spectacular — this is the dream,” said Lindsey Glickfeld, a neuroscientist at Duke University, who was not involved in the new study.

In the early 2000s, Dr. Karl Deisseroth, a psychiatrist and neuroscientist at Stanford, and other scientists engineered neurons in the brains of living mouse mice to switch on when exposed to a flash of light. The technique is known as optogenetics.

In the first wave of these experiments, researchers used light to learn how various types of neurons worked. But Dr. Deisseroth wanted to be able to pick out any individual cell in the brain and turn it on and off with light.

So he and his colleagues designed a new device: Instead of just bathing a mouse’s brain in light, it allowed the researchers to deliver tiny beams of red light that could strike dozens of individual brain neurons at once.

To try out this new system, Dr. Deisseroth and his colleagues focused on the brain’s perception of the visual world. When light enters the eyes — of a mouse or a human — it triggers nerve endings in the retina that send electrical impulses to the rear of the brain.

There, in a region called the visual cortex, neurons quickly detect edges and other patterns, which the brain then assembles into a picture of reality.

The scientists inserted two genes into neurons in the visual cortices of mice. One gene made the neurons sensitive to the red laser light. The other caused neurons to produce a green flash when turned on, letting the researchers track their activity in response to stimuli.

The engineered mice were shown pictures on a monitor. Some were of vertical stripes, others of horizontal stripes. Sometimes the stripes were bright, sometimes fuzzy. The researchers trained the mice to lick a pipe only if they saw vertical stripes. If they performed the test correctly, they were rewarded with a drop of water.

As the mice were shown images, thousands of neurons in their visual cortices flashed green. One population of cells switched on in response to vertical stripes; other neurons flipped on when the mice were shown horizontal ones.

The researchers picked a few dozen neurons from each group to target. They again showed the stripes to the mice, and this time they also fired light at the neurons from the corresponding group. Switching on the correct neurons helped the mice do better at recognizing stripes.

Then the researchers turned off the monitor, leaving the mice in darkness. Now the scientists switched on the neurons for horizontal and vertical stripes, without anything for the rodents to see. The mice responded by licking the pipe, as if they were actually seeing vertical stripes.

Anne Churchland, a neuroscientist at Cold Spring Harbor Laboratory who was not involved in the study, cautioned that this kind of experiment can’t reveal much about a mouse’s inner experience.

“It’s not like a creature can tell you, ‘Oh, wow, I saw a horizontal bar,’” she said.

Dr. Churchland said that it would take more research to better understand why the mice behaved as they did in response to the flashes of red light. Did they see the horizontal stripes more clearly, or were they less distracted by misleading signals?

One of the most remarkable results from the study came about when Dr. Deisseroth and his colleagues narrowed their beams of red light to fewer and fewer neurons. They kept getting the mice to lick the pipe as if they were seeing the vertical stripes.

In the end, the scientists found they could trigger the hallucinations by stimulating as few as two neurons. Thousands of other neurons in the visual cortex would follow the lead of those two cells, flashing green as they became active.

Clusters of neurons in the brain may be tuned so that they’re ready to fire at even a slight stimulus, Dr. Deisseroth and his colleagues concluded — like a snowbank poised to become an avalanche.

But it doesn’t take a fancy optogenetic device to make a few neurons fire. Even when they’re not receiving a stimulus, neurons sometimes just fire at random.

That raises a puzzle: If all it takes is two neurons, why are we not hallucinating all the time?

Maybe our brain wiring prevents it, Dr. Deisseroth said. When a neuron randomly fires, others may send signal it to quiet down.

Dr. Glickfeld speculated that attention may be crucial to triggering the avalanche of neuronal action only at the right times. “Attention allows you to ignore a lot of the background activity,” she said.

Dr. Deisseroth hopes to see what other hallucinations he can trigger with light. In other parts of the brain, he might be able to cause mice to perceive more complex images, such as the face of a cat. He might be able to coax neurons to create phantom sounds, or even phantom smells.

As a psychiatrist, Dr. Deisseroth has treated patients who have suffered from visual hallucinations. In his role as a neuroscientist, he’d like to find out more about how individual neurons give rise to these images — and how to stop them.

“Now we know where those cells are, what they look like, what their shape is,” he said. “In future work, we can get to know them in much more detail.”

Kumar Alagramam. PhD, Case Western Reserve University

The ability to hear depends on proteins to reach the outer membrane of sensory cells in the inner ear. But in certain types of hereditary hearing loss, mutations in the protein prevent it from reaching these membranes. Using a zebrafish model, researchers at Case Western Reserve University School of Medicine have found that an anti-malarial drug called artemisinin may help prevent hearing loss associated with this genetic disorder.

In a recent study, published in the Proceedings of the National Academy of Sciences (PNAS), researchers found the classic anti-malarial drug can help sensory cells of the inner ear recognize and transport an essential protein to specialized membranes using established pathways within the cell.

The sensory cells of the inner ear are marked by hair-like projections on the surface, earning them the nickname “hair cells.” Hair cells convert sound and movement-induced vibrations into electrical signals that are conveyed through nerves and translated in the brain as information used for hearing and balance.

The mutant form of the protein–clarin1–render hair cells unable to recognize and transport them to membranes essential for hearing using typical pathways within the cell. Instead, most mutant clarin1 proteins gets trapped inside hair cells, where they are ineffective and detrimental to cell survival. Faulty clarin1 secretion can occur in people with Usher syndrome, a common genetic cause of hearing and vision loss.

The study found artemisinin restores inner ear sensory cell function—and thus hearing and balance—in zebrafish genetically engineered to have human versions of an essential hearing protein.

Senior author on the study, Kumar N. Alagramam, the Anthony J. Maniglia Chair for Research and Education and associate professor at Case Western Reserve University School of Medicine Department of Otolaryngology at University Hospitals Cleveland Medical Center, has been studying ways to get mutant clarin1 protein to reach cell membranes to improve hearing in people with Usher syndrome.

“We knew mutant protein largely fails to reach the cell membrane, except patients with this mutation are born hearing,” Alagramam said. “This suggested to us that, somehow, at least a fraction of the mutant protein must get to cell membranes in the inner ear.”

Alagramam’s team searched for any unusual secretion pathways mutant clarin1 could take to get to hair cell membranes. “If we can understand how the human clarin1 mutant protein is transported to the membrane, then we can exploit that mechanism therapeutically,” Alagramam said.

For the PNAS study, Alagramam’s team created several new zebrafish models. They swapped the genes encoding zebrafish clarin1 with human versions—either normal clarin1, or clarin1 containing mutations found in humans with a type of Usher syndrome, which can lead to profound hearing loss.

“Using these ‘humanized’ fish models,” Alagramam said, “we were able to study the function of normal clarin1 and, more importantly, the functional consequences of its mutant counterpart. To our knowledge, this is the first time a human protein involved in hearing loss has been examined in this manner.”

Zebrafish offer several advantages to study hearing. Their larvae are transparent, making it easy to monitor inner ear cell shape and function. Their genes are also nearly identical to humans—particularly when it comes to genes that underlie hearing. Replacing zebrafish clarin1 with human clarin1 made an even more precise model.

The researchers found the unconventional cellular secretion pathway they were looking for by using florescent labels to track human clarin1 moving through zebrafish hair cells. The mutated clarin1 gets to the cell membrane using proteins and trafficking mechanisms within the cell, normally reserved for misfolded proteins “stuck” in certain cellular compartments.

“As far as we know, this is the first time a human mutant protein associated with hearing loss has been shown to be ‘escorted’ by the unconventional cellular secretion pathway,” Alagramam said. “This mechanism may shed light on the process underlying hearing loss associated with other mutant membrane proteins.”

The study showed the majority of mutant clarin1 gets trapped inside a network of tubules within the cell analogous to stairs and hallways helping proteins, including clarin1, get from place to place. Alagramam’s team surmised that liberating the mutant protein from this tubular network would be therapeutic and tested two drugs that target it: thapsigargin (an anti-cancer drug) and artemisinin (an anti-malarial drug).

The drugs did enable zebrafish larvae to liberate the trapped proteins and have higher clarin1 levels in the membrane; but artemisinin was the more effective of the two. Not only did the drug help mutant clarin1 to reach the membrane, hearing and balance functions were better preserved in zebrafish treated with the anti-malarial drug than untreated fish.

In zebrafish, survival depends on normal swim behavior, which in turn depends on balance and the ability to detect water movement, both of which are tied to hair cell function. Survival rates in zebrafish expressing the mutant clarin1 jumped from 5% to 45% after artemisinin treatment.

“Our report highlights the potential of artemisinin to mitigate both hearing and vision loss caused by clarin1 mutations,” Alagramam said. “This could be a re-purposable drug, with a safe profile, to treat Usher syndrome patients.”

Alagramam added that the unconventional secretion mechanism and the activation of that mechanism using artemisinin or similar drugs may also be relevant to other genetic disorders that involve mutant membrane proteins aggregating in the cell’s tubular network, including sensory and non-sensory disorders.

Gopal SR, et al. “Unconventional secretory pathway activation restores hair cell mechanotransduction in an USH3A model.” PNAS.

Drug to treat malaria could mitigate hereditary hearing loss